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.