Toxic Alcohols

Foundations

Methanol (methyl alcohol; CAS 67-56-1; H ₃ COH) is a clear, volatile, colorless, slightly sweet-tasting alcohol at room temperature. It is also known as wood alcohol due to methanol being produced from the destructive distillation of wood. Methanol is mainly used as a solvent or octane booster in gasoline. It is manufactured frequently as an intermediate in chemical reactions. As a solvent, it is present in many items found in the home, including cleaning solutions, adhesives, enamels, stains, dyes, and paint removers. Methanol is also commonly found in windshield washer fluid, antifreeze (particularly brake line antifreeze), embalming fluid, and fuel for camp stoves.

Many mass methanol poisonings have occurred throughout history, including outbreaks in Estonia (2001), Norway (2002–2004), the Czech Republic (2012), Libya (2013), Kenya (2014), Nigeria (2015), and Iran (2018). ^, Despite vast knowledge and experience with methanol, these outbreaks demonstrate the diagnostic challenge and difficulty in treating these patients. In 2018, 1828 single substance exposures to methanol were reported to US poison centers. The vast majority were unintentional exposures (89.4%), with few major complications (1.6%) and only 11 deaths. These data, however, rely on voluntary reporting and likely underrepresent the true burden of methanol exposures and mortality outcomes from forensic data in the United States.

Principles of Toxicology

Methanol is rapidly absorbed from the gastrointestinal (GI) tract with an average absorptive half-life of 5 minutes and reaches peak concentration in 30 to 60 minutes. While the majority of exposures occur through oral ingestion, occupational and recreational inhalation of methanol from cleaning and cooling fluids has resulted in toxicity causing neurologic dysfunction and necessitating antidote therapy and hemodialysis (HD). Transdermal exposure as well can lead to significant methanol toxicity. High-risk occupations for exposure to methanol include painting, varnishing, lithography, printing, and glazing.

Methanol itself has very low toxicity, but its metabolism results in toxic metabolites, in particular, formic acid, which dissociates into formate and hydrogen ions. Methanol is primarily metabolized in the liver by alcohol dehydrogenase (ADH) into formaldehyde. Formaldehyde is then metabolized by aldehyde dehydrogenase (ALDH) very rapidly, with a half-life of 1 to 2 minutes, into formic acid ( Fig. 136.1 ). Formic acid can combine with tetrahydrofolate (THF) to form 10-formyl THF, which can be metabolized into carbon dioxide and water.

Elimination of methanol is mainly characterized via zero-order kinetics in the poisoned patient but does have first-order metabolism at very low concentrations, with an elimination half-life of about 2 to 3 hours at low concentrations. Small amounts of methanol are eliminated by the renal and pulmonary systems.

At toxic concentrations, the elimination half-life of methanol is nearly 24 hours. The metabolite, formic acid, has a half-life of nearly 20 hours. With ADH inhibition by concurrent consumption of ethanol or administration of fomepizole, the half-life of methanol extends upward to more than 50 hours. With dialysis, the half-life of methanol is approximately 3 to 4 hours.

Formic acid will accumulate due to its slower metabolism as it exceeds the elimination rate. Formic acid binds iron efficiently, resulting in mitochondrial cytochrome oxidase inhibition, and interferes with oxidative metabolism in a manner similar to that of cyanide, carbon monoxide, and hydrogen sulfide. The dissociation of formic acid into formate and hydrogen ions leads to acidosis. The interference of oxidative metabolism, combined with acidosis, further promotes lactate production and worsens the acidotic state. Decreasing pH promotes formic acid diffusion across cell membranes, in particular to the central nervous system (CNS). Also, inhibition of cytochrome oxidase by formic acid is potentiated with decreasing pH. The net effect of this vicious cycle, coined the “ circulus hypoxicus ,” is tissue hypoxia and inhibition of intracellular respiration. Further mechanisms of toxicity include free radical formation, lipid peroxidation, and impairment of antioxidant reactions.

Formic acid uniquely targets the optic disk of the retina and retrolaminar optic nerve, potentially due to the high amount of blood and cerebrospinal fluid (CSF) flow through the choriocapillaris. These cells are more susceptible to cellular hypoxia due to low levels of mitochondria and cytochrome oxidase, making formic acid oxidation slower in the eye compared to the brain. Inhibition of mitochondrial cytochrome oxidase results in decreased adenosine triphosphate (ATP) production, leading to myelin sheath damage and loss of vision. Worsening acidosis potentiates these effects by enhancing the diffusion of formic acid across cell membranes into the neurons.

The basal ganglia and subcortical white matter are affected by formic acid in a similar manner to the ocular toxicity. Neuroimaging and autopsy findings classically demonstrate putamen hypodensity, with hemorrhages and necrosis. Bilateral putamen changes are not specific to methanol toxicity and can be found in Wilson disease, Leigh disease, Kearns-Sayre syndrome, toxic encephalopathy (e.g., carbon monoxide, cyanide, hydrogen sulfide), hemolytic-uremic syndrome, and hypoxic-ischemic injury. The severity of findings and extent of necrosis on imaging do not necessarily correlate with clinical outcomes. The vulnerability of the basal ganglia to formic acid toxicity may be due to its high metabolic activity, with poor venous drainage and inadequate arterial flow.

Clinical Features

Clinical signs and symptoms of methanol intoxication typically involve the GI tract, CNS, and optic system. Shortly after exposure, patients appear similar to other alcohol ingestions, with GI irritation, inebriation, and CNS depression. Methanol has a less inebriating effect than ethanol but causes similar slurred speech, ataxia, confusion, and CNS depression. Abdominal discomfort and vomiting occur from mucosal irritation, and patients can develop acute pancreatitis. Severe mucosal irritation can also result in hemorrhagic gastritis. A latency period, ranging from 1 to 72 hours, depending on the amount ingested, can occur with the improvement of inebriation symptoms and development of visual symptoms as methanol metabolizes and formic acid accumulates.

As formic acid accumulates, the most characteristic feature is some degree of visual disturbance, including seeing spots with blurred vision (commonly referred to as “snowstorm vision”), altered visual fields, and blindness. Visual disturbances occur in 30% to 70% of patients. Early ophthalmologic findings include reduced pupillary response to light and hyperemia of the optic disc. Peripapillary retinal edema and loss of optic disk cupping follow and often lead to decreased visual fields and central scotomata. Retinal dysfunction can be reversible. Blurred vision from formic acid induced retinal injury, is typically transient, and vision recovers. Optic atrophy and optic neuropathy suggest a poor prognosis for visual recovery. The incidence of ophthalmologic abnormalities correlates directly with the degree of acidosis. Long-term visual sequelae are associated with visual deficits at presentation, coma, and brain lesions on imaging. ^,

As acidosis progresses, compensatory tachypnea develops. Acidosis can be profound, with many patients presenting with an arterial pH less than 7.0 and serum bicarbonate level less than 10 mEq/L. Tachycardia is often noted, but patients rarely have significant cardiac dysrhythmias. Also, shock, seizures, myoglobinuria, and rhabdomyolysis have been reported. Death typically results from respiratory failure and sudden respiratory arrest, with cerebral edema and multiorgan failure.

Prognosis after methanol ingestion correlates with the degree of acidosis, time to presentation, and initiation of treatment. The strongest predictor of morbidity and mortality is the degree of acidosis, with high mortality rates observed at a pH less than 7.0. A comatose state at presentation also portends a worse outcome with high mortality rates and long-term neurologic sequelae. Aggregated data from mass methanol poisoning events demonstrate that a comatose state with a pH less than 6.74 has an 83% mortality rate and 100% of survivors had neurologic sequelae, while non-comatose patients with a pH greater than 7.0 had a 5% mortality rate and only 16% of survivors had neurologic sequelae. Patients that survive the acute toxicity of methanol can have permanent complications, including blindness and neurologic deficits. A Parkinson-like extrapyramidal syndrome, with bradykinesia, tremor, and dementia, can occur. These findings are generally associated with necrosis of the putamen and subcortical white matter on neuroimaging studies. Other neurologic sequelae include polyneuropathy, encephalopathy, ataxia, and cognitive deficits. Permanent vision deficits and evidence of brain hemorrhages on magnetic resonance imaging (MRI) are associated with decreased quality of life in survivors of methanol poisoning.

Differential Diagnoses

The differential diagnoses for methanol intoxication are broad, making it difficult to detect, particularly at the initial presentation. The inebriated state of the patient can easily be confused with ethanol intoxication. Further causes of altered mental status (AMS) include hypoglycemia, hypoxia, carbon dioxide narcosis, infections, trauma, seizures, metabolic disturbances, endocrinopathies, and encephalopathy. Poisoning or intoxication by other substances, including opiates, carbon monoxide, sedative-hypnotics, and benzodiazepines, often presents with AMS. The GI irritation can occur with ethanol intoxication and with other intra-abdominal pathologies, such as gastritis and pancreatitis.

After ingestion of methanol, serum osmolality will be elevated and can lead to an elevated osmolar gap. Other substances that contribute to an elevated osmolar gap include EG, isopropanol, ethanol, mannitol, glycerol, propylene glycol (PG), sorbitol, fructose, diatrizoate (IV dye), acetonitrile, and ethyl ether ( Table 136.1 ). Additionally, hyperlipidemia, hyperproteinemia, and sick cell syndrome cause an increase in the osmolar gap by decreasing the measured sodium concentration.

As the parent compound methanol is metabolized, the production of formic acid results in an elevated anion gap (AG) acidosis. In addition to methanol, causes of AG acidosis include lactic acidosis of varying causes (e.g., sepsis, ischemia), diabetic ketoacidosis, alcoholic ketoacidosis, uremia, inborn errors of metabolism, and toxins (e.g., salicylates, isoniazid, iron, carbon monoxide, cyanide, metformin, toluene, paraldehyde, PG, and EG; see Table 136.1 ). Worsening acidosis, despite adequate fluid hydration and no evidence of underlying ischemia producing lactic acidosis, should raise the concern for toxic alcohol ingestion.

The presence of a so-called double gap (elevated osmolar and AGs) is classically described for toxic alcohol ingestion. Many other situations, however, can cause a similar picture, including diabetic ketoacidosis, alcoholic ketoacidosis, renal failure, multiple organ failure, and septic shock (see Table 136.1 ). This double gap picture is also dependent on the timing of presentation because early presenters will have only an osmotically active parent compound and late presenters will have acidosis without an elevated osmolar gap ( Fig. 136.2 ).

The development of ocular manifestations with worsening acidosis is a strong indicator of methanol poisoning. Other toxins, however, can cause ophthalmologic conditions and blindness such as cinchonism with quinine intoxication, but this lacks the elevated osmolar and AGs. Cortical blindness can occur with various causes of toxic leukoencephalopathy, including carbon monoxide, hydrocarbons, steroids, metals (organic mercury), and various chemotherapeutic agents (e.g., carboplatin, cisplatin).

Diagnostic Testing

The classically described presentation of toxic alcohol ingestion includes an AG metabolic acidosis and an elevated osmolar gap. Due to the latency period of methanol metabolism, a normal AG does not exclude methanol ingestion. The AG is commonly calculated by the following equation:

with a normal AG of 8 to 12 mEq/L. Decreased albumin can falsely elevate the AG; the AG can be corrected by using the Figge equation:

Mortality correlates highly with the degree of acidosis and formate concentration rather than with a specific methanol concentration. Visual dysfunction occurs with a formate concentration greater than 20 to 30 mg/dL. Indicators for a poor prognosis include a formate concentration of more than 50 mg/dL and a pH less than 7.0

Many formulas exist for calculating serum osmolarity, but the most commonly used is the following:

where blood urea nitrogen (BUN), glucose, and the ethanol concentrations are measured in mg/dL. The difference between measured serum osmolality and calculated serum osmolarity is as follows:

If using the International System of Units (SI units), there are no corrections, and the various serum levels are simply added or subtracted. The normal osmolar gap has been arbitrarily defined as normal if it is less than 10 mOsm. However, a wide range of osmolar gaps is observed in the population, from −15 to +10 mOsm. As a result, individuals who begin with a negative osmolar gap can have significantly elevated concentrations of toxic alcohols but have a so-called normal osmolar gap. Many other substances can contribute to an osmolar gap and can be misleading. Also, if patients are acidotic, the parent compound (methanol, EG) has been metabolized into its respective acid and does not contribute to the osmotic load. Thus, a normal osmolar gap cannot exclude toxic alcohol ingestion. Methanol, however, is more likely than EG to have an elevated osmolar gap. An extremely elevated osmolar gap (>20–25 mOsm) however is highly suspicious for toxic alcohol ingestion. In methanol ingestions, the metabolite formic acid can be measured using enzymatic analysis but this test is not routinely available. ^,

Neuroimaging with MRI and computed tomography (CT) can be performed for patients with AMS. The most consistent finding for methanol poisoning is bilateral necrosis of the putamen. However, this finding is not specific for methanol poisoning, and neuroimaging is typically normal in the first 24 hours after methanol exposure because findings typically lag behind clinical symptoms. Patients with evidence of putaminal necrosis on imaging are at risk for an irreversible Parkinson-like extrapyramidal syndrome and chronic disability limiting daily functioning. The measurement of visual evoked potentials (VEP) is sensitive to detect impairment in the optic system.

Ultimately, the definitive diagnosis requires laboratory confirmation of the presence of methanol. Once toxic alcohol ingestion is suspected, directly measure methanol and EG concentrations and begin empirical therapy. Peak methanol concentrations less than 20 mg/dL are generally not associated with toxicity, but peak methanol concentrations greater than 50 mg/dL indicate significant and serious exposure. Peak methanol concentrations occur shortly after ingestion due to rapid GI absorption. Due to the variability of the timing of patient presentation, the methanol level interpretation must be based on clinical findings (e.g., AMS, vision complaints) as well as additional laboratory findings (e.g., metabolic acidosis, elevated osmolar gap). Depending on the location of the practice and laboratory capabilities, specific serum concentrations of methanol or EG may not be readily attainable in most hospitals, and blood specimens may need to be transported to regional reference laboratories for emergent analysis.

Management

Alcohols are rapidly absorbed from the GI tract, so GI decontamination has limited to no value. Gastric suctioning via a nasogastric or orogastric tube may be considered in a large volume exposure (such as an entire bottle of windshield washer fluid or antifreeze) in someone who presents immediately after ingestion, but there is no evidence to support routine use and gastric lavage is generally not recommended. Activated charcoal is not indicated for toxic alcohol ingestions. Aside from standard stabilization and resuscitation, the main priorities in toxic alcohol exposure are correction of acidosis, inhibition of the production of toxic metabolites, and elimination of the parent alcohol and its toxic metabolites. Therapy should be initiated based on strong clinical suspicion. Treatment should not be delayed while waiting for specific serum concentrations to be determined.

Because the degree of acidosis correlates with severity and outcome, treat a serum pH less than 7.3 with intravenous (IV) sodium bicarbonate to normalize the pH. Worsening acidosis from formic acid accumulation potentiates mitochondrial cytochrome oxidase inhibition and anaerobic metabolism, also generating lactic acidosis. Based on supporting patient data, correction of acidosis likely improves outcomes and ophthalmologic symptoms. Bicarbonate can be administered via intermittent boluses, combination of a bolus and infusion, or infusion alone based on the severity of symptoms. Administer bolus sodium bicarbonate at 1 to 2 mEq/kg and infuse 150 mEq/L of sodium bicarbonate in 5% dextrose at 1.5 to 2 times the maintenance fluid rate until normalization of the serum pH (7.35–7.45). Large amounts of bicarbonate may be necessary for even partial correction of acidosis due to metabolism of the parent alcohol into its toxic acid. With bicarbonate administration, monitor for the development of hypernatremia and hypokalemia. The use of bicarbonate should not deter definitive elimination of the parent alcohol and its toxic metabolites via HD.

Prevent the further production of formic acid by inhibiting ADH with fomepizole (methylpyrazole, 4-MP) or ethanol. Fomepizole is preferable due to its safety profile and ease of administration, with a sevenfold reduction in adverse drug event rate versus ethanol. ^{, ,} No contraindication exists for fomepizole use except for a severe allergic reaction, but currently, there have been no reported cases ^.18 Most adverse reactions to fomepizole are transient and do not require discontinuation of treatment. Specific indications for initiating ADH blockade are a documented methanol or EG concentration more than 20 mg/dL, documented history of methanol or EG ingestion with an osmolar gap more than 10 mOsm/L, or suspected methanol or EG ingestion with an arterial pH less than 7.3, serum carbon dioxide (bicarbonate) level less than 20 mmol/L, or oxalate crystalluria ( Box 136.1 ).

In clinical practice, however, initiate fomepizole therapy with a strong clinical suspicion for serious ingestion, and send for confirmatory levels, because a delay in ADH blockade can lead to the development of acidosis and deleterious consequences. Fomepizole dosing involves a loading dose of 15 mg/kg followed by 10-mg/kg doses every 12 hours, up to 48 hours. After 48 hours, give 15 mg/kg every 12 hours because repeated dosing of fomepizole induces its own cytochrome P-450 metabolism. Of note, the fomepizole dosing frequency does need to be adjusted with HD ( Box 136.2 ). Side effects of fomepizole include headache, nausea, dizziness, phlebitis, and reversible liver transaminase level elevation. One case of hypotension and bradycardia due to the rapid infusion of fomepizole has been described. ^,

If fomepizole is not available, and ethanol therapy is used to inhibit ADH, maintain serum ethanol concentrations between 100 and 150 mg/dL. The affinity of ADH for ethanol is 10 times greater than for methanol. Ethanol dosing is complex, however, and can cause worsening CNS and respiratory depression, with hypotension, vomiting, phlebitis, and hypoglycemia, particularly in children or malnourished individuals. ^, Given the widespread availability of fomepizole and its safety profile versus that of ethanol, the dosing of IV ethanol is not discussed here because its routine use is not recommended with the exception of mass outbreaks or lack of fomepizole availability. ^, With ADH inhibition, the half-life of methanol is significantly extended upward of 50 hours. Patients who present early after methanol ingestion without acidosis can potentially be treated with ADH inhibition alone but may have prolonged hospitalizations due to the extended half-life of the parent compound.

Elimination of the parent alcohol via HD is the mainstay of therapy in severe toxic alcohol ingestions, and consultation with a regional poison center or medical toxicologist will help determine whether the patient is a candidate. HD serves multiple purposes in that it removes the parent alcohol and its metabolites, corrects acidosis, and aids in fluid management and cardiovascular stabilization. Additionally, it can shorten the course and cost of hospitalization, particularly in methanol ingestions, due to methanol’s long half-life. Intermittent HD is preferred over continuous renal replacement therapy (CRRT) but CRRT is acceptable if HD is not available ^,

HD is indicated for acidosis (pH < 7.3), renal failure, vision abnormalities with methanol exposure, electrolyte imbalances unresponsive to conventional therapy (i.e., hyperkalemia), hemodynamic instability, and methanol or EG concentration more than 50 mg/dL. Traditional endpoints for discontinuing HD or ADH inhibition are a normal acid-base status and methanol-EG concentration less than 20 mg/dL. Ophthalmologic disturbances are not an indication for continued dialysis after correction of the acid-base disturbance and removal of methanol. There is no specific treatment for methanol-induced persistent optic nerve injury. Formic acid is converted to carbon dioxide and water via THF synthetase; therefore, folinic acid (leucovorin) may aid in formic acid elimination, but there have been no human trials to support its efficacy. The recommended dose is 1 mg/kg (maximum dose: 50 mg) of folinic acid IV every 4 to 6 hours until methanol has been eliminated and the acidosis resolves. The use of folinic acid (leucovorin) should not deter emergent HD if indicated.

Disposition

Admission is generally necessary for patients being treated for methanol exposure. Consult with nephrology early for possible HD. If HD is not available, administer fomepizole and transfer the patient to an institution where emergent HD can be initiated. Consult the regional poison center (1-800-222-1222) or a medical toxicologist to guide management. Consult an ophthalmologist to evaluate visual fields and the retina for methanol-induced ocular injury within 24 hours. Patients with a methanol concentration less than 20 mg/dL and no clinical symptoms or laboratory abnormalities may be discharged. If the patient has psychiatric issues or intent of self-harm, a psychiatric consultation is indicated.