Ethylene Glycol Intoxication: Case Report and Pharmacokinetic Perspectives

Nina Vasavada, M.D.; Craig Williams, Pharm.D.; Richard N. Hellman, M.D.


Pharmacotherapy. 2003;23(12) 

In This Article


The successful medical management of ethylene glycol toxicity is based on early recognition of the extent of toxicity of metabolites of ethylene glycol in the individual patient. This assessment is critical in determining the necessity of ADH inhibition and hemodialysis. Similar treatment guidelines apply after the ingestion of other toxic alcohols such as methanol. Our comparative analysis of care options at an urban inner city hospital demonstrates cost differences among various therapeutic approaches.

Ethylene glycol is highly miscible in water, with an oral bioavailability of 92-100% in animal studies.[9] It distributes into the total body water with a volume of distribution of 0.5-0.8 L/kg.[2] The toxicity of ethylene glycol relates to its metabolism by ADH to various acidic metabolites. Ethylene glycol itself exerts no obvious cytotoxicity on either isolated murine proximal tubular cells (measured by cellular release of lactate dehydrogenase [LDH]) or to cultured human proximal tubular cells.[10] Observational studies have not demonstrated a predictable relationship between serum ethylene glycol concentration and anion gap, pH, or bicarbonate concentration.[11]

Without inhibition of ADH, hepatic metabolism accounts for approximately 80% of ethylene glycol elimination, with the remaining 20% being eliminated unchanged in urine.[2] Elimination of ethylene glycol has been demonstrated to follow first-order pharmacokinetics between serum concentrations of 3.5 and 211 mg/dl.[6] Patients with abnormal kidney function (mean ± SD serum creatinine level 2.24 ± 0.21 mg/dl) experience a longer elimination half-life (48.9 ± 5.7 hrs) than that of patients with normal kidney function (16.8 ± 0.8 hrs).[6]

An overview of the metabolism of ethylene glycol is illustrated in Figure 2. In the first step of metabolism, ADH oxidizes ethylene glycol to glycoaldehyde. The addition of glycoaldehyde to cultured murine and human proximal tubular cells demonstrates cytotoxicity through increasing LDH release, decreasing adenosine triphosphate (ATP) concentration, and altering plasma membrane phospholipids.[10]

Overview of ethylene glycol metabolism.

Aldehyde dehydrogenase converts glycoaldehyde to glycolate, which subsequently is converted to glyoxylate in the rate-limiting step of ethylene glycol metabolism. The accumulation of glycolate induces the metabolic acidosis associated with ethylene glycol toxicity.[10] The endogenous elimination half-life of glycolate is 7 hours; hemodialysis reduces this to 2.4-3.6 hours.[12] A predictable relationship has been observed between initial serum glycolate concentration and anion gap, but not pH or bicarbonate.[12] The toxicity of glycolate is unclear. In vivo studies correlate serum glycolate concentrations with central nervous system toxicity and acute renal failure.[11] In vitro studies, however, demonstrate a lack of significant cytotoxicity based on LDH release by isolated murine proximal tubular cells and cultured human proximal tubular cells.[10]

The next metabolite, glyoxylate, induces cytotoxicity to isolated murine proximal tubular cells, as measured by LDH release and reduction in cellular ATP content, as well as to cultured human proximal tubular cells.[10] In vivo toxicity remains undefined.

Glyoxylate is metabolized to the final product, oxalate. In vitro toxicity of oxalate remains unclear. Some studies found that oxalate exerted cytotoxicity to human proximal tubular cell cultures.[13] A more recent in vitro study demonstrated that oxalate additions were not cytotoxic to isolated murine proximal tubular cells or to cultured human proximal tubular cells.[10] This discrepancy suggests that oxalate may cause acute renal failure through cast formation rather than direct cytotoxicity.[10] A common histologic abnormality of ethylene glycol-induced acute renal failure is intraluminal oxalate crystal accumulation. The observation that proximal tubular cell injury correlates poorly with intensity of oxalate deposition suggests toxicity of precursor metabolites.

In vivo, oxalate has the potential to exert numerous toxicities. Gastrointestinal irritation may occur by means of calcium oxalate deposits in the intestinal mucosa. As with ethanol, central nervous system depression may occur. Deposition of calcium oxalate crystals in the myocardium, along with interstitial edema and acidosis, may cause myocardial dysfunction. Oxalate chelates calcium, which may result in hypocalcemia with subsequent seizures and electrocardiographic abnormalities such as QT interval prolongation, which predispose the patient to ventricular arrhythmias.[2] Anion gap metabolic acidosis develops from the formation of acidic metabolites, as well as the accumulation of lactate. The oxidative metabolism of ethylene glycol depletes the oxidized form of nicotinamide adenine dinucleotide (NAD+) and reduces the biologically significant ratio of NAD+: nicotinamide adenine dinucleotide. This reduction inhibits the citric acid cycle and increases lactic acid production through anaerobic metabolism.

Alcohol dehydrogenase inhibition is a cornerstone of therapy whenever serum ethylene glycol levels are above 20 mg/dl, as this implies the risk for generating toxic quantities of metabolites. Alcohol dehydrogenase inhibitors should be administered during the treatment of ethylene glycol poisoning if one the following three criteria exist: documented plasma ethylene glycol concentration greater than 20 mg/dl, documented recent (hrs) history of ingesting toxic amounts of ethylene glycol and an osmol gap greater than 10, history or strong clinical suspicion of ethylene glycol poisoning. In addition, at least two of the following criteria should be present: arterial pH less than 7.3, serum bicarbonate less than 20 mEq/L, osmol gap greater than 10, or presence of urinary calcium oxalate crystals.[2] Administration of the ADH inhibitor should continue until the serum ethylene glycol concentration is less than 20 mg/dl and the patient is asymptomatic with normal arterial pH.[2]

Agents given for ADH inhibition include fomepizole and ethanol. Fomepizole is preferred over ethanol when the patient has ingested multiple substances and has a depressed level of consciousness, the patient has altered consciousness, or the hospital has inadequate intensive care staffing or laboratory support to monitor ethanol administration. Relative contraindications to ethanol include a critically ill patient with anion gap metabolic acidosis of unknown cause or patients with active hepatic disease, alcoholic cardiomyopathy, or chronic heart failure. Ethanol is advocated over fomepizole when a known hypersensitivity to fomepizole exists. In the presence of fomepizole, the elimination half-life of ethylene glycol is 19.7 hours.[6]

Accelerated blood clearance of ethylene glycol and its metabolites by hemodialysis is indicated when there is severe metabolic acidosis (pH < 7.3) unresponsive to medical therapy, renal failure, or a serum ethylene glycol concentration greater than 50 mg/dl. Hemodialysis is unnecessary if fomepizole is being administered and the patient is asymptomatic with normal arterial pH. Supportive measures include correcting fluid deficits, forced diuresis, correcting acidosis (pH < 7.3) with intravenous bicarbonate, and replacing magnesium, thiamine, and pyridoxine in depleted patients. In addition, close monitoring is required if an ethanol infusion is to be given. Patients should be placed in an intensive care unit or similar setting and monitored for metabolic acidosis, alterations in vital signs, and abnormal serum laboratory values including glucose and electrolytes. Also, serum ethanol concentrations must be monitored.[2] Hemodialysis accelerates blood clearance of ethylene glycol, yielding an elimination half-life of 2.68 ± 0.22 hours.[6]

The elimination pharmacokinetics in our patient were compared with those in a second patient admitted to our institution who received fomepizole with hemodialysis after antifreeze ingestion. This second patient was a 45-year-old man who came to the emergency department 15 hours after having consumed approximately 600 ml of antifreeze in a suicide attempt. Nine hours after ingesting the antifreeze, the patient consumed several servings of ethanol as well. He was hemodynamically stable and weighed 53 kg. On admission, he received fomepizole 15 mg/kg and underwent hemodialysis with an F80 dialyzer (Fresenius Medical Care North America, Lexington, MA) for 6 hours at a blood flow rate of 400 ml/minute through a temporary femoral venous hemodialysis catheter. The patient subsequently received fomepizole 10 mg/kg during hemodialysis at 5 and 9 hours after presentation and was discharged 2 days after admission. As demonstrated in Table 2 , hemodialysis dramatically shortened the elimination half-life of ethylene glycol from 15.3 to 3.15 hours.

Table 3 demonstrates cost estimates based on our initial patient had he been treated with various therapeutic modalities. Data estimating duration of hemodialysis required for blood clearance of ethylene glycol are calculated based on the initial serum concentration, type of dialyzer used, and total body water.[14] Cost data were obtained from an inner city county hospital. As illustrated in Table 3 , in the selected setting of a hemodynamically stable patient with normal renal function and arterial pH, fomepizole monotherapy provides an alternative therapy for ethylene glycol intoxication compared with ADH inhibition (ethanol or fomepizole) with hemodialysis, although cost is higher due to longer duration of hospitalization and ADH inhibition.

Patient consumption of ethanol at the time of ethylene glycol intake limits our analysis. It is possible that the patient's self-administration of ethanol inhibited ADH, subsequently minimizing the development of acidosis and toxicity by metabolites of ethylene glycol. The ethylene glycol and ethanol serum concentrations on presentation do not fully account for the measured serum osmolality, which may reflect laboratory error or unmeasured osmotically active substances.[15]


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