Ethanol is consumed on a daily basis worldwide, and regardless of country of origin, it is a common problem among children and adolescents. In China, high school pooled male drinking rate in a recent meta-analysis was 36.5%, while middle school male drinking rate was 23.6% over 30 days.¹ In East Africa, the prevalence of alcohol use in secondary school students was 33%, with problem drinking ranging from 3 to 15%.² According to a 2-year prospective study in Norway, 46% of poisonings in 8- to 15-year-old children involved ethanol.³ In the Slovak Republic, ethanol accounted for 34% of all intoxications in children 9 to 18 years old, and the proportion of children admitted for ethanol intoxication increased yearly over 10 years.⁴ In the United States, alcohol is the recreational substance most commonly used by youth. “Binge drinking” tendencies (five or more consecutive drinks on one occasion) have been reported in 4% to 17% of 8th through 12th graders, respectively, and up to 32% of college students.⁵ Intermittent ethanol exposure in adolescence is associated with lasting changes in the adult brain that can increase the risk for alcohol use disorder and dependence as well as all the complications of alcoholism.⁶

PHARMACOKINETICS AND PATHOPHYSIOLOGY

Ethanol undergoes hepatic metabolism via two metabolic pathways: alcohol dehydrogenase and the microsomal ethanol oxidizing system (MEOS). Alcohol dehydrogenase (ADH) is the major metabolic pathway and the rate-limiting step in converting ethanol to acetaldehyde. Acetaldehyde is then metabolized by aldehyde dehydrogenase (ALDH) into acetic acid, which is then converted to water and carbon dioxide. With consumption of large quantities of ethanol, the cytochrome P450 2E1 enzyme contributes to ethanol metabolism. In general, non-tolerant individuals metabolize ethanol at 10 to 25 mg/dL/h, and those with tolerance can metabolize it up to a rate of 30 mg/dL/h.⁷ Children may ingest large amounts of ethanol in relation to their body weight, resulting in rapid development of high blood concentrations. In children younger than 5 years, the ability to metabolize ethanol is diminished because of immature hepatic ADH activity.

CLINICAL PRESENTATION

Ethanol is a selective central nervous system (CNS) depressant at low concentrations and a general depressant at high concentrations. Initially, ethanol produces exhilaration and loss of inhibition, which progresses to lack of coordination, ataxia, slurred speech, gait disturbances, drowsiness, and ultimately stupor and coma. The intoxicated child may demonstrate a flushed face, dilated pupils, excessive sweating, gastrointestinal (GI) distress, hypoventilation, hypothermia, and hypotension. Death from respiratory depression may occur at serum ethanol concentrations >500 mg/dL. Convulsions and death have been reported in children with acute ethanol intoxication owing to alcohol-induced hypoglycemia. Hypoglycemia results from inhibition of hepatic gluconeogenesis and is most common in children younger than 5 years. It does not appear to be directly related to the quantity of ethanol ingested and it is not uniformly present in all cases of pediatric ethanol ingestion.⁸

LABORATORY STUDIES

In symptomatic children who have suspected ethanol intoxication, the most critical laboratory tests are the serum ethanol and glucose concentrations.⁹ Although blood ethanol concentrations roughly correlate with clinical signs, the physician must treat patients based on their clinical status, not the absolute level.⁹ If the ethanol level does not correlate with the clinical picture, consider coingestants or other causes of altered mental status. If children have experienced fluid losses, measure serum electrolytes and assess their acid–base status.

MANAGEMENT

The mainstay of treatment in the majority of children with accidental acute ingestions of ethanol is supportive care. Attention is directed toward management of the patient’s airway, circulation, and blood sugar status. If hypoglycemia is present, administer 2 to 4 mL/kg of D25W in children <50 kg, and 1 amp of D50W to those >50 kg. Serial glucose levels are followed to detect recurrent hypoglycemia. In obtunded patients, naloxone 0.01 mg/kg intravenous (IV) push can be given for suspected opiate cointoxication.

Gastric decontamination is not indicated in ethanol-poisoned patients because ethanol is absorbed rapidly from the stomach. Hemodialysis does increase ethanol clearance by three to four times and may be considered in massive ethanol ingestions with significant metabolic disturbances and in patients who do not respond to conventional therapy.

DISPOSITION

Any infant with significantly altered mental status following acute ethanol ingestion should be admitted for monitoring of respiratory and blood sugar status and for management of fluids and electrolytes. Consider contacting local child welfare authorities if maltreatment is suspected. Asymptomatic patients may be discharged home with reliable caretakers. Adolescents should be referred for counseling in an alcohol addiction program if a recurrent pattern of ethanol abuse is suspected.

Methanol is present in a variety of substances found around the home and workplace, including paint solvents, gasoline additives, air or brake line antifreeze, canned-heat products, windshield washer fluid, and embalming fluid, and is manufactured as an intermediate in many chemical reactions. It is also known as wood alcohol, as it was distilled from wood in the 1920s to 1930s prohibition era.¹⁰ Despite vast knowledge about the deleterious effects of methanol, it is still implicated in many recent mass poisonings, including Norway (2002–2004), Estonia (2007), Libya (2013), Iran (2013), and Kenya (2014).^11–13

PHARMACOKINETICS AND PATHOPHYSIOLOGY

Methanol is rapidly absorbed following ingestion, with an average absorption half-life of 5 minutes. Peak serum concentration can be reached as early as 30 to 60 minutes after ingestion. As with ethanol, methanol is primarily metabolized by hepatic ADH. Its immediate metabolite is formaldehyde, which is rapidly metabolized (half-life of 1–2 minutes) to formic acid. The half-life of methanol at toxic concentrations may be as long as 24 hours, but in the presence of ADH or fomepizole, it extends upward of 50 hours.^14–16 Elimination of methanol is mainly via zero-order kinetics, but at low concentrations can have first-order metabolism.^14,17,18 Methanol is harmless; however, its metabolite, formic acid, is extremely toxic. Formic acid inhibits mitochondrial cytochrome oxidase thus impairing oxidative metabolism and promotes lactic acidosis. It affects the optic disc of the retina due to low levels of mitochondria and cytochrome oxidase.¹⁹ Formic acid combines with tetrahydrofolate (THF) and is metabolized into water and carbon dioxide. Fatalities have been reported after ingestion of as little as 15 mL of a 40% methanol solution, although 30 mL is generally considered a minimal lethal dose. Ingestion of only 10 mL can lead to blindness. Adults have survived ingestions of 500 mL.

CLINICAL PRESENTATION

The onset of symptoms following methanol ingestion varies from 1 to 72 hours. Initial symptoms are similar to ethanol intoxication and include mental status depression, inebriation, ataxia, slurred speech, and potential gastric irritation. The classic triad of methanol poisoning consists of visual complaints, abdominal pain, and metabolic acidosis. The accumulation of formic acid leads to the delayed development of ophthalmologic signs and symptoms. Reported visual disturbances and findings include blurred vision (“snowstorm” appearance), photophobia, constricted visual fields, blindness, hyperemia of the optic disk, retinal edema, and reduced pupillary light response. The outcomes of patients who develop blindness cannot be predicted, as partial visual recovery can occur.^20,21

Patients typically complain of nausea and vomiting and can experience GI bleeding and acute pancreatitis. Unlike other alcohols, these patients often lack the odor of ethanol on their breath and can have a clear sensorium. Methanol toxicity should be suspected in patients with altered mental status and metabolic acidosis of unclear etiology, especially if they have complaints involving vision.²² Prognosis correlates with degree of acidosis, time from ingestion to presentation, and timing for initiation of treatment.^11,23 Necrosis of the putamen and subcortical white matter can lead to permanent neurologic complications such as a Parkinson-like extrapyramidal syndrome, polyneuropathy, and cognitive deficits.^24,25

LABORATORY STUDIES

Definitive diagnosis requires direct measurement of the serum methanol concentration. Additional recommended studies include a complete blood cell count, serum electrolytes and blood glucose, serum ethanol, lipase, blood urea nitrogen (BUN) and serum creatinine, a urinalysis, and a blood gas. If the type of toxic alcohol ingested is unclear, a serum ethylene glycol is also recommended along with the methanol concentration. Classically, methanol-intoxicated patients develop an elevated anion gap (AG) metabolic acidosis, although this may not be present if the patient presents before a significant quantity of formic acid has been generated.²⁶ The AG is calculated using the equation:

The presence of an elevated osmolar gap can suggest methanol ingestion but is not specific for methanol (or ethylene glycol, discussed later). The osmolar gap is the difference between the measured and calculated serum osmolarities. An elevated osmolar gap indicates the presence of an unmeasured osmotically active substance in the serum. The formula for calculating the serum osmolarity is:

Normally, the difference between the measured and calculated serum osmolalities is less than 10 mOsm. Additional causes of an elevated osmolar gap include ethanol, ethylene glycol, and isopropanol. Nontoxicological causes of an elevated osmolar gap include diabetic ketoacidosis, alcoholic ketoacidosis, renal failure, critical illness, and multiple organ failure. A normal osmolar gap does not rule out toxic alcohol poisoning^27,28 because the toxic alcohol may have been metabolized prior to patient presentation. Generally, peak methanol concentrations <20 mg/dL do not produce toxicity but peak levels >50 mg/dL indicate significant risk.¹⁰ Ocular effects occur at levels >100 mg/dL, and fatalities have been reported in untreated victims with levels >150 mg/dL.²⁹ Regardless of measured methanol concentration, comatose presentation and pH <7.0 are strong predictors of morbidity and mortality.²³

MANAGEMENT

Due to the rapid absorption of alcohols from the GI tract, gastric decontamination is not indicated. Initial management consists of standard supportive care and fluid resuscitation. The main priorities in methanol or ethylene glycol poisonings are correction of acidosis, inhibition of toxic acid generation, and elimination of the parent alcohol and toxic metabolites. If a significant ingestion of methanol (or ethylene glycol) is likely, begin empiric treatment with the intravenous ADH inhibitor fomepizole prior to confirmatory laboratory tests, thus inhibiting the generation of toxic metabolites.^30,31 The initial loading dose of fomepizole is 15 mg/kg followed by 10 mg/kg every 12 hours. After 48 hours of treatment with fomepizole, increase dosing to 15 mg/kg every 12 hours, as repeated administration of fomepizole induces its own metabolism via the cytochrome P4502E1 enzyme.^30,32 Specific indications for fomepizole therapy include serum methanol (or ethylene glycol) concentrations >20 mg/dL, history of ingestion with osmolar gap >10 mOsm/L, or suspected ingestion with acidemia (pH <7.30).³³ Fomepizole therapy should be continued until methanol or ethylene glycol concentration is less than 20 mg/dL.