Overview
Methanol is a highly toxic alcohol commonly
found in automobile windshield washer solvent, gas line antifreeze,
copy machine fluid, fuel for small stoves, paint strippers, and
as an industrial solvent (Budavari 1996B; Suit 1990). Many new uses
for methanol, predominantly as an alternative energy source, have
also been proposed. If these new applications are developed, methanol
is likely to become even more accessible in the future and therefore,
more available for misuse.
As with ethylene glycol, the clinical course of
methanol poisoning occurs over a number of hours. While methanol
itself is only mildly intoxicating, it is converted to highly toxic
metabolites responsible for acidosis, blindness, and potentially
death. Because the morbidity for methanol poisoning is related to
delay in treatment, real or suspected methanol poisoning creates
many challenges for clinicians because laboratory tests, antidotes
and intensive care facilities are not always available.
The lethal dose of pure methanol is estimates
to be 1-2 mL/kg (Jacobsen 1986); however, permanent blindness and
death have been reported with as little as 0.1 mL/kg (6-10 mL in
adults) (ATSDR 1993).
Occurrence
In the 2002 Annual Report of the Toxic Exposure
Surveillance System (TESS) by the American Association of Poison Control
Centers (AAPCC), 2,610 exposures to methanol were reported. There were 18
deaths attributed to methanol and 55 near fatalities (Watson 2002).
Chemistry
Methanol, also known as methyl alcohol and
wood alcohol, is a primary alcohol with the chemical formula CH3OH,
a molecular weight of 32.04, a specific gravity of 0.81 and a boiling
point of 65° C. It is colorless, volatile, flammable, and readily
miscible in water (Budavari 1996B). It also has a light odor that
is distinctly different from that of ethanol.
Pharmacokinetics
Methanol is readily absorbed from the gut,
skin, and lungs. Peak serum concentration usually occurs in 30-60
minutes following oral ingestions. Methanol distributes widely in body
water with a volume distribution of 0.6 L/kg. Methanol is slowly
and erratically metabolized in the liver and follows zero order
kinetics. Approximately 3% of a methanol dose is excreted through
the lungs or excreted unchanged in the urine. The half-life of methanol
is prolonged to 30-50 hours during antidotal therapy (Palatnick
1995).
Mechanism of Toxicity
Like ethylene glycol, methanol is relatively
non-toxic; however, it is metabolized to highly toxic compounds
that are responsible for the acidosis and blindness characteristic
of methanol poisoning.
As in ethylene glycol poisonings, the initial
step in the metabolism of methanol involves the enzyme alcohol dehydrogenase
(ADH) (see Figure 2). First, methanol is slowly oxidized by ADH
to yield formaldehyde. Next,formaldehyde is oxidized by formaldehyde
dehydrogenase to yield formic acid (or formate, depending on the
pH). This oxidation occurs rapidly so that little formaldehyde accumulates
in the serum. FInally, formic acid is metabolized to carbon dioxide
and water, which are excreted by the kidneys and lungs.
Figure 2. Metabolic Pathway of Methanol Toxicity
(Adapted from Brent 2001)
The accumulation of formic acid is responsible
for the presence of metabolic acidosis. Formic acid also inhibits
cellular respiration leading to lactic acidosis. The ocular injury
caused by methanol may be due to retinal injury, which results from
intra-retinal metabolism of methanol and the accumulation of formic
acid. Alternatively, it may be caused be the inhibition of normal
metabolism in optic nerve calls (Jacobsen 1997).
Clinical Course
Initial symptoms of methanol poisoning may
appear as soon as 12 hours post-ingestion, but usually develop 24
hours after ingestion. These may resemble ethanol intoxication and
consist of drowsiness, confusion, and ataxia, as well as weakness,
headache, nausea, vomiting, and abdominal pain. Collectively, these
symptoms may mimic an alcohol hangover and are due to mild intoxication,
caused by methanol itself.
As methanol metabolism proceeds, a severe anion
gap metabolic acidosis will develop. Severe metabolic acidosis in
conjunction with visual effects are the hallmark of methanol poisoning.
Patients usually describe blurred or misty vision, double vision,
or changes in color perception. There my be constricted visual field
and, occasionally, total loss of vision. Characteristic visual dysfunctions
include pupillary dilation and loss of pupillary reflex (Burkhart
1990; Suit 1990).
Further signs and symptoms may be shallow respiration,
cyanosis, tachypnea, coma, seizures, electrolyte disturbances, and
various hemodynamic changes including profound hypotension and cardiac
arrest. There may be mild to profound loss of memory, confusion,
and agitation, which may progress to stupor and coma as the severity
of the acidosis increases (Suit 1990). In severe cases, death is
possible. Surviving patients can be left with permanent blindness
or with other neurological deficits (Jacobsen 1997).
Diagnosis
Methanol poisonings can be relatively difficult
to diagnose when a specific history of ingestion is not available.
Diagnosis requires both clinical and laboratory data; however, there
may be an initial lack of clinical data for patients who are unable,
or unwilling, to supply a history of ingestion. In such situations,
obtaining a patient's history from family or friends can be valuable.
In addition, it is often difficult for a clinician to distinguish
between poisoning by methanol or by ethylene glycol.
The most direct means of diagnosing methanol poisoning
is through the measurement of serum methanol concentration. The
decision to perform a serum methanol determination may be based
on patient disclosure of methanol ingestion or the presence of a
methanol-containing product at the scene of ingestion. Other reasons
to suspect methanol poisoning may be based on clinical signs together
with laboratory findings such as anion gap metabolic acidosis and
an osmolal gap. According to Kearney et al. (1997), only
39% of teaching hospitals were able to perform serum methanol determinations
in-house.
An anion gap metabolic acidosis is not immediately
seen following ingestion of methanol and may be due to other types
of poisoning, including iron, salicylates, and ethylene glycol or
disease states such as diabetic ketoacidosis or uremia. The presence
of an osmolal gap may further support the diagnosis of methanol
poisoning; however, its absence does not rule it out, as the osmolal
gap will diminish as methanol metabolism proceeds. Also, other toxins,
including other alcohols, will produce an osmolal gap. Finally,
the co-ingestion of ethanol my produce a confusing clinical picture
as the toxic effects of methanol may be masked or delayed (Jacobsen
1997).
Other diagnostic clues are ophthalmic changes
and may include hyperemia of the optic disc or optic disc edema,
and eventually, pallor (Jacobsen 1997).
A serum methanol concentration greater than 20
mg/dL soon after ingestion generally indicates the need for antidotal
therapy; however, in late-presenting patients, any concentration
of methanol in the presence of systemic toxicity should be treated.
Treatment Objectives
As with ethylene glycol, the three primary
goals of therapy include treatment of metabolic acidosis, inhibition
of the methanol metabolism and enhanced elimination of the unmetabolized
compound and existing toxic metabolites.
Gastric decontamination is unlikely to be beneficial
because methanol is rapidly and completely absorbed from the gut.
Ipecac-induced emesis is contraindicated due to the risk of rapid
loss of consciousness. It is doubtful activated charcoal has the
ability to absorb significant amounts of methanol; however, it may
be useful if a co-ingestant is suspected. Gastric lavage would need
to be performed soon after ingestion to be beneficial.
Stabilization of the critical patient must be
performed before other therapies can be instituted. Correcting acid/base
status should be a priority because serious metabolic acidosis is
common and a pH less than 7 is associated with poor prognosis. Sodium
bicarbonate should be administered to correct serum pH. Fluid and
electrolyte replacement, airway management and the treatment of
serious cardiovascular and neurological signs, such as hypotension
and seizures, should also be a primary concern.
The elimination of methanol may be enhanced by
administering folic acid, a cofactor in the conversion of formic
acid to carbon dioxide, and by performing hemodialysis (Jacobson
1997).
Prognosis
Outcomes are excellent when asymptomatic
methanol-poisoned patients are treated promptly. Reversal of presenting
blindness, in one reported case, was attributed to prompt treatment
(Sivilotti 1998). According to one study, poor outcomes were associated
with coma or seizures on presentation or acidosis with pH less than
7 (Liu 1997).
|