Treatment of ethylene glycol and methanol poisoning: why ... · and methanol poisoning. Methanol...

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Netherlands Journal of Critical Care

NETH J CRIT CARE - VOLUME 13 - NO 6 - DECEMBER 2009

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 dehydro-

genase (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].

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

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 disadvan-

tages 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 me-

tabolites, 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

Copyright © 2009, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received February 2009; accepted July 2009

Treatment of ethylene glycol and methanol poisoning: why ethanol?

REVIEW

Correspondence

DRA Uges

E-mail: [email protected]

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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 by-

products 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 10-

20 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.

urinary excretion

Fomepizole inhibits ADHEthanol is substrate for ADH

oxalic acid

ethylene glycol

glycolic acid

glycoaldehyde

ADH

formic acid

formaldehyde

methanol

ADH

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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: Dl = Vd x Bw [Ct – Cm] Dl = 15 mg/kg x Bw

Dl = loading dose [mg]Vd = volume of distribution [male 0.7 L/kg, female 0.6 L/kg]Bw = body weight [kg]Ct = target concentration ethanol [mg/L]Cm = measured concentration ethanol [mg/L]

Dl = loading dose [mg]Bw = body weight [kg]

Maintenance dose: Dose per hour:Dm = Ct x Vmax x Bw/[Km + Ct]

Dose per 12 hours:Dm = 10 mg/kg x Bw

Dm´ = 15 mg/kg x Bw

Dm = maintenance dose [mg/h]Vmax = maximum enzyme capacity [mg/kg.h][adult, non-drinker: 75 mg/kg.h, chronic alcohol drinker 175 mg/kg.h]Km = Michaelis-Menten-constant [138 mg/L]

Dm = maintenance dose [mg/12h]Dm’ = maintenance dose, after 60h [mg/12h]

Maintenance dose during haemodialysis:

Dose per hour:Dhd = Dm + [Cld x Bw]

Dose per 4 hours:Dhd = Dm Dhd’ = Dm’

Dose per hour:Dhd ci = 1 mg/kg x Bw

Dhd = maintenance dose during haemodialysis [mg/h]Cld= variable, dependent on artificial kidney and blood flow [mg/kg.h]

Dhd = maintenance dose during haemodialysis [mg/4h]Dhd´ = maintenance dose during haemodialysis, after 60h [mg/4h]Dhd ci = maintenance dose during haemodialysis [mg/h]

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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

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.

Table 2. The differences between ethanol and fomepizole.

ETHANOl FOMEPIZOlE

Advantages Available in clinical settingExtensive experience in the NetherlandsAntidote in different alcohol poisoningsAdministration orally and intravenously

Minimal adverse effects Registered for ethylene glycol poisoning

Disadvantages Dose calculations based on blood-alcohol levelsHospitalization in intensive care unit necessary during treatment Not officially registered as antidote

High costsNot available in all clinical settingsLimited shelf lifeNot registered for methanol in the NetherlandsLack of experience in the NetherlandsLittle experience in other alcohol poisonings

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References

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 blood-

alcohol 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.

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Toxicologie behandelinformatie

Nederlandse Vereniging van Ziekenhuisapothekers -- Commissie Analyse en Toxicologie Nationaal Vergiftigingen Informatie Centrum van het RIVM

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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: ≥ 140 mg/kg Inhalatie: ≥ 350 ppm Oogcontact: ≥ 60% methanoloplossingen Levensbedreigend ≥ 1 ml/kg (zuivere methanol) Kinetiek Absorptie Na orale inname wordt methanol snel en vrijwel volledig geabsorbeerd; T½(abs) circa 5 min. en Tmax = 30-60 min. Opname vindt ook plaats door inhalatie (T½(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.




Zie 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

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 1e orde kinetiek met T½ = 2-3 u.; bij zeer ernstige vergiftigingen (> 2-3 promille) verloopt de klaring van methanol volgens 0e orde kinetiek (schijnbare T½ tot > 12-24u.). Tijdens therapie met ethanol resp. fomepizol kan de schijnbare T½ oplopen tot 30 - tot 72 u. (incidenteel tot 120 uur). Concentraties (volbloed):

Toxische conc. ≥ 200 mg/l; Ernstige intoxicatie > 500 mg/l;

Levensbedreigende conc. ≥ 800 mg/l; Door snelle absorptie en distributie worden binnen 30-60 minuten na orale inname maximale concentraties bereikt. Klinisch beeld Gedurende de eerste uren na inname overeenkomstig ethanol. Ernstige symptomen na een latentietijd van 12-24 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 12-18 uur metabole acidose met anion gap (dit kan tot 48 uur duren bij coïngestie ethanol door competitieve inhibitie ADH).




- 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-] + [HCO3

-]) > 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 CO2 + H2O.

- Convulsies: 5-10 mg diazepam iv in 2-3 min, evt. na 10 min herhalen max. 30 mg. Ook Ca2+ en Mg2+ 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




betrouwbare dosisadvisering. Mocht de claim dat fomepizoltherapie dialyse voorkomt d.m.v. studies onderbouwd worden, dan is dit een substantieel voordeel.

ethanol fomepizol

Doseringsregime (complexiteit) +/- + Doseringsregime(bewaking middels bloedspiegelbepaling)

+/- +

Bijwerkingen

� Hypoglycemie � Flebitis (lokaal) � Ethanolintoxicatie (zie

Toxicologie Behandel Informatie ethanol)

� Depressie CZS

� 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

Contra-indicaties/interacties (r = relatief)

Co-ingestie middelen met CZS-depressie(r), leverziekten (r), zwangerschap (r)

overgevoeligheid, ethanoltherapie (r), zwangerschap

Kosten geneesmiddel/ houdbaarheid

+ --

Tabel 1 Vergelijking pro’s en contra’s ethanol- versus fomepizoltherapie. + = positief 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 1000-1500 mg/l (Ct).

- 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.




Onderhoudsdosis (mg/uur) = 1500 x max. enzymcapaciteit (mg/kg/uur) x lich. gewicht (kg) 138 (=Michaelis-Menten-constante) + 1500 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 30-45 min

- Onderhoudsdosis tot methanolspiegel <200 mg/l. op geleide nierfunctie; zie tabel 3.

Nierfunctie onderhoudsdosering

geen dialyse

(indicatie: serum creatinine <265

µmol/l, zie *)

10 mg/kg elke 12 uur (3x); dan 15 mg/kg elke 12 uur (i.v.m. auto-inductie metabolisme fomepizol)

Dialyse

(indicatie: serum creatinine >265

µmol/l, zie *)

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




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;128:537-42.

2. Barceloux DG, Bond Gr, Krenzelok EP et al. American Academy of Clinical toxicology Practice Guidelines on the treatment of methanol poisoning. Clin Toxicol 2002;40:415-46.

3. Brent J. Antodotes and alcohols: has fomepizole made ethanol an obsolete therapy? Int J Med Toxicol 1998;1:2-8

4. Kerns W 2nd, Tomaszewski C, McMartin K, Ford M, Brent J. Formate kinetics in methanol poisoning. J Toxicol Clin Toxicol 2002;40(2):137-43

5. Megarbane B, Borron SW, Trout H et al. Treatment of acute methanol poisoning with fomepizole. Intensive Care Med. 2001 Aug;27(8):1370-8.

6. 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):424-9.

7. Ellenhorn MJ, Ellenhorn’s Medical Toxicology, Baltimore, Williams & Wilkins 1997;ed 2. 8. Sturkenboom MGG, Rieke vav HM, Uges DRA. Treatment of ethylene glycol and methanol

poisoning: why ethanol? Neth J Crit Care 2009 (13) 297-302 Revisie 11 juni 2012: doseringen eenvoudiger verwoord en formule-tabel als bijlage 1 geplaatst




Bijlagen

Dopl = Vd x G (Ct – C)

Dm = Ct x Vmax x G/(Km + Ct)

Dhd = Dm + (Cld x G)

Dopl = oplaaddosis (mg) Vd = 0,7 l/kg (man) en 0,6l/kg (vrouw) G = lichaamsgewicht (kg) Ct = target ethanolconcentratie (mg/l) C = gemeten ethanolconcentratie (mg/l)

Dm = onderhoudsdosering (mg/uur) Vmax = maximale enzymcapaciteit - Volw./niet-drinker: 75 mg/kg/uur

- Chron.drinker: 175 mg/kg/uur Km = Michaelis-Menten-constante (138 mg/l)

Dhd = Onderhoudsdosering tijdens dialyse, aanpassen voor extra klaring (mg/uur). Cld schatting start: 150 mg/kg/uur Cld = 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

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