Methemoglobinemia is a condition in which the iron within

hemoglobin is oxidized from the ferrous (Fe2+) state to the ferric

(Fe3+) state. Because iron needs to be in the ferrous state to
allow hemoglobin-to-oxygen binding, methemoglobinemia
results in variable degrees of deficiencies of oxygen transport.
Clinically, this condition causes cyanosis, often posing a
diagnostic dilemma.
Methemoglobinemia in children usually results from exposure
to oxidizing substances (such as nitrates or nitrites; aniline
dyes; or medications, including lidocaine, prilocaine,
phenazopyridine hydrochloride [Pyridium], and others) or is the
result of inborn errors of metabolism (especially glucose-6-
phosphate dehydrogenase [G6PD] deficiency and cytochrome
b5 oxidase deficiency) or severe acidosis, which impairs the
function of cytochrome b5 oxidase. This is particularly evident
in young infants with diarrhea,[1] in whom excessive stool
bicarbonate loss leads to metabolic acidosis, which exacerbates
the relatively immature cytochrome b5 oxidase system.

Note the chocolate brown color of

methemoglobinemia. Tube 1 and tube 2 have a methemoglobin
concentration of 70%; tube 3, a concentration of 20%; and tube
4, a normal concentration.

Pathophysiology

Hemoglobin molecules are tetrameric and contain iron within a

porphyrin heme structure. The iron moiety in hemoglobin is
normally in the ferrous state (Fe2+) in both oxyhemoglobin and
deoxyhemoglobin and is capable of reversibly binding with
oxygen only in this (ferrous) state. The oxidation of iron to the
ferric state (Fe3+) results in the formation of methemoglobin,
which alters absorption and causes a brownish discoloration of
the blood.
In healthy children, the ferric iron in methemoglobin is readily
reduced to the ferrous state, primarily through the function of
cytochrome b5 oxidase (also referred to as methemoglobin
reductase), which is present in erythrocytes and other cells.
Patients who are deficient in cytochrome b5 reductase are
particularly prone to methemoglobinemia, especially when
exposed to oxidizing medications and other chemicals,
including nitrates, nitrites, prilocaine and lidocaine, nitric oxide,
and aniline dyes. Because methemoglobin is incapable of
reversibly binding and transporting oxygen or carrying carbon
dioxide, if it is present in significant amounts,
methemoglobinemia can result in impaired oxygen delivery to
(and carbon dioxide removal from) all tissue beds.
Cyanosis is commonly caused by either an excess of
deoxygenated hemoglobin (usually in amounts >5 g/dL) or
significant amounts of abnormal hemoglobins such as
methemoglobin (>1.5 g/dL) or sulfhemoglobin (>0.5 g/dL),
resulting in a grayish-bluish coloration of the skin and mucous
membranes. Because the absolute amount of deoxygenated or
abnormal hemoglobin (rather than its percentage) is required
for cyanosis to be clinically evident, patients with moderate-to-
severe anemia may not appear cyanotic, even with elevated
percentages of deoxygenated or abnormal hemoglobins.
In healthy individuals, ongoing RBC exposure to various
oxidizing agents produces small amounts of methemoglobin;
however, the concentration of methemoglobin (as a fraction of
total hemoglobin) is maintained below 1% by a reduction
enzyme system (mainly cytochrome b5 along with nicotinamide
adenine dinucleotide [NADH] reductase), with additional
protection provided by other systems, including glutathione
reductase and G6PD. Methemoglobinemia occurs if the rate of
oxidation is significantly increased and overwhelms the
protective and reductive capacities of the cells, if the structure
of hemoglobin is altered and is resistant to reduction, or if the
rate of reduction of methemoglobin is decreased.
Methemoglobinemia may be acquired or congenital.

Acquired methemoglobinemia

Acquired methemoglobinemia is more common than congenital

forms. Exposure to oxidant drugs and toxins in amounts that
exceed the enzymatic reduction capacity of RBCs precipitates
symptoms of methemoglobinemia.[2]
Acquired methemoglobinemia is more frequent in premature
infants and infants younger than 4 months. The following
factors may have a role in the higher incidence in this age
group:

• Fetal hemoglobin may more easily (auto) oxidize than

adult hemoglobin.
• The level of NADH reductase is low at birth and increases
with age; it reaches reference range limits by age 4
months.
• Higher gastric pH in infants may facilitate bacterial
proliferation, resulting in increased conversion of dietary
nitrates to nitrites.
• An association between methemoglobinemia and acute
gastroenteritis in infants has been noted in several studies
and may be due to acidosis from stool bicarbonate loss
impairing the already immature function of the
methemoglobin reductase system in these young patients.

Congenital (ie, hereditary) methemoglobinemia

Hereditary methemoglobinemias may be divided into 2

categories: methemoglobinemia due to an altered form of
hemoglobin (hemoglobin M) and enzyme deficiency (NADH
reductase deficiency) that decreases the rate of reduction of
iron in the hemoglobin molecule.[3] Four types of hereditary
methemoglobinemias are secondary to deficiency of NADH
cytochrome b5 reductase. All types are autosomal recessive
disorders. Heterozygotes have 50% enzyme activity and no
cyanosis. Homozygotes that have elevated methemoglobin
levels above 1.5% have clinical cyanosis.

• Type I: This is the most common variant, and the enzyme

deficiency is limited to the erythrocytes causing cyanosis.
• Type II: Widespread deficiency of the enzyme occurs in
various tissues, including erythrocytes, liver, fibroblasts,
and brain. It is associated with severe CNS symptoms,
including encephalopathy, microcephaly, hypertonia,
athetosis, opisthotonus, strabismus, mental retardation,
and growth retardation. Cyanosis is evident at an early
age.
 • Type III: Although the hemopoietic system (platelets,
RBCs, white cells including lymphocytes and granulocytes)
is involved, the only clinical consequence is cyanosis.
• Type IV: Similar to type I, this type has isolated
involvement of the erythrocytes but results in chronic
cyanosis.

Deficiency of nicotinamide adenine dinucleotide phosphate

(NADPH)–flavin reductase can also cause methemoglobinemia.
An amino acid substitution in or near the heme pocket affects
the heme-globin bond, and the hemoglobin molecule becomes
more stable in the oxidized form, resisting reduction. Several
variants of hemoglobin M have been described, including
hemoglobin Ms, hemoglobin MIwate, hemoglobin MBoston,
hemoglobin MHydePark, and hemoglobin MSaskatoon. These are
usually autosomal dominant in nature. Alpha chain
substitutions cause cyanosis at birth, whereas those in the beta
chain become clinically apparent in infants aged 4-6 months.

Epidemiology

Frequency

United States

Theexact incidence is unknown.

International

The exact incidence is unknown.

Mortality/Morbidity

Patients with congenital methemoglobinemia are generally

asymptomatic other than cyanosis. Life expectancy is normal,
unless the methemoglobin level is above 25-40%. Acquired
methemoglobinemia is usually mild but may be severe and
rarely fatal, depending on the cause. Mild-to-moderate
transient methemoglobinemia may be present but may escape
clinical detection; a high index of suspicion must be
maintained.[4]

Age
Hereditary forms appear early in life. Young infants, especially
infants aged 3-4 months, are more susceptible to acquired
methemoglobinemia.
Proceed to Clinical Presentation

History

• Congenital methemoglobinemia: The characteristic history

is diffuse persistent slate-gray cyanosis, often present
from birth, without evidence of cardiopulmonary disease.
• Acquired methemoglobinemia
o Presentation may be dramatic, with cyanosis,
dyspnea, lethargy, headache, dizziness, deterioration
of mental functioning, or stupor.
o History of exposure to a known toxin or drug may not
always be available but should be sought because
long-term or repeated exposure may occur.
o Discussion with a toxicologist may be necessary,
especially when methemoglobinemia occurs shortly
after exposure to a new medication, because the list
of medications known to cause methemoglobinemia
constantly changes. A comprehensive review of all
medications, herbs, and other nutritional
supplements may disclose exposure to a toxin not
previously known to cause hemoglobinemia.

Physical

• Congenital methemoglobinemia
o These patients are described as being more blue
than sick.
o Patients appear cyanotic with a diffuse slate-gray
appearance.
o Cyanosis is easily observed on the nose, cheeks,
fingers, toes, and in the mucous membranes,
including the fundi, and may go unrecognized for a
long time in patients with more heavily pigmented
skin or in patients with moderate-to-severe anemia.
Clubbing is absent.
o Methemoglobin levels of 10-20% are tolerated with
no clinical symptoms, whereas levels of 30-40% may
 be associated with headaches and dyspnea,
especially upon exertion.
• Patients with hemoglobin M disease with the alpha chain
variant can present at birth with cyanosis, whereas
patients with the beta chain variants present in the later
half of infancy.

Causes

• Acquired methemoglobinemia: Exposure to various drugs

or toxins may result in acquired methemoglobinemia.
These include the following:
o Nitrites, particularly in well water (Prepackaged foods
[including baby food] may contain significant levels
of nitrites.)[5, 6]
o Aniline dyes
o Silver nitrate
o Nitroprusside
o Antimalarials
[7]
o Zopiclone
o Local anesthetics (eg, Benzocaine, prilocaine, and
lidocaine), particularly when applied to mucosa, such
as during bronchoscopy, or after repeated cutaneous
exposure to eutectic mixture of lidocaine-prilocaine
(EMLA(R) cream) over a short period of time
o Nitric and nitrous oxides
o Dapsone, rasburicase, and phenazopyridine
o Inadequately cooked vegetables (eg, spinach, beets,
carrots) contaminated with bacteria (Infants and
patients on gastric acid-reduction therapy are
particularly prone to developing methemoglobinemia
because gastric acid production may not be sufficient
to maintain low levels of nitrate-reducing bacteria in
the intestine.)
• Hereditary methemoglobinemia: This may be due to the
deficiency of nicotinamide adenine dinucleotide (NADH)
cytochrome b5 reductase or NADPH-flavin reductase or
the presence of hemoglobin M

vvLaboratory Studies

• An arterial blood sample from a patient with

methemoglobinemia is characteristically chocolate brown.
 Note the chocolate brown color of
methemoglobinemia. Tube 1 and tube 2 have a
methemoglobin concentration of 70%; tube 3, a
concentration of 20%; and tube 4, a normal concentration.
o Blood that is cyanotic or dark in color due to
cardiopulmonary disease turns red upon exposure to
oxygen, whereas blood with methemoglobin does
not.
o A quick and easy bedside test is to bubble 100%
oxygen in a tube that contains the dark blood. Blood
that remains dark likely does so because of the
presence of methemoglobin.
o Another simple test (and one that is less likely to
splash potentially infectious blood) is to place 1-2
drops of blood on white filter paper, then evaluate for
color change upon exposure to oxygen (this test can
be accelerated by gently blowing supplemental
oxygen onto the filter paper). Deoxygenated
hemoglobin changes from dark red or violet to bright
red, whereas methemoglobin remains brown.
• Serum methemoglobin levels of more than 1% are
considered abnormal, although higher levels are
commonly encountered in smokers (and patients with
long-term exposure to second-hand smoke). Symptomatic
individuals usually have levels of more than 40-50%.
• Serum levels of nitrites or other offending drugs may be
determined; however, most of these results are not
immediately available, and treatment must not be
withheld or delayed pending test results.
• Nicotinamide adenine dinucleotide (NADH) reductase
levels should be checked.
• Hemoglobin electrophoresis may be needed to confirm
hemoglobin M disease.
• Pulse oximetry may be a useful tool in patient with
cyanosis, although its results must be interpreted with
caution.
 o The blood is exposed to light using a small probe
placed across a capillary bed, usually on a finger or
toe. Light wavelengths of 660 nm and 940 nm are
used, and the ratio of absorption of light at each of
these wavelengths is converted into oxygen
saturation using calibration curves.
o A pulse oximetry reading in a child with respiratory or
cardiac disease reflects the degree of hypoxia and is
proportionate to the amount of reduced hemoglobin.
o Methemoglobin increases absorption of light at both
wavelengths (more at 940 nm) and, therefore, offers
optical interference to the pulse oximetry by falsely
absorbing light. This leads to the plateau in the
oxygen saturation at 85%.
o In a patient with methemoglobinemia, the severity of
the cyanosis does not correspond to the pulse
oximetry reading. The patient may appear extremely
cyanotic but have a pulse oximetry reading in the
high 80s.
o In methemoglobinemia, the oxygen saturations (as
determined by pulse oximetry) plateau at around
85%; therefore, a patient with a methemoglobin level
of 5% and a patient with a methemoglobin level of
40% both have pulse oximetry readings of around
85%.
• Co-oximetry should be performed to evaluate for
methemoglobinemia (although some equipment does not
differentiate between sulfhemoglobin and
methemoglobin).

Once the diagnosis of methemoglobinemia has been confirmed

and appropriate treatment has been initiated, the underlying
etiology should be sought.

• In acquired methemoglobinemia, the toxin or drug may be

identified by obtaining blood levels, performing gastric
lavage, or both. In asymptomatic patients with low levels
of methemoglobin, monitoring serial serum levels is all
that may be necessary. The levels normalize over time
unless recurrent or chronic exposure to the offending
agent occurs.
• If the methemoglobin levels are more than 30%,
methylene blue should be intravenously administered at
 1-2 mg/kg (up to 50 mg/dose in adults, adolescents, and
older children) as a 1% solution over 5 minutes; repeat in
1 hour, if necessary. Methylene blue is an oxidant at levels
of more than 7 mg/kg and, therefore, may cause
methemoglobinemia in susceptible patients; thus, care
must be taken in administration of this drug. Methylene
blue is contraindicated in patients with glucose-6-
phosphate dehydrogenase (G6PD) deficiency because it
can lead to severe hemolysis.
• Ascorbic acid is an antioxidant that may also be
administered in patients with methemoglobin levels of
more than 30%.
• N -acetylcysteine has been shown to reduce
methemoglobin in recent studies but is not yet an
approved treatment for methemoglobinemia.
• No pharmaceutical treatment for hereditary forms of
methemoglobinemia exists.
o Oral ascorbic acid (200-500 mg) has been found to
be partially effective, if continued on an ongoing
basis; however, this therapy has the potential risk of
renal stones and hyperoxaluria. Methylene blue has
also been used in these patients.
o In severe cases, exchange transfusion may be
necessary.

Consultations

• Consultation with other specialists, such as hematologists,

cardiologists, and pulmonologists, may be required to
assist in the search for the cause of the
methemoglobinemia.

Diet

• Some vegetables (eg, beets, spinach, and carrots) are

high in nitrite content and may need to be avoided in
susceptible patients.
• Well water can be contaminated with nitrites, nitrates, and
oxidants and could lead to methemoglobinemia, especially
in small infants (< 4 mo) when well water is used to
prepare formula or is given alone.

Activity
 • No change in activity is indicated.
• Medication Summary
• Unless the methemoglobinemia is severe or symptomatic,
the treatment is purely for cosmetic and/or psychological
reasons. Various agents can reduce the methemoglobin
levels to within the reference range or to acceptable levels
(5-10%). Methylene blue, ascorbic acid, and, rarely,
exchange transfusion may be used. N -acetylcysteine has
been shown to reduce levels of methemoglobin in studies
but is not yet approved for the treatment of
methemoglobinemia.
• Antidotes
• Class Summary
• These agents are used in the management of poisoning or
overdose to prevent toxic effects or in metabolic disorders
in which toxic substances accrue. Mechanisms of action
are variable (eg, antagonists, toxin transformation, altered
metabolism, chelation, directed antibodies).
• View full drug information
• Methylene blue (Urolene blue)
•
• Increases the activity of NADH-methemoglobin reductase
in RBCs, assisting in the conversion of ferric (Fe3+) to
ferrous (Fe2+) iron.
• View full drug information
• Ascorbic acid (Vita-C, Cecon, Cevalin)
•
• Antioxidant and coenzyme for reduction. It may be helpful
in the treatment of congenital methemoglobinemia if used
daily and on a continual basis.

Further Inpatient Care

• Acquired methemoglobinemia: The underlying cause

should be identified, and measures should be instituted to
avoid further exposure of the patient to precipitating
causes.
• Hereditary methemoglobinemia: Methemoglobin levels
and adverse effects of medication should be monitored on
an ongoing basis.