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Oxygen-Exacerbated Bleomycin Pulmonary Toxicity

1991; Elsevier BV; Volume: 66; Issue: 2 Linguagem: Inglês

10.1016/s0025-6196(12)60489-3

1942-5546

THEODORE S. INGRASSIA, Jay H. Ryu, Victor F. Trastek, Edward C. Rosenow,

Brain Metastases and Treatment

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 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 verticillus.1Umezawa H Maeda K Takeuchi T Okami Y New antibiotics, bleomycin A and B.J Antibiot [A]. 1966; 19: 200-209PubMed Google Scholar 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.2Blum RH Carter SK Agre K A clinical review of bleomycin—a new antineoplastic agent.Cancer. 1973; 31: 903-914Crossref PubMed Scopus (688) Google Scholar 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.2Blum RH Carter SK Agre K A clinical review of bleomycin—a new antineoplastic agent.Cancer. 1973; 31: 903-914Crossref PubMed Scopus (688) Google Scholar, 3Cooper Jr, JAD White DA Matthay RA Drug-induced pulmonary disease. Part 1. Cytotoxic drugs.Am Rev Respir Dis. 1986; 133: 321-340PubMed Google Scholar, 4Scheulen ME Reduction of pulmonary toxicity.Cancer Treat Rev. 1987; 14: 231-243Abstract Full Text PDF PubMed Scopus (7) Google Scholar In addition, potentiation of bleomycin pulmonary toxicity has been reported in those patients who have also been exposed to thoracic radiation therapy5Samuels ML Johnson DE Holoye PY Lanzotti VJ Large-dose bleomycin therapy and pulmonary toxicity: a possible role of prior radiotherapy.JAMA. 1976; 235: 1117-1120Crossref PubMed Scopus (127) Google Scholar, 6Catane R Schwade JG Turrisi III, AT Webber BL Muggia FM Pulmonary toxicity after radiation and bleomycin: a review.Int J Radiat Oncol Biol Phys. 1979; 5: 1513-1518Abstract Full Text PDF PubMed Scopus (78) Google Scholar and hyperoxia.7Goldiner PL Carlon GC Cvitkovic E Schweizer O Howland WS Factors influencing postoperative morbidity and mortality in patients treated with bleomycin.Br Med J. 1978; 1: 1664-1667Crossref PubMed Scopus (163) Google Scholar In this report, we discuss a recent case in which hyperoxia likely precipitated bleomycin pulmonary toxicity, and we review the pertinent literature. 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 20-pack-year history of use of tobacco. A chest roentgenogram revealed a right-sided anterior mediastinal mass. A computed tomographic scan of the 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 of mixed malignant germ cell tumor. The preoperative human chorionic gonadotropin level, β subunit, was 10.2 IU/liter (normal, less than 2.5), and the α-fetoprotein level was 3,690 ng/ml (normal, less than 6). The 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 of the 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 of 2.51 liters (64% of predicted), a forced vital capacity of 3.24 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 ml/min per mm Hg (67% of predicted). He underwent wedge resection of nodules in the upper, middle, and lower lobes of the 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 of the operation; however, it was increased to 71% for 30 minutes when the right half of the 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. 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 H2O). Arterial blood gas analysis showed a partial pressure of oxygen of 68 mm Hg, a partial pressure of carbon dioxide of 37 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 m2. 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 cm H2O 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.Fig. 2Chest roentgenogram of same patient as depicted in Figure 1, obtained 2 days after initiation of treatment with intravenously administered corticosteroids. Note substantial clearing of pulmonary infiltrates.View Large Image Figure ViewerDownload (PPT) 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 unremarkable. The alveolar parenchyma surrounding the removed malignant tissue was again normal histologically. In October 1989, the patient experienced right hemiparesis, and a craniotomy was performed to remove a large intracerebral metastatic lesion. Because of increased intracranial pressure, he received dexamethasone preoperatively. The inspired oxygen concentration reached 100% intraoperatively, and he was given 100% oxygen by face mask in the recovery room. The patient had no postoperative pulmonary complications. In 1978, Goldiner and associates7Goldiner PL Carlon GC Cvitkovic E Schweizer O Howland WS Factors influencing postoperative morbidity and mortality in patients treated with bleomycin.Br Med J. 1978; 1: 1664-1667Crossref PubMed Scopus (163) Google Scholar described five consecutive patients who received 135 to 595 U of bleomycin for testicular cancer and subsequently had adult respiratory distress syndrome that progressed to death within 3 to 5 days after retroperitoneal lymph node biopsy or removal of pulmonary metastatic lesions. During the surgical procedure, they received supplemental oxygen (a mean of 39%; range, 35 to 42%). The operation was performed within 6 to 12 months after bleomycin treatment. Mechanical ventilatory support, positive end-expiratory pressure, and, in one case, extracorporeal membrane oxygenation for 8 days did not affect the outcome of the patients. Autopsy revealed increased lung size, increased lung weight, and abnormal amounts of interstitial fluid. Microscopic examination of lung tissue showed increased intra-alveolar exudates, hyaline membranes, interstitial fibrosis, and squamous metaplasia of type I and type II pneumonocytes. Twelve subsequent patients matched for age, dosage of bleomycin, and incidence of pulmonary problems were studied prospectively to determine whether the concentration of inspired oxygen and the amount of intravenous fluid administered intraoperatively contributed to postoperative respiratory failure. During and after operation, the inspired oxygen concentration was maintained between 22 and 25%, and the fluid balance was carefully monitored. None of the 12 patients had evidence of bleomycin-induced pulmonary toxicity. This experience first implicated oxygen in exacerbating bleomycin pulmonary toxicity, inasmuch as the mean inspired oxygen concentration of the survivors was 24% in comparison with 39% in the nonsurvivors. The nonsurvivors also received more crystalloid intraoperatively (5.86 ml/kg hourly versus 3.87 ml/kg hourly). Several other authors have reported the association of bleomycin-related pulmonary toxicity with increased inspired oxygen concentrations intraoperatively and postoperatively.8Gilson AJ Sahn SA Reactivation of bleomycin lung toxicity following oxygen administration.Chest. 1985; 88: 304-306Crossref PubMed Scopus (43) Google Scholar, 9Cersosimo RJ Matthews SJ Hong WK Bleomycin pneumonitis potentiated by oxygen administration.Drug Intell Clin Pharm. 1985; 19: 921-923PubMed Google Scholar Animals exposed to oxygen after bleomycin treatment have demonstrated a mortality up to 15 times that among those treated with bleomycin alone.10Tryka AF Skornik WA Godleski JJ Brain JD Potentiation of bleomycin-induced lung injury by exposure to 70% oxygen.Am Rev Respir Dis. 1982; 126: 1074-1079PubMed Google Scholar, 11Rinaldo J Goldstein RH Snider GL Modification of oxygen toxicity after lung injury by bleomycin in hamsters.Am Rev Respir Dis. 1982; 126: 1030-1033PubMed Google Scholar, 12Tryka AF Godleski JJ Brain JD Differences in effects of immediate and delayed hyperoxia exposure on bleomycin-induced pulmonary injury.Cancer Treat Rep. 1984; 68: 759-764PubMed Google Scholar, 13Hay JG Haslam PL Dewar A Addis B Turner-Warwick M Laurent GJ Development of acute lung injury after the combination of intravenous bleomycin and exposure to hyperoxia in rats.Thorax. 1987; 42: 374-382Crossref PubMed Scopus (27) Google Scholar In contrast, Douglas and Coppin14Douglas MJ Coppin CML Bleomycin and subsequent anaesthesia: a retrospective study at Vancouver General Hospital.Can Anaesth Soc J. 1980; 27: 449-452Crossref PubMed Scopus (18) Google Scholar 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 colleagues15Einhorn LH Williams SD Mandelbaum I Donohue JP Surgical resection in disseminated testicular cancer following chemotherapeutic cytoreduction.Cancer. 1981; 48: 904-908Crossref PubMed Scopus (146) Google Scholar 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 of how 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.16Burger RM Peisach J Horwitz SB Mechanism of bleomycin action: in vitro studies.Life Sci. 1981; 28: 715-727Crossref PubMed Scopus (127) Google Scholar, 17Yamauchi T Raffin TA Yang P Sikic BI Differential protective effects of varying degrees of hypoxia on the cytotoxicities of etoposide and bleomycin.Cancer Chemother Pharmacol. 1987; 19: 282-286Crossref PubMed Scopus (16) Google Scholar, 18Cutroneo KR Sterling Jr, KM The biochemical and molecular bases of bleomycin-induced pulmonary fibrosis.Focus Pulmon Pharmacol Toxicol. 1988; 1: 1-22Crossref Google Scholar The genotoxicity of bleomycin is increased in the presence of 70% oxygen.19Cederberg H Ramel C Modifications of the effect of bleomycin in the somatic mutation and recombination test in Drosophila melanogaster.Mutat Res. 1989; 214: 69-80Crossref PubMed Scopus (27) Google Scholar The addition of superoxide dismutase, an antioxidant enzyme, to cell cultures pretreated with bleomycin attenuates the cytotoxicity of bleomycin.20Cunningham ML Ringrose PS Lokesh BR Inhibition of the genotoxicity of bleomycin by superoxide dismutase.Mutat Res. 1984; 135: 199-202Crossref PubMed Scopus (59) Google Scholar, 21Borek C Troll W Modifiers of free radicals inhibit in vitro the oncogenic actions of x-rays, bleomycin, and the tumor promoter 12-O-tetradecanoylphorbol 13-acetate.Proc Natl Acad Sci U S A. 1983; 80: 1304-1307Crossref PubMed Scopus (121) Google Scholar 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.22Larramendy ML Bianchi MS Padrón J Correlation between the anti-oxidant enzyme activities of blood fractions and the yield of bleomycin-induced chromosome damage.Mutat Res. 1989; 214: 129-136Crossref PubMed Scopus (20) Google Scholar Free radicals generated by bleomycin are also thought to participate in oxidation-reduction reactions that damage cell membranes and proteins.23Heffner JE Repine JE Pulmonary strategies of antioxidant defense.Am Rev Respir Dis. 1989; 140: 531-554Crossref PubMed Scopus (493) Google Scholar Bleomycin seems to be concentrated in lung tissue, where tissue oxygen tensions are highest.24Ohnuma T Holland JF Masuda H Waligunda JA Goldberg GA Microbiological assay of bleomycin: inactivation, tissue distribution, and clearance.Cancer. 1974; 33: 1230-1238Crossref PubMed Scopus (106) Google Scholar Bleomycin may be indirectly toxic to the lung by activating certain cell types, the mediators of which exacerbate the toxicity of bleomycin.18Cutroneo KR Sterling Jr, KM The biochemical and molecular bases of bleomycin-induced pulmonary fibrosis.Focus Pulmon Pharmacol Toxicol. 1988; 1: 1-22Crossref Google Scholar, 25Cooper Jr, JAD Zitnik RJ Matthay RA Mechanisms of drug-induced pulmonary disease.Annu Rev Med. 1988; 39: 395-404Crossref PubMed Scopus (46) Google Scholar Bronchoalveolar lavage fluid from patients with bleomycin-induced pulmonary toxicity has been noted to have increased numbers of lymphocytes and polymorphonuclear leukocytes.26White DA Kris MG Stover DE Bronchoalveolar lavage cell populations in bleomycin lung toxicity.Thorax. 1987; 42: 551-552Crossref PubMed Scopus (39) Google Scholar 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.27Fahey PJ Utell MJ Mayewski RJ Wandtke JD Hyde RW Early diagnosis of bleomycin pulmonary toxicity using bronchoalveolar lavage in dogs.Am Rev Respir Dis. 1982; 126: 126-130PubMed Google Scholar 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.18Cutroneo KR Sterling Jr, KM The biochemical and molecular bases of bleomycin-induced pulmonary fibrosis.Focus Pulmon Pharmacol Toxicol. 1988; 1: 1-22Crossref Google Scholar Another proposed mechanism for bleomycin-induced toxicity involves a direct effect on transcription within the fibroblast, increasing the production of collagen.18Cutroneo KR Sterling Jr, KM The biochemical and molecular bases of bleomycin-induced pulmonary fibrosis.Focus Pulmon Pharmacol Toxicol. 1988; 1: 1-22Crossref Google Scholar, 19Cederberg H Ramel C Modifications of the effect of bleomycin in the somatic mutation and recombination test in Drosophila melanogaster.Mutat Res. 1989; 214: 69-80Crossref PubMed Scopus (27) Google Scholar, 20Cunningham ML Ringrose PS Lokesh BR Inhibition of the genotoxicity of bleomycin by superoxide dismutase.Mutat Res. 1984; 135: 199-202Crossref PubMed Scopus (59) Google Scholar, 21Borek C Troll W Modifiers of free radicals inhibit in vitro the oncogenic actions of x-rays, bleomycin, and the tumor promoter 12-O-tetradecanoylphorbol 13-acetate.Proc Natl Acad Sci U S A. 1983; 80: 1304-1307Crossref PubMed Scopus (121) Google Scholar, 22Larramendy ML Bianchi MS Padrón J Correlation between the anti-oxidant enzyme activities of blood fractions and the yield of bleomycin-induced chromosome damage.Mutat Res. 1989; 214: 129-136Crossref PubMed Scopus (20) Google Scholar, 23Heffner JE Repine JE Pulmonary strategies of antioxidant defense.Am Rev Respir Dis. 1989; 140: 531-554Crossref PubMed Scopus (493) Google Scholar, 24Ohnuma T Holland JF Masuda H Waligunda JA Goldberg GA Microbiological assay of bleomycin: inactivation, tissue distribution, and clearance.Cancer. 1974; 33: 1230-1238Crossref PubMed Scopus (106) Google Scholar, 25Cooper Jr, JAD Zitnik RJ Matthay RA Mechanisms of drug-induced pulmonary disease.Annu Rev Med. 1988; 39: 395-404Crossref PubMed Scopus (46) Google Scholar, 26White DA Kris MG Stover DE Bronchoalveolar lavage cell populations in bleomycin lung toxicity.Thorax. 1987; 42: 551-552Crossref PubMed Scopus (39) Google Scholar, 27Fahey PJ Utell MJ Mayewski RJ Wandtke JD Hyde RW Early diagnosis of bleomycin pulmonary toxicity using bronchoalveolar lavage in dogs.Am Rev Respir Dis. 1982; 126: 126-130PubMed Google Scholar, 28Cutroneo KR Sterling Jr, KM A molecular basis for bleomycin-induced pulmonary fibrosis.Chest. 1986; 89: 121S-122SCrossref PubMed Scopus (9) Google Scholar 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.29Deneke SM Fanburg BL Normobaric oxygen toxicity of the lung.N Engl J Med. 1980; 303: 76-86Crossref PubMed Scopus (313) Google Scholar, 30Jackson RM Pulmonary oxygen toxicity.Chest. 1985; 88: 900-905Crossref PubMed Scopus (158) Google Scholar 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.31Clark JM Lambertsen CJ Pulmonary oxygen toxicity: a review.Pharmacol Rev. 1971; 23: 37-133PubMed Google Scholar The clinical and pathologic features of oxygen-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.32Lower EE Strohofer S Baughman RP Bleomycin causes alveolar macrophages from cigarette smokers to release hydrogen peroxide.Am J Med Sci. 1988; 295: 193-197Crossref PubMed Scopus (26) Google Scholar Prior radiation therapy increases the incidence of bleomycin-induced pulmonary fibrosis and may influence the likelihood of a toxic oxygen interaction as well.3Cooper Jr, JAD White DA Matthay RA Drug-induced pulmonary disease. Part 1. Cytotoxic drugs.Am Rev Respir Dis. 1986; 133: 321-340PubMed Google Scholar, 4Scheulen ME Reduction of pulmonary toxicity.Cancer Treat Rev. 1987; 14: 231-243Abstract Full Text PDF PubMed Scopus (7) Google Scholar Reports of treatment of bleomycin-induced pulmonary toxicity have been mainly anecdotal. Gilson and Sahn8Gilson AJ Sahn SA Reactivation of bleomycin lung toxicity following oxygen administration.Chest. 1985; 88: 304-306Crossref PubMed Scopus (43) Google Scholar 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-workers7Goldiner PL Carlon GC Cvitkovic E Schweizer O Howland WS Factors influencing postoperative morbidity and mortality in patients treated with bleomycin.Br Med J. 1978; 1: 1664-1667Crossref PubMed Scopus (163) Google Scholar with oxygen-exacerbated bleomycin pulmonary toxicity suggested that potentially fatal reactions could be avoided by maintaining an intraoperative inspired oxygen concentration of less than 30% and by close monitoring of replacement of fluids to avoid overhydration. Gilson and Sahn8Gilson AJ Sahn SA Reactivation of bleomycin lung toxicity following oxygen administration.Chest. 1985; 88: 304-306Crossref PubMed Scopus (43) Google Scholar suggested prophylactic administration of corticosteroids in bleomycin-treated 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.33Conley NS Yarbro JW Ferrari HA Zeidler RB Bleomycin increases superoxide anion generation by pig peripheral alveolar macrophages.Mol Pharmacol. 1986; 30: 48-52PubMed Google Scholar 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 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.