What causes methemoglobinemia and how is it managed?

Methemoglobinemia Causes

Methemoglobinemia results from oxidative stress converting hemoglobin's iron from the ferrous (Fe²⁺) to ferric (Fe³⁺) state, caused by hereditary enzyme deficiencies, hemoglobin variants, or exposure to oxidizing medications and toxins. 1

Hereditary Causes

Enzyme Deficiencies:

• Cytochrome b5 reductase (CYB5R) deficiency is the most common hereditary form, transmitted as an autosomal recessive disorder 2
• First-degree relatives of patients with hereditary methemoglobinemia should be tested 1

Hemoglobin Variants:

• Hemoglobin M variants have abnormal hemoglobin structure that stabilizes iron in the ferric state 2
• Unstable hemoglobins (Hb Cheverly, Hb Evans) allow water to enter the heme pocket during stressor events, causing intermittent methemoglobinemia 1, 2

Acquired Causes

Medications (Most Common):

• Local anesthetics: benzocaine, prilocaine, lidocaine, tetracaine, cocaine mixed with aniline 1, 3
• Dapsone and sulfonamides (dapsone accounts for up to 45% of medication-induced cases) 1, 4, 5
• Nitrates and nitroglycerin 1
• Hydrochlorothiazide (sulfa drug family) 5

Environmental Toxins:

• Nitrate-contaminated well water (particularly dangerous for infants) 1, 2
• Aniline dyes 3
• Pesticides 1
• Copper, sulfate, chlorite, chloramines, and chlorates 1

Clinical Conditions:

• Metabolic acidosis from sepsis or diarrhea/dehydration in infants, where higher intestinal pH promotes growth of Gram-negative organisms (E. coli, Campylobacter jejuni) that convert dietary nitrates to nitrites 1
• Inhaled nitric oxide therapy for pulmonary hypertension in critically ill infants 1

High-Risk Populations

Infants are at substantially greater risk due to:

• Lower erythrocyte CYB5R activity (50%-60% of adult values) 1
• Higher levels of HbF which oxidizes more readily than adult hemoglobin 1
• Higher intestinal pH promoting nitrate-converting bacteria 1
• Exposure to local anesthetics during circumcision or benzocaine in teething gels 1

Management Approach

Immediate Assessment:

• Identify and remove the precipitating factor immediately 1
• If continuous exposure suspected (pesticide), medical personnel should wear protective equipment and decontaminate the patient 1
• Test for G6PD deficiency history before administering methylene blue, as methylene blue is ineffective and can worsen hemolysis in G6PD-deficient patients 1, 4

Treatment Algorithm Based on Severity:

Asymptomatic or minimally symptomatic patients:

• Monitor without treatment if MetHb <10-20% 1
• Provide oxygen supplementation as needed 1
• Infants with diarrhea-induced methemoglobinemia and MetHb <20% may improve with aggressive hydration and bicarbonate to correct acidosis alone 1

Symptomatic patients with MetHb >20% (or 10-30% with cardiac disease, anemia, or carbon monoxide poisoning):

• Methylene blue 1-2 mg/kg IV (0.2 mL/kg of 1% solution) infused over 3-5 minutes is first-line treatment 1, 2, 4
• Repeat dose at 1 mg/kg if symptoms persist after 30-60 minutes 1
• MetHb levels should normalize within 1 hour 1
• For long-acting oxidants (dapsone), repeat dosing every 6-8 hours for 2-3 days or continuous IV infusion of 0.10-0.25 mg/kg/hr 1
• Total dose should not exceed 7 mg/kg due to risk of worsening methemoglobinemia 1

Alternative Treatments (when methylene blue contraindicated):

• Ascorbic acid 0.2-1.0 g/day orally in divided doses for chronic management 1
• Ascorbic acid can be given orally, intramuscularly, or IV for acute cases 1, 6
• Risk of sodium oxalate nephrolithiasis with chronic administration 1

Refractory Cases:

• Therapeutic whole blood exchange transfusion (81.6% survival rate in MB-refractory patients) 1
• Hyperbaric oxygen therapy 1, 6

Critical Pitfalls to Avoid

Do NOT use methylene blue in:

• G6PD deficiency patients - it is ineffective and can cause severe hemolytic anemia and paradoxically worsen methemoglobinemia 1, 4
• Hemoglobin M or unstable hemoglobin disorders - reducing ability is normal and iron oxidation is stabilized by globin chains, making MB and ascorbic acid ineffective 1

Do NOT perform phlebotomy in patients with polycythemia secondary to hemoglobin disorders, as higher erythrocyte mass allows normal tissue oxygenation 1

Ensure adequate glucose availability for endogenous reducing enzymes and NADPH formation via hexose monophosphate shunt, which is necessary for methylene blue effectiveness 1