Diethylene glycol (DEG) is a clear, colorless, odorless liquid with a sweet taste, and is an excellent solvent for water-insoluble chemicals and drugs. DEG is used as a component of multiple different products including antifreeze preparations, cosmetics, lubricants, brake fluids, wallpaper strippers, heating/cooling fuel and as a plasticizer. DEG has also been inappropriately substituted in pharmaceutical preparations for nontoxic constituents, resulting in more than a dozen epidemics of human poisoning, with resultant high mortality rates. The hallmark of DEG toxicity is acute renal failure, and deaths have been reported despite aggressive treatment with hemodialysis.
A 55 year-old male presented to a local emergency department in Panama with abdominal pain, vomiting and diarrhea. He had been using an prescription cough syrup in the preceding days to treat a viral illness. He was admitted to the hospital for intravenous fluids and supportive care. 24 hours after his initial presentation, the patient developed an anion gap metabolic acidosis and acute anuric renal failure with a serum creatinine of 11 mg/dL. Hemodialysis was instituted, however his renal function did not return and a week into his hospitalization, he developed flaccid extremity weakness and bilateral facial weakness. Despite continued dialysis and supportive care, the patient died 12 days after initial presentation. Further analysis of the cough syrup revealed it contained 8% DEG.
1) What is the typical clinical presentation of DEG poisoning?
2) How is DEG poisoning treated?
The majority of documented cases of DEG poisoning have been epidemics where DEG was substituted in pharmaceutical preparations for the more expensive, but nontoxic glycols or glycerins. These safe diluents have different manufacturing methods and DEG is not a byproduct, therefore simple errors of cross-contamination cannot account for the substitution of DEG in pharmaceuticals. The first mass poisoning was the sulfanilamide-Massengil disaster in the United States in 1937. DEG was used as a solvent in the elixir of sulfanilamide, an antibiotic. Shortly after it was distributed across the United States, reports of deaths emerged. There were over 100 deaths, a third were children. No toxicology testing had been conducted on either the ingredients or the finished product prior to marketing. This catastrophe lead to the passage of the 1948 Federal Food, Drug and Cosmetic Act, which requires drug manufacturers to demonstrate safety of the product prior to marketing.
There have subsequently been a dozen additional epidemics involving numerous cases, and many deaths, often despite aggressive treatment. Most of these epidemics have occurred in developing countries with limited access to medical care, inadequate adherence to safe manufacturing practices, and at times what appears to be intentionally deceptive drug manufacturing practices. DEG has also appeared in consumer products other than medications. An Austrian wine was found to be adulterated with DEG to give it a sweeter taste resulting in at least one case of renal failure. A toothpaste imported from China and sold in multiple countries including the United States, was recalled due to DEG contamination. No serious illnesses were reported from the toothpaste.
There is limited data regarding DEG and most information is derived from published experimental studies. DEG is readily absorbed orally. Dermal absorption has been reported through damaged skin involving a large surface area. In 1985, 5 patients being treated for burns in Spain developed renal failure and died from contaminated topical silver sulfadiazine ointment. DEG is metabolized in the liver via the same NAD-dependent pathway as ethanol and other toxic alcohols. DEG is oxidized to 2-hydroxyethoxyacetaldehyde by NAD-dependent alcohol dehydrogenase, and then further metabolized to 2-hydroxyethoxyacetic acid (HEAA) by aldehyde dehydrogenase. DEG and its metabolites are renally excreted.
The precise mechanisms of DEG toxicity are not fully known. Since DEG consists of two linked ethylene glycol molecules, it was originally thought that metabolism to ethylene glycol was responsible for toxicity. However studies have shown that metabolism to significant amounts of ethylene glycol does not occur, and that the type of renal toxicity seen with DEG is different than what is seen with ethylene glycol. Further studies have demonstrated that the major metabolite of DEG, HEAA, is the major contributor to toxicity, and there may be other metabolites involved.
The minimum dose needed to cause toxicity is not known. Dosage information available is based on retrospective analysis of the mass poisonings where patients were getting multiple doses over varying time periods. There is considerable overlap between non-fatal reported doses and fatal doses. Estimates of a typical human lethal dose are about 1mg/kg, however given the uncertainties regarding toxic doses, any ingestion would be best assessed by evaluation at a health-care facility.
The clinical effects of DEG can be divided into three intervals. The first phase typically involves gastrointestinal effects such as nausea, vomiting, abdominal pain and diarrhea. Patients may be inebriated and mild hypotension has been reported. Patients may have an abnormal osmolal gap and develop an anion gap metabolic acidosis. The onset of symptoms can develop soon after ingestion, or can be delayed depending on the amount ingested and co-ingestants (such as ethanol). Small ingestions may result in resolution of symptoms without further sequelae.
Progression to the second phase occurs 1-3 days following exposure and also depends on the amount ingested. The hallmark of the second phase is acute renal failure. If left untreated, patients may die within a week after the onset of anuria. Additionally, mild to moderate hepatotoxicity is often seen. Multiple other effects have been reported including cardiac dysrhythmias and pancreatitis, which may be secondary to the metabolic acidosis and renal failure.
The degree of renal injury predicts the severity of the third phase of this poisoning, which are neurologic complications. These effects can be delayed until 1-2 weeks post-ingestion. Multiple varying neurologic sequelae have been described. Peripheral neuropathies are a common occurrence. Cranial nerve abnormalities have been reported including bilateral facial paralysis. Widespread denervation of limb muscles has been demonstrated; patients may become quadraparetic and unresponsive. The clinical coarse during this phase is unpredictable with long-term recovery in some patients, and permanent neurologic damage with death in others.
Measurement of a serum DEG concentration is the most accurate means of diagnosing poisoning, however this test is not readily available at most hospitals. Therefore the diagnosis of DEG poisoning is often presumed based on the patientís history, clinical presentation and laboratory abnormalities. If there is no clear history of ingestion, the diagnosis is difficult to make. Like other toxic alcohol ingestions, the osmolal gap may be a helpful diagnostic test. However, the absence of an increased osmolal gap does not exclude DEG poisoning, especially considering DEG has a large molecular weight and contributes less to an osmolal gap.
As DEG is metabolized to its toxic metabolites, an elevated osmolal gap will return to normal and there will be an increasing anion gap. The metabolic acidosis that develops may be mild, or severe, and is usually present at 24h post-ingestion.
Both the osmolal gap and the anion gap are important diagnostic clues that support a diagnosis of DEG, but the absence of these laboratory abnormalities does not exclude the diagnosis of DEG exposure. A presumptive diagnosis of DEG poisoning should be considered if an elevated anion gap metabolic acidosis or an elevated osmolal gap is present and there is a history or suspicion of ingestion.
Management in the emergency department should be focused on initial stabilization with priorities given to monitoring and correcting acid-base status, serum electrolytes and fluid balance. Decontamination with activated charcoal is not recommended as it has a low binding affinity for alcohols in general. Since the metabolites of DEG are predominantly responsible for the renal toxicity, the use of antidotes to reduce the conversion to toxic metabolizes is recommended. Fomepizole is the preferred agent of choice. The dosing regimen includes a loading dose of 15mg/kg diluted in 100mL of normal saline or 5% dextrose in water, administered IV over 30 minutes; followed by maintenance dosing of 10mg/kg every 12 hours until the patient is asymptomatic with a normal pH. If the patient is getting hemodialysis, fomepizole should be given every 4 hours during dialysis. If fomepizole in not available, ethanol can be considered and should be given at an infusion rate to target a blood ethanol concentration of 100-150 mg/dL (22-33 mmol/L). As ethanol is also dialyzable, the infusion rates typically must be increased two to three-fold to maintain the target serum concentration.
There is limited information about the use of hemodialysis following DEG intoxication. However it is used successfully for both methanol and ethylene glycol toxicity and based on the properties of DEG, it is predicted to be helpful. Hemodialysis should be considered following poisoning, especially in more critical patients presenting late. There is no treatment available for the delayed neurologic sequelae. Reported mortality rates following epidemic poisoning have been high, despite aggressive management.
Discussion of case questions
1) There are three phases of DEG poisoning. The first phase is characterized by GI symptoms, inebriation and the development of a metabolic acidosis. The second phase is characterized by renal failure. In the third phase, patients develop a variety of neurologic complications. The mortality rate remains high despite aggressive therapy.
2) Treatment consists of 1) supportive therapy 2) fomepizole or ethanol to block the conversion of DEG to its toxic metabolites and 3) hemodialysis to remove DEG and metabolites, correct acid-base disturbances, and support renal function.
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 1-800-222-1222.
This issue of CALL US... was written by Alicia Minns, MD
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 F. Clark, MD, Richard Geller, MD, Kent R. Olson, MD; CPCS Managing Directors: Judith Alsop, PharmD, Thomas E. Kearney, PharmD, Lee Cantrell, PharmD; Editor:Binh T. Ly, MD; Assistant Editor: Alicia Minns, MD.
The California Poison Control System is operated by the School of Pharmacy, University of California, San Francisco (coadmin @calpoison.org)