Interact CardioVasc Thorac Surg 2009;8:45-48. doi:10.1510/icvts.2008.178749
© 2009 European Association of Cardio-Thoracic Surgery
Institutional report - Transplantation |
Aprotinin's effect on blood product transfusion in off-pump bilateral lung transplantation
Keki R. Balsaraa,*,
Steven T. Morozowichb,
Shu S. Lina,c,
Robert D. Davisa,
Barbara G. Phillips-Buteb,
Matthew Hartwiga,
James Z. Appela and
Ian J. Welsbyb
a Department of Surgery, Box 3443, Duke University Medical Center, Durham, NC 27710, USA
b Division of Cardiothoracic Anesthesia and Critical Care Medicine, Duke University Medical Center, Durham, NC, USA
c Department of Immunology, Duke University Medical Center, Durham, NC, USA
Received 28 February 2008;
received in revised form 13 July 2008;
accepted 15 July 2008
 This work was presented on February 13th as an oral presentation at the 2008 American Surgical Congress Annual Meeting in Huntington Beach, CA.
*Corresponding author. Tel.: +1 (919) 970-2729; fax: +1 (919) 684-7263.
E-mail address: balsa001{at}mc.duke.edu (K.R. Balsara).
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Abstract
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In lung transplants necessitating cardiopulmonary bypass (CPB), aprotinin has been shown to decrease transfusion requirements. More recently, off-pump transplantation has become the standard of care. The efficacy of aprotinin use in this population has yet to be definitively examined. We completed a retrospective review of all adult OP-BOLTs performed between January 2000 and January 2006 at a single university center (n=215). Aprotinin use was determined by the attending anesthesiologist or surgeon. It was administered at the time of induction. The primary outcome was total blood products utilized in terms of units transfused during postoperative days 0, 1 and 2. One-hundred and one patients received aprotinin and 114 did not. An overall analysis of all of the patients in this study demonstrated a trend towards statistical significance for reduced total blood product transfusion for the aprotinin group compared to the non-aprotinin group (P=0.13). A subgroup analysis was performed in relation to each diagnosis. The use of aprotinin was associated with a significant reduction in peri-operative total blood products transfused in COPD patients (P=0.03) undergoing OP-BOLT. Subgroup analysis demonstrated that the use of aprotinin in the COPD population did result in a statistically significant decrease in total blood products transfused, specifically the total number of units of packed red blood cells given. These findings suggest that aprotinin administration should be considered for all patients undergoing OP-BOLT to reduce exposure to blood products and potential immune sensitization and infectious complications.
Key Words: Blood loss; Lung transplantation; Postoperative complications; Aprotinin adverse effects; Blood transfusion
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1. Introduction
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Blood product transfusion may contribute to the overall morbidity and mortality of hospitalized patients [1, 2]. In patients undergoing transplantation, transfusion may result in the development of alloantibodies that may increase the risk of rejection [3, 4] or induce microchimerism or graft versus host disease [5]. Unique to the lung transplant population are the adverse pulmonary effects related to transfusion, most notably transfusion related acute lung injury.
Aprotinin is a serine protease inhibitor that limits bleeding by inhibiting contact activation and fibrinolysis. Until recently, it has been used extensively to reduce blood loss and transfusion in cardiac surgery requiring cardiopulmonary bypass (CPB) or procedures considered to be high risk. In lung transplantation, aprotinin use has been shown to reduce red blood cell transfusion when performed with CPB [6]. As with off-pump coronary artery bypass grafting surgery, off-pump lung transplantation has the theoretical benefit of less inflammatory activation, reduced coagulopathy, bleeding and transfusion, avoidance of embolization of air or debris, and elimination of non-pulsatile flow. Together, these advantages may reduce neurocognitive, renal, and pulmonary dysfunction [7].
The use of aprotinin, compared to historical controls, has also been reported to be associated with improved primary graft function [7], when administered both intravenously and as a component of the allograft perfusate in lung transplantation performed with and without CPB. Aprotinin is not approved as a component of the allograft perfusate in the United States.
The use of CPB during lung transplantation has been associated with a significantly higher mortality [8], and as a result, off-pump lung transplantation is becoming the technique of choice at many institutions. At our institution, off-pump double lung transplantation is the standard of care based on short and long-term outcome data [9, 10]. However, despite avoiding the apparent bleeding diathesis associated with the CPB circuit, lung transplantation performed off-pump remains a complex procedure fraught with difficulty. Triulzi et al. have identified off-pump lung transplantation as a high risk procedure frequently requiring blood product transfusion. Moreover, double lung transplantation significantly increases the risk of transfusion compared to single lung transplantation [11]. While bleeding and transfusion may be reduced by administering aprotinin, as shown by others in thoracic surgery without the use of CPB [12, 13] the efficacy of aprotinin use in off-pump bilateral orthotopic lung transplantation has not been well characterized. Furthermore, the value of intravenous aprotinin in improving primary graft function has not been demonstrated in a cohort of patients undergoing off-pump bilateral orthotopic lung transplantation. Therefore, our objective was to determine whether aprotinin use decreases perioperative blood product transfusion and improves primary graft function in off-pump bilateral orthotopic lung transplantation.
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2. Materials and methods
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After Institutional Review Board approval, we completed a retrospective chart review of every adult off-pump bilateral orthotopic lung transplantation (OP-BOLT) done between January 2000 and January 2006 at a single university center. January 2000 was chosen as our start date because a standardized immunosuppressive regimen of methylprednisolone, azathioprine, tacrolimus and basiliximab was introduced at this time. Patients with end-stage pulmonary disease due to our four commonest preoperative diagnoses were included: chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), and sarcoidosis.
Exclusions were single lung transplantation, repeat lung transplantation, the use of CPB at any time during the procedure, and the need for peri-operative plasmapharesis. Bilateral orthotopic lung transplantation is performed sequentially to avoid the use of CPB. When both sides are completed and the lung function appears to be stable, residual heparin is reversed with protamine as necessary.
The decision to use aprotinin (Trasylol; Bayer Pharmaceuticals, West Haven, CT, USA) during OP-BOLT was determined by the attending anesthesiologist or surgeon preoperatively. When used, aprotinin was administered at the time of anesthesia induction according to the full dose Hammersmith regimen typically used during cardiothoracic surgery: 10 min after a 10,000 kallikrein inactivator unit (KIU) test-dose, a loading dose of 2 million KIU was given over 30 min, followed by a constant infusion of 500,000 KIU/h until the patient left the operating room. To determine the safety of aprotinin use, charts were reviewed to determine adverse events attributable to aprotinin use and we compared renal function (maximum values of blood urea nitrogen and serum creatinine) between control and aprotinin group in the immediate (up to postoperative day 3), early (up to day 7) and late (from days 8–30) postoperative periods. These comparisons of renal function were repeated after adjusting for age, sex and baseline serum creatinine.
The decision to transfuse blood products was determined by the attending physicians participating in the patient's peri-operative care; in the operating room the anesthesiologist or surgeon directed transfusion, in the intensive care unit the intensivist or surgeon directed transfusion, and outside of the intensive care unit the surgeon directed transfusion. Transfusion of blood products is liberal during and after OP-BOLT, but as we also practice volume restriction, a patient who has bled less will typically receive fewer blood products. The ratio of arterial partial pressure of oxygen (PO2) and inspired fraction of oxygen (FiO2) or PF ratio was calculated on postoperative days 0, 1 and 2. Clinical covariates potentially related to bleeding or transfusion risk included the primary diagnosis, sex, height, weight, previous thoracotomy status, and the following preoperative laboratory tests: hemoglobin, activated partial thromboplastin time, international normalized ratio (INR), and platelet count. The INR was chosen as thromboplastin reagents and, therefore, the prothrombin time normal range changed during the study period.
The primary outcome was total blood product transfusion in units during postoperative days 0, 1, and 2, defined as the start of surgery through the first 24 h, 24–48 h, and 48–72 h postoperatively, respectively. Blood products were totaled in units and included packed red blood cells, fresh frozen plasma, and adult doses of cryoprecipitate and platelets. The secondary outcome was PF ratio over the same time period.
2.1. Statistical methods
Because this is a non-randomized trial, the administration of aprotinin is potentially subject to patient- or surgeon-related characteristics which could bias our results. However, we polled the anesthesia faculty and found that 30% always use aprotinin, 30% never use it, and 40% use if bleeding risk is deemed to be high or based on clinical characteristics related to bleeding; the number of procedures involving the last group was insufficient to create a propensity score. Given the usage pattern we identified, we compared the aprotinin and non-aprotinin groups on preoperative characteristics related to bleeding, including diagnosis type. Covariates determined to be associated with transfusion were included in a multivariate model to adjust for their effects on transfusion independent of aprotinin use.
All analyses were performed with SAS version 9.1. Statistical comparisons were performed with the Student's t-test or Wilcoxon Rank Sum test, as appropriate, for continuous variables, the  2-test was used for categorical variables. Multivariable analysis was performed with multiple linear regression, and P<0.05 was considered significant.
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3. Results
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A total of 283 OP-BOLTs were performed between January 2000 and January 2006. Of these, 67 were excluded due to the use of CPB, one was excluded due to repeat lung transplantation and 215 patients fitted our inclusion criteria: COPD (n=83), CF (n=52), idiopathic pulmonary fibrosis (n=52), sarcoidosis (n=12), and other (n=16). One-hundred and one patients received aprotinin (aprotinin group) and 114 did not (control group). The demographics and clinical covariates including age, sex, diagnosis and preoperative laboratory values were similar across both groups.
When analyzing clinical covariates by individual diagnosis, we found a lower preoperative hemoglobin in the CF patients who received aprotinin vs. those that did not (11.5±3.1 vs. 12.6±3.2 g/dl; P=0.047). There were no significant differences in clinical covariates between the control and aprotinin groups in the other diagnostic categories. Since preoperative hemoglobin and weight were associated with transfusion, we included these factors in a multivariate model to adjust for their effect on transfusion; adjusted P-values are presented in Table 1.
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Table 1 Comparing demographics and clinical covariates between the control and aprotinin groups. Continuous variables were compared with a Student's t-test and categorical variables were compared with a 2-test. Values are means (standard deviation) or percentages
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Results of the ‘primary outcome’ i.e. blood product usage, was examined in the whole group. An overall analysis of all the patients in this study demonstrated a trend towards statistical significance for reduced total blood product transfusion for the aprotinin group compared to the non-aprotinin group (P=0.13). Because of the recognized effect of diagnosis on recipient comorbidities and because COPD was the most common primary indication for this study, a subgroup analysis was performed in relationship to each diagnosis. The use of aprotinin was associated with a significant reduction in peri-operative total blood products transfused in COPD patients (P=0.03) undergoing OP-BOLT as presented in Table 2. This included a reduction in total perioperative blood product units [4 (2–7) vs. 6 (2–13); P=0.03], PRBC units [3 (2–4) vs. 4 (2–7); P=0.03], platelet doses [0 (0–0) vs. 0 (0–2); P=0.02] and FFP units [1 (0–3) vs. 2 (0–5); P=0.05]. These differences persisted after adjusting for the effect of weight and preoperative hemoglobin concentration. To confirm that we were not simply observing the effect of a different transfusion trigger between groups, we demonstrated no difference in the hemoglobin level of 11.15 (±1.40) g/dl in the aprotinin group and compared to 10.98 (±1.24) g/dl in controls. These hemoglobin concentrations were obtained in the immediate postoperative period upon patient arrival in the ICU. The secondary outcome, in the COPD cohort, comparing P/F ratio as a marker of allograft function demonstrated no difference between groups (P=0.13).
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Table 2 Peri-operative blood product units transfused in control and aprotinin groups for patients with COPD. The sums of products used during postoperative days 0, 1 and 2 are presented as medians (interquartile range). COPD (n=83)
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There were no allergic reactions or other adverse events attributed to aprotinin use noted in patient charts, nor was there any difference in renal function in the immediate, early or late postoperative periods between the control and aprotinin groups (Table 3). Similarly, there was no difference in renal function attributable to aprotinin after adjusting for age, sex and baseline serum creatinine in a multivariate model.
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4. Discussion
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While we rejected our primary hypothesis that aprotinin reduces transfusion after off-pump BOLT, our results demonstrated that aprotinin, in select patient populations only, reduced total perioperative blood product transfusion in patients undergoing OP-BOLT. In patients with diagnosis of COPD, a statistically significant reduction in total and individual blood product transfusion in the perioperative period was observed when aprotinin was used, compared to controls (non-aprotinin group). However, analysis of this population demonstrated no difference in graft function between the aprotinin and control groups. The use of aprotinin during OP-BOLT did not adversely affect renal function and, in this group of patients without known previous exposure to aprotinin, it was used without any apparent adverse events.
The reduction in the blood product exposure for lung transplant recipients has many potential benefits. These include infectious, physiologic and immunologic. It remains to be seen if these theoretical benefits translate into clinically significant improvements. Moreover, at a cost of nearly $1500 per patient, one must consider if the benefits derived are worth the cost.
We acknowledge that our work is in contrast to that performed by others [6, 14, 15]. Bittner et al. [16] suggest that aprotinin use in the perioperative period results in a significant reduction in ischemia reperfusion injury which translates into decreased morbidity and mortality. It is important to note, however, that this group included aprotinin in the perfusion solution prior to lung harvest. This is in contrast to our group as well as all known uses of aprotinin in this country.
Limitations of our work include our retrospective design which does not account for selection bias or residual confounding variables. Moreover, these patients reflect the collaborative efforts of three surgeons and five anesthesiologists, all with individualized practice algorithms. Our selection of a relatively homogeneous group of patients undergoing the same procedure performed by a small team of surgeons at a single institution limits our sample size but was intended to reduce uncontrolled confounders not identified by the chart review process. Also, sample stratification by diagnosis may have reduced our power to detect a difference in the smaller disease specific sub-groups.
In conclusion, these retrospective data confirm that OP BOLT is associated with a high risk of blood product transfusion and that the intraoperative administration of aprotinin demonstrates a statistically significant reduction in total peri-operative blood product transfusion in patients with a preoperative diagnosis of COPD without increasing the risk of peri-operative renal injury. While statistically significant it is not clear how this modest reduction represents a clinically relevant transfusion reduction as few patients avoided transfusion. Given the cost associated and its lack of clinically significant improvement in graft function, one must question its use as a matter of routine practice particularly in light of recent safety concerns regarding aprotinin use in other patient groups.
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Acknowledgements
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The authors wish to thank Mrs Jessica Whitfield for manuscript preparation.
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References
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Abstract
1. Introduction
