Now We Have Bad Blood: Oxidizers and Methemoglobinemia

Methemoglobinemia is a disorder of the red blood cells characterized by the oxidation of an iron atom in hemoglobin from Fe²⁺ to Fe³⁺ by an oxidant, which impairs hemoglobin’s capacity to deliver oxygen. Methemoglobinemia can be hereditary due to congenital enzyme deficiencies or acquired through exogenous oxidizers. In the emergency department, most cases of methemoglobinemia are acquired and linked to medications, chemicals, and illicit drugs that act as oxidizers. Common oxidizing agents include nitrates and nitrites, aniline and azo dyes (such as phenazopyridine), dapsone, sulfonamides, topical and local anesthetics (such as benzocaine, prilocaine, and lidocaine), and certain industrial compounds. Methemoglobin exists naturally in healthy individuals, but methemoglobinemia is defined as when serum methemoglobin levels exceed 1% in the blood. Under normal physiological circumstances, NAD+ serves as an electron donor to NADH to reduce Fe³⁺ to Fe²⁺ through the enzyme cytochrome b5 reductase in erythrocytes. A secondary mechanism for reducing Fe³⁺ to Fe²⁺ is through NADPH methemoglobin reductase, which becomes important when discussing treatment with methylene blue. Clinical manifestations arise from impaired oxygen-carrying capacity and reduced tissue oxygen delivery due to the leftward shift of the oxygen-hemoglobin dissociation curve. Patients may develop cyanosis unresponsive to supplemental oxygen, dyspnea, dizziness, headache, fatigue, and in more severe cases, seizures, coma, and dysrhythmias, which are seen with higher percentage levels of methemoglobin. One of the classic signs of methemoglobinemia is observed in arterial blood gas samples, which show a characteristic chocolate brown color. Management of methemoglobinemia begins with withdrawal of the offending oxidizing agent and administration of methylene blue if indicated. Patients with levels <30% may not require antidotal methylene blue therapy unless symptomatic. For patients with levels >30%, treatment with methylene blue is indicated. Methylene blue functions as an exogenous electron acceptor in the NADPH methemoglobin reductase pathway and promotes the rapid reduction of Fe³⁺ to Fe²⁺, leading to accelerated recovery. For treating methemoglobinemia, methylene blue is given at 1-2 mg/kg intravenously over 5 minutes and can be administered as needed if cyanosis does not improve after the first dose or if it recurs. Methylene blue is associated with hemolysis in patients with G6PD deficiency. However, for most patients presenting with methemoglobinemia, G6PD status is unknown, and there are few case reports that reveal true toxicity with methylene blue in patients with G6PD deficiency. It is important to consider other differential diagnoses that can mimic refractory hypoxemia if patients do not respond to methylene blue, such as sulfhemoglobinemia and hemoglobin M. In refractory methemoglobinemia cases, exchange transfusion and hyperbaric oxygen therapy can be used if methylene blue is ineffective.