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Ann Thorac Surg 2007;84:982-986
© 2007 The Society of Thoracic Surgeons
The University of Texas, MD Anderson Cancer Center, Houston, Texas
Accepted for publication March 19, 2007.
* Address correspondence to Dr Bakaeen, Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd, OCL (112), Houston, TX 77030 (Email: fbakaeen{at}bcm.edu).
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Abstract |
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Methods: Between March 1, 1999, and July 1, 2004, 27 (52%) of 52 patients who underwent extrapleural pneumonectomy received half-dose aprotinin (1 million kallikrein inhibition units load; 250,000 kallikrein inhibition units per hour infusion). A retrospective data review and analysis were performed.
Results: The mean age was 59.8 ± 11 years, and 45 of 52 patients (87%) were male. Indications for extrapleural pneumonectomy were malignant pleural mesothelioma (n = 50) and pleural-based sarcoma (n = 2). The administration of aprotinin had no significant effect on intraoperative blood loss (1,010 ± 599 versus 1,182 ± 688 mL; p = 0.34) or units of packed red blood cells transfused intraoperatively (2.0 ± 1.7 versus 1.9 ± 1.7 units; p = 0.86). None of the patients who received aprotinin required the use of non–packed red blood cells blood products, but 4 patients (16%) who did not receive aprotinin required such transfusion (p < 0.05). Postoperative chest tube output at 12 and 24 hours was lower in the aprotinin group (381 ± 195 and 867 ± 313 mL, respectively) compared with the control group (725 ± 527 and 1,221 ± 442 mL, respectively; p < 0.03). There was no significant difference in incidence of postoperative thromboembolic events between the aprotinin and the control group (5 versus 4 patients; p = 1.0), and 2 patients in each group experienced renal insufficiency (p = 1.0).
Conclusions: Half-dose aprotinin did not decrease intraoperative blood loss or packed red blood cells transfusion in extrapleural pneumonectomy. However, use of aprotinin was associated with decreased use of non–packed red blood cells blood products and lower postoperative chest tube output. Aprotinin administration was not associated with an increase in incidence of postoperative complications.
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Introduction |
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Complex thoracic procedures involving extensive dissection in the setting of bulky tumors or a hostile infected field often create a raw surface that is a source of troublesome hemorrhage. The accelerated rate of fibrinolysis associated with thoracic procedures [10, 11] is thought to exacerbate the bleeding, hence, the premise of using aprotinin, a potent antifibrinolytic, in an effort to reduce blood loss in thoracic surgery. Two randomized trials demonstrated a reduction in blood loss by aprotinin in thoracic surgical operations and a decrease in blood transfusion requirements in operations associated with a high risk of bleeding [12, 13]. Neither of the latter two studies nor others published in the literature evaluated the specific use of aprotinin in extrapleural pneumonectomy (EPP), a procedure frequently associated with significant bleeding owing to oozing from a large area of pleurectomized chest wall.
Recent studies of patients undergoing cardiac surgery [14, 15] stirred much controversy by concluding that aprotinin use was associated with end-organ damage. Therefore, the aims of this study were to examine whether use of aprotinin in EPP was associated with a reduction of intraoperative bleeding and to investigate whether it influenced operative morbidity, with particular emphasis on its effect on the incidence of renal, cardiac, cerebral, and thromboembolic events.
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Material and Methods |
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The aprotinin "half dose regimen" used consisted of a 10,000 kallikrein inhibition units test dose that preceded a 1,000,000 kallikrein inhibition units loading dose that was followed by a 250,000 kallikrein inhibition units per hour constant infusion. Aprotinin was started in the operating room before making the skin incision and was continued during the procedure. The infusion was generally stopped postoperatively in the intensive care unit when the last drip bottle was completed. Patients who did not receive aprotinin were designated as control subjects. This is a retrospective study, and there were no specific criteria or indications governing the use of aprotinin; however surgeons were more likely to use aprotinin during the later years of the study.
Data on a number of variables including patient demographics, risk factors, relevant medications, and operative details were collected. In addition, preoperative and postoperative laboratory values of hemoglobin, hematocrit, platelet count, activated partial thromboplastin, and prothrombin time were recorded. The number of units of packed red blood cells (PRBCs), fresh-frozen plasma, and platelets transfused intraoperatively and postoperatively were accurately recorded. We chose to quantify blood product transfusions up to postoperative day five, as this reflected the perioperative period of interest. Blood transfusion during this period was most likely administered to replenish loss incurred directly by surgery. The chest tube output at 12 and 24 hours after surgery was recorded. Time to chest drain removal was not measured as chest drains were routinely removed at 24 to 36 hours after surgery, independent of the quantity of drainage. All postoperative events were recorded prospectively in a departmental quality assurance database. All patient records were reviewed to ensure accuracy of the collected data. Specific attention was directed toward postoperative renal insufficiency and thromboembolic events that included myocardial infarction, neurologic adverse events, deep venous thrombosis, and pulmonary embolism.
The criteria for myocardial infarction were chest pain, congestive heart failure, or hemodynamic changes associated with electrocardiographic changes or elevation in cardiac enzymes. Renal insufficiency was defined as the need for dialysis or elevation of plasma creatinine (more than twice the preoperative value) with or without oliguria or anuria. Adverse neurologic outcome included all focal neurologic deficits, either transient or permanent. It excluded nonspecific confusion or delirium episodes that were not associated with imaging abnormalities (computerized tomography or magnetic resonance imaging) or were not labeled as defined deficits by the evaluating neurology consulting service.
Continuous values were expressed as mean ± standard deviation. The unpaired Student’s t test was performed for comparisons of continuous variables between groups (Tables 1, 2).
Categorical variables were analyzed with Fisher’s exact test and Pearson 
2 test. The level of significance was set as p less than 0.05. The data were analyzed with statistical package program SPSS 13.0 (Chicago, IL).
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Results |
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All patients had sequential pneumatic compressors applied to both lower extremities as part of the operating room protocol for major thoracic procedures. A subcutaneous prophylactic dose of heparin (5,000 units) was administered to 4 patients (15%) who received aprotinin and 6 patients (24%) who did not receive aprotinin (p = 0.34). Thirteen patients (48%) in the aprotinin group underwent a right-side EPP, and 17 (68%) of the control subjects underwent EPP on the right side (p = 0.15). The duration of the procedure was similar in the two groups: 7.90 ± 1.3 and 7.70 ± 2.0 hours in the aprotinin group and the control subjects, respectively (p = 0.61).
Blood Loss and Transfusions
The intraoperative blood loss and perioperative PRBC transfusions were similar in the aprotinin and control groups (Table 3). Non-PRBC blood products were not used intraoperatively in either group. However, postoperatively fresh-frozen plasma and platelets were administered to 4 patients (16%) who did not receive aprotinin. None of the patients who received aprotinin required non-PRBC transfusions (p < 0.05). There was no difference in the laboratory values of hemoglobin and hematocrit measured postoperatively in both groups. Figure 1
demonstrates less blood shed through chest tubes in the aprotinin group compared with controls at 12 and 24 hours.
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Comment |
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Aprotinin inhibits several serine proteases, including kallikrein and plasmin. Through those actions, aprotinin slows fibrinolysis and reduces bleeding [18]. Isolated studies documented the potential benefits of aprotinin as a blood-conserving agent in complicated thoracic procedures, including surgery for inflammatory and infectious disease, reoperations, and extensive resections [12, 13]. The literature is devoid of studies specifically addressing the use of aprotinin in patients undergoing EPP. Extrapleural pneumonectomy generates an extensive raw surface of pleurectomized chest cavity in the setting of a significant tumor burden. Such a milieu is likely to trigger bleeding cascades that could be blunted by the administration of aprotinin and potentially translate into a reduction in blood loss and transfusion requirements in patients undergoing EPP.
In this study, the use of non-PRBC blood products was less frequent when aprotinin was used. In addition postoperative chest tube output was less in the aprotinin-receiving group of patients. Such difference in the shed volume through chest tubes did not however result in a significant reduction in PRBC transfusions. That may be because the difference in chest tube output did not translate into a difference in postoperative hemoglobin and hematocrit, values that usually trigger the surgeon’s decision to transfuse PRBCs. However, the increased chest tube output likely prompted the more frequent use of non-PRBC blood products postoperatively in the control group.
The limitation of our study is that it is retrospective in nature with a small sample size; thus, it is vulnerable to all the weaknesses and biases associated with such a study format. The small number of patients is hard to overcome in a single institution setting because EPP is an infrequently performed procedure even in major referral centers. We used the estimated blood loss in the operating room to quantify the actual blood loss during the procedure. The estimated blood loss is a value that is rather crude and particularly prone to inaccuracies, especially in a retrospective setting. There was a clear bias in favor of using aprotinin as the study progressed, with 78% of the second half of patients in the study receiving aprotinin. The surgeon’s decision to use aprotinin more frequently later in the study was probably affected by a speculative assumption that aprotinin was reducing surgical blood loss.
Serious concerns have been recently raised by Mangano and associates [14] regarding the safety of aprotinin in patients undergoing myocardial revascularization. This was a large observational study involving institutions in many countries with no definite uniformity in indications for drug administration. The study concluded that aprotinin was associated with increased risk of renal failure, myocardial infarction or heart failure, and stroke; however, caveats relating to this study have been elegantly summarized by Ferraris and colleagues [19]. Also a previous meta-analysis of randomized clinical trials addressing the effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery did not support such safety concerns and, in fact, showed that aprotinin reduced the risk of stroke [1].
Our results show no significant increase in the incidence of renal dysfunction or cardiac or thromboembolic complications when aprotinin is used in patients undergoing EPP. This is in line with the findings of other studies in the field of cardiac [1] and noncardiac surgical specialties [7]. However, the number of patients in our study is small; therefore, rare side effects or complications related to the use of aprotinin are less likely to surface and be detected in our study. Also the age difference between the aprotinin and the control groups may have influenced outcomes. Nevertheless, no serious challenge to the safety of aprotinin was generated by our results.
The potential benefits of aprotinin are not limited to blood conservation. A recent review by Vaporicyan and coworkers [20] comprehensively summarized the role of aprotinin in cancer surgery in general. There is an evolving interest in the anticancer mechanisms that are possibly mediated by aprotinin. A follow-up study to evaluate the effect of aprotinin on mesothelioma recurrence and patient survival would shed further light on his subject.
It is simplistic and perhaps misleading to advocate the use of aprotinin in all general thoracic procedures. With the exception of a small decrease in the number of non-PRBC products transfused, we found little evidence to endorse the routine use of aprotinin in EPP. Reported adverse effects should temper excessive enthusiasm and lead to a more selective use of aprotinin in patients at high risk for bleeding. The US food and Drug Administration recommends that physicians should consider limiting aprotinin use to those situations in which the clinical benefit of reduced blood loss is essential to medical management of the patient and outweighs the potential risks [21]. Also, Bayer Healthcare has recently decided to end three ongoing clinical studies investigating the safety and efficacy of aprotinin on transfusion requirements and blood loss in adults undergoing: elective spinal fusion surgery, pneumonectomy or esophagectomy for cancer, and radical cystectomy in bladder cancer. This was prompted by regulatory recommendations for managing possible anaphylactic reactions, which stated that aprotinin should be administered only in surgical settings in which cardiopulmonary bypass can be rapidly initiated [22].
The average cost of aprotinin at is $2.25/mL, and this translates into approximately $675 per patient receiving aprotinin given the dosing regimen used and the average duration of surgery in this study. This added expense, which does not incorporate indirect costs associated with drug administration and delivery, is yet another factor that should be considered in the decision to use aprotinin.
In conclusion, aprotinin administration did not decrease intraoperative blood loss or PRBC transfusion in EPP. However, the use of non-PRBC blood products and postoperative chest tube output were significantly reduced. In addition, the use of aprotinin was not associated with an increase in the incidence of adverse events. In view of the potential safety concerns recently reported, aprotinin administration should be guided by good clinical judgment.
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Related Article
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  F. G. Bakaeen and D. Rice Reply. Ann. Thorac. Surg., July 1, 2008; 86(1): 355 - 355. [Full Text] [PDF]
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D. West and D. Prakash Aprotinin and Extrapleural Pneumonectomy Ann. Thorac. Surg., July 1, 2008; 86(1): 354 - 355. [Full Text] [PDF]
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J. H. Levy and S. Force Invited commentary Ann. Thorac. Surg., September 1, 2007; 84(3): 986 - 987. [Full Text] [PDF]
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