Treatment of ethylene glycol and methanol poisoning: why ethanol?

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1 Netherlands Journal of Critical Care Copyright 2009, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received February 2009; accepted July 2009 Review Treatment of ethylene glycol and methanol poisoning: why ethanol? MGG Sturkenboom, HM van Rieke, DRA Uges Department of Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Abstract - Ethanol and fomepizole are used as antidotes for poisoning with ethylene glycol or methanol. Both ethylene glycol and methanol are metabolized by the enzyme alcohol dehydrogenase. Ethanol is a substrate for alcohol dehydrogenase and fomepizole is an inhibitor of this enzyme. This review pays attention to the differences between ethanol and fomepizole. The advantages and disadvantages of both antidotes are reviewed. Some authors claim fomepizole may prove able to eliminate the need for haemodialysis in certain patient groups. This may only hold true if fomepizole treatment is started shortly after the intake of a relatively low quantity of a toxic alcohol. Contrary to many authors, it is our opinion that fomepizole will prove unable to obviate the need for haemodialysis. The use of haemodialysis in addition to treatment with the antidotes is described. Haemodialysis not only removes the toxic alcohol and its metabolites, but is also helpful in correcting the metabolic imbalance. Taking account of the low availability, the side effects, high costs, and limited registration of fomepizole, we believe that ethanol still is the antidote of choice for poisoning with ethylene glycol and methanol. Keywords - methanol, ethyllene glycol, poisoning, ethanol, fomepizolel, antidotes Introduction Ethanol is the antidote that has been used for poisoning with alcohols since the 1940s [1,2]. Fomepizole is an alcohol dehydrogenase inhibitor. It is used as an antidote for poisoning with ethylene glycol and methanol [3,4]. Lately, fomepizole has been recommended more often than ethanol, because of a supposed better adverse event profile [5-9]. However, it is worth noting that several of those authors are connected with the pharmaceutical industry [5,10-13]. In this review, both antidotes are compared in ethylene glycol and methanol poisoning. Methanol poisoning Methanol is used as a solvent for cleaning solutions, dyes, adhesives, thinners, and paint removers. It is widely available as antifreeze, windshield-wiper fluid, and as fuel for camp stoves [1,9]. Methanol is also a cheap substitute of ethanol [1,9]. Methanol itself causes little toxicity [14]. It is metabolized into toxic metabolites, principally in the liver [1]. Alcohol dehydrogenase (ADH) is the primary enzyme responsible for the oxidation of methanol to formaldehyde. Formaldehyde dehydrogenase rapidly converts this into formic acid [1]. Figure 1 shows the metabolism of methanol. Formic acid is primarily responsible for the metabolic acidosis, visual disturbances (e.g. decreased visual acuity and finally blindness), and mortality associated with methanol poisoning [14,15]. A lethal dose of pure methanol in humans is approximately 1-2 ml/kg [4,15,16]. Serum osmolality is sometimes used as a surrogate parameter to diagnose alcohol poisoning, when monitoring blood-alcohol levels is not available. However, calculations based on serum osmolality may be impossible when different alcohols, e.g. methanol and ethanol, have been ingested at the same time. The alcohols contribute differently to the serum osmolality. For instance, 500 mg/l of methanol adds 17 mosm/l, the same concentration of ethanol adds 12 mosm/l, and of ethylene glycol 9 mosm/l [6,9,14,16]. Furthermore, an osmolal gap of 10 to even 20 mosm/l is considered to be within the normal range [6,9,16]. A toxic level of 500 mg/l of ethylene glycol is possibly missed, because the osmolal gap falls within the normal range. Furthermore, the different metabolites of the toxic alcohols contribute only a little to the osmolality. The absence of an osmolal gap therefore does not exclude toxic alcohol poisoning [9]. Moreover, serum osmolality must be performed with the freezing point depression method, as the vapour pressure method will not determine the volatile alcohols [6]. For all these reasons, a diagnosis of methanol or ethylene glycol poisoning based on serum osmolality is unreliable and should always be confirmed by blood-alcohol analysis. A more accurate method is blood-alcohol analysis using gas chromatography, because all toxic alcohols are both identified and quantified. The recommended treatment of methanol poisoning includes supportive care, increasing renal elimination of formate and methanol, and the administration of antidotes. Infusion of sodium bicarbonate may be beneficial in correcting metabolic acidosis [7,9,16]. Correspondence DRA Uges d.r.a.uges@apoth.umcg.nl Ethylene glycol poisoning Ethylene glycol is used as an unauthorized wine sweetener and is present in coolants and antifreeze [17]. Ethylene glycol poisoning can occur accidentally and intentionally. Doses of 200 NETH J CRIT CARE - VOLUME 13 - NO 6 - DECEMBER

2 Netherlands Journal of Critical Care MGG Sturkenboom, HM van Rieke, DRA Uges mg/kg bodyweight are considered toxic [18]. The lethal dose of ethylene glycol in humans is approximately 1.4 ml/kg [4,9,18]. Ethylene glycol is metabolized more rapidly than methanol [16]. It is metabolized in the liver for approximately 80%. The first step in the metabolism is oxidation to glycoaldehyde by ADH, subsequently to glycolic acid, glyoxylic acid, and oxalic acid (Figure 1). Approximately 20% of ethylene glycol is excreted unchanged by the kidneys [11,18,19]. Ethylene glycol toxicity is complex [6,16]. Glycolic and oxalic acid are the metabolic byproducts primarily responsible for the metabolic acidosis and renal damage observed in ethylene glycol poisoning [9]. Oxalic acid binds to calcium, forming insoluble calcium oxalate crystals [18,20]. These crystals deposit in the organs and cause acute renal failure, myocardial dysfunction, neurological dysfunction, and possible pulmonary dysfunction [9]. The elimination of ethylene glycol is more rapid than that of methanol, which means that the latent period for metabolite accumulation to toxic concentrations is usually shorter [16]. Therefore, the start of antidote treatment for ethylene glycol poisoning is more urgent than for methanol. The treatment of ethylene glycol poisoning consists of administering sodium bicarbonate to counteract the ongoing production of acidic metabolites, administering an antidote to prevent ethylene glycol metabolism, and haemodialysis to remove ethylene glycol and glycolic acid [16,21]. Ethanol As ethanol has been used as an antidote for many decades [1,2], it has never been registered by the pharmaceutical industry. This also implies that a sterile injectable form of ethanol is not commercially available. The efficacy of ethanol as an antidote for toxic alcohol exposure is due to the higher affinity of endogenous ADH for ethanol compared to methanol and ethylene glycol, respectively times and 100 times [9,15,18]. This way, ethanol competitively inhibits the metabolism of toxic alcohols to their respective toxic metabolites [4,22]. Ethanol is used as an antidote for poisoning with methanol and ethylene glycol, but also for other alcohol poisonings, like diethylene glycol and propylene glycol [6,9]. Ethanol can be administered either orally or intravenously. Any kind of commercially available ethanol can be used for oral administration. For intravenous administration, ethanol can be infused as a 10% solution in 5% dextrose [15,20]. Ethanol 96% is declared as volume per cent. So, given the specific gravity of ethanol of 0.8, 100 ml ethanol 96% (v/v) contains only 77 g of ethanol [18]. Dose recommendations of ethanol in the treatment of toxic alcohol exposure are divided into a loading dose and a maintenance dose. The loading dose is 600-1,000 mg/kg bodyweight, depending on the blood level of ethanol [15,20]. A maintenance dose is needed to maintain the target ethanol concentration. Individual variability, e.g. chronic alcohol abuse, influences the rate of the ethanol metabolism. The target level of ethanol should be kept between 1000 and 1500 mg/l [15,16,20,23]. This concentration is enough to saturate ADH, thus inhibiting further toxic alcohol metabolism [20]. Figure 1. Metabolism of methanol and ethylene glycol. methanol ethylene glycol ADH Fomepizole inhibits ADH Ethanol is substrate for ADH ADH urinary excretion formaldehyde glycoaldehyde formic acid glycolic acid oxalic acid 298 NETH J CRIT CARE - VOLUME 13 - NO 6 - DECEMBER 2009

3 Netherlands Journal of Critical Care Treatment of ethylene glycol and methanol poisoning: why ethanol? Haemodialysis eliminates both toxic alcohol and ethanol [16]. Therefore, the maintenance dose of ethanol should be raised by approximately 150 mg/kg/h. The dose recommendations are mentioned in Table 1. In general, adverse events of ethanol are reported to be central nervous system depression, hypoglycaemia, altered mental status, and possible hepatotoxicity. The advantages of treatment using ethanol are the availability in a clinical setting, and the extensive experience in different toxic alcohol poisonings [1,2,9,16,20,21]. Furthermore, it can be administered both intravenously and orally [9] and it is relatively safe. The disadvantages of treatment with ethanol include a possible altered mental status, dose calculations based on blood-alcohol analysis, and hospitalisation in an ICU during treatment [24]. Fomepizole Fomepizole or 4-methylpyrazole is a competitive inhibitor of endogenous ADH. Its affinity for the enzyme is approximately 500 to 8000 times higher than that of ethanol [9,22,25]. Fomepizole has been registered in Europe as an antidote for poisoning with ethylene glycol since 2002 [3]. In the United States of America it is also registered for methanol poisoning [2,4]. Fomepizole may be useful in the treatment of poisoning with diethylene glycol and propylene glycol [7,9]. Both alcohols are metabolized by ADH to toxic metabolites. The toxic effects of their metabolites would theoretically be prevented by fomepizole [9]. The efficacy of fomepizole in the treatment of human poisonings derives from retrospective case series, and two prospective clinical trials [5,12,14]. None of the studies involving humans used untreated control subjects or compared fomepizole with ethanol therapy [9,14]. Fomepizole can be given orally, but is only registered as an intravenous preparation [9,26,27]. Like ethanol, fomepizole treatment should be started with a loading dose and continued with a different maintenance dose. The intravenous loading dose is 15 mg/kg. The maintenance dose increases over time. Dose recommendations are mentioned in Table 1. It is advised to maintain fomepizole treatment until the methanol or ethylene glycol levels have been reduced to 200 mg/l or lower [1,3,4,14-16,22,28]. The increase in fomepizole dosing is due to the auto-inducing activity of fomepizole on cytochrome P450 2E1 [1,14,22,25]. Fomepizole has negligible protein binding and is therefore removed almost completely by haemodialysis. The dosing of fomepizole should be increased to every four hours or should be a continuous infusion of 1 mg/kg/h during haemodialysis [1,3,4,7,14,26]. Indications for haemodialysis in patients treated with fomepizole are considered to be persistent metabolic acidosis, renal impairment or clinical deterioration despite treatment [8,15,18]. Fomepizole is not officially approved for use in children [23]. No controlled studies have been conducted [23]. However, several children have been treated with fomepizole, either alone or after a loading dose of ethanol [23,29]. One patient experienced a transient episode of hypoglycaemia. This 22-month-old child received only fomepizole [29]. No major complications were reported [29]. Table 1. Dose recommendations for ethanol and fomepizole [1,3,4,7,15,18,26]. Ethanol Fomepizole Loading dose: D l = V d x B w [C t C m ] D l = 15 mg/kg x B w Maintenance dose: Maintenance dose during haemodialysis: D l = loading dose [mg] V d = volume of distribution [male 0.7 L/kg, female 0.6 L/kg] B w = body weight [kg] C t = target concentration ethanol [mg/l] C m = measured concentration ethanol [mg/l] Dose per hour: D m = C t x V max x B w /[K m + C t ] D m = maintenance dose [mg/h] V max = maximum enzyme capacity [mg/kg.h] [adult, non-drinker: 75 mg/kg.h, chronic alcohol drinker 175 mg/kg.h] K m = Michaelis-Menten-constant [138 mg/l] Dose per hour: D hd = D m + [Cl d x B w ] D hd = maintenance dose during haemodialysis [mg/h] Cl d = variable, dependent on artificial kidney and blood flow [mg/kg.h] D l = loading dose [mg] B w = body weight [kg] Dose per 12 hours: D m = 10 mg/kg x B w D m = 15 mg/kg x B w D m = maintenance dose [mg/12h] D m = maintenance dose, after 60h [mg/12h] Dose per 4 hours: D hd = D m D hd = D m Dose per hour: D hd ci = 1 mg/kg x B w D hd = maintenance dose during haemodialysis [mg/4h] D hd = maintenance dose during haemodialysis, after 60h [mg/4h] D hd ci = maintenance dose during haemodialysis [mg/h] NETH J CRIT CARE - VOLUME 13 - NO 6 - DECEMBER

4 Netherlands Journal of Critical Care MGG Sturkenboom, HM van Rieke, DRA Uges The advantages of treatment with fomepizole are supposed to be its minimal adverse events [25]. The most common adverse effect is a burning feeling at the infusion site. Headache, nausea, dizziness, agitation, eosinophilia, and seizures have also been reported. It is unknown whether these side effects are related to fomepizole treatment or caused by the toxic alcohols [14]. A case of serious adverse events such as hypotension and bradycardia, was recently reported [30]. Contrary to ethanol, dose calculations based on serum levels are not needed for fomepizole, resulting in an easier administration scheme. The disadvantages of fomepizole are the high costs, combined with its limited shelf life, the low availability and the fact that it is only registered for ethylene glycol poisoning in Europe [3,9,11,15,31,32]. Haemodialysis The indications for haemodialysis in toxic alcohol poisoning are severe metabolic acidosis, deteriorating vital signs despite supportive care, renal failure, and electrolyte imbalances unresponsive to therapy [9,11,20,26,33]. Haemodialysis should also be considered if methanol or ethylene glycol levels are above 500 mg/l [7,9,34,35]. Haemodialysis is very effective in removing toxins from the blood. In case of ethylene glycol poisoning, unmetabolized ethylene glycol, glycolic acid, and calcium oxalate are eliminated [9,11,20,28]. In methanol poisoning, methanol and formate are removed [1,26,28,36,37]. Haemodialysis is also helpful in correcting the metabolic imbalance [9,11,20,26]. An advantage of fomepizole may prove to be the capability of eliminating the need for haemodialysis in certain patient groups [8,10,13,20,26,29,31,33,36]. Fomepizole, like ethanol, only inhibits the metabolism of ethylene glycol or methanol [21]. When ethanol or fomepizole are administered and renal failure Table 2. The differences between ethanol and fomepizole. Advantages Disadvantages Ethanol Available in clinical setting Extensive experience in the Netherlands Antidote in different alcohol poisonings Administration orally and intravenously Dose calculations based on bloodalcohol levels Hospitalization in intensive care unit necessary during treatment Not officially registered as antidote Fomepizole Minimal adverse effects Registered for ethylene glycol poisoning High costs Not available in all clinical settings Limited shelf life Not registered for methanol in the Netherlands Lack of experience in the Netherlands Little experience in other alcohol poisonings is present, haemodialysis is the only method for the removal of ethylene glycol [20]. Furthermore, haemodialysis not only removes the parent compound and their toxic metabolites, but also corrects the metabolic imbalance [9]. Kraut et al. state that controlled, prospective studies are useful to decide whether fomepizole will be able to obviate the need for haemodialysis [9]. It has been suggested that patients with normal renal function may survive on fomepizole treatment alone [11,33]. Twenty percent of ethylene glycol is excreted unchanged in the urine [11,19]. Fomepizole may reduce the need for haemodialysis, if the metabolism of ethylene glycol is fully inhibited by the antidote and ethylene glycol itself is completely eliminated [16]. However, inhibiting the metabolism by antidotal treatment and inhibiting excretion by the commonly observed renal failure reduces the endogenous elimination of ethylene glycol to a minimum [16]. Thus haemodialysis becomes the major way to remove ethylene glycol and its metabolites from the body [16]. Without haemodialysis, the duration of the fomepizole treatment will therefore increase. Furthermore, any metabolite formed before treatment will remain toxic, because it is not removed. Discussion Its high affinity for ADH is stated as an advantage of fomepizole [9]. This only means that a lower concentration of fomepizole is required compared to ethanol and shows that both antidotes target the same mechanism. Fomepizole is thought to be easier to administer, as dose calculations are based on body weight rather than on serum levels. It could be argued that it would be more elegant to dose fomepizole on its serum level, because of the auto-inducing activity of fomepizole. Furthermore, this does not eliminate the need for alcohol analyses, as these are still indicated to control the blood levels of the toxic alcohols during fomepizole treatment [3,4]. Some experts consider a suspicion of methanol or ethylene glycol ingestion sufficient to start fomepizole [10]. It is obvious that we do not agree. Kraut et al. state that the increase in serum osmolality is a disadvantage of ethanol treatment, as this would complicate the monitoring response [9]. We do not agree. As we argued before, serum osmolality is unreliable in toxic alcohol poisoning. Extensive experience with ethanol in different alcohol poisonings has demonstrated that ethanol is highly effective as an antidote [1,2,9,16,20]. In general, the adverse events of ethanol are reported to be central nervous system depression, hypoglycaemia, altered mental status, and possible hepatotoxicity. However, there is limited information about the adverse effects of ethanol when used as an antidote [1,2,5,11,26]. The altered mental status due to the administered ethanol should be considered relative to the other toxic alcohols consumed and to the patients who may be used to levels that exceed the target level. It goes without saying that the latter is not true for children or unintentional alcohol poisonings. 300 NETH J CRIT CARE - VOLUME 13 - NO 6 - DECEMBER 2009

5 Netherlands Journal of Critical Care Treatment of ethylene glycol and methanol poisoning: why ethanol? Experience with fomepizole in children is limited. Therefore, there can be no preference for the time being. However, it may be anticipated that this patient group may benefit from the newer antidote in the future, as these patients may be more susceptible to the altered mental status caused by ethanol. In our opinion, the need for haemodialysis should be considered in the same way for both fomepizole and ethanol, because both antidotes only affect the metabolism of the ingested substance and not the elimination of its metabolites. Without haemodialysis, the duration of the fomepizole treatment will increase. Any metabolite formed before treatment will remain toxic, because it is not removed. We agree with Kraut et al. [9] that controlled, prospective studies are needed before it is possible to conclude that fomepizole obviates the need for haemodialysis. Intravenous treatment with 96% sterile ethanol for 60 hours costs approximately 20. The treatment of ethylene glycol or methanol poisoning with fomepizole is far more expensive than with ethanol. One phial of fomepizole 100 mg (5 mg/ml, 20 ml) costs approximately 110. A loading dose of 15 mg/kg costs approximately 1,100. If five doses (treatment 48 hours) are needed, the treatment cost will amount to approximately 4,300. In the case of haemodialysis, the costs will even be higher. Fomepizole is dialyzable and therefore the frequency of dosing should be increased to every four hours during haemodialysis. So ethanol may be preferred, especially if resources are limited [21]. Table 2 reflects our point of view on the differences between ethanol and fomepizole. Conclusion In the Netherlands, in our opinion, ethanol still is the antidote of choice for poisoning with ethylene glycol or methanol, because of the extensive experience and the constant availability of the antidote. Furthermore, both gas chromatography for bloodalcohol analysis and haemodialysis are commonly available in most Dutch hospitals. It is our opinion that the minimal adverse effects of fomepizole do not justify the high costs of its treatment, whilst its low availability due to costs and limited shelf life is also problematic. In conclusion, ethanol can treat toxic alcohol poisonings safely and effectively. References 1. Barceloux DG, Bond GR, Krenzelok EP, Cooper H, Vale JA. American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol 2002; 40: Lepik KJ, Levy AR, Sobolev BG, Purssell RA, DeWitt CR, Erhardt GD et al. Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole. Ann Emerg Med 2009;3: Fomepizole OPi Samenvatting van productkenmerken. Available at (cited 01/30/2009). 4. Antizol(R) product monograph. Available at shtml (cited 01/30/2009). 5. Brent J, McMartin K, Phillips S, Burkhart KK, Donovan JW, Wells M et al. Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group. N Engl J Med 1999;340: Jacobsen D, McMartin KE. Antidotes for methanol and ethylene glycol poisoning. J Toxicol Clin Toxicol 1997;35: Megarbane B, Borron SW, Baud FJ. Current recommendations for treatment of severe toxic alcohol poisonings. Intensive Care Med 2005;31: Velez LI, Gracia R, Neerman MF. Ethylene glycol poisoning: current diagnostic and management issues. J Emerg Nurs 2007;33: Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol 2008;3: Borron SW, Megarbane B, Baud FJ. Fomepizole in treatment of uncomplicated ethylene glycol poisoning. Lancet 1999;354: Brent J. Current management of ethylene glycol poisoning. Drugs 2001;61: Brent J, McMartin K, Phillips S, Aaron C, Kulig K. Fomepizole for the treatment of methanol poisoning. N Engl J Med 2001;344: Sivilotti ML, Burns MJ, McMartin KE, Brent J. Toxicokinetics of ethylene glycol during fomepizole therapy: implications for management. For the Methylpyrazole for Toxic Alcohols Study Group. Ann Emerg Med 2000;36: Brent J. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med 2009;360: Grouls R, Ververs FF, Bindels AJ, Roos AN, Uges DR. Methanol: de oude en de nieuwe methode. Pharm Weekbl 2003;138: Jacobsen D, McMartin KE. Methanol and ethylene glycol poisonings. Mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol 1986;1: Pomara C, Fiore C, D Errico S, Riezzo I, Fineschi V. Calcium oxalate crystals in acute ethylene glycol poisoning: a confocal laser scanning microscope study in a fatal case. Clin Toxicol (Phila) 2008;46: Mestrom M, Grouls R, Wessels-Basten SJ, Bindels AJ, Roos AN. Toxicologie Behandelinformatie Ethyleenglycol. Available at frametox.asp?id=90 (cited 02/11/2009). 19. Boyer EW, Mejia M, Woolf A, Shannon M. Severe ethylene glycol ingestion treated without hemodialysis. Pediatrics 2001;107: Scalley RD, Ferguson DR, Piccaro JC, Smart ML, Archie TE. Treatment of ethylene glycol poisoning. Am Fam Physician 2002;66: Jacobsen D. New treatment for ethylene glycol poisoning. N Engl J Med 1999;340: Bestic M, Blackford M, Reed M. Fomepizole: a critical assessment of current dosing recommendations. J Clin Pharmacol 2009;49: McMartin K. Fomepizole. In Brent J, Wallace KL, Burkhart KK, Phillips S, Donovan JW [eds] Critical Care Toxicology. Diagnosis and management of the critically poisoned patient. Philadelphia, Elsevier Mosby 2005: Wiley JF. Novel therapies for ethylene glycol intoxication. Curr Opin Pediatr 1999;11: Mycyk MB, Leikin JB. Antidote review: fomepizole for methanol poisoning. Am J Ther 2003;10: Hovda KE, Jacobsen D. Expert opinion: fomepizole may ameliorate the need for hemodialysis in methanol poisoning. Hum Exp Toxicol 2008;27: NETH J CRIT CARE - VOLUME 13 - NO 6 - DECEMBER

6 Netherlands Journal of Critical Care MGG Sturkenboom, HM van Rieke, DRA Uges 27. 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: Abramson S, Singh AK. Treatment of the alcohol intoxications: ethylene glycol, methanol and isopropanol. Curr Opin Nephrol Hypertens 2000;9: Caravati EM, Heileson HL, Jones M. Treatment of severe pediatric ethylene glycol intoxication without hemodialysis. J Toxicol Clin Toxicol 2004;42: Lepik KJ, Brubacher JR, DeWitt CR, Lam GS, Lawson EJ, Erhardt GD et al. Bradycardia and hypotension associated with fomepizole infusion during hemodialysis. Clin Toxicol (Phila) 2008;46: Mycyk MB, DesLauriers C, Metz J, Wills B, Mazor SS. Compliance with poison center fomepizole recommendations is suboptimal in cases of toxic alcohol poisoning. Am J Ther 2006;13: Anseeuw K, Sabbe MB, Legrand A. Methanol poisoning: the duality between fast and cheap and slow and expensive. Eur J Emerg Med 2008;15: Green R. The management of severe toxic alcohol ingestions at a tertiary care center after the introduction of fomepizole. Am J Emerg Med 2007;25: Rozenfeld RA, Leikin JB. Severe methanol ingestion treated successfully without hemodialysis. Am J Ther 2007;14: Wallace EA, Green AS. Methanol toxicity secondary to inhalant abuse in adult men. Clin Toxicol (Phila) 2009;47: Hovda KE, Andersson KS, Urdal P, Jacobsen D. Methanol and formate kinetics during treatment with fomepizole. Clin Toxicol (Phila) 2005;43: Megarbane B, Borron SW, Trout H, Hantson P, Jaeger A, Krencker E et al. Treatment of acute methanol poisoning with fomepizole. Intensive Care Med 2001;27(8): NETH J CRIT CARE - VOLUME 13 - NO 6 - DECEMBER 2009

7 Methanol Algemeen Methanol is een kleurloze, vluchtige vloeistof. De toxiciteit wordt met name veroorzaakt door, en correleert met de concentratie van de cumulerende metaboliet mierenzuur (o.a. in nieren, nervus opticus, lever, hersenen). De mortaliteit van ernstige methanolvergiftigingen bedraagt, indien niet adequaat behandeld, circa 20%. Preparaten: Methanol wordt o.a. veel gebruikt als oplosmiddel (verf, lijm, inkt, parfum), in antivries, ruitensproeiervloeistof, en als toevoeging aan accijnsvrije ethanol (Spiritus). Het wordt gebruikt als aanmaak vloeistof voor de barbecue (veel brandwonden!). In tegenstelling tot vele landen is het in Nederland zuiver per liter te koop! Synoniemen Methyl alcohol. Toxische dosis Ingestie: Inhalatie: Oogcontact: Levensbedreigend 140 mg/kg 350 ppm 60% methanoloplossingen 1 ml/kg (zuivere methanol) Kinetiek Absorptie Na orale inname wordt methanol snel en vrijwel volledig geabsorbeerd; T ½(abs) circa 5 min. en T max = min. Opname vindt ook plaats door inhalatie (T ½(abs) =0,8u.) en via de huid. Vd Snelle verdeling over lichaamswater; Vd =0,6 0,8 l/kg. Eiwitbinding Geen. Metabolisme: Methanol wordt gemetaboliseerd in de lever (90-95%) tot achtereenvolgens formaldehyde, mierenzuur en uiteindelijk kooldioxide en water (fig. 1). Metabolisme vindt ook plaats in de nieren, nervus opticus en retina. Folinezuur is noodzakelijk voor de omzetting van mierenzuur (stap 3; figuur 1). Patiënten met folaat-deficiëntie lopen een groter risico tijdens een methanolintoxicatie. Monografie Methanol versie 2, 11 juni 2012 Pagina 1 van 8

8 Zie Figuur 1 metabolisme van methanol en aangrijpingspunten antidota. Stap 1 en 3 (T ½ tot 20 u.) zijn snelheidsbepalend; stap 2 verloopt zeer snel; T ½ = 1-2 min. ADH: alcohol dehydrogenase FDH: formaldehyde dehydrogenase F-THF-S : formyl-tetrahydrofolaat synthetase Figuur 1: metabolisme van methanol en aangrijpingspunten antidota. Stap 1 en 3 (T½ tot 20 u.) zijn snelheidsbepalend; stap 2 verloopt zeer snel; T½ = 1-2 min. ADH : alcohol dehydrogenase FDH : formaldehyde dehydrogenase F-THF-S : formyl-tetrahydrofolaat synthetase Eliminatie De eliminatie verloopt dosisafhankelijk. Bij lage concentraties 1 e orde kinetiek met T ½ = 2-3 u.; bij zeer ernstige vergiftigingen (> 2-3 promille) verloopt de klaring van methanol volgens 0 e orde kinetiek (schijnbare T ½ tot > 12-24u.). Tijdens therapie met ethanol resp. fomepizol kan de schijnbare T ½ oplopen tot 30 - tot 72 u. (incidenteel tot 120 uur). Concentraties (volbloed): Toxische conc. Ernstige intoxicatie Levensbedreigende conc. 200 mg/l; > 500 mg/l; 800 mg/l; Door snelle absorptie en distributie worden binnen minuten na orale inname maximale concentraties bereikt. Klinisch beeld Gedurende de eerste uren na inname overeenkomstig ethanol. Ernstige symptomen na een latentietijd van uur. - Gastro-intestinaal: anorexie, misselijk, buikpijn, braken. - Cardiopulmonaal: tachypneu, Kussmaul -ademhaling, respiratoire insufficiëntie; meestal als late symptomen: bradycardie, hypotensie. - Neurologisch: depressie CZS, slaperigheid, duizeligheid, verwardheid, dubbele tong, insulten, coma, hersenbloeding, ataxie, aantasting oogzenuw en basale ganglia. - Oog: aanvang stoornissen enkele uren na inname, onder andere: fotofobie, onscherp zien, sneeuwstorm, hyperemie, mydriasis, retinaoedeem, nystagmus, verminderde pupilrespons, blindheid. - Renaal: hematurie en acute nierinsufficiëntie (myoglobinurie) Na een latentietijd van uur metabole acidose met anion gap (dit kan tot 48 uur duren bij coïngestie ethanol door competitieve inhibitie ADH). Monografie Methanol versie 2, 11 juni 2012 Pagina 2 van 8

9 - Vloeistof/electrolyten: hypokaliemie en hypomagnesiemie. - Verder: hemorragische pancreatitis, leverfunctiestoornis. Differentiaaldiagnose Diabetische keto-acidose; pancreatitis, meningitis, subarachnoïdale bloeding. Metabole acidose (met anion gap): cyanide, koolmonoxide, isoniazide, ethyleenglycol, salicylzuur, tolueen, paraldehyde, ijzer, andere alcoholen. Serum-/plasma-/spiegelbepaling - gaschromatografie in volbloed; duur: ± 30 minuten (NB.: de concentratie indien gemeten in serum is een factor 1,1-1,35x hoger) Overige diagnostiek - Arteriële bloedgaswaarden: metabole acidose - Serumelectrolyten: o osmol-gap (binnen enkele uren optredend) >10 mosm/l; deze neemt af tijdens metabolisme; o anion-gap (later optredend na metabolisatie) = ([Na + ] + [K + ]) - ([Cl - ] + [HCO 3 - ]) > 20 mmol/ (normaal: 12 ± 4 mmol/l). - Urineanalyse: differentiaal diagnose bij aanwezigheid kristallen (ethyleenglycol) - Serum-/urineketonen: differentiaal diagnose (bijv. diabetische keto-acidose) - Serum glucose: tijdens ethanoltherapie (herhaald) Therapie Initieel - Ademhaling en circulatie (dehydratatie): evt. intuberen, vocht toedienen - Braken/maagspoelen/actieve kool: niet zinvol zonder indicatie co-ingestie. - Acidose: Na-bicarbonaat toedienen bij ph<7,2-7,3 - Metabolisme: foline-/foliumzuur 1 mg/kg/iv elke 4-6 uur. Dit katalyseert de omzetting van mierenzuur in CO 2 + H 2 O. - Convulsies: 5-10 mg diazepam iv in 2-3 min, evt. na 10 min herhalen max. 30 mg. Ook Ca 2+ en Mg 2+ concentratie controleren. - Thiamineconcentratie controleren en zonodig toedienen (100mg) Specifieke therapie op geleide van bloedspiegel (concentraties vermeld als gemeten in volbloed) Naast de in Nederland gebruikelijke ethanoltherapie is fomepizol beschikbaar voor therapeutische interventie tijdens methanolintoxicatie Beide stoffen remmen, door grotere affiniteit tot ADH, de omzetting van methanol naar formaldehyde (stap1, figuur 1). Momenteel zijn geen resultaten van vergelijkende klinische studies beschikbaar. Daardoor zal de keuze tussen ethanol- resp. fomepizoltherapie per instelling afhankelijk zijn van secundaire factoren (tabel 1). De hogere prijs en beperkte houdbaarheid van fomepizol zijn gezien de geringe incidentie van de methanolintoxicatie een nadeel. Daarnaast beschikken, in tegenstelling tot veel Angelsaksische landen, vrijwel alle Nederlandse ziekenhuisapotheken over ethanol infusen en over de mogelijkheid voor een snelle alcoholen analyse en over de deskundigheid voor een Monografie Methanol versie 2, 11 juni 2012 Pagina 3 van 8

10 betrouwbare dosisadvisering. Mocht de claim dat fomepizoltherapie dialyse voorkomt d.m.v. studies onderbouwd worden, dan is dit een substantieel voordeel. ethanol Doseringsregime (complexiteit) +/- + +/- + Doseringsregime(bewaking middels bloedspiegelbepaling) Bijwerkingen Hypoglycemie Flebitis (lokaal) Ethanolintoxicatie (zie Toxicologie Behandel Informatie ethanol) Depressie CZS Contra-indicaties/interacties (r = relatief) Kosten geneesmiddel/ houdbaarheid Co-ingestie middelen met CZSdepressie(r), leverziekten (r), zwangerschap (r) + -- fomepizol Tabel 1 Vergelijking pro s en contra s ethanol- versus fomepizoltherapie. + = positief 10%: hoofdpijn, sufheid, misselijkheid 1-10%: duizeligheid, convulsies brady- /tachycardie, braken, misselijkheid, diarree, visus- /spraakstoornissen, verhoging CPK/transaminasen, overgevoeligheidsreacties (rash, hypereosinofilie, anemie) 1%: angio-oedeem bronchospasmen, shock overgevoeligheid, ethanoltherapie (r), zwangerschap Ethanol: - Affiniteit tot ADH is 10-20x groter dan methanol. - Indicatie bij methanolconc. 200 mg/l; metabole acidose (ph<7.2), anion-/osmol-gap, dialyse. - Target: ethanolspiegel mg/l (C t ). - berekening dosis (op geleide spiegels) zie hieronder (voor formules zie bijlage 2): Oplaaddosis(mg) = lich.gewicht (kg) x verdelingsvolume (l/kg) x (1500 gemeten ethanolconcentratie in mg/l) NB: het verdelingsvolume bedraagt circa 0,7 l/kg voor mannen en circa 0,6 l/kg voor vrouwen. Monografie Methanol versie 2, 11 juni 2012 Pagina 4 van 8

11 Onderhoudsdosis (mg/uur) = 1500 x max. enzymcapaciteit (mg/kg/uur) x lich. gewicht (kg) 138 (=Michaelis-Menten-constante) NB: maximale enzymcapaciteit voor volw./niet-drinker: 75 mg/kg/uur; voor chronische drinker: 175 mg/kg/uur Dosering tijdens dialyse (mg/uur): = onderhoudsdosering + (150 x lich. gewicht (kg)) Fomepizol (4-methylpyrazole): - Affiniteit tot ADH is groter dan ethanol - Doel: fomepizol spiegel > 0,8 mg/l. - Indicatie: zie ethanoltherapie. Oplaaddosis 15 mg/kg in 100 ml glucose 5% of NaCl 0,9% in min - Onderhoudsdosis tot methanolspiegel <200 mg/l. op geleide nierfunctie; zie tabel 3. Nierfunctie geen dialyse (indicatie: serum creatinine <265 µmol/l, zie *) Dialyse (indicatie: serum creatinine >265 µmol/l, zie *) onderhoudsdosering 10 mg/kg elke 12 uur (3x); dan 15 mg/kg elke 12 uur (i.v.m. auto-inductie metabolisme fomepizol) Indien vorige dosis >6 uur voor start dialyse; dan een extra dosis geven. Tijdens dialyse: 1mg/kg/uur continu gedurende dialyse. Na staken dialyse: na 3 uur volgende dosis toedienen. * Het serum creatinine kan als grove grenswaarde worden gebruikt. Men moet zich natuurlijk wel realiseren dat bij nierfunctieverlies het serum creatinine achterloopt, dat wil zeggen dat de glomerulaire filtratie snelheid (GFR) slechter is dan het serum creatinine doet vermoeden. Tevens wordt de hoogte van het serum creatinine ook bepaald door de creatinine productie die bij vrouwen, ouderen en kleinere mensen laag is, zodat ook in die gevallen de GFR lager is dan de serum creatinine doet vermoeden Tabel 3 Onderhoudsdosering fomepizol Hemodialyse: - Indicatie: methanolconc. 500 mg/l (mierenzuurconcentratie >200 mg/l), ernstige acidose (ph<7,2) met elektrolytstoornissen (anion-/osmogap) niet reagerend op therapie, visusklachten (afwijkingen fundoscopie), nierfalen. - Dosiscorrectie ethanol resp. fomepizol tijdens dialyse. - Redistributie methanol na staken dialyse; herhaalde dialyse kan noodzakelijk zijn. - Continueren totdat metabole acidose is verdwenen en methanolspiegel <200 mg/l. De schijnbare halfwaardetijd van methanol neem tijdens dialyse in combinatie met ethanoltherapie af tot circa 2-4 uur. CAVH/CVVH overwegen indien hemodialyse door Monografie Methanol versie 2, 11 juni 2012 Pagina 5 van 8

12 hemodynamische instabiliteit is gecontra-indiceerd. Peritoneaaldialyse en hemoperfusie zijn niet geindiceerd (minder effectief en geen correctie van uremie en afwijkende electrolyten-/zuur-basebalans). Auteurs Dr. R. Grouls, Ziekenhuisapotheker klinisch farmacoloog, Apotheek Catharina-Ziekenhuis Eindhoven Drs. F.F.T. Ververs, Ziekenhuisapotheker, Apotheek UMCU, Universitair Medisch Centrum Utrecht Dr A.J.G.H. Bindels, Internist- intensivist Catharina-Ziekenhuis Eindhoven Dr A.N. Roos, Internist-intensivist, Catharina-Ziekenhuis Eindhoven Prof. Dr. D.R.A. Uges, Ziekenhuisapotheker klinisch farmacoloog, hoogleraar klinische en forenische toxicologie, Academisch Ziekenhuis, Groningen Literatuur 1. Touw DJ, Geus WP, Vinks AATMM, Dijk van A. Intoxicatie met methanol en ethyleenglycol: klinische toxicologie en berekening van de optimale dosis ethanol als antidotum.pharm Weekbl 1993;128: Barceloux DG, Bond Gr, Krenzelok EP et al. American Academy of Clinical toxicology Practice Guidelines on the treatment of methanol poisoning. Clin Toxicol 2002;40: Brent J. Antodotes and alcohols: has fomepizole made ethanol an obsolete therapy? Int J Med Toxicol 1998;1: Kerns W 2nd, Tomaszewski C, McMartin K, Ford M, Brent J. Formate kinetics in methanol poisoning. J Toxicol Clin Toxicol 2002;40(2): Megarbane B, Borron SW, Trout H et al. Treatment of acute methanol poisoning with fomepizole. Intensive Care Med Aug;27(8): Brent J, McMartin K, Phillips S, Aaron C, Kulig K. Fomepizole for the treatment of methanol poisoning. N Engl J Med 2001 Feb 8;344(6): Ellenhorn MJ, Ellenhorn s Medical Toxicology, Baltimore, Williams & Wilkins 1997;ed Sturkenboom MGG, Rieke vav HM, Uges DRA. Treatment of ethylene glycol and methanol poisoning: why ethanol? Neth J Crit Care 2009 (13) Revisie 11 juni 2012: doseringen eenvoudiger verwoord en formule-tabel als bijlage 1 geplaatst Monografie Methanol versie 2, 11 juni 2012 Pagina 6 van 8

13 Bijlagen D opl = Vd x G (C t C) D m = C t x V max x G/(K m + C t ) D hd = D m + (Cl d x G) D opl = oplaaddosis (mg) Vd = 0,7 l/kg (man) en 0,6l/kg (vrouw) G = lichaamsgewicht (kg) C t = target ethanolconcentratie (mg/l) C = gemeten ethanolconcentratie (mg/l) D m = onderhoudsdosering (mg/uur) V max = maximale enzymcapaciteit - Volw./niet-drinker: 75 mg/kg/uur - Chron.drinker: 175 mg/kg/uur K m = Michaelis-Menten-constante (138 mg/l) D hd = Onderhoudsdosering tijdens dialyse, aanpassen voor extra klaring (mg/uur). Cl d schatting start: 150 mg/kg/uur Cl d = variabel: afhankelijk van kunstnier en bloedfow. Volwassenen (70 kg) start met 10 g/uur dialyse extra. Bijlage 1 Berekening oplaad- en onderhoudsdosering ethanol Figuur 2 Flowchart behandeling methanolintoxicatie: ethanoltherapie (links) en fomepizoltherapie (rechts). Voor uitwerking diverse activiteiten zie tekst). M = methanol Monografie Methanol versie 2, 11 juni 2012 Pagina 7 van 8

14 Monografie Methanol versie 2, 11 juni 2012 Pagina 8 van 8