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Ethylene glycol poisoning

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Ethylene glycol poisoning
SpecialtyEmergency medicine Edit this on Wikidata

Ethylene glycol poisoning is caused by the ingestion of ethylene glycol. Ethylene glycol is most commonly found as the primary ingredient of automobile antifreeze and hydraulic brake fluids. It is a highly toxic, colorless, odorless, almost nonvolatile liquid with a sweet taste. Following ingestion the symptoms of poisoning follow a three step progression starting with intoxication and vomiting, before causing metabolic acidosis, cardiovascular dysfunction, and finally acute kidney failure. The major cause of toxicity is not the ethylene glycol itself but the metabolites of ethylene glycol when it is metabolized. The major metabolites causing toxicity are glycolic acid and oxalic acid.

Medical diagnosis of poisoning is most reliably done by measurement of ethylene glycol in the blood. However many hospitals do not have the facilities to perform this test and need to rely on abnormalities in the body’s biochemistry to diagnose poisoning. Diagnosis can also be aided by examining the urine for the presence of calcium oxalate crystals. Treatment consists of initially stabilizing the patient followed by the use of antidotes. The antidotes used are either ethanol or fomepizole. The antidotes work by blocking the enzyme responsible for metabolizing ethylene glycol and therefore halt the progression of poisoning. Hemodialysis is also used to help remove ethylene glycol and its metabolites from the blood. As long as medical treatment is undertaken the prognosis is generally good with most patients making a full recovery. Poisoning is relatively common and due to its taste, children and animals will sometimes consume large quantities of ethylene glycol. Denatonium benzoate, a bittering agent, is added to many antifreeze products to try to prevent ingestion.

Toxicity

Ethylene glycol was once thought innocuous, in 1931 it was suggested as being suitable for use as a vehicle or solvent for injectable pharmaceutical preparations.[1] Numerous cases of poisoning have been reported since then, and it has been shown to be highly toxic to humans.[2] A toxic dose requiring medical treatment varies but is considered more than 0.1 mL per kg body weight (mL/kg) of pure substance. Poison control centers often use more than a lick or taste in a child or more than a mouthful in an adult as a dose requiring hospital assessment.[3] An estimated oral lethal dose in humans has been reported as approximately 1.4 mL/kg of pure ethylene glycol.[4] Although survival with medical treatment has occurred with doses much higher than this, death has occurred with just 30 mL of the concentrate in an adult.[5][6][7]

Ethylene glycol has a low vapor pressure; it does not evaporate readily at normal temperatures and therefore high concentrations in air or intoxication are unlikely to occur following inhalational exposures.[8] There may be a slight risk of poisoning where mists or fogs are generated, although this rarely leads to poisoning as ethylene glycol causes irritation and coughing when breathed in, alerting victims to its presence.[9] Ethylene glycol is not well absorbed through skin meaning poisoning following dermal exposure is also uncommon.[10]

Signs and symptoms

Symptoms of ethylene glycol poisoning usually follow a three-step progression, although poisoned individuals will not always develop each stage.[4]

Pathophysiology

Glycolic acid is the major metabolite of ethylene glycol responsible for toxicity

The three main systems affected by ethylene glycol poisoning are the central nervous system, metabolic processes, and the kidneys.[4] The central nervous system is affected early in the course of poisoning as the result of a direct action of ethylene glycol. Similar to ethanol, it causes intoxication, followed by drowsiness or coma.[4] Seizures may occur due to a direct effect.[11] The toxic mechanism of ethylene glycol poisoning is mainly due to the metabolites of ethylene glycol. Initially it is metabolized by alcohol dehydrogenase to glycoaldehyde, which is then oxidized to glycolic acid. The increase in metabolites may cause encephalopathy or cerebral edema.[13] The metabolic effects occur 12 to 36 hours post ingestion, causing primarily metabolic acidosis which is due mainly to accumulated glycolic acid. Additionally, as a side effect of the first two steps of metabolism, an increase in the blood concentration of lactic acid occurs contributing to lactic acidosis. The formation of acid metabolites also causes inhibition of other metabolic pathways, such as oxidative phosphorylation.[4]

The renal toxicity of ethylene glycol occurs 24 to 72 hours post ingestion and is caused by a direct cytotoxic effect of glycolic acid. The glycolic acid is then metabolized to glyoxylic acid and finally to oxalic acid. Oxalic acid binds with calcium to form calcium oxalate crystals which may deposit and cause damage to many areas of the body including the brain, heart, kidneys, and lungs.[4] The most significant effect is accumulation of calcium oxalate crystals in the kidneys which causes kidney damage leading to oliguric or anuric acute kidney failure.[4] The rate-limiting step in this cascade is the conversion of glycolic to glyoxylic acid.[14] Accumulation of glycolic acid in the body is mainly responsible for toxicity.[15]

Diagnosis

As many of the clinical signs and symptoms of ethylene glycol poisoning are nonspecific and occur in many poisonings the diagnosis is often difficult.[16] It is most reliably diagnosed by the measurement of the blood ethylene glycol concentration. Ethylene glycol in biological fluids can be determined easily by gas chromatography.[17] Many hospital laboratories do not have the ability to perform this blood test and in the absence of this test the diagnosis must be made based on the clinical presentation of the patient.[4] In this situation a helpful test to diagnose poisoning is the measurement of the osmolal gap. The patients' serum osmolality is measured by freezing point depression and then compared with the predicted osmolality based on the patients' measured sodium, glucose, blood urea nitrogen, and any ethanol that may have been ingested. The presence of a large osmolal gap supports a diagnosis of ethylene glycol poisoning. However, a normal osmolar gap does not rule out ethylene glycol exposure because of wide individual variability.[18][19]

Urine microscopy showing calcium oxalate crystals in the urine

The increased osmolal gap is caused by the ethylene glycol itself. As the metabolism of ethylene glycol progresses there will be less ethylene glycol and this will decrease the blood ethylene glycol concentration and the osmolal gap making this test less useful.[20] Additionally, the presence of other alcohols such as ethanol, isopropanol, or methanol or conditions such as alcoholic or diabetic ketoacidosis, lactic acidosis, or kidney failure may also produce an elevated osmolal gap leading to a false diagnosis.[4]

Other laboratory abnormalities may suggest poisoning, especially the presence of a metabolic acidosis, particularly if it is characterized by a large anion gap. Large anion gap acidosis is usually present during the initial stage of poisoning. However, acidosis has a large number of differential diagnosis, including poisoning from methanol, salicylates, iron, isoniazid, paracetamol, theophylline, or from conditions such as uremia or diabetic and alcoholic ketoacidosis. The diagnosis of ethylene glycol poisoning should be considered in any patient with a severe acidosis.[4] Urine microscopy can reveal needle or envelope-shaped calcium oxalate crystals in the urine which can suggest poisoning; although these crystals may not be present until the late stages of poisoning.[21] Finally, many commercial radiator antifreeze products have fluorescein added to enable radiator leaks to be detected using a Wood's lamp. Following ingestion of antifreeze products containing ethylene glycol and fluorescein, a Wood's lamp may reveal fluorescence of a patient’s mouth area, clothing, vomitus, or urine which can help to diagnose poisoning.[22][23]

Treatment

Initial treatment consists of stabilizing the patient and gastric decontamination. As ethylene glycol is rapidly absorbed, gastric decontamination needs to be performed soon after ingestion to be of benefit. Gastric lavage or nasogastric aspiration of gastric contents are the most common methods employed in ethylene glycol poisoning.[4] The usefulness of gastric lavage has, however, been questioned, and it is now no longer used routinely in poisoning situations.[24] Ipecac-induced vomiting is not recommended. As activated charcoal does not adsorb glycols, it is not recommended as it will not be effective at preventing absorption.[4][25] It is only used in the presence of a toxic dose of a another poison or drug.[18] Patients with significant poisoning often present in a critical condition. In this situation stabilization of the patient including airway management with intubation is the most important initial management.[4] Patients presenting with metabolic acidosis or seizures require treatment with sodium bicarbonate and anticonvulsives such as a benzodiazepine respectively.[4] Sodium bicarbonate should be used cautiously as it can worsen hypocalcemia by increasing the plasma protein binding of calcium. If hypocalcemia occurs it can be treated with calcium replacement although calcium supplementation can increase the precipitation of calcium oxalate crystals leading to tissue damage.[16]

Following decontamination and the institution of supportive measures, the next priority is inhibition of further ethylene glycol metabolism using antidotes. The antidotes for ethylene glycol poisoning are ethanol or fomepizole. This antidotal treatment forms the mainstay of management of ethylene glycol poisoning. Ethanol is not an inhibitor of alcohol dehydrogenase since ADH also metabolizes ethanol. Ethanol acts by competing with ethylene glycol for alcohol dehydrogenase. Pharmaceutical grade ethanol is usually given intravenously as a 5 or 10% solution in 5% dextrose, but it is also sometimes given orally in the form of a strong spirit such as whisky, vodka, or gin. Alcohol dehydrogenase has about a 100 times greater affinity for ethanol than for ethylene glycol; ethanol therapy saturates the enzyme inhibiting further ethylene glycol metabolism thus limiting the formation of toxic metabolites.[4]

Fomepizole is a potent inhibitor of alcohol dehydrogenase, similar to ethanol it acts to block the formation of the toxic metabolites.[16][26] Fomepizole has been shown to be highly effective as an antidote for ethylene glycol poisoning.[26][27] It is the only antidote approved by the USA FDA for the treatment of ethylene glycol poisoning.[4] Both antidotes has advantages and disadvantages. Ethanol is readily available in most hospitals, inexpensive, and can be administered orally as well as intravenously. Its adverse effects include intoxication, hypoglycemia in children, and possible liver toxicity.[18] Patients receiving ethanol therapy also require frequent blood ethanol level measurements and dosage adjustments to maintain a therapeutic ethanol concentration. Patients therefore must be monitored in an intensive care unit. Alternatively, the adverse side effects of fomepizole are minimal and the approved dosing regimen maintains therapeutic concentrations without the need to monitor blood levels of the drug. The disadvantage of fomepizole is that it is expensive. Costing 1,000 USD per gram; an average course used in an adult poisoning would cost approximately $3,500 to 4,000.[28][29] Despite the cost, fomepizole is gradually replacing ethanol as the antidote of choice in ethylene glycol poisoning.[26][27] Adjunct agents including thiamine and pyridoxine are often given based on the fact that they may help prevent the formation of oxalic acid.[4] The use of these agents is based on theoretical observations and there is limited evidence to support their use in treatment; they may be of particular benefit in people who could be deficient in these vitamins such as malnourished or alcoholic patients.[16]

In addition to antidotes, an important treatment for poisoning is the use of hemodialysis. Hemodialysis is used to enhance the removal of unmetabolized ethylene glycol, as well as its metabolites from the body. It has been shown to be highly effective in the removal of ethylene glycol and its metabolites from the blood.[30][31] Hemodialysis also has the added benefit of correcting other metabolic derangements or supporting deteriorating kidney function. Hemodialysis is usually indicated in patients with severe metabolic acidosis (blood pH less than 7.3), kidney failure, severe electrolyte imbalance, or if the patients condition is deteriorating despite treatment.[16][11] Often both antidotal treatment and hemodialysis are used together in the treatment of poisoning. Because hemodialysis will also remove the antidotes from the blood, doses of antidotes need to be increased to compensate.[4] If hemodialysis is not available, then peritoneal dialysis also removes ethylene glycol, although less efficiently.[32]

Prognosis

Generally if the patient is treated and survives then a full recovery is expected.[33] Patients who present early to medical facilities and have prompt medical treatment typically will have a favorable outcome.[34] Alternatively, patients presenting late with signs and symptoms of coma, hyperkalemia, seizures, or severe acidosis have a poor prognosis.[3] Patients who develop severe central nervous system manifestations or stroke who survive may have long term neurologic dysfunction; in some cases they may recover, although convalescence may be prolonged.[35][36][37][38] The most significant long-term complication is related to the kidneys. Cases of permanent kidney damage, often requiring chronic dialysis or kidney transplantation, have been reported after severe poisoning.[39][40]

Epidemiology

Ethylene glycol poisoning is a relatively common occurrence worldwide.[40][41][42][43] Human poisoning often occurs in isolated cases, but may also occur in epidemics.[44][45][46] Many cases of poisoning are the result of using ethylene glycol as a cheap substitute for alcohol or intentional ingestions in suicide-attempts.[33] Less commonly it has been used as a means of homicide.[47][48] Children or animals may be exposed by accidental ingestion; children and animals often consume large amounts due to ethylene glycol having a sweet taste.[49] In the United States there were 5816 cases reported to poison centers in 2002.[3] Additionally, ethylene glycol was the most common chemical responsible for deaths reported by US poison centers in 2003.[41] In Australia there was 17 cases reported to the Victorian poison center and 30 cases reported to the New South Wales poison center in 2007.[50][51] However, these numbers may underestimate actual numbers because not all cases attributable to ethylene glycol are reported to poison control centers.[52] Most deaths from ethylene glycol are intentional suicides; deaths in children due to unintentional ingestion are extremely rare.[53]

In an effort to prevent poisoning, often a bittering agent called denatonium benzoate, known by the trade name Bitrex, is added to ethylene glycol preparations as an adversant to prevent accidental or intentional ingestion. The bittering agent is thought to stop ingestion as part of the human defense against ingestion of harmful substances is rejection of bitter tasting substances.[54] In the United States, three states (Oregon, California, New Mexico) have made the addition of bittering agents to antifreeze compulsory.[53][55] Follow up studies assessing the efficacy of bittering agents in preventing toxicity or death have, however, shown limited benefit of bittering ethylene glycol preparations.[53][56]

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  55. ^ Neumann CM, Giffin S, Hall R, Henderson M, Buhler DR (2000). "Oregon's Toxic Household Products Law". Journal of public health policy. 21 (3): 342–59. doi:10.2307/3343331. PMID 11021047.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  56. ^ Mullins ME, Zane Horowitz B (2004). "Was it necessary to add Bitrex (denatonium benzoate) to automotive products?". Veterinary and human toxicology. 46 (3): 150–2. PMID 15171494. {{cite journal}}: Unknown parameter |month= ignored (help)
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