Ethylene Glycol Toxicity

Practice Essentials

Several toxic alcohols are of medical and toxicological importance; the principal ones include ethanol, ethylene glycol (EG), methanol, and isopropanol. See Alcohol Toxicity. This article discusses ethylene glycol, which is extremely toxic. If untreated, ingestion of ethylene glycol can be fatal.

Ethylene glycol is the major ingredient of almost all radiator fluid products in the United States. It 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 tastes sweet, which is why some animals are attracted to it. Many veterinarians are familiar with ethylene glycol toxicity because of the frequent cases in dogs and cats that have licked up radiator fluid.

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^[1] :

• From 30 minutes to 12 hours after exposure, unmetabolized ethylene glycol produces 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.

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.

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Pathophysiology

^[2] Like the other toxic alcohols mentioned above, ethylene glycol is a parent compound that exerts most of its toxicity by conversion to metabolites. Ethylene glycol itself may cause some alteration of mental status but it is a relatively nontoxic compound before it is metabolized. The metabolites cause the distinctive toxicity associated with this compound.

Knowing the pathway of ethanol metabolism is necessary to understanding ethylene glycol toxicity properly. Ethanol is metabolized by the enzyme alcohol dehydrogenase (ADH), which is located in the liver and gastric mucosa, and by the cytochrome P-450 mixed function oxidase (MFO) system in the liver. The mixed function oxidase component is subject to greater inducibility than alcohol dehydrogenase.

Like ethyl alcohol and methanol, ethylene glycol is metabolized by ADH. In this step it forms glycoaldehyde. Through interaction with aldehyde dehydrogenase, ethylene glycol is then metabolized to glycolic acid (GA), which accumulates and can cause a profound metabolic acidosis. This glycolic acid is eventually converted into glyoxylic acid, and then into the highly toxic oxalate or the safer glutamate or α-ketoadipic acid metabolites.

Calcium oxalate crystals may form and accumulate in blood and other tissues. The precipitation of calcium oxalate in the renal cortex results in decreased glomerular filtration and renal insufficiency. The formation of these crystals consumes circulating calcium, and hypocalcemia may occur, though this is uncommon.

The rate-limiting step of ethylene glycol metabolism is the ADH-catalyzed step. Common ethyl alcohol (ethanol) binds much more easily to ADH than ethylene glycol or methanol does. Because ethanol is the preferred substrate for ADH, the presence of ethanol may essentially block metabolism of ethylene glycol. In addition, this enzyme is blocked by the administration of fomepizole (4-methylpyrazole [4-MP]), which is discussed below (see Emergency Department Care). This is the basis of one therapy used in the United States.

Upon oral ingestion, serum concentrations of ethylene glycol peak within 1-4 hours. The elimination half-life (assuming preserved renal function) is 3 hours. When alcohol dehydrogenase is inhibited by ethanol or fomepizole, the elimination half-life increases to about 16 hours.

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Epidemiology

Frequency

United States

Ethylene glycol is a relatively common cause of overdose in US emergency departments. Single exposures to ethylene glycol in antifreeze and other automotive products reported to the American Association of Poison Control Centers (AAPCC) rose from 5,282 in 2009 to 5,783 in 2016.^{[3, 4]}

Mortality/Morbidity

According to the AAPCC's National Poison Data System, in 2016, 934 had minor outcomes, 448 had moderate outcomes, 124 had severe outcomes, and 7 deaths were documented.^[4]

Age

The annual report of the AAAPCC's National Poison Data System in 2016 documented ethylene glycol exposure in 495 children younger than 6 years, 191 in those aged 6-12 years, 489 in those 13-19 years, and 4014 in those 20 years and older.^[4]

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History

As with all poisonings, ascertain the nature of the oral ingestion by talking with the patient or parents. Points to cover include the following:

• The timing of ingestion is important.
• The product involved is important. Try to obtain the original container of the ingested substance to confirm its identity.
• Determine the timing and quantity of liquor or other ethanol ingestion.
• Initially, patients may be asymptomatic; with time they will develop altered mental status and tachypnea.

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Physical

See the list below:

• After an adequate airway is ensured, monitor vital signs, including temperature.
• Deep and rapid breathing may be Kussmaul respirations, which are indicative of severe metabolic acidosis.
• Assess for altered mental status.

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Causes

Causes of ethylene glycol poisoning include the following:

• Suicide attempts
• Unintentional ingestions (mainly observed in children)
• Workplace beverage-container mix-ups

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Laboratory Studies

Patients who ingest ethylene glycol may initially have few, if any, metabolic disturbances. Serum concentrations of ethylene glycol may be measured; however, at most health care facilities, these results are not available for 2 or more days. Thus, ethylene glycol concentrations are often not determined early enough to be useful in emergency treatment, though they should still be sent to confirm the diagnosis.

For institutions that frequently treat ethylene glycol toxicity cases, in-hospital rapid laboratory confirmation may become cost-effective because of the institutional cost-benefit ratio evaluation that compares therapy with fomepizole, ethanol, and hemodialysis. Emergency departments located in larger metropolitan areas may negotiate availability of this test at regional clinical laboratories. It is important to check on this availability at your own clinical site.

The classic laboratory profile of ethylene glycol ingestion is an early osmolar gap (the ethylene glycol serves as an unmeasured osmole) that disappears as an anion gap metabolic acidosis develops (as the ethylene glycol is converted into its acidic derivatives). However, there is a wide range of normal osmolar gaps, and even patients with early presentations after consequential ethylene glycol ingestions may have a normal osmolar gap, so it should never be used to exclude toxicity. Listed below are laboratory tests that will be useful in the setting of ethylene glycol ingestion.

Serum osmolality

Because ethylene glycol concentrations are not reported in a clinically helpful or timely fashion in most institutions, ethylene glycol exposure level is often estimated through measurement of the serum osmolality. This estimate is obtained by sampling a set of electrolytes and other serum solutes (eg, sodium, blood urea nitrogen [BUN], creatinine, glucose) and calculating the expected osmolality in the patient's serum. A serum osmolality is then measured, and the difference between the measured and calculated osmolality (the osmolal gap) is determined.

Several formulas are effective for calculating the osmolality from serum electrolytes and other solutes. The most commonly used formula in the US is 2(Na⁺ level) + BUN level/2.8 + glucose level/18 = calculated osmolality. The sodium level is measured in mEq, and the BUN and glucose levels are measured in mg/dL.

The osmolal gap is determined by subtracting the calculated osmolality from the measured osmolality (osmol [measured] – osmol [calculated] = osmolal gap). The serum osmolality must be determined by freezing-point depression rather than by boiling point elevation. This is because, with the boiling technique, the toxic alcohols are vaporized rapidly, and, thus, a falsely low or normal estimate of the osmolality is obtained.

A normal osmolar gap can range from -14 to +10, and potentially toxic ethylene glycol ingestions can be hidden within an apparently normal osmolar gap. Additionally, as described above, the osmolar gap goes away as the ethylene glycol is metabolized. For these reasons, the osmolar gap should never be used to exclude ethylene glycol poisoning. Additionally, moderately elevated osmolar gaps (10-30) are common in sick patients with disease states unrelated to toxic alcohol poisoning, so osmolar gaps in this range are not necessarily indicative of poisoning. However, largely elevated osmolar gaps (greater than 40) are highly suggestive of toxic alcohol poisoning.

Serum electrolyte levels are also useful later in the course of intoxication because they can reveal the presence of anion gap acidosis. This information may be important when determining the need for dialysis and other interventions. The goal of therapy, however, is to treat the patient before acidosis develops.

Additional laboratory tests

The following tests should also be obtained in symptomatic patients:

• Serum calcium level
• Arterial blood gases
• Urinalysis: Urine may reveal the presence of calcium oxalate crystals, a sign usually observed late in the process of intoxication. Oxalate crystals typically have the shape of a folded envelope. (See the image below.)

View Image

Oxalate crystals. Courtesy of John D Schaldenbrand, MD, Department of Pathology, St Joseph Mercy Health System, Ann Arbor, MI.

Another technique, popularized by the television series "ER," is to shine a Wood's lamp (ultraviolet light) on an early sample of urine. If a sufficient fluorescein level is present in the radiator fluid, the urine fluoresces.^{[7, 8]} The urine should be compared with a control sample. If the radiator fluid contains fluorescein, a green-colored glow may be observed in a dark room. This light also may be used to detect possible ethylene glycol on clothing or the patient. It must be stated, however, that this is not a reliable means to confirm or eliminate the possibility of an ethylene glycol ingestion, for a multitude of reasons.^[9]

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Imaging Studies

Imaging rarely contributes to the specific diagnosis of ethylene glycol intoxication, though thalamic lesions may occur on computed tomography or magnetic resonance imaging scans of the brain in severe poisoning. Imaging may be useful as needed for routine care of these patients.

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Other Tests

Other tests that may be useful depending on the clinical status of the patient include electrocardiography (ECG). Use of a Wood's (ultraviolet) lamp has been discussed above. Urine microscopy may be useful for identifying calcium oxalate crystals, as noted above. However, calcium oxalate crystals do not develop in the urine for about 4-8 hours following ingestion and if significant renal insufficiency develops, they may not be present for 40 hours following the ingestion.^[10]

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Approach Considerations

Guidelines on the medical management of ethylene glycol poisoning are available from the Agency for Toxic Substances and Disease Registry. These include recommendations on prehospital, emergency department, and critical care treatment.^[1]

Initial emergency department 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.

 In centers where fomepizole is available, patients who present early and are without acidosis clinically well can be treated with fomepizole and hemodialysis on a regular floor. Any patients who are ill and acidotic or who present to centers where ethanol is used instead of fomepizole should be treated in an intensive care unit (ICU) or other setting with cardiac monitoring and close nursing care. Patients who present to a facility without those capabilities should be transferred to a facility where hemodialysis and an ICU are available.

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Prehospital Care

Emergency medical services should do the following:

• Ascertain as much specific information regarding the identity of the ingested substance as possible.
• If possible, obtain the bottle or container that held the ingested substance. Interviewing persons present at the site of the ingestion may be helpful in this regard.
• Obtain intravenous access and administer crystalloid infusions.
• Monitor cardiac function and determine blood dextrose level.
• Airway management is a priority because of the risk of aspiration.

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Emergency Department Care

Rapidly evaluate patients who present with signs, symptoms, or history of toxic alcohol ingestion; determine serum osmolal gap. The prehospital (EMS) personnel often can provide important details regarding the identity of the chemical(s) involved and the clinical characteristics of the patient.

Considerations in emergency department (ED) care include the following:

• Many patients with ethylene glycol ingestions are extremely obtunded and are at high risk of aspiration; endotracheal intubation may need to be considered.
• Obtain intravenous access and laboratory specimens.
• Activated charcoal and nasogastric lavage have no role in toxic alcohol poisoning; typically the alcohols will be absorbed too quickly for either of these modalities to have any efficacy.
• Measure levels of electrolytes, calcium, and magnesium, especially in patients with alcoholism because alcohol is a cofactor in oxalate metabolism. Obtain a ethylene glycol serum concentration if you have access to this at your institution or locally.
• Administer crystalloids at 250-500 mL/h IV initially to enhance renal clearance of the toxin and to limit deposition of oxalates in the renal cortices.
• Administer bicarbonate to correct severe acidosis (pH level ≤7.2); this of course should be done in conjunction with addressing the underlying cause of the acidosis.
• Pyridoxine and thiamine are cofactors in ethylene glycol metabolism that promote production of nontoxic metabolites, and are safe adjuncts with no significant disadvantages.They may be administered parenterally.
• Place symptomatic patients in a monitored setting.
• An electrocardiogram may be useful to detect arrhythmias that may result from hypocalcemia. With low serum calcium, the QT interval may also be prolonged.
• Foley catheterization may be considered for patients with altered mental status, to monitor urinary output and to allow serial examination of urine for crystals or fluorescence.
• If ethylene glycol poisoning is suspected, begin antidotal therapy empirically while awaiting confirmation. This is performed with either fomepizole (4-MP) or ethyl alcohol. The latter is usually administered intravenously but may be administered orally in remote settings where emergency hospital care is not immediately available. In the United States, contemporary treatment of this poisoning is most commonly done with fomepizole alone.

Treatment of patients with suspected ethylene glycol intoxication has traditionally been indicated in any of the following three circumstances. First, the plasma concentration of ethylene glycol is 25 mg/dL or more. Second, the patient has a definite history of recent ethylene glycol ingestion (especially if the osmolal gap is 10 mOsm/L or more, though patients with potentially toxic ethylene glycol ingestions may have an apparently normal osmolar gap; see Workup/Laboratory Studies). Third, a history or suspicion of ethylene glycol intoxication and the presence of at least two of the following^[11] :

• Arterial pH less than 7.3
• Serum bicarbonate level less than 20 mg/dL
• Osmol gap greater than 10 mOsm/L
• Oxalate crystals in the urine

However these criteria may be too conservative; if there is clinical concern or if laboratory testing will take an extended amount of time to return it is advisable to initiate therapy earlier. A review of 121 ethylene glycol poisoning cases found that patients who did not receive an antidote (ethanol and/or fomepizole) until more than 6 hours had passed had higher odds of dying or having prolonged renal insufficiency (odds ratio 3.34).^[12]

Fomepizole

Fomepizole (Antizol) is a convenient antidotal therapy for treatment of ethylene glycol or methanol intoxication. Fomepizole received US Food and Drug Administration (FDA) approval for use in ethylene glycol intoxication in December 1997, and it appears to have largely supplanted ethanol as the antidote of choice in toxic alcohol exposures in the US.^[13] Fomepizole is administered with a loading dose and twice-daily intravenous dosing.^[14]

Fomepizole is equally efficacious for the treatment of methanol intoxication but does not cause any alteration in mental status, hypoglycemia, or respiratory depression.

Fomepizole is advantageous because it does not depress the patient's mental status or airway and needs to be administered only every 12 hours. The main drawback of fomepizole is the cost, which can total thousands of dollars. Because this agent is so expensive, clinicians should check its availability at their institution and discuss the plan for use of this antidote, especially for empiric treatment of cases in which the cause of acidosis is unknown.

The availability of timely results of laboratory tests can be a problem. Weigh the benefits, risks, and costs of each therapeutic intervention at the treating institution.

Ethanol

If fomepizole is not used, oral or parenteral ethanol loading is less commonly used as a temporizing measure while awaiting test results. A loading dose of ethanol is administered based on body weight, followed by infusion to maintain a serum level of approximately 100 mg/dL.

Carefully calculate the loading dose and administration of ethanol antidote to prevent excessive administration. Overly aggressive ethanol administration has reportedly caused cases of apnea that required intubation and mechanical ventilation, so serum ethanol concentrations must be checked regularly and the infusion rate adjusted to prevent over- or undertreatment. When administering ethanol, determine glucose levels by fingerstick collection at regular intervals and confirm with laboratory analysis, as hypoglycemia is occasionally associated with ethanol therapy. Other potential adverse effects include hyponatremia, sclerosis of veins, and intoxication (which can be particularly distressing in pediatric patients).

Any patient receiving intravenous ethanol therapy requires ICU monitoring.

Hemodialysis

Hemodialysis is used to treat metabolic acidosis or to prevent renal insufficiency.

Early in the intoxication, the toxin is present as the parent compound, ethylene glycol. As time passes, toxic metabolites accumulate and the patient develops metabolic acidosis. Eventually, oxalate is deposited in the kidney and elsewhere; renal insufficiency may ensue. Once any of these manifestations occurs, antidotal therapy alone (used to block alcohol dehydrogenase with ethanol or fomepizole) is insufficient to treat the poisoning.

Alcohol dehydrogenase–blocking therapy must be accompanied by dialysis to remove the metabolites in these cases. Consulting a nephrologist early in the intoxication is prudent to facilitate the timely initiation of dialysis to these patients. Delays may result in renal failure or other severe complications.

Traditional dialysis indications include the following^[15] :

• pH < 7.25
• Acute kidney injury
• Ethylene glycol serum concentration >50 mg/dL
• Serum glycolic acid >8 mmol/L

Some clinicians have suggested that effective blockade of alcohol dehydrogenase may permit the treatment of ethylene glycol intoxication without dialysis. In one case report,^[16] a patient with an initial ethylene glycol level of 700 mg/dL was treated aggressively with fomepizole and was able to avoid dialysis. However, because of the cost of fomepizole and the safety of hemodialysis, the threshold for this approach should be carefully considered on the basis of the clinical setting.

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Consultations

It is highly recommended to include the regional poison center (or a toxicologist) in the management of these patients. The telephone number for certified poison centers anywhere in the United States and Puerto Rico is 1-800-222-1222.

If dialysis is considered, consult a nephrologist as early as possible to allow timely treatment of patients with toxic metabolite accumulation. Antidotal therapy is inadequate by itself in these circumstances, and dialysis should be performed as soon as possible.

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Medication Summary

If ethylene glycol poisoning is suspected, begin antidotal therapy empirically while awaiting confirmation. Antidotes are fomepizole and ethanol. B-vitamin therapy may be used as an adjunct to antidotal therapy.

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Fomepizole (Antizol)

• Dosing, Interactions, etc.

Clinical Context:  Antidote with better safety profile than ethanol. Easier to dose and administer. In contrast to ethanol, fomepizole levels do not need to be monitored during therapy. The biggest drawback is the cost of the antidote; however, compare the additional expenses of fomepizole with the high degree of required vigilance, need for intensive care unit monitoring, occasional treatment failure, and complications seen with ethanol.

Begin fomepizole treatment immediately upon suspicion of ethylene glycol ingestion based on patient history or anion gap metabolic acidosis, increased osmolar gap, oxalate crystals in urine, or documented serum methanol level.

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Ethanol

• Dosing, Interactions, etc.

Clinical Context:  Goal is to maintain blood ethanol concentrations at 100-150 mg/dL. This completely saturates alcohol dehydrogenase (ADH). May be administered PO or IV, but IV is preferred if available. Measuring initial blood concentration is important; if >100 mg/dL, loading dose may be unnecessary and patient can be started on maintenance dose.

Frequent monitoring of blood ethanol concentrations is important, with adjustment of the infusion rate to maintain the serum concentration in the therapeutic range.

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Pyridoxine (Nestrex)

• Dosing, Interactions, etc.

Clinical Context:  Water-soluble vitamin B6, which is a cofactor in conversion of GA to nonoxalate compounds. Involved in synthesis of GABA within CNS.

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Thiamine (Thiamilate)

• Dosing, Interactions, etc.

Clinical Context:  Vitamin B-1 is water-soluble and used in many cellular functions that involve energy formation and use. Promotes conversion of glyoxylate to a nontoxic metabolite, alpha-hydroxy-beta-ketoadipate.

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Class Summary

Pyridoxine enhances metabolism of glyoxylate to glycine. Thiamine catalyzes metabolism of glyoxylate from glycolic acid. Vitamin therapy is a safe and reasonable adjunct in patients with ethylene glycol poisoning. Regional poison centers may suggest the use of these therapies in certain cases.

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