CALL US...TM

The Official Newsletter of the California Poison Control System
Volume 1, Number 1.
February 2002


Diagnosis and Treatment of
Ethylene Glycol (Antifreeze) Ingestion


Introduction

Ethylene glycol (C2H6O2, CAS # 107-21-1) is a significant cause of poisoning morbidity and mortality in California. Ethylene glycol (EG) per se causes an altered mental status similar to ethyl alcohol. More importantly, metabolites of EG can cause acute renal failure, severe metabolic acidosis and, potentially, multi-system organ failure and death. While some poisonings with ethylene glycol are the result of using this substance as an alcohol substitute, most occur as self-harm or suicidal gestures.

Ethylene glycol is an odorless, colorless, sweet-tasting syrupy substance with a molecular weight of 62.07, freezing point of -13°C and a boiling point of 197.6°C. It is most commonly encountered as automotive antifreeze.

Diethylene glycol behaves similarly to ethylene glycol in an overdose. The ethylene glycol molecule is incorporated into the structure of several ethers (e.g., ethylene glycol mono butyl ether and ethylene glycol mono ethyl ether), which may in very large amounts behave similarly to EG.


Case presentation

A 27 year old male is found in a motel room, after telling an acquaintance that he was going to drink antifreeze. In the motel room is a glass with what looks like antifreeze. The patient says it is, and says that he drank one glass. He is brought to an ED in police custody. They are anxious to take him to jail.

In the ED he is alert and cooperative, oriented to person, place and time. PMH reveals multiple prior suicide attempts. Physical examination is unremarkable. (He has multiple old scars from apparent self-harm efforts.) Initial labs at 20:33 hours are Na 149, Cl 108, CO2 25, K 4.1, BUN 9 and Cr 1.1. Ethyl alcohol is 197 mg/dl. Urine tox screen is negative for drugs of abuse. Urine shows no crystals. Blood ethylene glycol level measurement will not be available for more than 24 hours. The hospital cannot do a measured serum osmolality on site. An EG sample is sent out.

In the absence of a stat EG level or a serum osmolality, the physician caring for the patient elects to follow the serum bicarbonate level as a possible marker of severity of ethylene glycol poisoning. His logic is that, since EG causes over time a profound metabolic acidosis, the absence of an acidosis over time would be presumptive evidence that no significant ingestion had occurred. The following laboratory values were obtained.

Time: HCO3:
22:33 25
00:20 23
01:10 24
01:55 22
03:42 23
06:48 27
06:48 Alcohol 74 mg/dl

By morning, no metabolic acidosis has developed and serum bicarbonate has actually risen. The ethylene glycol level is not back. The patient does not look sick and is released in the custody of police.

Within 24 hours the patient becomes acutely ill while in jail. He arrives back at the hospital profoundly acidotic and hypocalcemic. He suffers a cardiac arrest and cannot be resuscitated. After the patient died, the lab reports that the patient had a highly toxic ethylene glycol level drawn on the first visit.

Questions:

  1. Why did this patient, who was poisoned with ethylene glycol, not become acutely ill until after he left the ED?
  2. Why was the severity of this intoxication not recognized on the first ED visit?


Epidemiology

A significant number of poisonings with ethylene glycol occur in California each year. In calendar year 2000, the CPCS consulted on 469 exposures to EG. These included 5 patients who later died and 38 who had either moderate or major effects attributed to EG. Minor effects were attributed to 62 exposures. Only 2 serious cases, and no deaths, occurred in persons under age 20.

On a national basis, almost all deaths observed each year are caused by intentional ingestions, with the significant majority of those being suicides.


Pathophysiology

As the parent compound, ethylene glycol produces altered mental status similar to ethyl alcohol. This effect rarely produces serious morbidity or death by itself.

Acute renal failure as well as a severe anion-gap metabolic acidosis results from the metabolism of ethylene glycol into at least 4 distinct metabolites. Alcohol dehydrogenase, the same first step enzyme responsible for the metabolism of methyl and ethyl alcohols, slowly catalyzes conversion of EG to glycoaldehyde. This is, in turn, rapidly converted by aldehyde dehydrogenase into glycolic acid. Glycolate is then metabolized into glyoxylate and finally oxalate.

In addition to the metabolic acidosis and acute renal failure associated with glycolic acid and oxalic acid, metabolites of ethylene glycol cause cerebral and meningo-encephalitis, pulmonary edema and pneumonitis, as well as myocardial, hepatic and muscle pathology. Because calcium oxalate is a very low solubility product, significant hypocalcemia can result from precipitation of calcium by oxalic acid.


Clinical presentation

Some degree of altered mental status is usually the first sign of ethylene glycol intoxication. (Gastritis some times occurs early, as would symptoms caused by other substances in the case of a mixed ingestion). After a delay of 4 to 12 hours, metabolic acidosis gradually develops. If there simultaneously exists a blood ethyl alcohol level greater than 50-100 mg/dL, no metabolic acidosis will occur until the EtOH level falls. This is because ethanol ties up the rate limiting, first-step enzyme, alcohol dehydrogenase, and prevents metabolism of ethylene glycol into its toxic acid products. This is the basis for use of ethyl alcohol as an antidote.

Elevation of BUN and creatinine is usually not seen until at least 24 hours after ingestion (in the absence of an alcohol level above 50-100 mg/dL.) Other complications from products of toxic metabolism, such as brain damage, respiratory failure, and hepatitis are usually also delayed.

In the absence of a history of ethylene glycol ingestion, the most common presentation of EG intoxication is that of a severe anion gap metabolic acidosis in the context of altered mental status.


Diagnosis

A definitive diagnosis of EG poisoning is made with a serum ethylene glycol level. However, this is rarely immediately available, as almost all hospitals send this test to a reference lab, often to an out-of-state laboratory. We are aware of only 4 hospital laboratories in California that can perform this test on a "stat" basis. As a result, a level drawn at a given hospital can take up to 8-9 milli-years (several days) to be reported.

Lack of prompt access to EG measurements represents a significant management problem for this poisoning. Because effective treatment must be instituted before blood EG levels can be obtained in most cases, physicians caring for a patient potentially poisoned with ethylene glycol must be skilled at detecting this intoxication indirectly, i.e., in the absence of a blood level. The California Poison Control System offers the assistance of its medical toxicologists for diagnostic help with these and other exposures.

An osmolal gap is frequently utilized in an attempt to detect osmotically active substances, including ethylene glycol. An osmolal gap is the difference between the measured serum osmolality (freezing point depression or vapor pressure may be used for EG), and the estimated serum osmolality calculated using the following formula:

Calculated serum osmolality = 2[Na] + [glucose ÷ 18] + [BUN ÷ 2.8] + [EtOH ÷ 4.6], where Na is in mEq/L and glucose, EtOH and BUN are in mg/dL.

Unfortunately, the presence of an osmolal gap is neither sensitive nor specific for EG. Worse, the negative predictive value is poor, which means that one can have a significant ethylene glycol poisoning with a small or even absent osmolal gap. This is because of two factors. Because ethylene glycol is a large molecule relative to, say, ethanol or methanol, it produces significantly less effect on osmolality per equal weighted dose than do the smaller alcohols. More importantly, if one looks for an osmolal gap after EG has been metabolized, there may no longer be a gap despite the presence of considerable amounts of ethylene glycol metabolites which are the significant poisons.

The presence of an anion gap may suggest significant ethylene glycol poisoning, but false-positive and false-negative results also occur. While one can miss an osmolal gap by looking for one too late in this poisoning, one can miss an anion gap by looking too early. The anion gap will remain normal for several hours until a sufficient amount of EG has been metabolized to toxic acids. Because bicarbonate begins to fall generally after 6 to 12 hours (later if EtOH is present), no anion gap may be present early in even potentially fatal cases. The reason that the bicarbonate failed to fall earlier in the case presented is that the presence of EtOH prevented metabolism of EG into organic acids during the period observed. Other causes of an elevated anion gap acidosis may mimic EG poisoning, such as diabetic ketoacidosis and alcoholic ketoacidosis.

In order to assess a possible EG exposure, CPCS recommends obtaining simultaneous measured and calculated osmolalities (for which electrolytes, BUN and EtOH will be needed), an ethylene glycol level, blood glucose, creatinine, calcium and arterial blood gases. Also occasionally useful is a urinalysis looking for calcium oxalate crystals. Since most antifreeze products contain fluorescein, a Wood's lamp exam of the oral cavity and urine may be helpful, although recent reports suggest a large number of false positive urine tests due to reflection from plastic urine containers or suspended material in the urine.


Treatment

Treatment goals include: 1) prevention of further metabolism of ethylene glycol via us of antidotes (ethyl alcohol or fomepizole), 2) removal of ethylene glycol from the blood using hemodialysis, 3) correction of metabolic acidosis via administration of sodium bicarbonate and use of dialysis, 4) correction of hypocalcemia, 5) co-factor therapy to enhance elimination of toxic metabolites of EG, and 6) aggressive supportive care including management of fluids, electrolytes, ventilation, and in severe cases, supportive therapy for acute renal failure.

The most difficult aspect of management of ethylene glycol exposures is that aggressive treatment must often be instituted before a blood level is available. The most common mistake made in management of these patients is in waiting for a blood EG level from the lab while the patient gets progressively worse without appropriate intervention.

Either ethyl alcohol or fomepizole can be useful antidotes. Both inhibit alcohol dehydrogenase, the first enzyme necessary in the metabolism of ethylene glycol. EG remains in the blood as the parent compound, but causes only mild CNS depression. No further toxic metabolites can be formed during proper antidote administration. Keep in mind, though, that significant amounts of toxic metabolites may already have accumulated by the time antidotal therapy is initiated, and urgent hemodialysis is still necessary in these cases. Specific information on the proper use of alcohol or fomepizole can be obtained from the California Poison Control System.

Hemodialysis accomplishes three immediate goals. It will correct metabolic acidosis, and reduce both ethylene glycol levels and the toxic EG metabolites. A reasonable endpoint for dialysis is correction of metabolic acidosis and reduction of EG level to less than 50 mg/dL. Generally speaking, four hours of hemodialysis is required to reduce the serum level by 50%. Multiple runs of dialysis are necessary when levels are high. For example, an ethylene glycol level of 300 mg/dL may require 3 four-hour runs to achieve reduction to less than 50 mg/dL. If advanced EG intoxication has occurred, acute renal failure may necessitate continuation of hemodialysis.

Metabolic acidosis should be aggressively corrected with sodium bicarbonate prior to dialysis. Extremely low serum bicarbonate levels and pCO2 may be found in these patients. Starting doses of 1-2 mEq/Kg are frequently necessary. In patients with very low pCO2, intubation and ventilation without either first correcting the low bicarbonate and/or subsequently hyperventilating the patient may result in a precipitous drop in pH.

Co-factor therapy with pyridoxine, 50 mg, IV or IM q 6 hours, and thiamine, 100 mg IM or (slow) IV q 6 hours, may enhance the elimination of toxic metabolites. This is generally of much less importance than the above treatments.

Hypocalcemia may be treated with either intravenous calcium chloride or calcium gluconate. Both are usually available as 10 ml vials of 10% solution. Keep in mind that the chloride salt yields approximately three times as much calcium per vial as the gluconate salt. Both should be injected into large bore veins only.


Discussion of case questions

This patient presented to the hospital with a high alcohol level, which served as an effective antidote. Although he was seriously poisoned, he did not develop signs of EG poisoning until many hours later, when his alcohol level had dropped. Similarly, using a falling bicarbonate level as indirect evidence of ethylene glycol poisoning will not work if sufficient "blocking" levels of alcohol are present. The diagnosis of EG poisoning was not made on the first ED visit because the wrong diagnostic end point was observed. This case demonstrates how the long lab turnaround time for EG can negatively impact management.


Consultation assistance

Consultation with a specialist in poison information or with a medical toxicologist can be obtained free of charge by calling the California Poison Control System at 1-800-411-8080.

This issue of CALL US... was written by Rick Geller, MD, MPH, FACMT.


CALL US... is published by the California Poison Control System. Editorial Board: Executive Director, Stuart E. Heard, PharmD; CPCS Medical Directors Timothy E. Albertson, MD, Richard Clark, MD, Richard Geller, MD, Kent R. Olson, MD; CPCS Managing Directors Judith Alsop, PharmD, Thomas E. Kearney, PharmD, Anthony Manoguerra, PharmD. Managing Editor: Susan Kim, PharmD

The California Poison Control System is operated by the School of Pharmacy, University of California, San Francisco.

 

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