Case 2: Discussion
Definition of Methemoglobinemia
Methemoglobinemia describes a condition in which iron in the hemoglobin tetramer becomes transformed from the normal ferrous (Fe2+) state to the oxidized ferric (Fe3+) state (Figure 1). The iron in the Fe3+ state does not effectively bind oxygen and the remaining Fe2+ in the hemoglobin tetramer binds oxygen with enhanced affinity (Figure 2), causing a "left shift" in the oxygen dissociation curve. The dual effect of methemoglobinemia—poor oxygen binding and decreased oxygen release—can rapidly lead to tissue hypoxia, cyanosis, and, in some instances, death. The normal concentration of methemoglobin is less than 2%. Although multiple pathways exist for converting methemoglobin back to hemoglobin, the cytochrome b5 reductase pathway is the pathway of primary importance under normal physiologic conditions. Methemoglobinemia is most often acquired, occurring from exposure to oxidizing medications or toxins; rarely methemoglobinemia results from a congenital deficiency of the cytochrome b5 reductase enzyme[2,3,4].
Causes of Methemoglobinemia in HIV-Infected Persons
Acquired methemoglobinemia is generally the consequence of ingestion or contact of mucous membranes to oxidizing agents that accelerate the formation of methemoglobin. The most frequent culprit, both in the general population and in HIV-infected patients, is dapsone, which is commonly used as a second-line agent for Pneumocystis pneumonia prophylaxis, as well as for a variety of dermatological conditions. In one retrospective analysis involving two tertiary care hospitals over 28 months, 138 cases of methemoglobinemia were identified (defined as methemoglobin concentrations greater than 2%). Dapsone was the most common cause, accounting for 42% of cases. The second most common cause in the general population is topical anesthetics, such as benzocaine or xylocaine spray—agents commonly used for medical procedures that require an oral topical anesthetic. Other medications potentially used by HIV-infected patients that are known to cause methemoglobinemia include chloroquine, primaquine, metoclopramide, rifampin, sulfasalazine and sulfonamide-based antibiotics (though rare with modern sulfonamide-based antibiotics). In addition, trimethoprim may increase dapsone levels and this interaction may cause a patient to develop methemoglobinemia.
Dapsone is a sulfone antibiotic that is metabolized by cytochrome p450 to hydroxylamines, which oxidizes hemoglobin to methemoglobin. Methemoglobinemia can occur at standard doses of dapsone used for Pneumocystis pneumonia prophylaxis. Dapsone may cause other side effects, including hemolytic anemia, agranulocytosis, and aplastic anemia. The exact incidence, timing, and risk factors of methemoglobinemia secondary to dapsone have not been well defined in HIV-infected populations. In one study of children with acute lymphoblastic leukemia taking dapsone for Pneumocystis prophylaxis, symptomatic methemoglobinemia developed in 3 (20%) of 15 children and the average onset was 6.6 weeks (range 3.5 to 10 weeks) after starting dapsone. In an attempt to elucidate risk factors for development of methemoglobinemia, the investigators measured levels of the cytochrome b5 reductase enzyme levels, and all three patients who developed symptomatic methemoglobinemia had lower levels of the enzyme than the other patients, and two were heterozygous for congenital cytochrome b5 reductase deficiency. These findings suggest that heterozygosity for the congenital form of methemoglobinemia may be a risk factor for development of acquired methemoglobinemia. Other known risk factors include concomitant use of multiple drugs known to cause the condition, and anemia. The incidence of methemoglobinemia in persons who take dapsone does not correlate with glucose 6-phosphate dehydrogenase (G6PD) status.
Clinical Manifestations of Methemoglobinemia
The clinical manifestations associated with methemoglobinemia usually correlated with the methemogobin concentration and the percentage of total hemoglobin (Figure 3). Initially, patients typically develop a grayish-brown or blue cyanosis, which usually develops when methemoglobin concentrations exceed 10 to 15%. Patients characteristically develop brownish lips and mucous membranes and are often referred to as having "chocolate cyanosis." In patients with no underlying lung disease or co-morbid conditions, additional symptoms of methemoglobinemia generally arise only when the concentration reaches 20 to 30%, though symptoms can develop at lower levels, particularly in anemic patients, since their oxygen carrying capacity is already compromised [1,3]. Prominent symptoms of methemoglobinemia, such as headache, tachycardia, fatigue, weakness, dizziness, and dyspnea, are usually noted at concentrations around 20 to 45%. Levels greater than 45% lead to acidosis, cardiac dysrhythmias, heart failure, seizures, and coma. As methemoglobin concentrations increase, intravascular hemolysis and jaundice may also develop. Mortality rates become high when levels surpass 70%[1,3]. Typically, the more rapid the methemoglobin levels rise, the more severe the symptoms[1,4].
Diagnosis of Methemoglobinemia
Several key findings point toward the diagnosis of methemoglobinemia. First, the diagnosis of methemoglobinemia should be suspected in a patient who appears cyanotic but has a normal PaO2 on arterial blood gas[2,4]. Second, the blood of a patient with methemoglobinemia will typically appear dark brown or chocolate-colored and will not turn red on exposure to air; normal oxygenated blood is red, deoxygenated blood blue, and blood that contains abnormal amounts of methemoglobin is a dark red-to brown color. Third, although pulse oximetry is not reliable for monitoring oxygen saturation in patients with methemoglobinemia, the diagnosis should be suspected in any patient with a "saturation gap" (an oxygen saturation that is significantly less on pulse oximetry than that calculated from the PaO2 on the arterial blood gas). Fourth, oxygen saturation on pulse oximetry generally decreases to a plateau around 85% in patients with methemoglobinemia, even with severe tissue hypoxemia. Levels of methemoglobin can be measured by co-oximetry; the use of co-oximetry is an accurate way to diagnose methemoglobinemia because co-oximetry measures light at 4 different wavelengths and can determine the concentration of methemoglobin compared to hemoglobin. Fresh specimens of blood should be used for this analysis since levels of methemoglobin often increase with storage.
Management of Methemoglobinemia
Patients with methemoglobinemia do not respond to high concentrations of oxygen because methemoglobin is an ineffective oxygen transporter. The mainstay of treatment is to discontinue the offending agent and administer intravenous methylene blue 1 to 2 mg/kg (as a 1% solution) for one dose given over five minutes, which may be repeated after 1 hour if symptoms persist[1,3]. Methylene blue acts as a cofactor for the enzyme NADPH-methemoglobin reductase. The drug accepts an electron from NADPH, which converts it to leukomethylene blue, which then donates an electron to methemoglobin, thus reducing it back to hemoglobin. Treatment with methylene blue is usually considered if methemoglobin levels are above 30% in an asymptomatic patient or above 20% in a symptomatic patient. If, however, the patient has concurrent anemia and is symptomatic at concentrations lower than 20%, treatment is warranted.
Adverse Effects of Methylene Blue
Potential side effects of methylene blue include dyspnea, chest pain, hemolysis, nausea, diarrhea, oral dysesthesias, restlessness, tremor, apprehension, pre-cordial pain, and a bluish-gray discoloration of the skin[1,3,6]. Methylene blue can cause paradoxical worsening of hemolytic anemia or methemoglobinemia in patients with G6PD deficiency (these patients do not have adequate levels of NADPH to reduce methylene blue to leukomethylene blue). For this reason, reports have warned that methylene blue may be ineffective or dangerous in patients with G6PD deficiency, and some experts recommend avoiding the use of methylene blue in patients with G6PD deficiency.
Response to Methylene Blue
Generally, patients have a rapid improvement in symptoms and a decrease in methemoglobin concentration. After methylene blue administration the methemoglobin concentration should be rechecked and methylene blue therapy discontinued once the methemoglobin concentration is less than 10% and the patient is asymptomatic. In addition, administering dextrose may be important since glycolysis is the major source of NADPH in erythrocytes, and NADPH is necessary for methylene blue to be effective. Hypoglycemic patients and even euglycemic patients should probably receive dextrose infusions to ensure that NADPH levels are sufficient. Although no clear recommendations exist for the management of methemoglobinemia refractory to methylene blue, possible strategies include use of exchange transfusion, hyperbaric oxygen therapy, and cimetidine[3,10,11].
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