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Methemoglobin is an oxidized form of hemoglobin. Many oxidant chemicals and drugs are capable of inducing methemoglobinemia. Selected agents include nitrites and nitrates, bromates and chlorates, aniline derivatives, antimalarial agents, dapsone, propanil (an herbicide), sulfonamides, and local anesthetics (Table II–35). High-risk occupations include chemical and munitions work. An important environmental source for methemoglobinemia in infants is nitrate-contaminated well water. Amyl nitrite and butyl nitrite are abused for their alleged sexual enhancement properties. Oxides of nitrogen and other oxidant combustion products make smoke inhalation an important potential cause of methemoglobinemia.

Table II-35 Methemoglobinemia (Selected Causes)

  1. Mechanism of toxicity

    1. Methemoglobin inducers act by oxidizing ferrous (Fe2+) to ferric (Fe3+) hemoglobin. This abnormal hemoglobin is incapable of carrying oxygen, inducing a functional anemia. In addition, the shape of the oxygen-hemoglobin dissociation curve is altered, aggravating cellular hypoxia.

    2. Methemoglobinemia does not cause hemolysis directly; however, many oxidizing agents that induce methemoglobinemia may also cause hemolysis through either hemoglobin (Heinz body) or cell membrane effects, particularly in patients with low tolerance for oxidative stress (eg, those with glucose-6-phosphate dehydrogenase [G6PD] deficiency).

  2. Toxic dose. The ingested dose or inhaled air level of toxin required to induce methemoglobinemia is highly variable. Neonates and persons with congenital methemoglobin reductase deficiency or G6PD deficiency have an impaired ability to regenerate normal hemoglobin and are therefore more likely to accumulate methemoglobin after oxidant exposure. Concomitant hemolysis suggests either heavy oxidant exposure or increased cell vulnerability.

  3. Clinical presentation. The severity of symptoms usually correlates with measured methemoglobin levels (Table II–36).

    Table II-36 Methemoglobin Levels
    1. Symptoms and signs are caused by decreased blood oxygen content and cellular hypoxia and include headache, dizziness, and nausea; with greater compromise, these progress to dyspnea, confusion, seizures, and coma. Even at low levels, skin discoloration (“chocolate cyanosis”), especially of the nails, lips, and ears, can be striking.

    2. Usually, mild methemoglobinemia (<15–20%) is well tolerated and will resolve spontaneously. This presumes that preexisting anemia has not already compromised the patient, thus making a smaller proportional impairment more clinically relevant. Continued metabolism of oxidant compounds from a long-acting parent compound (eg, dapsone) may lead to prolonged effects (2–3 days).

  4. Diagnosis. A patient with mild to moderate ...

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