METHEMOGLOBINEMIA
Mita Sanghavi Goel, M.D.
March 13, 2003
Definition
Methemoglobin is formed by oxidizing normal ferrous (Fe2+) hemoglobin to ferric (Fe3+) hemoglobin, which is not
capable of binding oxygen or carbon dioxide.
Clinical Presentation
Depends on the level of methemoglobin
 1.5-3.0 g/dL
(10-20%)
 3.0-4.5 g/dL
(20-30%)
 4.5-7.5 g/dL
(30-50%)
 7.5-10.5 g/dL (50-70%)
 >10.5 g/dL
(>70%)
cyanosis
anxiety, lightheadedness, headache, tachycardia
fatigue, confusion, dizziness, tachypnea, increased tachycardia
coma, seizures, arrhythmia, acidosis
death
Pathophysiology
 Methemoglobin is regularly formed by oxidative stresses from a variety of sources, including oxygen free radicals.
RBCs do not have the ability to synthesize new proteins and do not have mitochondria that generate energy to
assist with redox reactions; therefore, RBCs (especially older ones) are highly susceptible to oxidation. About 1%
of total hemoglobin exists as methemoglobin.
 Methemoglobin causes increased oxygen affinity in the remaining normal heme moieties and a leftward shift of the
oxyhemoglobin dissociation curve. This leads to decreased release of oxygen and worsening tissue hypoxemia.
Mechanisms of Reducing Methemoglobin
Enzymatic Systems
 Nicotine Adenine Dinucleotide (NADH)-dependent
Cytochrome b5 Methemoglobin Reductase
o The major system for reduction of methemoglobinemia.
Accounts for 99% of daily reduction of methemoglobin.
o Can convert methemoglobin to hemoglobin at a rate of
about 15% per hour.
o Patients deficient in cytochrome b5 reductase can still
maintain methemoglobin levels below 50%, which
suggests that other minor pathways may become more
active.
 Nicotine Adenine Dinucleotide Phosphate (NADPH)dependent Methemoglobin Reductase
o Under normal conditions, this pathway has a minimal role
in methemoglobin reduction
o This pathway reduces methylene blue to leukomethylene
blue, which in turn reduces methemoglobin to
hemoglobin.
Cellular Antioxidants
 Vitamin C, Glutathione, etc.
o Normally play a small role in reducing
methemoglobin, but may be upregulated in
patients with NADH-dependent cytochrome b5
reductase deficiency.
Causes
Toxins
 In adults, the most common cause of
methemoglobinemia is toxins.
 The most frequent offenders are benzocaine, nitrates,
nitrites, anilines, naphthalene, and phenazopyridine
(pyridium).
 Of note, dapsone and anilines produce a rebound
methemoglobinemia 4-12 hours after treatment.
Beth Israel Deaconess Medical Center Interns’ Report
Genetic
 Generally present early in life.
 May be deficiencies in the enzymes for methemoglobin reduction, such as cytochrome b5 reductase.
 Also may be secondary to abnormal hemoglobin production of Hemoglobin M (autosomal dominant,
heterogeneous).
Diagnosis
Pulse Oximetry
 Regular pulse oximetry relies on measuring the absorbance of 2 wavelengths of light, 660nm and 940 nm.
Oxyhemoglobin and deoxyhemoglobin each absorb both wavelengths of light in different ratios. A ratio of 0.43
(660nm/940nm)=100% oxygen saturation and a ratio of 3.4=0% saturation.
 Methemoglobin also absorbs both wavelengths of light. 100% methemoglobin absorbs a ratio of 1
(660nm/940nm) and will register as 85% oxygen saturation.
 As a result, the lowest oxygen sat of 82-85% occurs at the absorbance ratio of 30-35% methemoglobin, unless
deoxyhemoglobin is also present.
 The appearance of cyanosis despite a reasonable oxygen saturation should trigger the thought of
methemoglobin.
ABG
 Because it measures PO2 based on the oxygen dissolved in the blood rather than the oxygen bound to
hemoglobin, PO2 will remain normal.
 Additionally, because the oxygen saturation is calculated from the pH and PCO2, assuming normal oxygenhemoglobin saturation curve and normal hemoglobin, the PO2 may appear normal.
Cooximetry
 THE method of diagnosing methemoglobinemia, cooximetry must be separately ordered.
 Uses 4 wavelengths of light, which can distinguish between deoxyhemoglobin, oxyhemoglobin,
carboxyhemoglobin, and hemoglobin. With the additional resolution from the wavelengths, cooximetry can
measure the percentage of methemoglobin in a blood gas sample.
Bedside Tests
 Methemoglobin has a characteristic chocolate-brown appearance that does not redden even when exposed to
oxygen (unlike deoxygenated blood)
Treatment
Treatment is generally reserved for patients with a level of 20% in symptomatic patients and 30% in asymptomatic
patients. Additional factors that may influence treatment are coexisting illnesses such as heart disease, lung disease,
anemia, etc.
Oxygen
 Although this does not assist with reducing methemoglobin, oxygen will decrease any effects of
deoxyhemoglobin.
Methylene blue
 The cornerstone of therapy.
 Methylene blue is reduced to leukomethylene blue by NADPH methemoglobin reductase, and then in turn,
reduces methemoglobin to hemoglobin.
 Significantly reduced methemoglobin within one hour if it works.
 Dosed at 1-2 mg/kg (0.2mL/kg of a 1% solution) over 3-5 minutes and repeated after 30 minutes.
 CAUTIONS:
o In patients with G6PD deficiency, methylene blue may produce a Heinz body hemolytic anemia.
o Large doses (>4 mg/kg) may worsen methemoglobinemia because of its oxidizing property.
o Is not effective in patients with NPDHP methemoglobin reductase deficiency.
o Is not effective with sulfhemoglobinemia, which can be created when methemoglobin forms a covalent
bond with sulfur.
Dextrose
 Dextrose is necessary to form NADPH for the methylene blue to be effective.
Miscellaneous Treatments
 Charcoal if necessary to reduce the enterohepatic circulation of some toxins, such as dapsone.
 P-450 inhibitors such as cimetidine and ketoconazole to block the metabolism of some toxins to their oxidizing
forms.
 N-acetylcysteine (NAC) may be a treatment option for patients with G6PD deficiency.
 Hyperbaric oxygen and exchange transfusions may be necessary in some patients.
Beth Israel Deaconess Medical Center Interns’ Report