INGESTIONS

• 3 alcohols can cause potentially fatal intoxication: isopropyl alcohol (isopropanol), methanol (wood alcohol) and ethylene glycol. 

• Isopropanol (found in rubbing alcohol, solvents, de-icers): metabolized by alcohol dehydrogenase to acetone.

• 80% of an oral dose of isopropyl alcohol is absorbed w/in 30 min, w/ complete absorption in 2 hours. 

• With large ingestion (150 - 240 ml) can be a lethal dose due to CNS and myocardial depression. 

• In comparison to methanol and ethylene glycol, it is the parent compound and not the metabolites that are toxic. 

• Toxic metabolites of methanol are formaldehyde and formic acid.  Ethylene glycol is metabolized to glycolic acid (can be toxic to renal tubules) and oxalic acid (can precipitate in renal tubules) and causes calcium oxalate crystals in urine.

 

DIAGNOSIS

• Suspect isopropyl alcohol ingestion if following findings seen following an ingestion: ataxia, lethargy (can progress to coma), elevated plasma osmolal gap (calculated osm- measured osm), and ketonuria and acetone on the breath in the absence of metabolic acidosis or hyperglycemia.

• Calculated plasma osmolality = 2 (Na) + (Glucose/18) + (BUN/2.8) + (Ethanol/4.6)

• If some additional solute is added to the plasma, the osmolality calculated will be well below the actual measured value.

• Major use of the osmolal gap has been as a rapid screening test for methanol or ethylene glycol or isopropyl alcohol intoxication. 

• The association of methanol and ethylene glycol with a severe high anion gap metabolic acidosis is typically utilized to help distinguish these ingestions from isopropanol intoxication.

• However, a normal anion gap and little or no metabolic acidosis may be seen in pts w/ methanol or ethylene glycol ingestion AND concurrent ETOH ingestion --- the ETOH limits the amount that can be metabolized by alcohol dehydrogenase to the toxic metabolites. 

• Can have a high anion gap metabolic acidosis with ingestion of large amt of isopropyl alcohol alone, as its myocardial depression/hypotension can cause a lactic acidosis secondary to hypoperfusion.

 

TREATMENT OF ISOPROPYL ALCOHOL INGESTON

• Most pts can be treated w/ supportive therapy, incl fluids, pressors and intubation for respiratory depression. 

• Rapid absorption limits utility of gastric lavage or emesis unless pt is seen w/in 2 hours of ingestion or has taken other medications. 

• Continuous gastric lavage is indicated b/c of reentry of circulating isopropanol into the stomach.

• Hemodialysis efficiently removes both isopropanol and acetone.  Indications for HD include hypotension, plasma levels above 400 mg/dl, prolonged coma, and underlying renal or hepatic insufficiency that will limit the metabolism and excretion of isopropanol.

 

TREATMENT OF METHANOL AND ETHYLENE GLYCOL INGESTION

FOMEPIZOLE — Fomepizole (4-methylpyrazole, Antizol®) rapidly and competitively inhibits alcohol

dehydrogenase more potently than ethanol, and is now the antidote of choice in cases of methanol

and ethylene glycol intoxication.  Fomepizole has been used extensively to treat ethylene glycol poisoning in France since 1990, and an intravenous formulation of the drug was approved for this indication in adults by the United States Food and Drug Administration in late 1997. Because other alcohols are also metabolized to toxic products by alcohol dehydrogenase, fomepizole is effective for the management of methanol, isopropanol, or diethylene glycol intoxication, and was approved by the United States Food and Drug Administration for treatment of methanol intoxication in late 2000.

• Small studies or case series have documented dramatic improvements in acidemia and prevention of renal injury when fomepizole is used to treat methanol or ethylene glycol intoxication. Fomepizole also prolongs the half-life of ethanol; the simultaneous use of both agents therefore is not recommended. Usually well-tolerated but can cause HA, nausea, bradycardia, dizziness, eosinophilia, or mild, transient elevation of liver enzymes.
   
• Treatment with fomepizole should be initiated as quickly as possible when there is a suspicion of methanol or ethylene glycol poisoning. A loading dose of 15 mg/kg should be given in 100 mL of D5W over 30 minutes, followed by doses of 10 mg/kg every 12 hours for 48 hours, then 15 mg/kg every 12 hours thereafter until methanol or ethylene glycol concentrations fall below 20 mg/dL. Fomepizole induces its own metabolism via the CYP (cytochrome P450) system, necessitating the increase in maintenance dose after 48 hours. The drug is dialyzable and its dosing interval must be decreased to every four hours during hemodialysis.

• As with an ethanol infusion, fomepizole is of no benefit late in the poisoning when the alcohol has already been metabolized. In addition, dialysis should be employed to remove the parent alcohol and its metabolites if severe poisoning is suspected from the magnitude of the anion gap or the metabolic acidosis.  Fomepizole is expensive (approximately $3000 U.S.dollars per treatment or $1200 for a 1.5 g vial).

 

ETHANOL— Intravenous or oral ethanol is an essential component of early therapy in these disorders unless fomepizole is administered. Alcohol dehydrogenase, the enzyme responsible for the formation of toxic metabolites, has more than a 10-fold greater affinity for ethanol than for other alcohols.  As a result, ethanol administration should be protective; furthermore, patients who ingest ethanol as well as methanol or ethylene glycol may present without metabolic acidosis, a high anion gap, or symptoms despite high circulating levels of the parent compound.  In this setting, the presence of high osmolal gap provides an important clue to the correct diagnosis.

• Ethanol is generally administered to patients with methanol or ethylene glycol intoxication unless fomepizole is available.  An unusual exception is the patient who presents late after the ingestion, a time at which the entire intoxicant has already been metabolized. Such patients present with a high anion gap metabolic acidosis but no osmolal gap.
   
• The efficacy of ethanol is most prominent when the plasma ethanol concentration is about 100 to 200 mg/dL This level can generally be achieved by the following regimen: a loading dose of 0.6 g/kg plus an hourly maintenance dose of 66 mg/kg in nondrinkers, 154 mg/kg in drinkers, and 240 mg/kg once hemodialysis is started.  If oral ethanol is given, the dose may have to be doubled if charcoal has been administered.  Regardless of the mode of administration, the plasma ethanol concentration should be monitored, since adjustments in dosage will be required in some patients. Ethanol and, if necessary, hemodialysis are continued until a low plasma drug level is achieved; for example, less than 10 to 20 mg/dL (3 to 6 mmol/L) with methanol intoxication.
   
• Ethanol administration: Intravenous ethanol comes in 5 or 10 % solutions (5 or 10 g per 100 mL) diluted in dextrose and water. Oral or nasogastric ethanol is usually given as a 20 percent solution, which can be created by adding 21 mL of 95 percent ethanol to 79 mL of water or another tolerable diluent. Different whiskeys vary in concentration from 90 proof (45 percent) to 190 proof (95 percent).

• Hemodialysis — Hemodialysis should be performed in severe intoxications to remove both the parent compound and metabolites.

 

General indications for hemodialysis have included a high plasma level (more than 50 mg/dL for methanol or more than 20 mg/dL for ethylene glycol), the presence of metabolic acidosis, and symptoms (such as visual or mental status changes with methanol).  Hemodialysis is continued until the plasma levels fall below the toxic range.

• Fomepizole is dialyzable and the frequency of its dosing should be increased to every 4 hours during hemodialysis. An additional dose should be given at the beginning of hemodialysis if 6 hours have elapsed since the prior dose.  If ethanol is used, adjustments in the dose also must be made during hemodialysis. A fall in ethanol levels can be avoided or ameliorated by increasing the rate of ethanol infusion and possibly by adding ethanol directly to the dialysate.
   
• Other —With methanol poisoning, folic acid (50 to 70 mg IV every four hours for the first day) may promote catalase-mediated metabolism of formate to carbon dioxide and water. Certain vitamins can also be effective with ethylene glycol intoxication. Pyridoxine (50 mg IM, four times daily) and thiamine (100 mg IM, four times daily) promote the conversion of glyoxalate into less toxic metabolites than oxalate such as glycine.
   
• Forced diuresis with fluids and mannitol may preserve renal function during ethylene glycol intoxication by minimizing tubular blockade by oxalate crystals.