Erythrocytes are constantly exposed to oxidative stress from normal metabolism. If the mechanisms that defend against oxidative stress are overwhelmed, the oxygen-carrying ferrous ion (Fe2+) of the heme group is oxidized to the ferric state (Fe3+). This converts hemoglobin to methemoglobin, a non-oxygen-binding form of hemoglobin that binds a water molecule instead of oxygen. Spontaneous formation of methemoglobin is counteracted by the protective enzyme systems cytochrome-b5 reductase (major pathway) and NADPH methemoglobin reductase (minor pathway). These pathways normally maintain methemoglobin levels at <1% of the total hemoglobin in healthy people18,47,48,71. Exposure to exogenous oxidizing drugs and their metabolites (such as benzocaine and dapsone) may accelerate the rate of formation of methemoglobin up to 1000-fold47, overwhelming the protective enzyme systems and acutely increasing methemoglobin levels36,65.
The presence of a ferric ion or ions on 1 or more heme groups causes the entire hemoglobin molecule to change conformation, shifting the oxygen-dissociation curve to the left36,71. The combined effect of less oxygen being carried and released at the tissues may cause acute severe functional anemia. Therefore, a patient with a hemoglobin level of 10 g/dL who has 50% in the methemoglobin form has only 5 g/dL of functional hemoglobin32,121. Cyanosis is observed in patients with methemoglobin concentrations ≥1.5 g/dL27,32,71. The characteristic chocolate-brown blood is diagnostic at the bedside (Figure 1)41,44. Increasing levels of methemoglobin interfere with pulse oximetry readings, reporting lower measured oxygen saturation than the calculated oxygen saturation yielded from the arterial blood gas5,112. This oxygen "saturation gap" may also be a diagnostic clue5,32. Methylene blue, the treatment for methemoglobinemia, acts as a cofactor to NADPH methemoglobin reductase, accelerating its activity and increasing the rate of conversion of methemoglobin to hemoglobin18.
Drugs that are ubiquitous in the hospital and outpatient setting may cause acquired methemoglobinemia (Table 1). Severe cases may lead to morbidity and mortality because of attendant tissue hypoxia. Delayed diagnosis of methemoglobinemia may lead to continued exposure of patients to the etiologic agent. Only the co-oximetry test can accurately detect the presence of abnormal and normal forms of hemoglobin by measuring the methemoglobin, carboxyhemoglobin, and oxyhemoglobin and reporting them as a percentage of the total hemoglobin concentration73. Healthy patients who are not anemic usually have few symptoms with methemoglobin levels <15%32,47. Levels of 20%-30% may cause mental status changes, headache, fatigue, exercise intolerance, dizziness, and syncope32,47. Levels greater than 50% may result in dysrhythmias, seizures, coma, and death32,47. Patients with comorbidities such as anemia, cardiovascular disease, lung disease, sepsis, or the presence of other abnormal hemoglobin species (eg, carboxyhemoglobin, sulfehemoglobin, or sickle hemoglobin) may experience moderate to severe symptoms at much lower levels32. Pediatric patients under 6 months old are at increased risk of developing methemoglobinemia in the setting of gastroenteritis, dehydration, and sepsis32.
In this paper, we explore the extent of diagnosed methemoglobinemia at 2 large teaching hospitals, attempt to identify the etiologies, and describe the patient characteristics of the affected individuals.
The Johns Hopkins Bayview Medical Center (JHBMC) and the Johns Hopkins Hospital (JHH) have a total of 1300 inpatient beds. All co-oximetry data from July 1, 1999, to October 25, 2002, were screened for methemoglobin levels >1.5%. Methemoglobinemia is defined as a methemoglobin level >1.5% in hospitalized patients2,3,78,107. In healthy subjects, methemoglobin levels do not exceed 1%. Methemoglobin levels between 1% and 2% were considered clinically insignificant and therefore were not investigated extensively. Some patients had serial co-oximetry tests performed over the course of hours or days. Only the peak methemoglobin percentage for each patient is described since the peak level was considered the most clinically relevant. We reviewed electronic medical records and paper charts for 138 cases of methemoglobinemia >2% and extracted all relevant clinical information (Table 2). Suspect medications (see Table 1) and the dates and times of administration were noted from the nursing and pharmacy records. Correct identification of the inciting drug was surmised from decreased serial methemoglobin levels, clinical improvement after withdrawal of the drug, and/or treatment with methylene blue. In 5 severe cases where documentation of events was inadequate, we communicated personally with the treating medical team. In some cases we could not determine the etiology of methemoglobinemia because the condition was unrecognized and therefore untreated. In these cases, the etiology was classified as "unknown" (Table 3).
Chiron Ciba-Corning Model 855 and Instrumentation Laboratories Model 682 blood gas analyzers measured methemoglobin percentage. To ensure accuracy of measurements, blood gas analyzers are calibrated weekly using a low- and high-level hemoglobin dye mix. One patient specimen is analyzed across each of 4 blood gas analyzers in each hospital to verify concordance on a weekly basis. In addition, 3 levels of control material are assayed every 8 hours. Every 4 months the American College of Pathologists surveys the blood gas analyzers with 5 challenge specimens.
The institutional review board approved this study.
Two clinical cases are described below to illustrate the range of presentations and diagnostic challenges of acquired methemoglobinemia when concomitant cardiopulmonary conditions are present or suspected.
A 52-year-old man was admitted to the hospital because of increasing dyspnea on exertion. As part of the evaluation, a transesophageal echocardiogram was performed to rule out a patent foramen ovale or other intracardiac shunt. Before the test, 20% benzocaine spray (Hurricaine Topical Anesthetic spray, Beutlich Pharmaceuticals, Waukegan, IL) was administered to anesthetize the posterior pharynx. Shortly after the procedure the patient became even more dyspneic, was intubated, and remained cyanotic despite pH of 7.37, PaO2 of 248 mm Hg, PaCO2 of 60 mm Hg, and calculated oxygen saturation (SaO2) of 99% on 100% oxygen. The oxygen saturation measured by pulse oximetry (SpO2) was 75%. The calculated oxygen saturation gap (arterial blood gas-calculated SaO2 − pulse oximetry-measured SpO2) was 24%. Co-oximetry showed a methemoglobin level of 51% and hemoglobin of 11.6 g/dL. Only 49% (5.7 g/dL) was functioning to carry and unload oxygen because 51% of hemoglobin (5.9 g/dL) was in the methemoglobin form. This acute drop in the patient's functional hemoglobin from 11.7 g/dL to 5.7 g/dL coupled with his known lung disease severely compromised his ability to oxygenate tissues. Methylene blue was administered intravenously and quickly reversed the methemoglobinemia. Despite therapy, respiratory failure, renal failure, liver dysfunction, and deteriorating mental status ensued, and the patient died after a cardiac arrest.
A 34-year-old man with acquired immunodeficiency syndrome (AIDS) and a CD4 count of 178/mm3 presented to his physician with several weeks of progressively worsening dyspnea on exertion such that climbing a flight of stairs had become difficult. He reported no cough, fever, or chills. One of his medications was dapsone (100 mg by mouth daily) for Pneumocystis carinii pneumonia prophylaxis that had been initiated 3 months earlier. Physical exam was notable only for cyanotic extremities. His resting pulse oximetry (SpO2) was 89%, arterial blood gas PaO2 was 59 mm Hg, PaCO2 was 37 mm Hg, and arterial blood gas-calculated SaO2 was 91% on room air. The calculated oxygen saturation gap was 2%. He was admitted to the hospital for evaluation of hypoxemia and for treatment of presumed Pneumocystis carinii pneumonia. The work-up, including chest X-ray, chest computed tomography (CT) scan, ventilation-perfusion scan, transthoracic echocardiogram, bronchoalveolar lavage, and culture, was negative for pathology. On the second hospital day, a co-oximetry test was performed and revealed a methemoglobin level of 12.1%, and the patient was diagnosed with acquired methemoglobinemia. He had a modest decrease in his functional hemoglobin from 13 g/dL to 11.4 g/dL since 12.1% was methemoglobin (1.6 g/dL). Dapsone was discontinued and pentamidine was started for Pneumocystis carinii pneumonia prophylaxis. Within 24 hours his oxygen saturation returned to normal, and dyspnea and cyanosis resolved. He had no recurrence of cyanosis or dyspnea on follow-up exams.
A total of 5248 co-oximetry tests were performed on 2167 patients during the 28 months reviewed. Of these, 3221 co-oximetry tests were performed on 1496 patients at JHBMC and 2027 co-oximetry tests on 671 patients at JHH. There were 660 co-oximetry test results with methemoglobin levels >1.5% in 414 patients. Thus, 12.5% of all co-oximetry tests and 19.1% of all patients who had a co-oximetry test showed elevated methemoglobin levels. Of these, 149 co-oximetry tests in 87 patients were from JHBMC and 511 co-oximetry tests in 327 patients were from JHH. Therefore, at JHBMC 4.6% of co-oximetry tests and 5.8% of patients tested showed elevated methemoglobin levels. At JHH, 25.2% of co-oximetry tests and 48.7% of patients tested showed elevated methemoglobin levels. The different distribution of positive tests between the 2 hospitals may be a reflection of the greater number of negative co-oximetry tests performed at the JHBMC in the cardiac catheterization lab, and the greater number of positive tests secondary to dapsone in the JHH patient population. For comparison, 358,805 arterial blood gas tests were performed in this academic teaching hospital system during the same time period.
One hundred thirty-eight patients with peak methemoglobin levels >2% were identified. The mean peak methemoglobin level was 8.4% (range, 2.1%-60.1%). The average age of patients with methemoglobinemia was 43.4 years (see Table 2). The youngest affected patient was aged 4 days and the oldest, 86 years. Forty-five percent of patients were female. Ninety-five percent of the women and 94% of the men were anemic at the time of the elevated methemoglobin, defined as hemoglobin <12 g/dL for women and <14 g/dL for men.
Methemoglobinemia occurred in virtually all locations of the hospital (see Table 2). The reasons for ordering co-oximetry tests varied based on the area of the hospital and the clinical context. In the intensive care units and the in-patient surgery, medicine, and pediatrics floors, co-oximetry tests were ordered to evaluate cyanosis and dyspnea. Co-oximetry tests were ordered in outpatient dermatology, rheumatology, and human immunodeficiency virus (HIV) clinics to detect methemoglobinemia in dyspneic patients on long-term dapsone treatment. Methemoglobinemia was sometimes found incidentally. For example, 32 cases were identified intra- or post-operatively, where co-oximetry tests were commonly ordered by anesthesiologists to obtain an immediate hemoglobin level to monitor blood loss or to evaluate cyanosis. Two patients with methemoglobinemia were identified during cardiac catheterizations. The hemoglobin concentration obtained from serial co-oximetry tests during cardiac catheterization is used in the Fick equation to calculate cardiac output. There were many cases in which the rationale for ordering co-oximetry testing could not be determined based on chart review.
Five of the most severe adult cases of acquired methemoglobinemia were caused by topical 20% benzocaine spray, with a mean peak methemoglobin level of 43.8% (range, 19.1%-60.1%) (see Table 3). In this group there was 1 fatality (Case 1), and 3 near-fatalities. The most common etiology of acquired methemoglobinemia was dapsone, with a mean peak methemoglobin level of 7.6%, accounting for 42% of all cases. Dapsone was primarily being used for Pneumocystis carinii prophylaxis in patients who were immunocompromised from AIDS, chemotherapy, or immunosuppressive drugs. However, 8 patients were taking dapsone for treatment of dermatologic disorders. In 56 cases of mild methemoglobinemia (mean peak, 3.6%), the etiology could not be determined based on chart review; 22 of these were detected incidentally in the operating room during long surgical procedures, and 10 were observed during the postoperative recovery period.
There were 11 pediatric patients (<12 yr) affected, with a mean peak methemoglobin of 22% (median, 15.5%; range, 2.8%-59.5%). Six of these patients, infants with a mean age of 30 days, were dehydrated. Dehydration occurred in the setting of gastroenteritis, sepsis, or caretaker neglect. Three pediatric patients with leukemia developed methemoglobinemia related to dapsone use for Pneumocystis carinii prophylaxis. Two pediatric cases of methemoglobinemia were detected during surgery. The 3 most severe cases were treated with methylene blue and hydration. The remaining 8 patients were treated with intravenous hydration, or discontinuation of dapsone, or were untreated.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a known, albeit rare, risk factor for acquired methemoglobinemia7,49,50. Of the 138 cases of methemoglobinemia, only 5 patients were tested for G6PD deficiency, 1 of the whom was found to be G6PD deficient.
Thirty-three (94%) of 35 patients with methemoglobinemia >8% had documented clinically significant signs and symptoms that were thought to be related to acquired methemoglobinemia. These symptoms included hypoxia, dyspnea, tachypnea, cyanosis, fatigue, change in mental status, headache, and chest pressure. Twelve of these 35 cases were treated with methylene blue and withdrawal of the offending drug, 9 cases were treated by withdrawal of the offending drug alone, 8 patients received no treatment, and 6 pediatric patients were treated with hydration.
Discontinuation of dapsone occurred in 18 (17.5%) of the 42 mild cases of dapsone-associated methemoglobinemia, and 2 of these were treated with methylene blue. In the mildest case of symptomatic methemoglobinemia treated with methylene blue, the patient had a peak level of 4.7%. This patient, with chronic lymphocytic leukemia and autoimmune hemolytic anemia, was taking dapsone for Pneumocystis carinii pneumonia prophylaxis. Two dermatologic patients with peak methemoglobin levels of 3.6% and 6.5%, respectively, were treated with cimetidine and the dapsone was continued at a reduced dosage.
Acquired methemoglobinemia is fairly common and causes morbidity and mortality in both the inpatient and outpatient settings. Drugs that may induce methemoglobinemia are widely used in clinical settings. Acquired methemoglobinemia is often unrecognized and thus untreated. The current study serves to identify the incidence of methemoglobinemia among patients who had co-oximetry performed over 28 months at an academic institution and to characterize the clinically significant cases. To our knowledge, this is the largest study of the problem.
In the current study, almost all patients with peak methemoglobin of 8% or higher had documented symptoms consistent with methemoglobinemia (see Table 2). Rapid recognition of methemoglobinemia and treatment with methylene blue may decrease morbidity. There was often a significant delay in the treatment of acquired methemoglobinemia. Arterial blood gas technicians who noticed the chocolate-colored blood and performed a co-oximetry test to confirm the diagnosis of methemoglobinemia detected 3 severe cases after benzocaine exposure. In other cases, extensive evaluation for other etiologies of cyanosis and dyspnea were performed before methemoglobinemia was considered, as in Case 2, described above.
The co-oximetry test is sensitive, inexpensive, and relatively noninvasive. Co-oximetry testing should be ordered for symptomatic patients with a recent history of exposure to 1 of the suspect drugs listed in Table 1. The decision-making process of when to treat acquired methemoglobinemia is somewhat analogous to that of transfusing an anemic patient. The underlying etiology, severity of symptoms, comorbidities, and potential for organ damage from tissue hypoxia guide treatment more than the absolute methemoglobin level. Previous treatment recommendations were based on healthy, young people32. While healthy patients may not become symptomatic until methemoglobin levels exceed 15%47, patients with concurrent hematologic, cardiovascular, or pulmonary disease have symptoms at much lower levels32,121.
Mild symptoms may be adequately treated with supplemental oxygen to maximize the oxygen-carrying capacity of remaining normal hemoglobin and with discontinuation of the causative medication. Red blood cells' cytochrome-b5 reductase pathway may reduce the methemoglobin to hemoglobin at a rate of approximately 15% per hour in healthy individuals, assuming no ongoing methemoglobin production28. Chronic low-level methemoglobinemia such as that often caused by dapsone has been reported to be partially controlled with cimetidine, which inhibits cytochrome P-450 conversion to the oxidizing metabolite responsible for the methemoglobinemia14. However, cimetidine works slowly, and therefore has no place in the management of acute symptomatic acquired methemoglobinemia32.
Moderate to severe symptoms may be further treated with methylene blue 1% solution (10 mg/mL) 1-2 mg/kg administered intravenously slowly over 5 minutes followed by intravenous flush with normal saline32. The treatment goals include resolution of symptoms and the reversion to a normal methemoglobin level. Improvement of cyanosis is a poor marker for adequate treatment. Serial methemoglobin levels are more reliable to monitor adequate response to treatment. Repeat methylene blue doses may be necessary44. Rebound methemoglobinemia up to 12 hours post-methylene blue treatment has been reported due to continued absorption of the inciting drug, toxic intermediate metabolites, and prolonged half-life in the setting of renal and/or liver dysfunction32,91,94. If symptoms persist despite adequate treatment, further work-up for additional etiologies of the patient's symptoms is indicated. Critical cases of methemoglobinemia may require hemodialysis or exchange transfusion therapy11,37,108.
Anemia may be a risk factor for acquired methemoglobinemia. Ninety-four percent of the patients with methemoglobinemia in the current study were anemic. Anemic patients may be more sensitive to symptoms of methemoglobinemia because of their lower functional hemoglobin reserve. Severe methemoglobinemia itself is associated with Heinz body hemolysis secondary to oxidative stress on the erythrocyte32,44. Also, dapsone is known to cause hemolytic anemia in some patients32.
Benzocaine spray was implicated in 5 cases of severe methemoglobinemia during the study period (see Table 3). Benzocaine spray gains rapid direct access to the blood stream through the highly vascular pharyngeal mucosa5. The amount of drug administered varies with the length of time the valve of the spray can is depressed. The manufacturer recommends 1 spray of the drug in a less-than-1-second burst. Three 1-second sprays administer a dose of up to 600 mg93. The current spray can does not allow consistent administration of the proper amount of the drug, which may have been a contributing factor in the 5 severe cases of methemoglobinemia caused by benzocaine spray. Benzocaine spray has been removed from the formulary of the pharmacies at JHBMC as a result of several cases of severe benzocaine-induced methemoglobinemia.
Several limitations of this study should be considered. First, the 414 patients with methemoglobin levels >1.5% are almost certainly an underrepresentation of the true number of cases of methemoglobinemia that occurred during the study period. One-quarter of the methemoglobinemia cases with methemoglobin >2% in this study were discovered incidentally. This occurred primarily perioperatively or in the cardiac catheterization lab when the co-oximetry test was used to evaluate other data provided by the test, such as the hemoglobin and/or oxyhemoglobin concentration. With large numbers of patients with HIV taking dapsone for Pneumocystis carinii pneumonia prophylaxis, the incidence may increase further. Second, the etiology of the methemoglobinemia could not be established in a number of patients based on chart review due to documentation that was inadequate. Third, co-oximetry testing is only performed with physicians' orders. Although performing co-oximetry testing on all patients being tested for arterial blood gases would provide better data about the incidence of methemoglobinemia (both acquired and congenital), the cost is prohibitive. If co-oximetry tests had been performed on every blood aliquot sent for arterial blood gas analysis during the 28-month study, the incurred cost at $25.00 per test would have been approximately $9 million. Finally, the technical limitation of the blood gas analyzers to measure methemoglobin is a source of potential bias.
Primary prevention efforts have the potential to reduce the morbidity and mortality associated with this condition. Strategies that may be effective include the following: 1) educating physicians about the incidence of methemoglobinemia, the culprit etiologies, the signs and symptoms, and the implications of "saturation gap" in patients monitored with SpO2; 2) instituting an automatic alert on co-oximetry reports for methemoglobin levels >2%; 3) training physicians and arterial blood gas technicians to look for the characteristic chocolate-brown color of blood containing methemoglobin and to order a co-oximetry test for such patients; and 4) discontinuing the use of 20% benzocaine spray.
The authors thank blood-gas technicians Lisa Glorioso, Gary Paxton, and Dan Sennett for their exemplary service to the patients of JHBMC. We gratefully acknowledge the assistance of Dr. John Boitnott with data collection for this study and Dr. Ali Mansouri for his insights.
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