PEDIATRICS Vol. 106 No. 6 December 2000, pp. 1489-1491

EXPERIENCE AND REASON:
Fomepizole Treatment of Ethylene Glycol Poisoning in an Infant

	ABSTRACT

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The enzyme alcohol dehydrogenase metabolizes ingested ethylene glycol (EG) to the toxic compounds glycolic and oxalic acids. Renal failure, acidosis, hypocalcemia, and death may follow. Traditional treatment of EG poisoning may require ethanol, a competitive substrate of alcohol dehydrogenase, and hemodialysis, that removes both EG and its toxic metabolites. A new alcohol dehydrogenase inhibitor, fomepizole (4-methylpyrazole), was approved in 1997 for patients at least 12 years old with suspected or confirmed EG poisoning.

Fomepizole has not been studied adequately in the pediatric population. We present a case of an 8-month-old male infant who drank up to 120 mL of EG and developed acidosis and oxalate crystalluria. He was treated with fomepizole and hemodialysis. Even after the completion of hemodialysis, fomepizole appeared to effectively block the production of EG toxic metabolites and to allow the resolution of acidosis; the patient recovered within 48 hours. This is the first report of fomepizole treatment of EG poisoning in an infant.4-methylpyrazole, fomepizole, poisoning, ethylene glycol, hemodialysis, infant, child, pediatrics.

Ethylene glycol (EG) is a compound whose viscosity and thermal properties have led to its role as an antifreeze agent in automobile radiators. The enzyme alcohol dehydrogenase metabolizes ingested EG, which in itself is not a toxic compound. The products of that metabolism, glycolic and oxalic acids, however, may lead to acidosis, renal failure, hypocalcemia, and death. Treatment of significant EG poisoning may require hemodialysis to remove EG and its metabolites in addition to oral or intravenous ethanol to serve as a competitive substrate of alcohol dehydrogenase. This competition effectively prevents the enzyme from converting EG to toxic acids. Ethanol, however, has its own toxicity, and its use may introduce logistic difficulties. Over a nearly 2-year period, a multicenter trial of the alcohol dehydrogenase inhibitor fomepizole (4-methylpyrazole) enrolled patients at least 12 years old with suspected or confirmed EG poisoning.¹ In December 1997, the US Food and Drug Administration (FDA) approved the use of fomepizole for the treatment of EG poisoning.

Fomepizole has not been studied adequately in the pediatric population. Safety, efficacy, and pharmacokinetics have not been formally evaluated in children. However, the use of ethanol for the treatment of EG poisoning has never been approved. Furthermore, younger children who have ingested EG and are treated with ethanol are more sensitive than adults or older children to its toxic effects, including respiratory depression, hypothermia, and hypoglycemia. Efficacy and pharmacokinetics of ethanol in children are unpredictable: whether a particular ethanol concentration is therapeutic is subject to debate, and maintenance of that concentration may be difficult. The use of fomepizole, with a mild side effect profile noted in adults, may be particularly useful in children who ingest EG. We present the case of an 8-month-old male infant who drank EG and was treated with fomepizole and hemodialysis. We believe that this is the first report of fomepizole administration for the treatment of EG poisoning in an infant.

	CASE REPORT

An 8-month-old 7.7-kg male infant drank up to 120 mL EG (95% EG). The ingestion occurred after an older child transferred antifreeze that had been stored in a juice container to the infant's bottle. The infant was taken to a community hospital, where he developed progressive lethargy and was intubated for airway protection. Intravenous ethanol was given as a loading dose and then infused at a constant rate. After transfer to our tertiary care children's hospital, ethanol was discontinued (serum ethanol concentration = 40 mg/dL). Laboratory analysis at our facility revealed serum electrolyte concentrations as follows: sodium, 140 mEq/L; potassium, 4.4 mEq/L; chloride, 110 mEq/L; and bicarbonate, 17.5 mEq/L (anion gap = 12.5). Renal function was normal, with serum blood urea nitrogen of 10 mg/dL and creatinine of 0.2 mg/dL. Also obtained were an arterial blood gas pH of 7.32 and a serum osmolality, measured by the freezing-point depression technique, of 358 mOsm/kg, representing an osmolal gap of approximately 60 mOsm/kg. Initial urinalysis approximately 4 hours postingestion was significant for calcium oxalate crystals. Based on this information, consent was obtained from the mother to administer the alcohol dehydrogenase inhibitor fomepizole. A loading dose of 15 mg/kg was administered to the patient intravenously. A reference laboratory later reported results from the first blood sample obtained at our facility: a serum methanol concentration below the limit of detection, and a serum EG concentration of 384 mg/dL.

A 9-French double-lumen hemodialysis catheter was placed in the right femoral vein by aseptic Seldinger technique. Hemodialysis began approximately 5 hours postingestion using a Cobe-100 (Gambro, Lakewood, CO) membrane and a dialysate containing 2 mEq/L of potassium and 24 mEq/L of bicarbonate. Blood flow was 100 mL/min for the approximately 4-hour procedure, which reduced the serum osmolality to 302 mOsm/kg H₂O and the EG level to 61 mg/dL. The dosing of fomepizole was changed to a 4-hour interval during the hemodialysis procedure, after which it was returned to a 12-hour interval in accordance with the drug manufacturer's recommendations. An ionized calcium concentration obtained after hemodialysis at approximately 10 hours postingestion was normal at 1.31 mM and remained within the normal range throughout the hospitalization. Despite renal injury and resultant hematuria, renal function remained normal as well. His hemoglobin decreased from an initial 9.5 g/dL to 7.8 g/dL around 21 hours postingestion, for which he was transfused 10 mL/kg packed red blood cells. After extubation 37 hours postingestion he developed moderate stridor; direct laryngoscopy several days later revealed subglottic stenosis unrelated to the ingestion. The patient's course was otherwise uncomplicated, and he recovered fully by 45 hours postingestion (details of the clinical course may be found in Table 1). Figure 1 compares acidosis, indicated by pH, and EG concentration in the patient versus time. Intravenous administration of fomepizole (total dose, 45 mg/kg) appeared to allow the correction of metabolic acidosis even after completion of hemodialysis, and prolonged EG half-life to approximately 9 hours.

View larger version (16K): [in this window] [in a new window]   Fig. 1.   Resolution of acidosis on fomepizole.

	DISCUSSION

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The American Academy of Clinical Toxicology has published practice guidelines on the treatment of EG poisoning.² The guidelines underscore the fact that the use of ethanol has never been studied prospectively as an antidote, and that the FDA has never approved it in this capacity. Although experience treating children with fomepizole is limited, the FDA has recently relieved Orphan Medical, Inc, the sole US marketer of fomepizole, from the requirement for a phase IV trial.

With the introduction of fomepizole, the need for hemodialysis in selected cases of uncomplicated EG patients has been called into question. Harry et al³ described the case of a 4-year-old child who developed acidosis after ingesting EG. The use of 4-methylpyrazole (chemically identical to fomepizole), administered 7 hours postingestion, corrected the metabolic acidosis without alkalinization or hemodialysis. EG half-life was prolonged from 4.4 hours before 4-methylpyrazole administration to 10 hours during treatment. Borron et al⁴ reported a case series of 38 adult patients poisoned with EG who were treated with fomepizole alone. The authors suggested that EG-poisoned patients who present with normal renal function and acid-base status might do well when treated with fomepizole but without hemodialysis.

The cause of the decreased hemoglobin is unclear. Possible explanations include oxalate-induced hematuria, anticoagulation during dialysis, and frequent blood draws. Fomepizole has not been reported to cause hemolysis.^1,3,4

Our patient presented with minor acidosis, significantly elevated osmolal gap, and oxalate crystalluria. We chose to hemodialyze the infant in light of evidence that significant EG had been ingested and that some degree of EG conversion to toxic organic acids had occurred. The use of fomepizole alone in this patient may have been effective, despite the prolongation of EG half-life to approximately 9 hours. The reduction in EG concentration accomplished by hemodialysis would have required approximately 16 additional hours if treated with fomepizole alone. Future studies must weigh the benefits of a lengthier but less invasive treatmentfomepizole aloneagainst the minor risks associated with acute hemodialysis.

	CONCLUSION

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The use of fomepizole has not been reported as an antidote in infants poisoned with EG. In this case, fomepizole appeared to prevent the metabolism of EG to toxic acids even after hemodialysis was discontinued.

Carl R. Baum, MD^{*, §}
Craig B. Langman, MD^*
Elif E. Oker, MD^{, §}
Craig A. Goldstein, DO^§
Sandra R. Aviles, MD^*
Jasmin K. Makar, MD^*
* Department of Pediatrics
Northwestern University Medical School
Chicago, IL 60614-3394
 Department of Emergency Medicine, University of Illinois at Chicago
Chicago, IL 60612
^§ Toxikon Consortium and the Illinois Poison Center
Chicago, IL 60612

	FOOTNOTES

Received for publication Feb 4, 2000; accepted Jun 8, 2000.

Presented at the North American Congress of Clinical Toxicology; October 1999; La Jolla, CA.

Reprint requests to (C.R.B.) Section of Pediatric Emergency Medicine, 333 Cedar St, Box 208064, New Haven, CT 06520-8064. E-mail: carl.baum{at}yale.edu

	ABBREVIATIONS

EG, ethylene glycol; FDA, Food and Drug Administration.

	REFERENCES

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1. Brent J, McMartin K, Phillips S, Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med. 1999; 340:832-838 [Abstract/Free Full Text]
2. Barceloux DG, Krenzelok EP, Olson K, Watson W American Academy of Clinical Toxicology practice guidelines on the treatment of ethylene glycol poisoning. J Toxicol Clin Toxicol. 1999; 37:537-560 [CrossRef][Medline]
3. Harry P, Jobard E, Briand M, Caubet A, Turcant A. Ethylene glycol poisoning in a child treated with 4-methylpyrazole. Pediatrics. 1998;102(3). URL: http://www.pediatrics.org/cgi/content/full/102/3/e31
4. Borron SW, Megarbane B, Baud FJ Fomepizole in treatment of uncomplicated ethylene glycol poisoning. Lancet. 1999; 354:831 [Medline]