- Email: [email protected]
Methemoglobinemia After Infusion of Ifosfamide Chemotherapy
3 Wood DJ, Krishna K, Stocks P, et al. Catamenial hemoptysis: a rare cause. Thorax 1993; 48:1048 –1049 4 Karpel JP, Appel D, Merav A. Pulmonary endometriosis. Lung 1985; 163:151–159 5 Elliot DL, Barker AF, Dixon LM. Catamenial hemoptysis: new methods of diagnosis and therapy. Chest 1985; 87:687– 688 6 Guidry GG, George RB. Diagnostic studies in catamenial hemoptysis. Chest 1990; 98:260 –261 7 Kuo PH, Wang HC, Liaw YS, et al. Bronchoscopic and angiographic findings in tracheobronchial endometriosis. Thorax 1996; 51:1060 –1061 8 Johnson WM, Tyndal CM. Pulmonary endometriosis: treatment with danazol. Obstet Gynecol 1987; 69:506 –507 9 Wolfe JD, Simmons DH. Hemoptysis: diagnosis and management. West J Med 1977; 127:303–309 10 Foster DC, Stern JL, Buscema J. Pleural and parenchymal endometriosis. Obstet Gynecol 1981; 58:552–556 11 Bateman ED, Morrison SC. Catamenial hemoptysis from endobronchial endometriosis: a case report and review of previously reported cases. Respir Med 1990; 84:157–161 12 Butler H, Lake KB, Dyke JJV. Bronchial endometriosis and bronchiectasis. Arch Intern Med 1978; 138: 991–992 13 Hertzanu Y, Hernier D, Hirsch M. Computed tomography of pulmonary endometriosis. Comput Radiol 1987; 11:81– 84 14 Espaulella J, Armengol J, Bella F, et al. Pulmonary endometriosis: conservative treatment with GnRH agonist. Obstet Gynecol 1991; 78:535–537 15 Lawrence HC. Pulmonary endometriosis in pregnancy. Am J Obstet Gynecol 1988; 159:733–734
Methemoglobinemia After Infusion of Ifosfamide Chemotherapy* First Report of a Potentially Serious Adverse Reaction Related to Ifosfamide Denis Hadjiliadis, MD; Joseph A. Govert, MD, FCCP
Acute formation of methemoglobin is a life-threatening condition caused by multiple medications. In this article we report the first case of methemoglobinemia in a patient with metastatic uterine leiomyosarcoma, after infusion of ifosfamide chemotherapy. The patient recovered after prompt diagnosis and treatment of the condition. A mechanism for the formation of methemoglobin as a result of the ifosfamide infusion is offered. (CHEST 2000; 118:1208 –1210) Key words: ifosfamide; methemoglobin; methylene blue
is a condition that results from M ethemoglobinemia formation of abnormal hemoglobin. Acute methemo-
globinemia is life threatening. Multiple medications can *From the Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC. 1208
cause methemoglobin formation, and the list is constantly growing, as more and more therapeutic agents enter the market.1 Prompt diagnosis, removal of the offending agent, and treatment can quickly reverse methemoglobin formation. We report the first case in the literature, to our knowledge, of methemoglobinemia induced by the chemotherapeutic agent ifosfamide, and we offer a mechanism for the formation of methemoglobin. MEDLINE (1966 to present), Current Contents (January 1999 to present), and CancerLit (1983 to present) were searched prior to this report.
Case Report A 58-year-old African-American women with stage IV metastatic leiomyosarcoma of probable uterine origin was admitted to the hospital for IV chemotherapy with mesna, adriamycin, ifosfamide, and dacarbazine (known as MAID). The cancer was diagnosed a month before admission, after metastases were found in the right shoulder. Past medical history was significant for hypertension, hypercholesterolemia, resection of an asymptomatic cerebral aneurysm in 1991, cholecystectomy, and fibrocystic breast disease. Her home medications included diltiazem and enalapril for hypertension, fluvastatin for hypercholesterolemia, estrogen and progesterone for hormone replacement, docusate for constipation, and phenobarbital for seizure prophylaxis after the cerebral aneurysm repair. In the hospital she was also receiving mesna, adriamycin, ifosfamide, and dacarbazine chemotherapy and dexamethasone. Alprazolam and prochlorperazine for anxiety and nausea were also ordered on an as-needed basis. On the day of admission, on the first infusion of ifosfamide the patient complained of mild dyspnea that resolved after supplemental oxygen administration. No further evaluation was undertaken. The following day, within 30 min of the ifosfamide infusion, the patient had dyspnea, mental status changes, and confusion. An arterial blood gas evaluation with co-oximetry (which is done routinely at our institution) revealed Pao2 of 56 mm Hg; Paco2, 29 mm Hg; pH, 7.49; oxygen saturation, 46.2%; and methemoglobin content, 49.8% while the patient was receiving 2 L/min of oxygen by nasal cannula. The rest of her laboratory evaluation was within normal limits. The patient required intubation and mechanical ventilation for airway protection. A repeat blood gas evaluation, just before methylene blue administration and 30 min after the first blood gas determination, showed improved oxygenation when the patient received 100% oxygen (Pao2, 346 mm Hg), but the methemoglobin concentration rose to 56.6%. Methylene blue was given at a dose of 90 mg (1 mg/kg), and all chemotherapy agents were discontinued. Methemoglobin concentrations at 1, 2, 3, 5, 7, and 24 h after methylene blue administration were 31.2, 24.9, 20.8, 14.6, 10.6, and 1.4%, respectively. Following intubation, the patient remained hemodynamically stable without evidence of organ dysfunction (ie, elevated anion gap, decreased urine output), and her mental status improved. She was extubated and discharged from the ICU within 24 h, had an uneventful recovery, and was discharged from the hospital 10 days later, with continuance of all her preadmission medications. Ten months after the original episode, she has not had any repeated episodes of symptomatic or asymptomatic methemoglobinemia after receiving other chemotherapeutic regimens. Manuscript received January 10, 2000; revision accepted March 1, 2000. Correspondence to: Joseph A. Govert, MD, FCCP, 8264 Hospital North, Box 31012 Medical Center, Duke University Medical Center, Durham, NC, 27710; e-mail: Gover00l @mc.duke.edu Selected Reports
Figure 1. Metabolism of ifosfamide. Reprinted with permission from Fleming.5
Discussion Methemoglobin is formed constantly in every RBC by the oxidation of iron (Fe) in hemoglobin from ferrous (Fe2⫹) to ferric (Fe3⫹) state. The nicotinamide adenine dinucleotide, the nicotinamide adenine dinucleotide phosphate, and the glutathione systems in the RBC reduce methemoglobin to hemoglobin and keep methemoglobin levels at around 1%.2 Methemoglobin has a different spectrum of light absorption than hemoglobin (631 nm vs 660 nm).2,3 This characteristic is useful in the diagnosis of methemoglobinemia. Blood gas machines measure the Pao2 and calculate the percentage saturation of hemoglobin (oxygen satura-
tion) from the hemoglobin saturation/desaturation curve and the pH.2 Pao2 is not affected by the formation of methemoglobin, since it depends on the alveolar oxygen tension, shunt fraction, and diffusion of oxygen across the alveolar membrane.2 Pulse oximetry is also unable to diagnose methemoglobinemia, since most such devices detect only the wavelength of hemoglobin absorption. The presence of significant amounts of methemoglobin causes interference in the light absorption, and pulse oximetry devices show oxygen saturation between 85% and 88%. The diagnosis of methemoglobinemia requires a spectrophotometer that tests blood for methemoglobin and carboxyhemoglobin (co-oximetry).3 CHEST / 118 / 4 / OCTOBER, 2000
1209
Methemoglobin is unable to transport and unload oxygen in the tissues, effectively reducing the amount of available hemoglobin in the body for oxygen transport. Methemoglobin levels up to 25% can be well tolerated in otherwise healthy patients, but levels ⬎50% are life threatening. High levels of methemoglobin cause a dark brown (chocolate) discoloration of blood, and patients appear cyanotic.2 Methylene blue, an electron donor, repletes the endogenous cellular antioxidant systems. Its effect is evident in minutes, and the effect lasts for up to 90 min. High doses (7 mg/kg) of methylene blue or its use in patients with glucose-6-phosphate deficiency can precipitate methemoglobinemia; it therefore needs to be used with caution.1–3 Ifosfamide is an alkylating chemotherapeutic agent that is used in the treatment of testicular, lung, breast, cervical, ovarian cancers, and sarcomas. The parent compound can be administered IV or po, but it requires transformation to 4-hydroxy-ifosfamide by the cytochrome P450 enzymes of the liver.4,5 In tumor cells, this compound is transformed to the active cytotoxic metabolites ifosfamide mustard and acrolein as well as carboxyifosfamide, 4-ketoifosfamide, and 4-thioifosfamide (Fig 1). The latter compound reacts with glutathione and can deplete cell antioxidant stores. Some of the parent compound is converted to chloroethylifosfamide and chloroacetaldehyde, which also react with glutathione.4,5 Ifosfamide has been shown to induce its own metabolism after administration of one dose (autoinduction). Our patient was receiving phenobarbital, a potent inducer of the cytochrome P450 enzymes, and probably metabolized ifosfamide faster than expected. On the second day, ifosfamide autoinduction further increased its rate of metabolism, causing increased amounts of ifosfamide metabolites, which in turn reduced glutathione stores in RBCs. This caused overt methemoglobinemia leading to respiratory distress. Mesna, when used with ifosfamide, protects the urinary system, but not the RBCs, and therefore did not adequately prevent the depletion of the cellular reducing systems of the RBCs. The prompt reversal with only one dose of methylene blue suggests that the offending agent had been removed. An extensive review of the literature did not reveal an obvious mechanism for adriamycin or dacarbazine to cause methemoglobinemia, nor did it show any reported cases. Cyclophosphamide, a compound related to ifosfamide in structure and metabolism, is reported to cause methemoglobinemia.6 Physicians need to have high clinical suspicion for methemoglobinemia in patients with cyanosis, respiratory symptoms out of proportion to their blood gas, equivocal oximetry, and use of new medications or medications known to cause methemoglobinemia. Our report suggests that ifosfamide should be added to the list of drugs causing methemoglobinemia and offers a potential mechanism for ifosfamide-induced methemoglobinemia. Physicians using ifosfamide should be aware of this potentially life-threatening reaction, especially in patients who are receiving agents that induce the cytochrome P450 system. 1210
References 1 Smith RP, Olson MV. Drug-induced methemoglobinemia. Semin Hematol 1973; 10:253–268 2 Jaffe ER Methaemoglobinemia. Clin Hematol 1981; 10:99 – 122 3 Coleman MD, Coleman NA. Drug-induced methaemoglobinaemia: treatment issues. Drug Saf 1996; 14:394 – 405 4 Wagner T. Ifosfamide clinical pharmacokinetics. Clin Pharmacokinet 1994; 26:439 – 456 5 Fleming RA. An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy 1997; 17(Suppl): 146S–154S 6 Nakao I, Harashima S, Narui T, et al. Two cases of methemoglobinemia caused by anti-cancer drugs [in Japanese]. Rinsho Ketsueki 1978; 19:246 –251
Successful Treatment of Juvenile Laryngeal Papillomatosis-Related Multicystic Lung Disease With Cidofovir* Case Report and Review of the Literature David R. Dancey, MD; Dean W. Chamberlain, MD; Mel Krajden, MD;† Joel Palefsky, MD; P.W. Alberti, MD; and Gregory P. Downey, MD, FCCP
Cidofovir, a nucleoside analog antiviral agent, has been used with moderate success in the treatment of juvenile laryngeal papillomatosis (JLP) by direct intralesional injection. We report the first case where IV cidofovir was used successfully to treat a rare but lethal multicystic lung disease complicating JLP. A 35-year-old woman with a history of JLP requiring multiple laser ablations of laryngeal papillomata each year presented with hemoptysis and was found on CT scan to have bilateral, multiple pulmonary nodules and cysts. The results of BAL fluid analysis demonstrated no evidence of malignancy, and cultures were negative for fungi and mycobacteria. Molecular DNA typing of a biopsy specimen ob*From the Division of Respirology (Drs. Dancey and Downey) and the Division of Medical Microbiology (Dr. Krajden), Department of Medicine, the Department of Laboratory Medicine and Pathobiology (Dr. Chamberlain), and the Division of Otolaryngology (Dr. Alberti), Department of Surgery, University of Toronto, Ontario, Canada; and the Department of Laboratory Medicine (Dr. Palefsky), University of California, San Francisco, CA. †Current address: Provincial Lab, British Columbia Centre for Disease Control, Vancouver, British Colombia, Canada. Manuscript received December 22, 1999; revision accepted March 29, 2000. Correspondence to: Gregory P. Downey, MD, FCCP, EN 10 –212, The Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4; e-mail: [email protected] Selected Reports
Methemoglobinemia After Infusion of Ifosfamide Chemotherapy* First Report of a Potentially Serious Adverse Reaction Related to Ifosfamide Denis Hadjiliadis, MD; Joseph A. Govert, MD, FCCP
Acute formation of methemoglobin is a life-threatening condition caused by multiple medications. In this article we report the first case of methemoglobinemia in a patient with metastatic uterine leiomyosarcoma, after infusion of ifosfamide chemotherapy. The patient recovered after prompt diagnosis and treatment of the condition. A mechanism for the formation of methemoglobin as a result of the ifosfamide infusion is offered. (CHEST 2000; 118:1208 –1210) Key words: ifosfamide; methemoglobin; methylene blue
is a condition that results from M ethemoglobinemia formation of abnormal hemoglobin. Acute methemo-
globinemia is life threatening. Multiple medications can *From the Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC. 1208
cause methemoglobin formation, and the list is constantly growing, as more and more therapeutic agents enter the market.1 Prompt diagnosis, removal of the offending agent, and treatment can quickly reverse methemoglobin formation. We report the first case in the literature, to our knowledge, of methemoglobinemia induced by the chemotherapeutic agent ifosfamide, and we offer a mechanism for the formation of methemoglobin. MEDLINE (1966 to present), Current Contents (January 1999 to present), and CancerLit (1983 to present) were searched prior to this report.
Case Report A 58-year-old African-American women with stage IV metastatic leiomyosarcoma of probable uterine origin was admitted to the hospital for IV chemotherapy with mesna, adriamycin, ifosfamide, and dacarbazine (known as MAID). The cancer was diagnosed a month before admission, after metastases were found in the right shoulder. Past medical history was significant for hypertension, hypercholesterolemia, resection of an asymptomatic cerebral aneurysm in 1991, cholecystectomy, and fibrocystic breast disease. Her home medications included diltiazem and enalapril for hypertension, fluvastatin for hypercholesterolemia, estrogen and progesterone for hormone replacement, docusate for constipation, and phenobarbital for seizure prophylaxis after the cerebral aneurysm repair. In the hospital she was also receiving mesna, adriamycin, ifosfamide, and dacarbazine chemotherapy and dexamethasone. Alprazolam and prochlorperazine for anxiety and nausea were also ordered on an as-needed basis. On the day of admission, on the first infusion of ifosfamide the patient complained of mild dyspnea that resolved after supplemental oxygen administration. No further evaluation was undertaken. The following day, within 30 min of the ifosfamide infusion, the patient had dyspnea, mental status changes, and confusion. An arterial blood gas evaluation with co-oximetry (which is done routinely at our institution) revealed Pao2 of 56 mm Hg; Paco2, 29 mm Hg; pH, 7.49; oxygen saturation, 46.2%; and methemoglobin content, 49.8% while the patient was receiving 2 L/min of oxygen by nasal cannula. The rest of her laboratory evaluation was within normal limits. The patient required intubation and mechanical ventilation for airway protection. A repeat blood gas evaluation, just before methylene blue administration and 30 min after the first blood gas determination, showed improved oxygenation when the patient received 100% oxygen (Pao2, 346 mm Hg), but the methemoglobin concentration rose to 56.6%. Methylene blue was given at a dose of 90 mg (1 mg/kg), and all chemotherapy agents were discontinued. Methemoglobin concentrations at 1, 2, 3, 5, 7, and 24 h after methylene blue administration were 31.2, 24.9, 20.8, 14.6, 10.6, and 1.4%, respectively. Following intubation, the patient remained hemodynamically stable without evidence of organ dysfunction (ie, elevated anion gap, decreased urine output), and her mental status improved. She was extubated and discharged from the ICU within 24 h, had an uneventful recovery, and was discharged from the hospital 10 days later, with continuance of all her preadmission medications. Ten months after the original episode, she has not had any repeated episodes of symptomatic or asymptomatic methemoglobinemia after receiving other chemotherapeutic regimens. Manuscript received January 10, 2000; revision accepted March 1, 2000. Correspondence to: Joseph A. Govert, MD, FCCP, 8264 Hospital North, Box 31012 Medical Center, Duke University Medical Center, Durham, NC, 27710; e-mail: Gover00l @mc.duke.edu Selected Reports
Figure 1. Metabolism of ifosfamide. Reprinted with permission from Fleming.5
Discussion Methemoglobin is formed constantly in every RBC by the oxidation of iron (Fe) in hemoglobin from ferrous (Fe2⫹) to ferric (Fe3⫹) state. The nicotinamide adenine dinucleotide, the nicotinamide adenine dinucleotide phosphate, and the glutathione systems in the RBC reduce methemoglobin to hemoglobin and keep methemoglobin levels at around 1%.2 Methemoglobin has a different spectrum of light absorption than hemoglobin (631 nm vs 660 nm).2,3 This characteristic is useful in the diagnosis of methemoglobinemia. Blood gas machines measure the Pao2 and calculate the percentage saturation of hemoglobin (oxygen satura-
tion) from the hemoglobin saturation/desaturation curve and the pH.2 Pao2 is not affected by the formation of methemoglobin, since it depends on the alveolar oxygen tension, shunt fraction, and diffusion of oxygen across the alveolar membrane.2 Pulse oximetry is also unable to diagnose methemoglobinemia, since most such devices detect only the wavelength of hemoglobin absorption. The presence of significant amounts of methemoglobin causes interference in the light absorption, and pulse oximetry devices show oxygen saturation between 85% and 88%. The diagnosis of methemoglobinemia requires a spectrophotometer that tests blood for methemoglobin and carboxyhemoglobin (co-oximetry).3 CHEST / 118 / 4 / OCTOBER, 2000
1209
Methemoglobin is unable to transport and unload oxygen in the tissues, effectively reducing the amount of available hemoglobin in the body for oxygen transport. Methemoglobin levels up to 25% can be well tolerated in otherwise healthy patients, but levels ⬎50% are life threatening. High levels of methemoglobin cause a dark brown (chocolate) discoloration of blood, and patients appear cyanotic.2 Methylene blue, an electron donor, repletes the endogenous cellular antioxidant systems. Its effect is evident in minutes, and the effect lasts for up to 90 min. High doses (7 mg/kg) of methylene blue or its use in patients with glucose-6-phosphate deficiency can precipitate methemoglobinemia; it therefore needs to be used with caution.1–3 Ifosfamide is an alkylating chemotherapeutic agent that is used in the treatment of testicular, lung, breast, cervical, ovarian cancers, and sarcomas. The parent compound can be administered IV or po, but it requires transformation to 4-hydroxy-ifosfamide by the cytochrome P450 enzymes of the liver.4,5 In tumor cells, this compound is transformed to the active cytotoxic metabolites ifosfamide mustard and acrolein as well as carboxyifosfamide, 4-ketoifosfamide, and 4-thioifosfamide (Fig 1). The latter compound reacts with glutathione and can deplete cell antioxidant stores. Some of the parent compound is converted to chloroethylifosfamide and chloroacetaldehyde, which also react with glutathione.4,5 Ifosfamide has been shown to induce its own metabolism after administration of one dose (autoinduction). Our patient was receiving phenobarbital, a potent inducer of the cytochrome P450 enzymes, and probably metabolized ifosfamide faster than expected. On the second day, ifosfamide autoinduction further increased its rate of metabolism, causing increased amounts of ifosfamide metabolites, which in turn reduced glutathione stores in RBCs. This caused overt methemoglobinemia leading to respiratory distress. Mesna, when used with ifosfamide, protects the urinary system, but not the RBCs, and therefore did not adequately prevent the depletion of the cellular reducing systems of the RBCs. The prompt reversal with only one dose of methylene blue suggests that the offending agent had been removed. An extensive review of the literature did not reveal an obvious mechanism for adriamycin or dacarbazine to cause methemoglobinemia, nor did it show any reported cases. Cyclophosphamide, a compound related to ifosfamide in structure and metabolism, is reported to cause methemoglobinemia.6 Physicians need to have high clinical suspicion for methemoglobinemia in patients with cyanosis, respiratory symptoms out of proportion to their blood gas, equivocal oximetry, and use of new medications or medications known to cause methemoglobinemia. Our report suggests that ifosfamide should be added to the list of drugs causing methemoglobinemia and offers a potential mechanism for ifosfamide-induced methemoglobinemia. Physicians using ifosfamide should be aware of this potentially life-threatening reaction, especially in patients who are receiving agents that induce the cytochrome P450 system. 1210
References 1 Smith RP, Olson MV. Drug-induced methemoglobinemia. Semin Hematol 1973; 10:253–268 2 Jaffe ER Methaemoglobinemia. Clin Hematol 1981; 10:99 – 122 3 Coleman MD, Coleman NA. Drug-induced methaemoglobinaemia: treatment issues. Drug Saf 1996; 14:394 – 405 4 Wagner T. Ifosfamide clinical pharmacokinetics. Clin Pharmacokinet 1994; 26:439 – 456 5 Fleming RA. An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy 1997; 17(Suppl): 146S–154S 6 Nakao I, Harashima S, Narui T, et al. Two cases of methemoglobinemia caused by anti-cancer drugs [in Japanese]. Rinsho Ketsueki 1978; 19:246 –251
Successful Treatment of Juvenile Laryngeal Papillomatosis-Related Multicystic Lung Disease With Cidofovir* Case Report and Review of the Literature David R. Dancey, MD; Dean W. Chamberlain, MD; Mel Krajden, MD;† Joel Palefsky, MD; P.W. Alberti, MD; and Gregory P. Downey, MD, FCCP
Cidofovir, a nucleoside analog antiviral agent, has been used with moderate success in the treatment of juvenile laryngeal papillomatosis (JLP) by direct intralesional injection. We report the first case where IV cidofovir was used successfully to treat a rare but lethal multicystic lung disease complicating JLP. A 35-year-old woman with a history of JLP requiring multiple laser ablations of laryngeal papillomata each year presented with hemoptysis and was found on CT scan to have bilateral, multiple pulmonary nodules and cysts. The results of BAL fluid analysis demonstrated no evidence of malignancy, and cultures were negative for fungi and mycobacteria. Molecular DNA typing of a biopsy specimen ob*From the Division of Respirology (Drs. Dancey and Downey) and the Division of Medical Microbiology (Dr. Krajden), Department of Medicine, the Department of Laboratory Medicine and Pathobiology (Dr. Chamberlain), and the Division of Otolaryngology (Dr. Alberti), Department of Surgery, University of Toronto, Ontario, Canada; and the Department of Laboratory Medicine (Dr. Palefsky), University of California, San Francisco, CA. †Current address: Provincial Lab, British Columbia Centre for Disease Control, Vancouver, British Colombia, Canada. Manuscript received December 22, 1999; revision accepted March 29, 2000. Correspondence to: Gregory P. Downey, MD, FCCP, EN 10 –212, The Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4; e-mail: [email protected] Selected Reports