Case Report Oxygen-Exacerbated Bleomycin Pulmonary Toxicity

THEODORE S. INGRASSIA III, M.D., JAY H. RYU, M.D., Division of Thoracic Diseases and Internal Medicine; VICTOR F. TRASTEK, M.D., Section of General Thoracic Surgery; EDWARD C. ROSENOW III, M.D., Division of Thoracic Diseases and Internal Medicine

Bleomycin is an antineoplastic agent with potential for producing pulmonary toxicity, attributed in part to its free radical-promoting ability. Clinical and research experiences have suggested that the risk of bleomycin-induced pulmonary injury is increased with the administration of oxygen. We report a case in which the intraoperative administration of oxygen in the setting of previous bleomycin therapy contributed to postoperative ventilatory failure.. Our patient recovered with corticosteroid therapy. Physician awareness of a potential interaction between oxygen and bleomycin may help reduce the morbidity and mortality related to bleomycin therapy.

Bleomycin, an anticancer agent, is an antibiotic complex isolated from a strain of Streptomyces uerticillus.' It has been useful in the management of several neoplasms, including squamous cell carcinoma, lymphoma, and testicular cell carcinoma. Contrary to most chemotherapeutic agents, it does not adversely affect the bone marrow.' Pulmonary toxicity is the most serious adverse effect associated with use of bleomycin, occurring in approximately 10% of treated patients and with increased frequency associated with both advanced age (older than 65 years) and dose greater than 300 U.2-4 In addition, potentiation of bleomycin pulmonary toxicity has been reported in those patients who have also been exposed to thoracic radiation theraPY',6 and hyperoxia.? In this report, we discuss a recent case in which hyperoxia likely precipitated bleomycin pulmonary toxicity, and we review the pertinent literature.

REPORT OF CASE

A previously healthy 28-year-old man sought medical assistance from his local physician on July 4, 1988, because of right-sided chest pain, dysphagia, and severe sore throat. He had a 20pack-year history of use of tobacco. A chest roentgenogram revealed a right-sided anterior mediastinal mass. A computed tomographic scan ofthe chest demonstrated multiple pulmonary nodules bilaterally and confirmed the presence of an anterior mediastinal mass. A right thoracotomy was performed. Tissue obtained from the mediastinal mass was diagnostic of mixed malignant germ cell tumor with elements of embryonal carcinoma and teratocarcinoma. Four days later, the patient's left testicle became painful and swollen. He was referred to our institution, where a left radical orchiectomy confirmed the presence ofmixed malignant germ cell tumor. The preoperative human chorionic gonadotropin level, p subunit, was 10.2 IU/liter Address reprint requests to Dr. J. H. Ryu, Division of (normal, less than 2.5), and the a-fetoprotein level was 3,690 ng/ml (normal, less than 6). The Thoracic Diseases, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 66:173-178,1991

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inspired oxygen concentration during anesthesia was 100%for 90 minutes. The patient had no postoperative complications. From July 23 to Nov. 9, 1988, the patient received four cycles of intravenously administered chemotherapy with bleomycin, VP-16 (etoposide), and cisdiamine dichloroplatinum. The total dose of bleomycin received was 240 U. A follow-up computed tomographic scan of the chest demonstrated shrinkage of some of the pulmonary nodules but also suggested the appearance of new nodules. On Nov. 29, 1988, the patient was readmitted to our hospital for surgical excision ofthe residual intrathoracic metastatic lesions. Preoperatively, the arterial blood gases while he was breathing room air revealed a partial pressure of oxygen of 85.5 mm Hg, a partial pressure of carbon dioxide of 40 mm Hg, and a pH of 7.39. Pulmonary function tests demonstrated a forced expiratory volume in 1 second of2.51 liters (64% of predicted), a forced vital capacity of3.24 liters (70% of predicted), a total lung capacity of 4.13 liters (68% of predicted), and a diffusing capacity of the lung for carbon monoxide of 18 mlfmin per mm Hg (67% of predicted). He underwent wedge resection of nodules in the upper, middle, and lower lobes ofthe right lung as well as resection of the residual mediastinal mass, which again showed metastatic mixed germ cell tumor. Histologically, the surrounding alveolar parenchyma was normal. A combination of fentanyl citrate and isoflurane anesthesia was used during the 4-hour operation. The inspired oxygen concentration was maintained at 33% during most ofthe operation; however, it was increased to 71% for 30 minutes when the right half ofthe double-lumen endotracheal tube was clamped. He received 2,400 ml of lactated Ringer's solution during the procedure. No blood transfusions were needed, and no intraoperative complications occurred. He was extubated in the recovery room. At that time, the arterial blood gases while the patient was receiving 3 liters/ min of oxygen by nasal cannula were as follows: partial pressure of oxygen, 86 mm Hg; partial pressure of carbon dioxide, 40 mm Hg; and pH, 7.40.

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Forty-two hours postoperatively, progressive dyspnea developed. A chest roentgenogram revealed bilateral pulmonary infiltrates (Fig. 1). Arterial blood gas studies while the patient was breathing room air demonstrated a partial pressure of oxygen of 24 mm Hg, which improved slightly after administration of increasing concentrations of supplemental oxygen by face mask. He was intubated and mechanically ventilated (initial inspired oxygen concentration of 70%, assisted control with 10 breaths/min, and positive end-expiratory pressure of 5 cm H 2 0 ). Arterial blood gas analysis showed a partial pressure of oxygen of 68 mm Hg, a partial pressure of carbon dioxide of37 mm Hg, and a pH of 7.41. A pulmonary artery catheter was inserted and revealed a pulmonary capillary wedge pressure of 14 mm Hg and a cardiac index of 3.85 liters/min per m", The presumptive diagnosis was bleomycin-induced pulmonary toxicity. He was initially given 1 g of methylprednisolone intravenously and then maintained on 60 mg of methylprednisolone intravenously three times daily. Sputum and blood cultures were negative. The inspired oxygen concentration was gradually decreased to 32% within 8 hours after intubation, and the positive end-expiratory pressure was increased to 18 em H 2 to maintain a satisfactory hemoglobin oxygen saturation (±90%). A chest roentgenogram showed substantial clearing of the infiltrates during the next 2 days (Fig. 2). He was extubated within 1 week and was dismissed from the hospital without need of supplemental oxygen (arterial blood gases on room air: partial pressure of oxygen, 83 mm Hg; partial pressure of carbon dioxide, 36 mm Hg; pH, 7.47; percentage saturation, 96%). The oral dose of prednisone (40 mg/day at dismissal) was tapered and ultimately discontinued during a period of 3 months. Because adjuvant chemotherapy (without bleomycin) was unsuccessful, the patient required reoperation for recurrent pulmonary metastatic lesions in May and again in August 1989. Corticosteroids were administered preoperatively and in the immediate postoperative period. The inspired oxygen concentration was maintained at less than 35%. Recovery was

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Fig. 1. Chest roentgenogram obtained during acute respiratory distress 42 hours after right thoracotomy for removal of thoracic metastatic lesions in patient who had had previous bleomycin therapy. Note bilateral pulmonary infiltrates.

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Fig. 2. Chest roentgenogram of same patient as depicted in Figure 1, obtained 2 days after initiation oftreatment with intravenously administered corticosteroids. Note substantial clearing of pulmonary infiltrates.

unremarkable. The alveolar parenchyma sur- ofthe patients. Autopsy revealed increased lung rounding the removed malignant tissue was size, increased lung weight, and abnormal amounts of interstitial fluid. Microscopic examagain normal histologically. In October 1989, the patient experienced right ination of lung tissue showed increased intrahemiparesis, and a craniotomy was performed to alveolar exudates, hyaline membranes, interstiremove a large intracerebral metastatic lesion. tial fibrosis, and squamous metaplasia of type I Because of increased intracranial pressure, he and type II pneumonocytes. Twelve subsequent received dexamethasone preoperatively. The patients matched for age, dosage of bleomycin, inspired oxygen concentration reached 100% and incidence of pulmonary problems were studintraoperatively, and he was given 100% oxygen ied prospectively to determine whether the conby face mask in the recovery room. The patient centration of inspired oxygen and the amount of had no postoperative pulmonary complications. intravenous fluid administered intraoperatively contributed to postoperative respiratory failure. During and after operation, the inspired oxygen DISCUSSION In 1978, Goldiner and associates? described five concentration was maintained between 22 and consecutive patients who received 135 to 595 U 25%, and the fluid balance was carefully moniof bleomycin for testicular cancer and subse- tored. None of the 12 patients had evidence of quently had adult respiratory distress syndrome bleomycin-induced pulmonary toxicity. This that progressed to death within 3 to 5 days after experience first implicated oxygen in exacerbatretroperitoneal lymph node biopsy or removal of ing bleomycin pulmonary toxicity, inasmuch as pulmonary metastatic lesions. During the sur- the mean inspired oxygen concentration of the gical procedure, they received supplemental survivors was 24% in comparison with 39% in oxygen (a mean of 39%; range, 35 to 42%). The the nonsurvivors. The nonsurvivors also reoperation was performed within 6 to 12 months ceived more crystalloid intraoperatively (5.86 after bleomycin treatment. Mechanical ventila- mllkg hourly versus 3.87 mllkg hourly). Several other authors have reported the assotory support, positive end-expiratory pressure, and, in one case, extracorporeal membrane ciation of bleomycin-related pulmonary toxicity oxygenation for 8 days did not affect the outcome with increased inspired oxygen concentrations

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intraoperatively and postoperatively.P-" Animals exposed to oxygen after bleomycin treatment have demonstrated a mortality up to 15 times that among those treated with bleomycin alone. 10 - 13 In contrast, Douglas and Coppinv' retrospectively reviewed 14 patients who received treatment for testicular carcinoma with bleomycin, 150 to 570 U, and underwent 20 surgical procedures, during which time the inspired oxygen concentration ranged from 30 to 100%. Respiratory failure developed in only one patient who received 100% oxygen during bronchoscopy. The patient recovered with intensive supportive care and an increased dose of corticosteroid. Einhorn and colleagues'! reported no operative deaths among 21 patients who underwent lateral thoracotomy or median sternotomy for residual pulmonary disease after they had received combination chemotherapy that included bleomycin for testicular cancer. The surgical procedures were performed 4 weeks after administration of the last dose of bleomycin. Intraoperative and postoperative concentrations of oxygen were not mentioned. An understanding ofhow bleomycin functions as an antineoplastic agent is helpful in identifying how its combination with oxygen can produce such devastating pulmonary toxicity. Bleomycin forms a complex with iron and oxygen and generates free radicals that preferentially cleave DNA at GT, GC, and GA dinucleotides.P" The genotoxicity of bleomycin is increased in the presence of 70% oxygen." The addition ofsuperoxide dismutase, an antioxidant enzyme, to cell cultures pretreated with bleomycin attenuates the cytotoxicity of bleomycin.w-" Indeed, lymphocyte chromosomal sensitivity to bleomycin has been shown to be inversely proportional to the concentration of superoxide dismutase present in a person's whole blood, plasma, or erythrocytes.P Free radicals generated by bleomycin are also thought to participate in oxidationreduction reactions that damage cell membranes and proteins." Bleomycin seems to be concentrated in lung tissue, where tissue oxygen tensions are highest.v' Bleomycin may be indirectly toxic to the lung by activating certain cell types, the mediators of

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which exacerbate the toxicity of bleomycin. 18,25 Bronchoalveolar lavage fluid from patients with bleomycin-induced pulmonary toxicity has been noted to have increased numbers of lymphocytes and polymorphonuclear leukocytes.P" Studies of bronchoalveolar lavage fluid from dogs treated with intratracheally administered bleomycin have shown an increase in polymorphonuclear leukocytes before the onset of radiographically identified pulmonary fibrosis. 27 The role of polymorphonuclear leukocytes and lymphocytes is unclear. Bleomycin is thought to cause lung tissue to release chemotactic factors for polymorphonuclear leukocytes and to induce them to produce superoxide anion. 18 Another proposed mechanism for bleomycininduced toxicity involves a direct effect on transcription within the fibroblast, increasing the production of collagen. 18,28 Injury to other lung cells precipitates the release of inflammatory mediators that increase the biosynthesis of collagen. Understandably, accumulation of collagen could have a role in bleomycin-induced pulmonary fibrosis, but its potential contribution to postoperative respiratory failure is less clear. Oxygen therapy itself has been well recognized as toxic to the lungs. 29 ,30 The degree of oxygen-induced lung injury has been thought to be directly proportional to the concentration of oxygen administered and the duration of treatment, although no injury is usually detectable in normal persons when a concentration of less than 50% is administered, regardless of the duration of exposure.P! The clinical and pathologic features ofoxygen-induced toxicity, including atelectasis, edema, alveolar hemorrhage, inflammation, deposition of fibrin, and formation of hyaline membranes, are the same as those seen in adult respiratory distress syndrome attributable to oxygen-exacerbated bleomycin pulmonary toxicity. Smoking has been implicated as a possible exacerbating agent in bleomycin toxicity by dramatically increasing the amount of hydrogen peroxide released from human alveolar macrophages incubated with bleomycin.P Prior radiation therapy increases the incidence of bleomycin-induced pulmonary fibrosis and may

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influence the likelihood of a toxic oxygen interaction as well.P:" Reports of treatment of bleomycin-induced pulmonary toxicity have been mainly anecdotal. Gilson and Sahn" described a 29-year-old man who was treated with 120 U of bleomycin for embryonal cell cancer; adult respiratory distress syndrome developed 60 hours after performance of a retroperitoneal node dissection, during which the inspired oxygen concentration was maintained at 33%. He was mechanically ventilated with the lowest inspired oxygen concentration possible, and the positive end-expiratory pressure was increased as necessary to maintain a hemoglobin oxygen saturation of 90%. Methylprednisolone, 125 mg, was administered intravenously every 6 hours; this regimen was tapered during a 6-month period to prednisone, 20 mg orally every other day. At that time, he reportedly had dyspnea only after heavy exertion. The experience of Goldiner and co-workers? with oxygen-exacerbated bleomycin pulmonary toxicity suggested that potentially fatal reactions could be avoided by maintaining an intraoperative inspired oxygen concentration ofless than 30% and by close monitoring of replacement of fluids to avoid overhydration. Gilson and Sahn" suggested prophylactic administration of corticosteroids in bleomycintreated patients who require more than a 30% inspired oxygen concentration to maintain a satisfactory hemoglobin oxygen saturation. Studies with pig alveolar macrophages incubated with bleomycin have shown that the addition of hydrocortisone reduces the generation of superoxides."

CONCLUSION The anesthesiologist and the surgeon must be made aware of any history of bleomycin treatment; the clinician must also be certain that the anesthesiologist is familiar with the increased risk of pulmonary injury associated with a fractional concentration of oxygen in inspired gas of more than 0.3 and prior bleomycin treatment. Our case is similar to other cases of respiratory failure attributed to oxygen-exacerbated bleomycin toxicity reported in the literature. A

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surgical procedure before the administration of bleomycin was tolerated well despite intraoperative use of oxygen in a concentration of 100% for 90 minutes. After bleomycin treatment, a second surgical procedure during which the inspired oxygen concentration was increased to 70% for 30 minutes precipitated respiratory failure 42 hours later. Respiratory insufficiency responded to administration of high-dose corticosteroids and reduction of the inspired oxygen concentration to the lowest tolerable level. His uneventful recovery from three subsequent surgical procedures performed after corticosteroid pretreatment (even with an inspired oxygen concentration of 100%) suggests that corticosteroids may protect against oxygen-exacerbated bleomycin toxicity. The fact that the alveolar parenchyma remained histologically normal in tissue from different lobes of the lung after bleomycin-induced acute respiratory distress suggests that his recovery was complete. Bleomycin is a useful antineoplastic agent. Physician awareness and further understanding of bleomycin-oxygen interactions should help to prevent catastrophic side effects.

ACKNOWLEDGMENT We thank Thomas V. Colby, M.D., for interpreting the pathologic specimens and Sharon M. Peterson, Patricia A. Muldrow, and Lori L. Oeltjenbruns for secretarial assistance in preparing the submitted manuscript. REFERENCES 1.

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Oxygen-exacerbated bleomycin pulmonary toxicity.

Bleomycin is an antineoplastic agent with potential for producing pulmonary toxicity, attributed in part to its free radical-promoting ability. Clinic...
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