An 87-year-old African-American woman with a history of peripheral vascular disease, hypertension, diabetes mellitus, chronic renal insufficiency, and mild dementia was admitted with gangrene of her right foot. She underwent a right below-knee amputation initially but subsequently required a right above-knee amputation due to poor stump healing. Her medications were amlodipine, hydralazine, metoprolol, famotidine, gabapentin, opioid analgesics, docusate, subcutaneous heparin, and she was on a course of ampicillin for a urinary tract infection. Six days postsurgery she became acutely short of breath with mild fever (99oF) and an oxygen saturation of 94% on 2 L/min of oxygen via nasal cannula. Chest auscultation revealed decreased breath sounds on the left. Chest radiograph revealed left lung atelectasis.
The patient was taken for therapeutic bronchoscopy the next morning. Her pharynx was sprayed with benzocaine as she was unable to gargle lidocaine. During the procedure she was given endobronchial lidocaine and acetylcysteine. The airways were patent and no endobronchial lesion was found. Thick secretions were seen and suctioned. Her oxygen saturation was stable during the procedure.
On transfer to the recovery room, the patient became cyanotic with a decrease in her level of consciousness, and her oxygen saturation dropped to 85% by pulse oximetry. She was placed on a nonrebreather mask, but her pulse oximeter reading remained at 85%. A repeat chest radiograph showed partial aeration of the left upper lobe. An arterial blood gas (ABG) demonstrated a pH of 7.41, pCO2 41 mm Hg, pO2 298 mm Hg, and oxygen saturation 99%. Cooximetry was requested and revealed a methemoglobin level of 57%. The patient received a 1 mg/kg dose of methylene blue intravenously. A repeat ABG with cooximetry done 1 hour later showed a methemoglobin level of 43%. A second 1 mg/kg dose of methylene blue was given and another hour later the methemoglobin level had dropped to 13%. The patient also showed clinical improvement with resolution of the cyanosis and return of her mental status to baseline.
Benzocaine (ethyl aminobenzoate) is a widely used topical anesthetic and is a recognized cause of methemoglobinemia. Although an infrequent complication, it can be potentially serious and even fatal. However, methemoglobinemia is not listed as a complication in the Physicians Desk Reference (PDR) nor the product inserts for some of the products containing benzocaine. Benzocaine is also contained in a variety of over-the-counter preparations (such as analgesic gels for teething) that are not listed in the PDR and methemoglobinemia has occurred with their use. It can pose a difficult diagnostic challenge if the physician is not aware of this effect of benzocaine, leading to a delay in reaching the correct diagnosis and in starting appropriate treatment.
A Medline search identified 71 case reports of benzocaine-induced methemoglobinemia. Review of listed references identified 18 additional case reports. The earliest reference to benzocaine-induced methemoglobinemia was by Ocklitz in 1949, who reported methemoglobin in two infants treated with benzocaine powder vaporized to the mouth for symptomatic relief of stomatitis (1). Table 1 lists the mode of administration of benzocaine for the reported cases. According to Severinghaus and coworkers (2) the Food and Drug Administration has 10 case reports of benzocaine-induced methemoglobinemia not listed in the medical literature.
Methemoglobin is formed when the deoxygenated heme molecule is oxidized from the ferrous to ferric state. Ferric iron is bound to either a water molecule at acid pH, or to a hydroxyl group at alkaline pH (3). At physiologic pH the acid form predominates. Methemoglobin is incapable of transporting oxygen and thus produces a functional anemia. In addition, the ferric heme group results in allosteric changes to the hemoglobin molecule which causes the ferrous heme moieties on the same hemoglobin tetramer to bind oxygen more tightly. The oxyhemoglobin dissociation curve is thus shifted to the left (4), further impeding oxygen delivery. This is known as the Darling-Roughton effect and bears similarity to the consequence of carbon monoxide poisoning. Normally small amounts of methemoglobin are continuously being formed, to a large extent by oxygen during the oxygenation-deoxygenation process of oxygen transport (autoxidation). Free ferrous heme in the blood is rapidly oxidized to ferric heme. However, as part of the hemoglobin molecule the heme moiety is embedded in a hydrophobic pocket that provides protection from rapid oxidation. It is estimated that approximately 3% of hemoglobin is autoxidized to methemoglobin daily (3). However, the concentration of methemoglobin is normally maintained below 1% of the total hemoglobin by two separate enzymatic reducing systems (3,5):
- The reduced nicotine adenine dinucleotide (NADH)-dependent cytochrome b5 methemoglobin reductase system in which NADH generated during glycolysis donates its hydrogen ion to cytochrome b5, which in turn reduces methemoglobin to hemoglobin. This system is responsible for almost 95% of the normal methemoglobin reducing activity in the body.
- The reduced nicotine adenine dinucleotide phosphate (NADPH)-dependent methemoglobin reductase system which reduces flavin; the reduced flavin in turn reduces methemoglobin. This pathway normally accounts for less than 5% of the normal methemoglobin reduction in the body, but in the presence of methylene blue this system is dramatically potentiated and can reduce large quantities of methemoglobin. The NADPH needed for this reaction is generated by the hexose monophosphate shunt.
Cellular antioxidants such as ascorbic acid and glutathione can directly reduce methemoglobin without the presence of any enzyme system, but under normal circumstances contribute little to methemoglobin reduction.
People living at high altitudes tend to have slightly higher levels of methemoglobin. Two possible reasons have been suggested. First, these individuals have a higher percentage of hemoglobin in the deoxygenated state. The iron moiety of deoxyhemoglobin lends itself more readily to oxidation than its oxyhemoglobin counterpart (6). Second, small amounts of oxygen have a greater oxidizing effect than large amounts (3). The clinical significance of this altitude effect is unknown.
CAUSES OF ACQUIRED METHEMOGLOBINEMIA
Exposure to certain drugs or chemicals can accelerate the rate of methemoglobin formation and result in acquired methemoglobinemia. More than 100 compounds have been implicated (7), some of which are listed in Table 2. Nitrites and aniline dyes are potent inducers, and the most frequent cause, of methemoglobinemia (8). Nitrates are also an important cause of methemoglobinemia but need first to be converted to nitrite by nitrate reductase producing bacteria (such as Escherichia coli, Pseudomonas aeruginosa, and Aerobacter aerogenes) in the gut or on the skin (9). Infants and children are more susceptible than adults (2,8) because: 1) fetal hemoglobin is more easily oxidized to methemoglobin; 2) newborns have lower levels of NADH-methemoglobin reductase and glutathione peroxidase activity than adults; 3) the pediatric exposure to the inducing agent represents a greater dose per kg body weight compared to adults; and 4) infants have higher gastric pH due to limited acid secretion, which allows bacterial proliferation and may thus increase conversion of nitrates to nitrites (10).
Aniline and its derivatives are found in many household products, such as ink, dye, shoe polish, paint, and varnish. It also has numerous commercial applications, such as the manufacture of pharmaceuticals, photographic developers and organic chemicals. Nitrites and nitrates are found in soil, fertilizers, room deodorizers, food additives, and preservatives, vegetables, and many pharmaceutical drugs and industrial compounds. Carrots, cabbage, beets, celery, lettuce, and spinach have the highest amounts of nitrates (9). Sodium nitrite has been inadvertently used as table salt with a resultant methemoglobinemia epidemic. Cases have also been reported with recreational use of inhalable nitrites, such as amyl, butyl, and isobutyl nitrites. There are many reports of cases resulting from well water contaminated with nitrites or nitrates being fed to infants, as well as from the use of contaminated water for home dialysis (11). It is estimated that approximately 4.5 million people (including some 66,000 infants) in rural America use water with nitrate levels that exceed the health advisory level (12). Silver nitrate applied on broken or denuded skin (e.g., burns) has also caused methemoglobinemia. Inhaled nitric oxide is now being used as a selective pulmonary vasodilator and has been associated with methemoglobin formation (13). Methemoglobin is induced intentionally with amyl or sodium nitrite in the treatment of cyanide or hydrogen sulfide poisoning.
Topical anesthetics (benzocaine, prilocaine, and, rarely, lidocaine) may also result in methemoglobinemia, generally from over-enthusiastic spraying of the oropharynx. Most formulations contain 14% to 20% of benzocaine. Just three 1-second sprays may deliver up to 600 mg of benzocaine (14). Benzocaine-containing surgical ointment is often used to lubricate endotracheal tube and rectal probes and has resulted in methemoglobin formation. There have also been cases reported with the use of both prescribed and over-the-counter preparations of benzocaine for toothaches and oral sores, application over skin that had lost its integrity, and accidental ingestion (usually by children).
Methemoglobinemia has occurred in victims of gas poisoning, fires, and exhaust fume poisoning; heat-induced hemoglobin denaturation and inhalation of nitrogen oxides have been suggested as causative factors (15). Methemoglobin formation can also occur in infants under 6 months of age who develop severe metabolic acidosis, most commonly as a result of diarrhea and dehydration (16). The exact cause is unclear, but no association with oxidant drugs has been established and the methemoglobinemia resolves with time, suggesting that it is not an inherited condition.
The hallmark of methemoglobinemia is central cyanosis. The cyanosis is more brown than blue and has classically been described as “chocolate-colored.” It usually becomes apparent at concentrations of methemoglobin above 15%. Symptoms depend on the percentage of methemoglobin present. Patients are usually asymptomatic until the concentration exceeds 20% to 30%. At levels between 20% and 50%, they may experience weakness, malaise, nausea, vomiting, headache, dyspnea, and tachycardia. Once levels exceed 50%, patients may develop lethargy, dizziness, and stupor. At these high levels there is inadequate oxygenation of tissues, which may result in acidosis, circulatory failure, cardiac arrhythmias, seizures, and coma. Levels above 70%, although rare, are associated with a high incidence of mortality (7,9).
The pulse oximeter can not be used to accurately assess oxygen saturation in a patient with methemoglobinemia (17,18). The pulse oximeter emits only two wavelengths of light: 660 nm and 940 nm. Oxyhemoglobin absorbs more light at 940 nm, whereas deoxyhemoglobin absorbs more light at 660 nm. The oxygen saturation is calculated with the presumption that other forms of hemoglobin are present only in very small quantities. The ratio of absorption of the two wavelengths of light is measured and related to oxygen saturation based on an in-built algorithm where a 660/940-nm absorption ratio of 0.43 correlates with 100% oxygen saturation, and a ratio of 1.0 with 85% saturation. Methemoglobin absorbs light equally at both these wavelengths, thus at high concentrations of methemoglobin the pulse oximeter will read 85% saturation regardless of the relative amounts of oxyhemoglobin and deoxyhemoglobin present. Low concentrations of methemoglobin (<10%) will produce similar qualitative effects on absorption at both light wavelengths, but a smaller quantitative effect at 940 nm resulting in an increase in the 660/940-nm ratio and thus underestimation of the oxygen saturation.
The ABG will typically show a normal arterial oxygen tension since it is dependent on the amount of dissolved oxygen and not on oxygen molecules bound to hemoglobin. A metabolic acidosis may be present, depending on the severity and duration of tissue hypoxia. It is important to note that routine ABG analysis does not measure the oxygen saturation, but calculates it from the measured oxygen tension and pH with the assumption that normal hemoglobin is present, and will be falsely high in methemoglobinemia. Cooximetry actually measures the various forms of hemoglobin in the blood and will not only provide a more accurate oxygen saturation but also measure methemoglobin level. Most hospitals do not routinely perform cooximetry on an ABG sample and this will need to be specifically requested. The difference between the calculated and measured oxygen saturations is called the saturation gap. Large saturation gaps (>5%) in arterial blood are almost always due to methemoglobinemia or carboxyhemoglobinemia and less commonly sulfhemoglobinemia (19).
The diagnosis should be considered in a patient who develops central cyanosis and has been exposed to benzocaine or one of the other drugs or chemicals known to cause methemoglobinemia. Measuring blood levels of the inducing agent is usually not necessary, but identifying it is important to prevent re-exposure. Characteristically the cyanosis does not respond to 100% oxygen therapy. A simple bedside test is to place a drop of the patient’s blood on a filter paper or paper towel (20). Dark blood due to deoxyhemoglobin will redden on exposure to air, whereas dark blood due to methemoglobin will not. Using a drop of control blood for comparison is helpful (21). However, the color of hemoglobin is dark brown only in acidic pH; it is reddish-brown in alkaline pH. As noted above, the diagnosis can be confirmed by multiple-wavelength cooximetry of an arterial blood sample. Most cooximeters, however, do not differentiate between sulfhemoglobin and methemoglobin since their peak absorbance is close (620 nm and 630 nm, respectively) and will report both as methemoglobin. A simple method of differentiating between the two is to repeat cooximetry after adding potassium or sodium cyanide to the blood sample. Cyanide combines with methemoglobin to form bright red cyanomethemoglobin which will no longer be read as methemoglobin on cooximetry; thus a persistent reading of methemoglobin can be attributed to sulfhemoglobin (or rarely hemoglobin M). Hyperlipidemia also interferes with cooximeter readings; triglyceride levels above 500 mg/dL will result in falsely elevated levels of methemoglobin (15). Methemoglobin levels have been shown to increase after death (22); therefore, postmortem measurement of methemoglobin concentrations will not correctly reflect its level before death. This carries implications in forensic pathology.
In general, there appears to be a low index of suspicion for this condition (14,21), which can result in considerable delay in diagnosis, unnecessary invasive investigations, and even therapeutic misadventure. Harley and colleages (21) described two neonates with acquired methemoglobinemia who typify this difficulty. Both infants had undergone cardiac catheterization for persistent cyanosis, with normal findings, before the diagnosis of methemoglobinemia was entertained.
Supportive care should be implemented as soon as methemoglobinemia is identified, including supplemental (100%) oxygen, ensuring airway patency and hemodynamic support. Further absorption of the toxic agent should be prevented, e.g., removal of any residual topical agent or gastric lavage and administration of activated charcoal in the case of oral ingestion. Some drugs undergo enterohepatic circulation and require repeated doses of activated charcoal to reduce the elimination half-life. Dapsone is one such drug for which activated charcoal may need to be given every 4 to 6 hours for up to 4 days. Decontamination of the skin may sometimes be required. Blood sample should be taken for evidence of hemolysis (hemoglobin, blood smear, Heinz body staining, and serum haptoglobin). An electrocardiogram should be obtained to look for myocardial ischemia. Although no specific data are available, some authors also recommend intravenous dextrose (16), because it is required for the production of NADPH via the hexose monophosphate shunt. In asymptomatic or mild cases no additional therapy is thought to be necessary, other than close observation. The half-life of methemoglobin is approximately 55 minutes (23). Once the inducing agent has been cleared, the methemoglobinemia will resolve in most cases, usually within 36 hours, due to the normal reducing mechanisms (19).
In more severe methemoglobinemia or in the presence of tissue hypoxia, anemia, cardiovascular instability, or central nervous system depression more aggressive medical therapy is required. Aggressive medical therapy may also be warranted in milder cases of methemoglobinemia in patients with coexisting medical problems (such as coronary artery disease or pulmonary insufficiency) who may be less able to tolerate a decrease in oxygen delivery (5). The total hemoglobin concentration must always be taken into consideration. For example, 20% methemoglobinemia, which is usually well tolerated in a healthy individual, occurring in a patient with baseline hemoglobin of 8 g/dL would reduce the effective hemoglobin to 6.4 g/dL and result in hypoxia more severe than expected for the degree of methemoglobinemia. In general, specific therapy is recommended when methemoglobin concentration exceeds 30% to 40%.
Methylene blue is the antidote for methemoglobinemia. It greatly accelerates the NADPH-dependent methemoglobin reductase system by acting as a cofactor (Figure 1). One to two mg/kg of a 1% solution is administered intravenously over 5 minutes. The slow infusion helps prevent a painful local response, and flushing the intravenous line after administering the drug also helps. A marked reduction in the methemoglobin concentration is usually seen within 30 to 60 minutes. Repeat doses may be given for persistent or recurrent methemoglobinemia, but the total dose should not exceed 7 mg/kg. Recurrence of methemoglobinemia after initial improvement may occur either due to inadequate decontamination of the inducing agent or cyclic production of methemoglobin by some drugs, such as aniline and dapsone. Both aniline and dapsone are metabolized to their respective hydroxylamine metabolites, and then to nitrosobenzene and nitrosodapsone, respectively, during methemoglobin formation. These nitroso-compounds are subsequently reduced back to the hydroxylamine metabolites by erythrocytic glutathione, thus enabling another round of methemoglobin induction. However, in aniline-induced methemoglobinemia, excessive methylene blue may enhance hemolysis, as both aniline and methylene blue can undergo coupled reactions with oxyhemoglobin to generate free radicals, and should be limited to no more than two doses (6,24). Continuous infusion of methylene blue (25) has been used for dapsone induced-methemoglobinemia which can persist for days as dapsone has a long half-life (average 30 hours). For obvious reasons, methylene blue is not indicated when methemoglobinemia is intentionally induced for the treatment of cyanide or hydrogen sulfide poisoning.
Methylene blue may discolor skin and mucous membranes (26), making assessment of cyanosis difficult. It also interferes with pulse oximeter readings (18,27). The absorption peak for methylene blue is 668 nm (28) and therefore it absorbs most of the 660-nm light emission from the pulse oximeter. The resulting increase in the 660/940-nm ratio will give spuriously low oxygen saturation readings. Therefore, repeat measurement of methemoglobin and oxygen saturation by cooximetry should usually be done before administering additional doses of methylene blue. Approximately 75% of methylene blue is excreted by the kidneys unchanged, and results in a blue-green discoloration of the urine. Side effects are uncommon but may include nausea, retrosternal chest pain, dizziness, tremor, tachycardia, hypertension, and urinary tract irritation. Infiltration of intravenous methylene blue is painful and can result in tissue necrosis. Electrocardiographic changes include ST-T wave changes and decrease in R wave amplitude (29). Mild hemolysis may occur and, rarely, a severe Heinz body hemolytic anemia occurs. Because of the potential of toxic effects, the decision to use methylene blue should be made carefully.
Methylene blue is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency for two reasons: 1) patients with G6PD deficiency have insufficient NADPH thus making methylene blue therapy ineffective; and 2) G6PD deficient individuals are more prone to methylene blue-induced hemolysis. However, in a symptomatic patient, it should not be withheld simply because a history of G6PD deficiency cannot be obtained. Some authors (15,16,19,29) suggest that judicious use of methylene blue may be warranted despite G6PD deficiency. With an estimated 200 million people worldwide having G6PD deficiency it is very likely that such patients have unknowingly been treated with methylene blue, yet reports of toxicity are few. In addition, some variants of G6PD retain partial enzyme activity (29) and may benefit from methylene blue. Thus, it is not possible to predict who will or will not respond to methylene blue and to what extent. It has been suggested that a lower dose of methylene blue (0.3 to 0.5 mg/kg) should be used in these patients and titrated upwards if effective (16).
In patients who do not respond to methylene blue, possible reasons for treatment failure include: 1) presence of G6PD deficiency; 2) NADPH methemoglobin reductase deficiency (rare); 3) oxidant drug may still be present (either due inadequate decontamination or a prolonged half-life) in the bloodstream with persistent methemoglobin formation; 4) presence of an abnormal hemoglobin other than methemoglobin, such as hemoglobin M or sulfhemoglobinemia; or 5) methylene blue may mask improvement and in very high doses may itself result in oxidation of hemoglobin to methemoglobin. There is no other specific therapy available if methylene blue fails, but a number of alternative therapeutic options may be attempted. Hyperbaric oxygen therapy may temporarily increase the delivery of dissolved oxygen (5,8,9), but may not be readily available and the duration of treatment is limited by the risk of oxygen therapy. Furthermore, hyperbaric oxygen has not demonstrated conclusive benefits in animal models (30). Ascorbic acid (300 to 1,000 mg/day intravenously in three to four divided doses) provides nonenzymatic reduction of methemoglobin and may be tried, but is slow and probably has little role in acute acquired methemoglobinemia (5,6,8). By inhibiting cytochrome P-450, cimetidine decreases methemoglobin fractions by 25% (31,32), thus increasing tolerance to chronic dapsone therapy. It may have some protective effect in an acute overdose as well. In severe cases with methemoglobin concentration above 70%, blood transfusion or exchange transfusion (5,6,8,9) may be indicated. Exchange transfusion not only replaces methemoglobin but also corrects hemolytic anemia and removes the absorbed toxin. Hemodialysis (5,6,7,19) may be considered to help remove the oxidant compound.
The current case highlights an unusual but potentially lethal complication of bronchoscopy, which has received little attention to date. However, the increasing use of procedures requiring local anesthesia of the posterior pharynx and the presence of benzocaine in a number of over-the-counter topical preparations requires heightened physician awareness for the dangers of methemoglobinemia. It should be suspected if cyanosis unresponsive to 100% oxygen develops suddenly, and the diagnosis confirmed by cooximetry. The majority of cases do not require specific treatment except for supportive care and removal of the inducing agent. Methylene blue is the specific antidote and is indicated in moderate to severe methemoglobinemia or if the patient has a concomitant medical condition that decreases tolerance to reduced oxygen delivery. Blood or exchange transfusion, hemodialysis or hyperbaric oxygen may be attempted in patients failing to respond to methylene blue.
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