ArticlePDF AvailableLiterature Review
Methemoglobinemia
.........................................................................................................
A 16-year-old boy is seen in the emergency
department after he had collapsed after a dental
extraction in which prilocaine hydrochloride 3%
was used as topical anesthesia. His mother tells
the emergency physician that he felt unwell after
the procedure and gradually became more and
more drowsy. The patient is deeply cyanosed
despite a good respiratory effort, a clear airway,
and bilateral breath sounds. Although he initially
responds to vocal commands, his level of
consciousness soon deteriorates. Oxygen
saturation is 60% with the patient breathing room
air. An endotracheal tube is introduced and
assisted ventilation started, but this does not
improve his cyanosis or level of consciousness.
The attending physician is alert to the possible
diagnosis of methemoglobinemia because the
patient is cyanosed, the cyanosis is unresponsive
to ventilation, there is no prior history of
respiratory problems, and the patient had been
exposed to a topical anesthetic that is known to
cause methemoglobinemia.
A blood specimen is drawn and test results
confirm the diagnosis.
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METHODS
Information on methemoglobinemia was obtained
through a literature search using MEDLINE and the fol-
lowing key words: methemoglobinemia, sulfhemoglobine-
mia, cyanosis, and methylene blue.
WHAT IS METHEMOGLOBINEMIA?
Methemoglobinemia is a condition characterized by in-
creased quantities of hemoglobin in which the iron of
heme is oxidized to the ferric (Fe
3+
) form. Methemoglo-
bin is useless as an oxygen carrier and thus causes a varying
degree of cyanosis.
WHAT ARE THE POSSIBLE CAUSES?
The condition may arise as a result of a genetic defect in
red blood cell metabolism or hemoglobin structure, or it
may be acquired following exposure to various oxidant
drugs or toxins.
Genetic defect
Hereditary methemoglobinemia is a rare recessively inher-
ited disorder due to deficiency of an enzyme, called re-
duced nicotinamide adenine dinucleotide (NADH) cyto-
chrome b
5
reductase. Normal erythrocytes are well
endowed with a system to convert useless methemoglobin
to functional hemoglobin. The major mechanism for this
reductive capacity resides in the soluble NADH cyto-
chrome b
5
reductase. The gene regulating the synthesis of
cytochrome b
5
reductase has been localized to chromo-
some 22q13qter, and a number of mutations have been
identified.
1,2
Hereditary methemoglobinemia due to
NADH cytochrome b
5
reductase deficiency is classified
into 2 typeserythrocyte (type I) and generalized (type II).
In the type I form, the soluble form of the enzyme is
deficient only in erythrocytes, and cyanosis is the only
symptom.
3
Type II hereditary methemoglobinemia is due
to deficiency of the membrane-bound form of the en-
zyme, which is located in the outer mitochondrial mem-
brane and the endoplasmic reticulum of somatic cells.
Type II hereditary methemoglobinemia is a rare disease
characterized by deficiency of the enzyme in all tissues and
manifesting with severe developmental abnormalities, se-
vere mental retardation, and neurologic impairment,
which often lead to premature death.
4
Heterozygotes with
NADH cytochrome b
5
reductase deficiency do not usu-
Summary points
Severe methemoglobinemia is a medical emergency,
requiring prompt recognition and appropriate
treatment
A good history and high level of suspicion are required
to make the diagnosis
Exposure to medication is the most common cause of
methemoglobinemia
For methemoglobinemia due to drug exposure,
traditional first-line therapy consists of the infusion of
methylene blue
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Best Practice
Habib Ur Rehman
Specialist registrar
Department of Medicine
Hull Royal Infirmary
Hull HU3 2JZ
UK
habib786@aol.com
Competing interests:
None declared
West J Med
2001;175:193-196
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Volume 175 September 2001 wjm 193www.ewjm.com
ally manifest signs of methemoglobinemia. However, un-
der the stress of oxidant drugs, severe cyanosis may de-
velop because of methemoglobinemia. Neurologic
abnormalities do not respond to methylene blue therapy.
There are several abnormal hemoglobin variants asso-
ciated with genetic methemoglobinemia, and these are
designated hemoglobin M. In most of the hemoglobin M,
tyrosine has been substituted for either the proximal or the
distal histidine. This results in reduced capacity of the
enzymatic machinery of the erythrocyte to efficiently re-
duce the iron to the divalent form and thus predisposes to
methemoglobinemia. These hemoglobin variants are as-
sociated with cyanosis, which is present from early life. In
the case of the -chain variants, it is present from birth,
whereas the -chain hemoglobin variants produce cyano-
sis only after the first few months of life as adult hemo-
globin synthesis becomes established. This disorder is in-
herited in an autosomal dominant pattern.
Exposure to drugs or toxins
The most common cause of methemoglobinemia, as in
this clinical case, is ingestion of or exposure of skin or
mucous membranes to oxidizing agents (see box). Some of
these oxidize hemoglobin directly to form methemo-
globin; others do it indirectly by reducing free oxygen
to the free radical O
2
, which in turn oxidizes hemoglo-
bin to methemoglobin. Outbreaks of methemoglobine-
mia have occurred due to nitrite poisoning from water
contamination.
5
Large amounts of nitric oxide are released in patients
with sepsis. Nitric oxide is converted to methemoglobin
and nitrate. It has been reported that methemoglobin lev-
els are significantly higher in patients with sepsis than in
nonseptic patients.
6
Methemoglobinemia has been reported in young in-
fants (<6 months) in whom severe metabolic acidosis de-
velops from diarrhea and dehydration.
7
Young infants
may be particularly susceptible to this complication be-
cause of their low stomach acid production, large number
of nitrite-reducing bacteria, and the relatively easy oxida-
tion of fetal hemoglobin. Small infants have lower eryth-
rocyte levels of cytochrome b reductase.
8
Higher intestinal
pH of infants may promote the growth of gram-negative
organisms that convert dietary nitrates to nitrites.
Methemoglobinemia has been reported in diarrhea
induced by hypersensitivity to cows milk proteins.
9
It
has also been reported in association with renal tubular
acidosis.
10
.........................................................................................................
This patient has no family history of the disease,
which makes genetic causes unlikely. Structural
alteration of -or-globin chains of hemoglobin
Drugs or toxins that can cause methemoglobinemia*
Acetanilid
Alloxan
Aniline
Arsine
Benzene derivatives
Benzocaine
Bivalent copper
Bismuth subnitrate
Bupivacaine hydrochloride
Chlorates
Chloroquine
Chromates
Clofazimine
Dapsone
Dimethyl sulfoxide
Dinitrophenol
Exhaust fumes
Ferricyanide
Flutamide
Hydroxylamine
Lidocaine hydrochloride
Metoclopramide hydrochloride
Methylene blue
Naphthalene
Nitrates
Nitric oxide
Nitrites
Nitrofuran
Nitroglycerin
Sodium nitroprusside
Paraquat
Phenacetin
Phenazopyridine hydrochloride
Phenol
Phenytoin
Prilocaine hydrochloride
Primaquine phosphate
Rifampin
Silver nitrate
Sodium valproate
Smoke inhalation
Sulfasalazine
Sulfonamides
Trinitrotoluene
*Certain drugs are more likely to cause methemoglobinemia than others. These are
dapsone, local anesthetics, phenacetin, and antimalarial drugs. Screening
everybody for methemoglobinemia before exposing them to these drugs is
impractical because of the rarity of the condition and because a growing number of
drugs are implicated in its causation.
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194 wjm Volume 175 September 2001 www.ewjm.com
would have presented early in infancy, and type I
hereditary methemoglobinemia can reasonably
be excluded on the basis that chronic low-grade
cyanosis is the only symptom. The absence of
neurologic signs excludes type II hereditary
methemoglobinemia. The most likely cause of
methemoglobinemia, therefore, is acquired by
exposure to prilocaine hydrochloride.
.........................................................................................................
WHAT ARE THE OTHER CLINICAL SIGNS
AND COMPLICATIONS?
Methemoglobinemia may be acute or chronic. The physi-
ologic level of methemoglobin in the blood is 0% to 2%.
2
Methemoglobin concentrations of 10% to 20% are tol-
erated well, but levels above this are often associated with
symptoms. Levels above 70% may cause death. Symp-
toms also depend on the rapidity of its formation. Many
patients with lifelong methemoglobinemia are asymptom-
atic, but patients exposed to drugs and toxins who
abruptly develop the same levels of methemoglobinemia
may be severely symptomatic.
Small infants with methemoglobinemia present with
cyanosis that fails to respond to supplemental oxygen. Cy-
anosis in those with congenital methemoglobinemia usu-
ally appears shortly after birth. Dyspnea, nausea, and
tachycardia occur at methemoglobin levels of 30% or
more. Lethargy, stupor, and deteriorating consciousness
occur as methemoglobin levels approach 55%. Higher
levels may cause cardiac arrhythmias and circulatory fail-
ure. Hemolytic anemia may follow drug-induced methe-
moglobinemia, especially with exposure to dapsone, sul-
fasalazine, or phenacetin. The anemia is characterized by
Heinz bodies (precipitated hemoglobin or globin subunits
due to denaturation of hemoglobin in erythrocytes) and
fragmented red blood cells. Occasionally acute intravas-
cular hemolysis can lead to renal failure. Hemolytic ane-
mia with jaundice may also be a feature of hemoglobin
M
Saskatoon
and hemoglobin M
Hyde Park
abnormal hemo-
globin variants associated with genetic methemoglobine-
mia and identified by where they were discovered.
.........................................................................................................
The patient is monitored for evidence of
intravascular hemolysis and acute renal failure.
His urine output, blood cell count, and urea and
electrolyte levels are monitored closely. Any
evidence of hemolysis should alert the physician
so that appropriate treatment can be instituted.
.........................................................................................................
WHAT IS THE DIFFERENTIAL DIAGNOSIS?
The differential diagnosis of methemoglobinemia in small
infants includes cyanotic congenital heart disease, particu-
larly when right to left shunting is present. Children with
cyanotic congenital heart disease who receive supple-
mental oxygen have a low partial pressure of oxygen
and a low calculated oxygen saturation, but children with
methemoglobinemia have a high partial pressure of oxy-
gen despite cyanosis and normal calculated oxygen
saturation.
Methemoglobinemia in older children should be dis-
tinguished from sulfhemoglobinemia. Sulfhemoglobine-
mia refers to the incorporation of a sulfur molecule into
the heme moiety. Most drugs, particularly sulfonamides
and phenacetin, that produce methemoglobinemia can
also cause sulfhemoglobinemia, although this condition is
less common than methemoglobinemia.
11
Symptoms
tend to be milder than in patients with methemoglobine-
mia. The diagnosis is confirmed by elevated levels of sulf-
hemoglobin by either spectrophotometry or gas chroma-
tography-mass spectrometry. Sulfhemoglobinemia does
not respond to methylene blue, and the treatment is sup-
portive.
12
In severe cases, exchange transfusion may be
useful.
The potassium cyanide test can distinguish between
methemoglobin and sulfhemoglobin. After the addition of
a few drops of potassium cyanide, methemoglobin turns
bright red, but sulfhemoglobin remains dark brown. This
is due to the binding of methemoglobin to cyanide, form-
ing cyanomethemoglobin, which is bright red in color.
Sulfhemoglobin, on the other hand, is inert and does not
bind cyanide.
13
A family history is usually helpful in differentiating
methemoglobinemia due to NADH cytochrome b
5
re-
ductase deficiency from hemoglobin M disease. Cyanosis
in successive generations suggests the presence of hemo-
globin M; normal parents but possibly affected siblings
implies the presence of NADH cytochrome b
5
reductase
deficiency.
HOW DO YOU CONFIRM THE DIAGNOSIS?
Blood containing high concentrations of methemoglobin
appears chocolate brown. Subjects with methemoglobine-
mia may have normal partial pressures of oxygen, despite
life-threatening methemoglobinemia. The oxygen satura-
tion values, measured by a pulse oximeter, are falsely
elevated.
In methemoglobinemia due to drug exposure, an el-
evated level of methemoglobin is found, but the activity of
NADH cytochrome b
5
reductase is normal. In hereditary
type II methemoglobinemia, the enzymes activity is less
than 20% of normal. Hemoglobin M may be differenti-
ated from methemoglobin formed from hemoglobin A by
its absorption spectrum in the range of 450 to 750 nm.
Electrophoresis at pH 7.1 is most useful for the separation
of hemoglobin M.
14
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Volume 175 September 2001 wjm 195www.ewjm.com
WHAT TREATMENT WORKS?
The course of hereditary methemoglobinemia type I is
benign, but these patients should not be administered oxi-
dant drugs. Treatment may be required for cosmetic rea-
sons or for an inadvertent use of oxidant drugs. Ascorbic
acid, 300 to 600 mg orally daily divided into 3 or 4 doses,
is helpful.
15
For methemoglobinemia due to drug exposure, tradi-
tional first-line therapy consists of an infusion of methy-
lene blue, whose action depends on the availability of
reduced nicotinamide adenine nucleotide phosphate
(NADPH) within the red blood cells. After an acute ex-
posure to an oxidizing agent, treatment should be consid-
ered when the methemoglobin is 30% in an asymptom-
atic patient and 20% in a symptomatic patient.
16
Patients
with anemia or cardiorespiratory problems should be
treated at lower levels of methemoglobin. Methemoglobi-
nemia due to hemoglobin M does not respond to ascorbic
acid or methylene blue.
Dextrose should be given
17
because the major source of
NADH in the red blood cells is the catabolism of sugar
through glycolysis. Dextrose is also necessary to form
NADPH through the hexose monophosphate shunt,
which is necessary for methylene blue to be effective.
Methylene blue is an oxidant; its metabolic product
leukomethylene blue is the reducing agent. Therefore,
large doses of methylene blue may result in higher levels of
methylene blue rather than the leukomethylene blue,
which will result in hemolysis and, paradoxically, methe-
moglobinemia in patients with glucose-6-phosphate dehy-
drogenase (G6PD) deficiency.
18
Patients with G6PD
deficiency also may not produce sufficient NADPH to
reduce methylene blue to leukomethylene blue; thus,
methylene blue therapy may be ineffective in these
patients.
18
Some drugs, such as dapsone, benzocaine, and aniline,
produce a rebound methemoglobinemia, in which met-
hemoglobin levels increase 4 to 12 hours after successful
methylene blue therapy.
19
N-Acetylcysteine, cimetidine, and ketoconazole are ex-
perimental therapies in the treatment of methemoglobi-
nemia that have shown some promising results.
20-22
Ex-
change transfusion is reserved for patients in whom
methylene blue therapy is ineffective.
.........................................................................................................
The patient is treated with intravenous methylene
blue and dextrose infusion, with a good response.
His cyanosis and blood oxygenation improve, as
does his consciousness level. His urine output is
monitored, and a close eye is kept on his
biochemistry. Blood tests are repeated after 24
hours for evidence of hemolysis and rebound
methemoglobinemia. His G6PD status is
ascertained and found to be normal. He does not
show any evidence of hemolysis or renal
impairment and makes a complete recovery.
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... The concentration level between 10% and 20% is associated with symptoms. 15 MetHb is classified into two types that are congenital and acquired. There are two forms of congenital MetHb, type I and II. ...
... 16 Examples of medications causing MetHb include chloroquine, dapsone and bupivacaine. 15 It has been reported that a 6-week-old infant presented to the hospital with a 2-day history of diarrhoea, poor feeding and lethargy. The initial pH was acidotic with a methaemoglobin of 29%. ...
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