Ethylene glycol poisoning

Ethylene glycol (C2H6O2) also known as antifreeze, is a useful industrial compound found in many consumer products, including automotive antifreeze, hydraulic brake fluids, some stamp pad inks, ballpoint pens, solvents, paints, plastics, films, and cosmetics; it also is used as a pharmaceutical vehicle ¹. Ethylene glycol is the major ingredient of almost all radiator fluid products in the United States. Ethylene glycol is used to increase the boiling point and decrease the freezing point of radiator fluid, which 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 identify the source of a radiator leak. The fluorescein in the fluid fluoresces when viewed under ultraviolet light.

Ethylene glycol is a odorless, colorless, sweet-tasting liquid which is why some animals are attracted to it and is often accidentally or intentionally ingested; odor does not provide any warning of inhalation exposure to hazardous concentrations. Many veterinarians are familiar with ethylene glycol toxicity because of the frequent cases in dogs and cats that have licked up radiator fluid. Antifreeze (ethylene glycol) is chemically broken down in your body into toxic compounds. Antifreeze (ethylene glycol) and its toxic byproducts first affect the central nervous system (CNS), then the heart, and finally the kidneys. Ingestion of sufficient amounts can be fatal. As little as 120 milliliters (approximately 4 fluid ounces) of ethylene glycol may be enough to kill an average-sized man.

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 ²:

• From 30 minutes to 12 hours after exposure, unmetabolized ethylene glycol produces central nervous system (CNS) depression, intoxication, and hyperosmolarity similar to that produced by ethanol.
• 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, kidneys, and heart.
• From 24 to 72 hours, acute kidney injury.can result from the direct renal toxic effects of the ethylene glycol metabolite calcium oxylate monohydrate.

The first symptom of ethylene glycol ingestion is similar to the feeling caused by drinking alcohol (ethanol). Within a few hours, more toxic effects become apparent. Symptoms may include nausea, vomiting, convulsions, stupor (decreased level of alertness), or even coma.

Ethylene glycol toxicity should be suspected in anyone who is severely ill after drinking an unknown substance, especially if they at first appear drunk and you can’t smell alcohol on their breath.

An overdose of ethylene glycol can damage the brain, lungs, liver, and kidneys. The poisoning causes disturbances in the body’s chemistry, including metabolic acidosis (increased acids in the bloodstream and tissues). The disturbances may be severe enough to cause profound shock, organ failure, and death.

Initial treatment includes infusion of crystalloids to enhance renal clearance of the toxic metabolites. Ethyl alcohol has traditionally been used for antidotal treatment, but it has largely been supplanted by fomepizole in the United States.

Ethylene glycol poisoning key points

• All patients with ethylene glycol poisoning should be managed in consultation with a medical toxicologist or the local poison center.
• If hemodialysis is determined to be indicated by toxicologist, then nephrology consultation is indicated.
• If ethanol is utilized as an antidote, critical care management is recommended.
• Ethylene glycol poisoning is an emergency. If you suspect that someone has ethylene glycol poisoning — even if you don’t see the classic signs and symptoms — seek immediate medical care. Here’s what to do:
  • Call your local emergency number immediately. Never assume the person will sleep off antifreeze (ethylene glycol).
  • Be prepared to provide information. If you know, be sure to tell hospital or emergency personnel the kind and amount of antifreeze the person drank, and when.
  • Don’t leave an unconscious person alone. Because antifreeze poisoning affects the way the gag reflex works, someone with antifreeze poisoning may choke on his or her own vomit and not be able to breathe. While waiting for help, don’t try to make the person vomit because he or she could choke.
  • Help a person who is vomiting. Try to keep him or her sitting up. If the person must lie down, make sure to turn his or her head to the side — this helps prevent choking. Try to keep the person awake to prevent loss of consciousness.

Ethylene glycol poisoning symptoms

Severity of ethylene glycol poisoning will vary with time from exposure to presentation, if coingestion of ethanol has occurred, or if early treatment was accessible.

Ethylene glycol poisoning usually presents with a varying degree of drunkenness early in the course, with the potential for central nervous system (CNS) depression. During this time, there is often an elevated osmolar gap without an elevated anion gap or acidosis. As the concentration of ethylene glycol shifts toward production of metabolites, the osmolar gap decreases and the anion gap increases with the development of a metabolic acidosis.

When calculating the osmolar gap, it is important to include ethanol in the calculation since ethanol is also osmotically active. The equation to measure the osmolar gap is as follows:

• Serum osmolality = [2(Na) + BUN/1.6 + Glucose/18 + Ethanol/4.6]

Ingestion of ethanol at any point will halt the metabolism of ethylene glycol. As ethylene glycol is progressively metabolized over the course of 4-12 hours, an anion gap metabolic acidosis develops secondary to the accumulaiton of glycolic acid. During this time, the patient may feel generally ill or be CNS depressed, and may begin to compensate with hyperventilation or hyperpnea. Tachycardia and hypertension may also occur. After about 12 hours, there may be evidence of nephrotoxicity, demonstrated by elevated creatinine, due to the precipitation of calcium oxalate crystals in the proximal tubules. This caclium oxalate deposition may predisopose to hypocalcemia, placing patient at risk for tetany, seizures, QT interval prolongation and dysrhythmias. After about 12-18 hours, oliguira may develop. If treatment occurs during this time, the acute renal injury is normally reversible and dialysis is often unnecessary. However, if treatment is delayed further, usually by delayed presentation or recognition, acute renal failure and systemic illness may develop, including acute respiratory distress syndrome, cerebral edema or infarction, and heart failure. Multisystem organ dysfunction is believed to be associated with calcioum oxalate deposition. If treatment does not occur early enough, the course of illness can lead to coma and death ³.

Time Course

After ingestion, ethylene glycol is rapidly absorbed (within 1 to 4 hours) through the stomach. Following absorption, 80% or more of ethylene glycol is chemically converted by the body into toxic compounds. The course of ethylene glycol toxicity is classically divided into three broad overlapping categories of adverse health effects.

• Stage 1 Mild to moderate stage also called the neurological stage: lasts from 30 minutes to 12 hours after ethylene glycol ingestion. Signs and symptoms include reduced level of consciousness (CNS depression), euphoria, dizziness, headache, slurred speech, drowsiness, disorientation, inability to coordinate movements (ataxia), irritation and restlessness, involuntary eye movements (nystagmus), and nausea and vomiting (emesis).
• Severe Stage 1: Decreased reflex responses, seizures, loss of consciousness, and coma.
• Stage 2 Mild to moderate stage also called the cardiopulmonary stage: occurs between 12 and 24 hours after ethylene glycol ingestion. Signs and symptoms include increased heart rate (tachycardia); abnormal or disordered heart rhythms (arrhythmia); increased blood pressure (hypertension); and build-up of toxic breakdown products in the blood stream (metabolic acidosis), resulting in increased rate and depth of breathing (hyperventilation).
• Severe Stage 2: More severe build-up of toxic breakdown products in the blood stream, resulting in increased rate and depth of breathing; heart damage, including congestive heart failure, resulting in accumulation of fluid in the lungs (pulmonary edema); lung damage, including adult respiratory distress syndrome (ARDS), resulting in a decreased oxygen supply to the body; multi-system organ failure; and death.
• Stage 3 Mild to moderate stage also called the renal stage: occurs between 24 and 72 hours after ethylene glycol ingestion. Stage 3 effects are unusual following a mild to moderate exposure.
• Severe Stage 3: Reduced urine excretion; absence of urine excretion; and acute kidney failure, causing a build-up of toxic chemicals and chemical imbalances in the blood stream.

Adverse health effects of ethylene glycol can be delayed significantly by the co-ingestion of alcohol.

Effects short-term (less than 8 hours) after exposure

Ethylene glycol poisoning resembles ethanol (drinking alcohol) intoxication but without the characteristic odor of alcohol on the patient/victim’s breath. Initial adverse health effects caused by ethylene glycol poisoning include central nervous system depression, intoxication, euphoria, stupor, and respiratory depression. Nausea and vomiting may occur as a result of gastrointestinal irritation. Severe toxicity may result in coma, loss of reflexes, seizures (uncommon), and irritation of the tissues lining the brain.

The toxic metabolic by-products of ethylene glycol metabolism cause a build-up of acid in the blood (metabolic acidosis). These toxic substances also affect the cardiopulmonary system and can cause renal failure. Metabolic acidosis commonly occurs after ethylene glycol poisoning, but absence of acidosis does not exclude ethylene glycol toxicity. Serum ethylene glycol levels do not correlate well with clinical presentation.

Untreated ethylene glycol poisoning can be fatal.

Eye exposure

• Exposure to vapors of ethylene glycol may cause irritation.
• Exposure to liquid ethylene glycol may result in swelling of the eyelid and around and of the cornea, inflammation of the conjunctiva and iris, and conjunctival or corneal injury.

Inhalation exposure

• Exposure to very high levels of ethylene glycol vapors causes irritation of mucous membranes and the upper respiratory tract.
• Exposure to levels of ethylene glycol concentrations higher than 80 ppm results in intolerable respiratory discomfort and cough.

Skin exposure

• Skin irritation.

Ethylene glycol poisoning treatment

Treatment options for ethylene glycol poisoning include supportive care, fomepizole (Antizole, 4-Methylpyrazole or 4MP), ethanol, dialysis and theoretically, thiamine, pyridoxine and magnesium ⁴. Fomepizole is the antidote for toxic alcohols, and it acts by inhibiting alcohol dehydrogenase to cease toxic alcohol metabolism. Ethanol may also be utilized therapeutically to inhibit alcohol dehydrogenase when fomepizole is unavailable. There are advantages and disadvantages to either treatment. Fomepizole is more easily dosed, does not cause any inebriation, and more strongly inhibits alcohol dehydrogenase, but is fairly expensive. Ethanol is less expensive but is harder to dose accurately, requires close monitoring of the serum ethanol concentration, and causes inebriation that may necessitate intensive care monitoring ⁵.

Indications for antidotal treatment include an elevated ethylene glycol concentration and severe or progressing acidosis, despite resuscitation, with clinical suspicion of exposure. Recommendations regarding specific ethylene glycol concentration treatment thresholds vary, with most conservative recommendations to treat if greater than 20 to 25 mg/dL. However, if metabolic acidosis is mild or not present, and there is no evidence of end-organ toxicity, particularly renal, then an ethylene glycol concentration of 62 mg/dL is an appropriate starting point for treatment as molar calculations indicate this would correlate with a maximum of 10mmol/L of a toxic metabolite. This concentration of metabolites should not alone account for more than a 10 mmol/L base deficit or a an assoicated toxic effect. Note: the molar based treatment cutoff for methanol is 32 mg/dL; see methanol toxicity chapter). When ethylene glycol concentration is not readily available, then treatment should be initiated when bicarbonate progresses below 15mmol/L or if there is evidence of renal toxicity. After fomepizole is administered, there are 12 hours in which ethylene glycol metabolism is halted. This allows for adequate time to obtain an ethylene glycol concentration and arrange for dialysis, if needed ⁶.

Fomepizole and ethanol inhibit alcohol dehydrogenase to stop the conversion of ethyelene glycol (and other alcohols) to its toxic metabolites. When alcohol dehydrogenase is inhibited, clearance of ethyelene glycol is prolonged from a half-life of 4-6 hours to an effective half-life of approximately 17 hours. Fomepizole is given intravenously with a loading dose of 15 mg/kg, followed by maintenance dosing of 10 mg/kg every 12 hours for four doses, or until the ethylene glycol concentration is at least less than 62 mg/dL with a normal acid-base status; however, more conservative recommendations of below 25 mg/dL exist. It is not mandatory to complete four doses. If additional dosing is required beyond four maintenance doses, then dose should be increased to 15 mg/kg every 12 hours due to fomepizole’s autoinduction of its own metabolism. During dialysis, fomepizole should be administered every 4 hours as it is removed during dialysis. For a standard 4-hour dialysis session, fomepizole should be dosed both before and after the session, with resumption of 12-hour dosing thereafter ⁵.

Using ethanol as an antidote is more complicated than treatment with fomepizole. It is difficult to titrate, monitor and is inebriating. Ethanol may be given intravenously or orally, but its use should be limited to the fomepizole is inaccessible. Although it is considered less expensive than fomepizole, it often carries a higher total cost during hospital stay. During treatment, the goal serum ethanol concentration is 80 to 120 mg/dL. Intravenous ethanol formulary is usually 10%, and the loading dose is calculated using the product of the goal plasma concentration (C = 100mg/dL), the volume of distribution of ethanol (V = 0.6L/kg), and the patient’s weight. Maintenance dosing is then based on elimination rate. Empirically, 10% intravenous ethanol may be administered with a loading dose of 8 mL/kg over 30 to 60 minutes, followed by maintenance dosing of 1-2 mL/kg per hour. Maintenance dosing is doubled during dialysis. Oral dosing may be calculated using the above equation for serum alcohol concentrations by using 100 mg/dL for the serum concentration and then solving for the percentage amount of ethanol ingested. Empirically, 50% (100 proof) oral ethanol may be administered with a loading dose of 2 mL/kg followed by 0.2-0.4mL/kg per hour. Maintenance dosing is doubled during dialysis ⁵.

Ethylene glycol and its metabolites are dialyzable; however, with proper administration of fomepizole, dialysis is generally not indicated in the absence of renal dysfunction. In addition, dialysis can unjustifiably increase risk and cost to the patient. Unlike methanol or diethylene glycol, fomepizole alone is the recommended treatment for a toxic exposure to ethylene glycol without renal dysfunction, and only minimal acid-base disturbances, as it is far less likley that any toxicity is associated with unmetabolized ethylene glycol. The effective half life of ethylene glycol is only increased to about 17 hours when alcohol dehydrogenase is inhibited; therefore, dialysis does not necessarily decrease length of stay either. Furthermore, its use often requires being in the intensive care unit in many hospitals, thus increasing costs. Hemodialysis should be strongly considered in the presence of renal dysfunction, severe metabolic acidosis and severe electrolyte abnormalities. Normal urinary output needs to be assured to treat with fomepizole alone so that ethylene glycol can be reliably excreted. The presence of severe acidosis indicates the active and likely incomplete metabolism of ethylene glycol, with the concern that circulating glycolic acid may be converted to oxalate, which increases the risk of worsened renal function. Continuous renal replacement, although less effective, therapy may be considered if intermittent hemodialsyis is not feasible, particularly in the setting of hemodynamic instability. The decision to utilize hemodialysis is complicated and should be made in consultation with a medical toxicologist ⁷.

Additional treatment options may also be considered. Sodium bicarbonate infusion may be helpful, particularly in severe metabolic acidosis, but is not universally considered a standard recommendation. Calcium gluconate may be indicated if complications occur as a result of hypocalcemia, but should otherwise be replaced cautiously and judiciously as exogenous calcium administration may enhance the precipitation of calcium oxylate crystals. Seizures in the presence of hypocalcemia should be treated with benzodiazepines. Theoretically, administration of thiamine and pyridoxine and magnesium may assist in shunting glycolic acid metabolism away from oxalic acid and toward its nontoxic metabolites, α-hydroxy-β-ketoadipic acid and glycine, respectively, utlizing the mechanism discussed in the pathophysiology section.

Admission to the intensive care unit should be considered in the presence of severe symptomatology, including obtundation, severe metabolic or electrolyte derangements. Intensive care admission should also be considered based on treatment complexity, including the use of dialysis and more importantly, if ethanol treatment is required.

Antifreeze poisoning in humans long term effects

Patients often recover when prompt ethylene glycol poisoning diagnosis and treatment occur. When patients present late or diagnosis is not recognized in a timely fashion, significant morbidity and mortality can occur ⁸.

When patients survive ethylene glycol poisoning, there is generally recovery from any associated nephropathy; although, additional nephrology management and dialysis may be required after discharge.

References

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