Purssell RA, Lynd LD, Koga Y.
The use of the osmole gap as a screening test for the presence of exogenous substances.
Toxicol Rev. 2004;23(3):189-202. doi: 10.2165/00139709-200423030-00005.
Abstract/Text
The rapid and accurate diagnosis of toxic alcohol poisoning due to methanol (methyl alcohol) [MeOH] and ethylene glycol (EG), is paramount in preventing serious adverse outcomes. The quantitative measurement of specific serum levels of these substances using gas chromatography is expensive, time consuming and generally only available at major tertiary-care facilities. Therefore, because these toxic substances are osmotically active and the measurement of serum osmolality is easily performed and more readily available, the presence of an osmole gap (OG) has been adopted as an alternative screening test. By definition, the OG is the difference between the measured serum osmolality determined using the freezing point depression (Osm(m)) and the calculated serum molarity (Mc), which is estimated from the known and readily measurable osmotically active substances in the serum, in particular sodium, urea, glucose, and potassium and ethanol (alcohol). Thus, the OG=Osm(m)-Mc, and an OG above a specific threshold (the threshold of positivity) suggests the presence of unmeasured osmotically active substances, which could be indicative of a toxic exposure. The objectives of this study were to review the principles of evaluating screening tests, the theory behind the OG as a screening test and the literature upon which the adoption of the OG as a screening test has been based. This review revealed that there have been numerous equations derived and proposed for the estimation of the Mc, with the objective of developing empirical evidence of the best equation for the determination of the OG and ultimately the utility of OG as a screening test. However, the methods and statistical analysis employed have generally been inconsistent with recommended guidelines for screening test evaluation and although many equations have been derived, they have not been appropriately validated. Specific evidence of the clinical utility of the OG requires that a threshold of positivity be definitively established, and the sensitivity and specificity of the OG in patients exposed to either EG or MeOH be measured. However, the majority of studies to date have only evaluated the relationship between the Osm(m) (mmol/kg H2O) and the Mc (mmol/L) in patients that have not been exposed to either MeOH or EG. While some studies have evaluated the relationship between the OG and serum ethanol concentration, these findings cannot be extrapolated to the use of the OG to screen for toxic alcohol exposure. This review shows that there has not been an appropriately designed empirical evaluation of the diagnostic utility of the OG and that its clinical utility remains hypothetical, having been theoretically extrapolated from the non-poisoned population.
Koga Y, Purssell RA, Lynd LD.
The irrationality of the present use of the osmole gap: applicable physical chemistry principles and recommendations to improve the validity of current practices.
Toxicol Rev. 2004;23(3):203-11. doi: 10.2165/00139709-200423030-00006.
Abstract/Text
The present clinical use of serum osmometry is erroneous in two respects. The first, and the most important, is the incorrect assumption that serum behaves as a dilute 'ideal' solution and that the osmotic activity of a substance depends solely on the number of solute particles. The amount of variance from ideal behaviour of serum containing an exogenous substance is expressed by the osmotic coefficient (phi). We have calculated the osmotic coefficient for serum containing ethanol (alcohol) and recommend that the osmotic coefficient for serum containing other low molecular weight substances such as methanol (methyl alcohol), isopropyl alcohol and ethylene glycol also be calculated. This is necessary for the accurate calculation of the contribution of these substances to the serum osmolality.Secondly, the practice of subtracting the calculated serum molarity from measured serum osmolality is not valid since it represents a mathematically improper expression. The units of these two terms are different. The 'osmole gap' (OG) is typically viewed as the difference between serum osmolality determined by an osmometer and the estimated total molarity of solute in serum by directly measuring the concentration of several substances and then substituting them into a published formula. Some authors call this sum the calculated or estimated osmolarity but, because the concentrations are measured directly and not with an osmometer, the calculated term represents molarity. The units of osmolality are mmol/kg of H2O and the units of molarity are mmol/L. Therefore, the practice of subtracting calculated serum molarity from measured serum osmolality is not mathematically sound and is an oversimplification for ease of application. This mathematical transgression necessarily adds an error to the incorrectly calculated OG. Despite this, the OG is commonly used in clinical medicine. Serum osmolality can be converted to molarity provided the weight percentage and the density of the solution are known and thus, we recommend that this conversion be done prior to calculation of the gap. We recommend that the gap between measured serum osmolarity and calculated serum molarity be called the 'osmolar gap'. After having corrected for non-ideality for serum and for inconsistency of units, the standard value and reference range for this gap must be determined in an adequate number of patient populations and in a variety of clinical settings. An example of this determination, using data from a group of ethanol-poisoned patients is given. This correction should be applied before the evaluation of the osmolar gap as a screening test for other low molecular weight substances proceeds.
Hoffman RS, Smilkstein MJ, Howland MA, Goldfrank LR.
Osmol gaps revisited: normal values and limitations.
J Toxicol Clin Toxicol. 1993;31(1):81-93. doi: 10.3109/15563659309000375.
Abstract/Text
A study was designed to define the osmol gap in patients whose serum ethanol concentrations are known, to reevaluate several accepted equations for calculating osmolarity, and to apply the results to the theoretical clinical scenario of a toxic alcohol ingestion. The design for the study used consecutive, prospective enrollment of all patients presenting to a large inner city hospital who clinically required determination of their serum ethanol and electrolytes. Three hundred and twenty one consecutive adult patients were enrolled in the study, sixteen were excluded from the final analysis. A stepwise multiple linear regression analysis was performed to determine the best coefficients for sodium, blood urea nitrogen, and ethanol from the data set. Osmolarity was then calculated using these coefficients and traditional models. The osmol gap (measured osmolality minus calculated osmolarity [2*Na + BUN/2.8 + Glu/18 + Etoh/4.6]) was -2 +/- 6 mOsm. Although different equations produced different osmol gaps (ranging from -5 to + 15 mOsm) the standard deviations and correlation coefficients were similar. Large variations exist in the range of osmol gaps. Absolute values are very dependent on the equations used to calculate osmolarity. Because of the larger range of values, small osmol gaps should not be used to eliminate the possibility of toxic alcohol ingestion.
Lynd LD, Richardson KJ, Purssell RA, Abu-Laban RB, Brubacher JR, Lepik KJ, Sivilotti ML.
An evaluation of the osmole gap as a screening test for toxic alcohol poisoning.
BMC Emerg Med. 2008 Apr 28;8:5. doi: 10.1186/1471-227X-8-5. Epub 2008 Apr 28.
Abstract/Text
BACKGROUND: The osmole gap is used routinely as a screening test for the presence of exogenous osmotically active substances, such as the toxic alcohols ethylene glycol and methanol, particularly when the ability to measure serum concentrations of the substances is not available. The objectives of this study were: 1) to measure the diagnostic accuracy of the osmole gap for screening for ethylene glycol and methanol exposure, and 2) to identify whether a recently proposed modification of the ethanol coefficient affects the diagnostic accuracy.
METHODS: Electronic laboratory records from two tertiary-care hospitals were searched to identify all patients for whom a serum ethylene glycol and methanol measurement was ordered between January 1, 1996 and March 31, 2002. Cases were eligible for analysis if serum sodium, blood urea nitrogen, glucose, ethanol, ethylene glycol, methanol, and osmolality were measured simultaneously. Serum molarity was calculated using the Smithline and Gardner equation and ethanol coefficients of 1 and 1.25 mOsm/mM. The diagnostic accuracy of the osmole gap was evaluated for identifying patients with toxic alcohol levels above the recommended threshold for antidotal therapy and hemodialysis using receiver-operator characteristic curves, likelihood ratios, and positive and negative predictive values.
RESULTS: One hundred and thirty-one patients were included in the analysis, 20 of whom had ethylene glycol or methanol serum concentrations above the threshold for antidotal therapy. The use of an ethanol coefficient of 1.25 mOsm/mM yielded higher specificities and positive predictive values, without affecting sensitivity and negative predictive values. Employing an osmole gap threshold of 10 for the identification of patients requiring antidotal therapy resulted in a sensitivity of 0.9 and 0.85, and a specificity of 0.22 and 0. 5, with equations 1 and 2 respectively. The sensitivity increased to 1 for both equations for the identification of patients requiring dialysis.
CONCLUSION: In this sample, an osmole gap threshold of 10 has a sensitivity and negative predictive value of 1 for identifying patients for whom hemodialysis is recommended, independent of the ethanol coefficient applied. In patients potentially requiring antidotal therapy, applying an ethanol coefficient of 1.25 resulted in a higher specificity and positive predictive value without compromising the sensitivity.
Kostic MA, Dart RC.
Rethinking the toxic methanol level.
J Toxicol Clin Toxicol. 2003;41(6):793-800. doi: 10.1081/clt-120025344.
Abstract/Text
INTRODUCTION: Treatment thresholds for methanol poisoning are based on case reports and published opinion. Most guidelines recommend treatment for a methanol level > or = 20 mg/dL in a nonacidotic patient. No supportive data have been offered nor has the time of the exposure been addressed. For instance, no distinction has been drawn between a methanol level drawn 1 hr vs. 24 hr from ingestion. We analyzed all published cases of methanol poisoning to determine the applicability of the 20 mg/dL threshold in a nonacidotic patient, specifically those arriving early for care (within 6 hr) with a peak or near-peak blood methanol concentration.
METHODS: Using predefined search criteria, a systematic review of the world literature was performed using MEDLINE and EMBASE. In addition, each article's references were hand searched for pre-1966 articles, as were fatality abstracts from all U.S. poison centers. Human cases were included if they reported a known time of a single methanol exposure, acid-base data, blood methanol, and blood ethanol (if not acidotic).
RESULTS: Dating to 1879, 372 articles in 18 languages were abstracted using a standard format; 329 articles (2433 patients) involved methanol poisoning, and 70 articles (173 patients) met inclusion criteria. Only 22 of these patients presented for care within 6hr of ingestion with an early methanol level. All but 1 patient was treated with an inhibitor of alcohol dehydrogenase (ADH). A clear acidosis developed only with a methanol level > or = 126 mg/dL. The patient that did not receive an ADH inhibitor was an infant with an elevated early methanol level (46 mg/dL) that was given folate alone and never became acidotic. Intra and inter-rater reliability were 0.95.
CONCLUSIONS: Nearly all reports of methanol poisoning involve acidotic patients far removed from ingestion. The small amount of data regarding patients arriving early show that 126 mg/dL is the lowest early blood methanol level ever clearly associated with acidosis. Contrary to conventional teaching, there are case reports of acidosis after only a few hours of ingestion. The data are insufficient to apply 20 mg/dL as a treatment threshold in a nonacidotic patient arriving early for care. Prospective studies are necessary to determine if such patients may be managed without antidotal therapy or dialysis.
Krenzelok EP, McGuigan M, Lheur P.
Position statement: ipecac syrup. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists.
J Toxicol Clin Toxicol. 1997;35(7):699-709. doi: 10.3109/15563659709162567.
Abstract/Text
In preparing this Position Statement, all relevant scientific literature was identified and reviewed critically by acknowledged experts using agreed criteria. Well-conducted clinical and experimental studies were given precedence over anecdotal case reports and abstracts were not usually considered. A draft Position Statement was then produced and subjected to detailed peer review by an international group of clinical toxicologists chosen by the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists. The Position Statement went through multiple drafts before being approved by the boards of the two societies and being endorsed by other societies. The Position Statement includes a summary statement for ease of use and is supported by detailed documentation which describes the scientific evidence on which the Statement is based. Syrup of ipecac should not be administered routinely in the management of poisoned patients. In experimental studies the amount of marker removed by ipecac was highly variable and diminished with time. There is no evidence from clinical studies that ipecac improves the outcome of poisoned patients and its routine administration in the emergency department should be abandoned. There are insufficient data to support or exclude ipecac administration soon after poison ingestion. Ipecac may delay the administration or reduce the effectiveness of activated charcoal, oral antidotes, and whole bowel irrigation. Ipecac should not be administered to a patient who has a decreased level or impending loss of consciousness or who has ingested a corrosive substance or hydrocarbon with high aspiration potential.
Jacobsen D, McMartin KE.
Antidotes for methanol and ethylene glycol poisoning.
J Toxicol Clin Toxicol. 1997;35(2):127-43. doi: 10.3109/15563659709001182.
Abstract/Text
Jones AL, Volans G.
Management of self poisoning.
BMJ. 1999 Nov 27;319(7222):1414-7. doi: 10.1136/bmj.319.7222.1414.
Abstract/Text
Caravati EM, Erdman AR, Christianson G, Manoguerra AS, Booze LL, Woolf AD, Olson KR, Chyka PA, Scharman EJ, Wax PM, Keyes DC, Troutman WG; American Association of Poison Control Centers.
Ethylene glycol exposure: an evidence-based consensus guideline for out-of-hospital management.
Clin Toxicol (Phila). 2005;43(5):327-45. doi: 10.1080/07313820500184971.
Abstract/Text
In 2002, poison centers in the US reported 5816 human exposures to ethylene glycol. A guideline that effectively determines the threshold dose for emergency department referral and need for pre-hospital decontamination could potentially avoid unnecessary emergency department visits, reduce health care costs, optimize patient outcome, and reduce life disruption for patients and caregivers. An evidence-based expert consensus process was used to create this guideline. Relevant articles were abstracted by a trained physician researcher. The first draft of the guideline was created by the primary author. The entire panel discussed and refined the guideline before distribution to secondary reviewers for comment. The panel then made changes based on the secondary review comments. The objective of this guideline is to assist poison center personnel in the out-of-hospital triage and initial management of patients with a suspected exposure to ethylene glycol by (1) describing the process by which the exposure might be evaluated, (2) identifying the key decision elements in managing the case, (3) providing clear and practical recommendations that reflect the current state of knowledge, and (4) identifying needs for research. This guideline is based on an assessment of current scientific and clinical information. The panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and health professionals providing care, considering all of the circumstances involved. Recommendations are in chronological order of likely clinical use. The grade of recommendation is in parentheses. (1) A patient with exposure due to suspected self-harm, misuse, or potentially malicious administration should be referred to an emergency department immediately regardless of the dose reported (Grade D). (2) Patients with inhalation exposures will not develop systemic toxicity and can be managed out-of-hospital if asymptomatic (Grade B). Patients with clinically significant mucous membrane irritation should be referred for evaluation (Grade D). (3) Decontamination of dermal exposures should include routine cleansing with mild soap and water. Removal of contact lenses and immediate irrigation with room temperature tap water is recommended for ocular exposures. All patients with symptoms of eye injury should be referred for an ophthalmologic exam (Grade D). (4) Patients with symptoms of ethylene glycol poisoning should be referred immediately for evaluation regardless of the reported dose (Grade C). (5) The absence of symptoms shortly after ingestion does not exclude a potentially toxic dose and should not be used as a triage criterion (Grade C). (6) Adults who ingest a "swallow" (10-30 mL), children who ingest more than a witnessed taste or lick, or if the amount is unknown of most ethylene glycol products should be referred immediately for evaluation. The potential toxic volume of dilute solutions (e.g., concentration <20%) is larger and can be estimated by a formula in the text (Grade C). (7) A witnessed taste or lick only by a child, or an adult who unintentionally drinks and then expectorates the product without swallowing, does not need referral (Grade C). (8) Referral is not needed if it has been >24 hours since a potentially toxic unintentional exposure, the patient has been asymptomatic, and no alcohol was co-ingested (Grade D). (9) Gastrointestinal decontamination with ipecac syrup, gastric lavage or activated charcoal is not recommended. Transportation to an emergency department should not be delayed for any decontamination procedures (Grade D). (10) Patients meeting referral criteria should be evaluated at a hospital emergency department rather than a clinic. A facility that can quickly obtain an ethylene glycol serum concentration and has alcohol or fomepizole therapy available is preferred. This referral should be guided by local poison center procedures and community resources (Grade D). (11) The administration of alcohol, fomepizole, thiamine, or pyridoxine is not recommended in the out-of-hospital setting (Grade D).
Lepik KJ, Levy AR, Sobolev BG, Purssell RA, DeWitt CR, Erhardt GD, Kennedy JR, Daws DE, Brignall JL.
Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole.
Ann Emerg Med. 2009 Apr;53(4):439-450.e10. doi: 10.1016/j.annemergmed.2008.05.008. Epub 2008 Jul 18.
Abstract/Text
STUDY OBJECTIVE: We investigate adverse drug events associated with antidotes ethanol and fomepizole in methanol or ethylene glycol poisonings. An "adverse drug event" is harm associated with normal or incorrect drug use. We describe type, frequency, severity, seriousness, and onset time of adverse drug events and test the hypothesis that fomepizole results in fewer adverse drug events than ethanol.
METHODS: This cohort study included patients aged 13 years or older, hospitalized between 1996 and 2005 for methanol or ethylene glycol poisoning (identified by International Classification of Diseases, Ninth Revision or 10th Revision codes) and treated with at least 1 dose of ethanol or fomepizole. Two abstractors separately reviewed each chart, identifying new clinical events during antidote treatment. Three toxicologists determined, by consensus, which events were adverse drug events. The primary outcome was at least 1 adverse drug event, expressed as adverse drug event rate per person-day of antidote treatment. Association between time to first adverse drug event and antidote type was modeled by Cox regression, adjusted for confounders.
RESULTS: Two hundred twenty-three charts were reviewed and 172 analyzed. Toxicologists identified at least 1 adverse drug event in 74 of 130 (57%) ethanol-treated and 5 of 42 (12%) fomepizole-treated cases. Central nervous system symptoms accounted for most adverse drug events (48% ethanol-treated, 2% fomepizole-treated). Severe adverse drug events occurred in 26 of 130 (20%) ethanol-treated (coma, extreme agitation, cardiovascular) and 2 of 42 (5%) fomepizole-treated (coma, cardiovascular). Serious (life-threatening) adverse drug events occurred in 11 of 130 (8%) ethanol-treated (respiratory depression, hypotension) and 1 of 42 (2%) fomepizole-treated (hypotension, bradycardia) cases. Median adverse drug event onset was within 3 hours after the start of either antidote. Ethanol and fomepizole adverse drug event rates were 0.93 and 0.13 adverse drug events per treatment-day, respectively. Adjusted hazard ratio was 0.16 (95% confidence interval 0.06, 0.40).
CONCLUSION: Given observational study limitations, results suggest lower occurrence of adverse drug events with fomepizole than ethanol.
Barceloux DG, Bond GR, Krenzelok EP, Cooper H, Vale JA; American Academy of Clinical Toxicology Ad Hoc Committee on the Treatment Guidelines for Methanol Poisoning.
American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning.
J Toxicol Clin Toxicol. 2002;40(4):415-46. doi: 10.1081/clt-120006745.
Abstract/Text
EPIDEMIOLOGY: Almost all cases of acute methanol toxicity result from ingestion, though rarely cases of poisoning have followed inhalation or dermal absorption. The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes.
MECHANISMS OF TOXICITY: Methanol has a relatively low toxicity and metabolism is responsible for the transformation of methanol to its toxic metabolites. Methanol is oxidized by alcohol dehydrogenase to formaldehyde. The oxidation of formaldehyde to formic acid is facilitated by formaldehyde dehydrogenase. Formic acid is converted by 10-formyl tetrahydrofolate synthetase to carbon dioxide and water. In cases of methanol poisoning, formic acid accumulates and there is a direct correlation between the formic acid concentration and increased morbidity and mortality. The acidosis observed in methanol poisoning appears to be caused directly or indirectly by formic acid production. Formic acid has also been shown to inhibit cytochrome oxidase and is the prime cause of ocular toxicity, though acidosis can increase toxicity further by enabling greater diffusion of formic acid into cells.
FEATURES: Methanol poisoning typically induces nausea, vomiting, abdominal pain, and mild central nervous system depression. There is then a latent period lasting approximately 12-24 hours, depending, in part, on the methanol dose ingested, following which an uncompensated metabolic acidosis develops and visualfunction becomes impaired, ranging from blurred vision and altered visual fields to complete blindness.
MANAGEMENT: For the patient presenting with ophthalmologic abnormalities or significant acidosis, the acidosis should be corrected with intravenous sodium bicarbonate, the further generation of toxic metabolite should be blocked by the administration of fomepizole or ethanol and formic acid metabolism should be enhanced by the administration of intravenous folinic acid. Hemodialysis may also be required to correct severe metabolic abnormalities and to enhance methanol and formate elimination. For the methanol poisoned patient without evidence of clinical toxicity, the first priority is to inhibit methanol metabolism with intravenous ethanol orfomepizole. Although there are no clinical outcome data confirming the superiority of either of these antidotes over the other, there are significant disadvantages associated with ethanol. These include complex dosing, difficulties with maintaining therapeutic concentrations, the need for more comprehensive clinical and laboratory monitoring, and more adverse effects. Thus fomepizole is very attractive, however, it has a relatively high acquisition cost.
CONCLUSION: The management of methanol poisoning includes standard supportive care, the correction of metabolic acidosis, the administration of folinic acid, the provision of an antidote to inhibit the metabolism of methanol to formate, and selective hemodialysis to correct severe metabolic abnormalities and to enhance methanol and formate elimination. Although both ethanol and fomepizole are effective, fomepizole is the preferred antidote for methanol poisoning.
Barceloux DG, Krenzelok EP, Olson K, Watson W.
American Academy of Clinical Toxicology Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Ad Hoc Committee.
J Toxicol Clin Toxicol. 1999;37(5):537-60. doi: 10.1081/clt-100102445.
Abstract/Text
Fomepizole (4-methylpyrazole, 4-MP, Antizol) is a potent inhibitor of alcohol dehydrogenase that was approved recently by the US Food and Drug Administration (FDA) for the treatment of ethylene glycol poisoning. Although ethanol is the traditional antidote for ethylene glycol poisoning, it has not been studied prospectively. Furthermore, the FDA has not approved the use of ethanol for this purpose. Case reports and a prospective case series indicate that the intravenous (i.v.) administration of fomepizole every 12 hours prevents renal damage and metabolic abnormalities associated with the conversion of ethylene glycol to toxic metabolites. Currently, there are insufficient data to define the relative role of fomepizole and ethanol in the treatment of ethylene glycol poisoning. Fomepizole has clear advantages over ethanol in terms of validated efficacy, predictable pharmacokinetics, ease of administration, and lack of adverse effects, whereas ethanol has clear advantages over fomepizole in terms of long-term clinical experience and acquisition cost. The overall comparative cost of medical treatment using each antidote requires further study.
Brent J, McMartin K, Phillips S, Burkhart KK, Donovan JW, Wells M, Kulig K.
Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group.
N Engl J Med. 1999 Mar 18;340(11):832-8. doi: 10.1056/NEJM199903183401102.
Abstract/Text
BACKGROUND: Ethylene glycol poisoning causes metabolic acidosis and renal failure and may cause death. The standard treatment is inhibition of alcohol dehydrogenase with ethanol, given in intoxicating doses, and adjunctive hemodialysis. We studied the efficacy of fomepizole, a new inhibitor of alcohol dehydrogenase, in the treatment of ethylene glycol poisoning.
METHODS: We administered intravenous fomepizole to 19 patients with ethylene glycol poisoning (plasma ethylene glycol concentration, > or =20 mg per deciliter [3.2 mmol per liter]). Patients who met specific criteria also underwent hemodialysis. Treatment was continued until plasma ethylene glycol concentrations were less than 20 mg per deciliter. Acid-base status, renal function, the kinetics of fomepizole, and ethylene glycol metabolism were assessed at predetermined intervals.
RESULTS: Fifteen of the patients initially had acidosis (mean serum bicarbonate concentration, 12.9 mmol per liter). Acid-base status tended to normalize within hours after the initiation of treatment with fomepizole. One patient with extreme acidosis died. In nine patients, renal function decreased during therapy; at enrollment, all nine had high serum creatinine concentrations and markedly elevated plasma glycolate concentrations (> or =97.7 mg per deciliter [12.9 mmol per liter]). None of the 10 patients with normal serum creatinine concentrations at enrollment had renal injury during treatment; all 10 had plasma glycolate concentrations at or below 76.8 mg per deciliter (10.1 mmol per liter). Renal injury was independent of the initial plasma ethylene glycol concentration. The plasma concentration of glycolate and the urinary excretion of oxalate, the major metabolites of ethylene glycol, uniformly fell after the initiation of fomepizole therapy. Few adverse effects were attributable to fomepizole.
CONCLUSIONS: In patients with ethylene glycol poisoning, fomepizole administered early in the course of intoxication prevents renal injury by inhibiting the formation of toxic metabolites.
Bekka R, Borron SW, Astier A, Sandouk P, Bismuth C, Baud FJ.
Treatment of methanol and isopropanol poisoning with intravenous fomepizole.
J Toxicol Clin Toxicol. 2001;39(1):59-67. doi: 10.1081/clt-100102881.
Abstract/Text
We report a case of mixed methanol and isopropanol poisoning in a patient who refused dialysis but agreed to treatment with intravenous fomepizole. The patient was asymptomatic on arrival, with initial blood methanol and isopropanol concentrations of 146 mg/dL and 39 mg/dL, respectively. Blood ethanol was undetectable. The patient was treated with fomepizole twice daily intravenously until blood methanol was undetectable. No side effects of therapy, other than transient eosinophilia, were observed. The evolution was uneventful and no metabolites of either alcohol were detected at any time during the hospitalization. The decay of plasma methanol and isopropanol under fomepizole treatment were well described by first-order kinetics. The plasma elimination half-lives of methanol and isopropanol were 47.6 hours and 27.7 hours, respectively. Fomepizole appears to have been effective in blocking the toxic metabolism of both methanol and isopropanol and was associated with a favorable outcome.
Trullas JC, Aguilo S, Castro P, Nogue S.
Life-threatening isopropyl alcohol intoxication: is hemodialysis really necessary?
Vet Hum Toxicol. 2004 Oct;46(5):282-4.
Abstract/Text
Isopropyl alcohol (IPA) is widely used in industrial and home-cleaning products, easily available to general public and inexpensive: intoxications can occur unintentionally, in suicide attempts or by alcohol abusers as a substitute for ethanol. Symptoms involve the gastrointestinal tract, central nervous system and at high doses cardiovascular manifestations may appear. Ketonemia, ketonuria without hyperglicemia or acidosis and elevated osmol gap are common laboratory findings. Mortality and morbidity is low, but some fatal cases have been reported in patients in deep coma and especially those with hypotension. We present a life-threatening intoxication, with deep coma and hypotension, treated successfully with hemodialysis. Whether hemodialysis must always be performed is a controversial question. Our opinion is hemodialysis is not needed, even in life-threatening situations. Arguments about this opinion are presented.
Noker PE, Tephly TR.
The role of folates in methanol toxicity.
Adv Exp Med Biol. 1980;132:305-15. doi: 10.1007/978-1-4757-1419-7_32.
Abstract/Text
In the monkey and human, methanol toxicity is characterized by a metabolic acidosis and an ocular toxicity which occur coincident with an accumulation of formate in blood. In contrast, methanol insensitive species such as the rat do not accumulate formate after methanol administration. Folate-dependent reactions are involved in the oxidation of formate to CO2 in both the rat and the monkey. Monkey liver contains a significantly lower hepatic folate level than does rat liver and, thus, formate accumulation in the monkey may be related to a functional folate deficiency in this species. Formate metabolism in the monkey can be stimulated with folate administration. After methanol administration, treatment of monkeys with repetitive doses of either 5-formyltetrahydrofolic acid or folic acid results in a marked decrease in blood formate accumulation, an absence of metabolic acidosis and no blood bicarbonate depletion. Also, methanol toxicity, once established in the monkey, can be reversed with 5-formyltetrahydrofolic acid administration. The results indicate that 5-formyltetrahydrofolic acid decreases formate accumulation after methanol by stimulating the rate of formate oxidation or utilization and provide additional evidence for the involvement of folate-dependent reactions in the metabolism and toxicity of methanol in the monkey.
.
From the NIH: Use of folate analogue in treatment of methyl alcohol toxic reactions is studied.
JAMA. 1979 Nov 2;242(18):1961-2. doi: 10.1001/jama.1979.03300180009005.
Abstract/Text
Roberts DM, Yates C, Megarbane B, Winchester JF, Maclaren R, Gosselin S, Nolin TD, Lavergne V, Hoffman RS, Ghannoum M; EXTRIP Work Group.
Recommendations for the role of extracorporeal treatments in the management of acute methanol poisoning: a systematic review and consensus statement.
Crit Care Med. 2015 Feb;43(2):461-72. doi: 10.1097/CCM.0000000000000708.
Abstract/Text
OBJECTIVE: Methanol poisoning can induce death and disability. Treatment includes the administration of antidotes (ethanol or fomepizole and folic/folinic acid) and consideration of extracorporeal treatment for correction of acidemia and/or enhanced elimination. The Extracorporeal Treatments in Poisoning workgroup aimed to develop evidence-based consensus recommendations for extracorporeal treatment in methanol poisoning.
DESIGN AND METHODS: Utilizing predetermined methods, we conducted a systematic review of the literature. Two hundred seventy-two relevant publications were identified but publication and selection biases were noted. Data on clinical outcomes and dialyzability were collated and a two-round modified Delphi process was used to reach a consensus.
RESULTS: Recommended indications for extracorporeal treatment: Severe methanol poisoning including any of the following being attributed to methanol: coma, seizures, new vision deficits, metabolic acidosis with blood pH ≤ 7.15, persistent metabolic acidosis despite adequate supportive measures and antidotes, serum anion gap higher than 24 mmol/L; or, serum methanol concentration 1) greater than 700 mg/L (21.8 mmol/L) in the context of fomepizole therapy, 2) greater than 600 mg/L or 18.7 mmol/L in the context of ethanol treatment, 3) greater than 500 mg/L or 15.6 mmol/L in the absence of an alcohol dehydrogenase blocker; in the absence of a methanol concentration, the osmolal/osmolar gap may be informative; or, in the context of impaired kidney function. Intermittent hemodialysis is the modality of choice and continuous modalities are acceptable alternatives. Extracorporeal treatment can be terminated when the methanol concentration is <200 mg/L or 6.2 mmol/L and a clinical improvement is observed. Extracorporeal Treatments in Poisoning inhibitors and folic/folinic acid should be continued during extracorporeal treatment. General considerations: Antidotes and extracorporeal treatment should be initiated urgently in the context of severe poisoning. The duration of extracorporeal treatment extracorporeal treatment depends on the type of extracorporeal treatment used and the methanol exposure. Indications for extracorporeal treatment are based on risk factors for poor outcomes. The relative importance of individual indications for the triaging of patients for extracorporeal treatment, in the context of an epidemic when need exceeds resources, is unknown. In the absence of severe poisoning but if the methanol concentration is elevated and there is adequate alcohol dehydrogenase blockade, extracorporeal treatment is not immediately required. Systemic anticoagulation should be avoided during extracorporeal treatment because it may increase the development or severity of intracerebral hemorrhage.
CONCLUSION: Extracorporeal treatment has a valuable role in the treatment of patients with methanol poisoning. A range of clinical indications for extracorporeal treatment is provided and duration of therapy can be guided through the careful monitoring of biomarkers of exposure and toxicity. In the absence of severe poisoning, the decision to use extracorporeal treatment is determined by balancing the cost and complications of extracorporeal treatment to that of fomepizole or ethanol. Given regional differences in cost and availability of fomepizole and extracorporeal treatment, these decisions must be made at a local level.
