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Toxic Methemoglobinemia Caused by Topical Anesthetic Given Before Transesophageal Echocardiography
CASE REPORTS
Toxic Methemoglobinemia Caused by Topical Anesthetic Given Before Transesophageal Echocardiography Pamela A. Marcovitz, MD, Brian D. Williamson, MD, and William F. Armstrong, MD, FACC, Ann Arbor, Michigan
Transesophageal echocardiography was performed on a patient with critical aortic stenosis and severe three-vessel coronary artery disease. Immediately after the procedure the patient experienced marked cyanosis (oxygen saturation of 53%) secondary to methemoglobinemia (methemoglobin saturation of 45%). Toxic methemoglobinemia was thought to be caused by topical anesthetic. He responded dramatically to treatment with intravenous methylene blue. Toxic methemoglobinemia should be suspected in unexplained cyanosis occurring after trans esophageal echocardiography and other endoscopic procedures during which potentially causative agents have been used. (J AM Soc ECHOCARDIOGR 1991;4:615-8.)
T
oxic methemoglobinemia is a rare complication of treatment with a variety of medications, including topical anesthetics. Symptoms range from mild cyanosis to dyspnea, frank coma, and death. The diagnosis can be confusing, especially in the setting of serious heart disease. Acute toxic methemoglobinemia as a complication of treatment with topical benzocaine, lidocaine, or prilocaine has been reported most frequently in adults with congenital deficiency of methemoglobin reductase and in children after dental procedures. 1,2 It has been reported only rarely in adults without predisposing factors. A case is reported of toxic methemoglobinemia resulting from treatment with topical 20% benwcaine spray (Hurricane Topical Anesthetic Spray, Beutlich, Inc., Niles, Illinois) and topical lidocaine spray (10% Xylocaine Oral Spray, Astra Pharmaceutical Products, Inc., Westborough, Massachusetts) before transesophageal echocardiography in a patient without predisposition to methemoglobinemia.
CASE REPORT A 64-year-old man with a history of coronary artery disease and aortic stenosis was referred for transFrom the Division of Cardiology, Department of Internal Medicine, University of Michigan School of Medicine. Reprint requests: William F. Armstrong, MD, Director, Echocardiographic Laboratory, University of Michigan Medical Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0022. 27/1/29984
esophageal echocardiography. He had experienced lightheadedness and presyncope while playing golf approximately 3 weeks previously. Cardiac catheterization revealed severe three-vessel coronary artery disease and a peak-to-peak gradient across the aortic valve of 100 mm Hg. He was referred for coronary artery bypass grafting and aortic valve replacement. Preoperative pulmonary function studies revealed a forced vital capacity of 2. 79 L, forced expiratory volume in the first second of 2.34 L, and diffusing capacity 76% of predicted. Measurements of aortic root diameter obtained by transthoracic echocardiography were suboptimal. A transesophageal echocardiogram was therefore performed to provide accurate measurements of aortic diameter in anticipation of homograft valve replacement. Topical pharyngeal anesthesia was achieved with lidocaine spray (three to four metered sprays, for an estimated dose of 30 to 40 mg) and benzocaine spray (one to two sprays of 1 to 2 seconds, for an estimated dose of 330 mg). Midazolam (6 mg) was administered intravenously in divided doses over a period of 10 minutes before the scope was inserted. The transesophageal echocardiogram revealed no abnormality. Heart rate monitored continuously and blood pressure monitored at 5-minute intervals throughout the 20-minute study remained stable. Combined transthoracic and transesophageal studies revealed a stenotic aortic valve with a peak pressure gradient of 130 mm Hg, a mean pressure gradient of 81 mm Hg, and a calculated valve area of 0.5 cm2 • Left ventricular hypertrophy with normal left ven615
616
Journal of [hc Amcrican Sociery of Echocardiography
Marcovitz, Williamson , and Armstrong
tricular function was noted. After the esophageal probe was removed, the patient was noted to have marked cyanosis. Oxygen was administered by nasal cannula at 2 L/ min without resolution of cyanosis. Mter several minutes the patient sat upright and complained of dizziness and nausea. He denied chest pain or shortness of breath. Oxygen (100%) was administered by face mask. Finger pulse oximeter revealed an oxygen saturation of 86%. Blood pressure was 120/80 mm Hg, respiratory rate was 28/min, and heart rate was 95 beats/min. He appeared ashen and had mild mental confusion. There was no jugular venous distention. Examination of the chest revealed clear lung fields and a grade III/VI systolic crescendo/decrescendo murmur heard loudest at the right upper sternal border and radiating to the carotids. There was no gallop. The rest of the results of physical examination were unremarkable. An electrocardiogram revealed left ventricular hypertrophy. Chest radiography revealed mild cardiomegaly and clear lung fields without evidence of congestive heart failure. Venous blood samples were analyzed for complete blood count, electrolytes, glucose, blood urea nitrogen, creatinine, and creatinine phosphokinase. Arterial samples were a dark, muddy blue, and blood gases revealed a POz of 226 mm Hg, Peo z of 33 mm Hg, pH of 7.39, and Oz saturation of 53% . A pulse oximeter continued to display oxygen saturations of 80% to 90%. Repeat blood gas measurements were similar to the initial set. Because of the patient's marked cyanosis and low measured oxygen saturation in the absence of respiratory distress, instability in vital signs, or objective evidence of hypoxia by blood gas determination, a blood methemoglobin study was ordered and revealed a methemoglobin level of 45%. Low-dose methylene blue was administered at I mg / kg over 15 minutes. Repeat measurements of blood gases revealed POz of 230 mm Hg, Peo 2 of 41 mm Hg, pH of 7.38, Oz saturation of 96%, and methemoglobin level of2% on administration of60% inspired oxygen. Because of his history of critical aortic stenosis and coronary artery disease, he was admitted to the cardiac intensive care unit for observation. Serial measurements of creatinine phosphokinase ranged from 27 to 68 IU / L, and the electrocardiogram remained unchanged. He was discharged the following day in good condition. Subsequent hemoglobin electrophoresis revealed a normal hemoglobin pattern, with 96% hemoglobin Al and 3% hemoglobin A z . He subsequently underwent uneventful coronary artery bypass grafting and aortic
valve replacement. Anesthetics of the amide and ester classes were avoided. A methemoglobin level obtained after surgery was less than 1%. DISCUSSION
Topical anesthetics are commonly applied to the mucous membranes before endoscopy, bronchoscopy, and dental procedures. They are regarded as safe agents without appreciable systemic absorption when used in recommended doses on intact mucosa. Despite this, plasma concentrations similar to those seen with intravenous lidocaine have been noted 15 minutes after administering a laryngotracheal spray of local anesthetic in preparation for bronchoscopy.3 It is believed that the high vascularity of the tracheobronchial tree leads to absorption of this agent in quantities that produce significant blood levels. Two cases of acute methemoglobinemia after treatment with topical lidocaine have been reported, one after preparation of the larynx with a 2% lidocaine solution and the other after two separate applications of 4% lidocaine spray to the posterior pharynx I hour apart. 4 •5 In the former case, topical benzocaine spray combined with topical lidocaine was applied to injured mucosa. In the latter case, methemoglobinemia secondary to treatment with topical benzocaine spray had been diagnosed in the same patient less than 24 hours earlier, perhaps rendering the red cells more susceptible to a second oxidant stress. Our patient had no known disruption of his pharyngeal mucosa, but he did receive a combination of topical benzocaine and lidocaine, perhaps rendering him more susceptible to methemoglobinemia. A few cases of acute methemoglobinemia secondary to topical benwcaine have been reported, most of these in children, in adults with hereditary deficiency of methemoglobin reductase, or in patients with injured mucosa. 6 . 11 Significant systemic levels are believed to occur rarely after benzocaine anesthetic is applied in recommended doses to intact mucous membranes to prepare the pharynx for upper endoscopy. Methemoglobin is formed when ferrous iron (Fe 2 -t ), chelated to the prophyrin ring in heme, is converted to ferric iron (Fe 3 +) by endogenous or exogenous oxidizing agents. The methemoglobin molecule is unable to bind oxygen for transport, and there is a left shift in the hemoglobin / oxygen dissociation curve. Hence, whereas oxygen tension in blood is normal, its total content (measured as saturation) for tissue delivery is markedly decreased.
Volume 4 Number 6 November·December 1991
When methemoglobinemia is severe, the capacity of blood to transport oxygen may be reduced to a level below that necessary for sustaining organ function. The serum level of methemoglobin is normally maintained at less than 2% by NADH-methemoglobin reductase, in which NADH functions as an electron donoL In hereditary deficiency of the enzyme and with abnormal hemoglobin (hemoglobin M), chronically elevated levels in the range of 5% to 10% can be seen. Acquired methemoglobinemia occurs when the methemoglobin-reductase system is overwhelmed by oxidant drugs or toxic exposures. Acute, acquired forms of methemoglobin have been attributed to a variety of medications including amyl nitrate, intravenous nitroglycerin, sodium nitroprusside, antimalarials, aniline dyes, phenacetin, sulfonamides, lidocaine, benzocaine, and prilocaine. 1218 Children and those with methemoglobin reductase deficiency are more susceptible to acquired methemoglobinemia. Our patient had recently begun treatment with a long-acting nitrate preparation; otherwise he had no known predisposing factors. Although we were not able to perform the assay for NADH-methemoglobin reductase, a baseline methemoglobin level after surgery was not elevated and he had no history of cyanosis. Clinically methemoglobinemia is not apparent if levels remain at less than 10%; whereas at 10% to 15%, asymptomatic cyanosis is seen. At serum levels of35%, dyspnea owing to decreased oxygen carrying capacity, headache, and generalized weakness can result. At levels of 70%, profound cyanosis, coma, and death can OCCUL Treatment is typically not necessary for methemoglobin levels of 10% to 15% or less. At levels above 30%, treatment is initiated when symptoms are present. The treatment of choice is methylene blue, 1 to 2 mg/kg given intravenously over 5 to 15 minutes. Methylene blue reduces methemoglobin by donating reduced hydrogen to oxidized FE3+ in exchange for an electron picked up from NADPH through the NADPH reductase reaction. Under normal conditions NADH functions as the electron donor, but in the presence of an exogenous electron carrier such as methylene blue, NADPH becomes more active than NADH in donating electrons to oxidized hemoglobin. The oxidized hemoglobin is rapidly reduced, and methemoglobin levels generally fall to normal within 30 to 60 minutes after initiation of treatment with intravenous methylene blue. In severe life-threatening toxic methemoglobinemia that does not respond to intravenous methylene blue, exchange transfusion or dialysis may be necessary. Oral ascorbic acid will also reduce oxidized
Toxic methemoglobinemia
617
hemoglobin but should not be used in the acute setting. As demonstrated by this case, the diagnosis of methemoglobinemia can be confusing when pulse oximetry is used to monitor oxygen saturation. Spectroscopic methods cannot distinguish between methemoglobin and reduced hemoglobin. 19,20 Thus oxygen saturation by pulse oximeter may continue to read 80% to 90%, despite lower actual levels of saturated oxyhemoglobin. Additionally, many blood gas laboratories use a calculated rather than a measured value for oxygen saturation. When calculated rather than measured values are used, the oxygen saturations in arterial samples will agree with those on the pulse oximeter, confusing or delaying the diagnosis. Confusion will be greatest when dealing with patients, who, because of underlying lung or heart disease, have potential other causes for cyanOSIS. Our patient experienced acute cyanosis with an oxygen saturation of80% to 90% by pulse oximetry. Since he was known to have critical aortic stenosis, it was suspected that he had hypotension secondary to the use of midazolam and that he was in danger of impending hemodynamic collapse. However, a normal blood pressure, absence of respiratory distress, and lack of pulmonary edema on chest radiographs made this diagnosis unlikely. The diagnosis of toxic methemoglobinemia should be suspected in a patient with cyanosis occurring after transesophageal echocardiography or other endoscopic procedure who has received topical anesthetics and for whom more serious causes of hypoxia can be ruled out. The presence of cyanosis in the setting of a normal arterial oxygen with a low oxygen saturation on a measured arterial blood gas sample should alert one to the diagnosis of methemoglobinemia. Early identification of cyanosis during the procedure may be difficult since transesophageal echocardiography, unlike endoscopy, is performed in a darkened room. Expedient treatment can be lifesaving, particularly when there is coexistent heart disease. REFERENCES
1. Smith RP, Olson MV. Drug·induced methemoglobinemia. Semin Hematol 1973;10:253·68. 2. Ludwig Sc. Acute toxic methemoglobinemia following den· tal analgesia. Ann Emerg Med 1981;10:265·6. 3. Ritchie JM, Green NM. Local anesthetics. In: Goodman LS, Gilman, AG, eds. Goodman and Gilman's the pharmacologic basis of disease. 6th ed. New York: Macmillan Publishing Co, Inc, 1980:311.
618
Journal of the American Society of Echocardiography
Marcovitz, Williamson, and Armstrong
4. O'Donohue WI, Moss LM, Angelillo VA. Acute methemoglobinemia induced by topical benzocaine and lidocaine. Arch Intern Med 1980;140:1508-9. 5. Kotler RL, Hansen-Flaschen J, Casey MP. Severe methemoglobinemia after flexible fiberoptic bronchoscopy. Thorax 1989;44:234-5. 6. Collins JF. Methemoglobinemia as a complication of 20% benzocaine spray for endoscopy. Gastroenterology 1990; 98:211-3. 7. Buckley AB, Newman A. Methemoglobinemia occurring after the use of a 20% benzocaine topical anesthetic prior to gastroscopy. Gastrointest Endosc 1987;33:466-7. 8. Sandza JG, Roberts RW, Shaw RC, Connors JP. Symptomatic methemoglobinemia with a commonly used topical anesthetic, cetacaine. Ann Thorac Surg 1980;30: 187-90. 9. Grum DF, Rice TW. Methemoglobinemia from topical benzocaine. Cleve Clin J Med 1990;57:357-9. 10. Porter JL, Hillman JV. Benzocaine-induced methemoglobinemia. Journal of the American College of Emergency Physicians 1979;8:26-7. 11. Townes PL, Geersma MA, White MR. Benzocaine-induced methemoglobinemia. Am J Dis Child 1977;131:697-8. 12. Kaplan KJ, Taber M, Teagarden JR, Parker M, Davison R.
13.
14.
15.
16. 17.
18. 19.
20.
Association of methemoglobinemia and intravenous nitroglycerin administration. Am J CardioI1985;55:181-3. Gibson G, Hunter JB, Raabe DS Jr, Manjoney DL, Ittleman FD. Methemoglobinemia produced by high-dose intravenous nitroglycerin. Ann Intern Med 1982;96:615-6. Harrison MR. Toxic methemoglobinemia. A case of acute nitrobenzene and aniline poisoning treated by exchange transfusion. Anaesthesia 1977;32:270-2. Bojar RM, Rastegar H, Payne DD, et al. Methemoglobinemia from intravenous nitroglycerin: a word of caution. Ann Thoracic Surg 1987;43:332-4. Pierce JM, Nielsen MS. Acute acquired methemoglobinemia after amyl nitrate poisoning. Br Med J 1989;198:1566. Kreutz RW, Kinni ME. Life threatening toxic methemoglobinemia induced by prilocaine. Oral Surg Oral Med Oral Pathol 1983;56:480-2. Finch CA. Methemoglobinemia and sulfhemoglobinemia. N Engl J Med 1948;239:470-8. Rieder HV, Frei FJ, Zbinden AM, Thomson DA. Pulse oximetry in methemoglobinemia. Failure to detect low oxygen saturation. Anaesthesia 1989;44:326-7. Watcha MF, Connor MT, Hing AV. Pulse oximetry in methemoglobinemia. Am J Dis Child 1989;143:845-7.
Toxic Methemoglobinemia Caused by Topical Anesthetic Given Before Transesophageal Echocardiography Pamela A. Marcovitz, MD, Brian D. Williamson, MD, and William F. Armstrong, MD, FACC, Ann Arbor, Michigan
Transesophageal echocardiography was performed on a patient with critical aortic stenosis and severe three-vessel coronary artery disease. Immediately after the procedure the patient experienced marked cyanosis (oxygen saturation of 53%) secondary to methemoglobinemia (methemoglobin saturation of 45%). Toxic methemoglobinemia was thought to be caused by topical anesthetic. He responded dramatically to treatment with intravenous methylene blue. Toxic methemoglobinemia should be suspected in unexplained cyanosis occurring after trans esophageal echocardiography and other endoscopic procedures during which potentially causative agents have been used. (J AM Soc ECHOCARDIOGR 1991;4:615-8.)
T
oxic methemoglobinemia is a rare complication of treatment with a variety of medications, including topical anesthetics. Symptoms range from mild cyanosis to dyspnea, frank coma, and death. The diagnosis can be confusing, especially in the setting of serious heart disease. Acute toxic methemoglobinemia as a complication of treatment with topical benzocaine, lidocaine, or prilocaine has been reported most frequently in adults with congenital deficiency of methemoglobin reductase and in children after dental procedures. 1,2 It has been reported only rarely in adults without predisposing factors. A case is reported of toxic methemoglobinemia resulting from treatment with topical 20% benwcaine spray (Hurricane Topical Anesthetic Spray, Beutlich, Inc., Niles, Illinois) and topical lidocaine spray (10% Xylocaine Oral Spray, Astra Pharmaceutical Products, Inc., Westborough, Massachusetts) before transesophageal echocardiography in a patient without predisposition to methemoglobinemia.
CASE REPORT A 64-year-old man with a history of coronary artery disease and aortic stenosis was referred for transFrom the Division of Cardiology, Department of Internal Medicine, University of Michigan School of Medicine. Reprint requests: William F. Armstrong, MD, Director, Echocardiographic Laboratory, University of Michigan Medical Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0022. 27/1/29984
esophageal echocardiography. He had experienced lightheadedness and presyncope while playing golf approximately 3 weeks previously. Cardiac catheterization revealed severe three-vessel coronary artery disease and a peak-to-peak gradient across the aortic valve of 100 mm Hg. He was referred for coronary artery bypass grafting and aortic valve replacement. Preoperative pulmonary function studies revealed a forced vital capacity of 2. 79 L, forced expiratory volume in the first second of 2.34 L, and diffusing capacity 76% of predicted. Measurements of aortic root diameter obtained by transthoracic echocardiography were suboptimal. A transesophageal echocardiogram was therefore performed to provide accurate measurements of aortic diameter in anticipation of homograft valve replacement. Topical pharyngeal anesthesia was achieved with lidocaine spray (three to four metered sprays, for an estimated dose of 30 to 40 mg) and benzocaine spray (one to two sprays of 1 to 2 seconds, for an estimated dose of 330 mg). Midazolam (6 mg) was administered intravenously in divided doses over a period of 10 minutes before the scope was inserted. The transesophageal echocardiogram revealed no abnormality. Heart rate monitored continuously and blood pressure monitored at 5-minute intervals throughout the 20-minute study remained stable. Combined transthoracic and transesophageal studies revealed a stenotic aortic valve with a peak pressure gradient of 130 mm Hg, a mean pressure gradient of 81 mm Hg, and a calculated valve area of 0.5 cm2 • Left ventricular hypertrophy with normal left ven615
616
Journal of [hc Amcrican Sociery of Echocardiography
Marcovitz, Williamson , and Armstrong
tricular function was noted. After the esophageal probe was removed, the patient was noted to have marked cyanosis. Oxygen was administered by nasal cannula at 2 L/ min without resolution of cyanosis. Mter several minutes the patient sat upright and complained of dizziness and nausea. He denied chest pain or shortness of breath. Oxygen (100%) was administered by face mask. Finger pulse oximeter revealed an oxygen saturation of 86%. Blood pressure was 120/80 mm Hg, respiratory rate was 28/min, and heart rate was 95 beats/min. He appeared ashen and had mild mental confusion. There was no jugular venous distention. Examination of the chest revealed clear lung fields and a grade III/VI systolic crescendo/decrescendo murmur heard loudest at the right upper sternal border and radiating to the carotids. There was no gallop. The rest of the results of physical examination were unremarkable. An electrocardiogram revealed left ventricular hypertrophy. Chest radiography revealed mild cardiomegaly and clear lung fields without evidence of congestive heart failure. Venous blood samples were analyzed for complete blood count, electrolytes, glucose, blood urea nitrogen, creatinine, and creatinine phosphokinase. Arterial samples were a dark, muddy blue, and blood gases revealed a POz of 226 mm Hg, Peo z of 33 mm Hg, pH of 7.39, and Oz saturation of 53% . A pulse oximeter continued to display oxygen saturations of 80% to 90%. Repeat blood gas measurements were similar to the initial set. Because of the patient's marked cyanosis and low measured oxygen saturation in the absence of respiratory distress, instability in vital signs, or objective evidence of hypoxia by blood gas determination, a blood methemoglobin study was ordered and revealed a methemoglobin level of 45%. Low-dose methylene blue was administered at I mg / kg over 15 minutes. Repeat measurements of blood gases revealed POz of 230 mm Hg, Peo 2 of 41 mm Hg, pH of 7.38, Oz saturation of 96%, and methemoglobin level of2% on administration of60% inspired oxygen. Because of his history of critical aortic stenosis and coronary artery disease, he was admitted to the cardiac intensive care unit for observation. Serial measurements of creatinine phosphokinase ranged from 27 to 68 IU / L, and the electrocardiogram remained unchanged. He was discharged the following day in good condition. Subsequent hemoglobin electrophoresis revealed a normal hemoglobin pattern, with 96% hemoglobin Al and 3% hemoglobin A z . He subsequently underwent uneventful coronary artery bypass grafting and aortic
valve replacement. Anesthetics of the amide and ester classes were avoided. A methemoglobin level obtained after surgery was less than 1%. DISCUSSION
Topical anesthetics are commonly applied to the mucous membranes before endoscopy, bronchoscopy, and dental procedures. They are regarded as safe agents without appreciable systemic absorption when used in recommended doses on intact mucosa. Despite this, plasma concentrations similar to those seen with intravenous lidocaine have been noted 15 minutes after administering a laryngotracheal spray of local anesthetic in preparation for bronchoscopy.3 It is believed that the high vascularity of the tracheobronchial tree leads to absorption of this agent in quantities that produce significant blood levels. Two cases of acute methemoglobinemia after treatment with topical lidocaine have been reported, one after preparation of the larynx with a 2% lidocaine solution and the other after two separate applications of 4% lidocaine spray to the posterior pharynx I hour apart. 4 •5 In the former case, topical benzocaine spray combined with topical lidocaine was applied to injured mucosa. In the latter case, methemoglobinemia secondary to treatment with topical benzocaine spray had been diagnosed in the same patient less than 24 hours earlier, perhaps rendering the red cells more susceptible to a second oxidant stress. Our patient had no known disruption of his pharyngeal mucosa, but he did receive a combination of topical benzocaine and lidocaine, perhaps rendering him more susceptible to methemoglobinemia. A few cases of acute methemoglobinemia secondary to topical benwcaine have been reported, most of these in children, in adults with hereditary deficiency of methemoglobin reductase, or in patients with injured mucosa. 6 . 11 Significant systemic levels are believed to occur rarely after benzocaine anesthetic is applied in recommended doses to intact mucous membranes to prepare the pharynx for upper endoscopy. Methemoglobin is formed when ferrous iron (Fe 2 -t ), chelated to the prophyrin ring in heme, is converted to ferric iron (Fe 3 +) by endogenous or exogenous oxidizing agents. The methemoglobin molecule is unable to bind oxygen for transport, and there is a left shift in the hemoglobin / oxygen dissociation curve. Hence, whereas oxygen tension in blood is normal, its total content (measured as saturation) for tissue delivery is markedly decreased.
Volume 4 Number 6 November·December 1991
When methemoglobinemia is severe, the capacity of blood to transport oxygen may be reduced to a level below that necessary for sustaining organ function. The serum level of methemoglobin is normally maintained at less than 2% by NADH-methemoglobin reductase, in which NADH functions as an electron donoL In hereditary deficiency of the enzyme and with abnormal hemoglobin (hemoglobin M), chronically elevated levels in the range of 5% to 10% can be seen. Acquired methemoglobinemia occurs when the methemoglobin-reductase system is overwhelmed by oxidant drugs or toxic exposures. Acute, acquired forms of methemoglobin have been attributed to a variety of medications including amyl nitrate, intravenous nitroglycerin, sodium nitroprusside, antimalarials, aniline dyes, phenacetin, sulfonamides, lidocaine, benzocaine, and prilocaine. 1218 Children and those with methemoglobin reductase deficiency are more susceptible to acquired methemoglobinemia. Our patient had recently begun treatment with a long-acting nitrate preparation; otherwise he had no known predisposing factors. Although we were not able to perform the assay for NADH-methemoglobin reductase, a baseline methemoglobin level after surgery was not elevated and he had no history of cyanosis. Clinically methemoglobinemia is not apparent if levels remain at less than 10%; whereas at 10% to 15%, asymptomatic cyanosis is seen. At serum levels of35%, dyspnea owing to decreased oxygen carrying capacity, headache, and generalized weakness can result. At levels of 70%, profound cyanosis, coma, and death can OCCUL Treatment is typically not necessary for methemoglobin levels of 10% to 15% or less. At levels above 30%, treatment is initiated when symptoms are present. The treatment of choice is methylene blue, 1 to 2 mg/kg given intravenously over 5 to 15 minutes. Methylene blue reduces methemoglobin by donating reduced hydrogen to oxidized FE3+ in exchange for an electron picked up from NADPH through the NADPH reductase reaction. Under normal conditions NADH functions as the electron donor, but in the presence of an exogenous electron carrier such as methylene blue, NADPH becomes more active than NADH in donating electrons to oxidized hemoglobin. The oxidized hemoglobin is rapidly reduced, and methemoglobin levels generally fall to normal within 30 to 60 minutes after initiation of treatment with intravenous methylene blue. In severe life-threatening toxic methemoglobinemia that does not respond to intravenous methylene blue, exchange transfusion or dialysis may be necessary. Oral ascorbic acid will also reduce oxidized
Toxic methemoglobinemia
617
hemoglobin but should not be used in the acute setting. As demonstrated by this case, the diagnosis of methemoglobinemia can be confusing when pulse oximetry is used to monitor oxygen saturation. Spectroscopic methods cannot distinguish between methemoglobin and reduced hemoglobin. 19,20 Thus oxygen saturation by pulse oximeter may continue to read 80% to 90%, despite lower actual levels of saturated oxyhemoglobin. Additionally, many blood gas laboratories use a calculated rather than a measured value for oxygen saturation. When calculated rather than measured values are used, the oxygen saturations in arterial samples will agree with those on the pulse oximeter, confusing or delaying the diagnosis. Confusion will be greatest when dealing with patients, who, because of underlying lung or heart disease, have potential other causes for cyanOSIS. Our patient experienced acute cyanosis with an oxygen saturation of80% to 90% by pulse oximetry. Since he was known to have critical aortic stenosis, it was suspected that he had hypotension secondary to the use of midazolam and that he was in danger of impending hemodynamic collapse. However, a normal blood pressure, absence of respiratory distress, and lack of pulmonary edema on chest radiographs made this diagnosis unlikely. The diagnosis of toxic methemoglobinemia should be suspected in a patient with cyanosis occurring after transesophageal echocardiography or other endoscopic procedure who has received topical anesthetics and for whom more serious causes of hypoxia can be ruled out. The presence of cyanosis in the setting of a normal arterial oxygen with a low oxygen saturation on a measured arterial blood gas sample should alert one to the diagnosis of methemoglobinemia. Early identification of cyanosis during the procedure may be difficult since transesophageal echocardiography, unlike endoscopy, is performed in a darkened room. Expedient treatment can be lifesaving, particularly when there is coexistent heart disease. REFERENCES
1. Smith RP, Olson MV. Drug·induced methemoglobinemia. Semin Hematol 1973;10:253·68. 2. Ludwig Sc. Acute toxic methemoglobinemia following den· tal analgesia. Ann Emerg Med 1981;10:265·6. 3. Ritchie JM, Green NM. Local anesthetics. In: Goodman LS, Gilman, AG, eds. Goodman and Gilman's the pharmacologic basis of disease. 6th ed. New York: Macmillan Publishing Co, Inc, 1980:311.
618
Journal of the American Society of Echocardiography
Marcovitz, Williamson, and Armstrong
4. O'Donohue WI, Moss LM, Angelillo VA. Acute methemoglobinemia induced by topical benzocaine and lidocaine. Arch Intern Med 1980;140:1508-9. 5. Kotler RL, Hansen-Flaschen J, Casey MP. Severe methemoglobinemia after flexible fiberoptic bronchoscopy. Thorax 1989;44:234-5. 6. Collins JF. Methemoglobinemia as a complication of 20% benzocaine spray for endoscopy. Gastroenterology 1990; 98:211-3. 7. Buckley AB, Newman A. Methemoglobinemia occurring after the use of a 20% benzocaine topical anesthetic prior to gastroscopy. Gastrointest Endosc 1987;33:466-7. 8. Sandza JG, Roberts RW, Shaw RC, Connors JP. Symptomatic methemoglobinemia with a commonly used topical anesthetic, cetacaine. Ann Thorac Surg 1980;30: 187-90. 9. Grum DF, Rice TW. Methemoglobinemia from topical benzocaine. Cleve Clin J Med 1990;57:357-9. 10. Porter JL, Hillman JV. Benzocaine-induced methemoglobinemia. Journal of the American College of Emergency Physicians 1979;8:26-7. 11. Townes PL, Geersma MA, White MR. Benzocaine-induced methemoglobinemia. Am J Dis Child 1977;131:697-8. 12. Kaplan KJ, Taber M, Teagarden JR, Parker M, Davison R.
13.
14.
15.
16. 17.
18. 19.
20.
Association of methemoglobinemia and intravenous nitroglycerin administration. Am J CardioI1985;55:181-3. Gibson G, Hunter JB, Raabe DS Jr, Manjoney DL, Ittleman FD. Methemoglobinemia produced by high-dose intravenous nitroglycerin. Ann Intern Med 1982;96:615-6. Harrison MR. Toxic methemoglobinemia. A case of acute nitrobenzene and aniline poisoning treated by exchange transfusion. Anaesthesia 1977;32:270-2. Bojar RM, Rastegar H, Payne DD, et al. Methemoglobinemia from intravenous nitroglycerin: a word of caution. Ann Thoracic Surg 1987;43:332-4. Pierce JM, Nielsen MS. Acute acquired methemoglobinemia after amyl nitrate poisoning. Br Med J 1989;198:1566. Kreutz RW, Kinni ME. Life threatening toxic methemoglobinemia induced by prilocaine. Oral Surg Oral Med Oral Pathol 1983;56:480-2. Finch CA. Methemoglobinemia and sulfhemoglobinemia. N Engl J Med 1948;239:470-8. Rieder HV, Frei FJ, Zbinden AM, Thomson DA. Pulse oximetry in methemoglobinemia. Failure to detect low oxygen saturation. Anaesthesia 1989;44:326-7. Watcha MF, Connor MT, Hing AV. Pulse oximetry in methemoglobinemia. Am J Dis Child 1989;143:845-7.