Methemoglobinemia

By Ilene B. Anderson, PharmD; and Susan Y. Kim, PharmD

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Treatment

Once a diagnosis of Mhgb has been made, it is important to recognize that cyanosis alone in an otherwise asymptomatic Mhgb patient does not necessarily require antidotal treatment. Removal of the offending agent is often the only treatment needed. Decontamination of skin and mucous membranes (for dermal exposures), activated charcoal for recent ingestions, and multiple-dose activated charcoal for drugs with long half-lives and enterohepatic recirculation, such as dapsone,¹⁹ are very important for preventing prolonged toxicity. Dextrose is essential for the glycolysis needed for production of NADH in erythrocytes, and it should be administered as soon as possible.

Patients with Mhgb levels > 30% or symptomatic patients with lower levels may be treated with methylene blue. Patients with underlying cardiovascular disease or anemia are candidates for treatment at lower Mhgb levels. Methylene blue is actually a potent oxidizer that is reduced to leukomethylene blue by NADPH-methemoglobin reductase. Leukomethylene blue then reduces methemoglobin, for which it has a high affinity, regenerating hemoglobin. The dose of methylene blue is 1 to 2 mg/kg of body weight administered IV over 3 to 5 min. Rapid disappearance of cyanosis should be noted within 30 min to 1 h. If not, a repeat dose of 1 mg/kg can be given, cautiously.²⁰ Patients who do not respond to methylene blue may have glucose-6-phosphate dehydrogenase (G6PD)²¹ or NADPH-methemoglobin reductase deficiencies or hemoglobin M, or may be suffering from sulfhemoglobinemia.

A potentially dangerous adverse reaction to methylene blue can occur in patients with G6PD deficiency. The sole source of NADPH in the erythrocyte is the hexose monophosphate shunt, of which G6PD is a key enzyme. Patients with G6PD deficiency are unable to produce NADPH normally in the erythrocytes. Therefore, they may not be able to convert methylene blue to leukomethylene blue, the active form of the antidote, rendering methylene blue ineffective for treatment of Mhgb. In addition, because methylene blue itself is an oxidizer, it can exacerbate oxidative stress in patients with G6PD deficiency, causing hemolysis and/or worsening Mhgb. Exchange transfusion may be the most effective option for G6PD-deficient patients with life-threatening Mhgb.¹

Even in patients without erythrocyte enzyme abnormalities, methylene blue may exacerbate Heinz body hemolytic anemia when used to treat patients who have taken drugs that have strong potential for causing hemolysis, such as dapsone.²² Intra-amniotic injections of methylene blue have caused hemolytic anemia in neonates, one of whom received only 3.6 mg/kg.²³ IV methylene blue used as a dye to aid in the removal of pancreatic tumors resulted in Mhgb, even at a dose of 5 mg/kg.²⁴ Treatment of chronic cyanosis from hereditary Mhgb is usually instituted for cosmetic reasons. In this context, oral ascorbic acid, 300 to 600 mg/d divided into three or four doses, has been advocated.²⁵ Use of ascorbic acid alone is not appropriate for treatment of acute, acquired Mhgb. Hyperbaric oxygen therapy was shown to improve survival in rats with sodium nitrite-induced Mhgb, but its role in human poisoning is unclear.

Treatment of hemolysis is directed toward preserving the patientÕs renal function with IV fluid hydration and, in the case of massive overdoses, administration of IV sodium bicarbonate. Treatment of sulfhemoglobinemia consists of removal of the offending agent and supportive care. Methylene blue is ineffective in treating sulfhemoglobinemia. In severe cases, exchange transfusion may be utilized.

 

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