LabMed

Overdose of Ethylene Glycol

At a Glance

Ethylene glycol poisoning is not common and is often unintentional, as it is a colorless slightly viscous sweet-tasting liquid. Rapid recognition and prompt treatment are crucial to prevent renal failure and other serious sequelae. In the absence of an exposure history, ethylene glycol intoxication is difficult to diagnose. Clinical manifestations are usually delayed for 12-24 hours, while toxic metabolites accumulate, and the patient may, therefore, already have severe metabolic compromise on presentation. It is important to know whether ethanol has also been ingested, as the latency period is markedly increased. Every effort should be made to identify the source of the exposure. A lethal dose is slightly greater than 1g/kg.

In its early stages, mild inebriation belies the severity of the situation, which evolves as ethylene glycol is converted into toxic metabolites. Ethylene glycol ingestion should be considered in any patient who presents with inebriation without the smell of alcohol, unexplained anion gap metabolic acidosis, and/or osmolal gap with hypocalcemia. Acute renal failure, seizures, arrhythmias, pulmonary edema, and congestive heart failure may ensue.

Loss of visual acuity and normocalcemia distinguish methanol intoxication from ethylene glycol poisoning.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

In contrast to ethanol measurements, there are no widely available or easily performed tests for ethylene glycol. A few labs offer enzymatic assays, but these are non-specific and unreliable in hyperlipidemia and diabetic ketoacidosis (DKA). Ideally, the diagnosis should be made by determination of ethylene glycol in the serum or urine by gas chromatography, but these methods are not standardized. If the ethylene glycol determination is negative, methanol intoxication should be considered because of its similarity in the initial phases. The limited availability and delay in reporting of these tests means diagnosis and decision to give antidote will invariably be based on clinical history and other tests.

The finding of birefringent calcium oxalate crystals in the urine is a good supportive test but does not rule out ethylene glycol intoxication if negative, especially if ingestion was recent. The presence of hypocalcemia, hypoglycemia, and a rising serum creatinine are also supportive. Few conditions besides ethylene glycol, propylene glycol, or methanol intoxication produce such a profound metabolic acidosis (bicarbonate < 8 mmol/L), and most of these present in a characteristic fashion with a high serum lactate (status epilepticus, shock, ischemic bowel, or diabetic ketoacidosis). In contrast, the majority of organic acid in ethylene glycol intoxication is glycolate and glyoxalate, and the relative lack of lactate may provide a clue to the diagnosis.

It is important to determine whether ethanol is present by a qualitative test, and, if positive, a quantitative serum or breath ethanol should be obtained. Early on, the presence of ethylene glycol in the serum elevates the osmolal gap, but this declines as the ethylene glycol is metabolized and is replaced by an anion gap metabolic acidosis (routine chemistries required).

Osmolality should be determined by freezing point depression, and the osmolal gap should be calculated. It is important to determine the osmolality prior to administration of ethanol antidote, as this will contribute to the elevated osmolal gap; 4-methylpyrazole antidote does not. A patient's progress should be monitored regularly by his or her acid-base status, renal function, serum calcium, and osmolality. These readily available tests are rapid and inexpensive to perform. They are not, however, sufficiently sensitive to detect a small ingestion, since the population variability means that the gap can still lie within the normal range (up to about 50 mg/dL ethylene glycol). Regular monitoring of serum ethanol antidote is required; 4-methylpyrazole monitoring is not indicated. (Table 1)

Table 1

Test Results Indicative of the Disorder
Ethylene Glycol Electrolytes and Blood Gas Osmolality Acids Routine Chemistry
Serum or urine >10 mg/dL (Metabolic acidosis, compensating respiratory alkalosis) pH <7.35 Bicarbonate <8 mmol/L pCO2 decreased Elevated anion gap >20 mmol/L, especially later Elevated >300 mOsm/kg Osmolal Gap >20 mOsm/kg, especially early Lactate variable depending on assay but often <3 mmol/L Creatinine rising, BUN less so Hypocalcemia Hypoglycemia

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Ethylene glycol is widely available and has many legitimate uses, such as degreasers, antifreeze, and windshield washers, and there can be confusion regarding whether methanol, ethylene glycol, or another glycol is present in the product. When the history is of social ethanol use, multiple victims might be anticipated.

Osmolality should be measured by freezing point depression; vapor dew point pressure methods are not reliable with volatile osmolytes. Any small osmolyte, such as methanol, ethanol, isopropanol, acetone, or propylene glycol, will contribute to an elevated osmolal gap. Of these, however, only ethylene glycol and methanol produce an elevated anion gap. For calculation of the osmolal gap, a simultaneous measurement of serum sodium, glucose, and blood urea nitrogen (BUN) are required.

There are two reasons co-ingestion of ethanol is important for the diagnosis and evolution of ethylene glycol intoxication. First, since it prevents the formation of toxic metabolites by inhibition of alcohol dehydrogenase, the onset of symptoms (and the possibility of detecting the anion gap) is diminished. Second, ethanol's contribution to the osmolal gap confounds the diagnosis and possibly delays treatment. When the patient has a significant ethanol load, together with a marked metabolic acidosis, the likelihood of ethylene glycol intoxication should be seriously reconsidered: consider propylene glycol, since its metabolism to lactate progresses in the presence of ethanol.

Because of the nature of the toxicity, serum ethylene glycol does not relate to the severity of the condition. It is considered non-toxic at almost any level, so long as its metabolism is blocked, although it does cause some fluid retention by osmosis, especially in the kidney, and this may contribute to the damage.

Ethylene glycol does not appreciably affect rapid point of care or enzymatic assays for ethanol or breathe ethanol tests.

What Lab Results Are Absolutely Confirmatory?

Ethylene glycol is stable in blood, but fluoride oxalate preservative should be used if ethanol determination is also required.

Ethylene glycol analysis by gas chromatography is the gold standard for establishing the diagnosis of ethylene glycol intoxication. In addition, this test can often detect and quantitate propylene glycol, ethanol, acetone, and isopropanol. A variety of home-brew solvent screens may be offered, and it is important to ascertain exactly what compounds are included, otherwise a diagnosis may be missed.

The serum ethylene glycol concentration does not correlate with the severity of the intoxication, even if the time of ingestion is known, since the degree of acidosis and the deposition of calcium oxalate within the kidney are the major determinants of outcome. Once the diagnosis is established and treatment instigated, repeat serum ethylene glycol determinations are not helpful, unless the intoxication does not resolve in the expected time. If the patient presents late, it may not be possible to demonstrate the presence of ethylene glycol. In this situation, or if ethylene glycol testing is unavailable, demonstration of calcium oxalate crystalluria is considered diagnostic.

In the absence of ethylene glycol assays, diagnosis and treatment is based predominantly on history, acid-base status, hypocalcemia, crystalluria, and exclusion of other metabolic causes.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Additional Useful Tests

Urine pregnancy test should be performed in age-appropriate females.

A urine drug screen should be requested if there is a suspicion that other agents are involved. This can be a set of simple immunoassays for recreational drugs, which can be performed as a Point of Care or a laboratory-based test. Laboratory tests frequently also include acetaminophen and salicylate. This determines whether the clinical picture is due to ethylene glycol alone or is confounded by co-ingestion of sedative hypnotic agents, such as benzodiazepines, barbiturates, or opioids, and can provide an indication of other toxins that might contribute to the metabolic acidosis.

Urinalysis can be helpful. Although the presence of birefringent calcium oxalate crystals favors the diagnosis of intoxication with ethylene glycol rather than methanol, it should not be used as confirmation (these can appear as little as 4-8 hours post-ingestion). Sometimes a fluorescent marker is added to the product by the manufacturer, and this may be detected in the urine with the use of a UV lamp. This test is subject to false positives, and the absence of fluorescence does not exclude a significant ingestion.

Although calcium and creatinine may be ordered for routine care, the presence of hypocalcemia and presence of an elevated creatinine direct the diagnosis toward ethylene glycol and away from methanol intoxication.

For calculation of the osmolal gap, a simultaneous measurement of serum sodium, glucose, and BUN are required. Once the presence of ethanol has been excluded, this information can be used cautiously to calculate the approximate amount of ethylene glycol present by the observed gap as follows:

Calculated osmolality mOsm/kg = 2[Na mmol/L] = [glucose mg/dL/18] + [BUN mg/dL/2.8]

Osmolal gap = Measured osmolality – Calculated osmolality, which is normally less than 10 mOsm/kg

Serum ethylene glycol (mg/dL) = (10 – osmolal gap) x 6.2

Remember to measure and factor in for any ethanol administered. Once the ethanol concentration is known, the portion of the osmolal gap attributed to the ethylene glycol can be used to calculate the ethylene glycol concentration:

Serum ethylene glycol mg/dL = 6.2 [(10 – Osmolal gap mOsm/kg) – (Serum ethanol mg/dL/4.6)]

Specimens for solvent screens are often requested in specific containers with special handling conditions but should always be drawn with minimal airspace to avoid loss during transport.

Metabolism

Ethylene glycol alone is relatively benign. Hepatic metabolism accounts for 80% of the dose and greatly increases its toxicity, but this can be effectively blocked either with ethanol (approximately 100 mg/dL in the serum) or preferably with 4-methylpyrazole (Fomepizole), as this does not compromise the patient's mental status. The first metabolic step is the enzymatic conversion by alcohol dehydrogenase (ADH) to glycolaldehyde, with subsequent rapid conversion to glycolate and then the rate-limiting conversion to glyoxalate by aldehyde dehydrogenase (ALDH).

All these reactions generate acid (H+), deplete nicotinamide adenine dinucleotide (NAD), and shift the cell toward anaerobic respiration, favoring hypoglycemia and a lactic acidosis. Glycolate and glyoxalate contribute further to the acidosis and further metabolism to oxalate which precipitates in tissues including the kidney. The remaining 20% of the dose is filtered at the glomerulus and the majority reabsorbed from the tubules.

Expected Kinetics

Peak ethylene glycol concentrations in the blood occur some 1-4 hours after ingestion. Elimination half-life is about 3 hours, increasing to 20 hours after 4-methylpyrazole or ethanol administration.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

If the diagnosis is based on the osmolal gap, the presence of other osmolytes may confound the diagnosis. A number of intravenous medicines are solubilized in propylene glycol, which may accumulate in the plasma over time. The contribution to the osmolal gap is predictable from the molecular weight of propylene glycol (mOsm/kg = Propylene glycol mg/dL/7.6).

A few laboratories offer enzymatic tests for ethylene glycol modified from triglyceride kits based on glycerol determination. These are subject to interference from excess glycerol present in DKA and the slow reaction of larger amounts of triglycerides (TG) in hyperlipidemia (TG > 400 mg/dL). In addition, there is cross-reactivity from propylene glycol. Hemodialysis is used frequently in severe ethylene glycol intoxication, not only to remove ethylene glycol, but also the accumulated metabolic acids and to replace renal function. If the patient is on an ethanol infusion, this is also removed during dialysis, and either the dose should be doubled or ethanol added to the dialysis fluid to prevent ethylene glycol metabolism. Careful ethanol monitoring is required.

Critically ill patients may have elevated osmolal gaps. Categorical ruling out of ethylene glycol intoxication on the basis of an osmolal gap less than 10 mOsm/kg is unjustified, as it is assuming that a small elevation in the osmolal gap in a patient with a low pretest probability is due to ethylene glycol. Osmolal gaps greater than 25 mOsm/kg are caused by few other substances, and a large unexplained gap is presumptive evidence of recent toxic alcohol ingestion in the appropriate clinical setting. Subsequent tests are needed to make the specific identification or narrow down the options.

Some lactate assays based on lactate oxidase give unreliably high results in the presence of high concentrations of the ethylene glycol metabolite glycolate. As ethylene glycol metabolism progresses, lactate does accumulate to some extent, but the presence of glycolate may make this rise appear much larger than it actually is, depending on the specific test used. Lactate results should be interpreted with caution.

Ethylene glycol analysis by gas chromatography is the gold standard for establishing the diagnosis of ethylene glycol intoxication. However, these methods are not standardized, and a number of different internal standards and derivatives are used. It is possible that, in some methods, other ingested or endogenous small molecules could coelute; mass spectometry is not usually used.

Large amounts of hippuric acid in the urine can produce crystals that may be mistaken for calcium oxalate and, hence, mislead the diagnosis erroneously toward ethylene glycol.

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