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Ann Thorac Surg 2000;70:1813-1819
© 2000 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA
b Divisions of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA
Address reprint requests to Dr. Pochettino, Division of Cardiothoracic Surgery, 6 Silverstein, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104
e-mail: pochetti{at}mail.med.upenn.edu
Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.
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Abstract |
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 TopFootnotes Abstract IntroductionPatients and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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Methods. We retrospectively reviewed 130 patients with chronic obstructive pulmonary disease: 84 underwent SLT, 46 BLT. The mean age was 51.1 ± 1.2 years for those who underwent BLT and 56.2 ± 0.7 years for those who underwent SLT (p < 0.0001). Male patients represented 65% of the BLT group and 46% of the SLT group (p = 0.04). Spirometry and 6-minute walk tests were obtained preoperatively and at 3- to 6-month intervals. Posttransplant survival and survival from time of onset of bronchiolitis obliterans syndrome were calculated by Kaplan-Meier method. The mean follow-up was 32.4 months.
Results. The 90-day mortality rate was 13.0% For BLT and 15.5% for SLT (p = 0.71). Actuarial survival rates at 1, 3, and 5 years were 82.6%, 74.6%, and 61.9% for BLT and 72.2%, 63.4%, and 57.4% for SLT; the favorable survival trend with BLT did not achieve statistical significance. There were no differences in preoperative spirometry or 6-minute walk tests. The improvements in forced expiratory volume in one second , forced vital capacity (FVC), and 6 MWT were significantly greater following BLT. The incidence of bronchiolitis obliterans syndrome was 22.4% in SLT and 22.2% in BLT; survival following onset of bronchiolitis obliterans syndrome was similar.
Conclusions. For patients with chronic obstructive pulmonary disease, BLT is associated with superior lung function, exercise tolerance, and a trend toward enhanced survival. Younger candidates may be best suited for BLT. Given the limited donor lungs, SLT remains the preferred alternative for all other patients.
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Introduction |
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TopFootnotesAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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Since our initial report, we have continued to favor BLT for younger recipients, but the scarcity of available donor organs and the increasing mortality rate of those on the waiting list have compelled us to perform SLT in increasing numbers. The purpose of this study was to reassess our experience with lung transplantation performed on patients with COPD, to ascertain whether BLT should continue to be viewed as the preferred procedure.
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Patients and methods |
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TopFootnotesAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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-1 antitrypsin deficiency. One patient who committed suicide three months following successful SLT was excluded from subsequent analysis, leaving a study population of 130 patients. Patients with COPD were generally listed when the forced expiratory volume in one second (FEV1) fell below 25% of the predicted value. Additional factors that prompted listing included the presence of pulmonary hypertension and the presence of significant hypercapnia (PCO2 > 50 mm Hg). Although strict criteria for selection of the transplant procedure were not delineated, our general guidelines were as follows: BLT was preferentially performed on patients younger than 55 years of age and, on occasion, when marginal donor lungs were available (donor PO2 < 300 mm Hg on FIO2=1.0 and positive end-expiratory pressure [PEEP] = 5.0 mm Hg, or the presence of an infiltrate in the donor chest radiograph). BLT was rarely considered in individuals above the age of 60. Single lung transplant was generally performed on patients older than 55 years of age and on younger, smaller women when a high-quality "oversized" donor lung could be obtained. During the initial 18 months of our program, SLT was the procedure performed exclusively; the first BLT was performed in 1993.
Preoperative data
The following preoperative data were recorded for all patients: (1) age and sex, (2) presence of -1 antitrypsin deficiency, (3) FEV1, (4) forced vital capacity (FVC), and (5) 6-minute walk test (6 MWT) performed by standard technique [10].
Operative procedure
A standard posterolateral thoracotomy was used for SLT until early 1995, when an anterior axillary muscle-sparing thoracotomy was adopted [11]. The smaller incision was used almost exclusively for SLT. Starting in 1995, anesthetic practices were modified for all patients undergoing SLT to facilitate extubation of the stable patient in the operating room at the completion of the procedure.
BLT was performed by a bilateral thoracosternotomy approach. Since 1998, we have been able in most patients to limit our incision for BLT by omitting division of the sternum. No patient undergoing BLT has been extubated in the operating room.
Intravenous prostaglandin (PGE1) has been used during the operation in all patients. Since becoming available in 1997, inhaled nitric oxide has also been utilized for most patients, often avoiding the need for cardiopulmonary bypass support.
Immunosuppressive therapy
Throughout the period of the study, a three-drug maintenance immunosuppressive regimen was used. Cyclosporine was dosed to achieve a whole blood trough level (as assessed by high-performance liquid chromatography) between 250 and 350 ng/mL during the first year and thereafter between 200 and 300 ng/mL. Tacrolimus was substituted for cyclosporine (with therapeutic trough levels between 10 and 20 ng/mL) in patients with refractory or recurrent acute rejection or with bronchiolitis obliterans syndrome (BOS). Prednisone was started at 0.5 mg · kg-1 · d-1 and then tapered as tolerated to 0.15 mg · kg-1 · d-1 by 3 months after transplant. Azathioprine was administered at a dose of 2 mg/kg daily. In the last year of the study, mycophenolate mofetil was used in place of azathioprine, at a dose between 1,000 and 1,500 mg twice daily unless limited by adverse gastrointestinal symptoms. Our protocol for induction of immunosuppression has evolved over time. In the initial two years, corticosteroids were withheld until the sixth postoperative day, and induction with antithymocyte immunoglobulin (ATGAM; 10 mg · kg-1 · d-1) was used instead. Beyond that period, we adopted a miniinduction protocol consisting of a 3-day course of antithymocyte globulin administered concurrently with the three maintenance immunosuppressive agents. More recently, we have used CD3 counts to better titrate our induction therapy.
Postoperative evaluation
No patients were lost to follow-up, although not all patients had complete functional assessment at all time-points. Kaplan-Meier analysis was used to calculate overall survival, as well as survival following onset of BOS. Formal spirometry and 6 MWT were performed in our pulmonary diagnostics laboratory at 3 and 6 months after the transplant and at a minimum of 6-month intervals thereafter.
Statistical analysis
Data are presented as a mean ± standard error of the mean. Continuous numerical data were compared between the SLT and BLT groups using a Student’s t test. For comparison of noncontinuous data, 
2 analysis was used. Kaplan-Meier survival curves were compared utilizing the Logrank (Mantel-Cox) test. Statistical significance was defined as a p value less than 0.05.
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Results |
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TopFootnotesAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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-1 antitrypsin deficiency. Preoperative FEV1 and FVC (expressed as percent of predicted) and 6 MWT distances did not differ significantly between the two groups.
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Comment |
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TopFootnotesAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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Early in our experience, patients undergoing SLT for COPD suffered a higher incidence of primary graft dysfunction and a higher early mortality rate than did those undergoing BLT [7]. We therefore advocated that BLT should be the preferred operation to maximize both functional and survival outcomes for this patient population. Under the pressure of a scarce donor pool and with the development of improved surgical and anesthetic methods allowing immediate postoperative extubation and better SLT operative survival, we subsequently felt justified in increasingly using SLT for patients with COPD. Although at our institution the short-term mortality of patients who have undergone SLT versus that of patients who have undergone BLT has become essentially equivalent in COPD recipients, we performed this retrospective analysis to assess whether intermediate-term survival and functional outcomes justify the greater use of SLT. This analysis clearly shows that BLT is associated with a significantly higher level of pulmonary function, as well as with superior exercise tolerance as assessed by standard 6 MWT. We believe that the superior functional outcomes justify the continued preferential use of BLT in young patients for whom the posttransplant expectation is an extremely vigorous lifestyle. Nonetheless, the functional improvements associated with SLT should not be underestimated, as this procedure permits resumption of usual activities of daily living in an unencumbered fashion.
Our analysis suggests that BLT confers a modest survival advantage over SLT, although the difference did not reach statistical significance. This observation is similar to the experience reported by Sundaresan and colleagues [8] and to international registry data [13]. However, in the face of the current scarcity of donor organs, we do not believe that the survival advantage is sufficiently great to justify the widespread use of BLT for all patients with COPD. Presently, the mortality rate of COPD patients awaiting lung transplantation in the United States approximates 10% per year [16]. If BLT were preferentially employed for this patient population, leading to increased waiting times, it is likely that the modest survival advantage achieved posttransplantation would be offset by an increased pretransplantation attrition rate of listed patients.
One limitation of the current study is the nonrandomized assignment of patients to the two surgical groups. Given our preferential use of BLT for younger patients, it is not surprising that the mean age of the BLT group was significantly lower than that of the SLT group. In light of this, it is distinctly possible that the superior 6 MWT performance and survival seen in association with BLT could reflect age-related rather than or in addition to procedure-related influences.
It has been theorized that the improved survival with BLT results from a greater ability to tolerate the functional decline associated with development of bronchiolitis obliterans [8]. In our study, the incidence of BOS in COPD patients who had undergone either SLT or BLT was similar. It is important to note that our data suggest that the mortality during the first two years after onset of BOS was similar for the two groups. Beyond the first two years, although the number of patients is too small to draw firm conclusions, there is a hint that BLT may provide a survival advantage. It has been observed that BOS can progress at a variable pace [17]. In some patients the disorder progresses at a rapid pace, and our data suggest that these patients rapidly succumb independent of the type of transplant that they received. A second group of patients can be identified, however, in whom the course of BOS is much more insidious and protracted. It is for this group that the greater functional reserve associated with BLT might translate into more-prolonged survival.
The use of SLT for patients with COPD occasionally results in allograft dysfunction because of hyperinflation of the native lung. This may be encountered in the early perioperative period as a result of positive pressure ventilation. We have been able to minimize this risk by modifying our anesthesia protocols to permit early extubation of stable patients, often in the operating room at the completion of surgery. Hyperinflation of the native lung may also occur more insidiously, months to years after SLT, contributing to allograft dysfunction. In this setting, we and others have successfully performed lung volume reduction surgery on the native lung, with resultant improvement in lung function [18, 19].
Based on our data in conjunction with recognition of ongoing donor organ limitations, we suggest the following guidelines for the selection of appropriate transplant procedures in patients with COPD. Bilateral lung transplant should be preferentially used in younger recipients because of the superior functional results and the vigorous lifestyle that this would likely afford. Identification of an absolute age cutoff, beyond which BLT should not be considered, is admittedly problematic. Nonetheless, we have previously demonstrated increased morbidity in patients over the age of 55 years who underwent BLT, and we would thus discourage its use in patients above this age [7]. The use of bilateral lung transplant should also be considered in the setting of marginal donor lungs that might otherwise be deemed unsuitable for SLT, thus enhancing use of the donor pool. Although the use of nitric oxide may permit successful performance of SLT for patients with the combination of COPD and cor pulmonale, we favor BLT in the presence of pulmonary hypertension to minimize the likelihood of early graft dysfunction because of overperfusion of the allograft. Single lung transplant should be used for older emphysema patients, who constitute the majority of patients currently on the waiting list. Younger patients of smaller stature (most commonly women) may benefit from SLT with a somewhat oversized donor organ, resulting in shorter waiting times while still affording them the opportunity to achieve excellent functional outcomes.
In summary, while both SLT and BLT effect marked improvement in lung function and exercise tolerance for patients with COPD, the magnitude of improvement is greater in those who receive BLT. Younger recipients would be well served by the functional advantages of BLT, but those advantages are a less compelling consideration in the older COPD population, for whom SLT is a suitable alternative. Should the observed trend toward inferior survival in association with SLT be borne out by future studies, the transplant community may be forced to decide between the competing interests of maximizing the use of a scarce donor pool and optimizing individual outcomes.
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Acknowledgments |
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TopFootnotesAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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Footnotes |
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TopFootnotesAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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Discussion |
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TopFootnotesAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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I noticed that you excluded from your analysis both the patients with lymphangioleiomyomatosis (LAM) and those with bronchiolitis obliterans syndrome (BOS), and I agree completely with that decision. Because the lymphangioleiomyomatosis patients are mostly young and female and have pleural disease, I thought that their outcomes are sufficiently distinct to view them separately from patients with -1 antitrypsin deficiency emphysema or standard panacinar COPD.
With respect to the prevalence of bronchiolitis obliterans syndrome, the updated data showed the gross percentage of patients in each group suffering from BOS to be equal, whereas in the abstract there was quite a discrepancy between the single lung and the bilateral recipients. I believe we ought to study actuarial freedom from bronchiolitis obliterans syndrome rather than gross prevalence among a cohort of patients, because if you follow any group of lung transplant patients long enough, the vast majority will acquire BOS. The prevalence is strictly time dependent.
I offer several reasons why patients who receive bilateral lung transplantation do better than patients with single lung transplantation. First, you showed in your data that bilateral lung transplant recipients are 5 years younger than the single lung recipients operated upon over the same period. Also, bilateral recipients have 2 opportunities to avoid phrenic nerve injury during the transplant, whereas a single lung transplant recipient has only 1. Bilateral recipients also have 2 opportunities to avoid the consequences of an anastomotic complication, whereas the single lung transplant patients have only 1 opportunity.
Finally, on occasion, we saddle the single lung recipient group with a subgroup of patients who were initially intended to receive bilateral transplantation but in whom severe graft dysfunction developed after the implantation of first lung. Because they had emphysema and a functioning native lung, we have stopped after one implantation when the result of that procedure was poor. The single lung recipient group was therefore biased to have an overall worse outcome, even though we have saved the individual patient from bilateral reperfusion injury and early lung dysfunction, a very severe clinical scenerio.
I end by saying that I enjoyed your presentation and I thank you and the Society for the opportunity to comment on the paper.
DR POCHETTINO: I thank you for your comment. Bronchiolitis obliterans syndrome is indeed a moving target. The data we had submitted in the abstract data were analyzed in October of last year; when we updated it 3 weeks ago, we realized that BOS had since developed in a significant number of patients. Some of the criteria for BOS used in our recent analysis were more strict . In particular, we only looked at patients who had survived for 1 year. We did exclude the patients with LAM and those who had undergone transplantation for obliterative bronchiolitis; because those patients were clearly at higher risk for subsequent obliterative bronchiolitis.
DR FEDERICO VENUCA (Rome, Italy): In the group of patients receiving single lung transplantation, did you observe any complication arising in the native lung, such as infection or early and late overexpansion of the native lung?
DR. POCHETTINO: The primary late complication of the patients undergoing single lung transplant has been overinflation of the native lung. We have actually performed three volume reductions in the contralateral lung, all of which were late, beyond 2 years after the transplant. Two of the 3 have done well. Most of the other patients did not have any significant long-term difficulty from the native residual lung.
DR JOEL D. COOPER (St. Louis, MO): My comments will be mainly historical. First of all, congratulations on a nice series and a nice analysis. For your interest, the first, the second, and the third patients on whom we did the en bloc operation at the end of 1986 and 1987 all underwent the procedure for COPD. Thirteen years later, 2 go to work every day and 1 is unfortunately oxygen-dependent. So sometimes you get lucky; we were very lucky with those first 3.
Over the years we have gone back and forth with the same debate that you presented: Is it better to do a greater number of transplants or to give a greater boost to a smaller number of patients using the bilateral option? Clearly the mortality rates have fallen; today they are usually single-digit, and the risks of one versus the other is no longer a major factor. It was more of a factor in the early days, and we were able to do about 40 consecutive single lungs for emphysema without a mortality. This encouraged us, but then we began seeing, as you saw, at 3 to 4 years, the functional problems associated with chronic rejection.
We are still speculating, wondering whether or not the one retained nontransplanted lung following single lung transplant might end up later on being a salvage for those patients who get severe BOS and who, if they had two lungs might end up in worse trouble.
I don’t think we know the answer.
It was an excellent presentation, and I think the continuing dilemma in an era when we don’t have enough transplants is between the provision of the greatest number of transplants versus trying to get the greatest function for the recipient. We tend to end up exactly as your algorithm proposed at the end. I enjoyed your paper very much.
DR POCHETTINO: I appreciate your comments. Thank you.
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