Practice Essentials
Ethylene glycol is one of several toxic alcohols that have medical and toxicologic importance. The other principal ones are methanol and isopropanol (see Alcohol Toxicity). If untreated, ingestion of ethylene glycol can be fatal.
Ethylene glycol is the major ingredient of almost all radiator fluid products in the United States. It is used to increase the boiling point and decrease the freezing point of the fluid that circulates through the automotive radiator. These changes to the boiling and freezing points result from the colligative properties of the solute (ie, they depend on the number of particles in the solution). Hence, ethylene glycol is added to prevent the radiator from overheating or freezing, depending on the season.
Fluorescein dye is often added to radiator fluid to help mechanics localize the site of a radiator leak. The fluorescein in the fluid fluoresces when viewed under ultraviolet light.
Ethylene glycol tastes sweet, which is why some animals are attracted to it. Many veterinarians are familiar with ethylene glycol toxicity because of the frequent cases in dogs and cats that have licked up radiator fluid.
Initially, patients may be asymptomatic, but ethylene glycol is rapidly absorbed (within 1 to 4 hours), and altered mental status and tachypnea then begin to appear as the ethylene glycol is successively metabolized to very toxic compounds. The progression of toxic effects can be roughly divided into the following three stages, although overlap is possible [1] :
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From 30 minutes to 12 hours after exposure, unmetabolized ethylene glycol produces CNS depression, intoxication, and hyperosmolality similar to that produced by ethanol.
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From 12 to 48 hours, ethylene glycol metabolites produce severe anion gap metabolic acidosis with compensatory hyperventilation. The acidosis results primarily from an increase in glycolic acid, although glyoxylic, oxalic, and lactic acids also contribute in small part. Calcium oxalate crystals are deposited in the brain, lungs, heart, and kidneys.
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From 24 to 72 hours, acute kidney injury can result from the direct renal toxic effects of the ethylene glycol metabolite calcium oxylate monohydrate.
Initial treatment includes infusion of crystalloids to enhance renal clearance of the toxic metabolites. Ethyl alcohol (ethanol) has traditionally been used for antidotal treatment, but it has largely been supplanted by fomepizole in the United States. It is important to engage the participation of a nephrologist for potential of dialysis early in the clinical course.
Pathophysiology
Like the other toxic alcohols mentioned above, ethylene glycol is a parent compound that exerts most of its toxicity by conversion to metabolites. Ethylene glycol itself may cause some alteration of mental status but it is a relatively nontoxic compound before it is metabolized. The metabolites cause the distinctive toxicity associated with this compound. [2]
Knowing the pathway of ethanol metabolism is necessary to properly understand ethylene glycol toxicity. Ethanol is metabolized by the enzyme alcohol dehydrogenase (ADH), which is located in the liver and gastric mucosa. An additional pathway is the cytochrome P-450 mixed function oxidase (MFO) system in the liver. The mixed function oxidase component is subject to greater inducibility than alcohol dehydrogenase.
Like ethyl alcohol and methanol, ethylene glycol is metabolized by ADH. In this step it forms glycoaldehyde. Through interaction with aldehyde dehydrogenase, ethylene glycol is then metabolized to glycolic acid (GA), which accumulates and can cause a profound metabolic acidosis. This glycolic acid is eventually converted into glyoxylic acid, and then into the highly toxic oxalate or the safer glutamate or α-ketoadipic acid metabolites.
Calcium oxalate crystals may form and accumulate in blood and other tissues. The precipitation of calcium oxalate in the renal cortex results in decreased glomerular filtration and kidney insufficiency. The formation of these crystals consumes circulating calcium, and hypocalcemia may occur, though this is uncommon.
The rate-limiting step of ethylene glycol metabolism is the ADH-catalyzed step. Common ethyl alcohol (ethanol) binds much more easily to ADH than ethylene glycol or methanol does. Because ethanol is the preferred substrate for ADH, the presence of ethanol may essentially block metabolism of ethylene glycol. In addition, this enzyme is blocked by the administration of fomepizole (4-methylpyrazole [4-MP]), which is discussed below (see Emergency Department Care). [3] Fomepizole is now the primary antidotal modality used in the United States.
Upon oral ingestion, serum concentrations of ethylene glycol peak within 1-4 hours. The elimination half-life (assuming preserved kidney function) is 3 hours. When alcohol dehydrogenase is inhibited by ethanol or fomepizole, the elimination half-life increases to about 16 hours. Ethylene glycol undergoes first-order elimination at concentrations under 250 mg/dL (13.9 mmol/L) and zero-order elimination at concentrations above that. Ethylene glycol is metabolized by the kidneys and is typically undetectable in serum or urine after 48-72 hours. [4]
Etiology
Causes of ethylene glycol poisoning include the following:
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Suicide attempts
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Unintentional ingestions (most often observed in children)
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Workplace beverage-container mix-ups
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Other industrial exposures
Epidemiology
Ethylene glycol is a relatively common cause of overdose in US emergency departments. In 2022, 6079 single exposures to ethylene glycol in antifreeze and other automotive products were reported to the American Association of Poison Control Centers (AAPCC). Of those, 5248 were unintentional.There were 901 minor outcomes, 352 moderate outcomes, 90 major outcomes, and 8 deaths reported. [5]
As in previous years, ethylene glycol exposure was most common in adults, with 4280 single case exposures; there were 424 single case exposures in children younger than 6 years, 126 in those aged 6-12 years, and 483 in those 13-19 years. In addition, the AAPCC reported 566 single exposures to ethylene glycol that was not an automotive, aircraft, or boat product, with 50 major outcomes and 13 deaths. [5]
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Oxalate crystals. Courtesy of John D Schaldenbrand, MD, Department of Pathology, St Joseph Mercy Health System, Ann Arbor, MI.
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Ethylene glycol metabolic pathway.
