Metanol

Clinical Effects:

SUMMARY OF EXPOSURE
A)  USES: One of the toxic alcohols that is found in windshield wiper fluid, gas line antifreeze, fuels, photocopy fluid, solvents, carburetor cleaner, and as an adulterant in homemade ethanol distillates.
B)  TOXICOLOGY: An alcohol that causes intoxication similar to ethanol and is metabolized to formaldehyde and formic acid via alcohol dehydrogenase and aldehyde dehydrogenase, respectively. Formic acid causes a metabolic acidosis and causes blindness through direct retinal toxicity. Toxicity is most common after ingestion but has been reported with inhalation and dermal exposures.
C)  EPIDEMIOLOGY: Uncommon exposure that can result in significant morbidity and mortality.
D)  WITH POISONING/EXPOSURE
1)  MILD TO MODERATE TOXICITY: Patients will initially have signs of acute intoxication, such as ataxia, sedation, and disinhibition. Patients may also complain of abdominal pain, nausea, vomiting, and headache. Acidosis or signs of visual impairment suggest a more severe poisoning.
2)  SEVERE TOXICITY: Severe metabolic acidosis develops hours after exposure (if ethanol is not coingested) and may lead to multiorgan dysfunction including hypotension, tachycardia, dysrhythmias, seizures, coma, pancreatitis, and acute renal failure. Rhabdomyolysis may occur in severe poisonings. Hypomagnesemia, hypokalemia, and hypophosphatemia have also been reported. In addition, ocular toxicity may develop; manifestations include mydriasis, hyperemic optic discs, and papilledema. Visual impairment may develop, which may range from blurry/hazy vision to color vision defects to “snowfield” vision to total blindness. Permanent sequelae after severe intoxication may include basal ganglia necrosis with parkinsonian features (ie, tremor, rigidity, bradykinesia) and blindness.
VITAL SIGNS
A)  WITH POISONING/EXPOSURE
1)  Mild tachycardia is common with significant poisoning. Tachypnea secondary to metabolic acidosis is common.
REPRODUCTIVE
A)  Methanol, together with other solvents, has been linked with birth defects of the central nervous system in humans (Holmberg, 1979), but methanol cannot be considered a human reproductive hazard, because of mixed or poorly documented exposures.
Lab/Monitoring:
A)  Monitor mental status, vital signs, and ECG.
B)  In patients with significant CNS depression or metabolic acidosis, obtain arterial or venous blood gases.
C)  Obtain a serum methanol and ethanol concentration and serial serum electrolytes; calculate anion gap.
D)  If serum methanol cannot be obtained in a timely fashion, measure serum osmolality and calculate osmolal gap. The osmolal gap is equal to the measured serum osmolality minus (2 x serum sodium + BUN/2.8) + glucose/18 + ethanol/4.6). An elevated osmolal gap (greater than 10) suggests the presence of toxic alcohols, but a normal osmolal gap does NOT rule this out.
Treatment:
ORAL/PARENTERAL EXPOSURE
A)  MANAGEMENT OF MILD TO MODERATE TOXICITY
1)  Obtain a methanol level, serum chemistry, and a serum pH. A thorough visual exam should be performed, including visual acuity. An elevated osmolar gap suggests the presence of methanol or another alcohol but cannot be used to rule out a significant exposure. If a methanol concentration is readily available (results known within 2 hours) and the patient is asymptomatic, then alcohol dehydrogenase (ADH) inhibition can be delayed until the methanol concentration is available. Patients with a methanol concentration of more than 25 mg/dL or metabolic acidosis should be treated with ADH inhibition. If methanol concentrations cannot readily be measured, patients with a history of a potentially toxic ingestion, symptomatic patients, and those with suspected methanol intoxication with an anion gap metabolic acidosis or an osmolal gap greater than 10 mOsm should be treated with ADH inhibition. Folate should also be intravenously administered to patients requiring ADH inhibition. In patients who receive ADH inhibition who have a significant methanol concentration, consider hemodialysis since the apparent half-life of methanol under these circumstances is quite prolonged.
B)  MANAGEMENT OF SEVERE TOXICITY
1)  Patients presenting with severe acidosis, signs or symptoms of visual changes, or depressed level of consciousness should be started immediately on an ADH inhibitor and intravenous folate. Hemodialysis should be initiated and should be continued until the methanol concentration is undetectable and the serum pH is normal. Treat seizures with benzodiazepines.
C)  DECONTAMINATION
1)  PREHOSPITAL: There is no role for prehospital decontamination.
2)  HOSPITAL: In general, gastrointestinal decontamination is not very useful because methanol is rapidly absorbed and binds poorly to activated charcoal. Insertion of a nasogastric tube to aspirate gastric contents may be useful in rare patients who present shortly after large ingestions.
D)  AIRWAY MANAGEMENT
1)  Endotracheal intubation may be necessary in patients with significant CNS or respiratory depression. Extreme care must be taken to increase minute ventilation sufficiently to prevent severe acidemia in intubated patients.
E)  ANTIDOTE
1)  Treat patients with either fomepizole or ethanol to prevent the production of formate. Indications include documented plasma methanol concentration greater than 20 mg/dL (greater than 200 mg/L) OR documented recent history of ingesting toxic amounts of methanol and osmolal gap greater than 10 mOsm/L OR history or strong clinical suspicion of methanol poisoning with at least 2 of the following criterion: arterial pH less than 7.3; serum bicarbonate less than 20 mEq/L; osmolol gap greater than 10 mOsm/L.
FOMEPIZOLE VS ETHANOL: Fomepizole is easier to use clinically, requires less monitoring, does not cause CNS depression or hypoglycemia, and may obviate the need for dialysis in some patients. Ethanol requires continuous administration and frequent monitoring of serum ethanol and glucose levels and may cause CNS depression and hypoglycemia (especially in children). The drug cost associated with ethanol use is generally much lower than with fomepizole; however, other costs associated with ethanol use (eg, continuous intravenous infusion, hourly blood draws, nursing costs, and ethanol levels, possibly greater use of hemodialysis) may make the costs more comparable.
FOMEPIZOLE: Fomepizole is administered as a 15 mg/kg loading dose, followed by 4 bolus doses of 10 mg/kg every 12 hours. If therapy is needed beyond this 48-hour period, the dose is then increased to 15 mg/kg every 12 hours for as long as necessary. Fomepizole is also effectively removed by hemodialysis; therefore, doses should be repeated following each round of hemodialysis.
ETHANOL: Ethanol is given to maintain a serum ethanol concentration of 100 to 150 mg/dL. This can be accomplished by using a 5% or 10% ethanol solution administered intravenously through a central line. Intravenous therapy dosing, which is preferred, is 0.8 g/kg as a loading dose (8 mL/kg of 10% ethanol) administered over 20 to 60 minutes as tolerated, followed by an infusion rate of 80 to 150 mg/kg/hr (for 10% ethanol, 0.8 to 1.3 mL/kg/hr for a nondrinker; 1.5 mL/kg/hr for a chronic alcoholic). During hemodialysis, either add ethanol to the dialysate to achieve 100 mg/dL concentration or increase the rate of infusion during dialysis (10% ethanol, 2.5 to 3.5 mL/kg/hr). Oral ethanol may be used as a temporizing measure until intravenous ethanol or fomepizole can be obtained, but it is more difficult to achieve the desired stable ethanol concentration. The loading dose is 0.8 g/kg (4 mL/kg) of 20% {40 proof}) ethanol diluted in juice administered orally or via nasogastric tube. Maintenance dose is 80 to 150 mg/kg/hr (20% {40 proof}) ethanol; 0.4 to 0.7 mL/kg/hr for a nondrinker; 0.8 mL/kg/hr for a chronic alcoholic). Concentrations greater than 30% (60 proof) ethanol should be diluted. For both modalities, blood ethanol levels must be monitored hourly and adjusted accordingly, and both require patient monitoring in an ICU setting.
FOLATE: Folate increases the metabolism of formate. Either folic acid or leucovorin (folinic acid) may be used. In symptomatic patients (anion gap acidosis, visual disturbances) and asymptomatic patients with known or suspected methanol intoxication, administer intravenous folic acid 1 to 2 mg/kg every 4 to 6 hours for the first 24 hours, and continue until methanol is cleared and acidosis resolved. Folate is removed by hemodialysis so in patients undergoing hemodialysis, administer one dose prior to and another at the completion of hemodialysis.
F)  ENHANCED ELIMINATION
1)  Methanol and its metabolites (formaldehyde and formic acid) are readily removed by hemodialysis. Emergent hemodialysis is indicated in any methanol-intoxicated patient with an anion gap metabolic acidosis (pH less than 7.3), visual disturbances, or CNS depression. Because methanol is cleared very slowly once ADH inhibitors are administered, hemodialysis should also be considered in patients with methanol concentrations greater than 50 mEq/L, even in the absence of acidosis or severe symptoms.
G)  PATIENT DISPOSITION
1)  OBSERVATION CRITERIA: Intentional ingestions should be evaluated in a health care facility. Potential serum levels can be calculated using methanol percentage, amount ingested, and patient weight and all levels potentially greater than 25 mg/dL should be evaluated in a health care facility.
2)  ADMISSION CRITERIA: Patients who are acidotic, have visual symptoms, or have serum methanol concentrations above 25 mg/dL should be admitted.
3)  CONSULT CRITERIA: Consult a poison center or medical toxicologist in cases of severe poisonings, in cases where a methanol level is not readily available, or in cases where the ingestion is uncertain. Consult a nephrologist for any patient who may require hemodialysis.
H)  PITFALLS
1)  Depending on the timing of the presentation, an increased osmolar gap or an increased anion gap may not always be present. An increased anion gap will not be present in patients presenting early, and an increased osmol gap may not be present in patients presenting late. When calculating osmolarity, the ethanol level needs to be taken into account in the calculation. A normal osmolal gap does not rule out the possibility of methanol intoxication. Patients who are ethanol intoxicated will have a later presentation of their acidosis, as the ethanol is effectively blocking the metabolism of the methanol.
I)  PHARMACOKINETICS
1)  Methanol is rapidly and readily absorbed. The apparent half-life of methanol is approximately 8 to 28 hours. The volume of distribution is approximately 0.6 L/kg. It is not protein bound.
J)  TOXICOKINETICS
1)  When alcohol dehydrogenase inhibitors are being used, the apparent half-life is increased to approximately 50 hours.
K)  DIFFERENTIAL DIAGNOSIS
1)  Exposure to other alcohols, such as ethanol, ethylene glycol, isopropyl alcohol, and other glycol ethers. A broad variety of other toxins and medical causes can also result in a metabolic acidosis.
INHALATION EXPOSURE
A)  Intentional inhalational exposures can result in significant methanol levels and should be treated similarly to oral ingestions.
B)  INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
EYE EXPOSURE
A)  DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
DERMAL EXPOSURE
A)  OVERVIEW
1)  Rarely has repeated dermal exposure resulted in severe methanol toxicity. It should be treated similarly to an ingestion exposure.
2)  DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
Range of Toxicity:
A)  TOXICITY: Most experts agree that a methanol concentration of 25 mg/dL is the threshold for treatment. An ingestion of 0.25 mL/kg of 100% methanol would theoretically (assuming 100% absorption) result in a toxic methanol concentration.
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