Ingestion of toxic alcohols such as methanol and ethylene glycol is uncommon, but not rare, in the UK and US. These substances are found in all sorts of household and industrial products, including antifreeze, paint strippers, coolants, and cosmetics. Historically, methanol was a common finding in illicitly distilled (“moonshine”) spirits. Exposure to toxic alcohols can occur accidentally, and there have been several recent outbreaks of contaminated drinks — including a tragic methanol incident in Laos this year. However, these compounds are usually consumed intentionally to achieve inebriation or suicide.
This is the third in a series of blog posts on new research in emergency toxicology. The last post was about GLP-1A toxicity (think Ozempic® and Wegovy®) and can be found here. We deal with all sorts of poisons here in Virchester, so be prepared for anything.
Once swallowed, toxic alcohols are rapidly absorbed in the stomach and small intestine. Intoxication follows as they enter the bloodstream, causing a level of drunkenness out of proportion to what would be expected with ethanol. Coma, respiratory depression, and haemodynamic instability are common. A characteristic finding in the initial hours after ingestion is an unexplained osmolar gap — i.e. a large difference between the sum of measured osmolytes (sodium, potassium, glucose, urea) and the total plasma osmolality, which includes osmolytes not measured in routine blood tests.
There is no antidote for intoxication with ethylene glycol or methanol. Care at this stage is supportive only. However, specific treatments can be provided to prevent the secondary injury associated with their metabolites. Roughly four hours after ingestion, ethylene glycol is broken down by the liver to form compounds including glycolic acid and oxalic acid. These cause metabolic acidosis and renal tubular necrosis, respectively. Methanol is metabolised more slowly (~6 hours) to formic acid — the same substance in ant venom! — which also causes acidosis, but is additionally associated with retinal injury or “moonshine blindness.” These reactions all require the enzyme alcohol dehydrogenase.
There are two treatments currently recommended by the National Poisons Information Service (NPIS) to prevent toxic metabolite formation. One of them is ethanol, which for many years was the only option for these patients. Ethanol binds to alcohol dehydrogenase with very high affinity, diverting the enzyme to produce less harmful metabolites — mainly acetaldehyde, which is the compound responsible for hangovers. The advantage of ethanol is that it is widely available, and can be given enterally in the form of whiskey, vodka, or any other high-concentration drink. The disadvantage is that the patient has to be kept drunk until the toxic alcohols are out of their system, which can take days. A lot of monitoring and dose-adjustment is required to make this work, and this is generally not possible outside of critical care.
The preferred treatment is fomepizole, which is a direct alcohol dehydrogenase inhibitor. Fomepizole has high oral bioavailability but is typically administered intravenously. The dosing is straightforward, and no special monitoring is required. Good outcomes have been achieved with fomepizole in two trials and a large prospective study. For patients with ethylene glycol poisoning, there is evidence that its use may prevent renal injury both in the acute setting and after hospital discharge. This is because when therapeutic blood concentrations of fomepizole are achieved, the elimination of toxic alcohols can only occur through renal excretion. No nephrotoxic metabolites are formed. The poison just circulates around, causing inebriation but not much else. Patients treated early with fomepizole in this way have avoided haemodialysis.
Drawing all this together: it is clear that there is a window of opportunity in toxic alcohol poisoning for emergency clinicians to give fomepizole early and make a huge difference to the prognosis. The problem lies in diagnosis. As summarised in a recent REBEL EM podcast these patients may not be able or willing to tell us what they have taken. Blood and urine can be tested for toxic alcohols, but the samples are rarely processed on-site, and results are unlikely to be available early enough to make a difference on the shop floor. Starting treatment requires a clinical decision, and there is usually some uncertainty about the exposure. In a recent French study of 536 patients prescribed fomepizole, a high proportion were found to have trace (27%) or zero (21%) toxic alcohols in their blood or urine.
To make informed decisions in this context, emergency clinicians need to know about the adverse effects of fomepizole — and how these stack up against the risks of “missing the window” with toxic alcohols. Fortunately, a study was published on this exact topic earlier this year in Expert Opinion On Drug Safety.
Abstract
Background: Fomepizole is a competitive alcohol dehydrogenase inhibitor used for the treatment of ethylene glycol and methanol poisoning. We evaluated the safety and effectiveness of fomepizole in patients with ethylene glycol or methanol poisoning in Japan.
Yoshioka T, Koyanagi M, Yoshida N. Real-world safety and effectiveness of intravenous fomepizole in patients with ethylene glycol and methanol poisoning in Japan: results of a 7-year post-marketing surveillance study. Expert Opin Drug Saf. 2024 Jul 22:1-9. doi: 10.1080/14740338.2024.2372410. Epub ahead of print. PMID: 38932699.
Research design and methods: This retrospective post-marketing surveillance study conducted in Japan registered patients who received fomepizole intravenous infusion per the package insert (January 2015-June 2022). Endpoints included adverse drug reactions/infections (ADRs), arterial blood pH, and treatment outcomes.
Results: Of 147 patients registered (91 institutions), 131 and 126 were included in the safety and effectiveness analysis sets, respectively. Mean age was 43.6 years, and 66.4% were male. Mean time from poison ingestion to treatment was 15.1 hours; 66.4% received concomitant hemodialysis. No serious ADRs were reported. ADRs were reported in seven patients; the most-reported ADR was vomiting (2.3%). Seven patients died, 105 survived without sequelae, and 19 survived with sequelae. Most common sequelae were renal failure or renal dysfunction. Mean arterial blood pH increased to 7.4 by 4 hours of treatment, remaining stable for 24 hours post-treatment.
Conclusions: Fomepizole is well tolerated and helps improve clinical outcomes in patients with ethylene glycol or methanol poisoning in Japan.
Trial registration: Japanese Pharmaceutical Information Center (JapicCTI-152817).
What kind of study are we looking at?
This was a post-marketing surveillance study conducted by the Japanese Poison Information Service (JPIC) over seven years (2015-2022) at 91 hospitals in Japan.
Post-marketing surveillance studies collect data on the use of approved (“post-market”) medications to determine their safety in everyday clinical use. They are particularly important when drugs have been tested in trials with small samples, or samples that are non-representative of the wider population. This is true of fomepizole, which, since its development, has been tested in only two clinical trials for ethylene glycol (n=19) and methanol (n=11) poisoning.
The researchers in this study used a survey design. It is described as a retrospective methodology in the published paper, but I am not sure that this is entirely correct. When a patient at one of these centres was given fomepizole, a local investigator filled out an enrollment form contained in the product packaging and sent it to the research team. They then completed the study survey, detailing the patient’s clinical course from fomepizole initiation to the study end-point. The end-point could be death, hospital discharge, or transfer to another department. The authors specify that local investigators had up to a month to return their survey after the study end-point, but do not state how many investigators collected data contemporaneously.
Can you tell me about the patients?
Enrollment forms were submitted for 147 patients. However, sixteen were excluded because the survey was not done or incomplete.
The final sample included 131 patients. Most had confirmed toxic alcohol poisoning with either methanol (n=65) or ethylene glycol (n=35). The remainder had “suspected” exposures only.
Two-thirds of the sample were male, and most were middle-aged. Sadly, the most common reason provided for ingestion (67.2%) was suicide.
What outcome measures were used?
The key safety outcome was the incidence of adverse drug reactions, which were defined as “all [adverse events] except those with a causal relationship of ‘not related’ to fomepizole as assessed by he investigator.’
Adverse drug reactions were divided into serious and non-serious according to the Japanese version of the Medical Dictionary for Regulatory Activities (MEDRA). Among reactions classified as ‘serious’ were death, hospitalisation, and permanent damage to health.
The survey also collected information on adverse events that were not considered to be related to fomepizole. These included mortality, requirement for organ support, and long-term sequelae.
What were the main results?
This was a sick group of patients. Seven (5.3%) died, and a high proportion required renal replacement therapy (66.4%) or ventilatory support (37.4%). Nineteen (14.5%) sustained long-term injury from their poisoning, including renal impairment (n=9).
Eleven adverse drug reactions occurred with use of fomepizole. None of them were classified as serious according to MEDRA criteria. The reactions included vomiting (n=3), abdominal pain (n=1), nausea (n=1), hypotension (n=1), hypoglycaemia (n=1), hyponatraemia (n=1), fever (n=1), abnormal liver function tests (n=1) and creatinine rise (n=1).
None of these reactions caused clinicians to stop fomepizole.
What should we take away from this study?
Overall, this is a helpful study. The findings suggest that it is safe to trial fomepizole in uncertain cases because the drug is unlikely to cause much harm to patients diagnosed in error. The mild side effects described here — and in other surveillance studies — are clearly outweighed by the potential benefits of intervening early in toxic alcohol poisoning. This is not always the case in emergency medicine. Think about pulmonary embolism, for example the diagnosis is frequently uncertain, and the treatment we give in suspected cases is associated with significant bleeding risk.
There are a few methodological issues to consider. The first is that this is, more or less, a retrospective study. It is not clear how many clinicians completed their survey contemporaneously, but the impression I get is that the majority submitted their data after the study end-point had been reached. This means that the findings are subject to the usual problems that come with retrospective studies — namely, recall bias and chart incompletion. Adverse reactions may have been missed that would have been picked up in a prospective cohort study, although it is worth noting that nothing additional was found in an earlier cohort study conducted by NPIS.
The second drawback to this study, in my view, is the nature of the sample. From a toxicological perspective, these patients are brilliant, as most of them are confirmed cases of ethylene glycol and methanol poisoning. But as an emergency physician, I would rather see a broader sample, including patients who were misdiagnosed. I am interested in the risks I might create if I am wrong about what someone has ingested. There is a theoretical concern that administering fomepizole to patients with ethanol or isopropyl alcohol (rubbing alcohol) toxicity will prolong the time to elimination and cause harm to the patient. No study, to date, has put this to the test.
Should this study change our practice?
The current guidance from NPIS is for emergency clinicians to administer fomepizole as soon as possible if the patient is believed to have swallowed a significant volume of toxic alcohol, has a raised anion gap, or has evidence of metabolite formation. The findings of this study support an aggressive treatment strategy. They also provide further evidence that some of these patients can be treated safely outside of critical care settings.
If you are interested in learning more about toxic alcohol poisoning, I recommend this EMCRIT article written on the topic.
Greg Yates
References.
- Yoshioka T, Koyanagi M, Yoshida N. Real-world safety and effectiveness of intravenous fomepizole in patients with ethylene glycol and methanol poisoning in Japan: results of a 7-year post-marketing surveillance study. Expert Opin Drug Saf. 2024 Jul 22:1-9. doi: 10.1080/14740338.2024.2372410. Epub ahead of print. PMID: 38932699.
- Josh Farkas. Ethylene glycol & methanol poisoning. https://emcrit.org/ibcc/alcohols/
