Methemoglobinemia

Learning objectives

• Describe the definition and underlying mechanisms of methemoglobinemia
• Diagnose methemoglobinemia
• Manage patients with methemoglobinemia

Background

• Methemoglobin is the form of the hemoglobin molecule where the iron moiety is oxidized (Fe3+)
• It is formed in the presence of an oxidizing substrate and does not carry oxygen
• It shifts the oxygen-hemoglobin dissociation curve to the left, hindering the unloading of oxygen to the tissues
• These effects are proportional to the concentration of methemoglobin and reversible
• Normal methemoglobin levels: 1-2 %
• Methemoglobinemia refers to an abnormally high concentration of methemoglobin and results in functional anemia
• Methemoglobinemia can be a life-threatening condition

Etiology

• Congenital (rare)
  • Autosomal recessive defects in cytochrome b5 reductase (CYB5R)
    • Congenital methemoglobinemia type I: CYB5R defect only in erythrocytes
    • Congenital methemoglobinemia type II: CYB5R defect in all cells
  • Autosomal dominant mutations in hemoglobins M (hemoglobin M disease)
• Acquired
  • Exposure to oxidizing agents leading to methemoglobin production that exceeds the body’s reduction capacity
  • Oxidizing agents:
    • Direct
      • Benzocaine
      • Prilocaine
      • Lidocaine
      • Tetracaine
    • Indirect
      • Nitrates, nitrites
    • Metabolic activation
      • Aniline
      • Dapsone

Pathophysiology

Reduction of methemoglobin by cytochrome b5 reductase:

• Hemoglobin M disease: 
  • Mutation in globin protein allows for stabilization of iron in the ferric state (Fe3+)
  • Most patients have methemoglobin levels between 15-30% and remain asymptomatic
• Congenital methemoglobinemia: Defect in CYB5R function raising methemoglobin levels
• Acquired methemoglobinemia: CYB5R is overwhelmed by oxidative stress resulting in raised methemoglobin levels

Diagnosis

• Pulse oximetry measurements of oxygen saturation (SpO2): Refractory hypoxemia
• Refractory hypoxemia is usually not detected using blood gas analysis using the partial oxygen pressure (SaO2)
• Saturation gap: Difference between depressed SpO2 measurement and falsely normal SaO2 calculation
• A saturation gap >5% indicates the presence of abnormal forms of hemoglobin

Management

Suggested reading

• Ludlow JT, Wilkerson RG, Nappe TM. Methemoglobinemia. [Updated 2022 Aug 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537317/
• Guay J. Methemoglobinemia related to local anesthetics: a summary of 242 episodes. Anesth Analg. 2009;108(3):837-845.

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