eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Alcohols

Michael D Levine, MD, Physician, Department of Medical Toxicology, Banner Good Samaritan Medical Center
Tobias D Barker, MD, Attending Physician, Department of Emergency Medicine; Director, Harvard Medical School Dubai Center Simulation Center

Updated: Nov 11, 2009

Introduction

Background

Although any alcohol can be toxic if ingested in large enough quantities, the term toxic alcohol has traditionally referred to isopropanol, methanol, and ethylene glycol. Prompt recognition and treatment of patients intoxicated with these substances can reduce the morbidity and mortality associated with these alcohols.

This article discusses not only the 3 toxic alcohols but also ethanol. Ethanol withdrawal is a serious and potentially life-threatening problem, which is discussed in Withdrawal Syndromes.

Pathophysiology

Ethanol

Ethyl alcohol (ethanol; CH₃ -CH₂ -OH) is a low molecular weight hydrocarbon, which is derived from the fermentation of sugars and cereals. It is widely available both as a beverage and as an ingredient in food extracts, cough and cold medications, and mouthwashes. 

Ethanol is rapidly absorbed across both the gastric mucosa and the small intestines, reaching a peak concentration 20-60 minutes after ingestion. Once absorbed, it is converted to acetaldehyde. This conversion involves 3 discrete enzymes: the microsomal cytochrome P450 isoenzyme CYP2E1, the cytosol-based enzyme alcohol dehydrogenase (ADH), and the peroxisome catalase system. Acetaldehyde is then converted to acetate, which is converted to acetyl Co A, and ultimately carbon dioxide and water.¹

Genetic polymorphisms coding for alcohol dehydrogenase, the amount of alcohol consumed, and the frequency at which ethanol is consumed all affect the speed of metabolism. Chronic alcoholics and those with severe liver disease have increased rates of metabolism. However, as a general rule, ethanol is metabolized at a rate of 20-25 mg/dL in the nonalcoholic but at an increased rate in chronic alcoholics.

Isopropanol

Isopropyl alcohol (isopropanol; CH₃ -CHOH-CH₃) is a low molecular weight hydrocarbon. It is commonly found as both a solvent as well as a disinfectant. It can be found in many mouthwashes, skin lotions, and rubbing alcohol. Because of its widespread availability, lack of purchasing restrictions, and profound intoxicating properties, it is commonly used as an ethanol substitute.

Isopropanol is rapidly absorbed across the gastric mucosa and reaches a peak concentration approximately 30-120 minutes after ingestion. Isopropanol is primarily metabolized via alcohol dehydrogenase to acetone. A small portion of isopropanol is excreted unchanged in the urine. The peak concentration of acetone is not present until approximately 4 hours after ingestion. Both the CNS depressant effects and the fruity odor on the patient's breath are due to acetone.

Methanol

Methyl alcohol (methanol; CH₃ OH) is widely used as an industrial and marine solvent and paint remover. It is also used in photocopying fluid, shellacs, and windshield-washing fluids. Although toxicity primarily occurs from ingestion, it can also occur from prolonged inhalation or skin absorption.^2,3 Methanol is rapidly absorbed from the gastric mucosa, and achieves a maximal concentration 30-90 minutes after ingestion.

Methanol is primarily metabolized in the liver via alcohol dehydrogenase into formaldehyde. Formaldehyde is subsequently metabolized via aldehyde dehydrogenase into formic acid, which ultimately is metabolized to folic acid, folinic acid, carbon dioxide, and water. A small portion is excreted unchanged by the lungs. Formic acid is responsible for the majority of the toxicity associated with methanol. Without competition for alcohol dehydrogenase, methanol undergoes zero-order metabolism, and is thus is excreted at a rate of 8.5 mg/dL/h to 20 mg/dL/h. Once methanol experiences competitive inhibition, from either ethanol or fomepizole, the metabolism changes to first order. In this later scenario, the excretion half-life ranges from 22-87 hours.

Ethylene glycol

Ethylene glycol (CH₂ OH-CH₂ OH) is an odorless, colorless, sweet-tasting liquid, which is used in many manufacturing processes. Around the house, it is probably most commonly encountered in antifreeze. It is absorbed somewhat rapidly from the gastrointestinal tract, and peak concentrations are observed 1-4 hours after ingestion.

Ethylene glycol itself is nontoxic, but it does get metabolized into toxic compounds. Ethylene glycol is oxidized via alcohol dehydrogenase into glycoaldehyde. Glycoaldehyde subsequently undergoes metabolism via aldehyde dehydrogenase into glycolic acid.⁴ The conversion to glycolic acid is somewhat rapid. In contrast, the conversion of glycolic acid to glyoxylic acid is slower and is the rate-limiting step in the metabolism of ethylene glycol.

Glyoxylic acid is subsequently metabolized into several different products, including oxalic acid (oxalate), glycine, and alpha-hydroxy-beta-ketoadipate. The conversion to glycine requires pyridoxine as a cofactor, while the conversion to alpha-hydroxy-beta-ketoadipate requires thiamine as a cofactor. The oxalic acid combines with calcium to form calcium oxalate crystals. In the presence of normal renal function and no competitive inhibition for alcohol dehydrogenase, the excretion half-life of ethylene glycol is approximately 3 hours. However, in the presence of fomepizole or ethanol, alcohol dehydrogenase undergoes competitive inhibition, and the resulting excretion half-life increases to approximately 17-20 hours.

Frequency

Alcohol intoxication is common in modern society, largely because of its widespread availability. More than 8 million Americans are believed to be dependent on alcohol, and up to 15% of the population is considered at risk. In some studies, more than half of all trauma patients are intoxicated with ethanol at the time of arrival to the trauma center. In addition, ethanol is a common coingestant in suicide attempts.

Mortality/Morbidity

Acute intoxication with any of the alcohols can result in respiratory depression, aspiration, hypotension, and cardiovascular collapse. 
 
Ethanol

Although many patients present with ethanol intoxication as their sole issue, many other patients have ethanol intoxication as part of a larger picture. Thus, the morbidity is often from coingestants or coexisting injuries and illnesses. 

Chronic use results in hepatic and gastrointestinal injuries. Coma, stupor, respiratory depression, hypothermia, and death can result from high concentrations of acute ethanol intoxication. Chronic alcoholics, as well as children, are at risk for hypoglycemia.

Isopropanol, methanol, and ethylene glycol

In 2007, 7,447 cases of isopropanol ingestions were reported to the US Poison Control Centers. Of these, 36 patients were classified as experiencing "major" morbidity with one patient dying. In the same year, 2,252 cases of methanol and 5,395 cases of ethylene glycol were reported. Of those intoxicated with methanol, 26 patients were classified as experiencing "major" disability, and 11 additional patients died. For those patients who were intoxicated with ethylene glycol, 135 patients were classified as having "major" disability, with an additional 16 patients dying.⁵ It is important to recognize that these numbers likely underestimate the true incidence of exposure, however, because of both a failure to recognize the ingestion as well as a failure to report the suspected or known ingestion to a poison control center.

The primary toxicity with isopropanol is CNS depression. These CNS manifestations can include lethargy, ataxia, and coma. In addition, isopropanol is irritating to the GI tract. Therefore, abdominal pain, hemorrhagic gastritis, and vomiting can be observed. Unlike methanol and ethylene glycol, isopropanol does not cause a metabolic acidosis.

The toxicity with methanol occurs from both the ensuing metabolic acidosis, as well as the formate anion (formic acid) itself.⁶ Although the eye is the primary site of organ toxicity, in the later stages of severe methanol toxicity, specific changes can occur in the basal ganglia as well. Pancreatitis has been reported following methanol ingestion. Hyperventilation will occur as a compensatory mechanism to counteract the acidosis.

As previously stated, ethylene glycol by itself is nontoxic. The majority of the metabolic acidosis occurs from glycolic acid. One form of morbidity occurs when oxalate combines with calcium to form calcium oxalate crystals, which accumulate in the proximal renal tubules, thereby inducing renal failure. Hypocalcemia can ensue, and cause coma, seizures, and dysrhythmias. Autopsy studies have confirmed the calcium oxalate crystals are deposited not only in the kidneys but in many organs, including the brain, heart, and lungs.

Age

Ethanol intoxication is common in older teenagers through adulthood. The toxic dose for an adult is 5 mg/dL, whereas the toxic dose in a child is 3 mg/dL. Children are at higher risks of developing hypoglycemia following a single ingestion than are adults. 
 
Most isopropanol ingestions occur in children younger than 6 years. Most methanol and ethylene glycol ingestions occur in adults older than 19 years. 

Clinical

History

A history of inebriation with associated slurred speech, ataxia, and impaired judgment is common in the initial stages of intoxication of each of these alcohols. Depending on the dose ingested, this may be followed by progressive levels of CNS depression, coma, and premorbid multiorgan failure. The history that is able to be obtained varies with the timing of presentation. The timing of the later stages of toxic alcohol intoxication can also be delayed if ethanol is coingested, prolonging the time it takes to develop metabolic acidosis and other symptoms. The following focuses on symptoms that may be unique to each alcohol.

• Ethanol ingestion
  • The history itself can often point to a diagnosis of ethanol intoxication. An associated history of chronic alcoholism alters metabolism, associated comorbidities, and the expected course of recovery. A detailed discussion of this topic is beyond the scope of this article (see Toxicity, Ethanol).
  • Attempting to elicit what has changed recently may reveal the immediate reason for presentation. A history of coingestants may also alter the patient's course.
• Isopropanol ingestion
  • Following an isopropanol ingestion, the patient may not complain of anything specific. Rather, the patient may simply appear intoxicated, as with ethanol intoxication. 
  • A history of abdominal pain, nausea, and sometimes hematemesis may be obtained. 
• Methanol ingestion
  • Following methanol ingestion, a patient is initially inebriated as with the other alcohols. Other symptoms can be delayed for up to 12-24 hours. 
  • The patient may complain of headache, nausea, or anorexia. Occasionally, the patient may complain of shortness of breath related to hyperventilation. 
  • Because one of the primary end-organs involved in methanol is the eye, the patient may complain of difficulty seeing. Specifically, vision is often described as a "snow field," though a variety of visual complaints may be verbalized.
• Ethylene glycol ingestion
  • Ethylene glycol toxicity occurs in 3 stages.
    • The first stage, called the neurologic phase, can occur in less than 1 hour after ingestion and lasts up to 12 hours. During this stage, the patient appears inebriated. The patient may not have any other significant findings during this stage. Occasionally, hypocalcemia can occur at this point and induce muscle spasms and abnormal reflexes. 
    • The second stage, which occurs between 12 and 24 hours after ingestion, is referred to as the cardiopulmonary stage. During this stage, the patient frequently develops mild tachycardia and hypertension. Acute respiratory distress syndrome (ARDS) can also occur. These findings are believed to result from calcium oxalate crystal deposition in the lung parenchyma and myocardium. Significant hypocalcemia can occur at this stage, with QT prolongation and associated arrhythmias. Expect hyperventilation as metabolic acidosis progresses.
    • The third stage, also called the renal stage, typically starts after 24 hours. During this stage, flank pain and acute renal failure can occur. A premorbid patient presenting with ethylene glycol toxicity typically presents comatose, hyperventilating, and in multiorgan failure.

Physical

• Ethanol ingestion
  • The symptoms of ethanol intoxication depend on both the serum concentration as well as the frequency at which an individual ingests ethanol. Thus, a person who consumes large amounts of ethanol on a daily basis may appear sober at the same serum ethanol level at which a novice drinker exhibits cerebellar dysfunction.
  • As a general rule, levels less than 25 mg/dL are associated with a sense of warmth and well-being. Euphoria and decreased judgment occur at levels between 25-50 mg/dL. Incoordination, decreased reaction time/reflexes, and ataxia occur at levels of 50-100 mg/dL. Cerebellar dysfunction (ie, ataxia, slurred speech, nystagmus) are common at levels of 100-250 mg/dL. Coma can occur at levels of greater than 250 mg/dL, whereas respiratory depression, loss of protective reflexes, and death occur at levels greater than 400 mg/dL.
• Isopropanol ingestion
  • As previously stated, the patient who consumes isopropanol may appear inebriated, as with ethanol. Isopropanol concentrations of 50-100 mg/dL typically result in intoxication, which can progress to include symptoms such as dysarthria and ataxia, while lethargy or coma can be seen with levels exceeding 150 mg/dL. Cardiovascular depression can occur with levels exceeding 450 mg/dL. 
  • The presence of acetone may induce a fruity odor on the patient's breath.  
• Methanol ingestion
  • Unlike ethanol or isopropanol, methanol does not cause nearly as much of an inebriated state. If a patient has coingested ethanol, signs or symptoms specific to methanol intoxication are delayed. 
  • The patient may be hyperventilating.
  • If vision is impaired, ocular examination may reveal dilated pupils that are minimally or unreactive to light with hyperemia of the optic disc. Over several days, the red disc becomes pale, and the patient may become blind. Typically, subjective complaints precede physical findings in the eye. 
• Ethylene glycol ingestion
  • The physical findings depend on the stage of the presentation. Thus, the patient may present simply inebriated or progressively more acidotic as renal failure, cardiovascular dysfunction, and coma develop.
  • Examination findings correlate with the symptoms, as previously described. 
  • In patients who survive severe intoxication, calcium oxalate crystal deposition may occur in the brain parenchyma and can induce cranial neuropathies. These findings typically occur as the patient is recovering from the initial intoxication. The cranial nerves most commonly involved include cranial nerve II, V, VII, VIII, IX, X, and XII.

Differential Diagnoses

Other Problems to Be Considered

Intracranial hemorrhage
Seizure

Workup

Laboratory Studies

Following consumption of any type of alcohol, the extent of the workup depends partly on the history. However, because the patient's sensorium is likely to be altered and a history unobtainable or inaccurate, a thorough physical examination is important to evaluate for occult injuries and laboratory clues can also become invaluable.

If the the possibility of a suicide attempt is raised, an electrocardiogram and basic toxicology screen, including measurement of salicylate and acetaminophen concentrations, become important.

In addition, if ingestion of a toxic alcohol is suspected, a serum ethanol level and basic electrolytes, including a serum bicarbonate level are vital, as the latter are needed to calculate an anion gap. In such a situation, specific serum toxic alcohol levels immensely help guide management. If these are unavailable, calculation of an osmolar gap can sometimes be helpful, though its exclusive use is fraught with pitfalls.⁷ These issues are best discussed with the local poison control center. Arterial blood gases and other tests that measure associated organ dysfunction also become important in cases of poisoning with toxic alcohols.

An important point is that laboratory abnormalities vary dramatically over the course of the patient's presentation and any laboratory abnormalities must be interpreted with the time frame of the patient's presentation in mind. Failing to do so is a common and important pitfall. Thus, early in the course of intoxication with a toxic alcohol, a patient will have neither an anion gap nor an osmolar gap though their serum toxic alcohol level will be highest shortly after ingestion. However, as metabolism of the toxic alcohol occurs, the anion and osmolar gaps develop as metabolites are formed and the toxic alcohol level drops.⁸ Other laboratory abnormalities also develop as end-organ damage occurs. Coingestion of alcohol delays all the laboratory value changes as well as the signs and symptoms of toxic alcohol-induced injury.

• Ethanol
  • The single most important laboratory test in a patient who appears intoxicated with ethanol is a serum glucose level. Hypoxia, head injury, seizures, and other metabolic disturbances must be excluded by either history or physical examination or sought with the appropriate tests. The routine use of a serum blood alcohol level is controversial, largely because it is unlikely to affect management in a patient who is awake and alert. Many clinicians consider the patient safe for discharge once they are clinically (not numerically) no longer intoxicated.
  • In patients who are chronic alcoholics, anemia, thrombocytopenia, elevation of hepatic transaminase levels, and a prolongation of the prothrombin time can be observed. These need not be routinely checked in a patient who presents simply for alcohol intoxication but may be useful if changes from baseline are suspected.
• Isopropanol
  • Serum levels of isopropanol can be obtained but are somewhat of limited value, as the treatment is largely supportive. However, they can be useful in confirming the diagnosis. After correcting for all other variables, including ethanol, the serum isopropanol level can be estimated by multiplying the remaining osmolar gap by 6.0. Serum ketones will often be positive, although the patient should not be acidotic. Because ketones will be present in the serum as recently as 30 minutes after ingestion, if there is no coexisting ethanol ingestion, the absence of ketones effectively rules out isopropanol ingestion.
  • Depending on the assay used in the laboratory, significant ketosis can cause interference with the creatinine assay. As such, the serum creatinine level can be falsely elevated.
• Methanol
  • Serum methanol levels should be obtained when this diagnosis is suspected. As previously stated, both the osmolar and anion gap should be obtained.
  • After correcting for all other variables, including ethanol, the serum methanol level can be estimated by multiplying the remaining osmolar gap by 3.2.
• Ethylene glycol
  • A serum ethylene glycol level should be obtained when this diagnosis is suspected. The osmolar gap and anion gap should also be obtained. After correcting for other variables, including ethanol, the serum ethylene glycol level can be estimated by multiplying the remaining osmolar gap by 6.2.
  • A baseline creatinine and BUN level should be obtained in all cases of ethylene glycol intoxication. These values can then be followed to check for the development of renal failure.
  • In addition, the urine can be examined for evidence of fluorescence. In antifreeze, fluorescein is added to the liquid to permit mechanics to identify the source of a fluid leaking from a car. However, fluorescein is excreted in the urine faster than ethylene glycol. Thus, fluorescence can be eliminated before the patient even arrives in the emergency department. As such, the presence of fluorescence of urine under a Wood's lamp is not a sensitive test. In addition, because certain containers themselves fluoresce, the presence of fluorescence is neither sensitive nor specific. Despite this, a positive test that differentiates urine fluorescence from that of its container may be a quick bedside clue pointing toward ethylene glycol intoxication. Both a serum calcium level and an electrocardiogram should be obtained, since hypocalcemia may occur as calcium combines with oxalate in the form of calcium oxalate crystals.

Procedures

Measuring the osmolar gap is important when toxic alcohols ingestion is suspected. The osmolar gap is determined by subtracting the calculated osmolality from the measured osmolality. The serum osmolality should be determined by freezing point depression rather than by heat of vaporization. 
 
The serum osmolality can be calculated by the following formula:
Osm = (2) (Na⁺) + BUN+ Glucose+ EtOH+ Isopropanol+ MeOH+ Ethylene glycol 
                         2.8         18       4.6             6.0            3.2                6.2                 

In the above formula, if, for example, an ingestion of methanol is suspected, the osmolality should be calculated using the sodium, BUN, and glucose. The ethanol level is also measured and then factored into the equation. If isopropanol and ethylene glycol are not suspected, they can be eliminated from the equation. Then, once the osmolar gap is determined, multiply the osmolar gap by 3.2 to determine the estimated methanol level.
 
It is important to recognize that neither the presence nor absence of an osmolar gap can be used to confirm or exclude a toxic alcohol ingestion. With both methanol and ethylene glycol, the alcohols are metabolized from an alcohol to an aldehyde, and ultimately to an acid. As such, shortly after an ingestion, the patient may have an osmolar gap without an anion gap. Similarly, in the later stages of an ingestion, a patient may have an anion gap without an osmolar gap.

Treatment

Prehospital Care

The prehospital care provider has several important interventions available. First, the prehospital provider should search for any empty containers near the patient. In addition, a blood sugar level should be obtained on anyone who appears intoxicated. Local protocols and the skill level of the provider dictate additional prehospital care for patients with altered mental status.

Emergency Department Care

As with all emergency patients, initial treatment should focus on the airway, breathing, and circulation. Gastric decontamination is rarely necessary for any of the alcohols. An exception to this may be a patient who presents immediately after ingestion of a toxic alcohol in whom one might reasonably expect to be able to recover a significant amount of the toxin via aspiration through a nasogastric tube.

• Treatment of ethanol and isopropanol intoxication is largely supportive.⁹ Because of the hemorrhagic gastritis that can follow isopropanol ingestion, H2 blockade or proton-pump inhibitors may be helpful. Hemodialysis, while effective, is rarely indicated, and should only be used in the setting of profound hemodynamic compromise.
• Once either methanol or ethylene glycol intoxication are suspected, treatment should be initiated without delay. Fortunately, since both alcohols are metabolized by alcohol dehydrogenase, the treatment is the same, and differentiating which of the two toxic alcohols is responsible is not necessary before implementing treatment.⁹  
  • The primary antidotal treatment of methanol or ethylene glycol involves blocking alcohol dehydrogenase. This enzyme can be inhibited by either ethanol or fomepizole.^10,11,12 Toxic alcohol levels are frequently not immediately available. Thus, ideally, if methanol or ethylene glycol poisoning is suspected, the patient should receive a loading dose of fomepizole while the levels are being obtained. Because the next dose of fomepizole is not due for an additional 12 hours, this strategy allows 12 hours for the blood to be processed at a reference laboratory before additional treatment is needed. Inhibition of alcohol dehydrogenase with ethanol may be substituted for treatment with fomepizole (see below), though recent studies have highlighted the greater safety of fomepizole as a treatment, when available.^6,4 In some patients, treatment with fomepizole alone may represent definitive treatment and can prevent the need for hemodialysis.¹³
  • In addition to blocking alcohol dehydrogenase, significant metabolic acidosis should be treated with sodium bicarbonate infusions. If methanol is suspected, folinic acid should be administered at a dose of 1 mg/kg, with a maximal dose of 50 mg. It should be repeated every 4 hours. If folinic acid is not immediately available, folic acid can be substituted at the same dose. If ethylene glycol overdose is suspected, the patient should also receive 100 mg of intravenous thiamine every 6 hours and 50 mg of pyridoxine every 6 hours. The purpose of the thiamine and pyridoxine is to shunt metabolism of glyoxylic acid away from oxalate and favor the formation of less toxic metabolites.
  • In methanol overdose, sodium bicarbonate should be administered liberally, with the goal being to completely reverse the acidosis. Based on experimental studies, formate appears to be excreted in the kidneys at a much higher rate when the patient is not acidotic. In addition, when the patient is not acidotic, formic acid dissociates to formate at lower rates so that less formate crosses the blood-brain barrier. Thus, in methanol intoxication, correcting the acidosis actually speeds up elimination of the toxic compound and decreases toxicity.
  • If ethanol is used, the recommended target serum concentration is 100-150 mg/dL. Because ethanol inhibits gluconeogenesis, hypoglycemia is common in patients on an ethanol infusion.¹⁴ Hypoglycemia is particularly prevalent in pediatric patients on such drips. Thus, serum glucose levels must be checked frequently, at least every 2 hours. In addition, because it is difficult to attain a steady serum concentration of ethanol, the ethanol level also must be checked frequently, and titrations made.
    • A 5% or 10% ethanol solution can be made in the pharmacy. If giving ethanol, a loading dose of 600 mg/kg should be given, followed by a drip of 66-154 mg/kg/h with chronic alcoholics requiring doses at the higher end of the scale. Ethanol can be given either intravenously or orally.
    • In addition to hypoglycemia, additional adverse effects from ethanol infusion include inebriation, CNS depression, pancreatitis, and local phlebitis. Because of the phlebitis that occurs with ethanol infusions, some advocate that ethanol should only be administered via a central venous line.
• Ethanol infusions are not only labor intensive, but once the costs of the frequent blood glucose and serum ethanol levels are accounted for, the cost of the ethanol drip is frequently more expensive than fomepizole. Thus, because of the lower overall cost and the ease of administration and safety considerations, fomepizole has become the preferred antidote for methanol or ethylene glycol poisoning. Fomepizole should be administered as a loading dose of 15 mg/kg. Subsequent doses should be at 10 mg/kg every 12 hours for 4 doses. Because fomepizole actually induces its own metabolism after 48 hours of treatment, if additional doses are needed, the dose should be increased to 15 mg/kg. Fomepizole needs to be re-dosed during hemodialysis. The package insert or local poison center can help with the re-dosing strategy. Fomepizole should be continued until the serum ethylene glycol or methanol concentrations are less than 20 mg/dL.
• Hemodialysis is frequently required in patients with significant methanol or ethylene glycol ingestions.^9,13 Indications for hemodialysis include (1) arterial pH <7.10, (2) a decline of >0.05 in the arterial pH despite bicarbonate infusion, (3) pH <7.3 despite bicarbonate therapy, (4) rise in serum creatinine level by 90 mmol/L, and (5) initial plasma methanol or ethylene glycol concentration >50 mg/dL.

Consultations

• For patients with ethanol intoxication who appear to have issues with dependence or abuse, one can consider referral to an alcohol detoxification facility. Consult a toxicologist for all known or suspected cases of isopropanol, methanol, or ethylene glycol ingestion. If a toxicologist is not immediately available at the medical center where the patient is located, the regional poison control center can be contacted at (800) 222-1222.
• Consult a nephrologist for any known or suspected cases of methanol or ethylene glycol intoxication to assist in the decision making for hemodialysis.

Medication

Fomepizole (eg, 4-methylpyrizole, 4-MP, Antizol) has greater affinity for alcohol dehydrogenase than ethanol or methanol and has a considerably better safety profile than ethanol. Fomepizole has been approved by the US Food and Drug Administration (FDA) for ethylene glycol poisoning, but it is also useful for managing methanol poisoning.

Pharmacologic antidotes

These agents prevent formation of toxic metabolites in methanol ingestions (not useful with isopropanol or ethanol ingestions). Therapy generally is maintained until methanol levels are less than 20 mg/dL.

Fomepizole (4-MP, Antizol)

DOC for ethylene glycol and methanol poisoning because of ease of administration and better safety profile than ethanol. Inhibitor of alcohol dehydrogenase. In contrast to ethanol, 4-MP levels do not require monitoring during therapy.
Begin fomepizole treatment immediately upon suspicion of methanol/ethylene glycol ingestion based on the patient's history or anion gap metabolic acidosis, increased osmolar gap, oxalate crystals in the urine, or a documented serum methanol/ethylene glycol level. Adjust dosing during hemodialysis; see package insert.

Dosing

Adult

Loading dose: 15 mg/kg IV over 30 min
Maintenance doses: 10 mg/kg IV q12h for 4 doses and 15 mg/kg IV q12h thereafter until methanol/ethylene glycol in the blood has been reduced to safe levels

Pediatric

Not established; cautiously administer as in adults

Interactions

PO fomepizole (10-20 mg/kg) may reduce rate of elimination of ethanol by 40% in healthy volunteers; ethanol may decrease rate of elimination of fomepizole by 50%

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Risk of toxic reactions may be greater in patients with impaired renal function (eg, elderly patients); do not administer undiluted or by bolus injection, as venous irritation and phlebosclerosis may occur; associated with seizures, asymptomatic hepatic transaminitis, eosinophilia, and rash

Ethanol

Has 10-20 times greater affinity for enzyme alcohol dehydrogenase than methanol does, blocking production of toxic metabolites.
Believed to inhibit ADH when serum levels exceed 0.05 g/dL (50 mg/dL). Titration to serum levels between 0.10 g/dL (100 mg/dL) and 0.15 g/dL (150 mg/dL) typically used.
Measure patient's initial blood level. May be administered PO/IV.

Dosing

Adult

If BAC <100 mg/dL, loading dose may be unnecessary, thus patient can be started on a maintenance dose
IV load: 7.6-10 mL/kg IV of 10% ethanol (V/V) in D5W over 30 min to achieve a blood EtOH concentration of 100-130 mg/dL (21.7-28.2 mmol/L
Oral load: 0.8-1 mL/kg PO of 95% ethanol (V/V) in 6 oz of orange juice over 30 min
Average maintenance doses: 0.15 mL/kg/h PO of 95% EtOH; 1.4 mL/kg/h IV of a 10% solution
Frequently monitor BAC; adjust dose to reduce methanol/ethylene glycol levels to <20 mg/dL

Pediatric

Administer as in adults on mL/kg basis; obtain serum BAC 100-150 mg/dL

Interactions

May increase toxicity of benzodiazepines and result in death

Contraindications

Extreme caution if patient has ingested other CNS depressants

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Administered IV may cause thrombophlebitis; may cause gastritis when administered PO; watch for hypoglycemia, especially in children

Folic acid (Folvite)

Adjunctive agent in methanol ingestion. Member of vitamin B-complex that may enhance elimination of toxic metabolite formic acid produced when methanol is metabolized. Useful in methanol and possibly ethylene glycol toxicity. Leucovorin (folinic acid) is active form of folate and may be substituted for folic acid.
Folic acid should be administered for several days to enhance folate-dependent metabolism of formic acid to carbon dioxide and water.

Dosing

Adult

50 mg IV q4-6h to increase rate of formic acid metabolism; leucovorin can be administered 1-2 mg/kg IV q4-6h

Pediatric

Sodium folate: 1 mg/kg IV q4-6h
Leucovorin: 1 mg/kg IV q4-6h

Interactions

Increase in seizure frequency and a decrease in subtherapeutic levels of phenytoin reported when used concurrently

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Benzyl alcohol may be contained in some products as a preservative (associated with a fatal gasping syndrome in premature infants); resistance to treatment may occur in patients with alcoholism and deficiencies of other vitamins

Follow-up

Further Inpatient Care

• Patients with significant ingestions of toxic alcohols require hospital admission in a closely monitored setting such as the intensive care unit.  
• Patients who are chronic alcoholics may be at risk of alcohol withdrawal if admitted to the hospital.

Transfer

• Patients with ethanol intoxication can be observed until they are no longer clinically intoxicated and then discharged. 
• Patients with isopropanol ingestion may require observation in the hospital. 
• Patients with known or suspected methanol or ethylene glycol intoxication should be monitored closely, probably in an intensive care unit.

Complications

• Ethanol ingestion complications
  • Hypoglycemia is common.¹⁴ The etiology is multifactorial but largely related to decreased glycogen stores and malnutrition in children and chronic alcoholics, as well as ethanol’s inhibition of glycogenolysis.
  • Patients with acute intoxication may exhibit "holiday heart," in which dysrhythmias, especially atrial fibrillation, occur following a heavy drinking episode.
  • Ethanol lowers the threshold for developing atrial fibrillation. Cirrhosis, esophageal varices, and erosive gastritis are common in patients who use ethanol on a frequent basis.
• Ingestion of isopropanol is associated with hemorrhagic gastritis.
• Ingestion of methanol is associated with blindness, acidosis, coma, cardiovascular collapse, and death.
• Ingestion of ethylene glycol is associated with renal failure, acidosis, coma, cardiovascular collapse, and death.¹⁰

Miscellaneous

Medicolegal Pitfalls

• Patients with alcohol intoxication should be evaluated for coexisting injuries. A common error is to assume that a patient with altered mental status is simply intoxicated without adequate consideration of other possible causes of an altered mental status.  
• Hypoglycemia should always be sought, particularly in the setting of an altered mental status because it can occur both as a result of intoxication with alcohol and as a result of treatment with ethanol after toxic alcohol ingestion. At-risk populations include children, chronic alcoholics, and others whose glycogen stores are depleted such as malnourished patients.  
• Additional pitfalls include assuming that intoxication is due to simply ethanol without adequate consideration of the possible presence of a toxic alcohol, either exclusively or as a coingestant.
• Patients who have accidentally ingested a mouthful of methanol or ethylene glycol can ingest enough to be at risk of developing significant toxicity.
• As noted in earlier sections, exclusive use of the osmolar gap to rule out intoxication with a toxic alcohol is fraught with pitfalls and guidance from a toxicologist or poison center is recommended (see Lab Studies). 
• Another pitfall is to assume that the absence of an anion gap rules out the possibility of toxic alcohol poisoning. As noted above, this is especially true early in the course when a patient appears inebriated without other symptoms and before significant metabolism has occurred so that an anion gap has not yet developed (see Lab Studies). 
• Not considering the use of hemodialysis, particularly in the presence of metabolic abnormalities, is another potential pitfall. Consultation with a nephrologist and/or toxicologist may be of assistance. 
• Failure to initiate treatment while awaiting laboratory tests to confirm the presence of a toxic alcohol is another common source of medical error.

References

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Keywords

alcohol toxicity, alcohol poisoning, alcohol ingestion, ethanol poisoning, ethanol toxicity, methanol poisoning, methanol toxicity, isopropanol toxicity, isopropanol poisoning, ethyl alcohol toxicity, ethyl alcohol poisoning, ethyl alcohol, methyl alcohol toxicity, methyl alcohol poisoning, isopropyl alcohol toxicity, isopropyl alcohol poisoning, alcohol metabolism, acute alcohol intoxication

Contributor Information and Disclosures

Author

Michael D Levine, MD, Physician, Department of Medical Toxicology, Banner Good Samaritan Medical Center
Michael D Levine, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, American College of Medical Toxicology, American Medical Association, Emergency Medicine Residents Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Tobias D Barker, MD, Attending Physician, Department of Emergency Medicine; Director, Harvard Medical School Dubai Center Simulation Center
Tobias D Barker, MD is a member of the following medical societies: American College of Emergency Physicians, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Jeffrey Glenn Bowman, MD, MS, Consulting Staff, Highfield MRI, Columbus, Ohio
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center
Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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