Methanol Toxicity

Etiology

Methanol toxicity can occur via ingestion, dermal absorption, and inhalation. The most common reported ingestions are secondary to drinking windshield washer fluid as a suicide attempt. Accidental ingestions can occur via exploratory behavior in children. Methanol has also been abused as a substitute for ethanol with agents such as food-warming fuel, and carburetor cleaner as a source of abuse via inhalation.[4]

Epidemiology

Individuals at risk include toddlers and young children exploring their environment, alcoholics, and suicidal individuals. Most cases are isolated incidents; however, epidemics have occurred secondary to tainted ethanol and improper distilling.[5]

Pathophysiology

When ingested, methanol is absorbed rapidly via the gastrointestinal tract in less than 10 minutes. Methanol is not protein-bound and is absorbed directly into the total body water compartment with a volume of distribution of approximately 0.7 L/kg. Serum concentrations peak immediately after absorption and follow a zero-order elimination rate. Metabolism occurs mainly in the liver through serial oxidation via alcohol dehydrogenase and aldehyde dehydrogenase but begins with alcohol dehydrogenase present in the gastric mucosa. Alcohol dehydrogenase oxidizes methanol to formaldehyde, and aldehyde dehydrogenase subsequently oxidizes formaldehyde to formic acid. Each of these two oxidation steps is associated with a reduction of NAD to NADH. This enzymatic metabolism provides a zero-order elimination rate of about 8 to 9 mg/dL/h when methanol concentration is between 100 and 200 mg/dL. Formic acid is not easily eliminated and mostly accumulates, while a small amount in its unprotonated form, formate, interacts with folate to create carbon dioxide and water for exhalation. Unmetabolized methanol is not sufficiently cleared through the kidneys or the lungs and has an effective half-life of about 30 to 85 hours.[6]

Toxicokinetics

A potentially lethal dose of methanol is approximately 30 to 240 mL or 1 gram per kilogram. Permanent visual damage may occur with minimum ingestion of 30 mL of methanol. The parent compound, methanol, accounts for the increased osmolality. Unlike most other alcohols, methanol itself is not inebriating, and this may be related to its lower molecular weight. Formic acid is the primary toxic metabolite that accounts for the associated anion gap metabolic acidosis and end-organ damage. Therefore, as methanol is metabolized, the osmolar gap decreases, and the anion gap increases. The development of an anion gap metabolic acidosis associated with formate accumulation is multifactorial, due to the accumulation of organic acids that are not easily eliminated (for example, formic acid and formate), and the disruption of oxidative phosphorylation due to formate’s inhibition of cytochrome oxidase. Formate’s hindrance of mitochondrial respiration can also cause a degree of lactatemia, which can enhance formate’s ability to cross the blood-brain barrier as formic acid. Lactate is also elevated secondary to enhanced shunting of pyruvate to lactate from the increased NADH/NAD ratio associated with alcohol metabolism. End organ damage and retinal toxicity are primarily due to formic acid’s oxidative stress.  Also reported is parkinsonian-like symptomatology associated with observed basal ganglia lesions, particularly in the putamen and globus pallidus. This is potentially due to the parent compound, methanol.

History and Physical

History is often challenging to acquire in an intentional, self-harm attempt or substance abuse scenario and physical exam can often be normal in early ingestions. Many patients may be embarrassed or may not want to admit to their actions. It is also common for patients to underestimate the magnitude and severity of their ingestion. Accidental ingestions, however, are often self-reported or witnessed. Many times, there is a diagnostic dilemma, and it is up to the clinician to consider toxic alcohol exposure as an etiology for a finding such as metabolic acidosis with an elevated anion gap.

Patients who present within the first 12 to 24 hours following ingestion may appear normal, and this is described as the latent period. Nausea, vomiting, and abdominal pain subsequently ensue, followed by central nervous system (CNS) depression and hyperventilation as metabolic acidosis occurs. Ocular symptoms associated with retinal toxicity are often evident in the form of blurry vision, decreased visual acuity, photophobia, and “halo vision.” These symptoms are associated with physical exam findings that may include papilledema, optic disc hyperemia, and pupillary defects on fundoscopic evaluation. Symptoms associated with basal ganglia toxicity are not detectable early on due to mental status depression and the acuity of illness. Without treatment, patients may progress to coma, respiratory or circulatory failure, and death.

Evaluation

A patient who has ingested methanol will present somewhere along the spectrum of asymptomatic with an increased osmolar gap to very ill with end-organ toxicity and anion gap metabolic acidosis. The evaluation of the methanol intoxicated patient should follow a diagnostic approach that utilizes historical and objective data. An electrocardiogram, basic metabolic panel, and acetaminophen concentration should be obtained on all toxicology patients with suspected self-harm. Additional tests to be considered when self-harm is a concern are a complete blood count, transaminases, lipase, pregnancy status, serum or urine ketones, lactate, ethanol, and salicylate concentrations. In the case of toxic alcohols, salicylate toxicity is very important to rule out, especially when evaluating a patient with metabolic acidosis. Ethanol concentration is also required in the evaluation of a patient with toxic alcohol ingestion because ethanol inhibits the metabolism of methanol.[5]

Toxic alcohol concentrations are confirmatory and are measured by gas chromatography, which is not readily available in all healthcare facilities. Concentration is reported in milligrams per deciliter (mg/dL) and, since it typically peaks soon after absorption, is expected to decrease by zero-order kinetics as described above. The time of ingestion is also important to consider, as the toxic alcohol concentration may not reflect the level of toxicity if metabolism has already progressed because the metabolites are primarily responsible for the toxic effects. In the case of methanol, a formate concentration may be assessed to correlate with acidosis or any clinical findings of end-organ damage.

Obtaining toxic alcohol concentrations often requires sending a serum sample to an outside facility which may take hours to days to result, and diagnosis is usually required sooner. Therefore, a methodological approach to the diagnosis needs to be considered in which the patient is monitored for the anticipated effects of toxicity. Since anion gap acidosis is a later finding, a patient presenting with normal acid-base status early after ingestion should be observed for a minimum of 12 hours with serial basic metabolic panels every 2 to 4 hours to monitor for the development of metabolic acidosis and an elevated anion gap. This observation period can only begin once it is confirmed that the patient’s ethanol concentration is undetectable. A 12-hour observation period has been accepted as the standard of care, but it is based on collective experience more than specific data since acidosis is likely to occur earlier than 12 hours.

Many prefer to utilize the measurement of the osmolar gap for further risk stratification in the early presenting patient. An increased osmolar gap is nonspecific and indicates the presence of any osmotically active agent, such as an alcohol. There is an inverse relationship between the osmolar gap and the anion gap. The osmolar gap should be elevated early after ingestion of alcohol and progressively decrease as anion gap metabolic acidosis develops. This increased osmolality is due to the abundance of the osmotically active parent compound, and the acidosis is due to the production of its metabolites. When calculating the osmolar gap, it is important to include ethanol in the calculation since ethanol is also osmotically active. The equation to measure the osmolar gap is as follows:

• Serum osmolality = [2(Na) + BUN/1.6 + Glucose/18 + Ethanol/4.6]

The osmolar gap cannot be used to rule out the presence of toxic alcohol but may be useful as an indication to start treatment when the osmolar gap is greater than 25 mOsm/kg HO; although, some references cite the use of an osmolar gap of greater than 50 mOsm/kg HO. Using the above equation, a toxic alcohol concentration can theoretically be extrapolated from the gap using the molar mass of methanol or ethylene glycol, 32 g/mol, and 62 g/mol, respectively. It should be noted that a baseline osmolality gap is believed to be within a range from -9 to 19 mOsm/kg HO. This should be considered when calculating the osmolar gap, and the true result of the calculation may be +/- 20 compared to the finding. Serial measurements of serum osmolality and osmolar gap calculations are not necessary or indicated in evaluation. 

When methanol toxicity is being considered in a patient presenting with an anion gap metabolic acidosis, the patient should be screened for the aforementioned associated symptoms, particularly visual disturbances and a funduscopic exam should be performed. In addition, when a serum methanol concentration cannot be confirmed, it is especially important to rule out salicylate toxicity. An osmolality gap may not be significantly elevated once the patient is acidotic, as the parent compound will have already metabolized to an unknown degree and if presenting significantly late, the osmolar gap may be normal. A 12-hour observation period should not be pursued if the patient is already acidotic; however, if stable, the patient should be checked for serum or urine ketones and treated with 1 to 2 liters of isotonic, dextrose-containing intravenous fluids. If improvement occurs as evidenced by improved acidosis and a decrease in the anion gap, then toxic alcohol ingestion should be considered less likely, and other etiologies should be more strongly considered.

Oftentimes, a serum alcohol concentration can also be estimated. (Note, the term "alcohol" does not specifically refer to only ethanol). This approach may be useful in risk stratification of small, inadvertent ingestions with very clear, accurate histories. The estimation is based on the dose or amount ingested in milliliters (D), percent concentration of ingested alcohol, bioavailability (BV), the volume of distribution (V) expressed as liters per kilogram, and patient weight (W) in kilograms. This is most useful when assessing for toxicity in small, accidental ingestions, usually by children. The equation is as follows:

• Serum concentration = (D x BV)/(V x W)

This is performed by first determining the percent concentration of the ingested agent, with 1% being equal to 1 gm/100 mL. The amount ingested is then determined by multiplying the percent concentration by the volume ingested. This product is then multiplied by bioavailability, which is conservatively assumed to be 100%. This is then divided by the product of the volume of distribution (0.7L/kg) and the patient’s weight in kilograms. The result will be in grams per liter which will need to be converted to milligrams per deciliter (or multiplying by 100). The resulting serum concentration assumes that the total ingestion occurred instantaneously with complete absorption. With small mouthfuls, it can be assumed that an adult’s mouthful is approximately 30 mL and a toddler’s mouthful is approximately 10 mL. (See associated practice question).

Toxic alcohol exposure is confirmed when a serum concentration demonstrates the diagnosis. It should be suspected in a patient with developing metabolic acidosis with an elevated anion gap, preceded by an osmolality gap that is decreasing over time, with associated symptoms as described above. Lactate and ketones may be detectable but are nonspecific.[7]

Treatment / Management

Treatment options for methanol toxicity include supportive care, fomepizole (Antizole, 4-Methylpyrazole or 4MP), ethanol, dialysis, and theoretically, folate. Fomepizole is the antidote for toxic alcohols, and its mechanism of action is the inhibition of alcohol dehydrogenase. Ethanol may also be utilized therapeutically to inhibit alcohol dehydrogenase when fomepizole is unavailable. There are advantages and disadvantages to either treatment. Fomepizole is more easily dosed, does not cause any inebriation, strongly inhibits alcohol dehydrogenase, but is fairly expensive. Ethanol is less expensive but is harder to dose accurately, requires close monitoring of the serum ethanol concentration, and causes inebriation that may necessitate intensive care monitoring.[1][4]

Indications for treatment include an elevated methanol concentration and severe or progressing acidosis, despite resuscitation, with clinical suspicion of methanol ingestion. Recommendations regarding specific methanol concentrations vary concerning when to start treatment. Most conservative recommendations are to start treatment if the methanol concentration is greater than 20 to 25 mg/dL. However, if metabolic acidosis is mild or not present, and there is no evidence of end-organ toxicity, then a methanol concentration of 32 mg/dL is an appropriate starting point for treatment as molar calculations indicate this would correlate with a maximum of 10mmol/L of a toxic metabolite (formate). This should not alone account for more than a 10 mmol/L base deficit or a toxic amount of metabolite. (Note: the molar-based treatment cutoff for ethylene glycol is 62 mg/dL; see ethylene glycol chapter). When methanol concentration is not attainable, then an appropriate indication for treatment should be when bicarbonate progresses below 15mmol/L or if there is evidence of retinal toxicity. After empiric treatment with fomepizole, there are 12 hours in which metabolism of methanol is halted, allowing adequate time to obtain a methanol concentration and arrange for dialysis, if needed.

Fomepizole or ethanol serves as alcohol dehydrogenase inhibitors to stop the conversion of methanol to its toxic metabolite, formate. When alcohol dehydrogenase is inhibited, clearance of methanol is prolonged from approximately 8.5 mg/dL/hr to an effective half-life of 45 to 90 hours. Fomepizole is given intravenously, with a loading dose of 15 mg/kg, and then maintenance dosing of 10 mg/kg every 12 hours for 4 doses or until the methanol concentration is less than 32 mg/dL with normal acid-base status. If additional dosing is required beyond 4 maintenance doses, then dosing increases to 15 mg/kg every 12 hours due to autoinduction of increased metabolism. During dialysis, fomepizole should be dosed every 4 hours as it is dialyzable.

Dosing of ethanol is more complicated, difficult to monitor, and has the added side effect of inebriation. Ethanol may be given intravenously or orally. However, it should only be given if fomepizole is unavailable as it would be inappropriate to cause the patient to be inebriated for such an extended period. When treating with ethanol, the goal therapeutic serum concentration is a range of 80 to 120 mg/dL. Intravenous ethanol formulary is usually 10%, and a loading dose is calculated using the product of the goal plasma concentration (C = 100mg/dL), the volume of distribution of ethanol (V = 0.6L/kg), and the patient’s weight. Maintenance dosing is then based on elimination rate. Empirically, 10% intravenous ethanol may be administered with a loading dose of 8 mL/kg over 30 to 60 minutes, followed by maintenance dosing of 1 to 2 mL/kg per hour. Maintenance dosing is doubled during dialysis. Oral dosing may be calculated using the above equation for serum alcohol concentrations by using 100 mg/dL for the serum concentration and then solving for the amount ingested. Empirically, 50% (100 proof) oral ethanol may be administered with a loading dose of 2 mL/kg followed by 0.2 to 0.4mL/kg per hour. Maintenance dosing is doubled during dialysis.

Patients with toxic methanol ingestion should be strongly considered for hemodialysis. Due to its low volume of distribution and lack of protein-binding, both methanol and the toxic metabolite, formate, are dialyzable. Hemodialysis is often beneficial for methanol toxicity because it can significantly decrease the patient’s length of stay. Once alcohol dehydrogenase is inhibited, clearance of methanol is prolonged from approximately 8.5 mg/dL per hour to an effective half-life of 45 to 90 hours. However, the only absolute indication for hemodialysis in methanol toxicity is a new visual impairment in the presence of metabolic acidosis. Relative indications for hemodialysis include methanol concentration greater than 50 mg/dL, severe metabolic acidosis refractory to resuscitation, history of ingestion of a lethal dose of 1gm/kg, renal failure, and other standard indications for dialysis.

Additional treatment of methanol toxicity includes folate. Folate administration is of theoretical benefit as it may enhance the metabolism of the toxic metabolite, formate, to carbon dioxide and water.

Admission to the intensive care unit is appropriate when a patient has severe symptomatology, severe metabolic derangements, is in need of dialysis, or is being treated with ethanol as an antidote.[8](B2)

Differential Diagnosis

The differential diagnosis of toxic alcohol ingestion includes other etiologies of metabolic acidosis, as well as various alcohols that may also be ingested. Important toxicological considerations for metabolic acidosis are salicylates, acetaminophen, iron, carbon monoxide, cyanide, alcoholic ketoacidosis, and ingestion of other alcohols, such as ethylene glycol, diethylene glycol, or toluene. Ingestion of agents containing more than one alcohol or toxic substance should also be considered. Nontoxicological considerations should include diabetic ketoacidosis, sepsis, and uremia.

Prognosis

Patients often recover when prompt diagnosis and treatment occur. Retinal toxicity and basal ganglia toxicity may result in permanent symptoms. When patients present late or diagnosis is not recognized in a timely fashion, significant morbidity and mortality can occur.

Complications

• Metabolic acidosis
• Permanent visual deficits 
• Parkinson-like disease
• Coma
• Respiratory failure
• Circulatory failure 
• Complications associated with dialysis 
• Death