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HISTORY AND EPIDEMIOLOGY

Methemoglobinemia is a disorder of the red blood cells (RBCs). Exposure to various xenobiotics can adversely affect the RBC membrane and intracellular metabolism and, interfere with hemoglobin function. Methemoglobin occurs when the iron atom in hemoglobin loses one electron to an oxidant, and the ferrous (Fe2+) or reduced state of iron is transformed into the ferric (Fe3+) or oxidized state. Although methemoglobin is always present at low concentrations in the body, methemoglobinemia is defined herein as an abnormal elevation of the methemoglobin level above 1%. The ubiquity of oxidants, both in the environment and xenobiotics prescribed in the hospital, has increased the number of cases of reported methemoglobinemia.

Methemoglobin was first described by Felix Hoppe-Seyler in 1864.42 Subsequently, in 1891, a case of transient drug-induced methemoglobinemia was reported.85 In the late 1930s, methemoglobinemia was recognized as a predictable adverse effect of sulfanilamide use, and methylene blue was recommended for treatment of the ensuing cyanosis.56,125 Some authors even recommended concurrent use of methylene blue when sulfanilamides were used.125 Methylene blue was used prophylactically during general surgery to treat an individual with congenital methemoglobinemia.7,26 In 1948, an enzyme identified as coenzyme 1 was reported in six patients in two families who had idiopathic methemoglobinemia. The defect in coenzyme 1 (nicotinamide adenine dinucleotide {NADH} methemoglobin reductase) caused cyanosis in the absence of cardiopulmonary disease and responded to ascorbic acid.44

Methemoglobinemia is either hereditary or acquired. The hereditary types are rare and grouped into four types depending on their clinical manifestations. To date there are only several hundred reported cases.57,115 Although the frequency with which xenobiotic-induced methemoglobinemia occurs is unknown, the American Association of Poison Control Centers’ annual data over the past 5 years reports approximately 100 yearly uses of methylene blue as an antidote. These data substantially underestimate the incidence of this poisoning because poison control centers are not notified in most cases (Chap. 130).

Methemoglobinemia is relatively common and generally produces no clinical findings. Cooximetry data collected at two teaching hospitals noted a significant number of elevated methemoglobin levels.4 Of a total of 5,248 cooximetry tests over 28 months on 1,267 patients, 660 tests revealed methemoglobin levels above 1.5% in 414 patients (some patients had more than one test). Thus, 12.5% of all tests and 19.1% of all patients who had cooximetry performed had an abnormal methemoglobin level. A total of 138 patients with peak methemoglobin levels greater than 2% were identified. The mean peak methemoglobin level was 8.4% (range, 2.1%–60.1%), and the patients ranged from 4 days to 86 years of age.4

Benzocaine spray accounted for the most seriously poisoned patients (n = 5), with a mean peak methemoglobin level of 43.8% (range, 19.1%–60.1%).4 Dapsone accounted for the largest number of cases (n = 58), ...

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