Is hyperoxia exposure (FIO2 >or=to 30%) in a patient previously treated with bleomycin (BLM) safe? This question is controversial and has elicited many conflicting case reports and studies.
This paper examines the following: 1) the history of BLM use; 2) the mechanism of damage and pharmacokinetics of BLM; 3) the risk factors predisposing the patients to pulmonary toxicity from BLM; 4) conflicting case studies of BLM-treated patients and hyperoxia exposure; 5) animal studies on BLM hyperoxia exposure which help explain the conflicting human data; and 6) a new chemotherapy drug which may replace BLM.
Pharmacology of BLM
BLM is an antitumor antibiotic isolated from the fungus Streptomyces verticillus in 1966 . BLM has minimal myelotoxicity and thus is advantageous as an additional drug in chemotherapy regimens already limited by the extent of myelotoxicity. BLM has been used primarily in the treatment of testicular cancers, lymphomas, and squamous cell carcinomas .
Mechanism of Damage
BLM is composed of two major structures which facilitate binding both ferrous (Fe II) iron and the deoxyribonucleic acid (DNA) within the cell. A bithiazole portion intercalates with the DNA helix and a pyrimidine and imidazole component binds to iron and oxygen [3,4]. Upon exposure to molecular oxygen, the ferrous BLM compound is oxidized to an activated ferric (Fe III) BLM compound and the bound molecular oxygen is reduced to oxygen-free radicals, including superoxide and hydroxyl radicals Figure 1[3,4]. The combination of activated Fe (III) BLM and release of oxygen-free radicals in close proximity to the already partially intercalated BLM DNA complex causes DNA cleavage and subsequent cell damage . Furthermore, activated Fe (III)-BLM and oxygen-free radicals initiate lipid peroxidation (decomposition of long-chain unsaturated fatty acids) leading to cell membrane destruction independent of DNA destruction [3,5,6].
BLM is eliminated primarily by renal excretion with approximately 50% of the dose cleared within 4 h and 70% by 24 h [3,4]. Renal insufficiency can markedly decrease clearance of BLM, but renal clearance of BLM is not affected unless creatinine clearance is less than 35 mL/min .
On a cellular level, inactivation of BLM is accomplished through a detoxifying enzyme known as BLM hydrolase . The enzyme BLM hydrolase cleaves a particular amide group within the pyrimidine component of BLM that binds iron and other metal ions . This cleavage results in the inability of BLM to bind a metal ion cofactor and BLM is thus inactivated.
The enzyme BLM hydrolase is found in all cells, but is lowest in skin and lung and particularly in the alveolar epithelium cells [3,4,8]. Hence, the primary toxicity of BLM occurs at the lung and skin. Likewise, minimal myelosuppression occurs in bone marrow where BLM hydrolase activity is high.
BLM Pulmonary Toxicity
The sequence of BLM lung injury has been well studied in rodent and other animal models. The initial injury after intravenous BLM occurs within the pulmonary endothelium . Subsequently, the capillary endothelium becomes separated from the basement membrane, resulting in increased permeability and interstitial edema [9,10]. The increased permeability of the vascular endothelium allows BLM to reach the alveolar epithelial cells in high concentrations. This results in necrosis of the Type I alveolar epithelium (pneumocytes) and increased migration of intraalveolar macrophages.
These intraalveolar macrophages release chemoattractant factors that recruit further inflammatory cells such as neutrophils . Also, the alveolar macrophages with BLM exposure release further oxygen radicals and appear to release growth factors that increase fibroblast activity [12-14]. The increased fibroblast activity is followed by increased collagen synthesis and decreased collagen degradation leading to pulmonary fibrosis. The level of enzyme activity of prolyl hydroxylase, a key enzyme responsible for the production of collagen by fibroblast, has been shown in rodents to increase after BLM exposure [10,15,16].
Normally, after limited exposure to BLM, the damaged Type I alveolar epithelial cells are replaced by slower growing Type II epithelial cells that transform back into Type I cells with little or no fibrosis. However, after repeated exposure, BLM is able to damage the more resilient, slower growing Type II cells [9,17]. The damaged Type II cells undergo abnormal differentiation into metaplastic cuboidal cells and thus prevent effective repair of the alveolar epithelium . This lack of adequate repair of alveolar epithelium, along with continued pulmonary endothelium damage with repeat BLM exposure, allows fibroblasts to continue to migrate into the alveoli and interstitium and pulmonary fibrosis occurs.
Several factors increase the risk of BLM pulmonary toxicity, including total dose, radiation therapy, age, other concurrent chemotherapy, and renal insufficiency. A linear increase in pulmonary toxicity occurs at total doses of more than 450 mg [often referred in the literature as units of cytotoxic activity, with 1 U approximately equaling 1 mg ], but severe pulmonary toxicity can occur with much smaller doses [18,19]. In rare instances, a steroid-responsive hypersensitive pneumonitis can occur with small doses of BLM .
Patients older than 70 yr have increased risk of BLM pulmonary toxicity . Prior or concurrent radiation therapy to the chest increases the risk of BLM pulmonary toxicity [22,23]. Multiple chemotherapy combinations often used in the treatment of lymphomas, especially the combination of cyclophosphamide with BLM, have been associated with increasing pulmonary toxicity [18,24]. Cis-platinum, a known nephrotoxic agent, is often given with BLM in the treatment of testicular cancer. Cis-platinum renal damage may increase the toxicity because of delayed renal clearance of BLM .
At present, the use of hyperoxia (FIO2 >or=to 30%) with BLM is a controversial topic. There are many conflicting studies and case reports in the literature on the safety of hyperoxia exposure to BLM-treated patients. Goldiner et al. [26,27] reported in 1979 five consecutive patients undergoing retroperitoneal node dissection or wedge resections of the lung 6-12 mo after receiving BLM. Average total doses of BLM were 426 mg with an average FIO2 of 39% and a duration of 5.9 h. These five patients subsequently developed adult respiratory distress syndrome (ARDS) at 3-5 days after surgery and died of respiratory failure. Postmortem autopsies showed severe alveolar wall damage compatible with previously described BLM pulmonary injury. The subsequent 12 patients Goldiner and Schweizer  studied with similar medical profiles were maintained on FIO2 <or=to 25%. These patients had no reported respiratory complications. Both groups showed similar restrictive lung changes and decreases in diffusion capacity. Goldiner and Schweizer  also reported more than 200 subsequent BLM-treated patients given <or=to25% FIO2 in the operating room who developed no respiratory complications.
The Goldiner et al. [26,27] articles are considered the landmark articles supporting the use of low FIO2. However, other authors have been skeptical of Goldiner et al.'s recommendation of using low FIO2. These criticisms focus on the small number of patients in Goldiner et al.'s study and the fact that their first group of patients was studied retrospectively and the second group was studied prospectively with more invasive monitoring .
In contrast to Goldiner et al., La Mantia et al.  studied 13 patients undergoing abdominal or lung surgeries similar to those in the Goldiner group. The mean BLM dose was 407 mg with the average duration between the last BLM dose and surgery being 6.1 mo and an average FIO2 of 41% during intraoperative and postoperative periods . This group was similar to the Goldiner BLM hyperoxia fatal group, but La Mantia et al.'s group had no respiratory complications. La Mantia et al.  concluded that higher oxygen concentrations were safe in the operating room with BLM-treated patients. However, one difference between these two studies was that Goldiner et al. had documented restricted lung disease and decreased carbon monoxide diffusion capacity secondary to BLM treatment [26,29]. La Mantia et al. did not do pulmonary function tests on all his patients and the majority of the patients receiving these tests were normal. Hence, preexisting BLM lung damage, as evidenced by pulmonary function tests, may be a key factor in the risk of hyperoxia lung injury with BLM. Most notably, the measurement of single breath carbon monoxide diffusing capacity (DLCO) has been found to be the most sensitive indicator of subclinical pulmonary damage from BLM . One should consider a decrease of 10%-15% from baseline DLCO a marker of subclinical pulmonary damage until further studies determine what decrease in the DLCO significantly increases the risk of hyperoxia exposure .
Douglas and Coppin  did a retrospective study on 14 patients who had received an average of 296 mg of BLM and subsequently underwent general anesthesia with a FIO2 >30%. Only one patient developed respiratory failure after undergoing bronchoscopy and mediastinoscopy with a FIO2 of 50%-100% for 95 min. Of interest, this patient had several risk factors for BLM pulmonary injury, including age, renal impairment from prior cis-platinum treatment, documented decreased diffusion capacity, interstitial changes on chest radiograph 3 mo prior to surgery, and a short interval of 3 mo from the last BLM dose. They concluded that BLM patients with resulting pulmonary damage are at the greatest risk for hyperoxia causing respiratory failure.
A short interval between the last BLM dose and exposure to hyperoxia may increase the risk of respiratory failure. Three case reports illustrate this potential risk. Hulbert et al.  reported a 21-yr-old patient who underwent a retroperitoneal exploration on a FIO2 of 40% for 9.5 h. The patient had received a total of 360 mg of BLM with the last dose being administered 10 days prior to surgery. The patient developed postoperative respiratory failure and subsequently died. Ingrassia et al.  reported that a 28-yr-old man with testicular cancer underwent resection of a residual pulmonary metastatic lesion for 4 h on a FIO2 of 33%, except for 30 min of 71% FIO2 during one-lung ventilation . The patient received a total of 240 mg of BLM with the last dose 20 days before surgery. On postoperative Day 2, the patient developed ARDS but was successfully extubated and remained on room air after high-dose corticosteroids. Eleven months later, this patient, who had received dexamethasone preoperatively, was given a general anesthetic with 100% FIO2 and experienced no respiratory complications. Gilson and Sahn  reported that a 29-yr-old man with testicular cancer developed interstitial pneumonitis after receiving a total of 120 mg of BLM with a marked decrease in diffusion capacity to 32% and forced vital capacity of 43% of the predicted levels. Prednisone therapy 60 mg/day was begun with improvement of diffusion capacity to 62% and forced vital capacity to 73%. Four months later the patient underwent retroperitoneal node dissection on 33% FIO2 for 10 h. On postoperative Day 3 the patient developed ARDS and was placed on methylprednisolone and his respiratory status rapidly improved. Case reports by both Ingrassia et al.  and Gilson and Sahn  raise an interesting question on the use of prophylactic corticosteroids with hyperoxia and BLM exposure. Further studies are needed to examine this question.
To begin to understand the conflicting reports of hyperoxia exposure and BLM in the operating room one must review the studies in the animal model. Although many of these animal studies have limited application to humans, they are the only way to examine, in a controlled fashion, the various factors seen in the operating room. These animal studies were often limited by such factors as the intratracheal mode of administration, significantly higher doses of BLM being used on a milligram per kilogram basis, prolonged hyperoxia exposure not seen in the operating room, and species specific effects of BLM .
Clearly, upon reviewing the animal model literature, the use of continuous FIO2 >or=to30% immediately after exposure to BLM increases pulmonary damage with increased interstitial and alveolar edema and pulmonary fibrosis. These effects were not seen in control groups with BLM and room air, or continuous exposure to an increased FIO2 but no BLM [37-40]. Also, the more the FIO2 exceeded 30%, the more extensive was the pulmonary damage [38,39]. Hay et al.  found that as little as 4 h of 70% O2 exposure immediately after intravenous BLM caused increased interstitial edema not seen with BLM alone. Shen et al.  found that as little as 2 min of 100% O2 exposure immediately after intratracheal BLM in rabbits enhanced pulmonary toxicity. Thus, hyperoxia exposure shortly after BLM administration synergistically increases the pulmonary toxicity of BLM in many animal models.
However, the anesthesiologist does not normally find patients in the operating room with prolonged hyperoxia exposure for >24 h or hyperoxia exposure immediately after BLM. A more practical question for the anesthesiologist is whether delayed hyperoxia exposure for short periods is a risk factor for BLM damage.
Hay et al.  studied delayed hyperoxia exposure in rats treated with intravenous BLM. They used increases in pulmonary extravascular albumin as a marker for pulmonary damage after acute oxygen exposure and delayed hyperoxia exposure at Days 1, 3, and 7 post-BLM. They found significant decreases in total pulmonary extravascular albumin when exposed to 90% O2 after 1 and 3 days post-BLM compared to acute exposure to oxygen, but still found extravascular albumin increased over controls exposed to BLM and room air. However, 7 days after BLM exposure, the rats given 48 h of 90% FIO2 showed no increase in pulmonary extravascular albumin compared to controls.
Hay et al.  studied radiolabeled BLM clearance from the lung. BLM peak concentration occurs 1 h after injection with 0.2% of intravenous dose reaching the lung. This is followed by a rapid decline in the lung and plasma over the first 24 h, then first order decay decline of BLM in the lung with t1/2 approximately 3 days. They concluded that adequate clearance of BLM from the lung was an important factor in preventing hyperoxia toxicity as evidenced by lack of hyperoxia toxicity seen at 7 days versus 1 and 3 days post-BLM exposure.
Of interest, Hay et al.  found no evidence of any increased pulmonary damage with immediate or delayed hyperoxia exposure in the group of rats that received 0.15 mg of BLM (0.5 to 0.75 mg/kg), which is much closer to the actual dose given in adults . This is one of the major criticisms of extrapolating to humans the results of animal models using higher doses of BLM . However, Adamson and Bowden  showed in mice that BLM may continue to accumulate in the lung with repeated low doses of BLM. This accumulation may be a particular concern in patients with renal insufficiency.
Several other animal studies have confirmed that delayed hyperoxia exposure after BLM is not harmful [42-46]. Blom-Muilwijk et al.  found that 4 h exposure to 50% FIO2 1 mo after 6 wk of intraperitoneal injection of BLM in doses higher than used in humans caused no increase in lung toxicity. Hakkinen et al.  found increased hydroxyproline (a marker of collagen production) in the lungs of mice exposed to 70% FIO2 within 8 days of BLM exposure, but no increase in hydroxyproline with 72 h of 70% FIO2 on Days 9-16 . Rinaldo et al.  found a significant decrease in the extent of pulmonary injury in hamsters exposed to prolonged 60% FIO2 at 21 days compared to 8 days after intratracheal BLM.
Tryka et al.  found exposure to 72 h of 70% FIO2 immediately after intratracheal BLM greatly enhanced the extent of pulmonary damage compared to room air exposure. However, exposure to 72 h of 70% FIO2 30 and 60 days after intratracheal BLM showed no increase in pulmonary damage compared to controls with room air. They concluded that BLM is not synergistic in causing pulmonary injury if hyperoxia exposure was 1 mo after BLM exposure . Matalon et al. , finding no enhancement in pulmonary injury from 100% FIO2 exposure 21 days after intravenous BLM exposure, concluded that hyperoxia use in the operating room was safe.
Thus, from the animal models, the risk of hyperoxia-induced BLM pulmonary toxicity is greatly lowered or not a factor when hyperoxia exposure is delayed. Yet these animal data do not explain the many case reports of respiratory failure with FIO2 >or=to30% in patients last exposed to BLM up to 6-12 mo before hyperoxia exposure. The anesthesiologist needs to consider many other possible risk factors for hyperoxia exposure. As discussed, these include: 1) prior residual pulmonary injury from BLM; 2) renal insufficiency with creatinine clearance <35 mL/min; or 3) a large total dose, each of which may make delayed hyperoxia exposure still a significant risk factor.
Another potential risk factor may be a genetic predisposition to BLM pulmonary injury from hyperoxia exposure [10,18]. This hypothesis has not been verified, but different species and strain variations of animals have markedly different pulmonary responses to BLM exposure . Also, idiopathic pulmonary fibrosis has been linked with the major histocompatibility complex HLA-DR2 . A genetic predisposition toward BLM toxicity would explain the case reports of pulmonary fibrosis occurring with small doses of BLM such as 50 mg, despite other individuals having no evidence of pulmonary toxicity with doses as high as 700 mg. The activity level of the enzyme BLM hydroxylase in the lung may vary greatly among individuals. This would also explain the many contradictory case reports on the danger or safety of hyperoxia exposure in the operating room.
Two major risk factors have been linked to hyperoxia exposure (FIO2 >or=to30%) and BLM pulmonary damage. These major risk factors include either of the following: 1) patients with evidence of preexisting pulmonary injury from BLM; or 2) prior exposure to BLM within a 1- to 2-mo period. Other risk factors discussed for BLM pulmonary damage, specifically, a total dose of BLM >450 mg, or a creatinine clearance <35 mL/min are not, in themselves, likely risk factors for hyperoxia exposure. Instead, these risk factors may lead to BLM pulmonary damage and delayed clearance of BLM from the lung, and subsequently increase the risk of hyperoxia exposure. Thus, the anesthesiologist needs to review each patient individually for risk factors for hyperoxia exposure.
Patients with prior exposure to BLM, but with no risk factors, appear to be at minimum risk from hyperoxia exposure. However, those individuals with one or more major risk factors are at a higher risk for the development of BLM and hyperoxia pulmonary injury in the operating room. These patients should be maintained on the minimum FIO2 that can be used safely in the operating room to provide O2 saturation of >or=to90% by pulse oximetry. In those surgical procedures in which higher FIO2 concentrations are normally needed, more invasive monitoring, such as continuous mixed venous oximetry, may allow the anesthesiologist to minimize FIO (2) concentrations safely . Also, several authors have supported pretreatment with corticosteroids in patients with risk factors in which greater than 30% FIO (2) may be used [34,35]. However, no controlled studies have been done to support pretreatment with corticosteroids.
More case reports and studies need to examine the above-mentioned risk factors. Indeed, a large multicenter prospective trial and retrospective review are needed to examine hyperoxia and BLM exposure, and especially to identify risk factors, including genetic markers .
In the future, BLM may become obsolete. Peplomycin is a new analog of BLM which has lower pulmonary toxicity and a broader effectiveness against multiple types of tumors [18,51]. Currently, peplomycin is being used for a wide range of cancers, including prostatic, testicular, and head and neck, with minimal pulmonary toxicity observed [51-53]. The effects of hyperoxia exposure with peplomycin should also be evaluated.
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