Overview
Ethylene glycol poisoning is considered a medical emergency. Despite being recognized as a poison for nearly 50 years, ethylene glycol remains readily available and continues to be fatally ingested. The most common sources of ethylene glycol are automotive antifreeze (generally available as a 95% concentration), engine coolants and hydraulic brake fluids.

In ethylene glycol poisoning, the clinical course is initially characterized by mild symptoms that may gradually develop to produce serious or even fatal toxicity. Ethylene glycol poisoning presents many challenges in making a definitive diagnosis. If treatment is initiated early, prognosis is excellent; however, a disturbing proportion of patients are admitted at a late stage to hospitals that are not capable of performing analysis which identifies ethylene glycol toxicity on a 24-hour basis. Therefore, rapid treatment is often prevented because of a delayed diagnosis, which may result in fatal consequences (Jacobsen 1986).

The lethal dose of ethylene glycol is usually 1.4-1.6 mL/kg (about 100 mL in an adult), but as little as 30 mL may be fatal (Walder 1994).

Occurrence
Ethylene glycol poisoning occurs infrequently, either intentionally through misuse or accidental (environmental or occupational).

There is a lack of comprehensive data available on the incidence of ethylene glycol poisoning in the United States; however, the American Association of Poison Control Centers (AAPCC) publishes an annual report of Toxic Exposure Surveillance System (TESS) data. This report is a compilation of human toxic exposure cases reported to the AAPCC by the majority of U.S. poison centers.

In the 2002 annual report of the TESS data by the AAPCC, 6,077 exposures to ethylene glycol were reported in the United States, resulting in 40 deaths and 254 near-fatalities (Watson 2002).

Chemistry
Ethylene glycol, also known as 1,2-ethanediol or glycol alcohol, is a dihydroxy alcohol derivative of the aliphatic hydrocarbons. Ethylene glycol has a molecular formula of C₂H₆O₂ and a molecular weight of 62.07 grams/mole. It is colorless, odorless, slightly viscous and considerably hygroscopic liquid (Budavari 1989A).

Pharmacokinetics
Ethylene glycol is rapidly absorbed from the gastrointestinal tract, reaching peak blood concentrations one to four hours after ingestion. The volume of distribution has been reported to range from 0.5-0.8 L/kg (Barceloux 1999). Primary metabolism takes place in the liver. Approximately 80% of ethylene glycol is metabolized hepatically, and 20% is really excreted unchanged. The elimination half-life of ethylene glycol is approximately three hours, but is prolonged to 17-18 hours following inhibition of alcohol dehydrogenase (Barceloux 1999).

Mechanism of Toxicity
Knowledge of the metabolism of ethylene glycol is critical to the understanding of the pathogenesis of its toxicity and the rational behind therapy. While the parent compound is essentially nontoxic, ethylene glycol metabolites are responsible for extensive cellular damage in various tissues, especially the kidneys, caused principally by the metabolites glycolate and oxalate (or glycolic and oxalic acid, depending upon the serum pH).

The metabolism of ethylene glycol is a four-step process, taking place primarily in the liver (see Figure 1). During the first step, ethylene glycol is metabolized to glycoaldehyde via alcohol dehydrogenase (ADH). Glycoaldehyde is then rapidly converted to glycolate via aldehyde dehydrogenase in the second step. The third step is the further metabolism from glycolate to glyoxylate, which occurs relatively slowly, allowing for accumulation of glycolate. The production of glycolate interferes with cellular metabolic enzymes and is also responsible for the severe metabolic acidosis characteristic of poisoning by ethylene glycol. The small amounts of lactate and formate produced are clinically insignificant. Glyoxylate and formate, although more toxic than glycolate on a weight-for-weight basis, are only formed in micromolar amounts and do not contribute to toxicity. The fourth step is the metabolism of glyoxylate to produce oxalate, which rapidly precipitates as calcium oxalate and is deposited in a crystalline form, especially the kidneys (Walder 1994).

Figure 1. Metabolic Pathway of Ethylene Glycol Toxicity (Adapted from Walder 1994)

Clinical Course
Many authors describe three stages of ethylene glycol poisoning: a neurological stage, followed by a cardiopulmonary stage, and finally, a renal stage. In many cases, however, there is a considerable overlap among the three phases. One may predominate while another may be absent and they may occur at different times than described here (Barceloux 1999).

Stage 1: Neurological (30 minutes to 12 hours after ingestion)
The early neurological effects follow a biphasic course. Within minutes to several hours after ethylene glycol poisoning, transient inebriation and euphoria, similar to the symptoms of ethanol intoxication, may be observed. Nausea and vomiting can also occur. As ethylene glycol metabolism progresses, metabolic acidosis and central nervous system (CNS) depression can replace earlier symptoms. Approximately 4-12 hours after ingestion, symptoms associated with toxic metabolites of ethylene glycol predominate; however, their onset can be delayed if a patient has also ingested substantial amounts of ethanol, which inhibits ethylene glycol metabolism. In severe cases, these symptoms can include coma associated with hypotonia, hyporeflexia, occasional seizures, and meningismus. Cytotoxicity and the deposition of calcium oxalate can lead to cerebral damage and contribute to CNS depression. Other neurological symptoms may include nystagmus, ataxia, opthalmoplegias, and myoclonic jerks. In most cases of ethylene glycol poisoning, the optic fundus is normal; however, in some situations, the presence of papilledema may confuse the clinical presentation with that of methanol poisoning (Barceloux 1999).

Stage 2: Cardiopulmonary (12-24 hours after ingestion)
In the second stage of ethylene glycol poisoning, tachycardia and mild hypertension frequently occur. In serious cases, severe metabolic acidosis with compensatory hyperventilation can develop accompanied by multiple organ failure. Most deaths occur in this stage (Barceloux 1999).

Stage 3: Renal (24-72 hours after ingestion)
The symptoms of the third stage can include oliguria, flank pain, acute tubular necrosis, renal failure and, in rare instances, bone marrow suppression. In severe cases of ethylene glycol poisoning, renal failure may appear early and progress to anuria. Recovery of renal function is often complete but may require several months of hemodialysis. Even when renal damage is severe, chronic hemodialysis or renal transplantation are rarely required. Serious damage to the liver is rare (Barceloux 1999).

Diagnosis
Many of the clinical signs and symptoms associated with ethylene glycol and methanol poisonings (i.e. nausea, vomiting, CNS depression) are nondescript, and are similar to the clinical signs and symptoms for many poisonings and illnesses; however, there are a few key features that should immediately lead the physician to consider ethylene glycol poisoning. In a thorough patient history, there should be a distinct period of latency between consumption and the appearance of toxic symptoms. Respiratory distress with hyperventilation would suggest metabolic acidosis and is present in most cases. Metabolic acidosis can be rapidly determined by electrolyte or arterial blood gas analysis. Increases in the anion and osmolal gap also point to this poisoning. Ethylene glycol poisoning must always be considered in any patient presenting with metabolic acidosis of unknown origin.

Rapid diagnosis of ethylene glycol toxicity is critical because therapy can be very effective when applied within a reasonable period of time after ingestion. Conversely, in many cases when diagnosis is delayed, antidotal therapy is of little use, often with fatal consequences (Jacobsen 1986).

The key to rapid diagnosis is to obtain thorough history from the patient, a friend, or family member. This can be challenging in some cases because patients are often confused, distressed, or even comatose. The time delay between consumption and patient presentation to a health care facility may hinder communication with friends or family (Jacobsen 1997).

The most conclusive method of diagnosing this poisoning is direct measurement of serum or urine ethylene glycol concentration; however, patients are sometimes admitted at a late stage to hospitals that are not capable of performing analysis of this compound on a 24-hour basis. Because this compound becomes toxic after conversion to its metabolites, there is little correlation between blood concentrations of the ethylene glycol, per se, and the severity of the poisoning. In many cases, poisoned patients do not seek treatment until the syndrome is well developed, when blood ethylene glycol concentrations are low, but toxic metabolite concentrations are high. Other patients present asymptomatically during the latent period immediately following ingestion (Jacobsen 1997).

In situations where specific analysis are not available, the calculation of the anion and osmolal gaps can provide relatively certain and early diagnosis, allowing treatment to be started immediately. Calculation of the anion and osmolal gaps should be performed be the clinician whenever facing a metabolic acidosis of unknown origin (Jacobsen 1997). The anion gap may be calculated as follows:

Anion gap - (Na⁺ + k⁺) - (Cl^- + HCO₃^-),
Where normal = 12-6 mmol/L

or by convention:

Anion gap - (Na⁺) - (Cl^- + HCO₃^-),
Where normal = 8-12 mmol/L

A metabolic acidosis with an increased anion gap and a normal chloride concentration indicates retention of nonvolatile organic acids, such as may be present in renal failure, ketoacidosis, lactic acidosis, and ingestion of substances such as methanol, ethylene glycol, salicylate or iron. In the absence of circulatory failure, diabetes, alcoholism, and uremia, an increased anion gap clearly indicates poisoning with one or more of these substances (Jacobsen 1997).

The diagnostic importance of the anion gap increases if combined with consideration of the osmolal gap (Jacobsen 1986). The osmolal gap is the difference between the measured osmolality and the calculated osmolality in serum. Normally, sodium, glucose, and urea (BUN) principally determine the osmolality of serum as expressed by the formula:

Osmolal gap (mOsm/kg) = (1.86 x Na⁺ [mEq/L]) + (BUN [mg/dL]/2.8) + (glucose [mg/dL]/18)
where normal = 270-290 mOsm/kg

or

SI units (mmol/kg) = (1.86 x Na⁺ [mmol/L] = BUN [mmol/L] = glucose [mmol/L])/0.93
where normal = 280-300 mmol/kg

An increased osmolal gap indicates that one or more intoxicants are present in high molar concentrations. Most drugs, including salicylates, are not identified this way because they are dissociated or do not attain high enough serum concentration on a molar basis. The intoxicants best able to increase the osmolal gap are those that have a low molecular weight and are present in high mass units. The lower alcohols and glycols are such substances. Methanol and ethylene glycol regularly cause severe metabolic acidosis and elevation of both the anion and osmolal gaps (Jacobsen 1997).

The osmolal gap should be cautiously interpreted in the critically ill patient, because circulatory failure may increase its value. Parenteral infusions with hyperosmolar solutions and the presence of diabetic ketoacidosis may also expand the osmolar gap. Chronic renal failure also contributes to a slight elevation, while acute renal failure leaves it unaltered (Jacobsen 1986).

Serum osmolality must be performed with the freezing point depression method; the vapor pressure method is not valid and should not be used. If ethanol is co-ingested with ethylene glycol, there may be no metabolic acidosis until most of the ethanol is metabolized due to the competitive ADH-inhibiting effect of ethanol. In such circumstances, calculation of the gaps must be repeated. In late stages of a poisoning, most of the ethylene glycol may be metabolized to its acidic metabolites. In this situation, there may be a pronounced metabolic acidosis with a high anion gap but the osmolal gap may be close to normal values. Under these conditions, a small/normal osmolal gap does not eliminate the possibility of toxic alcohol ingestion (Jacobsen 1997).

Urinary calcium oxalate crystals are present on admission in almost 50% of ethylene glycol-poisoned patients and this percentage increases if urine microscopy is repeated later in the course of the intoxication. X-ray diffraction studies in humans have shown that the needle-shaped monohydrate crystals (Whewellite) are more common than the envelope-shaped dihydrate crystals (Weddelite). The dihydrate is meta-stable and will undergo transformation to the monohydrate form. The crystalluria may be massive and generally accompanied by some red cells and different types of casts. If specific analyses are not available, repeated urine microscopy is very useful in the different diagnosis in patients presenting with metabolic acidosis of unknown origin (Jacobsen 1997).

Treatment Objectives
Rapid diagnosis of ethylene glycol toxicity is critical because therapy can be very effective when administered within a reasonable period of time after ingestion. Conversely, in many cases when diagnosis is delayed, antidotal therapy may be of little value. often with fatal consequences. The metabolic products of ethylene glycol can produce acidosis; when considerable time has elapsed after ingestion, mortality correlates best with severity of acidosis rather than blood ethylene glycol concentration. Therefore, both ethylene glycol concentrations and acid base balance, as determined by electrolyte (anion gap) and/or arterial blood gas analysis, should be frequently monitored and used to guide treatment.

Treatment of ethylene glycol poisoning involves three primary goals: correction of the patient's metabolic acidosis, prevention of metabolism of the compound to its toxic metabolites, and removal of ethylene glycol and its toxic metabolites with hemodialysis, if necessary.

Gastric lavage may be indicated if performed soon after ingestion, or in patients who are comatose or at risk of convulsions. Ipecac is considered contraindicated because of the potential for CNS depression from the ethylene glycol and the potential for convulsions (Barceloux 1999). Charcoal is of little benefit as ethylene glycol is not significantly absorbed by activated charcoal; in cases of multiple chemical ingestions, however, it would be used for the co-ingestant(s) (Jacobsen 1997).

Because of the potential for CNS depression, airway protection may be indicated and respiratory support provided as needed. Intravenous (IV) fluids may be needed to correct electrolyte imbalance and to maintain adequate urine output. Urine output needs to be carefully monitored; however, if renal failure develops, IV fluids may need to be withdrawn to avoid fluid overload. Pyridoxine and thiamine may be administered to patients with ethylene glycol poisoning to promote alternate metabolism or conversion to nontoxic metabolites glycine and alpha-hydroxy-beta-ketoadipate; although, data supporting a beneficial effect of pyridoxine and thiamine is sparse.

Calcium should not be given for hypocalcemia, per se, as this may increase precipitation of calcium oxalate crystals in the tissues (Jacobsen 1997). However, in ethylene glycol poisoned patients, tetany and seizures may require treatment with IV calcium gluconate/chloride, as hypocalcemia is an important cause of these complications.

Early and aggressive treatment with sodium bicarbonate is generally considered essential to correct the initial acidosis. With the emphasis on antidotal therapy, physicians must not forget the importance of alkali therapy. More than 500-1000 mmol bicarbonate may be needed within the first hours, especially if antidotal therapy has not been initiated. In ethylene glycol poisoning, clinical experience has shown that hypocalcemia may be worsened during aggressive alkali therapy because alkalinization increases the protein binding of calcium (Jacobsen 1997).

The dialysance of ethylene glycol and its major metabolite glycolate has been well established. According to the traditional toxicology literature, hemodialysis should be considered in cases with a serum ethylene glycol concentration greater than 50 mg/dL (Barceloux 1999).

Unfortunately, hemodialysis is not available in all hospitals. In the event of a serious poisoning where extracorporeal removal of ethylene glycol may be indicated, transferring the patient to a facility with renal dialysis capabilities should be considered.

Peritoneal dialysis also removes ethylene glycol and its metabolites, although not as effectively as hemodialysis. Hemoperfusion is ineffective (Jacobsen 1997).

Prognosis
Outcomes are excellent for ethylene glycol poisoned patients, provided there is early treatment with alkali to combat acidosis, antidotal therapy and hemodialysis, if necessary, to remove the ethylene glycol and its toxic metabolites (Jacobsen 1986).