Is there a connection between earlier treatment with bleomycin and pulmonary injury due to hyperoxi

Fråga: Is there a connection between earlier treatment with bleomycin and pulmonary injury due to hyperoxia (Fraction inspired oxygen (FiO2) > 30%) during anaesthesia?

The question relates to a patient being treated with bleomycin one year ago. He is now going to be subjected to anaesthesia during a surgical procedure.

Sammanfattning: The evidence for oxygen-induced pulmonary damage during anaesthesia in patients earlier treated with bleomycin must be considered sparse and there is conflicting data in the literature regarding a worse prognosis for patients needing high FiO2. Available studies have unfortunately not been performed in a way that permits definitive conclusions regarding oxygen-induced pulmonary damage to be drawn, as there are to many confounding factors.

However, patients treated with bleomycin have an increased risk for pulmonary fibrosis and reduced diffusion capacity and must be considered as patients at increased risk when subjected to anaesthesia. To better evaluate these patients preoperatively, pulmonary function tests should be considered.

Svar: Bleomycin is an antitumor antibiotic isolated from the fungus Streptomyces verticillus. The action of the drug is mediated through DNA damage, which may lead to cell death either directly, or indirectly through apoptosis. Bleomycin has minimal myelotoxicity and is advantageous as an additional drug in chemotherapy regimens already limited by the extent of myelotoxicity. Bleomycin has been used primarily in the treatment of testicular cancers, lymphomas, and squamous cell carcinomas (1).

Pulmonary toxicity in the form of pulmonary fibrosis is a well-known complication to bleomycin therapy. The drug may produce subacute or chronic interstitial pneumonitis, which can develop into progressive interstitial fibrosis with hypoxia and ultimately death. The most important risk factor for developing pulmonary toxicity is cumulative dose of bleomycin and reported incidence of pulmonary injury is approximately 10% of all treated patients, depending on the definition of pulmonary toxicity (1). Mortality between 2 to 10 % of patients with pulmonary injury has been reported. The incidence of subclinical pulmonary injury is unknown.

In bleomycin-induced pulmonary fibrosis pulmonary function tests show a restrictive pattern with decreased total lung capacity, vital capacity, and carbon monoxide diffusion capacity (DLCO). DLCO has been found to be the most sensitive indicator of subclinical pulmonary injury from bleomycin, and DLCO declines progressively with increasing cumulative bleomycin dose (2).

In 1979 Goldiner et al published a study where the use of hyperoxia (FiO2 > 30%) in bleomycin treated patients during anaesthesia was questioned. In their study they retrospectively analyzed five patients subjected to retroperitoneal lymph node dissection or pulmonary wedge resection 6-12 months after bleomycin treatment. Average total doses of bleomycin were 426 mg with an average FiO2 of 39 % and procedure duration of 5.9 hours. All patients developed adult respiratory distress syndrome after 3-5 days and died of respiratory failure (3). The subsequent 12 patients, with similar medical history, were maintained on FiO2 < 25 %. These patients had no respiratory complications (3). The patients in these studies had documented restricted lung disease and decreased carbon monoxide diffusion capacity secondary to bleomycin treatment. The studies by Goldiner et al can be criticized for the small number of patients included and the first group being retrospectively studied and the second being studied prospectively with more invasive monitoring and restrictive fluid substitution than the first group. In conclusion these studies indicated a worse prognosis for patients needing higher FiO2.

In contrast to these studies La Mantia et al studied 13 patients undergoing abdominal or lung surgery at an average 6.1 months after bleomycin therapy (4). The mean bleomycin dose was 407 mg and the average FiO2 during surgery was 41%. In this study no patients developed respiratory complications after surgery. However, pulmonary function tests were not performed on all patients and the majority of patients receiving these tests had normal pulmonary function.

In a more recent study, including 77 patients, no connection between high FiO2 during anaesthesia and postoperative respiratory failure was seen in patients subjected to surgery after earlier bleomycin treatment (5). Fluid balance was singled out as the most critical factor in pulmonary morbidity, as the patients with post-operative pulmonary problems had a higher mean positive fluid balance.

Animal studies have not been able to demonstrate a relation between, or a plausible explanation for pulmonary damage in relation to delayed hyperoxia (1). Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999. p. B72-B73. Mathes DD. Bleomycin and hyperoxia exposure in the operating room. Anesth Analg 1995;81.624-9. Goldiner PL, Carlon GC, Cvitkovic E, Schweizer O, Howland WS. Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. Br Med J 1978;1:1664-7. Lamantia KR, Glick JH, Marshall BE. Supplemental oxygen does not cause respiratory failure in bleomycin-treated surgical patients. Anesthesiology 1984;60:65-7. Donat SM, Levy DA. Bleomycin associated pulmonary toxicity: is perioperative oxygen restriction necessary? J Urol 1998;160(4):1347-52.