Introduction

Ethylene glycol is a common low volatility constituent in antifreezes, deicing, and brake fluids. In 2006, there were 5,343 ethylene glycol exposures reported to poison centers in the USA, resulting in 17 deaths and 152 major adverse outcomes [1]. The actual number of cases is probably far higher.

Although not highly toxic itself, ethylene glycol is metabolized by alcohol dehydrogenase (ADH) to metabolites, which can result in metabolic acidosis, renal injury, cerebral edema, multiorgan failure, and death.

The mainstay of treatment of ethylene glycol poisoning is inhibition of ADH, supplemented by hemodialysis in selected patients [2]. Traditionally, ADH inhibition was accomplished by the administration of the competitive substrate ethanol. However, ethanol treatment is fraught with difficulties and potential complications [3–8].

Fomepizole is an alcohol dehydrogenase inhibitor approved for the treatment of ethylene glycol poisonings in 2000. The pharmacokinetics of fomepizole is very predictable [9–11]. Because it is free of the potential adverse effects associated with ethanol [5, 9, 12–14], fomepizole therapy may obviate the need for hemodialysis in selected cases.

Current practice guidelines recommend considering hemodialysis in patients with renal failure, metabolic acidosis, electrolyte disturbances, hemodynamic instability, or plasma ethylene glycol concentrations ≥50 mg/dL [15]. However, several case reports [16–20] and a case series [13] have indicated that it is possible to forgo hemodialysis in patients with substantially higher ethylene glycol concentrations if they are treated with fomepizole.

We report a patient with a serum ethylene glycol concentration of 700 mg/dL effectively and safely treated with fomepizole alone. This represents the highest reported ethylene glycol level in a patient who did not co-ingest ethanol and was treated solely with fomepizole.

Case Report

A 48-year-old male with no significant past medical history presented to the emergency department after reportedly ingesting >1 liter of automotive product containing antifreeze in a self-harm attempt. Upon presentation, he was conscious, dysarthric, and reported a single episode of emesis. He denied ethanol co-ingestion. His initial vital signs were heart rate 70 beats per minute, blood pressure 168/90 mmHg, respiratory rate 27 per minute, temperature 37°C, and he had an oxygen saturation of 94% on 2 l administered by nasal cannula. The exact time of exposure was unknown, but it reportedly occurred as a single ingestion on the evening of emergency department arrival.

His presenting serum laboratory values were anion gap 20 mEq/L, sodium 135 mEq/L, bicarbonate 18 mEq/L, creatinine 0.9 mg/dL, and ethylene glycol 700 mg/dL. Other values are shown in Table 1. One hour after presentation, a loading dose of 15 mg/kg of intravenous fomepizole was administered followed by 10 mg/kg every 12 h for a total of five doses. Fomepizole treatment continued until the patient's serum ethylene glycol concentration was 16 mg/dL, 72 h after the peak measurement. There were no treatment-related adverse events. The patient was discharged to the psychiatric service on day 4 with normal renal function (Table 1) and without sequelae of his poisoning.

Table 1 Laboratory values
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The elimination profile of ethylene glycol was consistent with first order kinetics and an apparent half-life of 21 h (Fig. 1).

Fig. 1
figure 1

Time course of serum ethylene glycol elimination. Log10 ethylene glycol concentration over time

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Discussion

We report a case of massive ethylene glycol ingestion with an extremely high serum concentration in a patient presenting with normal renal function and mild metabolic acidosis. Because the patient had normal renal function and a mild metabolic acidosis at presentation, he was not dialyzed. The patient was successfully treated with fomepizole alone without hemodialysis, despite his very high serum ethylene glycol concentration. He did not develop signs of renal injury and had no adverse effects from fomepizole therapy.

Velez et al. reported a patient with an ethylene glycol level of 706 mg/dL, normal renal function, and blood ethanol concentration of 84 mg/dL who was treated with fomepizole alone without adverse effect [16]; however, in contrast to our case, that patient co-ingested ethanol. In the META study, a prospective clinical trial of fomepizole use in ethylene glycol poisoned patients, those with normal renal function at the time of initiation of fomepizole treatment did not develop renal injury; however, hemodialysis was utilized in patients with plasma concentrations over 50 mg/dL [9]. Borron et al. reported a retrospective case series of 11 ethylene glycol poisoned patients treated with fomepizole [13]. Eight of these patients were not hemodialyzed. In that series, all patients with normal renal function at the time fomepizole therapy was started did not develop any subsequent signs of renal injury. These findings are consistent with the results of our case and those of the META trial [9].

Fomepizole inhibits ADH thus preventing oxidative metabolism of ethylene glycol [5]. The metabolic acidosis associated with ethylene glycol poisoning is due to the production of the metabolite glycolate, which is further metabolized to oxalate [9, 21, 22]. Injury to the kidneys and other organs caused by ethylene glycol poisoning is predominantly due to precipitation of calcium oxalate crystals [23]. Glycolate is dialyzable; however, it is unknown whether removal of glycolate by hemodialysis affects patient outcome in cases of ethylene glycol poisoning. Since our patient presented with a mild metabolic acidosis and did not sustain detectable renal injury, it is likely that some amount of glycolate may be well tolerated.

Fomepizole effectively inhibited ethylene glycol metabolism in our patient demonstrated by the resolution of his metabolic acidosis once fomepizole therapy was initiated. Despite inhibition of its metabolism, ethylene glycol can be effectively eliminated by renal clearance in the absence of kidney injury or failure [24]. This was demonstrated by the apparent first order elimination of ethylene glycol during fomepizole therapy (Fig. 1) and is consistent with the results of the META study [9]. Although previous studies demonstrated fomepizole therapy is an effective treatment for ethylene glycol poisoning [9, 13], they did not show efficacy in the absence of adjunctive hemodialysis in patients with very high levels. Our case adds to the mounting body of anecdotal evidence [7, 9, 16–20] that such patients may not require hemodialysis if their renal function is intact and they do not have a significant metabolic acidosis.

Although this patient did not have a blood ethanol determination on admission, he gave us a history of no ethanol ingestion, appeared to be a good historian, and did not have an odor of ethanol on his breath. A formal blood ethanol determination was done 24 h after admission and was negative (<10 mg/dL). Given that fomepizole would have blocked ethanol metabolism, it is likely that if he had substantial quantities in his blood at the time of admission, some would have still been detectable.

Hemodialysis was considered in our patient and that treatment might have shortened his hospital stay. However, hemodialysis has potential for complications, imparts additional costs, and affects resource allocation. Hemodialysis may not be available at all hospitals or may require long transport times to a center with this capability. Hemodialysis can also be technically challenging in small infants. Because of these factors, and based on the experience reviewed above, treatment of patients with fomepizole alone appears to be a viable option in those patients with very high serum ethylene glycol concentrations, without a severe metabolic acidosis, and normal renal function.