• Methemoglobin refers to ferric form of hemoglobin (Fe3+) that is unable to bind O2
  • Suspect in any patient with cyanosis not responsive to supplemental O2
    • Consider in pediatric patient (<6 months) with diarrhe and low oxygen saturation


  • Rarely congenital, NADH reductase deficiency - unable to reduce ferric to ferrous iron (Fe3+ → Fe2+)
  • Exposure to oxidizing agent[1][2]
    • Benzocaine and other local anesthetics
    • Cyanokit, nitrites, nitrates, well water (nitrates)
    • Antimalarials
    • Quinolones
    • Dapsone (used to treat leprosy, PCP pneumonia, toxoplasmosis, dermatitis herpetiformis, brown recluse bite)
    • Aniline dyes
    • Phenazopyridine[3]

Clinical Features

Cyanosis from methemoglobinemia.
Cyanosis resolved after methylene blue.
Severe methemoglobinemia.
Chocolate-brown blood due to methemoglobinemia.
MetHb level (%) Signs & Symptoms^
<3 None
3-15 Blue/slate-gray skin
15-30 Cyanosis, chocolate-brown blood
30-50 Breathlessness, headache, dizziness, syncope
50-70 Tachypnea, myocardial ischemia, lactic acidosis, arrythmia, seizure, CNS depression, coma
>70 Death

^Patients with anemia or preexisting cardiopulmonary disease will show symptoms sooner

Differential Diagnosis

  • Consider rare entity of sulfhemoglobinemia
    • Sulfonamides, sulfasalazine, phenazopyridine
    • Occupational exposure
    • Conventional co-oximerty misidentifies sulfhemoglobin as methemoglobin so diagnosis is suspected when patient does not respond to methylene blue
    • Typically requires no treatment other than removal of offending agent
    • Blue-green discoloration of blood

Acute dyspnea




Chocolate-brown blood due to methemoglobinemia.
Color chart for the detection of the amount of methemoglobin in the blood.
  • Diagnosis requires high index of suspicion; lack of improvement in oxygen saturation with high-flow oxygen plus discrepancy in oxygen saturation >5% between measurements by ABG vs pulse oximetry ("saturation gap") should raise suspicion. Diagnosis is then confirmed by measuring level of methemoglobin in blood
  • Co-oximetry
    • Measures relative levels of oxyhemoglobin, carboxyhemoglobin, methemoglobin, reduced hemoglobin
    • Usually performed on arterial blood sample, but fingertip CO-oximeter devices are available
  • Normal PaO2
  • SpO2 will initially be falsely elevated
    • Once MetHb >30% → SpO2 will fall to 80-85%
    • Mid-80s SpO2 due to light absorption of both oxyHb and deoxyHb
  • "Chocolate brown" color of blood


  • High-Flow Oxygen
    • All patients warrant supplemental oxygen. Symptoms may improve with a non-rebreather but the pulse oximeter reading will remain unchanged and patients may remain cyanotic. This is a diagnostic clue.
  • Methylene blue
    • Treat if symptomatic OR asymptomatic with MetHb >25%
    • 1-2mg/kg Methylene blue IV over 5min; repeat dose if no effect
    • Improvement seen within 20min
    • Contraindicated in G6PD deficiency
      • May induce acute hemolytic anemia
      • Instead use moderate dose of ascorbic acid (vitamin C), 300 to 1000 mg/day orally in divided doses
  • Other treatment modalities[5]
    • Exchange transfusion for symptomatic methemoglobinemia in patient with G6PD deficiency
    • Hyperbaric O2 when methylene blue ineffective or contraindicated
    • IV hydration and bicarbonate for metabolic acidosis


  • Will vary depending on response to the antidote and persistence of symptoms. Discuss with toxicologist/poison control

See Also

External Links


  1. Fernandez-Frackelton M, Bocock J: Cyanosis, in Marx JA, Hockberger RS, Walls RM, et al (eds): Rosen’s Emergency Medicine: Concepts and Clinical Practice, ed 7. St. Louis, Mosby, Inc., 2010, (Ch) 29:p 211-216.
  2. Mody, A., Silverman, B.: Problems in the Early Neonatal Period, In Fleisher and Ludwig's Textbook of Pediatric Emergency Medicine, Lippincott, WIlliams and Wilkins 2010, Page 995.
  3. Jeffery WH, Zelicoff AP, Hardy WR. Acquired methemoglobinemia and hemolytic anemia after usual doses of phenazopyridine. Drug Intell Clin Pharm. 1982 Feb;16(2):157-9.
  4. Denshaw-Burke et al. Methemoglobinemia: Practice Essentials. Jan 4, 2016.
  5. Denshaw-Burke et al. Methemoglobinemia: Practice Essentials. Jan 4, 2016.