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 kidney failure. The major cause of toxicity is not the ethylene glycol itself but the metabolites of ethylene glycol when it is metabolized.
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. 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. Many antifreeze products have denatonium benzoate, a bittering agent, added to try and prevent ingestion.
Once thought innocuous, ethylene glycol has been shown to be highly toxic to humans. The toxic dose varies but an estimated oral lethal dose in humans has been reported as approximately 1.4 mL/kg of pure ethylene glycol. 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. A toxic dose requiring medical treatment is considered more than 0.1 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. Because of its low vapor pressure and as it poorly absorbed through skin, ethylene glycol poisoning is uncommon following inhalational or dermal exposure.
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 glycolic acid is 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. The rate-limiting step in this cascade is the conversion of glycolic to glyoxylic acid. Accumulation of glycolic acid in the body is mainly responsible for toxicity.
The three main systems affected by ethylene glycol poisoning are the central nervous system, metabolic processes, and the kidneys. 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. As time passes, the increase in metabolites causes encephalopathy or cerebral edema. Seizures may occur due to a direct effect or due to hypocalcemia. The metabolic effects are primarily metabolic acidosis which is caused by 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 acidosis. The formation of acid metabolites also causes inhibition of other metabolic pathways, such as oxidative phosphorylation. The renal toxicity of ethylene glycol is caused by direct cytotoxic effects of glycolic acid. In addition, accumulation of calcium oxalate crystals in the kidneys causes kidney damage leading to oliguric or anuric kidney failure.
As many of the clinical signs and symptoms of ethylene glycol poisoning are nonspecific and occur in many poisonings the diagnosis is often difficult. 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. 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. 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.
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. Additionally, the presence of other alcohols such as ethanol, isopropanol, or methanol or conditions such as alcoholic or diabetic ketoacidosis, lactic acidosis, or renal failure may also produce an elevated osmolal gap leading to a false diagnosis.
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. 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. 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 perioral area, clothing, vomitus, or urine which can help to diagnose poisoning.
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. Although the usefulness of gastric lavage has been questioned in poisoning situations. Ipecac-induced vomiting is not recommended. As activated charcoal does not adsorb glycols, it is not indicated and should only be used in the presence of a toxic dose of a co-ingestant. Patients with significant poisoning often present in a critical condition. In this situation stabilization of the patient including airway management with endotracheal intubation is the most important initial management. Patients presenting with metabolic acidosis or seizures require treatment with sodium bicarbonate and anticonvulsives such as a benzodiazepine respectively. 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.
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, both of which act by inhibiting the enzyme alcohol dehydrogenase. This antidotal treatment forms the mainstay of management of ethylene glycol poisoning. 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. Ethanol acts by competing with ethylene glycol for alcohol dehydrogenase. 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.
Fomepizole is a potent inhibitor of alcohol dehydrogenase, similar to ethanol it acts to block the formation of the toxic metabolites. Fomepizole has been shown to be highly effective as an antidote for ethylene glycol poisoning. It is the only antidote approved by the USA FDA for the treatment of ethylene glycol poisoning. Both antidotes has advantages and disadvantages. Ethanol is readily available in most hospitals, inexpensive, and can be administered orally as well as intravenously. Although its adverse effects include intoxication, hypoglycemia in pediatric patients, and possible hepatotoxicity. 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 serum levels of the drug. The disadvantage of fomepizole is that it is expensive. Costing 1,000 United States dollars per gram; an average course used in an adult poisoning would cost approximately $3,500 to 4,000. Despite the cost, fomepizole is gradually replacing ethanol as the antidote of choice in ethylene glycol poisoning. Adjunct agents including thiamine and pyridoxine are often given based on the fact that they may help prevent the formation of oxalic acid. 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.
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. 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), renal failure, severe electrolyte imbalance, or if the patients condition is deteriorating despite treatment. 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. If hemodialysis is not available, then peritoneal dialysis also removes ethylene glycol, although less efficently.
Generally if the patient is treated and survives then a full recovery is expected. Patients who present early to medical facilities and have prompt medical treatment typically have a favorable outcome. Alternatively, patients presenting late with signs and symptoms of coma, hyperkalemia, seizures, or severe acidosis have a poor prognosis. Patients who develop severe central nervous system manifestations or cerebral infarcts who survive may have long term neurologic dysfunction; in some cases they may recover, although convalescence may be prolonged. 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.
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. In the United States, 3 states (Oregon, California, New Mexico) have made the addition of bittering agents to antifreeze compulsory. Follow up studies assessing the efficacy of bittering agents in preventing toxicity or death have, however, shown limited benefit of bittering ethylene glycol preparations.
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