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Introduction ⬇

Ethylene glycol is the primary ingredient (up to 95%) in antifreeze. It may be consumed intentionally as an ethanol substitute by alcoholics and is tempting to children and pets because of its sweet taste. Ethylene glycol intoxication causes inebriation and mild gastritis. More importantly, its metabolites cause a severe metabolic acidosis, renal failure, and death. Other glycols may also produce toxicity (Table II-25).

TABLE II-25. OTHER GLYCOLS
CompoundsToxicity and CommentsTreatment
Diethylene glycol (DEG)Highly nephrotoxic and neurotoxic. Epidemic poisonings have occurred when DEG has been inappropriately used in consumer products or as a diluent for water insoluble pharmaceuticals. Toxicity has also occurred after large acute ingestions and repeated dermal application in burn patients. Clinical presentation includes initial ethanol-like inebriation and gastritis, metabolic acidosis, acute renal injury, dysphonia, cranial nerve VII paresis or paralysis, facial and peripheral extremity weakness, coma, and death. Metabolic acidosis may be delayed for 12 hours or longer after ingestion. DEG is primarily metabolized to 2-hydroxyethoxyacetic acid and diglycolic acid. Diglycolic acid is likely responsible for the nephrotoxicity; however, DEG itself may also be toxic. Molecular weight is 106. Vd 1 L/kg (animal).Ethanol and fomepizole may limit toxicity due to DEG metabolites. Hemodialysis is indicated for patients with large ingestions, anuric renal failure, or severe metabolic acidosis nonresponsive to medical treatments.
Dioxane (dimer of ethylene glycol)May cause coma, liver and kidney damage. The vapor (>300 ppm) may cause mucous membrane irritation. Dermal exposure may result in defatting of the skin. Metabolites unknown. Molecular weight is 88.Role of ethanol and fomepizole is unknown, but they may be effective.
Dipropylene glycolRelatively low toxicity. Central nervous system depression, hepatic injury, and renal damage have occurred in animal studies after massive exposures. There is a human report of acute renal failure, polyneuropathy, and myopathy after an ingestion of dipropylene glycol fog solution. Molecular weight is 134.Supportive care. There is no role for ethanol or fomepizole therapy.
Ethylene glycol monobutyl ether (EGBE, 2-butoxyethanol, butyl cellosolve)Clinical toxic effects include lethargy, coma, anion gap metabolic acidosis, hyperchloremia, elevated lactate, hypotension, respiratory depression, hemolysis, renal and hepatic dysfunction; rare disseminated intravascular coagulation (DIC), noncardiogenic pulmonary edema, and acute respiratory distress syndrome (ARDS). Oxalate crystal formation and osmolar gap elevation have been reported, but not in all cases. Serum levels in poisoning cases have ranged from 0.005 to 432 mg/L. Butoxyethanol is metabolized by alcohol dehydrogenase to butoxyaldehyde and butoxyacetic acid (BAA); however, the affinity of alcohol dehydrogenase for butoxyethanol is unknown. Molecular weight is 118.Ethanol, fomepizole, and hemodialysis may be effective.
Ethylene glycol monoethyl ether (EGEE, 2-ethoxyethanol, ethyl cellosolve)Calcium oxalate crystals have been reported in animals. Animal studies indicate that EGEE is metabolized in part to ethylene glycol; however, the affinity of alcohol dehydrogenase is higher for EGEE than for ethanol. One patient developed vertigo, unconsciousness, metabolic acidosis, renal insufficiency, hepatic damage, and neurasthesia after ingesting 40 mL. Teratogenic effect has been reported in humans and animals. Molecular weight is 90.Ethanol and fomepizole may be effective.
Ethylene glycol monomethyl ether (EGME, 2-methoxyethanol, methyl cellosolve)Delayed toxic effects (8 and 18 hours after ingestion) similar to those of ethylene glycol have been reported. Calcium oxalate crystals may or may not occur. Cerebral edema, hemorrhagic gastritis, and degeneration of the liver and kidneys were reported in one autopsy. Animal studies indicate that EGME is metabolized in part to ethylene glycol; however, the affinity of alcohol dehydrogenase is about the same for EGME as for ethanol. Oligospermia has been reported with chronic exposure in humans. Teratogenic effects have been reported in animals. Molecular weight is 76.Effectiveness of ethanol and fomepizole uncertain; in one report, fomepizole did not prevent acidosis.
Polyethylene glycolsVery low toxicity. A group of compounds with molecular weights ranging from 200 to more than 4,000. High-molecular-weight compounds (>500) are poorly absorbed and rapidly excreted by the kidneys. Low-molecular-weight compounds (200-400) may result in metabolic acidosis, renal failure, and hypercalcemia after massive oral ingestions or repeated dermal applications in patients with extensive burn injuries. Acute respiratory failure occurred after accidental nasogastric infusion into the lung of a pediatric patient. Alcohol dehydrogenase metabolizes polyethylene glycols.Supportive care.
Propylene glycol (PG)Relatively low toxicity. Lactic acidosis, central nervous system depression, coma, hypoglycemia, seizures, and hemolysis have been reported rarely after massive exposures or chronic exposures in high-risk patients. Risk factors include renal insufficiency, small infants, epilepsy, burn patients with extensive dermal application of propylene glycol, and patients in alcohol withdrawal receiving ultra-high doses of IV lorazepam or diazepam. Osmolar gap, anion gap, and lactate are commonly elevated. PG levels of 6-42 mg/dL did not result in toxicity after acute infusion. A PG level of 1,059 mg/dL was reported in an 8-month-old with extensive burn injuries after repeated dermal application. A level of 400 mg/dL was measured in an epileptic patient who experienced status epilepticus, respiratory depression, elevated osmolar gap, and metabolic acidosis. Metabolites are lactate, acetate, and pyruvate. Molecular weight is 76.Supportive care, sodium bicarbonate. There is no role for ethanol or fomepizole therapy. Hemodialysis is effective but rarely indicated unless renal failure or severe metabolic acidosis unresponsive to medical treatment. Discontinue any drugs containing PG.
Triethylene glycolUncommon intoxication in humans. Single case report of metabolic acidosis and coma following small ingestion. Treated with ethanol and recovered by 36 hours.Ethanol and fomepizole may be effective.

Mechanism of Toxicity ⬆ ⬇

  1. Ethylene glycol is metabolized by alcohol dehydrogenase to glycoaldehyde, which is then metabolized by aldehyde dehydrogenase to glycolic, glyoxylic, and oxalic acids. These acids, and to a lesser extent excess lactic acid, are responsible for the anion gap metabolic acidosis. Oxalate readily precipitates with calcium to form insoluble calcium monohydrate oxalate crystals. Tissue injury is caused by widespread deposition of oxalate crystals and the toxic effects of glycolic and glyoxylic acids. Calcium oxalate monohydrate crystal accumulation in the kidney results in acute kidney injury.
  2. Overdose in pregnancy. Ethylene glycol crosses the placenta. Fetal toxicity is expected to mimic maternal toxicity in overdose.
  3. Pharmacokinetics. Ethylene glycol is well absorbed when ingested. The volume of distribution is about 0.6-0.8 L/kg. It is not protein bound. Primary metabolism is by alcohol dehydrogenase, with a half-life of about 3-5 hours. In the presence of fomepizole or ethanol (see below), both of which block ethylene glycol metabolism, elimination is entirely renal with a half-life of 14.2-17 hours.
  4. Other glycols (see Table II-25). Propylene and dipropylene glycols are considered less toxic, although metabolism of propylene glycol generates lactate and a lactic acidosis. Polypropylene glycol and other high-molecular-weight polyethylene glycols are poorly absorbed and virtually nontoxic. However, diethylene glycol and glycol ethers produce toxic metabolites, with toxicity similar to that of ethylene glycol.

Toxic Dose ⬆ ⬇

The approximate lethal oral dose of 95% ethylene glycol (eg, antifreeze) is 1.0-1.5 mL/kg; however, survival has been reported after an ingestion of 2 L in a patient who received treatment within 1 hour of ingestion.

Clinical Presentation ⬆ ⬇

  1. Ethylene glycol
    1. During the first few hours after ingestion, the patient may appear inebriated similar to ethanol intoxication. The osmol gap is increased, but there is no initial acidosis. Vomiting due to gastritis may also occur.
    2. After a delay of 4-12 hours, accumulation of toxic metabolites results in an anion gap metabolic acidosis. Hyperventilation, seizures, coma, and dysrhythmias can also be seen. Renal failure is common but usually reversible. Pulmonary edema and cerebral edema may also occur. Hypocalcemia with tetany has been reported.
    3. After a delay of days to weeks, neurologic sequelae are uncommonly reported, including cranial nerve VI and VII palsies, cerebral edema, Parkinson disease, diaphragmatic paralysis, gastroparesis, and postural hypotension.
  2. Other glycols (see Table II-25). Diethylene glycol and glycol ethers are extremely toxic and may produce central nervous system depression, acute renal failure, metabolic acidosis, and delayed neurotoxicity.

Diagnosis ⬆ ⬇

Of ethylene glycol poisoning is based on the history of antifreeze ingestion, typical symptoms, and elevation of the osmol or anion gap. Oxalate or hippurate crystals may be present in the urine (calcium oxalate crystals may be monohydrate [cigar-shaped] or dihydrate [cuboidal]). Glycol ethers increase plasma osmolality but the increase may be too small to reflect clinical risk. Because many antifreeze products contain fluorescein, the urine may exhibit fluorescence under a Wood's lamp. However, false-positive and false-negative Wood's lamp results have been reported.

  1. Specific levels. Tests for ethylene glycol levels are usually available from regional commercial toxicology laboratories but are difficult to obtain quickly.
    1. The minimum level associated with toxicity is unknown. An arbitrary level of 25 mg/dL has been established as a conservative threshold for treatment based on a single study of methanol poisoning. Lower levels do not rule out poisoning if the parent compound has already been metabolized (in such a case, the anion gap should be markedly elevated). In the absence of a serum level, an elevated osmol gap is suggestive of early ethylene glycol exposure, in the appropriate clinical setting, and may be used to estimate the ethylene glycol level.
    2. False-positive ethylene glycol levels can be caused by 2,3-butanediol, lactate, glycerol, elevated triglycerides (see Table I-32), and other substances when glycerol dehydrogenase is used in enzymatic assays. An elevated ethylene glycol level should be confirmed by gas chromatography (GC). Falsely negative EG levels may occur in the presence of glycerol or propylene glycol when using some enzymatic assays.
    3. Glycolic and glyoxylic acid can produce a false-positive result for lactic acid in some point-of-care assays.
    4. In the absence of a serum ethylene glycol level, if the osmol and anion gaps are both normal and the patient is asymptomatic, serious exposure is unlikely.
  2. Other useful laboratory studies include electrolytes, lactate, ethanol, glucose, BUN, creatinine, calcium, hepatic aminotransferases (ALT, AST), urinalysis (for crystals), measured osmolality, arterial blood gases, triglycerides, and ECG monitoring. Serum beta-hydroxybutyrate levels may help distinguish ethylene glycol poisoning from alcoholic ketoacidosis which also may cause increased anion and osmol gaps. (Patients with alcoholic ketoacidosis may not have markedly positive tests for ketones, but the beta-hydroxybutyrate level will usually be elevated.)

Treatment ⬆

  1. Emergency and supportive measures
    1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen.
    2. Treat coma, seizures, cardiac dysrhythmias, and metabolic acidosis (p 36) if they occur. Observe the patient for several hours to monitor for development of metabolic acidosis, especially if the patient is symptomatic or there is known co-ingestion of ethanol.
    3. Treat hypocalcemia with IV calcium gluconate or calcium chloride.
  2. Specific drugs and antidotes
    1. Administer fomepizole or ethanol to saturate alcohol dehydrogenase and prevent metabolism of ethylene glycol to its toxic metabolites. Indications for therapy include:
      1. Ethylene glycol level higher than 25 mg/dL.
      2. History of ethylene glycol ingestion with an osmol gap greater than 10 mOsm/L, not accounted for by ethanol or other alcohols.
    2. Administer pyridoxine, folate, and thiamine, which may enhance the metabolism of glyoxylic acid to nontoxic metabolites.
  3. Decontamination. Aspiration of gastric contents with a small-bore tube may be useful if done early (within 30-60 min) after ingestion. Activated charcoal is not likely to be of benefit, but can be considered if other drugs or toxins were ingested.
  4. Enhanced elimination. Hemodialysis efficiently removes ethylene glycol and its toxic metabolites and rapidly corrects acidosis. Continuous venovenous hemodiafiltration (CVVHDF) is an acceptable alternative in unstable patients, but the rate of elimination is slower.
    1. Indications for hemodialysis include the following:
      1. Suspected ethylene glycol poisoning with an osmol gap greater than 10 mOsm/L not accounted for by ethanol or other alcohols and accompanied by metabolic acidosis (pH <7.25-7.30) unresponsive to therapy.
      2. Ethylene glycol intoxication accompanied by renal failure.
      3. Ethylene glycol serum concentration greater than 25-50 mg/dL unless the patient is asymptomatic and is receiving fomepizole or ethanol therapy.
      4. Severe metabolic acidosis in a patient with a history of ethylene glycol ingestion, even if the ethylene glycol level or osmol gap is not elevated (late presenter).
    2. End point of treatment. The minimum serum concentration of ethylene glycol associated with serious toxicity is not known. In addition, ethylene glycol levels are reported to rebound after dialysis. Therefore, treatment with fomepizole or ethanol should be continued until the osmol and anion gaps normalize (if available) or serum ethylene glycol and glycolic acid levels are no longer detectable.