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 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].
Correspondence
DRA Uges
E-mail: [email protected]
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
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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 1020 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.
ethylene glycol
methanol
ADH
Fomepizole inhibits ADH
Ethanol is substrate for ADH
ADH
urinary excretion
formaldehyde
glycoaldehyde
formic acid
glycolic acid
oxalic acid
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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 [1,3,4,1416,22,28]. 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].
Loading dose:
Maintenance dose:
Maintenance dose during
haemodialysis:
Ethanol
Fomepizole
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]
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]
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
Table 2. The differences between ethanol and fomepizole.
Ethanol
Fomepizole
Advantages
Available in clinical
setting
Extensive experience
in the Netherlands
Antidote in different
alcohol poisonings
Administration orally
and intravenously
Minimal adverse effects
Registered for ethylene
glycol poisoning
Disadvantages
Dose calculations
based on bloodalcohol levels
Hospitalization in
intensive care unit
necessary during
treatment
Not officially
registered as antidote
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
300
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.
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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.
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