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, some pesticides (indoxacarb, metaflumizone, propanil), antimalarial agents, rasburicase, sulfonamides, dapsone, and local anesthetics (exposure to these can occur topically) (Table II–39). 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 Graphic Jump Location TABLE II–39.METHEMOGLOBINEMIA (SELECTED CAUSES) ||Download (.pdf) TABLE II–39. METHEMOGLOBINEMIA (SELECTED CAUSES)
Nitrites and nitrates
Industrial Chemicals and Pesticides
MECHANISM OF TOXICITY
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.
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).
The dose required to induce methemoglobinemia is highly variable and depends on the substance and the route of exposure. 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.
The severity of symptoms usually correlates with measured methemoglobin levels (Table II–40).
++ Table Graphic Jump Location TABLE II–40.METHEMOGLOBIN LEVELS ||Download (.pdf) TABLE II–40. METHEMOGLOBIN LEVELS
|Methemoglobin Level (%)a ||Typical Symptoms |
|<15 ||Often asymptomatic |
|15–20 ||Cyanosis, mild symptoms |
|20–45 ||Marked cyanosis, moderate symptoms |
|45–70 ||Severe cyanosis, severe symptoms |
|>70 ||Usually lethal |
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.
Typically, mild methemoglobinemia ...