Numerous drugs can cause acquired methemoglobinemia when administered in a relative overdose (Table 1
). Infants, especially when premature, are particularly susceptible due to lower erythrocyte cytochrome b5 reductase activity (50 to 60% of adult values). Thus, methemoglobinemia may develop after a standard dose of the inciting drug. Congenital deficiencies in the erythrocyte enzyme systems, most commonly b5 reductase, lead to inherited methemoglobinemias. In patients with acquired methemoglobinemia, there is a disruption in the erythrocyte reductive metabolic pathways. An inciting agent oxidizes normal ferrous hemoglobin to the ferric form (ie, to metHb). metHb has no oxygen-carrying capacity and, under physiologic conditions, is quickly converted to oxyhemoglobin by Nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), thereby keeping its concentration to < 1%. Ascorbic acid and glutathione help by inactivating the oxidants. Overwhelming these reductive systems results in excessive metHb levels (Fig 234
). Precise data on the incidence of the iatrogenic causes of acquired methemoglobinemia are lacking, however, local anesthetics are among the most frequently cited in published case reports. Nevertheless, drug-induced methemoglobinemia remains a rare condition when one considers the relatively widespread use of some of the inciting agents. A review quotes 58 case reports since the first publication of a report of benzocaine-induced methemoglobinemia in 1950. Excessive metHb levels (ie, > 15%) often produce asymptomatic cyanosis that is unresponsive to therapy with supplemental O2. With metHb levels of > 20 to 30%, most patients will show symptoms of fatigue, weakness, dizziness, anxiety, nausea, and vomiting. A metHb level of > 45% leads to tissue ischemia presenting as arrhythmias, seizures, acidosis, stupor, and coma. A metHb level of > 70% is invariably fatal.