ALTHOUGH relatively uncommon, poisonings with ethylene glycol (EG) and methanol can result in significant morbidity and mortality in the emergency patient population (Abramson & Singh, 2000; Megarbane, Borron, & Baud, 2005). The unique characteristics of these toxins provide potentially adventitious aspects for treatment. If treated early, the toxicity of these agents can be minimized and the risk of death and permanent organ damage can be decreased. The intent of this review is to discuss relevant management issues in the emergency department as well as the current therapeutic principles for the treatment of EG and methanol intoxication.
Ethylene glycol is a colorless and odorless, sweet-tasting substance that can be found in common household solutions, such as antifreeze, detergents, and polishes (Abramson & Singh, 2000). In the United States in 2007, EG was the primary substance in 5,731 exposures and resulted in 27 deaths as reported in the Toxic Exposure Surveillance System (Bronstein et al., 2008). The primary route of exposure is from oral ingestion through which it is rapidly absorbed and reaches a peak concentration in 1–4 hr (Barceloux, Krenzelok, Olson, & Watson, 1999). This may occur as a result of an attempt to commit suicide, a substitute for ethanol, or an accidental ingestion. More than 80% of exposures in 2007 were accidental and 583 were in children younger than 6 years. Although wide variations exist regarding the quantity of EG that represents a lethal dose, it is typically referenced as 1.4–1.5 ml/kg body weight or approximately 100 ml in adults (Abramson & Singh, 2000; Eder et al., 1998). On the basis of its dependency on metabolic processes however, it should be noted that any quantity of consumption can lead to toxicity.
Pathophysiology and Clinical Symptoms
The toxicity of EG is largely related to its metabolites rather than the parent compound itself. Hepatic metabolism is responsible for 80% of the absorbed dose, with alcohol and aldehyde dehydrogenase serving large roles in this conversion (Barceloux et al., 1999). The accumulation of large quantities of the metabolite glycolate is primarily responsible for the ensuing metabolic acidosis characterized by a wide anion gap. Subsequent metabolism results in the formation of oxalate, which precipitates with calcium to form calcium oxalate crystals. These crystals can form in various tissues throughout the body; however, their formation in the renal tubules leads to the subsequent renal dysfunction associated with this toxic ingestion. The clinical course following a toxic EG ingestion can typically be broken up into three stages as described in Table 1 (Abramson & Singh, 2000; Barceloux et al., 1999). Because of multiple interpatient variables and the typical coingestion of ethanol, this course is often variable.
Both urine and serum can present evidence of EG toxicity as well as serving to monitor potential endpoints of therapy. On admission, about half of patients will present with two forms of calcium oxalate crystals (monohydrate or dehydrate) in the urine, often in combination with a concomitant hypocalcemia (Jacobsen, Akesson, & Shefter, 1982). These crystals may be present after a period of about 4–8 hr and up to 40 hr (Barceloux et al., 1999; Flanagan & Libcke, 1964). An elevated serum EG level can also be useful in confirming the diagnosis of a toxic EG ingestion. Although false positives can exist, these are exceedingly rare (Eder et al., 1998; Martinez, Lubbos, Rose, Swartz, & Kayne, 1998). Interestingly, because of the mechanism of this disorder, there are limited correlations between serum EG and patient outcome. As each patient's EG level declines, this is indicative of its conversion to more toxic metabolites rather than the resolution of intoxication. Fortunately, correlations can be made between arterial pH, serum bicarbonate or glycolate levels, and clinical outcome (Borron, Megarbane, & Baud, 1999; Brent et al., 1999). In the first several hours following ingestion, patients will often present with an elevated serum osmolality due to the EG parent compound (Barceloux et al., 1999; Jacobsen, Bredesen, Eide, & Ostborg, 1982). However, as this compound is metabolized to glycolate, this elevation will return to normal and a high anion gap metabolic acidosis will develop primarily because of the formation of glycolic acid (Hewlett, McMartin, Lauro, & Ragan, 1986; Jacobsen, Ovrebo, Ostborg, & Sejersted, 1984). As metabolism continues, serum bicarbonate levels will decrease, contributing to the ensuing acidosis. The elimination of any existing EG concentration in conjunction with the resolution of acid-base abnormalities and signs of systemic toxicity are typically considered the endpoints of therapy (Barceloux et al., 1999).
Methanol, also known as wood alcohol, is a clear, colorless liquid with a slightly alcoholic odor that is an additive found in several commercial products, including antifreeze, windshield cleaner, paint thinner, and rubbing alcohol (Abramson & Singh, 2000; Barceloux, Bond, Krenzelok, Cooper, & Vale, 2002). It is frequently used as a solvent in multiple products. In 2007, methanol was the primary substance in 2,059 exposures and resulted in 11 deaths in the United States, according to the Toxic Exposure Surveillance System (Bronstein et al., 2008). Similar to EG, the primary route of exposure is ingestion, with common reasons being intended suicide, substitution when ethanol is not available, or unintentional exposure. Oral absorption is rapid, reaching its peak in 30–60 min (Barceloux et al., 2002). Close to 90% of cases in 2007 were unintentional exposures, and 510 of these were patients younger than 6 years (Bronstein et al., 2008). The quantity of methanol necessary to cause toxicity is dependent on the concentration of the solution and the metabolic process involved but has been documented with as little as 15–500 ml of a 40% solution in adults (Bennett, Cary, Mitchell, & Cooper, 1953; Jacobsen & McMartin, 1986).
Pathophysiology and Clinical Symptoms
Analogous to EG, methanol itself has a relatively low toxicity. Largely its metabolism, predominantly by the liver, is responsible for the production of toxic metabolites (Barceloux et al., 2002; Brent, McMartin, Phillips, Aaron, & Kulig, 2001). Alcohol dehydrogenase and formaldehyde dehydrogenase are the primary enzymes in this metabolic process, and it is this later metabolism that is responsible for the formation of formic acid, the agent responsible for the toxicity of methanol ingestion. Formic acid can have an impressively large number of clinical effects that lead to the significant morbidity and mortality associated with this toxicity (Barceloux et al., 2002). Formic acid can inhibit mitochondrial oxidative metabolism leading to an increase in lactate levels (Nicholls, 1976). This effect, combined with formic acid itself, produces the high anion gap metabolic acidosis seen in acute methanol poisoning (McMartin, Ambre, & Tephly, 1980). Formic acid also contributes to the signature ocular toxicity seen in this clinical scenario causing optic disc edema and nerve lesions (Martin-Amat, McMartin, Hayreh, Hayreh, & Tephly, 1978). In addition, an intricate toxic neurological process can develop, which presents as cerebral edema and necrotic damage in the basal ganglia (Barceloux et al., 2002). The clinical course of methanol toxicity is less structured than that of EG toxicity. Often there is an initial period of 12–24 hr during which only mild central nervous system depression symptoms are present followed by a latent period during which the metabolic conversion to formic acid occurs (Barceloux et al., 2002). Similar to EG, this process can also be delayed by several hours with the coingestion of ethanol. Following this latent period, the patient typically develops a profound metabolic acidosis and visual disturbances. Common symptoms are outlined in Table 2.
Serum methanol concentrations provide several unique challenges with regards to interpretation. Small concentrations of methanol are present in several fruits and vegetables and can accumulate in binge drinking scenarios (Barceloux et al., 2002). The mean methanol concentration in one study of drivers suspected of driving under the influence of alcohol was 7.3 mg/dl (Jones & Lowinger, 1988). As a result, the American Academy of Clinical Toxicology recommends the use of a methanol concentration greater than 20 mg/dl to indicate those at risk for toxicity in conjunction with the presence of an anion gap metabolic acidosis (Barceloux et al., 2002). Although this level should be interpreted within the context of when the methanol ingestion occurred, as lower levels may also indicate toxicity (Kostic & Dart, 2003).
Of more clinical value, and correlated more closely with clinical symptoms and mortality, is the ensuing anion gap metabolic acidosis (Jacobsen, Jansen, Wiik-Larsen, Bredesen, & Halvorsen, 1982). Early in the course following methanol ingestion, the patient will develop an osmolal gap due to the parent compound and any coingestion of ethanol (Barceloux et al., 2002). However, as this parent compound is metabolized, the patient will begin to develop a metabolic acidosis and a bicarbonate deficit, which subsequently leads to the creation of an anion gap (McMartin et al., 1980). Treatment is typically recommended to continue until these abnormalities are corrected and the serum methanol concentration falls below 20 mg/dl (Barceloux et al., 2002).
According to the American Academy of Clinical Toxicology Practice Guidelines on EG and methanol poisonings, available options for the treatment of toxic ingestions include an antidote, hemodialysis, and/or supportive care (Barceloux et al., 1999, 2002). Because of the rapid absorption of EG and methanol, gut decontamination is of limited use in this setting. Activated charcoal is not recommended because EG and methanol are not likely adsorbed by this agent. The antidotes, ethanol or fomepizole, are indicated for use if the patient has a documented plasma EG or methanol concentration greater than 20 mg/dl, a witnessed ingestion of either substance in toxic amounts with an osmolal gap greater than 10 mOsm/L or a history or high suspicion of poisoning in addition to two of the following criteria: arterial pH less than 7.3, serum bicarbonate less than 20 mEq/L, osmolal gap greater than 10 mOsm/L, and urinary oxalate crystals in the case of EG toxicity (Barceloux et al., 1999). The cofactors pyridoxine, thiamine, and magnesium should be replenished in patients with suspected vitamin deficiencies, such as alcohol-dependent patients, to promote the conversion of glyoxylate, glycolic acid, and glyoxylic acid to nontoxic metabolites, respectively. In the setting of EG overdose, hypocalcemia is typically not corrected unless the patient is symptomatic because of concerns over the formation of calcium oxalate crystals. Folinic acid (leucovorin) or folic acid given intravenously may be used as adjunctive agents to increase the metabolism of formic acid in methanol overdose (Barceloux et al., 2002). Typically, folinic acid given at a dose of 1 mg/kg (maximum of 50 mg) administered over 30–60 min every 4–6 hr is preferred over folic acid (50 mg every 4–6 hr) because it does not require metabolic reduction to a bioactive form. However, it should be noted that currently no human studies exist supporting the use of these agents for this purpose.
Although ethanol has been used as an antidote for EG and methanol poisonings since the 1940s, there are no prospective trials to support its use and consequentially it is not Food and Drug Administration (FDA)–approved for either indication. Ethanol binds to the enzyme alcohol dehydrogenase more efficiently than does EG or methanol and inhibits the subsequent formation of toxic metabolites. It may be administered intravenously, orally, or via nasogastric tube depending on the clinical status of the patient. An initial loading dose of 600–700 mg/kg of ethanol (equivalent to 7.6–8.9 ml/kg of 10% ethanol solution) should be administered over 60 minutes, assuming that the patient's baseline ethanol level is undetectable, followed by a maintenance dose based on the patient's drinking history (Table 3). If the baseline ethanol level is elevated, a loading dose should account for the difference between the target ethanol level and the patient's current level. Ethanol levels should be monitored every 1–2 hr until a steady state concentration between 100 and 150 mg/dl is achieved, after which levels should be checked every 2–4 hr. If the infusion rate or dose is changed at any time, more frequent monitoring (i.e., every 1–2 hr) is indicated until therapeutic levels are reestablished. The levels achieved after oral ethanol are highly patient dependent and thereby require the same intensity of monitoring as the continuous infusion. Because of the labor-intensive monitoring required, patients receiving ethanol should be cared for in a critical care unit. In addition to necessitating frequent therapeutic drug-level monitoring, ethanol can cause a number of adverse events, including hypoglycemia, respiratory depression, visual impairment, vomiting, slurred speech, and mental status changes. Infusion through a central catheter may be necessary as the intravenous formulation has been associated with local phlebitis (Barceloux et al., 1999, 2002).
Fomepizole is FDA approved for the treatment of methanol and EG toxicities. It inhibits alcohol dehydrogenase, preventing the formation of toxic metabolites responsible for the sequelae associated with methanol or EG ingestion. A one-time loading dose of 15 mg/kg should be administered intravenously over 30 min, followed by four doses of 10 mg/kg every 12 hr, and then a subsequent increase in the maintenance dose to 15 mg/kg every 12 hr is warranted because of autoinduction of drug metabolism occurring after 48 hr. This regimen should be continued until EG or methanol concentrations are less than 20 mg/dl, and the patient is asymptomatic with a normal pH (Barceloux et al., 1999, 2002). If hemodialysis is used in combination with fomepizole, dose adjustments are required because of the removal of this agent by dialysis. Table 4 includes the appropriate fomepizole dosing in relation to the timing of the hemodialysis session (Jazz Pharmaceuticals, 2006). No therapeutic drug monitoring is required for fomepizole, allowing patients to be cared for in an acute care setting rather than an obligatory intensive care unit. The primary adverse effects of fomepizole reported in clinical trials included headache, nausea, and dizziness (Brent et al., 1999, 2001; Megarbane et al., 2001).
Because of the low incidence of methanol and EG toxicities, comparison studies between ethanol and fomepizole are challenging. However, such investigations are necessary not only to help determine the superiority of one agent over another but also to help reconcile the cost and adverse event profiles of these agents. A recent retrospective analysis found that 57% of ethanol-treated patients had at least one side effect compared with 12% of fomepizole-treated patients (Lepik et al., 2009). In addition, ethanol is much more labor intensive with regards to critical care nursing and laboratory monitoring (Megarbane et al., 2005). Fomepizole, on the other hand, has the disadvantage of having a high acquisition cost that has contributed to this agent being avoided as an option and leading to delays in its administration (Mycyk, DesLauriers, Metz, Wills, & Mazor, 2006).
Hemodialysis rapidly clears EG and methanol in addition to their toxic metabolites. Traditionally, a serum EG or methanol concentration greater than 50 mg/dl has been used as an indication for dialysis, although there are insufficient data to suggest that any concentration represents a starting point for renal toxicity. Current recommendations suggest that hemodialysis should be considered in patients presenting with an EG or methanol ingestion who have a significant metabolic acidosis (pH less than 7.25–7.30), renal failure, electrolyte imbalances refractory to pharmacological treatments, and/or hemodynamic instability secondary to the toxic alcohol. The duration of therapy should be determined on the basis of the individual patient case but may be terminated when the metabolic acidosis is corrected and serum concentrations are less than 20 mg/dl. Another option is to cease hemodialysis following the correction of the metabolic acidosis and continue an antidote until EG or methanol concentrations are less than 20 mg/dl and the patient is asymptomatic (Barceloux et al., 1999, 2002; Megarbane et al., 2005).
Although they represent a relatively small portion of poisonings overall, EG and methanol can cause significant toxicities to various organ systems. It is imperative for all healthcare personnel to become knowledgeable about the signs and symptoms of ingestion of these agents, as well as the various monitoring parameters essential for accurate diagnosis and treatment. The availability of ethanol and fomepizole as antidotes has dramatically enhanced our ability to treat these overdoses and subsequently reduce related toxicities.
Abramson, S., & Singh, A. K. (2000). Treatment of the alcohol
intoxications: Ethylene glycol
and isopropanol. Current Opinion in Nephrology and Hypertension, 9
Barceloux, D. G., Bond, G. R., Krenzelok, E. P., Cooper, H., & Vale, J. A. (2002). American Academy of Clinical Toxicology practice guidelines on the treatment of methanol
poisoning. Journal of Toxicology: Clinical Toxicology, 40
Barceloux, D. G., Krenzelok, E. P., Olson, K., & Watson, W. (1999). American Academy of Clinical Toxicology practice guidelines on the treatment of ethylene glycol
poisoning. Ad hoc committee. Journal of Toxicology: Clinical Toxicology, 37
Bennett, I. L., Jr., Cary, F. H., Mitchell, G. L., Jr., & Cooper, M. N. (1953). Acute methyl alcohol
poisoning: A review based on experiences in an outbreak of 323 cases. Medicine (Baltimore), 32
Borron, S. W., Megarbane, B., & Baud, F. J. (1999). Fomepizole
in treatment of uncomplicated ethylene glycol
poisoning. Lancet, 354
Brent, J., McMartin, K., Phillips, S., Aaron, C., & Kulig, K. (2001). Fomepizole
for the treatment of methanol
poisoning. The New England Journal of Medicine, 344
Brent, J., McMartin, K., Phillips, S., Burkhart, K. K., Donovan, J. W., Wells, M., et al. (1999). Fomepizole
for the treatment of ethylene glycol
poisoning. Methylpyrazole for Toxic Alcohols Study Group. The New England Journal of Medicine, 340
Bronstein, A. C., Spyker, D. A., Cantilena, L. R., Jr., Green, J. L., Rumack, B. H., & Heard, S. E. (2008). 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clinical Toxicology (Philadelphia), 46
Eder, A. F., McGrath, C. M., Dowdy, Y. G., Tomaszewski, J. E., Rosenberg, F. M., Wilson, R. B., et al. (1998). Ethylene glycol
poisoning: Toxicokinetic and analytical factors affecting laboratory diagnosis. Clinical Chemistry, 44
Flanagan, P., & Libcke, J. H. (1964). Renal biopsy observations following recovery from ethylene glycol
nephrosis. American Journal of Clinical Pathology, 41
Hewlett, T. P., McMartin, K. E., Lauro, A. J., & Ragan, F. A., Jr. (1986). Ethylene glycol
poisoning. The value of glycolic acid determinations for diagnosis and treatment. Journal of Toxicology: Clinical Toxicology, 24
Jacobsen, D., Akesson, I., & Shefter, E. (1982). Urinary calcium oxalate monohydrate crystals in ethylene glycol
poisoning. Scandanavian Journal of Clinical and Laboratory Investigation, 42
Jacobsen, D., Bredesen, J. E., Eide, I., & Ostborg, J. (1982). Anion and osmolal gaps in the diagnosis of methanol
and ethylene glycol
poisoning. Acta Medica Scandinavica, 212
Jacobsen, D., Jansen, H., Wiik-Larsen, E., Bredesen, J. E., & Halvorsen, S. (1982). Studies on methanol
poisoning. Acta Medica Scandinavica, 212
Jacobsen, D., & McMartin, K. E. (1986). Methanol
and ethylene glycol
poisonings. Mechanism of toxicity, clinical course, diagnosis and treatment. Medical Toxicology, 1
Jacobsen, D., Ovrebo, S., Ostborg, J., & Sejersted, O. M. (1984). Glycolate causes the acidosis in ethylene glycol
poisoning and is effectively removed by hemodialysis. Acta Medica Scandinavica, 216
Jazz Pharmaceuticals. (2006). Antizol [Package insert]. Palo Alto, CA: Author.
Jones, A. W., & Lowinger, H. (1988). Relationship between the concentration of ethanol
in blood samples from Swedish drinking drivers. Forensic Science International, 37
Kostic, M. A., & Dart, R. C. (2003). Rethinking the toxic methanol
level. Journal of Toxicology: Clinical Toxicology, 41
Lepik, K., Levy, A., Sobolev, B., Purssell, R., DeWitt, C., Erhardt, G., et al. (2009). Adverse drug events associated with the antidotes for methanol
and ethylene glycol
poisoning: A comparison of ethanol
. Annals of Emergency Medicine, 53
Martin-Amat, G., McMartin, K. E., Hayreh, S. S., Hayreh, M. S., & Tephly, T. R. (1978). Methanol
poisoning: Ocular toxicity produced by formate. Toxicology and Applied Pharmacology, 45
Martinez, C., Lubbos, H., Rose, L. I., Swartz, C., & Kayne, F. (1998). False-positive ethylene glycol
levels in patients with diabetic ketoacidosis. Endocrine Practice, 4
McMartin, K. E., Ambre, J. J., & Tephly, T. R. (1980). Methanol
poisoning in human subjects: Role for formic acid accumulation in the metabolic acidosis. The American Journal of Medicine, 68
Megarbane, B., Borron, S. W., & Baud, F. J. (2005). Current recommendations for treatment of severe toxic alcohol
poisonings. Intensive Care Medicine, 31
Megarbane, B., Borron, S. W., Trout, H., Hantson, P., Jaeger, A., Krencker, E., et al. (2001). Treatment of acute methanol
poisoning with fomepizole
. Intensive Care Medicine, 27
Mycyk, M. B., DesLauriers, C., Metz, J., Wills, B., & Mazor, S. S. (2006). Compliance with poison center fomepizole
recommendations is suboptimal in cases of toxic alcohol
poisoning. American Journal of Therapeutics, 13
Nicholls, P. (1976). The effect of formate on cytochrome aa3 and on electron transport in the intact respiratory chain. Biochimica et Biophysica Acta, 430