What causes methemoglobinemia and how is it treated?

Causes and Treatment of Methemoglobinemia

Methemoglobinemia is primarily caused by oxidative stress that converts hemoglobin's iron from ferrous (Fe²⁺) to ferric (Fe³⁺) state, rendering it unable to bind oxygen, and is treated with methylene blue as first-line therapy for symptomatic cases. 1

Causes of Methemoglobinemia

Congenital Causes

• Cytochrome b5 reductase (CYB5R) deficiency - most common hereditary form 1
• Hemoglobin M variants - abnormal hemoglobin structure that stabilizes iron in ferric state 1
• Unstable hemoglobins (e.g., Hb Cheverly, Hb Evans) - allow water to enter the heme pocket during stressor events 1

Acquired Causes (Most Common)

• Medications:

  • Local anesthetics: benzocaine, lidocaine, prilocaine, articaine 1, 2
  • Antimicrobials: dapsone, sulfonamides, trimethoprim 1, 3
  • Other drugs: phenazopyridine, chloroquine, primaquine, rasburicase, cyclophosphamide, flutamide, metoclopramide 1
  • Nitrate derivatives: nitroglycerin, nitroprusside, amyl nitrite, nitric oxide 1
  • Hydrochlorothiazide (rare) 4

• Chemical exposures:

  • Industrial products: aniline dyes, naphthalene, aminophenols 1
  • Pesticides and herbicides 1
  • Chlorates, bromates 1

• Environmental factors:

  • Nitrate-contaminated well water (particularly dangerous for infants and pregnant women) 1
  • Foods grown in areas with nitrate-contaminated groundwater 1

• Clinical conditions:

  • Infections (can exacerbate methemoglobinemia) 1
  • Metabolic acidosis from sepsis or diarrhea (especially in infants) 5

Clinical Presentation

• Cyanosis unresponsive to oxygen therapy is the hallmark sign 6, 7
• Symptoms correlate with methemoglobin levels 1:
  • Asymptomatic or mild symptoms: <15% methemoglobin
  • Headache, fatigue, dizziness: 15-30% methemoglobin
  • Tachycardia, weakness, confusion: 30-50% methemoglobin
  • Arrhythmias, seizures, coma: 50-70% methemoglobin
  • Death: >70% methemoglobin
• Chocolate-colored blood on blood draw 7
• Discrepancy between pulse oximetry readings and arterial blood gas oxygen saturation 1

Diagnosis

• Co-oximetry is the gold standard for diagnosis 6, 7
• Arterial blood gas showing normal PaO2 with low calculated oxygen saturation 6
• Testing for G6PD deficiency before administering methylene blue 5

Treatment Algorithm

Asymptomatic or Mildly Symptomatic Patients

• Remove the offending agent 5
• Provide supplemental oxygen 5
• Monitor methemoglobin levels 5

Symptomatic Patients with Methemoglobin >20% or Any Level with Symptoms

1. First-line treatment: Methylene Blue

   • Dosing: 1-2 mg/kg IV (0.2 mL/kg of 1% solution) over 3-5 minutes 5, 3
   • May repeat at 1 mg/kg if methemoglobin doesn't decrease within 30-60 minutes 5
   • Do not exceed total dose of 7 mg/kg due to risk of worsening methemoglobinemia 5
   • Expected normalization of levels within 1 hour 5
   • For long-acting oxidants: repeat dosing every 6-8 hours for 2-3 days or continuous IV infusion of 0.10-0.25 mg/kg/hr 5

2. Contraindications to Methylene Blue:

   • G6PD deficiency - can cause hemolytic anemia and worsen methemoglobinemia 5, 3
   • Hemoglobin M variants - methylene blue is ineffective 1

3. Alternative/Adjunctive Treatments:

   • Ascorbic Acid (Vitamin C):
     • Treatment of choice when methylene blue is contraindicated 1
     • Adult dosing ranges from 0.5-10g in various regimens 1
     • For chronic management: 0.2-1.0 g/day orally in divided doses 1
     • Note: Reaction rate is slow and may take 24+ hours to lower methemoglobin levels 1

4. Rescue Therapies for Refractory Cases:

   • Exchange transfusion - especially if methemoglobinemia worsens after methylene blue 1
   • Hyperbaric oxygen therapy - may be reasonable when methylene blue is ineffective 1
   • Not recommended: N-acetylcysteine and ascorbic acid alone for acute, severe cases 1

Special Considerations

• Infants and children:

  • More susceptible due to lower erythrocyte CYB5R activity 5
  • For infants with methemoglobinemia due to diarrhea and acidosis: aggressive hydration and bicarbonate correction 5
  • Monitor closely when receiving inhaled nitric oxide therapy 5

• Hereditary methemoglobinemia:

  • Treatment often for cosmetic reasons (cyanosis) 1
  • Oral methylene blue 100-300 mg daily with dose adjustment based on levels 1
  • Ascorbic acid 0.2-1.0 g/day orally in divided doses 1
  • Medical alert system recommended 1
  • Test first-degree relatives 1

Prevention

• Avoid known triggers in susceptible individuals 1
• Promptly treat infections and other conditions that may increase methemoglobin levels 1
• Avoid well water or food from areas with nitrate-contaminated groundwater 1
• Consider prophylactic measures before surgery in patients with known methemoglobinemia 1