Fomepizole

Ethylene glycol is an inexpensive, readily available substance that may be associated with accidental or intentional toxicity. Toxicity from this substance may be encountered in the military and civilian populations. Because it is highly toxic and can result in death if not treated appropriately, it is imperative to recognize the signs and symptoms of intoxication. Two cases are presented and the diagnosis and treatment of ethylene glycol toxicity are discussed. Fomepizole, a new medication for ethylene glycol toxicity, has changed the management of this poisoning. It increases the elimination half-life of ethylene glycol, thus delaying the formation of toxic metabolites.

Introduction

Ethylene glycol is a colorless sweet-tasting liquid. It is mainly used as a coolant in commercial antifreeze and in de-icing solutions and some brake fluids. There were 5,833 cases of ethylene glycol exposures reported by the American Association of Poison Control Centers in 2001.1 Most were unintentional and there were 33 fatalities. Because ethylene glycol is inexpensive and widely available, it is a common source of toxic exposures worldwide. American military personnel are likely to encounter cases of ethylene glycol toxicity. During World War 11,18 soldiers died as a result of drinking ethylene glycol as a substitute for ethanol.2,3 Approximately 22 soldiers became ill and 1 died from drinking water contaminated with antifreeze during the Arab-Israeli conflict in 1973.4

We present two cases of intentional ethylene glycol poisoning successfully treated with fomepizole and hemodialysis, and we present a review of the toxicological mechanism of ethylene glycol and its treatment.

Case 1

A 16-year-old Caucasian male presented with a depressed level of consciousness and agonal respirations. he had last been seen 3 hours before presentation. he was immediately endotracheally intubated. Subsequent history from his mother revealed the likelihood of antifreeze ingestion earlier in the day. The amount he ingested was unknown. he was hydrated with normal saline, given 80 g of activated charcoal per nasogastric tube, 3 ampules of NAHCO^sub 3^ intravenously, and 800 mg of fomepizole intravenously. he was then transferred to a tertiary care facility for further care.

On arrival, physical examination revealed a well-developed Caucasian male who was intubated. Vital signs were a temperature of 97°F, heart of rate 114, blood pressure of 146/76, and ventilator rate of 12. The physical examination was normal except for a tachycardie heart rate and depressed mental status. Neurological examination showed minimal withdrawal to pain, diffusely diminished reflexes, no clonus, and a Glasgow Coma Score of 6. Subsequent history from his family revealed a past history of depression and asthma with recent increased despondency after a friend's suicide.

Pertinent laboratory results are shown in Table I. Other laboratory results included a white blood cell count of 29,000/ mm^sup 3^, hematocrit 53%, and a platelet count of 290,000/mm^sup 3^. Serum ethanol and urine drug screens were negative. The urinalysis was positive for microscopic hematuria, but no crystals.

Fomepazole was given at a dose of 15 mg/kg intravenously and then 10 mg/kg every 4 hours during dialysis. Thiamine, 100 mg, was given per nasogastric tube every 12 hours and pyridoxine, 50 mg, was given intravenously every 6 hours for 2 days. he was admitted to the medical intensive care unit and underwent emergent hemodialysis over the next 6.5 hours. His urine output was maintained at 1 to 2 mL/kg/hour. His serum creatinine peaked at 2.1 mg/dL and then fell to 1.9 mg/dL where it remained. he was extubated on the second hospital day and was transferred to the psychiatry unit for further care.

Case 2

A 59-year-old African-American female presented with a chief complaint of depression and an acute ingestion of an unknown amount of antifreeze. Her family found her lying on the floor at home in the dark. Her past medical history was remarkable for depression, hypertension, and left breast cancer for which she had undergone a mastectomy.

Physical examination revealed a well-developed AfricanAmerican female who was somnolent but responded to stimulation. Her vital signs were a temperature of 95.40F, heart rate of 87, blood pressure of 127/88, respiratory rate 24, and an O2 saturation of 96%. Her physical examination was normal except for her somnolence.

Pertinent laboratory results are shown in Table I. Other laboratory results included a white blood cell count of 20,000/mm3 and a normal platelet count and hematocrit. A urinalysis revealed microscopic hematuria with no crystals. The ethyl alcohol level was 10 mg/dL.

Her initial treatment included 2.5 L of normal saline intravenously and 44 mEq of NaHCO^sub 3^ intravenously. She received a loading dose of fomepazole, 15 mg/kg, followed by 10 mg/kg intravenously for four more doses. She was also treated with 50 mg of pyridoxine intravenously every 6 hours and 100 mg of thiamine intravenously every 12 hours. She underwent hemodialysis for 6 hours. Her electrolytes and arterial pH normalized within 12 hours. She was subsequently transferred to the psychiatric unit and was discharged from the hospital on the eighth hospital day.

Toxicology

Ethylene glycol is rapidly absorbed after oral administration, with peak levels occurring 1 to 4 hours after ingestion. It is highly water soluble with a low volume of distribution (0.5-0.8 L/kg).5 It is metabolized by cytosolic enzymes in the liver. The metabolism occurs in a sequential process, as shown in Figure 1. The first step involves oxidation of one of the alcohol moieties forming glycoaldehyde. This step is catalyzed by the enzyme alcohol dehydrogenase (AD). This step is inhibited by ethanol because AD has a much greater affinity for ethanol than it does for ethylene glycol. It is also the site of action of the drug fomepizole. The elimination half-life of ethylene glycol is typically approximately 3 hours, but may be up to 8 hours.6-8 Ethanol at a concentration of 100 mg/dL increases the elimination half-life to approximately 17 to 18 hours.6 Fomepizole increases the half-life to approximately 20 hours.8

The toxicity of ethylene glycol is primarily a result of its metabolic by-products and not the parent compound. Glycolic acid, glyoxylic acid, and oxalic acid all contribute to the metabolic acidosis. The rate-limiting step in the metabolism of ethylene glycol is the conversion of glycolic acid to glyoxylic acid.5 This results in an accumulation of glycolic acid in the blood. Furthermore, because the numerous metabolic steps require the conversion of nicotine adenine dinucleotide to its reduced form reduced nicotine adenine dinucleotide, the increased reduced nicotine adenine dinucleotide to nicotine adenine dinucleotide ratio favors the conversion of pyruvate to lactate, resulting in a lactic acidosis.

The primary toxic effects of ethylene glycol are metabolic derangements and renal toxicity. An anion gap metabolic acidosis is the main metabolic effect. The renal toxicity results in an acute tubular necrosis with deposition of calcium oxalate crystals in the tubular lumen. Hypocalcemia may occur, presumably as a result of the formation of calcium oxalate crystals. Ethylene glycol is also a direct irritant on the gastric mucosa, resulting in focal hemorrhages in severe toxicity. Ethylene glycol is a central nervous system (CNS) depressant and may cause cerebral edema. Myocardial depression can occur from calcium oxalate crystals depositing in the myocardium, but it is more likely a result of the metabolic derangements.

Clinical Presentation

Although symptoms of ethylene glycol toxicity most often occur in 4 to 8 hours, they may be delayed when ethanol is coingested. The early neurological manifestations of ethylene glycol poisoning mirror those seen with ethanol intoxication. More severe poisonings may cause seizures and coma. Ocular manifestations may be seen, although these are not nearly as prominent as in methanol toxicity. The severe metabolic acidosis and cardiopulmonary manifestations usually occur 12 to 24 hours after ingestion, although coingestion of ethanol will delay these. Early hypertension and tachycardia are seen, and hypotension and respiratory distress may occur as the metabolic acidosis worsens. Hypocalcemia occurs in approximately onethird of cases.9 Renal effects typically occur 1 to 3 days postingestion. These may include flank pain, hematuria, proteinuria, and calcium oxalate crystalluria. Although renal dysfunction may require dialysis for up to several months, recovery usually occurs to the point that chronic hemodialysis is rarely necessary.5 Delayed neurological findings have been reported to occur 1 to 2 weeks postingestion, involving cranial neuropathies (usually the facial nerve), cerebellar findings, and personality changes.10

The diagnosis of ethylene glycol toxicity is made using historical, clinical, and laboratory factors. It should be suspected in any individual who appears inebriated but does not have an ethanol odor. Several laboratory abnormalities are indicative of ethylene glycol intoxication. Patients with significant toxicity typically have an elevated anion gap metabolic acidosis and an elevated osmol gap. Calcium oxalate crystals in the urine are generally a late finding, appearing 4 to 8 hours after the ingestion. These are only found in approximately 50% of patients on admission, but this increases during the hospital course." Two forms of oxalate crystals may be found. The monohydrate form is an elongated crystal that may be confused with hippurate or urate crystals. The dihydrate form occurs at higher oxalate concentrations and is octahedral-shaped, appearing as pyramids. Fluorescein is a green fluorescent dye that is added to antifreeze products in the United States to assist in leak detection. This can be detected in the urine early after ethylene glycol ingestion, but is usually cleared within 4 hours of the ingestion.12 Testing for urinary fluorescence is a simple, rapid test that can easily be performed in the emergency department or a clinic setting. To detect fluorescein, the urine is poured through white filter paper or a white paper towel and the paper is then is examined for fluorescence with a Wood's lamp. A control sample with water is recommended. Plastic urine containers are not recommended because many of these have some degree of fluorescence. The results must be interpreted with caution. False positive results can be obtained if the urine is placed in certain plastic containers. A negative test does not rule out ethylene glycol toxicity because the fluorescein is usually cleared within 4 hours and the ethylene glycol will persist.

The anion gap represents the presence of unmeasured anions in the blood. Normally, the anion gap is between 12 and 16 mmol/L for most hospitals. Early in the course of ethylene glycol toxicity, there may be a low or minimal anion gap. This is because insufficient amounts of ethylene glycol have been metabolized to the organic acids responsible for the anion gap. When there has been a coingestion of ethanol, the appearance of an anion gap is delayed.

Osmolality is a measure of the number of dissolved solutes in the serum. The osmolality gap is the difference between the measured and calculated serum osmolality. Serum osmolality can be measured by freezing point depression or vapor point osmometry, with freezing point depression being the more accurate and preferred method. The difference between the measured osmolality and the calculated osmolarity is usually 10 to 15 mOsm/kg water. Anything larger than this suggests the presence of uncharged solutes. Low molecular weight alcohols and ketones (methanol, ethanol, acetone, isopropanol, and ethylene glycol), if present, will elevate the osmol gap. At low concentrations of ethylene glycol, the osmol gap may still remain in the normal range. For example, an ethylene glycol concentration of 50 mg/dL will only raise the osmolality gap by 8 mOsm/kg water. Also, only ethylene glycol and glycoaldehyde (Fig. 1) contribute to the osmolality gap. Thus, early in the course of toxicity the osmolality gap may be elevated, whereas later in the course, the osmolality gap decreases as the anion gap increases. A normal osmolality gap does not exclude ethylene glycol toxicity, but a very elevated osmolalality gap is suggestive.

The most accurate laboratory measurement is a quantitative gas Chromatographie determination for ethylene glycol. Unfortunately, this is not readily available in field hospitals. Even when this is available, it is important to remember that late in the course, only low levels of ethylene glycol may remain because most of it has been converted to toxic metabolites such as glycolic acid.

Treatment of ethylene glycol poisoning involves interrupting the conversion of ethylene glycol to toxic metabolites, the removal of ethylene glycol and the toxic metabolites, and supportive care. Two treatments are available to help block the conversion of ethylene glycol to its toxic metabolites: ethanol and fomepizole. Ethanol has been used to treat ethylene glycol intoxication since the 1940s, although it does not have Food and Drug Administration approval for this indication. It works by competitively inhibiting the conversion of ethylene glycol to glycoaldehyde (Fig. 1) via AD. To be effective, an ethanol level of 100 mg/dL should be maintained.7 The loading dose of ethanol is 0.6 g/kg when none is initially present. A maintenance infusion of 66 mg/kg/hour for nondrinkers and roughly twice this for chronic alcoholics is required. Maintaining an appropriate ethanol level can be challenging because of the large individual variability in ethanol metabolism. Frequent monitoring of ethanol levels is required. Ethanol may be given intravenously or orally. If given intravenously, ethanol is first diluted to a 10% solution. When only commercial alcohol products are available, the loading dose for a 70-kg adult would be approximately four 1-ounce shots of an 80-proof whiskey.

The other method of inhibiting the conversion of ethylene glycol to its toxic metabolites is the drug fomepizole. Fomepizole is also an inhibitor of AD, blocking the first step in ethylene glycol metabolism.13 It does have Food and Drug Administration approval for the treatment of ethylene glycol toxicity. It is dosed at an initial loading dose of 15 mg/kg followed by 10 mg/kg every 12 hours or every 4 hours during dialysis. Fomepizole is very expensive compared with the price of ethanol. When it is available, it is the agent of choice. Ethanol causes known CNS depression and hypoglycemia in children and malnourished individuals and fomepizole does not. If appropriate doses of ethanol or fomepizole are used, there is no advantage to combining the two agents. There is no information available on appropriate dosing regimens if both ethanol and fomepizole are used.

Hemodialysis removes ethylene glycol and its toxic metabolites. Hemodialysis should be considered if there is hemodynamic instability despite aggressive therapy in a known case of ethylene glycol toxicity, in the case of significant metabolic acidosis (pH 50 mg/dL. The ethylene glycol concentration must be interpreted with caution. This only represents the nonmetabolized portion of the ethylene glycol. If there is a significant delay between the ingestion and diagnosis, then the majority of the ethylene glycol may have already been metabolized. Thus, an ethylene glycol concentration of 40 mg/dL with a large anion gap metabolic acidosis may still require dialysis. Conversely, early after an ingestion, the ethylene glycol level may be 70 mg/dL without any acidosis or anion gap. If treatment is initiated early, this patient could possibly be treated with only fomepizole and no dialysis.8 In these cases, fomepizole may be required for 4 to 5 days, resulting in significant drug cost.

The most common serious complications of ethylene glycol toxicity are CNS depression, metabolic acidosis, and renal failure. CNS depression to the point of respiratory compromise should be treated with endotracheal intubation. Hypoglycemia can occur in children and those with malnutrition. The metabolic acidosis should be treated aggressively with sodium bicarbonate, and an adequate fluid output should be maintained with intravenous fluids. Mild hypocalcemia does not require treatment. Severe hypocalcemia resulting in seizures or QT prolongation should be treated with intravenous calcium carbonate. Thiamine, pyridoxine, and magnesium are cofactors for alternative pathways in the metabolism of glyoxylic acid that potentially may decrease the amount of calcium oxalate that is formed. There is no clinical data that support the effectiveness of these vitamin cofactors as treatments.5 They should be considered in those who are malnourished or in situations where vitamin deficiencies are suspected. The dose of thiamine and pyridoxime is 100 mg, one to four times daily. Magnesium replenishment should be guided by serum levels and on the suspicion of depleted states such as in alcoholics.

Discussion

Both patients showed a typical clinical picture for ethylene glycol poisoning: a profound metabolic acidosis requiring bicarbonate therapy and hemodialysis. Patient 1 had a relatively more acute ingestion with profound CNS depression, and patient 2 had a delayed presentation with the only CNS finding being somnolence. Both patients had a large anion gap metabolic acidosis and an elevated osmolality gap. Both patients had moderate creatinine elevations, neither of which returned completely to normal. Neither patient exhibited oliguria or crystalluria, although both showed microscopic hematuria, indicative of tubular dysfunction. Serum calcium levels were normal in both patients. There were no overt cardiac manifestations in either case. Patient 2 clearly underscores how subtle the presenting symptoms may be, confounded by her near-normal respiratory rate despite a profound acidosis. Had she not provided needed pertinent history, the diagnosis could clearly have been more delayed.

Fomepazole was chosen in both cases because of its ease of administration over ethanol, particularly during hemodialysis. Each patient responded well to aggressive hemodialysis with negligible ethylene glycol levels by the following day and rapid correction of the metabolic acidosis. There were no obvious delayed neurological abnormalities in either case. Neither patient sustained any severe long-term renal insufficiency.

When there is suspicion of ethylene glycol ingestion, medical evaluation is indicated. If the initial encounter is in a facility that does not have the ability to perform the necessary laboratory tests, the patient should be transferred to an emergency department that can perform the tests. If the patient does not appear ill, one approach would be to perform electrolyte measurements and calculate an anion gap. If this is normal, it can be repeated in several hours. If it is still normal and the patient appears well, serious ethylene glycol intoxication is unlikely. If a decision is made to send the patient to another health care facility and there will be a considerable delay before arrival, consider loading the patient with ethanol and having several doses administered en route. Oral alcohol products will suffice if that is all that is available. The decision to do this must be based on the clinical suspicion and the patient's condition.

References

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11. Jacobsen D, Akesson I, Shefter E: Urinary calcium oxalate monohydrate crystals in ethylene glycol poisoning. Scand J Clin Lab Invest 1982; 146: 231-4.

12. Winter ML, Ellis MD, Snodgrass WR: Urine fluorescence using a Wood's lamp to detect the antifreeze additive sodium fluorescein: a quantitative adjunclive lest in suspected ethylene glycol ingestions. Ann Emerg Med 1990; 19: 663-7.

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Guarantor; Robert D. Cox, MD PhD

Contributors: Robert D. Cox, MD PhD*; LTC William J. Phillips, SF USAR[dagger]

* Professor, Emergency Medicine, and Medical Director, Mississippi Regional Poison Control Center, University of Mississippi Medical Center, Jackson, MS 39216.

[dagger] Assistant Professor, Emergency Medicine and Anesthesiology, Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS 39216.

This manuscript was received for review in March 2003. The revised manuscript was accepted for publication in September 2003.

Reprint & Copyright © by Association of Military Surgeons of U.S., 2004.

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