Ethylene Glycol and Acute Kidney Injury
The Indonesian Ministry of Health reports that there were 208 cases of acute kidney injury in Indonesia in 20 provinces as of 18 October 2022. The death rate for these cases in Indonesia was 56.7 percent.
In July 2022, medical officials in Gambia detected a massive case of atypical acute kidney injury. Two months later, on 14 October 2022, the government of Gambia reported that 70 children had died of acute kidney injury.
In this case, the World Health Organization (WHO) conducted an investigation into the drugs used by the patients reported by the government of Gambia.
Based on the results of the investigation, WHO strongly suspects that the cause of acute kidney injury is ethylene glycol (EG) and diethylene glycol (DEG), which contaminate cough medicine in the form of syrup. WHO suspects that the cough medicine used by the patients contained solvents contaminated with EG and DEG.
WHO strongly suspects that the cause of acute kidney injury is ethylene glycol (EG) and diethylene glycol (DEG), which contaminate cough medicine in the form of syrup.
Some of the suspected cough medicines were imported from India produced by the pharmaceutical company Maiden Pharmaceutical Limited.
Cases of mass poisoning of EG and DEG have actually been recorded since 1937 in 18 countries. The earliest cases of poisoning occurred in the United States (1937), known as the Massengill incident, followed by cases recorded in South Africa, Spain, India, China and a number of other countries until the last occurred in Gambia in 2022.
Syrup medicine solvent contamination
The Indonesian Ministry of Health reports that there were 208 cases of acute kidney injury in Indonesia in 20 provinces as of 18 October 2022. The death rate for these cases in Indonesia was 56.7 percent. At Cipto Mangunkusumo Hospital, the death rate is reported to have been 65 percent. An epidemiologist proposed this outbreak of acute kidney injury as an extraordinary event (KLB) in Indonesia.
So far, many manufacturers of medicinal cough syrup use glycerin or propylene glycol as a solvent. The manufacture of these solvents for the pharmaceutical-grade category must be carried out with very strict supervision and must fully comply with current good manufacturing practices (cGMP) regulations.
The process of producing glycerin and propylene glycol that is not correct and not in accordance with cGMP can risk causing contamination, including EG and DEG contamination. This contaminated solvent, when used for the manufacture of drugs in the form of syrup, can cause fatal poisoning, especially for children under five.
The incident in Gambia is most likely due to the manufacturers not complying with the cGMP regulations and not performing a purification test on the solvent. The occurrence of cases of mass poisoning indicates that there has been contamination that exceeds the maximum tolerable limit, especially among children under five.
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In this context, WHO should be able to conduct a thorough and comprehensive investigation, starting from the manufacture of the solvent to where it is distributed, both in the Indian domestic market and for supply to the international market.
If the contaminated glycerin and propylene glycol were exported to many countries, cases of poisoning could be very widespread with a far greater number of casualties.
It is necessary to observe whether there are pharmaceutical manufacturing companies or importers of medicinal raw materials in Indonesia that import glycerin and propylene glycol from India, especially producers that rely on Maiden Pharmaceutical for their supply of syrup solvents.
In this context, it should be underlined that pharmaceutical manufacturing companies in Indonesia are required to test all materials before they are used in the production process. Even though these materials are imported with a Certificate of Analysis (CoA) and produced by suppliers who meet cGMP requirements, they are still required to carry out laboratory testing to ensure the quality and safety of the materials to be used.
Clinical manifestations of EG and DEG poisoning
Some parties state that cases of acute kidney injury that have occurred in Indonesia are not necessarily caused by the use of syrup preparations that are contaminated with EG and DEG.
According to them, it is possible that these incidents were caused by other unknown diseases. However, the Ministry of Health itself indicated that the patients did not have viral or other microbial infections. The clinical manifestations of patients with acute kidney injury are very similar to the clinical manifestations of EG and DEG poisoning.
EG or DEG exerts a central nervous system depressant effect that is very similar to that of ethanol. Its metabolites, namely glycolic acid and oxalic acid, can damage many organs, especially the kidneys.
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Calcium oxalate that precipitates in various tissues, especially kidney tissue, will cause acute kidney failure. Recent cases of acute kidney failure have been manifested by nausea, vomiting and decreased urine volume, even the inability to excrete urine.
Clinical manifestations, according to one doctor, occur rapidly within one to two hours after the patient ingested EG. Within four to 12 hours, dyspepsia, hypertension, loss of consciousness, coma, convulsions and oliguria occur, indicating acute kidney injury which can lead to death.
Intentional or unintentional use of EG greater than one milligram per kilogram of body weight (mg/kg) in children has the potential to result in death.
The Ministry of Health's conservative measures and the use of antidotes
The Indonesian Ministry of Health, with a view to saving children, took a conservative step, namely by temporarily banning the use of drugs in the form of syrups.
This prohibition is valid until there is clarity on the results of a thorough investigation of the problem of EG and DEG contamination in drug preparations in the form of syrup. In order to protect children from the dangers of acute kidney injury, this temporary ban may be justified as long as a thorough investigation is carried out.
Meanwhile, it was reported that to treat cases of acute kidney failure due to EG poisoning, the Ministry of Health will import an antidote from Singapore, namely an antizole injection containing fomepizole.
If hemodialysis must be done, will the hemodialysis be reversible or irreversible?
If the case is still in the early stages, this antidote may be very effective; but if the patient's condition is already severe, the results are certainly less than optimal.
According to the literature, for EG and DEG poisoning, a temporary antidote in the form of ethanol can be given to block the metabolism of EG into its toxic metabolites. The provision of ethanol was carried out before hemodialysis. Femeprizole can also be used as a temporary antidote before hemodialysis.
The question is: if hemodialysis must be done, will the hemodialysis be reversible or irreversible?
Sampurno
Sampurno
Director General of POM 1998-2001, Head of POM 2001-2006
This article was translated by Kurniawan Siswo.
