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Managing ethylene glycol toxicity (Proceedings)

Article

The gastrointestinal tract is the primary route of exposure. Ethylene glycol is a small molecule (62 dalton) which undergoes rapid absorption from the gastrointestinal tract, distributes to the liver where it is rapidly metabolized by the hepatic alcohol dehydrogenase pathway to toxic metabolites (glycoaldehyde, glycolic acid, glyoxlic acid, oxalic acid, and formic acid), and is excreted in the urine. These metabolic intermediates (organic acids) induce severe metabolic acidosis, kidney failure and subsequent death, in exposed animals and humans.

Ethylene Glycol (Anti-freeze) Toxicity

     • Ethylene glycol is a clear, odorless, sweet to the taste, highly hygroscopic synthetic

     • Liquid found commonly in automotive fluids – antifreeze, coolants, and brake fluid; photographic supplies, solvents, rust removers, and taxidermist's preservative solutions to name a few.

     • Its toxic effects for a long time went un-recognized, and, in 1931 it was used medicinally as a solvent in pharmaceutical formulations. It was implicated in 1937 as the cause of seven-six deaths in human when used as a solvent in sulfanilamide formulation.

     • It is the most toxic of similarly used alcohols (ethyl alcohol, butylene glycol and propylene glycol). Its concentration in automotive radiator fluid is high (95%), a source to which pets (dogs and cats) have easy access. Whereas all animal species are susceptible, to ethylene glycol toxicity, cats remain more susceptible.

Toxicokinetics

The gastrointestinal tract is the primary route of exposure. Ethylene glycol is a small molecule (62 dalton) which undergoes rapid absorption from the gastrointestinal tract, distributes to the liver where it is rapidly metabolized by the hepatic alcohol dehydrogenase pathway to toxic metabolites (glycoaldehyde, glycolic acid, glyoxlic acid, oxalic acid, and formic acid), and is excreted in the urine. These metabolic intermediates (organic acids) induce severe metabolic acidosis, kidney failure and subsequent death, in exposed animals and humans. Calcium – oxalic acid interaction produces calcium oxalate crystals which are widely deposited in tubular cells and lumen. Since the metabolites rather than parent compound (ethylene glycol), are the primary toxins, toxicity is best characterized as lethal synthesis.

Reported toxic dose (exposure by ingestion)

Cats:      1.5 ml/kg

Dogs:      6.6 ml/kg (other reports suggest less)

Man:       1.4 ml/kg

Clinical Presentation

Clinical signs are characterized as triphasic: (Phase 1 Gastrointestinal and CNS: The first 12 hours post ingestion; Phase 11 – Cardio-pulmonary: 12-24 hours post ingestion; and Phase 111 - Renal: 24 hours and beyond), post ingestion of a toxic dose. Clinical signs are always acute and dose related, and are attributable to both the chemical and physical characteristics of the parent compound and its metabolites. Initial clinical signs (vomiting, ataxia, weakness, CNS depression, dehydrated, and muscle fasciculation) develop within minutes of ingestion, becoming progressively worse over the next 12 hours post ingestion of a toxic dose. These clinical signs impact primarily the gastrointestinal and central nervous systems and are attributable to high blood levels of ethylene glycol and its aldehyde metabolites "Glycoaldehydes".

Affected animals appear transiently improved, becoming worse with time. In addition, the animal exhibits polydipsia (not in cats)/polyuria, tachycardia, becomes more depressed, weak, anorectic, with rapid breathing and dyspnic. This phase impacts the cardio-pulmonary systems due to severe metabolic acidosis resulting from metabolite interactions. Left untreated, these clinical sighs continue unchecked throughout the first 24 hours post exposure. Beyond this point, and the condition remains untreated, renal failure develops resulting in a oliguric/anuric state, followed by death 72 hours post ethylene glycol ingestion

Pathophysiology

     • Ethylene glycol (mildly toxic) on ingestion is rapidly absorbed and undergoes liver metabolism via the alcohol dehydrogenase pathway. Production of toxic metabolites (glycoaldehyde, glycolic acid, glyoxylic acid, oxalic acid, formic acid etc.) follow. Aldehyde metabolites lead to cytotoxicity, calcium oxalate crystal deposition and secondary cerebral edema.

     • The presence of these metabolites induces severe metabolic acidosis leading to metabolic changes – increased ionic gap, osmolarity, osmotic diuresis, polydipsia/polyuria, dehydration leading to calcium oxalate crystal formation. Calcium oxalic acid reaction forming soluble complexes which are filtered through the glomeruli, and re-crystallize within tubular lumen. where they are deposited and excreted in urine. Metabolites are cytotoxic to proximal tubular cells, resulting in the deposition of these calcium oxalate crystals (monohydrate) within the lumen of kidney tubules, thereby causing interstitial edema and their subsequent urinary excretion.

Lesion

Calcium oxalate crystals (monohydrate) widely deposited in the lumen of tubular cells of the kidney. In cats, the kidneys become enlarged and painful on palpation.

Diagnosis

Based on history of exposure, clinical signs, laboratory findings (specimens positive for ethylene glycol and its metabolites, changes in serum/plasma chemistry profile, and histo-pathologic evaluation.

Early stages: Ethylene glycol Toxicity – Laboratory abnormalities

Ethylene glycol detection in Blood: - test kit: detection limit >50mg/dl. Indicate exposure. Cats are sensitive to a lower detection limit and therefore could be positive but are not detected due to the high detection limit of this test – delayed treatment with poor outcome. Blood ethylene glycol levels can be detected as early as 30 minutes post ingestion. This procedure cross reacts with propylene glycol and/or glycerol, therefore the possibility of false positive results. Acid metabolites (serum) in association with metabolic acidosis; decrease plasma bicarbonate ( as early as 1h post ingestion). Serum and urine ethylene glycol concentrations are non-detectable 48-72h post ethylene glycol ingestion.

     • Serum osmolality (N = 280-310 mOsm/kg) – Starts increasing 1h post ingestion; increase parallel serum EG concentrations. Increases in Osmolality is detected as early as three hours post ethylene glycol ingestion, and, remain high for at least 18 hours

     • Dogs isosthenuric (urine SG = 1.008-1.012) 3h following EG ingestion (osmotic diuresis and serum hyperosmolality-induced polydipsia: cats – decreased urine SG 3h but may be above isosathenuric range

     • Cats and dogs: Calcium oxalate crystalluria – common as early as 3h (cats) - 6h (dogs) following ingestion – strong supporting diagnostic proof. Urine pH – consistently low

     • Woods lamp – oral cavity, face, paws, vomitus, and urine – fluorescent sodium fluorescein" in urine up to 6h post ingestion. Negative tests does not rule out EG toxicity

Late Lab. Abnormalities:

     • Increased BUN and Creatinine (dogs 24-48h; cats 12h). Note in cats, no polydipsia so this could be due to dehydration.

     • Increased serum phosphorus due to decreased glomerular filtration

     • Hyperkalemia with onset of oliguria and anuria

     • Serum calcium decrease (not in all cases) from insoluble calcium oxalate formation.

     • Infrequently observed with acidosis – a shift to the ionized, physiologically active form of calcium

     • Serum glucose increases in some cases >> inhibition of glucose metabolism by aldehydes, increased epinephrine, endogenous corticosteroid, and uremia

     • Little or no osmole gap increase but will for osmolality due to azotemia and hyperglycemia

     • Remain isosthenuric in late stage due to renal dysfunction and impaired ability to concentrate urine

     • Calcium oxalate crystalluria persist as long as animal produces urine

     • Urine abnormalities – associated with renal damage – hematuria, protein urea and glucose urea, granular/cellular cell casts, WBC, RBC, renal epithelial calls

Treatment

     • Best to start 8h (dogs) Cats 3h post ingestion

     • Aimed at preventing absorption, increasing excretion, metabolism (critical)

     • Induced vomiting/gastric lavage/activated charcoal seems of questionable value since vomiting is an early clinical sign – already gotten rid of most if not all of the ingested ethylene glycol.

Antidote

Reduce Ethylene glycol metabolism – Alcohol dehydrogenase Inhibitor:

Although ADH induces diuresis or hyperosmolality at recommended dosage, 4-

Methylpyrazole (fomepizole, antizol-Vet) is the preferred antidote in both cats and dogs.

     • Dog: 20mg/kg IV initially, followed by 15 mg/kg IV @12 and 24h, and 5mg/kg IV @ 36h.

     • Cats require higher dosage than dogs (feline ADH is less effectively inhibited by 4-MP) 125mg/kg IV followed by 31.25mg/kg IV@ 12, 24, 36h. CNS depression observed.

Reduce Ethylene glycol metabolism – Alcohol dehydrogenase substrate inhibitor:

Ethanol has a higher affinity for alcohol dhydrogenase than ethylene glycol and would be metabolized in preference to ethylene glycol by this enzyme.

     • Supportive care (correct fluid, acid-base, and electrolyte imbalances). Maintain patient renal tubular regeneration, peritoneal dialysis. Hemodialysis has been attempted, renal transplantation (cats)

     • Monitor urine production, Serum urea nitrogen and creatinine, blood pH, bicarbonate,

     • ionized calcium and electrolyte (twice daily).

Bicarbonate Therapy

Administered slowly IV to correct metabolic acidosis.

Differential diagnosis

     • All toxic causes of increased anion gap metabolic acidosis – methanol, salicylates, alcoholic ketoacidosis, lacticacidosis; non-toxic causes – diabetic ketoacidosis, lactic acidosis (any form)

     • Other chemicals with similar clinical signs – ataxia and CNS depression

     • Acute renal failure (other causes)

     • Acute gastroenteritis

     • Pancreatitis

     • Diabetic keto-acidosis

Prognosis

Excellent in dogs treated 5h post ingestion with 4-MP, Good with cats treated 3h following ingestion

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