Acute renal failure in children can have a variety of causes. There have been several epidemics of acute renal failure affecting predominantly young children where the cause has been diethylene glycol (DEG) poisoning. These children have presented with gastrointestinal bleeding, seizures and liver failure as well as renal failure. The poisoning has been the result of either contamination of the medicinal products by DEG or the deliberate illegal use of DEG as a solvent. More than 300 children worldwide have died from DEG poisoning. Health professionals need to be aware of the clinical presentation of DEG poisoning as prompt action is likely to save lives by the removal of the contaminated/illegal medicine from pharmacies and shops in the affected area.
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There have been several epidemics where predominantly young children have presented with an acute onset of renal failure.1,–,5 Incidents of mass poisoning with diethylene glycol (DEG) have occurred in a number of countries over the last 20 years, with more than 300 children having died as a consequence. These deaths have occurred in separate incidents in different countries from three continents.1,–,5 The deaths were the result of either contamination1 2 5 of medicinal products by DEG or deliberate illegal use of DEG as a solvent for a medicinal product.3 4 Symptoms of DEG poisoning include renal and liver failure, seizures and gastrointestinal bleeding. Outbreaks of unexplained renal failure should raise a particular concern. Early recognition of DEG poisoning within the community is likely to prevent further deaths by the removal of the contaminated/illegal medicines.
What is DEG?
DEG consists of two ethylene glycol molecules joined by an ether bond. Although first produced in France in 1869, commercial production did not begin until 1928. It proved useful in a variety of industrial settings as an excellent solvent or ingredient in consumer products including antifreeze, brake fluids, lubricants, cosmetic creams, inks, dyeing agents and binding adhesive.6 It has also been used as a softening agent for textiles, paper and packaging materials. It unfortunately has a sweet taste which makes it appealing to children.
What effect does DEG have on the body?
Information obtained over the past few decades has demonstrated that DEG is a powerful nephrotoxic and neurotoxic poison.6 7 There are some uncertainties regarding the principal cause of renal toxicity and neurological effects in DEG poisoning. Some people have raised concern that renal toxicity may be induced by the parent compound, but others think that toxic effects are related to the metabolites. DEG is converted to 2-hydroxyethoxyacetic acid via oxidation by alcohol dehydrogenase.
The minimum lethal dose of DEG in humans is uncertain. There appears to be a wide range in relation to toxicity. Analysis of the data from the outbreak in Haiti suggested that the minimum lethal dose was 0.35 mg/kg2. An outbreak that occurred in Argentina involving adults (age range 50–93 years) suggested that the minimal lethal dose in adults is likely to be between 0.014 mg/kg and 0.17 mg/kg.7
Clinical signs and symptoms
Most victims of DEG poisoning have a variety of clinical signs and symptoms depending on the amount and duration of the exposure. During the first period of ingestion, intoxicants stimulate gastrointestinal discomfort, which usually begins with nausea, vomiting, diarrhoea, abdominal pain and bleeding. Other later symptoms include oliguria, anuria, metabolic acidosis, liver failure, seizures and acute renal failure (table 1).
Previous episodes of DEG poisoning
The first reported episode of poisoning in association with the use of DEG in a medicine was in 1938.8 DEG was used as a solvent in the preparation of sulphanilamide elixir. The makers of the product were unaware of the toxicity of DEG. It is estimated that there were 105 deaths of which one-third were children.8 Following this episode, legislation was introduced in the USA that required formulations of new medicines to be tested for safety. Since then there have been numerous other reported cases of DEG poisoning. These have followed either the use of DEG as a solvent3 4 8,–,11 (table 2) or the contamination of either a medicinal product or a constituent of the medicinal product1 2 5 7 12,–,16 (table 3). The number of deaths per outbreak has ranged from 5 to over 200.
The time to recognise that the outbreak was associated with DEG poisoning has been a major contributing factor to the number of deaths—that is, the sooner there is recognition that this is DEG poisoning, the fewer the number of deaths. Unfortunately, even prompt recognition, as in Nigeria recently, following the use of a teething formula that was contaminated with DEG, can still be associated with a large number of deaths.1 16 This particular incident was probably associated with a high death rate (84 children died) because of the young age of the patients exposed to the contaminated medicinal product. There have been cases of contamination of toothpaste affecting adults in both the USA and Spain.17 18 Fortunately there were no deaths.
Why does DEG poisoning occur?
All medicines contain a variety of excipients and solvents alongside the active drug; this is to make the medicine palatable or soluble. No major pharmaceutical company would deliberately use DEG as a solvent because they are aware of its toxicity. Unfortunately the financial profit from medicines is huge and because of this there is a proliferation of smaller manufacturers who will cut corners to maximise profits. Counterfeit drugs have become a major problem in low and lower-middle income countries with estimates of one in four medicines thought to be counterfeit. This may result in toxicity, as in the cases highlighted in this paper, or a lack of efficacy, as on many occasions the counterfeit drug does not actually contain the active substance.19 20 In many cases, the individual/company responsible for the use of DEG as a solvent is not identified. Judiciary investigations in China identified the pharmaceutical company that deliberately used DEG as a solvent.11 Five individuals from the company were subsequently jailed for between 4 and 7 years and the deputy director of the Food and Drug Administration of the region was sacked for negligence.21
Can we prevent future episodes?
The World Health Organization has recognised the importance of ensuring that medicines are prepared safely. They have established WHO Good Manufacturing Practice Guidelines and also established a certification scheme to ensure the quality of pharmaceutical preparations sold in international markets.1 These efforts will help to improve the quality of medicines available especially within low and lower-middle income countries. It is essential that the Departments of Health and national regulatory agencies support these efforts.
When to suspect DEG poisoning
Despite the numerous deaths that have occurred in children as a result of DEG poisoning, the vast majority of health professionals worldwide will fortunately never see a case. The key issue, however, is for health professionals who see more than one case of acute unexplained renal failure in children to be aware that DEG poisoning is a possibility. It is established that adverse drug reactions are often not recognised.22 The lack of awareness of possible drug toxicity is even greater in relation to the toxicity of excipients.23 Additionally, the signs and symptoms in association with DEG poisoning (table 1) are extremely diverse. Rare causes of acute renal failure such as primary hyperoxaluria may affect a single individual but will not result in an outbreak. Doctors and pharmacists involved in renal units alongside those involved in public health, however, should be aware of the possibility of DEG poisoning, especially if they work in low and middle-income countries.
Case reports of young children ingesting poisons such as brake fluid which contains DEG, have however highlighted the possibilities of enhancing the clearance of DEG.24 This case report alongside others25 has suggested the use of fomepizole, which is an alcohol dehydrogenase inhibitor that can be administered intravenously.24 25 Fomepizole (4-methylpyrazole) is increasingly being used in adults and children following poisoning with methanol or ethylene glycol.26 It has minimal toxicity and a dose of 15 mg/kg is recommended over a 30-minute period. A further 10 mg/kg can be administered at 12-hour intervals.26 27
In the case report involving a child,24 haemodialysis was used and this was associated with a fall in the plasma concentration of DEG. If concurrent haemodialysis is used then the fomepizole can be administered over 4 hours.26 These two case reports were associated with a good clinical outcome but hospitals in communities where poisoning usually occurs are extremely unlikely to be able to cope with an outbreak involving large numbers of children experiencing acute renal failure. DEG poisoning unfortunately usually occurs in those communities with the poorest access to healthcare. If available, fomepizole and haemodialysis are the treatment of choice for children with acute renal failure. Options that are more likely to be available in low-income countries include peritoneal dialysis and oral ethanol (0.8–1.0 ml/kg loading dose followed by 0.15 ml/kg/h of 95% ethanol diluted in orange juice).28 Ethanol, although cheaper, is more toxic than fomepizole and is often not available.29 30
More than 300 children worldwide have died from DEG poisoning. With the increase in proliferation of counterfeit medicines, DEG poisoning unfortunately is likely to occur again. The clinical symptoms of the children affected are quite diverse but include gastrointestinal bleeding and seizures, as well as acute renal failure and liver failure. The sudden outbreak of an epidemic of acute renal failure in children should make individuals consider the possibility of DEG poisoning as a cause of the outbreak.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.