Methemoglobinemia is a topic covered in the 5-Minute Emergency Consult.

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  • Iron molecule in hemoglobin is oxidized from ferrous (Fe2+) to ferric (Fe3+) state resulting in a form of hemoglobin that cannot transport oxygen.
  • Oxygen-carrying capacity of blood is reduced and cyanosis is generally present with significant levels.
  • Normal methemoglobin levels are ≤1%; symptoms usually occur with levels >20%.
  • More serious with coexisting anemia
  • Methemoglobin:
    • Decreases total oxygen-carrying capacity (functional anemia)
    • Shifts hemoglobin oxygen-dissociation curve to the left, impairing O2 release to tissues
    • Maintained at physiologic level (1–2%) by nicotinamide adenine dinucleotide (NADH)-methemoglobin (cytochrome B5) reductase in red blood cells (RBCs)
  • Congenital methemoglobinemia:
    • NADH-methemoglobin (cytochrome B5) reductase deficiency (homozygous or heterozygous)
    • Heterozygous hemoglobin M and other abnormal hemoglobins
  • Acquired methemoglobinemia results from oxidant stress on RBCs:
    • Some methemoglobin-inducing agents are direct oxidants (e.g., nitrites)
    • Many substances produce oxidant injury via N-hydroxylamine metabolites.
    • Methemoglobinemia may be delayed relative to initial substance exposure.
  • Many methemoglobin-inducing agents also cause Heinz body hemolytic anemia (HA):
    • Caused by oxidant injury of RBC proteins
    • Glucose-6-phosphate dehydrogenase (G6PD)–deficient patients have higher risk.
    • Patients with methemoglobinemia should be worked up for HA.
  • Methemoglobinemia may serve as marker for genetic abnormalities:
    • Heterozygous NADH-methemoglobin (cytochrome B5) reductase deficiency


  • Cyanide (CN) antidote kit:
    • Induces methemoglobinemia via amyl and sodium nitrite
    • CN will preferentially complex with methemoglobin, which can then be chelated by sodium thiosulfate.
  • Nitrates/nitrites:
    • Nitrites (NO2)
    • Nitrates (NO3) (e.g., nitroglycerine, via metabolic conversion to nitrites)
    • Nitric oxide (NO)
  • Dyes:
    • Aniline dyes
    • Methylene blue (excessive)
  • Antiparasitic drugs (high potential for MetHb formation):
    • Dapsone
    • Primaquine
    • Chloroquine
  • Local anesthetics (high potential for MetHb formation):
    • Benzocaine
    • Lidocaine
    • Prilocaine
  • Analgesics:
    • Phenazopyridine (Pyridium)
    • Phenacetin
  • Antibiotics:
    • Nitrofurantoin
    • Sulfones
    • Sulfonamides
  • Others:
    • Metoclopramide
    • Naphthalene (mothballs)
    • Paraquat (herbicide)
    • Arsine gas (AsH3)
    • Chlorates (ClO4)
    • Phenols (e.g., dinitrophenol, hydroquinone)

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