Toxic Alcohols

GENERAL PRINCIPLES

• The classic toxic alcohols are methanol, ethylene glycol, and isopropanol. Other agents include diethylene glycol, propylene glycol, and glycol ethers.

• Toxic alcohols may be found in automotive and household products, including brake and wiper fluid, antifreeze, coolant fluids, and hand sanitizer.

• Methanol is produced during the process of liquor distillation and may contaminate alcoholic beverages, especially when these are illicitly produced by people not familiar with the distillation process.

Pathophysiology

• Metabolism of toxic alcohols by alcohol dehydrogenase and aldehyde dehydrogenase generates toxic organic acids which are responsible for acidosis and end-organ damage.

î Methanol is metabolized to formic acid, which is toxic to the retina.

î Ethylene glycol is metabolized to glycolic acid (which is primarily responsible for the metabolic acidosis seen in this poisoning) and oxalic acid (which is nephrotoxic).

î Isopropanol is metabolized to acetone (a ketone) and cannot be further metabolized by aldehyde dehydrogenase.

DIAGNOSIS

Clinical Presentation

The clinical presentation of toxic alcohol poisoning varies depending on the time from ingestion to presentation.

• Patients presenting relatively rapidly after ingestion will present with inebriation and may be mistakenly diagnosed with ethanol intoxication.

• Patients presenting late may have tachypnea, tachycardia, mental status changes, or frank shock due to acidosis. Patients presenting late after methanol poisoning may complain of vision changes.

Suspect toxic alcohol poisoning in an inebriated patient who does not clinically improve over time as would be typical in ethanol intoxication.

Differential Diagnosis

Alcoholic ketoacidosis, sepsis, occult hemorrhage, and cardiogenic shock, poisonings by other xenobiotics that produce shock, mental status changes, and acidosis (metformin, iron, cyanide, salicylates, dinitrophenol, and nucleoside reverse transcriptase inhibitors).

Diagnostics

LABORATORIES

• Rapid laboratory testing for toxic alcohols and their metabolites is not usually readily available in most institutions. Send-out laboratories for methanol and ethylene glycol should be obtained.

• Because rapid reliable laboratory tests are not available, the initial diagnosis of toxic alcohol poisoning must frequently be made by inference from other laboratory tests.

î A significantly elevated osmolar gap, which is the difference between the calculated osmolarity and the measured serum osmolarity, may indicate the presence of “unmeasured osmoles,” which include toxic alcohols.

#9632; A normal or low osmolar gap does not rule out toxic alcohol poisoning. There is significant interindividual variation in the normal or baseline osmolar gap.

#9632; The osmolar gap declines over time as toxic alcohols are metabolized to organic acids; patients presenting late may have a normal osmolar gap.

î A significantly elevated anion gap with metabolic acidosis may indicate the presence of “unmeasured anions,” which include the organic acid products of toxic alcohol metabolism.

#9632; The anion gap increases over time as organic acids are generated and accumulate; patients presenting early may have a normal anion gap.

#9632; An anion gap acidosis that worsens significantly over time despite appropriate resuscitative care may suggest toxic alcohol poisoning.

#9632; An anion gap acidosis that improves with resuscitative care alone (i.e., without antidote or hemodialysis) essentially rules out significant toxic alcohol poisoning.

• Obtain a BMP (to assess for renal function, anion gap, and acid-base status), ethanol concentration (to aid in calculation of the osmolar gap and in treatment decisions), and serum osmolarity (to aid in calculation of the osmolar gap).

• Certain point of care lactate analyzers misinterpret glycolic acid as lactic acid, whereas laboratory­based lactate testing typically does not suffer from this error.

A significantly elevated point of care lactate with a normal laboratory-run lactate may suggest the presence of glycolic acid, which suggests ethylene glycol poisoning.

• Urinalysis may show calcium oxalate crystals in ethylene glycol poisoning.

• Isopropanol poisoning classically produces ketosis without acidosis.

TREATMENT

• Empiric treatment before laboratory confirmation is frequently required, given the difficulties involved in obtain direct laboratory confirmation of toxic alcohol poisoning described above.

• The mainstay of treatment is fomepizole.

î Fomepizole is an alcohol dehydrogenase inhibitor, which functionally blocks the metabolism of toxic

alcohols into organic acids. It will not reverse acidosis or end-organ damage.

î The initial dose of fomepizole is 15 mg/kg IV, followed by maintenance dosing of 10 mg/kg IV every 12 hours.

#9632; If more than 48 hours of therapy is required, the maintenance dose should be increased to 15 mg/kg IV every 12 hours, as fomepizole induces its own metabolism.

#9632; Fomepizole must be dose-adjusted if the patient undergoes hemodialysis.

î Fomepizole therapy should be continued until the toxic alcohol concentration (methanol or ethylene glycol) is lt;20 mg/dL.

• Ethanol therapy was previously widely used to treat toxic alcohol poisoning, as ethanol is an effective competitive antagonist of alcohol dehydrogenase.

î Ethanol therapy is difficult to dose and titrate and has significant associated adverse effects; it is not indicated unless fomepizole is completely unavailable.

• Hemodialysis effectively clears toxic alcohols, clears the organic acid metabolites, and corrects acidosis.

î Hemodialysis is indicated in any patient with toxic alcohol poisoning who has significant acidosis (pH #8804; 7.15), coma, seizures, shock, significant renal impairment, or evidence of end-organ damage (acute kidney injury in ethylene glycol poisoning or vision deficits in methanol poisoning).

î Hemodialysis is frequently required in methanol poisoning because of the extremely prolonged half­life of methanol in patients being treated with fomepizole.

o Hemodialysis may be more cost-effective than prolonged hospitalization and fomepizole therapy in patients with extremely high ethylene glycol concentrations.

• Sodium bicarbonate should be a temporizing therapy for severe acidosis only and does not directly treat or reverse toxicity.

• Intravenous high-dose vitamin supplementation may promote the metabolism of toxic alcohols via alternative metabolic pathways that produce nontoxic end products.

î Methanol poisoning: administer folate or leucovorin 1 mg/kg (max 50 mg) IV q4-6 hours.

î Ethylene glycol poisoning: administer thiamine 100 mg IV q4-6 hours and pyridoxine 50 mg IV q6- 12 hours.

• Severely poisoned patients may require aggressive resuscitative care, including fluid resuscitation, vasopressors and inotropes for shock, and intubation and mechanical ventilation.

• Isopropanol poisoning rarely requires any treatment beyond close observation and supportive care.