Acid-Base and Electrolyte Teaching Case

Approach to the Treatment of Methanol Intoxication

Jeffrey A. Kraut, MD

Methanol intoxication is an uncommon but serious poisoning. Its adverse effects are due primarily to the impact
of its major metabolite formic acid and lactic acid resulting from cellular hypoxia. Symptoms including abdominal
pain and loss of vision can appear a few hours to a few days after exposure, reflecting the time necessary for
accumulation of the toxic byproducts. In addition to a history of exposure, increases in serum osmolal and anion
gaps can be clues to its presence. However, increments in both parameters can be absent depending on the
nature of the toxic alcohol, time of exposure, and coingestion of ethanol. Definitive diagnosis requires mea-
surement with gas or liquid chromatography, which are laborious and expensive procedures. Tests under study to
detect methanol or its metabolite formate might facilitate the diagnosis of this poisoning. Treatment can include
administration of ethanol or fomepizole, both inhibitors of the enzyme alcohol dehydrogenase to prevent for-
mation of its metabolites, and hemodialysis to remove methanol and formate. In this Acid-Base and Electrolyte
Teaching Case, a patient with methanol intoxication due to ingestion of model airplane fuel is described, and the
value and limitations of current and new diagnostic and treatment measures are discussed.
Am J Kidney Dis. -(-):---. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This
is a US Government Work. There are no restrictions on its use.

INDEX WORDS: Toxic alcohols; serum osmolal gap; serum anion gap; fomepizole; methanol; methanol
intoxication; ethanol; hemodialysis.

in Table 1 and revealed a low serum bicarbonate level, elevated

Note from the editors: This article is part of a series of invited
case discussions highlighting either the diagnosis or treat-
ment of acid-base and electrolyte disorders.
INTRODUCTION
Methanol intoxication can cause severe cellular
dysfunction and death,1 primarily due to the accu-
mulation of organic acids and their anions produced
by its metabolism.2-4 Effective methods of treatment
that include administering inhibitors of the enzyme
alcohol dehydrogenase to prevent its metabolism5 and
hemodialysis6 to remove it and its toxic metabolites
from the body are readily available. However,
recognition of the intoxication is often hampered by
the lack of specific signs and symptoms and the
limitation of present diagnostic modalities.7 Although
mortality is low if treatment is initiated promptly,8 a
delay can cause it to increase to as high as 44%.9,10
In this Acid-Base and Electrolyte Teaching Case, a
case of methanol intoxication is presented, which was
previously reported by Rastogi et al,11 and current
methods of diagnosis and treatment are discussed.
CASE REPORT
Clinical History and Initial Laboratory Data
A 22-year-old woman presented to the emergency department
30 hours after ingesting 16 ounces of model airplane fuel. She
reported no abdominal pain, nausea, vomiting, visual disturbances,
or headache. On physical examination, temperature was 37.2 C;
pulse rate, 100 beats/min; blood pressure, 132/50 mm Hg in the
sitting position; and respirations, 16 breaths/min. Lungs were clear
to auscultation, and cardiac, abdominal, and neurologic examina-
tion findings were normal. No ophthalmic changes were reported.
Laboratory studies performed during the hospitalization are shown
serum osmolality and osmolal gap, and increased serum creatinine
level. The latter was shown to be due to laboratory error caused
by interference of nitromethane in the airplane fuel with serum
creatinine measurement as performed by the usual Jaffé method.11
Additional Investigations
Urinalysis showed no cells or crystals. Serum acetaminophen,
ethyl alcohol, acetone, and isopropyl alcohol results were negative.
Methanol concentration obtained on admission reported 2 days
later was 71 mg/dL.
Diagnosis
Acute methanol intoxication.
Clinical Follow-up
The patient initially was given fomepizole and dialyzed for 4
hours. Additional doses of fomepizole were given and dialysis was
From the Medical and Research Services Veterans Adminis-
tration Greater Los Angeles Healthcare System, UCLA Membrane
Biology Laboratory, and Division of Nephrology, Veterans
Administration Greater Los Angeles Healthcare System, and
David Geffen School of Medicine, Los Angeles, CA.
Received October 16, 2015. Accepted in revised form February
4, 2016.
Because the author of this article is the editor for this feature,
the peer-review and decision-making processes were handled
without his participation. Details of the journal’s procedures for
potential editor conflicts are given in the Information for Authors
& Journal Policies.
Address correspondence to Jeffrey A. Kraut, MD, Division of
Nephrology, VHAGLA Healthcare System, 11301 Wilshire Blvd,
Los Angeles, CA 90073. E-mail: jkraut@ucla.edu
Published by Elsevier Inc. on behalf of the National Kidney
Foundation, Inc. This is a US Government Work. There are no
restrictions on its use.
0272-6386
http://dx.doi.org/10.1053/j.ajkd.2016.02.058

Am J Kidney Dis. 2016;-(-):--- 1

 Jeffrey A. Kraut

Table 1. Laboratory Studies During Hospitalization

Methanol
17 h After
Test Admission Admission Day 2 Day 3
Alcohol
Sodium, mEq/L 141 140 143 142 dehydrogenase
Potassium, mEq/L 3.5 3.2 3.8 3.6
Chloride, mEq/L 111 104 109 112
Total carbon dioxide, 18 28 25 25
Formaldehyde
mEq/L
SUN, mg/dL 14 5 7 4
Formaldehyde
Serum creatinine, 23.7b 10b 8.4b 6.0
mg/dLa dehydrogenase
eGFR,c mL/min/1.73 m2 2 5 6 9
Anion gap, mEq/L 11 8 9 5
Serum osmolality, 357 303 303 303
Formic acid
mOsm/kg/H2O
Osmolal gap, mOsm/ 70 — — —
kg/H2O Folinic acid
Methanol, mg/dL 71 26 — —
Serum albumin, g/dL 4 — — —
Note: Conversion factors for units: serum creatinine in mg/dL CO2 + H2O
to mmol/L, 388.4; SUN in mg/dL to mmol/L, 30.357.
Abbreviations: eGFR, estimated glomerular filtration rate;
SUN, serum urea nitrogen. Figure 1. Metabolism of methanol. Methanol undergoes
a
Values obtained using the Jaffé reaction. serial oxidation: methanol is catalyzed by the enzyme alcohol
b dehydrogenase to formaldehyde and then formaldehyde is cata-
Values proved to be inaccurate due to interference of nitro-
lyzed by the enzyme formaldehyde dehydrogenase to formic
methane in ingested airplane fuel with measurement of serum acid. Folinic acid given to a patient will accelerate the conversion
creatinine. to carbon dioxide (CO2) and water (H2O). Adapted from Rastogi
c
As calculated by the Chronic Kidney Disease Epidemiology et al11 with permission of the National Kidney Foundation.
Collaboration creatinine equation.
Adapted from Rastogi et al11 with permission of the National
Kidney Foundation.
hypoxia and lactic acidosis.13 Clinical abnormalities
can be delayed as long as 96 hours if ethanol or
certain antiviral medication, such as abacavir, are
repeated during the hospitalization. With treatment, acid-base pa- coingested because both inhibit the enzyme that
rameters and serum osmolality (Table 1) returned to normal and catalyzes the metabolism of methanol, alcohol dehy-
the patient was discharged. drogenase.3,16-19 Both the nonspecificity of the clin-
ical abnormalities and the delay between exposure
DISCUSSION and their appearance can hinder establishing the
This patient had a history of exposure to methanol, diagnosis, thus resulting in high mortality.10 An in-
a markedly increased serum osmolal gap, and meta- crease in the serum osmolal gap (caused by accu-
bolic acidosis. These features are suggestive of mulation of methanol in the blood) and anion gap
methanol intoxication.7,12 Methanol intoxication is a (caused by accumulation of formate and sometimes
relatively uncommon but important poisoning: lactate in the blood) can also serve as clues to the
approximately 5,000 cases are reported to the US presence of methanol intoxication.16,20 The marked
Poison Control each year.2,8,13 Methanol is present in increase in serum osmolal gap in the present case
several household cleaning solutions and dyes, model (70 mOsm/kg/H2O) reflects in part a high methanol
airplane fuel, windshield washer fluid, gas line anti- concentration and is indicative of toxic alcohol
freeze, and illegally produced alcoholic beverages. ingestion because an osmolal gap greater than 15 to
Intoxication is most commonly due to ingestion, but 20 mOsm/kg/H2O is rarely observed with other cau-
can also result from inhalation or absorption through ses of increased osmolal gap.2,13 However, the
the skin.13 Symptoms can include dyspnea, nausea, osmolal gap exceeds the level predicted based on the
vomiting, abdominal pain, impaired sensorium, and measured methanol concentration (71 mg/dL; osmo-
impaired vision.14 Ophthalmologic examination can lality, 23 mOsm/kg/H2O). The explanation for this
reveal optic papillitis (found in 10% of cases). Muscle disparity is not clear, but possibly could reflect
rigidity and masked facies can be observed when the accumulation of osmotically active substances such
putamen is damaged.15 The majority of the clinical as nitromethane and/or polyalkylene glycol found in
abnormalities are due to the effects of formic acid, the the airplane fuel.
major metabolite of methanol (Fig 1). Interference Although the osmolal gap and anion gap were
with cytochrome oxidase by formate causes tissue increased in this case, individuals can have methanol

2 Am J Kidney Dis. 2016;-(-):---

Treatment of Methanol Intoxication
intoxication in the absence of an increase in osmolal
and/or anion gaps.21,22 The reasons for this can best
be appreciated by examining the evolution of these
gaps in patients with methanol intoxication. Serum
osmolal gap depends on the baseline osmolal gap
and the increment in osmolality produced by the
methanol in the blood at the time it is sampled. It is
often stated that a normal baseline osmolal gap is 10
to 20 mOsm/kg/H2O. Values greater than this indi-
cate accumulation of toxic alcohols, such as meth-
anol.23 However, baseline serum osmolal gaps in
apparently healthy individuals can vary from 211
to 110 mOsm/kg/H2O.21,22,24-27 If the osmolal gap
should prove to be negative, a methanol concentra-
tion of 20 mg/dL (the level when treatment is rec-
ommended) would not produce an osmolal gap
. 10 mOsm/kg/H2O. Also, osmolal gap is highest
early in the course of the intoxication, but will
decrease substantially as methanol is metabolized.
Sampling of blood later in the course when methanol
concentration has decreased would also lessen the
chances of detecting a markedly elevated osmolal
gap.
The baseline serum anion gap can be as low as 3
mEq/L in healthy individuals.28,29 As a result, the
anion gap might not exceed the upper limit of normal
even if there is an increment in the concentration of
organic acid anions, as long as their concentration is
less than 7 to 8 mEq/L. Also, blood sampling early
after exposure before much of the methanol is
metabolized will lessen the chance of detecting an
increased anion gap.18,30
Even if the osmolal gap is elevated (as long as the
increase is modest, ie, ,15 mOsm/kg/H2O), the in-
crease might be caused by other disorders. A retro-
spective study of 346 patients with an increased
osmolal gap (averaging 14 mOsm/kg/H2O) revealed
that in a majority of cases, the increase was due to the
presence of lactic acidosis, ketoacidosis, kidney fail-
ure, and/or sick cell syndrome rather than a toxic
alcohol.31,32
Given the nonspecificity of the signs and symptoms
and inconsistency of the changes in serum osmolal and
anion gaps, more specific methods for detection of
methanol and monitoring of changes in its concentra-
tion are required. Presently, detection of methanol is
best achieved using gas or liquid chromatog-
raphy,2,7,33 a laborious and expensive method that is
not available in many clinical chemistry laboratories.
Methanol concentration was not reported for 48 hours
in the present case. Other direct and indirect methods
to assess methanol concentrations are shown in
Table 2. An enzymatic method that detects the
metabolite formate in blood has been described.34
Formate dehydrogenase and nicotinamide adenine
dinucleotide are used to measure serum formate. The
Am J Kidney Dis. 2016;-(-):---
day-to-day coefficient of variation is 5%. The assay
can be done using most autoanalyzers and requires
only commercially available reagents. In one study,
the majority of patients (14 of 15) with an elevated
methanol concentration also had an elevated serum
formate concentration.34
A dipstick impregnated with alcohol oxidase is
available that detects methanol, ethanol, and ethylene
glycol in blood and saliva.35 Methanol strongly reacts
to the strip and at similar concentrations, gives a more
intense color than ethanol. A liquid-based colori-
metric method using the enzymes alcohol oxidase or
alcohol dehydrogenase or the oxidizing agents so-
dium periodate and potassium permanganate was able
to detect methanol and other alcohols when added to
saliva at concentrations as low as 1 to 10 mg/dL.36
Validation of these methods can improve treatment
by facilitating the diagnosis of methanol intoxication.
Treatment with stomach gavage is generally not
useful because methanol is rapidly absorbed. Rather,
treatment can include inhibition of the enzyme
alcohol dehydrogenase37 and removal of the parent
alcohol and its metabolites by hemodialysis.6
Inhibition of alcohol dehydrogenase was initially
accomplished by infusion of ethanol, which binds to
the enzyme, preventing metabolism of methanol.2-5
Achieving a concentration of 100 to 150 mg/dL in
the blood has been recommended, although lower
concentrations might be sufficient to maximally
inhibit the enzyme.13 The infusion has to be contin-
uous and is usually done in an intensive care unit to
facilitate maintenance of an adequate ethanol con-
centration and prevent complications of therapy.38,39
One major advantage is that this therapy is inexpen-
sive and readily available.
Fomepizole, a specific inhibitor of alcohol dehy-
drogenase, was approved by the US Food and Drug
Administration for the treatment of methanol intoxi-
cation in 2000.37,40,41 It has substantially greater
binding affinity for the enzyme (.8,000 than for
ethanol) and therefore is more effective than ethanol. It
can be given both intravenously and orally at the same
dosage,42 although presently, only the intravenous
form is available in the United States. It has minimal
side effects and in contrast to ethanol, can be admin-
istered to the patient without requiring hospitalization
in the intensive care unit. Comparisons of both agents
showed that their side-effect profiles were not different
and mortality was identical.43
A systematic review of MEDLINE and Embase
databases including articles from 1966 to 2010
revealed that 80% of patients were treated with ethanol
and 16% were treated with fomepizole.5 Importantly,
the authors did not compare usage patterns before and
after fomepizole was approved, theoretically biasing
the study. By contrast, a retrospective study of all
3
 Jeffrey A. Kraut

Table 2. Methods to Diagnose Methanol Intoxication

Parameter Mechanism Comments

History and physical Obtain historical evidence of exposure; Findings often nonspecific; long delay between onset
examination suggestive symptoms and physical evidence and symptoms and signs can obscure the diagnosis
of optic papilitis or neurologic abnormalities
Serum osmolal gap Increased osmolality reflects accumulation of Should be performed using freezing point depression
parent alcohol in blood rather than vapor pressure osmometry; can be
helpful in many cases but osmolal gap might not be
elevated if baseline osmolal gap is negative (osmolal
gap also might not be elevated late when parent
alcohol has been fully metabolized); despite
limitations, good correlation between osmolal gap
and methanol concentration has been found in some
studies
Serum anion gap Detects accumulation of organic acid anion Might not be elevated if baseline serum anion gap is
formate and in some cases lactate low; might not be elevated early in the course of
intoxication prior to significant metabolism of alcohol
to formate and development of lactic acidosis
Gas or liquid Detects methanol in blood using gas or liquid Gold standard for determination of methanol
chromatography chromatography methods concentrations; labor intensive and expensive; not
available in most clinical laboratories
Measurement of serum Detects accumulation of primary metabolite Indirectly estimates methanol concentration; might not
formate formate in blood using enzymatic test based be positive early in the course of intoxication prior to
on formate dehydrogenase metabolism of methanol; not yet in clinical use
Dipstick impregnated with Detects methanol, ethanol, and ethylene glycol Detects ethanol, methanol, and ethylene glycol in
alcohol oxidase strip based on enzyme alcohol oxidase blood and saliva, but most sensitive to methanol
Liquid-based test of Uses combination of enzymes (alcohol oxidase Methods work only with saliva; detects concentrations
saliva using enzyme or or dehydrogenase) and/or oxidizing agents of methanol as low as 1 mg/dL; uses readily
oxidizing agents such as potassium permanganate and available chemicals; costs of procedures likely to be
sodium periodate less than few dollars; liquid-based analysis or strip
test might be used

electronic entries from the American Association of
Professional Code Center (AAPC) National Poison
Data System Database revealed that in 2012 to 2013,
fomepizole was used in 90% of patients with meth-
anol or ethylene glycol toxicity.8 However, use of
ethanol in other countries has been reported to be
greater than that of fomepizole.44 This presumably
reflects less access to the latter drug because it was
only added to the World Health Organization
essential medicine list in 2013.45 Because fomepizole
or ethanol will prevent the formation of toxic me-
tabolites, theoretically, this therapy could be suffi-
cient for the patient with methanol intoxication
without the need for dialysis. In the absence of
kidney failure, fomepizole alone has been shown to
be effective in the treatment of methanol intoxica-
tion.46,47 In patients without severe symptoms, se-
vere acidemia, or kidney failure, fomepizole alone
has been recommended by some experts.47
A major disadvantage of using fomepizole alone is
that by preventing its metabolism, the methanol is
eliminated only by the lungs and kidney, a relatively
slow process that increases the mean half-life to 54
hours.47 This increases the duration of hospitalization
substantially and thus the cost of treatment.48
With hemodialysis, rapid removal of methanol and
formate can be achieved.49 With the usual intermittent
hemodialysis protocol (4 hours with blood flow of
400 mL/min and dialysis flow of 800 mL/min),
methanol clearance of 200 mL/min can be achieved,
resulting in a half-live of 2 hours.50 Clearance of
formate is w223 mL/min under these conditions,
resulting in a half-life of 1.8 hours.50
The decision to use an inhibitor alone or in com-
bination with dialysis therefore remains an area of
controversy.6,47 In 2002, the American Academy of
Clinical Toxicology published criteria for the use of
dialysis in the treatment of methanol intoxication13
(Box 1). Indications included metabolic acidosis
with blood pH , 7.25, deteriorating vital signs
despite supportive care, and serum methanol con-
centration . 50 mg/dL. In 2015, the Extracorporeal
Treatment in Poisoning Workgroup published their
criteria after careful examination of the literature
(Box 1).6 Some differences included a lower target
blood pH (7.15) and use of different blood concen-
trations depending on the specific conditions: serum
methanol concentrations . 70 mg/dL with fomepi-
zole therapy, .60 mg/dL with ethanol therapy, and
.50 mg/dL in the absence of inhibitors. Recom-
mendations by both committees favored intermittent
hemodialysis over continuous renal replacement
dialysis. Dialysis can be terminated when methanol
levels are ,20 mg/dL.

4 Am J Kidney Dis. 2016;-(-):---

Treatment of Methanol Intoxication
Box 1. Indications for Hemodialysis for Treatment of
Methanol Intoxication
American Academy of Clinical Toxicology Practice
Guidelines13
pH , 7.25 to 7.35
or visual signs and/or symptoms
or decreased vital signs despite intensive supportive care
or kidney failure
or substantial electrolyte disturbances unresponsive to
supportive care
or serum methanol concentration . 50 mg/dL
Extracorporeal Treatment in Poisoning Workgroup6
pH , 7.15
Severe visual defects
or coma
or worsening vital signs despite intensive supportive care
or kidney failure
or serum methanol:
.70 mg/dL with fomepizole
.60 mg/dL with ethanol
.50 mg/dL in absence of inhibitor
Note: Intermittent hemodialysis is preferred over continuous
renal replacement therapy.
Randomized controlled studies of the different
approaches to treatment in order to provide
evidence-based recommendations have not been
performed. Factors to take into consideration in
making a decision include effectiveness, cost,
availability of resources, and potential complica-
tions of therapy. In large academic centers with
ready access to dialysis and fomepizole, combina-
tion therapy is often favored, as it was in the present
case. However, in smaller centers, ready access to
hemodialysis and fomepizole might not be avail-
able. As noted, several experts have concluded that
inhibitor alone might be sufficient in the treatment
of certain cases of methanol intoxication.47 Use of
the inhibitor, whether it be ethanol or fomepizole,
will markedly increase the half-life of methanol to
between 40 and 70 hours.30,51 This will increase the
duration of hospitalization and theoretically increase
the risk for complications.
When acidemia is severe (blood pH , 7.2), base is
recommended, although its value has not been subject
to rigorous examination. In addition to negating
the adverse effects of the acidic tissue environment,
some have suggested that it lessens the severity of
ophthalmic injuries13 and facilitates the urinary
excretion of formate.52 Administration of folinic acid
is said to speed the metabolism of formic acid and is
often recommended.13
The ability to monitor blood concentrations of
methanol and possibly its metabolites is theoretically an
Am J Kidney Dis. 2016;-(-):---
Box 2. Teaching Points
 Symptoms including abdominal pain, nausea, vomiting,
and decreased vision are nonspecific and can occur hours
to days after exposure
 An increase in serum osmolality and/or anion gap can be
clues to methanol intoxication, but their presence depends
on the baseline serum osmolal gap, baseline serum anion
gap, methanol concentration in blood, time after exposure,
and absence or presence of coingested ethanol
 Definitive diagnosis of methanol intoxication presently
requires measurement with gas or liquid chromatography,
a laborious and expensive procedure. Newer methods of
diagnosis including use of an alcohol oxidase strip to
detect methanol in blood, enzymatic test to detect formate
in blood, or liquid-based test using alcohol oxidase and
potassium permanganate to detect methanol in saliva
might improve the effectiveness of diagnosis
 Treatment should be initiated when estimated serum
methanol concentration is $20 mg/dL or signs and
symptoms of significant acidemia are present. Some ex-
perts also recommend initiation of treatment with only a
high suspicion of exposure
 Treatment can include administration of ethanol or
fomepizole, 2 inhibitors of alcohol dehydrogenase.
Although both are effective, the latter is often preferred
because of ease of administration, absence of impact on
the central nervous system, and lack of need for close
observation in an intensive care unit
 Hemodialysis can remove both methanol and formate
while providing base. Controversy remains about its use
because in many cases, intoxication can be treated alone
with the inhibitor. We have a low threshold for its use
because it will accelerate recovery, reduce hospitalization
duration, and minimize exposure to methanol
essential aspect of therapy. However, most centers do
not have the ability to obtain timely measurements of
serum methanol or its major metabolite formate. In the
absence of these measurements, serum osmolal gap has
often served as a surrogate for blood methanol concen-
tration.48,53-55 Several investigators have shown there is
a strong direct correlation between serum methanol
concentration and serum osmolal gap.48,55 For every 10-
mg/dL increase in serum methanol concentration,
osmolal gap will be increased by w3 mOsm/kg/H2O.
The clinician can used this estimated serum methanol
concentration to assess the clearance of methanol from
the body. When serum osmolal gap is decreased
to ,6 mOsm/kg (equivalent to serum methanol con-
centration of 20 mg/dL), dialysis therapy and treatment
with inhibitor can theoretically be discontinued.
However, in situations such as the present case
when a portion of the increase in serum osmolality
appears to be due to accumulation of other substances
than methanol, osmolal gap is not as precise a mea-
sure of changes in methanol concentration.
Monitoring serum formate concentrations has also
been found to be helpful in the assessment of the
severity of intoxication and in its management.9
Serum formate levels $ 3.7 mmol/L indicate the
5

need for hemodialysis, and serum formate levels
$ 17.5 mmol/L are associated with 90% risk for
death.
In summary, optimal treatment of methanol intox-
ication requires early recognition and rapid initiation
of effective therapy. A high degree of suspicion must
be present given the nonspecific nature of many of the
symptoms and signs. Abnormalities in serum osmolal
and anion gaps can be suggestive, but are not always
present. Tests that determine methanol and/or formate
concentrations in blood or saliva are under investi-
gation and could improve the detection of this
poisoning.
Therapy should include administration of an in-
hibitor, preferably fomepizole, although ethanol can
be effective should fomepizole not be readily avail-
able. Controversy about the value of hemodialysis
exists with recommendations by committees of
experts restricting it to specific circumstances.
Randomized controlled studies to establish the safest
and most cost-effective therapies are warranted.
However, in their absence, I advocate using fomepi-
zole and hemodialysis for the treatment of methanol
intoxication, particularly when the intoxication is
perceived to be severe. Combination therapy will
substantially reduce the days of hospitalization and
limit the exposure to the drug. Teaching points are
summarized in Box 2.
ACKNOWLEDGEMENTS
Support: The manuscript was supported by funds from the
UCLA Academic Senate and Veterans Administration.
Financial Disclosure: The author declares that he has no
relevant financial interests.
Peer Review: Evaluated by 2 external peer reviewers, the
Education Editor, and the Editor-in-Chief.
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