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Approach to the Treatment of Methanol Intoxication
Acid-Base and Electrolyte Teaching Case Approach to the Treatment of Methanol Intoxication Jeffrey A. Kraut, MD Methanol intoxication is an uncommon but serious poisoning. Its adverse effects are due primarily to the impact of its major metabolite formic acid and lactic acid resulting from cellular hypoxia. Symptoms including abdominal pain and loss of vision can appear a few hours to a few days after exposure, reflecting the time necessary for accumulation of the toxic byproducts. In addition to a history of exposure, increases in serum osmolal and anion gaps can be clues to its presence. However, increments in both parameters can be absent depending on the nature of the toxic alcohol, time of exposure, and coingestion of ethanol. Definitive diagnosis requires measurement with gas or liquid chromatography, which are laborious and expensive procedures. Tests under study to detect methanol or its metabolite formate might facilitate the diagnosis of this poisoning. Treatment can include administration of ethanol or fomepizole, both inhibitors of the enzyme alcohol dehydrogenase to prevent formation of its metabolites, and hemodialysis to remove methanol and formate. In this Acid-Base and Electrolyte Teaching Case, a patient with methanol intoxication due to ingestion of model airplane fuel is described, and the value and limitations of current and new diagnostic and treatment measures are discussed. Am J Kidney Dis. -(-):---. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. INDEX WORDS: Toxic alcohols; serum osmolal gap; serum anion gap; fomepizole; methanol; methanol intoxication; ethanol; hemodialysis.
Note from the editors: This article is part of a series of invited case discussions highlighting either the diagnosis or treatment of acid-base and electrolyte disorders.
INTRODUCTION Methanol intoxication can cause severe cellular dysfunction and death,1 primarily due to the accumulation of organic acids and their anions produced by its metabolism.2-4 Effective methods of treatment that include administering inhibitors of the enzyme alcohol dehydrogenase to prevent its metabolism5 and hemodialysis6 to remove it and its toxic metabolites from the body are readily available. However, recognition of the intoxication is often hampered by the lack of specific signs and symptoms and the limitation of present diagnostic modalities.7 Although mortality is low if treatment is initiated promptly,8 a delay can cause it to increase to as high as 44%.9,10 In this Acid-Base and Electrolyte Teaching Case, a case of methanol intoxication is presented, which was previously reported by Rastogi et al,11 and current methods of diagnosis and treatment are discussed.
CASE REPORT Clinical History and Initial Laboratory Data A 22-year-old woman presented to the emergency department 30 hours after ingesting 16 ounces of model airplane fuel. She reported no abdominal pain, nausea, vomiting, visual disturbances, or headache. On physical examination, temperature was 37.2 C; pulse rate, 100 beats/min; blood pressure, 132/50 mm Hg in the sitting position; and respirations, 16 breaths/min. Lungs were clear to auscultation, and cardiac, abdominal, and neurologic examination findings were normal. No ophthalmic changes were reported. Laboratory studies performed during the hospitalization are shown Am J Kidney Dis. 2016;-(-):---
in Table 1 and revealed a low serum bicarbonate level, elevated serum osmolality and osmolal gap, and increased serum creatinine level. The latter was shown to be due to laboratory error caused by interference of nitromethane in the airplane fuel with serum creatinine measurement as performed by the usual Jaffé method.11
Additional Investigations Urinalysis showed no cells or crystals. Serum acetaminophen, ethyl alcohol, acetone, and isopropyl alcohol results were negative. Methanol concentration obtained on admission reported 2 days later was 71 mg/dL.
Diagnosis Acute methanol intoxication.
Clinical Follow-up The patient initially was given fomepizole and dialyzed for 4 hours. Additional doses of fomepizole were given and dialysis was
From the Medical and Research Services Veterans Administration Greater Los Angeles Healthcare System, UCLA Membrane Biology Laboratory, and Division of Nephrology, Veterans Administration Greater Los Angeles Healthcare System, and David Geffen School of Medicine, Los Angeles, CA. Received October 16, 2015. Accepted in revised form February 4, 2016. Because the author of this article is the editor for this feature, the peer-review and decision-making processes were handled without his participation. Details of the journal’s procedures for potential editor conflicts are given in the Information for Authors & Journal Policies. Address correspondence to Jeffrey A. Kraut, MD, Division of Nephrology, VHAGLA Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073. E-mail: [email protected] Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2016.02.058 1
Jeffrey A. Kraut Table 1. Laboratory Studies During Hospitalization
Methanol
Test
Admission
17 h After Admission
Sodium, mEq/L Potassium, mEq/L Chloride, mEq/L Total carbon dioxide, mEq/L SUN, mg/dL Serum creatinine, mg/dLa eGFR,c mL/min/1.73 m2 Anion gap, mEq/L Serum osmolality, mOsm/kg/H2O Osmolal gap, mOsm/ kg/H2O Methanol, mg/dL Serum albumin, g/dL
141 3.5 111 18
140 3.2 104 28
143 3.8 109 25
142 3.6 112 25
14 23.7b
5 10b
7 8.4b
4 6.0
2 11 357
5 8 303
6 9 303
9 5 303
70
—
—
—
71 4
26
— —
— —
—
Day 2
Day 3
Note: Conversion factors for units: serum creatinine in mg/dL to mmol/L, 388.4; SUN in mg/dL to mmol/L, 30.357. Abbreviations: eGFR, estimated glomerular filtration rate; SUN, serum urea nitrogen. a Values obtained using the Jaffe´ reaction. b Values proved to be inaccurate due to interference of nitromethane in ingested airplane fuel with measurement of serum creatinine. c As calculated by the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Adapted from Rastogi et al11 with permission of the National Kidney Foundation.
repeated during the hospitalization. With treatment, acid-base parameters and serum osmolality (Table 1) returned to normal and the patient was discharged.
DISCUSSION This patient had a history of exposure to methanol, a markedly increased serum osmolal gap, and metabolic acidosis. These features are suggestive of methanol intoxication.7,12 Methanol intoxication is a relatively uncommon but important poisoning: approximately 5,000 cases are reported to the US Poison Control each year.2,8,13 Methanol is present in several household cleaning solutions and dyes, model airplane fuel, windshield washer fluid, gas line antifreeze, and illegally produced alcoholic beverages. Intoxication is most commonly due to ingestion, but can also result from inhalation or absorption through the skin.13 Symptoms can include dyspnea, nausea, vomiting, abdominal pain, impaired sensorium, and impaired vision.14 Ophthalmologic examination can reveal optic papillitis (found in 10% of cases). Muscle rigidity and masked facies can be observed when the putamen is damaged.15 The majority of the clinical abnormalities are due to the effects of formic acid, the major metabolite of methanol (Fig 1). Interference with cytochrome oxidase by formate causes tissue 2
Alcohol dehydrogenase
Formaldehyde Formaldehyde dehydrogenase
Formic acid Folinic acid
CO2 + H2O Figure 1. Metabolism of methanol. Methanol undergoes serial oxidation: methanol is catalyzed by the enzyme alcohol dehydrogenase to formaldehyde and then formaldehyde is catalyzed by the enzyme formaldehyde dehydrogenase to formic acid. Folinic acid given to a patient will accelerate the conversion to carbon dioxide (CO2) and water (H2O). Adapted from Rastogi et al11 with permission of the National Kidney Foundation.
hypoxia and lactic acidosis.13 Clinical abnormalities can be delayed as long as 96 hours if ethanol or certain antiviral medication, such as abacavir, are coingested because both inhibit the enzyme that catalyzes the metabolism of methanol, alcohol dehydrogenase.3,16-19 Both the nonspecificity of the clinical abnormalities and the delay between exposure and their appearance can hinder establishing the diagnosis, thus resulting in high mortality.10 An increase in the serum osmolal gap (caused by accumulation of methanol in the blood) and anion gap (caused by accumulation of formate and sometimes lactate in the blood) can also serve as clues to the presence of methanol intoxication.16,20 The marked increase in serum osmolal gap in the present case (70 mOsm/kg/H2O) reflects in part a high methanol concentration and is indicative of toxic alcohol ingestion because an osmolal gap greater than 15 to 20 mOsm/kg/H2O is rarely observed with other causes of increased osmolal gap.2,13 However, the osmolal gap exceeds the level predicted based on the measured methanol concentration (71 mg/dL; osmolality, 23 mOsm/kg/H2O). The explanation for this disparity is not clear, but possibly could reflect accumulation of osmotically active substances such as nitromethane and/or polyalkylene glycol found in the airplane fuel. Although the osmolal gap and anion gap were increased in this case, individuals can have methanol Am J Kidney Dis. 2016;-(-):---
Treatment of Methanol Intoxication
intoxication in the absence of an increase in osmolal and/or anion gaps.21,22 The reasons for this can best be appreciated by examining the evolution of these gaps in patients with methanol intoxication. Serum osmolal gap depends on the baseline osmolal gap and the increment in osmolality produced by the methanol in the blood at the time it is sampled. It is often stated that a normal baseline osmolal gap is 10 to 20 mOsm/kg/H2O. Values greater than this indicate accumulation of toxic alcohols, such as methanol.23 However, baseline serum osmolal gaps in apparently healthy individuals can vary from 211 to 110 mOsm/kg/H2O.21,22,24-27 If the osmolal gap should prove to be negative, a methanol concentration of 20 mg/dL (the level when treatment is recommended) would not produce an osmolal gap . 10 mOsm/kg/H2O. Also, osmolal gap is highest early in the course of the intoxication, but will decrease substantially as methanol is metabolized. Sampling of blood later in the course when methanol concentration has decreased would also lessen the chances of detecting a markedly elevated osmolal gap. The baseline serum anion gap can be as low as 3 mEq/L in healthy individuals.28,29 As a result, the anion gap might not exceed the upper limit of normal even if there is an increment in the concentration of organic acid anions, as long as their concentration is less than 7 to 8 mEq/L. Also, blood sampling early after exposure before much of the methanol is metabolized will lessen the chance of detecting an increased anion gap.18,30 Even if the osmolal gap is elevated (as long as the increase is modest, ie, ,15 mOsm/kg/H2O), the increase might be caused by other disorders. A retrospective study of 346 patients with an increased osmolal gap (averaging 14 mOsm/kg/H2O) revealed that in a majority of cases, the increase was due to the presence of lactic acidosis, ketoacidosis, kidney failure, and/or sick cell syndrome rather than a toxic alcohol.31,32 Given the nonspecificity of the signs and symptoms and inconsistency of the changes in serum osmolal and anion gaps, more specific methods for detection of methanol and monitoring of changes in its concentration are required. Presently, detection of methanol is best achieved using gas or liquid chromatography,2,7,33 a laborious and expensive method that is not available in many clinical chemistry laboratories. Methanol concentration was not reported for 48 hours in the present case. Other direct and indirect methods to assess methanol concentrations are shown in Table 2. An enzymatic method that detects the metabolite formate in blood has been described.34 Formate dehydrogenase and nicotinamide adenine dinucleotide are used to measure serum formate. The Am J Kidney Dis. 2016;-(-):---
day-to-day coefficient of variation is 5%. The assay can be done using most autoanalyzers and requires only commercially available reagents. In one study, the majority of patients (14 of 15) with an elevated methanol concentration also had an elevated serum formate concentration.34 A dipstick impregnated with alcohol oxidase is available that detects methanol, ethanol, and ethylene glycol in blood and saliva.35 Methanol strongly reacts to the strip and at similar concentrations, gives a more intense color than ethanol. A liquid-based colorimetric method using the enzymes alcohol oxidase or alcohol dehydrogenase or the oxidizing agents sodium periodate and potassium permanganate was able to detect methanol and other alcohols when added to saliva at concentrations as low as 1 to 10 mg/dL.36 Validation of these methods can improve treatment by facilitating the diagnosis of methanol intoxication. Treatment with stomach gavage is generally not useful because methanol is rapidly absorbed. Rather, treatment can include inhibition of the enzyme alcohol dehydrogenase37 and removal of the parent alcohol and its metabolites by hemodialysis.6 Inhibition of alcohol dehydrogenase was initially accomplished by infusion of ethanol, which binds to the enzyme, preventing metabolism of methanol.2-5 Achieving a concentration of 100 to 150 mg/dL in the blood has been recommended, although lower concentrations might be sufficient to maximally inhibit the enzyme.13 The infusion has to be continuous and is usually done in an intensive care unit to facilitate maintenance of an adequate ethanol concentration and prevent complications of therapy.38,39 One major advantage is that this therapy is inexpensive and readily available. Fomepizole, a specific inhibitor of alcohol dehydrogenase, was approved by the US Food and Drug Administration for the treatment of methanol intoxication in 2000.37,40,41 It has substantially greater binding affinity for the enzyme (.8,000 than for ethanol) and therefore is more effective than ethanol. It can be given both intravenously and orally at the same dosage,42 although presently, only the intravenous form is available in the United States. It has minimal side effects and in contrast to ethanol, can be administered to the patient without requiring hospitalization in the intensive care unit. Comparisons of both agents showed that their side-effect profiles were not different and mortality was identical.43 A systematic review of MEDLINE and Embase databases including articles from 1966 to 2010 revealed that 80% of patients were treated with ethanol and 16% were treated with fomepizole.5 Importantly, the authors did not compare usage patterns before and after fomepizole was approved, theoretically biasing the study. By contrast, a retrospective study of all 3
Jeffrey A. Kraut Table 2. Methods to Diagnose Methanol Intoxication Parameter
History and physical examination Serum osmolal gap
Mechanism
Comments
Obtain historical evidence of exposure; suggestive symptoms and physical evidence of optic papilitis or neurologic abnormalities Increased osmolality reflects accumulation of parent alcohol in blood
Findings often nonspecific; long delay between onset and symptoms and signs can obscure the diagnosis
Serum anion gap
Detects accumulation of organic acid anion formate and in some cases lactate
Gas or liquid chromatography
Detects methanol in blood using gas or liquid chromatography methods
Measurement of serum formate
Detects accumulation of primary metabolite formate in blood using enzymatic test based on formate dehydrogenase Detects methanol, ethanol, and ethylene glycol based on enzyme alcohol oxidase Uses combination of enzymes (alcohol oxidase or dehydrogenase) and/or oxidizing agents such as potassium permanganate and sodium periodate
Dipstick impregnated with alcohol oxidase strip Liquid-based test of saliva using enzyme or oxidizing agents
electronic entries from the American Association of Professional Code Center (AAPC) National Poison Data System Database revealed that in 2012 to 2013, fomepizole was used in 90% of patients with methanol or ethylene glycol toxicity.8 However, use of ethanol in other countries has been reported to be greater than that of fomepizole.44 This presumably reflects less access to the latter drug because it was only added to the World Health Organization essential medicine list in 2013.45 Because fomepizole or ethanol will prevent the formation of toxic metabolites, theoretically, this therapy could be sufficient for the patient with methanol intoxication without the need for dialysis. In the absence of kidney failure, fomepizole alone has been shown to be effective in the treatment of methanol intoxication.46,47 In patients without severe symptoms, severe acidemia, or kidney failure, fomepizole alone has been recommended by some experts.47 A major disadvantage of using fomepizole alone is that by preventing its metabolism, the methanol is eliminated only by the lungs and kidney, a relatively slow process that increases the mean half-life to 54 hours.47 This increases the duration of hospitalization substantially and thus the cost of treatment.48 With hemodialysis, rapid removal of methanol and formate can be achieved.49 With the usual intermittent 4
Should be performed using freezing point depression rather than vapor pressure osmometry; can be helpful in many cases but osmolal gap might not be elevated if baseline osmolal gap is negative (osmolal gap also might not be elevated late when parent alcohol has been fully metabolized); despite limitations, good correlation between osmolal gap and methanol concentration has been found in some studies Might not be elevated if baseline serum anion gap is low; might not be elevated early in the course of intoxication prior to significant metabolism of alcohol to formate and development of lactic acidosis Gold standard for determination of methanol concentrations; labor intensive and expensive; not available in most clinical laboratories Indirectly estimates methanol concentration; might not be positive early in the course of intoxication prior to metabolism of methanol; not yet in clinical use Detects ethanol, methanol, and ethylene glycol in blood and saliva, but most sensitive to methanol Methods work only with saliva; detects concentrations of methanol as low as 1 mg/dL; uses readily available chemicals; costs of procedures likely to be less than few dollars; liquid-based analysis or strip test might be used
hemodialysis protocol (4 hours with blood flow of 400 mL/min and dialysis flow of 800 mL/min), methanol clearance of 200 mL/min can be achieved, resulting in a half-live of 2 hours.50 Clearance of formate is w223 mL/min under these conditions, resulting in a half-life of 1.8 hours.50 The decision to use an inhibitor alone or in combination with dialysis therefore remains an area of controversy.6,47 In 2002, the American Academy of Clinical Toxicology published criteria for the use of dialysis in the treatment of methanol intoxication13 (Box 1). Indications included metabolic acidosis with blood pH , 7.25, deteriorating vital signs despite supportive care, and serum methanol concentration . 50 mg/dL. In 2015, the Extracorporeal Treatment in Poisoning Workgroup published their criteria after careful examination of the literature (Box 1).6 Some differences included a lower target blood pH (7.15) and use of different blood concentrations depending on the specific conditions: serum methanol concentrations . 70 mg/dL with fomepizole therapy, .60 mg/dL with ethanol therapy, and .50 mg/dL in the absence of inhibitors. Recommendations by both committees favored intermittent hemodialysis over continuous renal replacement dialysis. Dialysis can be terminated when methanol levels are ,20 mg/dL. Am J Kidney Dis. 2016;-(-):---
Treatment of Methanol Intoxication Box 1. Indications for Hemodialysis for Treatment of Methanol Intoxication
Box 2. Teaching Points
American Academy of Clinical Toxicology Practice Guidelines13 pH , 7.25 to 7.35 or visual signs and/or symptoms
or decreased vital signs despite intensive supportive care or kidney failure or substantial electrolyte disturbances unresponsive to supportive care
or serum methanol concentration . 50 mg/dL Extracorporeal Treatment in Poisoning Workgroup6 pH , 7.15 Severe visual defects or coma
or worsening vital signs despite intensive supportive care or kidney failure or serum methanol: .70 mg/dL with fomepizole
.60 mg/dL with ethanol .50 mg/dL in absence of inhibitor Note: Intermittent hemodialysis is preferred over continuous renal replacement therapy.
Randomized controlled studies of the different approaches to treatment in order to provide evidence-based recommendations have not been performed. Factors to take into consideration in making a decision include effectiveness, cost, availability of resources, and potential complications of therapy. In large academic centers with ready access to dialysis and fomepizole, combination therapy is often favored, as it was in the present case. However, in smaller centers, ready access to hemodialysis and fomepizole might not be available. As noted, several experts have concluded that inhibitor alone might be sufficient in the treatment of certain cases of methanol intoxication.47 Use of the inhibitor, whether it be ethanol or fomepizole, will markedly increase the half-life of methanol to between 40 and 70 hours.30,51 This will increase the duration of hospitalization and theoretically increase the risk for complications. When acidemia is severe (blood pH , 7.2), base is recommended, although its value has not been subject to rigorous examination. In addition to negating the adverse effects of the acidic tissue environment, some have suggested that it lessens the severity of ophthalmic injuries13 and facilitates the urinary excretion of formate.52 Administration of folinic acid is said to speed the metabolism of formic acid and is often recommended.13 The ability to monitor blood concentrations of methanol and possibly its metabolites is theoretically an Am J Kidney Dis. 2016;-(-):---
Symptoms including abdominal pain, nausea, vomiting, and decreased vision are nonspecific and can occur hours to days after exposure An increase in serum osmolality and/or anion gap can be clues to methanol intoxication, but their presence depends on the baseline serum osmolal gap, baseline serum anion gap, methanol concentration in blood, time after exposure, and absence or presence of coingested ethanol Definitive diagnosis of methanol intoxication presently requires measurement with gas or liquid chromatography, a laborious and expensive procedure. Newer methods of diagnosis including use of an alcohol oxidase strip to detect methanol in blood, enzymatic test to detect formate in blood, or liquid-based test using alcohol oxidase and potassium permanganate to detect methanol in saliva might improve the effectiveness of diagnosis Treatment should be initiated when estimated serum methanol concentration is $20 mg/dL or signs and symptoms of significant acidemia are present. Some experts also recommend initiation of treatment with only a high suspicion of exposure Treatment can include administration of ethanol or fomepizole, 2 inhibitors of alcohol dehydrogenase. Although both are effective, the latter is often preferred because of ease of administration, absence of impact on the central nervous system, and lack of need for close observation in an intensive care unit Hemodialysis can remove both methanol and formate while providing base. Controversy remains about its use because in many cases, intoxication can be treated alone with the inhibitor. We have a low threshold for its use because it will accelerate recovery, reduce hospitalization duration, and minimize exposure to methanol
essential aspect of therapy. However, most centers do not have the ability to obtain timely measurements of serum methanol or its major metabolite formate. In the absence of these measurements, serum osmolal gap has often served as a surrogate for blood methanol concentration.48,53-55 Several investigators have shown there is a strong direct correlation between serum methanol concentration and serum osmolal gap.48,55 For every 10mg/dL increase in serum methanol concentration, osmolal gap will be increased by w3 mOsm/kg/H2O. The clinician can used this estimated serum methanol concentration to assess the clearance of methanol from the body. When serum osmolal gap is decreased to ,6 mOsm/kg (equivalent to serum methanol concentration of 20 mg/dL), dialysis therapy and treatment with inhibitor can theoretically be discontinued. However, in situations such as the present case when a portion of the increase in serum osmolality appears to be due to accumulation of other substances than methanol, osmolal gap is not as precise a measure of changes in methanol concentration. Monitoring serum formate concentrations has also been found to be helpful in the assessment of the severity of intoxication and in its management.9 Serum formate levels $ 3.7 mmol/L indicate the 5
Jeffrey A. Kraut
need for hemodialysis, and serum formate levels $ 17.5 mmol/L are associated with 90% risk for death. In summary, optimal treatment of methanol intoxication requires early recognition and rapid initiation of effective therapy. A high degree of suspicion must be present given the nonspecific nature of many of the symptoms and signs. Abnormalities in serum osmolal and anion gaps can be suggestive, but are not always present. Tests that determine methanol and/or formate concentrations in blood or saliva are under investigation and could improve the detection of this poisoning. Therapy should include administration of an inhibitor, preferably fomepizole, although ethanol can be effective should fomepizole not be readily available. Controversy about the value of hemodialysis exists with recommendations by committees of experts restricting it to specific circumstances. Randomized controlled studies to establish the safest and most cost-effective therapies are warranted. However, in their absence, I advocate using fomepizole and hemodialysis for the treatment of methanol intoxication, particularly when the intoxication is perceived to be severe. Combination therapy will substantially reduce the days of hospitalization and limit the exposure to the drug. Teaching points are summarized in Box 2.
ACKNOWLEDGEMENTS Support: The manuscript was supported by funds from the UCLA Academic Senate and Veterans Administration. Financial Disclosure: The author declares that he has no relevant financial interests. Peer Review: Evaluated by 2 external peer reviewers, the Education Editor, and the Editor-in-Chief.
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Treatment of Methanol Intoxication effectiveness be improved? Clin J Am Soc Nephrol. 2013;8(11): 2018-2024. 29. Iberti TJ, Leibowitz AB, Papadakos PJ, Fischer EP. Low sensitivity of the anion gap as a screen to detect hyperlactatemia in critically ill patients. Crit Care Med. 1990;18(3):275-277. 30. Hovda KE, Andersson KS, Urdal P, Jacobsen D. Methanol and formate kinetics during treatment with fomepizole. Clin Toxicol. 2005;43(4):221-227. 31. Krasowski MD, Wilcoxon RM, Miron J. A retrospective analysis of glycol and toxic alcohol ingestion: utility of anion and osmolal gaps. BMC Clin Pathol. 2012;12:1. 32. Kraut JA, Xing SX. Approach to the evaluation of a patient with an increased serum osmolal gap and high-anion-gap metabolic acidosis. Am J Kidney Dis. 2011;58(3):480-484. 33. Kerns W, Tomaszewski C, McMartin K, Ford M, Brent J. Formate kinetics in methanol poisoning. J Toxicol Clin Toxicol. 2002;40(2):137-143. 34. Hovda KE, Urdal P, Jacobsen D. Increased serum formate in the diagnosis of methanol poisoning. J Anal Toxicol. 2005;29(6):586-588. 35. Hack JB, Early J, Brewer KL. An alcohol oxidase dipstick rapidly detects methanol in the serum of mice. Acad Emerg Med. 2007;14(12):1130-1134. 36. Shin JM, Sachs G, Kraut JA. Simple diagnostic tests to detect toxic alcohol intoxications. Transl Res. 2008;152(4):194-201. 37. Brent J. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009;360(21):2216-2223. 38. Hantson P, Wittebole X, Haufroid V. Ethanol therapy for methanol poisoning: duration and problems. Eur J Emerg Med. 2002;9(3):278-279. 39. Hantson P. Ethanol therapy for toxic alcohols poisoning: drawbacks and side-effects. Przegl Lek. 2002;59(4-5):396-397. 40. Megarbane B, Borron SW, Trout H, et al. Treatment of acute methanol poisoning with fomepizole. Intensive Care Med. 2001;27(8):1370-1378. 41. Burns MJ, Graudins A, Aaron CK, McMartin K, Brent J. Treatment of methanol poisoning with intravenous 4-methylpyrazole. Ann Emerg Med. 1997;30(6):829-832. 42. Marraffa J, Forrest A, Grant W, Stork C, McMartin K, Howland MA. Oral administration of fomepizole produces similar blood levels as identical intravenous dose. Clin Toxicol (Phila). 2008;46(3):181-186.
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43. Zakharov S, Navratil T, Pelclova D. Fomepizole in the treatment of acute methanol poisonings: experience from the Czech mass methanol outbreak 2012-2013. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014;158(4):641-649. 44. Zakharov S, Pelclova D, Navratil T, et al. Fomepizole versus ethanol in the treatment of acute methanol poisoning: comparison of clinical effectiveness in a mass poisoning outbreak. Clin Toxicol (Phila). 2015;53(8):797-806. 45. World Health Organization (WHO). WHO Model List of Essential Medicines 18th List. Geneva, Switzerland: World Health Organization; 2013. 46. Borron SW, Megarbane B, Baud FJ. Fomepizole in treatment of uncomplicated ethylene glycol poisoning. Lancet. 1999;354(9181):831. 47. Hovda KE, Froyshov S, Gudmundsdottir H, Rudberg N. Fomepizole may change indication for hemodialysis in methanol poisoning: prospective study in seven cases. Clin Nephrol. 2005;64(5):190-197. 48. Hovda KE, Hunderi OH, Rudberg N, Froyshov S, Jacobsen D. Anion and osmolal gaps in the diagnosis of methanol poisoning: clinical study in 28 patients. Intensive Care Med. 2004;30(9):1842-1846. 49. Peces R, Fernandez R, Peces C, et al. [Effectiveness of preemptive hemodialysis with high-flux membranes for the treatment of life-threatening alcohol poisoning]. Nefrologia. 2008;28(4):413-418. 50. Hantson P, Haufroid V, Wallemacq P. Formate kinetics in methanol poisoning. Hum Exp Toxicol. 2005;24(2):55-59. 51. Palatnick W, Redman LW, Sitar DS, Tenenbein M. Methanol half-life during ethanol administration - implications for management of methanol poisoning. Ann Emerg Med. 1995;26(2):202-207. 52. Jacobsen D, Webb R, Collins TD, McMartin KE. Methanol and formate kinetics in late diagnosed methanol intoxication. Med Toxicol Adverse Drug Exp. 1988;3(5):418-423. 53. ten Bokkel Huinink DT, de Meijer PH, Meinders AE. Osmol and anion gaps in the diagnosis of poisoning. Neth J Med. 1995;46(2):57-61. 54. Glaser DS. Utility of the serum osmol gap in the diagnosis of methanol or ethylene glycol ingestion. Ann Emerg Med. 1996;27(3):343-346. 55. Hunderi OH, Hovda KE, Jacobsen D. Use of the osmolal gap to guide the start and duration of dialysis in methanol poisoning. Scand J Urol Nephrol. 2006;40(1):70-74.
7
Note from the editors: This article is part of a series of invited case discussions highlighting either the diagnosis or treatment of acid-base and electrolyte disorders.
INTRODUCTION Methanol intoxication can cause severe cellular dysfunction and death,1 primarily due to the accumulation of organic acids and their anions produced by its metabolism.2-4 Effective methods of treatment that include administering inhibitors of the enzyme alcohol dehydrogenase to prevent its metabolism5 and hemodialysis6 to remove it and its toxic metabolites from the body are readily available. However, recognition of the intoxication is often hampered by the lack of specific signs and symptoms and the limitation of present diagnostic modalities.7 Although mortality is low if treatment is initiated promptly,8 a delay can cause it to increase to as high as 44%.9,10 In this Acid-Base and Electrolyte Teaching Case, a case of methanol intoxication is presented, which was previously reported by Rastogi et al,11 and current methods of diagnosis and treatment are discussed.
CASE REPORT Clinical History and Initial Laboratory Data A 22-year-old woman presented to the emergency department 30 hours after ingesting 16 ounces of model airplane fuel. She reported no abdominal pain, nausea, vomiting, visual disturbances, or headache. On physical examination, temperature was 37.2 C; pulse rate, 100 beats/min; blood pressure, 132/50 mm Hg in the sitting position; and respirations, 16 breaths/min. Lungs were clear to auscultation, and cardiac, abdominal, and neurologic examination findings were normal. No ophthalmic changes were reported. Laboratory studies performed during the hospitalization are shown Am J Kidney Dis. 2016;-(-):---
in Table 1 and revealed a low serum bicarbonate level, elevated serum osmolality and osmolal gap, and increased serum creatinine level. The latter was shown to be due to laboratory error caused by interference of nitromethane in the airplane fuel with serum creatinine measurement as performed by the usual Jaffé method.11
Additional Investigations Urinalysis showed no cells or crystals. Serum acetaminophen, ethyl alcohol, acetone, and isopropyl alcohol results were negative. Methanol concentration obtained on admission reported 2 days later was 71 mg/dL.
Diagnosis Acute methanol intoxication.
Clinical Follow-up The patient initially was given fomepizole and dialyzed for 4 hours. Additional doses of fomepizole were given and dialysis was
From the Medical and Research Services Veterans Administration Greater Los Angeles Healthcare System, UCLA Membrane Biology Laboratory, and Division of Nephrology, Veterans Administration Greater Los Angeles Healthcare System, and David Geffen School of Medicine, Los Angeles, CA. Received October 16, 2015. Accepted in revised form February 4, 2016. Because the author of this article is the editor for this feature, the peer-review and decision-making processes were handled without his participation. Details of the journal’s procedures for potential editor conflicts are given in the Information for Authors & Journal Policies. Address correspondence to Jeffrey A. Kraut, MD, Division of Nephrology, VHAGLA Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073. E-mail: [email protected] Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2016.02.058 1
Jeffrey A. Kraut Table 1. Laboratory Studies During Hospitalization
Methanol
Test
Admission
17 h After Admission
Sodium, mEq/L Potassium, mEq/L Chloride, mEq/L Total carbon dioxide, mEq/L SUN, mg/dL Serum creatinine, mg/dLa eGFR,c mL/min/1.73 m2 Anion gap, mEq/L Serum osmolality, mOsm/kg/H2O Osmolal gap, mOsm/ kg/H2O Methanol, mg/dL Serum albumin, g/dL
141 3.5 111 18
140 3.2 104 28
143 3.8 109 25
142 3.6 112 25
14 23.7b
5 10b
7 8.4b
4 6.0
2 11 357
5 8 303
6 9 303
9 5 303
70
—
—
—
71 4
26
— —
— —
—
Day 2
Day 3
Note: Conversion factors for units: serum creatinine in mg/dL to mmol/L, 388.4; SUN in mg/dL to mmol/L, 30.357. Abbreviations: eGFR, estimated glomerular filtration rate; SUN, serum urea nitrogen. a Values obtained using the Jaffe´ reaction. b Values proved to be inaccurate due to interference of nitromethane in ingested airplane fuel with measurement of serum creatinine. c As calculated by the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Adapted from Rastogi et al11 with permission of the National Kidney Foundation.
repeated during the hospitalization. With treatment, acid-base parameters and serum osmolality (Table 1) returned to normal and the patient was discharged.
DISCUSSION This patient had a history of exposure to methanol, a markedly increased serum osmolal gap, and metabolic acidosis. These features are suggestive of methanol intoxication.7,12 Methanol intoxication is a relatively uncommon but important poisoning: approximately 5,000 cases are reported to the US Poison Control each year.2,8,13 Methanol is present in several household cleaning solutions and dyes, model airplane fuel, windshield washer fluid, gas line antifreeze, and illegally produced alcoholic beverages. Intoxication is most commonly due to ingestion, but can also result from inhalation or absorption through the skin.13 Symptoms can include dyspnea, nausea, vomiting, abdominal pain, impaired sensorium, and impaired vision.14 Ophthalmologic examination can reveal optic papillitis (found in 10% of cases). Muscle rigidity and masked facies can be observed when the putamen is damaged.15 The majority of the clinical abnormalities are due to the effects of formic acid, the major metabolite of methanol (Fig 1). Interference with cytochrome oxidase by formate causes tissue 2
Alcohol dehydrogenase
Formaldehyde Formaldehyde dehydrogenase
Formic acid Folinic acid
CO2 + H2O Figure 1. Metabolism of methanol. Methanol undergoes serial oxidation: methanol is catalyzed by the enzyme alcohol dehydrogenase to formaldehyde and then formaldehyde is catalyzed by the enzyme formaldehyde dehydrogenase to formic acid. Folinic acid given to a patient will accelerate the conversion to carbon dioxide (CO2) and water (H2O). Adapted from Rastogi et al11 with permission of the National Kidney Foundation.
hypoxia and lactic acidosis.13 Clinical abnormalities can be delayed as long as 96 hours if ethanol or certain antiviral medication, such as abacavir, are coingested because both inhibit the enzyme that catalyzes the metabolism of methanol, alcohol dehydrogenase.3,16-19 Both the nonspecificity of the clinical abnormalities and the delay between exposure and their appearance can hinder establishing the diagnosis, thus resulting in high mortality.10 An increase in the serum osmolal gap (caused by accumulation of methanol in the blood) and anion gap (caused by accumulation of formate and sometimes lactate in the blood) can also serve as clues to the presence of methanol intoxication.16,20 The marked increase in serum osmolal gap in the present case (70 mOsm/kg/H2O) reflects in part a high methanol concentration and is indicative of toxic alcohol ingestion because an osmolal gap greater than 15 to 20 mOsm/kg/H2O is rarely observed with other causes of increased osmolal gap.2,13 However, the osmolal gap exceeds the level predicted based on the measured methanol concentration (71 mg/dL; osmolality, 23 mOsm/kg/H2O). The explanation for this disparity is not clear, but possibly could reflect accumulation of osmotically active substances such as nitromethane and/or polyalkylene glycol found in the airplane fuel. Although the osmolal gap and anion gap were increased in this case, individuals can have methanol Am J Kidney Dis. 2016;-(-):---
Treatment of Methanol Intoxication
intoxication in the absence of an increase in osmolal and/or anion gaps.21,22 The reasons for this can best be appreciated by examining the evolution of these gaps in patients with methanol intoxication. Serum osmolal gap depends on the baseline osmolal gap and the increment in osmolality produced by the methanol in the blood at the time it is sampled. It is often stated that a normal baseline osmolal gap is 10 to 20 mOsm/kg/H2O. Values greater than this indicate accumulation of toxic alcohols, such as methanol.23 However, baseline serum osmolal gaps in apparently healthy individuals can vary from 211 to 110 mOsm/kg/H2O.21,22,24-27 If the osmolal gap should prove to be negative, a methanol concentration of 20 mg/dL (the level when treatment is recommended) would not produce an osmolal gap . 10 mOsm/kg/H2O. Also, osmolal gap is highest early in the course of the intoxication, but will decrease substantially as methanol is metabolized. Sampling of blood later in the course when methanol concentration has decreased would also lessen the chances of detecting a markedly elevated osmolal gap. The baseline serum anion gap can be as low as 3 mEq/L in healthy individuals.28,29 As a result, the anion gap might not exceed the upper limit of normal even if there is an increment in the concentration of organic acid anions, as long as their concentration is less than 7 to 8 mEq/L. Also, blood sampling early after exposure before much of the methanol is metabolized will lessen the chance of detecting an increased anion gap.18,30 Even if the osmolal gap is elevated (as long as the increase is modest, ie, ,15 mOsm/kg/H2O), the increase might be caused by other disorders. A retrospective study of 346 patients with an increased osmolal gap (averaging 14 mOsm/kg/H2O) revealed that in a majority of cases, the increase was due to the presence of lactic acidosis, ketoacidosis, kidney failure, and/or sick cell syndrome rather than a toxic alcohol.31,32 Given the nonspecificity of the signs and symptoms and inconsistency of the changes in serum osmolal and anion gaps, more specific methods for detection of methanol and monitoring of changes in its concentration are required. Presently, detection of methanol is best achieved using gas or liquid chromatography,2,7,33 a laborious and expensive method that is not available in many clinical chemistry laboratories. Methanol concentration was not reported for 48 hours in the present case. Other direct and indirect methods to assess methanol concentrations are shown in Table 2. An enzymatic method that detects the metabolite formate in blood has been described.34 Formate dehydrogenase and nicotinamide adenine dinucleotide are used to measure serum formate. The Am J Kidney Dis. 2016;-(-):---
day-to-day coefficient of variation is 5%. The assay can be done using most autoanalyzers and requires only commercially available reagents. In one study, the majority of patients (14 of 15) with an elevated methanol concentration also had an elevated serum formate concentration.34 A dipstick impregnated with alcohol oxidase is available that detects methanol, ethanol, and ethylene glycol in blood and saliva.35 Methanol strongly reacts to the strip and at similar concentrations, gives a more intense color than ethanol. A liquid-based colorimetric method using the enzymes alcohol oxidase or alcohol dehydrogenase or the oxidizing agents sodium periodate and potassium permanganate was able to detect methanol and other alcohols when added to saliva at concentrations as low as 1 to 10 mg/dL.36 Validation of these methods can improve treatment by facilitating the diagnosis of methanol intoxication. Treatment with stomach gavage is generally not useful because methanol is rapidly absorbed. Rather, treatment can include inhibition of the enzyme alcohol dehydrogenase37 and removal of the parent alcohol and its metabolites by hemodialysis.6 Inhibition of alcohol dehydrogenase was initially accomplished by infusion of ethanol, which binds to the enzyme, preventing metabolism of methanol.2-5 Achieving a concentration of 100 to 150 mg/dL in the blood has been recommended, although lower concentrations might be sufficient to maximally inhibit the enzyme.13 The infusion has to be continuous and is usually done in an intensive care unit to facilitate maintenance of an adequate ethanol concentration and prevent complications of therapy.38,39 One major advantage is that this therapy is inexpensive and readily available. Fomepizole, a specific inhibitor of alcohol dehydrogenase, was approved by the US Food and Drug Administration for the treatment of methanol intoxication in 2000.37,40,41 It has substantially greater binding affinity for the enzyme (.8,000 than for ethanol) and therefore is more effective than ethanol. It can be given both intravenously and orally at the same dosage,42 although presently, only the intravenous form is available in the United States. It has minimal side effects and in contrast to ethanol, can be administered to the patient without requiring hospitalization in the intensive care unit. Comparisons of both agents showed that their side-effect profiles were not different and mortality was identical.43 A systematic review of MEDLINE and Embase databases including articles from 1966 to 2010 revealed that 80% of patients were treated with ethanol and 16% were treated with fomepizole.5 Importantly, the authors did not compare usage patterns before and after fomepizole was approved, theoretically biasing the study. By contrast, a retrospective study of all 3
Jeffrey A. Kraut Table 2. Methods to Diagnose Methanol Intoxication Parameter
History and physical examination Serum osmolal gap
Mechanism
Comments
Obtain historical evidence of exposure; suggestive symptoms and physical evidence of optic papilitis or neurologic abnormalities Increased osmolality reflects accumulation of parent alcohol in blood
Findings often nonspecific; long delay between onset and symptoms and signs can obscure the diagnosis
Serum anion gap
Detects accumulation of organic acid anion formate and in some cases lactate
Gas or liquid chromatography
Detects methanol in blood using gas or liquid chromatography methods
Measurement of serum formate
Detects accumulation of primary metabolite formate in blood using enzymatic test based on formate dehydrogenase Detects methanol, ethanol, and ethylene glycol based on enzyme alcohol oxidase Uses combination of enzymes (alcohol oxidase or dehydrogenase) and/or oxidizing agents such as potassium permanganate and sodium periodate
Dipstick impregnated with alcohol oxidase strip Liquid-based test of saliva using enzyme or oxidizing agents
electronic entries from the American Association of Professional Code Center (AAPC) National Poison Data System Database revealed that in 2012 to 2013, fomepizole was used in 90% of patients with methanol or ethylene glycol toxicity.8 However, use of ethanol in other countries has been reported to be greater than that of fomepizole.44 This presumably reflects less access to the latter drug because it was only added to the World Health Organization essential medicine list in 2013.45 Because fomepizole or ethanol will prevent the formation of toxic metabolites, theoretically, this therapy could be sufficient for the patient with methanol intoxication without the need for dialysis. In the absence of kidney failure, fomepizole alone has been shown to be effective in the treatment of methanol intoxication.46,47 In patients without severe symptoms, severe acidemia, or kidney failure, fomepizole alone has been recommended by some experts.47 A major disadvantage of using fomepizole alone is that by preventing its metabolism, the methanol is eliminated only by the lungs and kidney, a relatively slow process that increases the mean half-life to 54 hours.47 This increases the duration of hospitalization substantially and thus the cost of treatment.48 With hemodialysis, rapid removal of methanol and formate can be achieved.49 With the usual intermittent 4
Should be performed using freezing point depression rather than vapor pressure osmometry; can be helpful in many cases but osmolal gap might not be elevated if baseline osmolal gap is negative (osmolal gap also might not be elevated late when parent alcohol has been fully metabolized); despite limitations, good correlation between osmolal gap and methanol concentration has been found in some studies Might not be elevated if baseline serum anion gap is low; might not be elevated early in the course of intoxication prior to significant metabolism of alcohol to formate and development of lactic acidosis Gold standard for determination of methanol concentrations; labor intensive and expensive; not available in most clinical laboratories Indirectly estimates methanol concentration; might not be positive early in the course of intoxication prior to metabolism of methanol; not yet in clinical use Detects ethanol, methanol, and ethylene glycol in blood and saliva, but most sensitive to methanol Methods work only with saliva; detects concentrations of methanol as low as 1 mg/dL; uses readily available chemicals; costs of procedures likely to be less than few dollars; liquid-based analysis or strip test might be used
hemodialysis protocol (4 hours with blood flow of 400 mL/min and dialysis flow of 800 mL/min), methanol clearance of 200 mL/min can be achieved, resulting in a half-live of 2 hours.50 Clearance of formate is w223 mL/min under these conditions, resulting in a half-life of 1.8 hours.50 The decision to use an inhibitor alone or in combination with dialysis therefore remains an area of controversy.6,47 In 2002, the American Academy of Clinical Toxicology published criteria for the use of dialysis in the treatment of methanol intoxication13 (Box 1). Indications included metabolic acidosis with blood pH , 7.25, deteriorating vital signs despite supportive care, and serum methanol concentration . 50 mg/dL. In 2015, the Extracorporeal Treatment in Poisoning Workgroup published their criteria after careful examination of the literature (Box 1).6 Some differences included a lower target blood pH (7.15) and use of different blood concentrations depending on the specific conditions: serum methanol concentrations . 70 mg/dL with fomepizole therapy, .60 mg/dL with ethanol therapy, and .50 mg/dL in the absence of inhibitors. Recommendations by both committees favored intermittent hemodialysis over continuous renal replacement dialysis. Dialysis can be terminated when methanol levels are ,20 mg/dL. Am J Kidney Dis. 2016;-(-):---
Treatment of Methanol Intoxication Box 1. Indications for Hemodialysis for Treatment of Methanol Intoxication
Box 2. Teaching Points
American Academy of Clinical Toxicology Practice Guidelines13 pH , 7.25 to 7.35 or visual signs and/or symptoms
or decreased vital signs despite intensive supportive care or kidney failure or substantial electrolyte disturbances unresponsive to supportive care
or serum methanol concentration . 50 mg/dL Extracorporeal Treatment in Poisoning Workgroup6 pH , 7.15 Severe visual defects or coma
or worsening vital signs despite intensive supportive care or kidney failure or serum methanol: .70 mg/dL with fomepizole
.60 mg/dL with ethanol .50 mg/dL in absence of inhibitor Note: Intermittent hemodialysis is preferred over continuous renal replacement therapy.
Randomized controlled studies of the different approaches to treatment in order to provide evidence-based recommendations have not been performed. Factors to take into consideration in making a decision include effectiveness, cost, availability of resources, and potential complications of therapy. In large academic centers with ready access to dialysis and fomepizole, combination therapy is often favored, as it was in the present case. However, in smaller centers, ready access to hemodialysis and fomepizole might not be available. As noted, several experts have concluded that inhibitor alone might be sufficient in the treatment of certain cases of methanol intoxication.47 Use of the inhibitor, whether it be ethanol or fomepizole, will markedly increase the half-life of methanol to between 40 and 70 hours.30,51 This will increase the duration of hospitalization and theoretically increase the risk for complications. When acidemia is severe (blood pH , 7.2), base is recommended, although its value has not been subject to rigorous examination. In addition to negating the adverse effects of the acidic tissue environment, some have suggested that it lessens the severity of ophthalmic injuries13 and facilitates the urinary excretion of formate.52 Administration of folinic acid is said to speed the metabolism of formic acid and is often recommended.13 The ability to monitor blood concentrations of methanol and possibly its metabolites is theoretically an Am J Kidney Dis. 2016;-(-):---
Symptoms including abdominal pain, nausea, vomiting, and decreased vision are nonspecific and can occur hours to days after exposure An increase in serum osmolality and/or anion gap can be clues to methanol intoxication, but their presence depends on the baseline serum osmolal gap, baseline serum anion gap, methanol concentration in blood, time after exposure, and absence or presence of coingested ethanol Definitive diagnosis of methanol intoxication presently requires measurement with gas or liquid chromatography, a laborious and expensive procedure. Newer methods of diagnosis including use of an alcohol oxidase strip to detect methanol in blood, enzymatic test to detect formate in blood, or liquid-based test using alcohol oxidase and potassium permanganate to detect methanol in saliva might improve the effectiveness of diagnosis Treatment should be initiated when estimated serum methanol concentration is $20 mg/dL or signs and symptoms of significant acidemia are present. Some experts also recommend initiation of treatment with only a high suspicion of exposure Treatment can include administration of ethanol or fomepizole, 2 inhibitors of alcohol dehydrogenase. Although both are effective, the latter is often preferred because of ease of administration, absence of impact on the central nervous system, and lack of need for close observation in an intensive care unit Hemodialysis can remove both methanol and formate while providing base. Controversy remains about its use because in many cases, intoxication can be treated alone with the inhibitor. We have a low threshold for its use because it will accelerate recovery, reduce hospitalization duration, and minimize exposure to methanol
essential aspect of therapy. However, most centers do not have the ability to obtain timely measurements of serum methanol or its major metabolite formate. In the absence of these measurements, serum osmolal gap has often served as a surrogate for blood methanol concentration.48,53-55 Several investigators have shown there is a strong direct correlation between serum methanol concentration and serum osmolal gap.48,55 For every 10mg/dL increase in serum methanol concentration, osmolal gap will be increased by w3 mOsm/kg/H2O. The clinician can used this estimated serum methanol concentration to assess the clearance of methanol from the body. When serum osmolal gap is decreased to ,6 mOsm/kg (equivalent to serum methanol concentration of 20 mg/dL), dialysis therapy and treatment with inhibitor can theoretically be discontinued. However, in situations such as the present case when a portion of the increase in serum osmolality appears to be due to accumulation of other substances than methanol, osmolal gap is not as precise a measure of changes in methanol concentration. Monitoring serum formate concentrations has also been found to be helpful in the assessment of the severity of intoxication and in its management.9 Serum formate levels $ 3.7 mmol/L indicate the 5
Jeffrey A. Kraut
need for hemodialysis, and serum formate levels $ 17.5 mmol/L are associated with 90% risk for death. In summary, optimal treatment of methanol intoxication requires early recognition and rapid initiation of effective therapy. A high degree of suspicion must be present given the nonspecific nature of many of the symptoms and signs. Abnormalities in serum osmolal and anion gaps can be suggestive, but are not always present. Tests that determine methanol and/or formate concentrations in blood or saliva are under investigation and could improve the detection of this poisoning. Therapy should include administration of an inhibitor, preferably fomepizole, although ethanol can be effective should fomepizole not be readily available. Controversy about the value of hemodialysis exists with recommendations by committees of experts restricting it to specific circumstances. Randomized controlled studies to establish the safest and most cost-effective therapies are warranted. However, in their absence, I advocate using fomepizole and hemodialysis for the treatment of methanol intoxication, particularly when the intoxication is perceived to be severe. Combination therapy will substantially reduce the days of hospitalization and limit the exposure to the drug. Teaching points are summarized in Box 2.
ACKNOWLEDGEMENTS Support: The manuscript was supported by funds from the UCLA Academic Senate and Veterans Administration. Financial Disclosure: The author declares that he has no relevant financial interests. Peer Review: Evaluated by 2 external peer reviewers, the Education Editor, and the Editor-in-Chief.
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