In a fictional case, three friends arrive together at the emergency department the morning after a party. They had bought a bottle of cheap spirits from an informal stall. The first is drowsy and breathing fast and deep. The second says he sees as if there were fog. The third is fine, just with a headache. The first one's blood gas shows severe metabolic acidosis with a high anion gap, and the on-call physician wonders whether the other two need the same treatment.

Methanol and ethylene glycol are toxic alcohols that kill through what the liver does with them. The first hour decides a lot: recognize the pattern, block the enzyme that generates the metabolites and call nephrology early. The World Health Organization (WHO) records methanol outbreaks in every region of the world, and so this reasoning belongs in any emergency department (WHO, 2014).

This text shows how to read the anion gap and the osmolal gap together, when to use fomepizole or ethanol, how to apply the criteria of the international EXTRIP group for hemodialysis and what outbreaks of adulterated drink teach about organizing care.

Key points

• Methanol and ethylene glycol have little toxicity of their own; the metabolites (formate, glycolate and oxalate) cause the acidosis, the blindness and the kidney injury (WHO, 2014; Ghannoum et al., 2023).
• At first, the osmolal gap rises and the anion gap is still normal; hours later, the osmolal gap falls and the anion gap rises, and a near-normal osmolal gap does not rule out the diagnosis (Ahmed et al., 2020).
• Fomepizole and ethanol block alcohol dehydrogenase; fomepizole has more than 8000 times greater affinity for the enzyme and has been on the WHO list of essential medicines since 2013 (Mégarbane, 2010; WHO, 2014).
• EXTRIP recommends hemodialysis in ethylene glycol poisoning with an anion gap above 27 mmol/L, glycolate above 12 mmol/L or coma, seizure and acute kidney injury (Ghannoum et al., 2023).
• In methanol poisoning, intermittent hemodialysis removed methanol and formate in half the time of continuous dialysis (Zakharov et al., 2014).
• In outbreaks of adulterated drink, lethality exceeded 20 percent in some episodes described by international teams (Rostrup et al., 2016).

Summary

• Why these alcohols are so dangerous
• The reasoning of the two gaps
• How each alcohol presents
• The antidote: fomepizole or ethanol
• Hemodialysis: when and how
• Outbreaks of adulterated drink
• How NEXO helps train this reasoning
• Frequently asked questions
• Take-home messages

Why these alcohols are so dangerous

The poison is in the metabolite

Methanol has relatively low toxicity of its own, but the body converts it into highly toxic compounds capable of causing blindness, coma and severe metabolic disturbances (WHO, 2014). Alcohol dehydrogenase converts methanol into formaldehyde, and aldehyde dehydrogenase converts it into formic acid, which accumulates because the body eliminates it slowly (Nekoukar et al., 2021).

The same happens with ethylene glycol. The original molecule has little toxicity, but glycolate produces the acidosis and calcium oxalate crystals deposited in tissues cause acute kidney injury and neurological complications (Ghannoum et al., 2023).

Where the patient finds these substances

Methanol is in varnishes, antifreezes, windshield cleaners and fuels, and the world uses about 225 million liters per day (WHO, 2014). Ethylene glycol appears mainly in coolants and de-icers (Ghannoum et al., 2023).

In outbreaks, the source is illicit alcohol, which a review divided into three types (Manning and Kowalska, 2021):

• Legal products diverted or counterfeited.
• Illegal beverages, produced and sold outside any control.
• Substitutes not intended for consumption, used as a drink.

A window of hours

The initial symptoms of methanol appear between half an hour and four hours and resemble drunkenness: nausea, vomiting, abdominal pain, confusion and drowsiness (Nekoukar et al., 2021). Then comes a latent period of 6 to 24 hours, and only then do decompensated acidosis and blurred vision appear (Nekoukar et al., 2021).

The WHO highlights that victims usually seek care late precisely because of this interval, and that the delay explains much of the deaths and sequelae in outbreaks (WHO, 2014).

The reasoning of the two gaps

Anion gap and metabolic acidosis

Metabolic acidosis with a high anion gap is the central finding of advanced poisoning. It results from the accumulation of formic acid in methanol and glycolate in ethylene glycol (Nekoukar et al., 2021; Ghannoum et al., 2023). A high anion gap, however, has many other causes, such as ketoacidosis, lactic acidosis, kidney failure and other toxins.

How to calculate the osmolar gap

The osmolar gap is the difference between the osmolality measured in the laboratory and the one calculated from sodium, glucose and urea. A common formula, in conventional units, is twice the sodium plus glucose divided by 18 plus urea nitrogen divided by 2.8; if there is ethanol in the blood, add ethanol divided by 3.7 (Ahmed et al., 2020). A gap above 10 mOsm/kg is usually considered high (Ahmed et al., 2020).

In a series of 260 samples from 158 patients, the osmolar gap had a strong linear relationship with measured methanol and ethylene glycol, but converting the gap into a concentration tended to overestimate the real value (Greene and Krasowski, 2020). Propylene glycol and acetone also raise the gap, so it suggests, but does not prove, a toxic alcohol.

Both gaps change over time

The most important point is the dynamics. Soon after ingestion, the alcohol is still intact in the blood: the osmolar gap rises and the anion gap may be normal. As the liver metabolizes it, the alcohol disappears and the acids appear: the osmolar gap falls and the anion gap rises.

One report describes an older man with ethylene glycol poisoning, acidosis with a high anion gap and an osmolar gap of only 12 mOsm/kg; the authors attributed the near-normal gap to the fact that the alcohol had already been metabolized (Ahmed et al., 2020). The practical lesson is that a normal osmolar gap does not rule out poisoning when the history is late.

This is the same reasoning as for any test: the result changes the probability, but it depends on the timing and the context. The post on pretest probability details this reading.

Laboratory clues that help

Besides the two gaps, some findings point to ethylene glycol (Ghannoum et al., 2023):

• Calcium oxalate crystals in the urine.
• Low serum calcium.
• Falsely high lactate on some devices, because glycolate interferes with the measurement.
• Acute kidney injury that appears hours after ingestion.

High lactate can lead to a mistaken diagnosis of shock or sepsis, and EXTRIP notes that the so-called lactate difference requires knowing the specific interference of each device (Ghannoum et al., 2023).

How each alcohol presents

Methanol: the eyes and the brain

Blurred vision with preserved consciousness is a strong clue to methanol (Nekoukar et al., 2021). Complaints range from blurred vision and photophobia to snowfield vision and blindness, and can appear up to 72 hours after ingestion (Nekoukar et al., 2021).

In a report of two outbreaks in Riyadh, visual impairment was the most common sequela, present in 58 percent of the patients evaluated by the ophthalmologist (Alhusain et al., 2024). Lesions in the basal ganglia, especially in the putamen, can leave parkinsonism (Nekoukar et al., 2021).

Ethylene glycol: the kidney

Ethylene glycol starts as intoxication and ataxia and, as it is metabolized, acidosis appears; then come acute kidney injury and neurological complications (Ghannoum et al., 2023). Delays of 6 to 12 hours between ingestion and treatment were associated with more complications in some studies, although others have not confirmed this finding (Ghannoum et al., 2023).

Who has a worse prognosis

In a Finnish cohort of severely ill patients on dialysis, 46 percent of those poisoned by methanol and 20 percent of those poisoned by ethylene glycol died within 90 days (Kuusela et al., 2022). A higher anion gap, lower pH and bicarbonate, a lower Glasgow scale and the need for mechanical ventilation on admission were associated with death (Kuusela et al., 2022).

The differential diagnosis

A drowsy patient with alcohol on the breath may have simple intoxication, but may also have head trauma, hypoglycemia, mixed intoxication or a toxic alcohol. The post about the patient who is just drunk shows how to avoid that label. Slow breathing with pinpoint pupils suggests an opioid, discussed in opioid overdose, and combined toxic agents are common. Building the differential diagnosis with clues helps keep these hypotheses open.

The antidote: fomepizole or ethanol

How the block works

Fomepizole and ethanol compete with the toxic alcohol for alcohol dehydrogenase and prevent the formation of metabolites (Ghannoum et al., 2023). Fomepizole has more than 8000 times greater affinity for the enzyme than ethanol and low toxicity (Mégarbane, 2010). It was first used in these poisonings in 1981 (Mégarbane, 2010), and the WHO added it to the list of essential medicines in 2013 (WHO, 2014).

With the enzyme blocked, the toxic alcohol no longer turns into acid, but it leaves the body very slowly. The half-life of ethylene glycol is longer with fomepizole than with ethanol (Ghannoum et al., 2023). That is where hemodialysis comes in: the antidote prevents damage, and dialysis removes the alcohol and the toxic metabolites already formed (Nekoukar et al., 2021).

What the evidence compares

A systematic review gathered 145 studies and 897 patients and found no randomized trial comparing the two antidotes (Beatty et al., 2013). Mortality with ethanol was 21.8 percent in methanol and 18.1 percent in ethylene glycol, and with fomepizole it was 17.1 percent and 4.1 percent, but the authors considered the data inconclusive for preferring one of the two (Beatty et al., 2013).

Practical advantages of each one

In practice, each option has strengths and weaknesses (Mégarbane, 2010; Ghannoum et al., 2023):

• Fomepizole reaches effective levels with the proposed regimen, with no need to measure the blood concentration.
• Fomepizole rarely causes nervous system depression, hypoglycemia, liver injury or pancreatitis, unlike ethanol.
• Ethanol requires measuring the blood concentration to keep the target and admission to a unit with closer monitoring.
• Both are removed by hemodialysis, and the dosage must be adjusted during the session, because the half-life of both falls to 1.5 to 3 hours.

Starting before confirmation

Measuring methanol and ethylene glycol takes hours or is not available in many hospitals. In a review of services with few resources, the authors report referral hospitals without the capacity to measure toxic alcohols, osmolality or chloride (Nekoukar et al., 2021). Therefore, a strong suspicion, with a compatible history and acidosis without another explanation, is enough to start the antidote.

Measures that accompany the antidote

Supportive treatment includes bicarbonate to correct acidosis, intubation when needed and folic or folinic acid in methanol, to speed up the elimination of formate (WHO, 2014; Nekoukar et al., 2021). In ethylene glycol, thiamine and pyridoxine are used to divert metabolism toward less toxic products, but their clinical usefulness has never been demonstrated (Ghannoum et al., 2023).

Hemodialysis: when and how

The EXTRIP criteria for ethylene glycol

EXTRIP is an international group of experts from several areas that reviews the evidence on extracorporeal treatments in poisonings (Ghannoum et al., 2023). For ethylene glycol, the 2023 review analyzed 226 articles and graded the quality of evidence as very low in all recommendations, which is expected in a topic without randomized trials.

Table: when to dialyze in ethylene glycol

Situation	Strength	Criterion	Source
Dialysis recommended	Strong	Coma, seizure or acute kidney injury	Ghannoum et al., 2023
Dialysis recommended	Strong	Glycolate above 12 mmol/L or anion gap above 27 mmol/L	Ghannoum et al., 2023
Dialysis suggested	Weak	Glycolate between 8 and 12 mmol/L or anion gap between 23 and 27 mmol/L	Ghannoum et al., 2023
Dialysis recommended with ethanol	Strong	Ethylene glycol above 50 mmol/L or osmolal gap above 50	Ghannoum et al., 2023
Dialysis suggested with fomepizole	Weak	Ethylene glycol above 50 mmol/L or osmolal gap above 50	Ghannoum et al., 2023
Dialysis recommended without antidote	Strong	Osmolal gap above 10	Ghannoum et al., 2023
When to stop	Strong	Anion gap below 18 mmol/L	Ghannoum et al., 2023
When to stop	Weak	Ethylene glycol below 4 mmol/L	Ghannoum et al., 2023

How to read the table

The table shows that the available antidote changes the indication. With fomepizole, a high ethylene glycol level without acidosis can be treated with the blockade alone, because the alcohol does not turn into acid; dialysis only shortens the hospital stay. With ethanol, the long blockade time brings more risks, and dialysis is recommended. Without an antidote, dialysis is the only way to prevent the formation of acids.

In the review, overall mortality was 18.7 percent, but it fell to 3.6 percent in the subgroup with glycolate up to 12 mmol/L or anion gap up to 28 mmol/L, and in that subgroup dialysis did not improve the outcome (Ghannoum et al., 2023). The time calculation also matters: with ethylene glycol above 50 mmol/L and a half-life of 14 hours under ethanol, the patient would need more than 48 hours of treatment to reach a safe level (Ghannoum et al., 2023).

And in methanol

In methanol, the indications cited in the review are persistent metabolic acidosis, with pH below 7.25 or anion gap above 30, and signs of organ damage, such as visual, neurological or renal changes (Nekoukar et al., 2021). With the antidote already started and no severe clinical signs, dialysis can be scheduled rather than done in a hurry (Nekoukar et al., 2021).

Intermittent or continuous

During an outbreak in the Czech Republic, the elimination half-life of methanol was 3.7 hours on intermittent hemodialysis and 8.1 hours on continuous dialysis; for formate it was 1.6 and 3.6 hours (Zakharov et al., 2014). In the same outbreak, mortality was higher in the continuous dialysis group (15 of 40 patients) than in the intermittent group (5 of 41), although the association did not hold after adjustment for severity (Zakharov et al., 2017).

For ethylene glycol, EXTRIP recommends intermittent hemodialysis and, when it is not available, continuous renal therapy (Ghannoum et al., 2023). If continuous therapy is the only option, higher blood and dialysate flows increase removal (Zakharov et al., 2014).

The antidote during the session

Dialysis removes fomepizole and ethanol, and the half-life of both during the session is between 1.5 and 3 hours (Ghannoum et al., 2023). If the dose is not increased, the enzyme starts working again and glycolate can rise during or after the session.

Outbreaks of adulterated drink

What the WHO describes

Methanol outbreaks arise when alcohol is added to illicit or informally produced drinks, and they can quickly overwhelm health services (WHO, 2014). The WHO cites recent outbreaks in countries in Asia, Africa, the Americas and Europe, with 20 to more than 800 victims and case fatality above 30 percent in some of them (WHO, 2014).

Illicit alcohol includes counterfeit products, homemade drinks and substitutes not intended for consumption, such as perfumes and cleaning products, and it is a global public health problem (Manning and Kowalska, 2021).

Examples of outbreaks

In Tripoli, more than a thousand people were poisoned in 2013, with a case fatality of 10 percent; in two outbreaks in Kenya in 2014, the fatality rate was 29 percent and 21 percent (Rostrup et al., 2016). The international team that responded concluded that basic training, simple protocols, bedside tests and rapid support are the measures with the most impact (Rostrup et al., 2016).

Ethylene glycol also causes outbreaks, by another route. In 2022, after a WHO alert about kidney injury linked to syrups contaminated with ethylene glycol and diethylene glycol, a pediatric team in Jakarta treated 19 children with fomepizole; 14 recovered and five died (Prawira et al., 2025).

How to organize the response

In an outbreak, individual reasoning becomes service organization. The sources point to a few principles:

1. Basic training of teams and simplified protocols (Rostrup et al., 2016).
2. Bedside tests and specialized support right from the start (Rostrup et al., 2016).
3. Use the available dialysis method, because, adjusted for severity, the outcome was similar between intermittent and continuous (Zakharov et al., 2017).
4. Public health campaigns about the risk of informal beverages, aimed at the most exposed groups (WHO, 2014).
5. National strategy and legal framework to reduce the harmful use of alcohol (WHO, 2014).

The post about chronic diseases in disasters discusses how to keep dialysis running when demand explodes.

Prevention and harm reduction

For individuals, the WHO recommends being wary of beverages sold in informal settings, at a very low price, in unlabeled containers or with a broken seal, and seeking immediate care if symptoms appear (WHO, 2014). The harm reduction approach helps get these messages across without pushing away people who drink, and the conversation must be genuinely understood, as the post about health literacy shows.

Back to the three friends

All three drank from the same batch, and the latent period of 6 to 24 hours explains why the third one is still well (Nekoukar et al., 2021). All three now receive the antidote, with blood gas analysis, osmolality, electrolytes, creatinine and alcohol levels when available. The first, with severe acidosis and a high anion gap, needs intermittent hemodialysis with adjustment of the antidote during the session. The second, with visual changes, has organ damage and should also undergo dialysis. The third stays under observation with the antidote and serial blood gas tests, and the team thinks about who else may have drunk from the same batch. Stopping before closing the case, as the post about the diagnostic pause describes, avoids sending home the friend who seemed well.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by searching for the ICD-10 code.

The limits of using the game are described on the NEXO economy page. If you research clinical reasoning teaching, the page for researchers explains how to get in touch. Professionals who write or review cases find information under curation and under creators, and institutions can learn about the proposal on the partnerships page. Searching for the right ICD-10 code completes this training.

Frequently asked questions

Does a normal osmolal gap rule out toxic alcohol poisoning?

That result alone is insufficient. If the patient arrives late, the alcohol has already been metabolized, and the osmolal gap may be nearly normal while the anion gap is high (Ahmed et al., 2020).

Is fomepizole better than ethanol?

Both block the same enzyme. Fomepizole is simpler to use and has fewer adverse effects (Mégarbane, 2010), but the available systematic review considered the data insufficient to claim superiority in mortality (Beatty et al., 2013).

Should I wait for the methanol level to treat?

The antidote should start with suspicion, because the level takes time or is not available in many hospitals (Nekoukar et al., 2021).

When is hemodialysis indicated in ethylene glycol poisoning?

With coma, seizure or acute kidney injury, glycolate above 12 mmol/L or anion gap above 27 mmol/L, among other EXTRIP criteria (Ghannoum et al., 2023).

Does continuous dialysis work?

It works when intermittent dialysis is unavailable, but it removes methanol and formate more slowly (Zakharov et al., 2014).

Why does everyone who drank from the same batch need attention?

Because of the latent period of 6 to 24 hours: someone who seems well may develop acidosis and vision loss hours later (Nekoukar et al., 2021).

Take-home messages

• Methanol and ethylene glycol kill through their metabolites; the time between ingestion and the antidote decides the prognosis (WHO, 2014).
• Read both gaps together and remember the dynamics: high osmolal gap early, high anion gap later.
• Blurred vision with preserved consciousness suggests methanol; oxalate crystals and kidney injury suggest ethylene glycol.
• Start fomepizole or ethanol on suspicion, without waiting for confirmation.
• Apply EXTRIP: significant acidosis, organ damage or a high level indicate hemodialysis, preferably intermittent.
• Adjust the antidote during dialysis.
• In an outbreak, think about everyone exposed to the same batch, use the available dialysis and simplify the protocols.

Milestone inventory

• 1981: fomepizole begins to be used in ethylene glycol and methanol poisonings (Mégarbane, 2010).
• 2013: the WHO includes fomepizole in the list of essential medicines (WHO, 2014).
• 2013: a systematic review compares ethanol and fomepizole and finds no randomized trials (Beatty et al., 2013).
• 2014: the WHO publishes an information note on methanol outbreaks, and a study measures the removal of methanol and formate by type of dialysis (WHO, 2014; Zakharov et al., 2014).
• 2016: international teams describe outbreaks in Libya and Kenya (Rostrup et al., 2016).
• 2023: EXTRIP publishes its recommendations for ethylene glycol (Ghannoum et al., 2023).
• 2025: report on the use of fomepizole in children after the outbreak of contaminated syrups (Prawira et al., 2025).

Play the case of the day on NEXO.

References

1. World Health Organization. Methanol poisoning outbreaks. Information note. Geneva: WHO; 2014. Full text.
2. Ghannoum M, Gosselin S, Hoffman RS, et al. Extracorporeal treatment for ethylene glycol poisoning: systematic review and recommendations from the EXTRIP workgroup. Crit Care. 2023;27(1):56. PMID 36765419. DOI 10.1186/s13054-022-04227-2.
3. Nekoukar Z, Zakariaei Z, Taghizadeh F, et al. Methanol poisoning as a new world challenge: A review. Ann Med Surg (Lond). 2021;66:102445. PMID 34141419. DOI 10.1016/j.amsu.2021.102445.
4. Rostrup M, Edwards JK, Abukalish M, et al. The Methanol Poisoning Outbreaks in Libya 2013 and Kenya 2014. PLoS One. 2016;11(3):e0152676. PMID 27030969. DOI 10.1371/journal.pone.0152676.
5. Zakharov S, Pelclova D, Navratil T, et al. Intermittent hemodialysis is superior to continuous veno-venous hemodialysis/hemodiafiltration to eliminate methanol and formate during treatment for methanol poisoning. Kidney Int. 2014;86(1):199-207. PMID 24621917. DOI 10.1038/ki.2014.60.
6. Zakharov S, Rulisek J, Nurieva O, et al. Intermittent versus continuous renal replacement therapy in acute methanol poisoning: comparison of clinical effectiveness in mass poisoning outbreaks. Ann Intensive Care. 2017;7(1):77. PMID 28730555. DOI 10.1186/s13613-017-0300-7.
7. Beatty L, Green R, Magee K, Zed P. A systematic review of ethanol and fomepizole use in toxic alcohol ingestions. Emerg Med Int. 2013;2013:638057. PMID 23431453. DOI 10.1155/2013/638057.
8. Mégarbane B. Treatment of patients with ethylene glycol or methanol poisoning: focus on fomepizole. Open Access Emerg Med. 2010;2:67-75. PMID 27147840. DOI 10.2147/OAEM.S5346.
9. Greene HR, Krasowski MD. Correlation of osmolal gap with measured concentrations of acetone, ethylene glycol, isopropanol, methanol, and propylene glycol in patients at an academic medical center. Toxicol Rep. 2020;7:81-88. PMID 31908969. DOI 10.1016/j.toxrep.2019.12.005.
10. Ahmed M, Janikowski C, Huda S, et al. Ethylene Glycol Poisoning with a Near-Normal Osmolal Gap: A Diagnostic Challenge. Cureus. 2020;12(12):e11937. PMID 33425517. DOI 10.7759/cureus.11937.
11. Kuusela E, Järvisalo MJ, Hellman T, et al. Mortality and associated risk factors in patients with severe methanol or ethylene glycol poisoning treated with dialysis: a retrospective cohort study. J Int Med Res. 2022;50(2):3000605221081427. PMID 35209742. DOI 10.1177/03000605221081427.
12. Alhusain F, Alshalhoub M, Homaid MB, et al. Clinical presentation and management of methanol poisoning outbreaks in Riyadh, Saudi Arabia: a retrospective analysis. BMC Emerg Med. 2024;24(1):64. PMID 38627622. DOI 10.1186/s12873-024-00976-1.
13. Prawira Y, Tartila T, Putri ND, et al. Lessons learned from the outbreak: the use of fomepizole in children with acute kidney injury due to ethylene glycol/diethylene glycol poisoning. BMC Pediatr. 2025;25(1):748. PMID 41039271. DOI 10.1186/s12887-025-06107-4.
14. Manning L, Kowalska A. Illicit Alcohol: Public Health Risk of Methanol Poisoning and Policy Mitigation Strategies. Foods. 2021;10(7):1625. PMID 34359495. DOI 10.3390/foods10071625.