Thirteen-Year Experience in Lung Transplantation for Emphysema

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1 Thirteen-Year Experience in Lung Transplantation for Emphysema Stephen D. Cassivi, MD, Bryan F. Meyers, MD, Richard J. Battafarano, MD, Tracey J. Guthrie, RN, Elbert P. Trulock, MD, John P. Lynch, MD, Joel D. Cooper, MD, and G. Alexander Patterson, MD Divisions of Cardiothoracic Surgery and Pulmonary Medicine, Washington University Medical Center, St. Louis, Missouri Background. Emphysema is the most common indication for lung transplantation. Recipients include younger patients with genetically determined alpha-1 antitrypsin deficiency (AAD) and, more commonly, patients with chronic obstructive pulmonary disease (COPD). We analyzed the results of our single-institution series of lung transplants for emphysema to identify outcome differences and factors predicting mortality and morbidity in these two groups. Methods. A retrospective analysis was undertaken of the 306 consecutive lung transplants for emphysema performed at our institution between 1988 and 2000 (220 COPD, 86 AAD). Follow-up was complete and averaged 3.7 years. Results. The mean age of AAD recipients (49 6 years) was less than those with COPD (55 6 years; p < 0.001). Hospital mortality was 6.2%, with no difference between COPD and AAD, or between single-lung transplants and bilateral-lung transplants. Hospital mortality during the most recent 6 years was significantly lower (3.9% vs 9.5%, p 0.044). Five-year survival was 58.6% 3.5%, with no difference between COPD (56.8% 4.4%) and AAD (60.5% 5.8%). Five-year survival was better with bilateral-lung transplants (66.7% 4.0%) than with singlelung transplants (44.9% 6.0%, p < 0.005). Independent predictors of mortality by Cox analysis were single lung transplantation (relative hazard 1.98, p < 0.001), and need for cardiopulmonary bypass during the transplant (relative hazard 1.84, p 0.038). Conclusions. AAD recipients, despite a younger age, do not achieve significantly superior survival results than those with COPD. Bilateral lung transplantation for emphysema results in better long-term survival. Accumulated experience and modifications in perioperative care over our 13-year series may explain recently improved early and long-term survival. (Ann Thorac Surg 2002;74: ) 2002 by The Society of Thoracic Surgeons Since the advent of lung transplantation as a treatment for end-stage lung disease, the list of its indications has grown. In most adult lung transplant programs, obstructive lung disease, pulmonary fibrosis, cystic fibrosis, and pulmonary vascular disease are the most common indications. Emphysema, encompassing chronic obstructive pulmonary disease (COPD) and alpha 1 antitrypsin deficiency (AAD), remains the single most common indication, accounting for approximately 45% of cases worldwide [1]. We evaluated our series of lung transplants for emphysema from 1988 to 2000 (N 306) at Washington University in order to determine factors predicting morbidity and mortality, and to identify differences in outcome between recipients with COPD and AAD. Presented at the Forty-eighth Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 8 10, Address reprint requests to Dr Patterson, Division of Cardiothoracic Surgery, Washington University Medical Center, Queeny Tower, Suite 3108, One Barnes-Jewish Hospital Plaza, St. Louis, MO ; pattersona@msnotes.wustl.edu. Material and Methods Retrospective Data Analysis We retrospectively reviewed the records of 306 adult patients receiving lung transplants for emphysema (COPD, n 220; AAD, n 86) at Barnes-Jewish Hospital in St. Louis between July 1988 and December Preoperative recipient characteristics are included in Table 1. To determine preoperative, operative, and postoperative risk factors for operative and long-term mortality and morbidity, we evaluated the following variables: preoperative characteristics including age, gender, and dependence on mechanical ventilator support pulmonary physiologic measures such as forced vital capacity (FVC), forced expiratory volume in 1 second (FEV 1 ), 6-minute walk test (6MW), and arterial carbon dioxide tension (P a CO 2 ) operative characteristics such as total ischemic time, single- (SLT) versus bilateral- (BLT) lung transplantation, use of cardiopulmonary bypass (CPB), and use of a marginal donor [2] and postoperative characteristics including duration of intubation, length of intensive care unit (ICU) and hospital stay, and use of an extracorporeal membrane oxygenator (ECMO). Complete patient selection was assured by reviewing our 2002 by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (02)04064-X

2 1664 CASSIVI ET AL Ann Thorac Surg LUNG TRANSPLANTATION FOR EMPHYSEMA 2002;74: Table 1. Preoperative Clinical Indices COPD (n 220) AAD (n 86) p Value Age (years) Gender (% female) 134 (60.9%) 29 (33.7%) Ventilator dependent (%) 4 (1.8%) 2 (2.3%) 0.68 Waiting list time (days) FVC (% of predicted) FEV 1 (% of predicted) MW (feet) P a CO 2 (mm Hg) Values are expressed as means standard deviation. FEV 1 forced expiratory volume in 1 second; FVC forced vital capacity; 6MW 6-minute walk test; P a CO 2 arterial carbon dioxide tension. computerized transplant patient database and hospital records. We analyzed the impact of preoperative, operative, and postoperative characteristics on operative and longterm morbidity and mortality. Morbid outcomes evaluated are primary graft dysfunction, acute organ rejection, bronchiolitis obliterans syndrome (BOS), and posttransplant malignancy. Operative Method The donor procurement technique used by our institution has been previously described [3]. All donors received intravenous, broad-spectrum antibiotics within a few hours before retrieval. Donors were pretreated with intravenous heparin (4 mg/kg) and a bolus dose of prostaglandin E 1 (500 g) administered directly into the pulmonary artery immediately before aortic cross-clamp. Lungs were flushed with cold antegrade, modified Euro- Collins solution (60 to 80 ml/kg). In the last 4 years, retrograde pneumoplegia, using the same solution (5 ml/kg), has been administered into each pulmonary vein [4]. In the last 3 years, nitroprusside (10 mg/l) has been added to the flush solution. Lungs are harvested en bloc and preserved by immersion in cold saline solution for transportation to our institution. The operative technique employed at our institution for recipient implantation has also been previously described [5, 6]. Recipient Criteria Our standard recipient selection criteria have been previously reported [7]. Recipients are listed for transplantation when they have developed disabling lung disease with a limited prognosis and no other systemic illness that would complicate or be complicated by lung transplantation and immunosuppression. All patients listed for lung transplantation were enrolled in an active pulmonary rehabilitation program. Postoperative Care In our institution, the early postoperative care is relatively standardized. Mechanical ventilation is discontinued when gas exchange and weaning parameters permit. Routine empiric perioperative antibiotics with broadspectrum gram-negative and gram-positive coverage are administered. Subsequent antibiotic selection is based on the results of donor and recipient bronchial cultures. Prophylaxis against Pneumocystis carinii consists of trimethoprim-sulfamethoxazole given once daily until discharge, at which time the regimen is changed to administration three times per week. Cytomegalovirus (CMV) mismatches (donor CMV seropositive and recipient seronegative) with a high risk for infection receive intravenous ganciclovir prophylaxis for 12 weeks. All patients were monitored for viremia with weekly blood cultures. A standard immunosuppressive protocol consisting of cyclosporine, corticosteroids, and azathioprine is employed. Other agents, including tacrolimus, mycophenolate mofetil, and sirolimus, have been used depending upon clinical course. Immunosuppression induction typically includes antithymocyte globulin. We perform routine surveillance flexible bronchoscopy, bronchoalveolar lavage, and transbronchial biopsies at 2, 3, and 6 weeks and at 12 months, as well as on an as-needed basis thereafter. For the purpose of our study, a diagnosis of acute rejection required pathologic confirmation from a transbronchial biopsy specimen obtained during the first year after transplantation. Rejection was graded according to the grading system of the International Society for Heart and Lung Transplantation (ISHLT) [8]. Severe acute rejection was deemed to be present if any transbronchial biopsy was graded A3 or higher. Increased frequency of rejection was ascribed to those patients with rejection scored A2 or worse on three or more biopsies in the first year [9]. BOS was diagnosed and classified according to the grading system devised by the ISHLT [10]. Data Collection and Statistical Analysis We collected preoperative and postoperative data from recipient medical charts and our lung transplantation database. Recipient follow-up was complete in all patients transplanted through December Normally distributed continuous data are expressed as means standard deviation. Medians with interquartile ranges are used when continuous data are skewed. Categorical data are expressed as counts and proportions. Unrelated two-group comparisons employ unpaired, two-tailed t tests for means of normally distributed continuous variables and the Wilcoxon s rank-sum tests for nonparametric data. 2 or Fisher s exact tests are used to analyze differences among the categorical data. Kaplan-Meier estimates are used to depict survival and freedom from BOS. Survival and BOS-free survival comparison between groups of patients was completed using the Mantel-Haenszel log-rank test. Cox multivariate proportional hazards regression method was used to identify risk factors for survival after transplantation. The time to death was selected as the principal outcome. The regression model was constructed using dependent variables known or suspected to be independent predictors of the outcome based on previous published results and the

3 Ann Thorac Surg CASSIVI ET AL 2002;74: LUNG TRANSPLANTATION FOR EMPHYSEMA 1665 receiving SLT ( days, p 0.001). Other preoperative physiologic parameters are shown in Table 1. The only physiologic measure that was different was P a CO 2, which was higher in COPD patients ( mm Hg) as compared with AAD patients ( mm Hg, p 0.001). Fig 1. Lung transplants performed for alpha 1 antitrypsin deficiency (Alpha-1), chronic obstructive pulmonary disease (COPD), and all other diagnoses at Washington University in St. Louis by year. univariate differences observed between our two groups (COPD and AAD). The following categorical variables were considered: marginal versus ideal donor, recipient gender, recipient diagnosis (COPD vs AAD vs other), single versus bilateral transplant, recipient ventilator dependent or not at time of transplant, use of CPB, requirement for extracorporeal membrane oxygenator (ECMO), primary graft dysfunction as defined by the pulmonary arterial oxygen tension (P a O 2 ) divided by the fraction of inspired oxygen (F i O 2 ) being less than 150 mm Hg, CMV cytomegalovirus mismatch, presence of A3 rejection in recipient, three or more versus less than three distinct bouts of A2 rejection, and date of transplant (1988 to 1994 vs 1995 to 2000). The following continuous variables were considered: recipient age in years and ischemic time in minutes.all data analysis was performed using Systat (Systat 7.0 for Windows SPSS Inc., Chicago, IL). All p values 0.05 were considered to be statistically significant. Results Case Volume and Distribution by Diagnosis Since the inception of the lung transplantation program at our institution, the number of lung transplants for emphysema has steadily increased to about 35 per year (Fig 1). This accounts for 55.2% of lung transplant cases performed at our center. AAD recipients account for 28.1% of lung transplants for end-stage emphysema in our series. Preoperative Clinical Indices With an average age of 49 6 years, AAD recipients were significantly younger than the COPD recipients, at 55 6 years of age (p 0.001). Whereas almost two-thirds (60.5%) of COPD recipients are female, this gender distribution is reversed in AAD recipients (33.7%, p 0.001). The mean waiting list time for all emphysema recipients was days. Whereas there was no difference between COPD and AAD patients, BLT patients had a longer waiting list time ( days) than patients Operative Parameters Intraoperative parameters are shown in Table 2. AAD patients received, as a group, a significantly higher proportion of BLT than the COPD group (84.9% vs 66.8%; p 0.002). The mean age of BLT recipients from both AAD and COPD groups (48 and 54 years) was lower than SLT recipients from these respective groups (53 and 57 years, p 0.02). Ischemic times were measured in both groups. For BLT, we used the ischemic time of the second implanted lung. Total ischemic time in minutes for AAD cases was longer than that for COPD cases ( vs , p 0.038). When indexed to the proportion of BLT performed in each group, the difference in total ischemic time was no longer evident. Cardiopulmonary bypass was employed proportionately over twice as often in AAD cases, though this difference did not reach statistical significance. ECMO was used in 1 COPD patient. Survival Overall hospital mortality was 6.2%, with no difference between COPD recipients (5.5%) and AAD recipients (8.1%, p 0.43). There was no difference in hospital mortality between single (7.0%) and bilateral (5.9%) transplant recipients (p 0.79). Hospital mortality was lower in our most recent experience (1995 to 2000, n 180), with 3.9% versus 9.5% from our early series (1988 to 1994, n 126; p 0.044). Overall 5-year survival was 58.6% 3.5%. AAD recipients had a 5-year survival of 60.5% 5.8%, whereas COPD recipients had a 56.8% 4.4% rate (p 0.53; Fig 2). Table 2. Operative Parameters COPD (n 220) AAD (n 86) p Value Marginal donor (%) 74 (33.6%) 35 (40.7%) 0.29 Bilateral lung transplant 147 (66.8%) 73 (84.9%) (%) Total ischemic time (minutes) Total ischemic time per NA lung index (minutes/lung transplanted) a CPB (%) 13 (5.9%) 11 (12.8%) CMV mismatch (%) 103 (46.8%) 32 (37.2%) Values are expressed as means standard deviation. CMV cytomegalovirus; CPB cardiopulmonary bypass; NA not applicable. a Total ischemic time per lung index [(no. of bilateral-lung transplants no. of single-lung transplants) (total ischemic time)]/[(no. of bilaterallung transplants 2) (no. of single lung transplant)].

4 1666 CASSIVI ET AL Ann Thorac Surg LUNG TRANSPLANTATION FOR EMPHYSEMA 2002;74: Fig 4. Actuarial survival of lung transplantation for emphysema by era (1988 to 1994, 1995 to 2000). Fig 2. Lung transplant actuarial survival by diagnosis. (Alpha-1 alpha 1 antitrypsin deficiency; COPD chronic obstructive pulmonary disease; Other lung transplant recipients with other diagnoses.) Five-year survival for all other diagnoses receiving lung transplantation (n 248) was 54.4% 3.5%. Emphysema patients receiving BLT had a significantly higher 5-year survival at 66.7% 4.0%, as compared with SLT recipients at 44.9% 6.0% (p 0.001; Fig 3). This improved survival for BLT recipients was also observed within the groups of AAD and COPD patients. Whereas the 5-year survival for BLT recipients with AAD and COPD was 69.7% and 64.1%, respectively; for SLT recipients it was 23.1% and 50.3% (p 0.001). Figure 4 shows the overall Kaplan-Meier survival curves for the initial experience Fig 3. Actuarial survival of lung transplantation for emphysema by type of procedure (single vs bilateral lung transplantation). (1988 to 1994) and recent experience (1995 to 2000). The latter group demonstrated a trend toward a higher 5-year survival (70.4% 4.6%) than the earlier group (53.7% 4.5%, p 0.06). Mean follow-up was years and years, respectively. Cox multivariate proportional hazards regression analysis determined that only single-lung transplants and use of CPB were determinants of poor survival results. Patients receiving a single-lung transplant had relative hazard of higher mortality of 1.98 (p 0.001; 95% CI, 1.37 to 2.86), whereas those undergoing CPB during their transplantation had a relative hazard of 1.84 (p 0.038; 95% CI, 1.03 to 3.28). Factors not associated with an increased risk were use of marginal donor, early graft dysfunction (P a O 2 /F i O mm Hg) within 4 to 6 hours and within 24 hours, diagnosis of AAD, recipient age or gender, multiple episodes of rejection, an episode of severe (A3) rejection, total ischemic time, cytomegalovirus mismatch, use of ECMO, diagnosis of BOS, and date of transplant. Posttransplantation Functional Results Table 3 details the forced vital capacity (FVC), forced expiratory volume in 1 second (FEV 1 ), 6-minute walk test (6MW), and arterial carbon dioxide tension (P a CO 2 ) from the preoperative time of evaluation to the 5-year time point posttransplantation. Whereas there are no differences between AAD and COPD groups at each time point, both groups show statistically significant improvement in all the above measures when comparing the preoperative baseline with the function at the 1-year time point As another measure of early postoperative function, 22 of 220 (10%) COPD patients demonstrated early graft dysfunction as defined by a P a O 2 /F i O mm Hg in the first 4 to 6 hours posttransplantation. Early graft dysfunction was seen in 14 of 86 (16.3%) AAD recipients

5 Ann Thorac Surg CASSIVI ET AL 2002;74: LUNG TRANSPLANTATION FOR EMPHYSEMA 1667 Table 3. Posttransplantation Functional Results COPD AAD Forced vital capacity (% predicted) Evaluation months year year FEV 1 (% predicted) Evaluation months year years minute walk (feet) Evaluation months year years PaCO 2 (mm Hg) Evaluation months year years Values are expressed as means standard deviation. AAD alpha 1 antitrypsin deficiency; COPD chronic obstructive pulmonary disease; FEV 1 forced expiratory volume in 1 second; P a CO 2 arterial carbon dioxide tension. (p 0.167). By 24 hours, the number of recipients fulfilling this criterion for graft dysfunction had decreased to 7 of 220 (3.2%) in the COPD group and 8 of 86 (9.3%) in the AAD group (p 0.037). Overall graft dysfunction in the first 24 hours posttransplantation was 4.9%. Details regarding other measures of early postoperative morbidity, including length of intubation, length of ICU stay, and length of hospital stay, are found in Table 4. Late Morbidity The overall prevalence of BOS was 37.9%, with no significant difference between COPD and AAD patients (36.8% and 40.7%, p 0.60). Kaplan-Meier freedom from BOS curves for COPD and AAD recipients and for SLT and BLT recipients are found in Figures 5 and 6, respectively. There was no difference between AAD and COPD groups, but a significant difference was found between SLT and BLT recipients (p 0.006). Posttransplant malignancy was found in 7.7% of COPD recipients as compared with 9.3% in the AAD group (p 0.65). Comment Emphysema currently affects nearly 2 million Americans and is responsible for approximately 110,000 deaths annually in the United States [11, 12]. AAD is a hereditary form of emphysema with autosomal recessive transmission, accounting for approximately 2% of emphysema cases. The gene locus is on chromosome 14, and disease severity is determined by variations in the genotype. Decreased antiprotease production results in an accelerated loss of lung function at a much earlier age than with COPD patients. The deterioration in lung function is even more rapid if the AAD patient is a smoker. Anatomically, AAD patients develop a premature, diffuse, or lower lobe, panlobular form of emphysema secondary to uninhibited proteolytic destruction of the connective tissue scaffolding of the lung. This is in contrast to the more commonly seen emphysema secondary to cigarette smoking, which primarily affects the upper lobes in a centrilobular distribution. At our institution, 55.2% of lung transplants are performed for emphysema (COPD and AAD). This is a higher proportion than the worldwide experience (45.9%) as reported by the ISHLT in their most recent annual report [1]. In our series, AAD cases accounted for 28% of lung transplants for emphysema, a larger percentage than is reported in the ISHLT registry (22.8%). Our lung transplant program may have a proclivity for emphysema patients as a byproduct of our institution s early and continued interest in lung volume reduction surgery (LVRS). Increased referrals of end-stage emphysema patients for LVRS evaluation may yield an increased number of potential transplant candidates with this di- Table 4. Early Postoperative Morbidity and Mortality COPD AAD p Value Hospital mortality 12/220 (5.5%) 7/86 (8.1%) 0.43 Duration of intubation (days) a 1.5 [1,3] 2 [1,3] 0.06 Length of ICU requirement (days) a 3 [2,4] 3 [2,5] 0.07 Length of hospital stay (days) a 16 [11,21] 18 [13,23] 0.06 Severe acute rejection 23/219 (10.5%) 5/86 (5.8%) 0.27 Increased frequency of rejection 34/219 (15.5%) 10/86 (11.6%) 0.47 Primary graft dysfunction (P a O 2 / F i O mm Hg) 4 6 hours 22/220 (10%) 14/86 (16.3%) hours 7/220 (3.2%) 8/86 (9.3%) 0.04 a Values are expressed as medians with 25th and 75th percentile interquartile ranges in brackets. AAD alpha 1 antitrypsin deficiency; COPD chronic obstructive pulmonary disease; F i O 2 fraction of inspired oxygen; ICU intensive care unit; P a O 2 arterial oxygen tension.

6 1668 CASSIVI ET AL Ann Thorac Surg LUNG TRANSPLANTATION FOR EMPHYSEMA 2002;74: Fig 5. Freedom from bronchiolitis obliterans by diagnosis. (Alpha-1 alpha 1 antitrypsin deficiency; COPD chronic obstructive pulmonary disease.) agnosis. We have previously reported on the impact of LVRS on subsequent lung transplantation [13]. Emphysema patients have 77% less risk of dying on the lung transplant waiting list than patients with all other diagnoses [14, 15]. The current recipient waiting list algorithm used in the United States is based solely on the individual waiting time of each listed patient rather than on disease severity. Only in the case of a local donor or a rare UNOS-approved variance may a program allocate donor lungs on the basis of other criteria. Particular to our lung transplant program is the fact that approximately 75% of our donor lungs originate from outside our region, and are offered only to the patient with the longest waiting time regardless of diagnosis. The increased waiting list longevity of patients with emphysema, therefore, favors them in terms of obtaining a transplant. AAD recipients, when compared with their COPD counterparts, demonstrated relatively similar outcomes. No statistical significance was found in the 5-year survival of the two groups, despite the significantly younger age of the AAD group and the generally held perception that AAD recipients, though similarly disabled from a pulmonary standpoint, have less comorbidity than their COPD counterparts [16]. Improved long-term survival of BLT over SLT in emphysema has been previously reported [17, 18] and remains a favorable prognostic factor in the ISHLT registry [1]. Our results show a similar survival advantage for BLT over SLT. Our institutional preference of BLT for emphysema patients is evident in our series. Whereas the ISHLT registry reports 27.9% of emphysema patients receive BLT worldwide, our series posts a proportion of 71.9%. We favor the BLT procedure in emphysema patients due to its record of superior survival, and our finding that postoperative ventilator management is much easier in the emphysema patients with BLT. The BLT procedure also allows us to use marginal donor lungs without significantly affecting our results, offsetting considerations of maximal donor organ use that would otherwise favor SLT. We also feel that BLT, although a longer procedure, is not any more complex an operation. A number of factors have been raised to explain the superiority in terms of survival of BLT over SLT. Of particular importance is selection bias, which may occur if BLT is being chosen preferentially for younger or healthier recipients. We found in our study that BLT recipients were, in fact, younger than those receiving SLT. This was true in both the AAD group and the COPD group. However, a selection bias favoring BLT was not universally the case, as all 6 ventilator-dependent patients in our series underwent bilateral transplantation. Another form of selection bias is operative tolerability, where it is decided to forego implanting the second lung when the procedure to implant the first lung has been difficult. This factor would select BLT only for patients able to tolerate a bilateral procedure. This bias may be of particular significance in a program such as ours where BLT is used preferentially and the preoperative intention to treat with SLT is relatively infrequent. The corollary to the above hypothesis is the bias to persist with a BLT in a younger patient despite difficulties during implantation of the first lung, to the extent of instituting CPB. The similar situation in an older, COPD patient may have resulted in aborting the second side of a previously planned BLT, even before the use of CPB. This may have been a factor in AAD patients receiving more BLT with more CPB usage. Whereas 9.5% of BLT procedures were performed with the assistance of CPB, only 3.5% of SLT procedures employed CPB. BLT recipients may be favored as well by having two grafts, and thus more reserve. This may be especially important if chronic rejection (BOS) develops. As well, operative complications such as phrenic nerve injury or Fig 6. Freedom from bronchiolitis obliterans by type of procedure (single vs bilateral lung transplantation).

7 Ann Thorac Surg CASSIVI ET AL 2002;74: LUNG TRANSPLANTATION FOR EMPHYSEMA 1669 bronchial anastomotic complications are uncommon but of much greater significance in SLT recipients. In our series, CPB was used in only 7.8% of all cases. There is a conscious effort at our institution to employ CPB only as necessary, because we believe that its routine use is unwarranted and possibly deleterious [19, 20]. The fact that, by regression analysis, CPB was one of two factors found to be associated with a statistically higher risk of mortality is not unexpected. Our strategy of CPB use only when needed selects out cases of particular difficulty and therefore increased risk. The evolution of our lung transplant program has not only seen an increase in volume of cases but has clearly benefited from the continuing growth of experience. Evolution and improvements in preoperative patient selection, operative technique, and perioperative management have seen a reduction in hospital mortality in the last 6 years (3.9%) as compared with the initial 7-year cohort (9.5%). The long-term survival results from our most recent experience are improved over those of our initial years. Though promising, results such as these should always be viewed in the context of the differing follow-up periods. Inevitably, the earlier cohort has a longer follow-up and is more fully representative of the long-term results. All survivors from the early group have reached the 5-year time point, whereas this is not the case in the later group. The earlier cohort has, therefore, had more opportunity to develop complications such as BOS, which most certainly affect survival results. This review of our single-institution experience in lung transplantation for emphysema confirms the very satisfactory results obtainable for both COPD and AAD recipients. Although AAD recipients are generally younger than their COPD counterparts, they have similar long-term survival after lung transplantation. Our series further underlines the survival advantage of bilateralover single-lung transplantation for emphysema. Moreover, our results demonstrate the infrequent need for cardiopulmonary bypass and argue against its routine use in lung transplantation for emphysema. References 1. Hosenpud JD, Bennet LE, Berkeley MK, Boucek MM, Novick RJ. The registry of the international society for heart and lung transplantation: eighteenth official report J Heart Lung Transpl 2001;20: Sundaresan S, Semenkovich J, Ochoa L, et al. Successful outcome of lung transplantation is not compromised by the use of marginal donor lungs. J Thorac Cardiovasc Surg 1995;109: Sundaresan S, Trachiotis GD, Aoe M, Patterson GA, Cooper JD. Donor lung procurement: assessment and operative technique. Ann Thorac Surg 1993;56: Varela A, Cordoba M, Serrano-Fiz S, et al. Early lung allograft function after retrograde and antegrade preservation. J Thorac Cardiovasc Surg 1997;114: Meyers BF, Patterson GA. Technical aspect of adult lung transplantation. Semin Thorac Cardiovasc Surg 1998;10: Meyers BF, Sundaresan RS, Cooper JD, Patterson GA. Bilateral sequential lung transplantation without sternal division eliminates posttransplantation sternal complications. J Thorac Cardiovasc Surg 1999;117: Trulock EP. Lung transplantation. Am J Respir Crit Care Med 1997;155: Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transpl 1996;15: Bando K, Paradis IL, Similo S, et al. Obliterative bronchiolitis after lung and heart-lung transplantation. J Thorac Cardiovasc Surg 1995;110: Cooper JD, Billingham M, Egan T. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. J Heart Lung Transpl 1993;12: American Lung Association. Estimated prevalence and incidence of lung disease by lung association territory. Epidemiology and Statistics Unit of the American Lung Association: New York, National Center for Health Statistics. National Vital Statistics Reports: Hyattsville, MD, 1999;47(19). 13. Meyers BF, Yusen RD, Guthrie TJ, et al. Outcome of bilateral lung volume reduction in patients with emphysema potentially eligible for lung transplantation. J Thorac Cardiovasc Surg 2001;122: De Meester J, Smits JM, Persijn GG, Haverich A. Lung transplant waiting list: differential outcome of type of endstage lung disease, one year after registration. J Heart Lung Transpl 1999;18: Geertsma A, Ten Vergert EM, Bonsel GJ, de Boer WJ, van der Bij W. Does lung transplantation prolong life? A comparison of survival with and without transplantation. J Heart Lung Transpl 1998;17: Trulock EP. Lung transplantation for alpha 1-antitrypsin deficiency emphysema. Chest 1996;110(Suppl 6):284S 94S. 17. Sundaresan RS, Shiraishi Y, Trulock EP, et al. Single or bilateral lung transplantation for emphysema? J Thorac Cardiovasc Surg 1996;112: Bavaria JE, Kotloff R, Palevsky H, et al. Bilateral versus single lung transplantation for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1997;113: Aeba R, Griffith BP, Kormos RL, et al. Effect of cardiopulmonary bypass on early graft dysfunction in clinical lung transplantation. Ann Thorac Surg 1994;57: McRae K. Con: lung transplantation should not be routinely performed with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2000;14: DISCUSSION DR W. ROY SMYTHE (Houston, TX): I enjoyed your paper. It was a great presentation. Could you comment on your use of volume reduction as a bridge to lung transplantation in your COPD patients? And a related question, how many patients have you been able to list for lung transplant with COPD who did not qualify for listing prior to volume reduction? Thanks very much. DR CASSIVI: In our program, we obviously have a certain proclivity for emphysema patients due to our institutional interest in lung volume reduction and transplantation. We have transplanted patients who have had previous lung volume reduction, and they have not had any worse results in terms of short- and long-term outcomes. The operation is somewhat

8 1670 CASSIVI ET AL Ann Thorac Surg LUNG TRANSPLANTATION FOR EMPHYSEMA 2002;74: different in that the pneumonectomy is sometimes more challenging. However, in terms of the outcomes, these patients do just as well. With regard to lung volume reduction surgery as a bridge to transplantation, it is certainly a topic that has been previously discussed. As a generality, age is a major factor a person who is younger may benefit from lung volume reduction first and thus allow them to then be bridged over to a transplant at a later date. Extent and distribution of disease is another important factor in our evaluation of emphysema patients. Some patients being evaluated for lung volume reduction surgery have homogenous disease and are therefore more appropriate candidates for transplantation. At evaluation, we do try to categorize the patients as candidates for one or the other operation if appropriate. DR ROBERT D. DAVIS, JR (Durham, NC): Dr Cassivi, that was an excellent presentation and, again, compliments on the excellent results that your group has continued to have with these patients. We recently analyzed combined data from Duke and Toronto lung transplant programs. We found the same survival benefit and lower rates of bronchiolitis in patients receiving bilateral-lung transplants versus single-lung transplants. My question is, what is the role of single-lung transplant for patients with emphysema? Obviously there is a donor shortage, but are we just doing a poor palliative operation by offering single-lung transplants for this disease? When you compare results, I think that your data suggest that the outcomes doing a bilateral-lung transplant for emphysema essentially becomes equivalent to what we would expect with the best recipient cohort, the cystic fibrosis population, and that a 70% 5-year survival is achievable with a double-lung transplant, where everyone is finding 35% to 45% 5-year survival in the patients getting single-lung transplants for emphysema. It is a difficult question, to essentially take more patients out of the mix by doing bilateral lung transplants, but is it really fair to those patients by performing single-lung transplants? DR CASSIVI: Thank you for your question. We have a similar attitude in St. Louis in terms of our preference for the bilateral sequential lung transplantation procedure. We believe it has better long-term results. We also believe that it does not add significantly to the complexity of the operation. A bilateral-lung transplant is just a bit longer. As well, at Washington University in St. Louis, we often use marginal donors for the bilateral procedures in emphysema. We do not use marginal donors for the other diseases. With better long-term outcomes and expansion of the donor pool by using marginal organs that would otherwise be wasted, we propose that these strategies go a long way in overcoming any ethical questions of donor organ allocation. Therefore, we would prefer, when the possibility avails itself, to perform bilateral transplants for our patients. The role of single-lung transplantation is therefore in question. I believe there are certain cases where, in an older patient, after the first lung has been gone into and it has been somewhat difficult, we have tended to cut our losses and proceed only with the single lung. That scenario has happened only on very rare occasions. Without any specific cases to demonstrate this point, I believe there is a corollary to the scenario that I have just presented. It is in the younger patients, the alpha-1 s particularly, where instead of stopping at one lung, we may proceed along on cardiopulmonary bypass to put in that second lung. In general, our institutional preference a priori is for bilateral-lung transplantation for the reasons that I have mentioned here and in my presentation.