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, sulfonamides, dapsone, and local anesthetics (Table II-37). 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 may be used recreationally for their alleged sexual enhancement properties. Oxides of nitrogen and other oxidant combustion products make smoke inhalation an important potential cause of methemoglobinemia.

1. Methemoglobin inducers act by oxidizing the iron atom in hemoglobin from the ferrous (Fe²⁺) to ferric (Fe³⁺) state. This abnormal hemoglobin is incapable of carrying oxygen, resulting in a functional anemia. In addition, the shape of the oxygen-hemoglobin dissociation curve is altered (shifted to the left), aggravating cellular hypoxia.
2. Methemoglobinemia does not directly cause hemolysis; however, many oxidizing agents that induce methemoglobinemia 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 serum methemoglobin levels (Table II-38).

1. Signs and symptoms are due to 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. Typically, mild methemoglobinemia (<15-20%) is well tolerated and will resolve spontaneously. In patients with pre-existing anemia, symptoms may occur at lower methemoglobin levels. Continued metabolism of long-acting parent compounds (eg, dapsone) to oxidant intermediates can lead to prolonged effects.

A patient with mild-to-moderate methemoglobinemia appears markedly cyanotic yet may be relatively asymptomatic. The arterial oxygen partial pressure (PO₂) is normal. The diagnosis is suggested by the finding of “chocolate brown” blood (dry a drop of blood on filter paper and compare with normal blood), which is usually apparent when the methemoglobin level exceeds 15%. Differential diagnosis includes other causes of cellular hypoxia (eg, carbon monoxide, cyanide, and hydrogen sulfide) and sulfhemoglobinemia.

1. Specific levels. Co-oximetry directly measures oxygen saturation and methemoglobin percentages (measure as soon as possible because levels fall rapidly in vitro).
   1. Note: Sulfhemoglobin and the antidote methylene blue can both lead to erroneous co-oximeter measurements; a dose of 2 mg/kg methylene blue can lead to a false-positive methemoglobin reading of approximately 15%.
   2. Routine arterial blood gas machines measure the serum PO₂ (which is normal) and calculate a falsely normal oxygen saturation in the face of methemoglobinemia.
   3. Routine 2-wavelength pulse oximetry is not reliable; it does not accurately reflect the degree of hypoxemia in a patient with severe methemoglobinemia (or sulfhemoglobinemia) and may appear falsely low in a patient who has been given methylene blue. Newer multi-wavelength pulse oximetry devices may be able to better assess methemoglobin, but their reliability compared to co-oximetry remains uncertain.
2. Other useful laboratory studies include electrolytes and glucose. Consider testing for G6PD deficiency. If hemolysis is suspected, add CBC, haptoglobin, bilirubin (total and direct), peripheral smear, and urinalysis dipstick for occult blood (free hemoglobin is positive) and urine bilirubin and urobilinogen. With substantial hemolysis, carboxyhemoglobin levels may be elevated in the 5-10% range.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen.
   2. Usually, mild methemoglobinemia (<15-20%) will resolve spontaneously and requires no intervention.
2. Specific drugs and antidotes
   1. Methylene blue is indicated in symptomatic patients with methemoglobin levels higher than 20% or for those in whom even minimal compromise of oxygen-carrying capacity is potentially harmful (eg, pre-existing anemia, congestive heart failure, lung disease, acute coronary syndrome). Administer methylene blue, 1-2 mg/kg (0.1-0.2 mL/kg of 1% solution), over several minutes. Caution: Methylene blue can slightly worsen methemoglobinemia when given in excessive amounts (>7 mg/kg). In patients with G6PD deficiency, it may substantially worsen methemoglobinemia and cause hemolysis.
   2. Ascorbic acid, which can reverse methemoglobin by an alternate metabolic pathway, is of minimal use acutely because of its slow onset of action.
3. Decontamination depends on the specific agent involved.
4. Enhanced elimination
   1. If methylene blue is contraindicated (eg, G6PD deficiency) or has not been effective, red blood cell transfusion or exchange transfusion may be necessary in patients with severe methemoglobinemia.
   2. Hyperbaric oxygen is theoretically capable of supplying sufficient oxygen independently of hemoglobin and may be useful in extremely serious cases that do not respond rapidly to antidotal treatment.