Antifreeze poisoning in humans

Antifreeze also known as ethylene glycol (C2H6O2), 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 a odorless, colorless, sweet-tasting liquid most commonly found in antifreeze and is often accidentally or intentionally ingested; odor does not provide any warning of inhalation exposure to hazardous concentrations. 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. As little as 120 milliliters (approximately 4 fluid ounces) of ethylene glycol may be enough to kill an average-sized man.

Antifreeze (ethylene glycol) exposure can be extremely dangerous, with significant morbidity and mortality if left untreated ². A potentially lethal dose of antifreeze (ethylene glycol) is approximately 1-2 mL per kg body weight of 95% concentrated solution or about 1,500 mg/kg ³.

Antifreeze (ethylene glycol) poisoning can cause varying degrees of toxicity and management generally requires supportive care, close laboratory monitoring and antidotal therapy. The primary treatments for antifreeze poisoning are either ethanol or fomepizole and occasionally, dialysis ⁴. Fomepizole is exceptionally safe with no significant adverse effects ⁵. When ethanol is used as an antidote, it can be difficult to manage, requiring critical care management for close titration and intoxciation with its associated complications, such as encephalopathy and respiratory depression ⁶. Dialysis carries its own risks and benefits, including decreased blood pressure, bleeding from catheter placement, and infection.

Antifreeze (ethylene glycol) poisoning is most commonly due to ingestion. Antifreeze (ethylene glycol) poisoning has fairly limited dermal absorption, unlike other alcohols, such as methanol ⁷. Most exposures are intentional as suicide attempts or occasionally, for inebriation. Children who may ingest antifreeze while exploring their environments may be prone to consuming significantly toxic amounts due to its sweet taste ⁸.

Individuals at risk of antifreeze poisoning include toddlers and young children exploring their environment, alcoholics, and suicidal individuals ⁴. According to the Annual Report of the American Association of Poison Control Centers’ National Poison Data System, the number of case mentions of antifreeze poisoning in 2016 was 6,374. The majority of these cases were in adults greater than 20 years old and were intentional ⁹. Children under the age of 12 made up 686 of the known total 6,374 cases with 13 unknown child age cases ⁹.

Antifreeze poisoning key points

• All patients with antifreeze (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.
• Antifreeze poisoning is an emergency. If you suspect that someone has antifreeze 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.

Antifreeze poisoning pathophysiology

Antifreeze (ethylene glycol) is rapidly absorbed through the gastrointestinal tract after ingestion with serum concentrations peaking very soon after ingestion. The volume of distribution is about 0.7 L.kg. Elimination is primarily first order when concentrations are under 250 mg/dL, with a half-life of approximately 4-6 hours ¹⁰. With concentrations above 250 mg/dL, elimination becomes zero order at likely around 10 mg/kg/hr. When alcohol dehydrogenase is inhibited, preventing metabolism, elimination half-life of ethylene glycol is prolonged to 10-18 hours and is renally dependent ¹¹.

Like ethanol and methanol, metabolism begins with gastric mucosal alcohol dehydrogenase, and occurs primarily in the liver through serial oxidation by alcohol dehydrogenase and aldehyde dehydrogenase, with each step reducing NAD+ to NADH. Ethylene glycol is first oxidized by alcohol dehydrogenase to glycoaldehyde, which is then oxidized by aldehyde dehydrogenase to glycolic acid, which is primarily responsible for the associated metabolic acidosis. Glycolic acid is then oxidized to glyoxylic by glycolic acid oxidase, or lactate dehydrogenase due to its resemblence of lactate. Glyoxylic acid is a precursor for oxalic acid, the nephrotoxic metabolite; and also for the nontoxic metabolites, α-hydroxy-β-ketoadipic acid and glycine, which is further converted to hippuric acid. Thiamine is a cofactor in the production of α-hydroxy-β-ketoadipic acid and pyridoxine and magnesium are cofactors in the production of glycine ⁴.

Toxicokinetics

Ethylene glycol, the parent compound, is inebriating but generally considered nontoxic. The parent compound is osmotically active, and is responsible for the increased osmolality observed in the early course of exposure prior to metabolism. Ethylene glycol’s metabolites are responsible for the anion gap metabolic acidosis. Although there is evidence that each of the metabolites are toxic, it is glycolic acid that is believed to be long-lived enough to be primarily responsible for the anion gap metabolic acidosis, while oxalic acid is responsible for the associated end-organ injury, nephrotoxicity. Oxalic acid deposits in renal tubules as insoluble calcium oxylate monohydrate, leading to proximal tubular necrosis. Oxalic acid’s affinity for calcium may lead to hypocalcemia, which can be associated with tetany, seizures, and QT interval prolongation on electrocardiogram. It is important to realize that the increased osmolar gap can be present early after toxic exposure prior to significant metabolism, but as the course progresses the osmolar gap closes, with metabolism leading to the development of an anion gap metabolic acidosis without increased osmolar gap ¹².

Antifreeze poisoning signs and symptoms

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

Antifreeze (ethylene glycol) poisoning usually presents with a varying degree of drunkenness early in the course, with the potential for central nervous system depression (CNS). 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 ¹².

Time Course

After ingestion, antifreeze (ethylene glycol) is rapidly absorbed (within 1 to 4 hours) through the stomach. Following absorption, 80% or more of antifreeze (ethylene glycol) is chemically converted by the body into toxic compounds. The course of antifreeze (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 antifreeze (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 antifreeze (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 antifreeze (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 antifreeze (ethylene glycol) can be delayed significantly by the co-ingestion of alcohol.

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

Early antifreeze (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 antifreeze (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 antifreeze (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 antifreeze (ethylene glycol) may cause irritation.
• Exposure to liquid antifreeze (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.

How to treat antifreeze poisoning?

Treatment options for antifreeze (ethylene glycol) poisoning include supportive care, fomepizole (Antizole, 4-Methylpyrazole or 4MP), ethanol, dialysis and theoretically, thiamine, pyridoxine and magnesium ². 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 ⁴.

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 ¹³.

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 ⁴.

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 ⁴.

Antifreeze (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 ¹⁴.

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 antifreeze (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 ¹⁵.

When patients survive antifreeze (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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