PEDIATRICS Vol. 107 No. 1 January 2001, pp. 172-173

EXPERIENCE AND REASON:
Severe Ethylene Glycol Ingestion Treated Without Hemodialysis

	ABSTRACT

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Fomepizole (4-methylpyrazole, Antizol) is being increasingly used in the treatment of ethylene glycol toxicity in adults. Little experience exists with this drug, however, in the pediatric population. We present a case of ethylene glycol poisoning in a child where use of fomepizole averted intravenous ethanol infusion and hemodialysis, limited the duration of intensive care monitoring, and decreased the overall cost of treatment.

Of all alcohols, ethylene glycol has the greatest clinical toxicity. In 1998, >5376 ethylene glycol exposures were reported in the United States, with 1538 exposures occurring in the pediatric population.¹ Formerly, treatment for ethylene glycol poisoning required intravenous ethanol infusion, hemodialysis, or both. Fomepizole (4-methylpyrazole, Antizol) was recently approved by the Food and Drug Administration as an antidote for ethylene glycol poisoning in adult patients.² In selected patients, fomepizole may eliminate the need for ethanol therapy and dialysis with attendant cost savings.^3-5 Although clinical experience with fomepizole has been expanding, pediatric use remains uncommon.^6-9 We report a case of ethylene glycol poisoning in a child treated with fomepizole. Fomepizole obviated the need for intravenous ethanol infusion and hemodialysis, limited the duration of intensive care monitoring, and decreased the overall cost of treatment.

	CASE REPORT

A 13-year-old female ingested approximately 4 fluid ounces of antifreeze after an argument with her father. She was brought to a local emergency department approximately 30 minutes after the ingestion. Initial vital signs were temperature, 99.4°F; pulse, 115 beats per minute; blood pressure, 144/76 mm Hg; respiratory rate 20 breaths per minute. She weighed 80 kg. The physical examination was normal with no evidence of intoxication.

Initial laboratory evaluation revealed a white blood cell count of 9900/mm³, hemoglobin 11.8 g/dL, and platelets of 317 000/mm³. Serum chemistries were sodium 144 mg/dL, potassium 4.3 mg/dL, chloride 105 mg/dL, bicarbonate 25 mg/dL, blood urea nitrogen 11.0 mg/dL, creatinine 0.8 mg/dL, and glucose 105 mg/dL. Anion gap was 14 mg/dL. An arterial blood gas showed pH 7.38, PCO₂ 38 mm Hg, and PO₂ 116 mm Hg. Aspirin, acetaminophen, blood alcohol, and pregnancy tests were negative.

An initial urinalysis was unremarkable, although the urine fluoresced beneath a Wood's lamp. The serum osmolarity was 351 mosM/L; the calculated osmolarity was 298 mosM/L, yielding an osmolar gap of 53 mosM/L. The measured serum ethylene glycol concentration was 103 mg/dL.

Transfer to a tertiary care center was arranged. Before transfer, however, the patient became ataxic and dysarthric. She therefore received an intravenous ethanol bolus of 600 mg/kg, followed by a continuous infusion of 20% ethanol administered at 30 mL/hour. She promptly became obtunded after the bolus and required orotracheal intubation for airway protection. On arrival at the referral intensive care unit she had a serum ethanol concentration of 144 g/dL, and an arterial blood gas of pH 7.34, PCO₂ 38 mm Hg, and PO₂ 277 mm Hg. Urinalysis revealed calcium oxalate crystals.

Six hours after the ingestion she received a 15 mg/kg intravenous loading dose of fomepizole. Arterial pH remained above 7.35. She was successfully extubated and transferred to a general medical floor approximately 12 hours after arrival. Intravenous fomepizole, 10 mg/kg, was administered every 12 hours. A serum ethylene glycol concentration drawn 24 hours after ingestion was 23 mg/dL. By 36 hours after ingestion it had decreased to 13 mg/dL. At discharge on the third hospital day, she had a blood urea nitrogen of 10 mg/dL and a serum creatinine of 0.6 mg/dL. Psychiatric follow-up was arranged on an outpatient basis. During her hospitalization she required a total of 5 doses of fomepizole. A copy of the patient's hospital charges was reviewed. Based on the hospital's current cost structure, an analysis of intensive care versus general medical floor fees (excluding physician's charges) is provided in Table 1.

	DISCUSSION

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Ethylene glycol is found in radiator antifreeze, deicing solutions, and other formulations. Pure ethylene glycol, which has a slightly sweet taste, is odorless and colorless. After ingestion, ethylene glycol is rapidly absorbed from the gastrointestinal tract. The presence of ethylene glycol in blood produces the osmolal gap.¹⁰ Nontoxic itself, ethylene glycol is converted enzymatically to toxic compounds. More than 85% of ethylene glycol is oxidized to glycoaldehyde by alcohol dehydrogenase (ADH). Acidosis is attributable to the presence of glycolic, glyoxylic, and oxalic acids.¹¹ Ethylene glycol is unique among alcohols in that a significant amount is eliminated unchanged in the urine.¹²

The diagnosis of ethylene glycol poisoning is supported by the clinical findings of mental status alteration, metabolic acidosis, and oxalate crystals in the urine. The diagnosis is established, however, by the measurement of serum ethylene glycol concentration or by an estimate of the toxin's concentration extrapolated from the osmolal gap.¹⁰ Antidotal therapy is reserved for serum ethylene glycol concentrations >20 mg/dL. Ethanol, preferably a 10% solution, is administered as a 600 mg/kg intravenous bolus followed by continuous infusion. The goal of therapy is to achieve a minimum serum ethanol concentration of 100 mg/dL; at this level and above, ethanol inhibits ADH and prevents the metabolism of ethylene glycol. Hemodialysis, in conjunction with ethanol therapy, is recommended for patients with ethylene glycol levels >50 mg/dL.^5,12,13

Fomepizole, a competitive inhibitor of ADH, has been approved as an antidote for ethylene glycol intoxication in adults.² Like many pharmaceuticals, fomepizole is not approved for use in children. Independent of patient age, fomepizole potentially offers a significant advantage because it eliminates the need for intravenous ethanol therapy with its attendant problems. In children, the hyperosmolarity of an ethanol solution (1713 mosM/L) often requires central venous access.¹⁴ Side effects of ethanol in young children include obtundation, hypoglycemia, and hypothermia.⁴ Maintaining a serum ethanol concentration of 100 mg/dL is a difficult task that requires frequent monitoring. An ethanol infusion may itself produce frank intoxication as a result of individual variations in metabolism and response to ethanol. As this case illustrates, even appropriate ethanol doses may inadvertently produce obtundation. In contrast, fomepizole does not cause hypoglycemia and has no sedating side effects.² Also, fomepizole is administered as an intravenous infusion every 12 hours; serum fomepizole concentrations do not require monitoring. Consequently, fomepizole has substantially greater safety and ease of administration compared with ethanol therapy.²

As this case also illustrates, fomepizole can eliminate the need for hemodialysis in those with severe ethylene glycol poisoning. In addition to the risks associated with its invasiveness, hemodialysis is more technically demanding for children than adults. Also, hemodialysis has relatively limited availability for pediatric patients.¹³ Having an affinity for ADH >8000 times that of ethanol, fomepizole interrupts the enzymatic metabolism of ethylene glycol so that the parent compound can be eliminated in the urine.¹⁵ In our patient, maintenance of urine output during fomepizole therapy was sufficient to avert hemodialysis, despite an elevated ethylene glycol concentration. Current recommendations still call for hemodialysis in those who have already developed metabolic acidosis.⁵

Finally, fomepizole offers significant cost savings over existing therapies. Current protocols require that patients receiving ethanol infusions be admitted to an intensive care unit.⁵ Because of the sedating effect of ethanol, these patients may require intubation for airway protection and ventilatory support. As Table 1 indicates, fomepizole has the potential to reduce the cost of treating this intoxication by at least 40%. Moreover, Table 1 does not include costs typically associated with intensive care monitoring, such as portable chest radiographs and serial arterial blood gases. In addition, nursing costs for hemodialysis and intensive care, typically much higher than those for general floors, are not included in the analysis. Finally, the recommended course of fomepizole requires approximately 4 multiuse vials, at a cost of $4000. Because our institutional pharmacy does not permit successive withdrawal of medicine from a single vial, an additional container was required at a cost of $1000. The aforementioned estimate is therefore conservative. As a result, the actual cost savings of fomepizole are more significant than described here. Although the patient in this report did not enjoy all the cost savings described above, primarily because of complications of ethanol therapy, fomepizole shortened her intensive care unit course and decreased her cost of hospitalization.

As pediatric experience with fomepizole grows, the drug is being shown to be safe and effective. For children it offers the added benefits of eliminating ethanol administration and, potentially, hemodialysis. Cost savings from fomepizole can be substantial.

Edward W. Boyer, MD, PhD^*
Mauricio Mejia
Alan Woolf, MD, MPH^*
Michael Shannon, MD, MPH^*
* Children's Hospital
Boston, MA 02155
 University of Colorado School of Medicine
Denver, CO 80262

	FOOTNOTES

Received for publication Jan 3, 2000; accepted Mar 31, 2000.

Reprint requests to (E.W.B.) Children's Hospital, 300 Longwood Ave, Boston, MA 02155. E-mail: boyer_e{at}hub.tch.harvard.edu

	ABBREVIATIONS

ADH, alcohol dehydrogenase.

	REFERENCES

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