Definition: A hemoglobinopathy characterized by an abnormal elevation of methemoglobin (MetHb) – hemoglobin in which iron (ferrous Fe2+) has been oxidized(ferric Fe3+). An abnormal MetHb level is any level > 1%.

Methemoglobinemia Pathophysiology

Mechanism of Action

  • Pathophysiology
    • Oxidized iron sites on MetHb unable to bind oxygen
    • Remaining binding sites with increased affinity for binding oxygen
    • Causes a leftward shift in the oxyhemoglobin dissociation curve
    • Results in decreased tissue oxygen delivery
  • Normal situation
    • Red cells constantly exposed to oxidant stress
    • NADH MetHb reductase keeps oxidative stress in check by reducing MetHb to Fe2+ state
  • Methemoglobinemia occurs when either
    • There is an deficiency of the reducing enzyme (NADH MetHb reductase)
    • There is increased oxidative stress that cannot be handled by the body
  • Presence of MetHb renders pulse-oximetry readings inaccurate

Common Causative Agents

  • Benzocaine
  • Dapsone
  • Nitroglycerin
  • Nitrofurantoin
  • Nitroprusside
  • Phenazopyridine
  • Sodium Nitrite
  • Amyl nitrite
  • Contaminated well water
  • Isobutyl Nitrite (“poppers”)

Signs + Symptoms

  • Low O2 saturation that does not respond to supplemental O2
    • Key diagnostic feature (sat < 85% w/o response to 100% FiO2)
    • Wavelength averaging by the pulse oximeter causes a falsely low O2 reading
    • Since there is no true decrease in O2 saturation, there will be no response to 100% FiO2
  • Severity of symptoms correlates closely to MetHb level and severity of impaired O2 delivery
  • Symptoms will be worse for any MetHb level in patients with baseline impairment of O2 delivery (i.e. CHF, pneumonia, COPD, anemia)
  • Methemoglobinemia Signs and Symptoms (Goldfrank’s Toxicology)

    MetHb: < 15%

    • May be asymptomatic
    • Low pulse oximeter reading
  • MetHb: 15-20%
    • Cyanosis (peripheral and central)
    • Fatigue
    • Chocolate brown colored blood
  • MetHb: 20-50%
    • Dyspnea
    • Headache
    • Exercise intolerance
    • Dizziness
    • Syncope
    • Weakness
  • MetHb: 50-70%
    • Tachypnea
    • Metabolic acidosis
    • Dysrhythmias
    • Seizures
    • CNS depression
    • Coma
  • MetHb > 70%
    • Severe hypoxemia
    • Death

Toxicologic Assessment of Cyanosis (Goldfrank’s Toxicology)


  • Source identification, removal (if possible) and decontamination
  • Basic Supportive Care
    • Provide 100% FiO2lack of response should raise suspicion of methemoglobinemia
    • Due to unreliability of pulse oximetry, O2 saturation should not be sole indication for advanced airway management
  • Diagnostic Testing
    • Blood gas
      • Venous blood gas (VBG) adequate
      • Arterial blood gas (AG) if obtained, will reveal a normal PaO2
    • Co-oximeter panel for MetHb level
      • Can use a venous or arterial sample
      • Half-life 1-3 hours
  • Obtain toxicology consultation (800-222-1222 in US)
  • Methylene Blue
    • Mechanism of action
      • Converted to cofactor for NADPH MetHb reductase
      • Helps increase reduction of MetHb
    • Which patients should get treatment?
      • MetHb < 25% with symptoms
        • Abnormal vital signs
        • Metabolic acidosis
        • End organ dysfunction (i.e. AMS, seizures)
      • MetHb > 25% regardless of symptoms
    • Dosing
      • 1-2 mg/kg IV
      • Medication can cause local painful reaction
        • Minimize with slower infusion (over 5 minutes)
        • Flush line after infusion completed
    • Clinical improvement should occur rapidly
    • Warning: Will cause transient decrease in puse-ox level due to color of medication

Take Home Points

  • Methemoglobinemia can result from exposure to a number of different medications. The most common are dapsone and topical anesthetic agents (i.e. benzocaine)
  • Consider the diagnosis in any patient with cyanosis and hypoxia that doesn’t respond to oxygen administration
  • Administer methylene blue to any patient with abnormal vital signs, metabolic acidosis, end organ dysfunction or, a serum level > 25%

Read More

Core EM: Episode 97.0 – Methemoglobinemia

Price DP. Chapter 127. Methemoglobin Inducers. In: Nelson LS, Lewin NA, Howland M, Hoffman RS, Goldfrank LR, Flomenbaum NE. eds. Goldfrank’s Toxicologic Emergencies, 9e New York, NY: McGraw-Hill; 2011.. Link