Discussion:
Methemoglobinemia is defined as an increased methemoglobin level in the
blood. The underlying mechanism includes changing the hemoglobin heme
iron from a ferrous to a ferric state which eventually may lead to
decreased oxygen delivery to the tissues (1). Drugs rarely induce
methemoglobinemia when given to a healthy patient. However, some of the
oxidizing drugs may have the capability to convert normal hemoglobin to
methemoglobin. For instance, some antimicrobials have been reported to
cause methemoglobinemia, such as dapsone, sulfonamides, chloroquine,
nitrofurantoin and clofazimine (2). After a thorough workup and
medication review, we confirmed that there were no other contributing
factors for the development of methemoglobinemia except exposure to
SMX/TMP.
SMX/TMP is a sulfonamide derivative that is used as an antibacterial
drug for the treatment of various infectious diseases. It can be given
an oral or intravenous dosage forms. SMX/TMP is rapidly and completely
absorbed after oral administration with a large volume of distribution
through bodily fluid. It is metabolized mainly by the liver and excreted
via renal clearance. The hematological side effects of SMX/TMP include
aplastic anemia, leukopenia, hemolytic anemia, thrombocytopenia, and
eosinophilia (3).
The risk factors for methemoglobinemia with oxidizing agents include
patients with medical conditions such as renal failure, anemia, sickle
cell disease, sepsis, lung disease and taking large doses of SMX/TMP for
a prolonged period (2). Because the patient developed VAP due to
stenotrophomonas maltophilia, he was started on a high dose of SMX/TMP
at a dose of 5 mg per kg given every 6 hours.
Methemoglobinemia is a rare disease that is difficult to diagnose.
Therefore, any patient with unexplained cyanosis and hypoxia that does
not improve with supplemental oxygen with normal calculated arterial pO2
should be suspected of methemoglobinemia. The symptoms may vary from
being asymptomatic to cyanosis, dyspnea, or metabolic acidosis and may
eventually lead to cardiovascular collapse and death (4). Similarly, our
patient developed cyanosis, metabolic acidosis and hypoxia that did not
improve with increasing oxygen support.
The cornerstone of management for patients with acquired
methemoglobinemia is to stop the offending agent and to establish
appropriate supportive care, such as hydration for hypotension and
ventilatory support for respiratory compromise. Methylene blue is
considered the drug of choice for symptomatic acute methemoglobinemia.
Ascorbic acid has been reported to be beneficial in methemoglobinemia
and should be used when methylene blue is contraindicated or
inaccessible (4-5).
We have found only four cases of methemoglobinemia induced by SMX/TMP in
pediatric patients (6-7-8-9). Three of them received SMX/TMP combined
with another oxidizing agent and the fourth case received SMX/TMP as
prophylaxis for more than two weeks (8). In our case, methemoglobinemia
occurred within a few days of starting SMX/TMP therapy and was resolved
rapidly after cessation of SMX/TMP therapy.