Methemoglobinemia

Condition with life-threatening potential in which diminution of the oxygen-carrying capacity of circulating hemoglobin occurs due to conversion of some or all of the four iron species from the reduced ferrous [Fe²⁺] state to the oxidized ferric [Fe³⁺] state.

• Ferric iron is unable to bind and transport oxygen. Increased levels of methemoglobin results in functional anemia.

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Physiology

Methhaemoglobin metabolism:

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Aetiology

Congenital methemoglobinemia (rare):

• Autosomal recessive defects in enzyme cytochrome b5 reductase (CYB5R):
  • Congenital methemoglobinemia type I (only erythrocytes express defect)
  • Congenital methemoglobinemia type II (all cells express defect)
• Hemoglobin M disease: Autosomal dominant mutations in the genes that code for globin proteins collectively known as hemoglobins M. The mutation leads to easier oxidation of the iron to the ferric [Fe3+] state.
  • Multiple variants: Boston, Fort Ripley, Hyde Park, Iwate, Kankakee, Osaka, Saskatoon

Acquired methemoglobinemia (common):

Result of exposure to substances that cause oxidation of the hemoglobin either directly or indirectly. This exposure results in the production of methemoglobin that exceeds the body’s capacity to convert the iron within the hemoglobin back to its ferrous state.

Classic examples include patient exposure to benzocaine in endoscopy suite and infantile exposure to nitrites from well water.

• Direct oxidizing agents (e.g. benzocaine and prilocaine)
• Indirect oxidation (e.g. nitrates)
• Metabolic activation (e.g. aniline and dapsone)

Agents causing methemoglobinemia:

DAPSONE mnemonic

• Dapsone
• Anaesthetics
• Primaquine
• Sulfamethoxazole
• Others (eg. herbicides, pesticides)
• Nitroglycerin, nitroprusside
• Environmental (eg. nitrates in well water)

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Clinical features

Physiologic level of methemoglobin in the blood is 0-2%. Methemoglobin concentrations of 10-20% are tolerated well, but levels above this are often associated with symptoms. Levels above 70% may cause death. Symptoms also depend on the rapidity of its formation. Many patients with lifelong methemoglobinemia are asymptomatic, but patients exposed to drugs and toxins who abruptly develop the same levels of methemoglobinemia may be severely symptomatic.

Clinical spectrum:

The clinical presentation of methemoglobinemia is based on a spectrum illness that is associated with cyanosis, pallor, fatigue, weakness, headache, central nervous system depression, metabolic acidosis, seizures, dysrhythmias, coma, and death. The degree of symptom severity is multifactorial and depends on the patient’s percentage of methemoglobin, the rate at which methemoglobin was accumulated, the individual’s ability to intrinsically clear it, and the underlying health status of the patient.

Presents as dyspnea/cyanosis and hypoxemia refractory to supplemental oxygen, especially in the setting of exposure to a known oxidative agent.

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Diagnosis

Clinical diagnosis based on history and presenting symptoms, including hypoxemia refractory to supplemental oxygen and the likely presence of chocolate-colored blood.

Arterial/venous blood gas with co-oximetry:

Diagnotic test which speciates hemoglobin to determine the methemoglobin concentration and percentage

Pulse oximetry shows 80-85% irrespective of actual arterial saturation.

• Refractory hypoxemia
• Saturation gap
• Chocolate-colored blood

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Peripheral blood smear:

Show picture of hemolytic anaemia (may follow drug-induced methemoglobinemia, especially with exposure to dapsone, sulfasalazine, or phenacetin)

• Heinz bodies (precipitated hemoglobin or globin subunits due to denaturation of hemoglobin in erythrocytes)
• Fragmented RBCs

Differential diagnosis:

D/D of cyanosis:

• Anemia
• Asthma
• Congestive heart failure
• Cyanotic congenital heart disease
• Peripheral cyanosis
• Polycythemia
• Sulfhemoglobinemia

D/D of bluish skin discoloration also includes:

• Acrodermatitis enteropathica
• Amiodarone-induced skin pigmentation
• Argyria

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Management

Treatment of methemoglobinemia includes removal of the inciting agent and consideration of treatment with the antidote, methylene blue (tetramethylthionine chloride). Treatment decision should be made on clinical presentation and not withheld for confirmational laboratory values.

High flow oxygen:

Delivered by non-rebreather mask increases oxygen delivery to tissues and enhances the natural degradation of methemoglobin.

Methylene blue (tetramethylthionine chloride)

Antidote that works rapidly and effectively through its interaction with secondary pathway of methemoglobin reduction, where NADPH-MetHb reductase reduces methylene blue to leukomethylene blue using NADPH from the G6PD-dependent hexose monophosphate shunt. Leukomethylene blue then acts as an electron donor to reduce methemoglobin to hemoglobin.

• NOTE: Methylene blue is a MAOI and, when administered to a patient taking any other serotonergic drug, can lead to serotonin syndrome.