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Lung Transplantation After Lung Volume Reduction Surgery

Shigemura, Norihisa1,3; Gilbert, Sebastien1; Bhama, Jay K.1; Crespo, Maria M.2; Zaldonis, Diana1; Pilewski, Joseph M.2; Bermudez, Christian A.1

doi: 10.1097/TP.0b013e31829853ac
Clinical and Translational Research
Free

Background Lung volume reduction surgery (LVRS) as a bridge to lung transplantation was first advocated in 1995 and published studies have supported the concept but with limited data. The risk-benefit tradeoffs of the combined procedure have not been thoroughly examined, although substantial information regarding LVRS has emerged.

Methods Of 177 patients who underwent lung transplantation for end-stage emphysema between 2002 and 2009 at our center, 25 had prior LVRS (22 bilateral and 3 unilateral). Lung transplantation was performed 22.9±15.9 months after LVRS. We compared in-hospital morbidity, functional capacity, and long-term outcomes of patients who underwent LVRS before lung transplantation with a matched cohort of patients without prior LVRS to assess the influence of LVRS on posttransplantation morbidity and mortality.

Results The incidence of postoperative bleeding requiring reexploration and the incidence of renal dysfunction requiring dialysis were higher in patients with LVRS before lung transplantation. Posttransplantation peak forced expiratory volume in 1 s was worse in patients with LVRS before lung transplantation (56.7% vs. 78.8%; P<0.05). Five-year survival was not significantly different (59.7% in patients with LVRS before lung transplantation vs. 66.2% in patients with lung transplantation alone). In multivariate analysis, age more than 65 years, prolonged cardiopulmonary bypass time, and severe pulmonary hypertension were significant predictors for mortality (P<0.05).

Conclusions Although LVRS remains a viable option as a bridge to lung transplantation in appropriately selected patients, LVRS before lung transplantation can impart substantial morbidity and compromised functional capacity after lung transplantation. LVRS should not be easily considered as a bridge to transplantation for all lung transplant candidates.

1 Division of Cardiothoracic Transplantation, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.

2 Division of Pulmonary Allergy and Critical Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA.

3 Address correspondence to: Norihisa Shigemura, M.D., Ph.D., University of Pittsburgh Medical Center Presbyterian, Suite C-900, 200 Lothrop Street, Pittsburgh, PA 15213.

The authors declare no funding or conflicts of interest.

Presented at CHEST 2011, Honolulu, HI, October 22–26, 2011.

E-mail: shigemuran@upmc.edu

N.S. contributed to organizing the study, data collection, data analysis, and writing of the article. S.G. contributed to organizing the study, data collection, and writing of the article. J.K.B. contributed to the data analysis. M.M.C. and J.M.P. contributed to the data collection and writing of the article. D.Z. contributed to the data analysis and statistical review. C.A.B. contributed to the data analysis and writing of the article.

N.S. takes responsibility for (is the guarantor of) the content of this article, including the data and analysis.

Received 25 February 2013. Revision requested 12 March 2013.

Accepted 22 April 2013.

Accepted June 4, 2013

Lung volume reduction surgery (LVRS) has long been considered an effective and safe bridge to lung transplantation. This concept of a staged procedure, LVRS followed by a later lung transplantation, was first described by our center in 1995 (1). Since then, many studies have associated good clinical outcomes with the staged procedure (2–5). However, the risk to the patient in exchange for bridging time to transplantation has not been fully defined and the risk-benefit tradeoffs have not been thoroughly discussed. Using the United Network for Organ Sharing (UNOS) transplant database, Nathan et al. (6) reported good outcomes in lung transplant patients who had a history of LVRS and concluded that a history of LVRS does not impact negatively on patients’ subsequent lung transplant outcomes and hence on their candidacy for lung transplantation. However, this was a multicenter study with 31 centers and a total of only 50 LVRS cases (1.6 cases per center). The highest volume center in the study had only six cases over 3 years. The study also lacked technical details, detailed demographics, and operative data and had very limited postoperative data. Additionally, single lung transplantation was the predominant procedure in the study; only 28% of the patients who underwent LVRS had a double lung transplant. This motivated us to revisit the value of a staged surgery with lung transplantation after LVRS. Herein, we report our large, single-center experience with lung transplantation in patients with prior LVRS.

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RESULTS

LVRS Details

Lung transplantation was performed an average of 22.9±15.9 months (median, 25.5 months; range, 14–62 months) after LVRS. Surgical approaches for LVRS included 22 bilateral lung volume reductions and 3 unilateral lung volume reductions. LVRS was performed via video-assisted thoracic surgery in 14 patients, thoracotomy in 7, and median sternotomy approaches in 4.

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Operative Data

Intraoperative data are shown in Table 1. All the patients included in this study underwent double lung transplantation. The operative time was significantly longer in patients with prior LVRS than in patients without prior LVRS (551 vs. 445 min; P<0.05). There were no significant differences in ischemic time; however, there was a significant difference in the need for cardiopulmonary bypass (CPB) and the required CPB time between the two groups. Patients with LVRS before lung transplantation required more blood products during lung transplantation surgery and for the first 48 hr after surgery than patients without prior LVRS (9.0 vs. 2.1; P<0.05). According to the operative notes, 23 of 25 (92%) patients with LVRS before lung transplantation had greater than moderate adhesions to the chest wall, and interestingly, 5 (20%) patients had moderate or severe hilar adhesions. In contrast, only 3 (12%) patients without prior LVRS had pleural adhesions, and none had hilar adhesions (Table 1).

TABLE 1

TABLE 1

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Early and Long-term Postoperative Outcomes

Early postoperative outcomes are shown in Table 2. Patients who had LVRS before lung transplantation had a higher incidence of postoperative bleeding requiring reexploration and higher incidence of renal insufficiency requiring dialysis (both 16% vs. 4.0%; P<0.05) and phrenic nerve injury (12% vs. 4.0%; P<0.05). There was no significant difference in respiratory complications, including prolonged mechanical ventilatory support, between the groups. The incidence of severe primary graft dysfunction (PGD) requiring extracorporeal membrane oxygenation (ECMO) and the incidence of acute cellular rejection in the first year were also similar between the groups.

TABLE 2

TABLE 2

Allograft quality during routine follow-up of up to 5 years was evaluated using posttransplantation peak forced expiratory volume in 1 s (FEV1.0) and peak 6-min walk test (6MWT) values. Posttransplantation allograft quality was significantly inferior by both measures in the LVRS-Lung Transplant Group (Table 2); however, survival 5 years after lung transplantation was not significantly different between the groups (LVRS-Lung Transplant Group 59.7% and Lung Transplant Alone Group 66.2%; Fig. 1).

FIGURE 1

FIGURE 1

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Risk Factors for Mortality in Patients With Prior LVRS

Finally, we assessed the unique factors contributing to the risk of mortality in patients who underwent lung transplantation after LVRS. Recipient age, lung allocation score more than 50, severe pulmonary hypertension (pulmonary artery [PA] systolic pressure >60 mmHg), transfusion requirements, CPB usage, and prolonged CPB time were associated with a significantly greater risk of death after lung transplantation in univariate analysis (P<0.05). However, in multivariate analysis, only advanced age (>65 years), severe pulmonary hypertension with PA systolic pressure more than 60 mmHg, prolonged CPB time (>4 hr), and high transfusion requirements (>20 units) were identified as significant risk factors for death after lung transplantation (Table 3). None of these factors that were identified as risk factors for death in the LVRS-Lung Transplant Group were identified as risk factors in the Lung Transplant Alone Group.

TABLE 3

TABLE 3

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DISCUSSION

This study demonstrated the high risks associated with lung transplantation after LVRS. Substantial information on the benefits and risks of LVRS, including the results of the National Emphysema Treatment Trial, has become available to the medical community (7–9). The role of LVRS as a bridge to later lung transplantation in patients with chronic obstructive pulmonary disease (COPD), while advocated, had not been widely examined. This study report details possible complications, functional compromise, and risk factors for mortality in patients with LVRS before lung transplantation and, to the best of our knowledge, is the first report of this nature and the largest single-center experience to date.

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Lung Transplantation in Patients with Prior LVRS Is Technically Challenging

Our findings indicate that lung transplantation in patients with prior LVRS is technically challenging. Intraoperative complexity was not examined in previous reports. Even at our high-volume center, the outcomes of patients with prior LVRS were not equivalent to those seen in patients without prior LVRS with otherwise similar backgrounds. The incidence of life-threatening postoperative complications including bleeding and acute renal insufficiency was higher in patients with prior LVRS. This may be attributed to the intraoperative factors; operative time was longer, and CPB was needed more often and for longer durations in patients with prior LVRS compared with those without LVRS. Our data also demonstrated that the intrathoracic adhesions noted in patients with prior LVRS were not restricted to the chest wall and diaphragm and extended to the hilum in some cases, which may augment technical complexity. It needs to be thoroughly recognized that adverse intraoperative and perioperative factors affect long-term functional quality after lung transplantation. There is strong evidence that these operative factors are associated with increased risk of PGD (10–13), and more profound implication is the effect immediate posttransplantation PGD seems to have on long-term outcomes, specifically the incidence of chronic rejection, or bronchiolitis obliterans syndrome. As is commonly recognized, bronchiolitis obliterans syndrome remains the most significant barrier to long-term success in lung transplantation (14–17). Patients with prior LVRS are not reaching the same level of posttransplantation function as patients without prior LVRS.

Lung transplantation for patients with prior cardiothoracic surgery requires a definitive surgical plan, particularly for CPB including the cannulation approach (18). It is also crucial to secure a high-quality donor lung that can tolerate prolonged cold ischemic time because of the potential for prolonged CPB time during a challenging lung transplantation after LVRS. This can be achieved with a high-quality procurement technique and assurance of baseline donor lung quality, which was addressed in a previous report (19).

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Pulmonary Hypertension After LVRS Is a Significant Risk Factor for Poor Prognosis After Lung Transplantation

The biggest difference between the previous series using the UNOS data (6) and ours is the patient cohort. In series using the UNOS data, only 28% of the patients underwent double lung transplantation, whereas in our cohort 100% had double lung transplantation. This difference may be reflected in the fact that the cohort with prior LVRS from the UNOS database included fewer patients with pulmonary hypertension compared with ours (35 mmHg of systolic PA pressure in the UNOS cohort vs. 58 mmHg in our study group). Although the National Emphysema Treatment Trial report suggests that LVRS may not raise PA pressure, based on their data from right-sided heart catheterization performed before and 6 months after lung transplantation (20), there is very little information to date regarding long-term follow-up of pulmonary hemodynamics after LVRS. Previous reports demonstrated that some patients develop pulmonary hypertension after LVRS (21). Approximately half of the patients with prior LVRS in this study were turned down by other lung transplant centers before being referred to our center. In contrast, the UNOS database study included very few patients with prior LVRS and pulmonary hypertension. Although this issue has not been previously discussed in the literature, individuals who develop severe pulmonary hypertension after LVRS are likely recognized as high-risk patients for lung transplantation by transplant community.

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Risk-Benefit Tradeoffs of LVRS as a Bridge to Later Lung Transplantation

LVRS remains a viable option as a bridge to lung transplantation as it can bridge approximately 2 years in selected patients; however, our data suggest that proper patient selection is crucial because patients who develop severe pulmonary hypertension after LVRS are at a significantly higher risk for mortality after lung transplantation, have a higher incidence of life-threatening complications, and may have compromised functional outcomes.

In spite of substantial documented/evidenced therapeutic efficacy (22–25), LVRS remains an underused therapy with reportedly only 120 LVRS cases being performed nationwide in 2008 under Medicare (26), whereas the number of patients with COPD continues to increase (~4 million in the United States). In contrast, lung transplantation is an established treatment, particularly for COPD with approximately 1000 cases being performed yearly, with robust evidence supporting long-term benefits with acceptable risks (27, 28). Given these current circumstances/limitations together with the results demonstrated in this study, at this point, we advocate that surgeons be very selective in their use of LVRS as a bridge to later lung transplantation and provide careful follow-up for patients with prior LVRS, making every effort to perform the lung transplantation before the patient develops severe pulmonary hypertension.

The primary limitations of this study are its retrospective nature and the sample size. Although it is the largest single-center series of patients who underwent lung transplantation after LVRS, the study is notably smaller than the study done with the UNOS database. However, our data shed a new light on the outcomes of a patient population that has not been discussed previously in the literature, leading to the relevant, new findings that should impact the treatment decision-making for patient with end-stage COPD. To the best of our knowledge, this report is the first challenge the conventional recognition of a role of LVRS in conjunction with lung transplantation as a treatment strategy for COPD.

In conclusion, our experience demonstrates that LVRS should not be easily considered as a bridge to transplantation for all possible candidates for lung transplantation. We should be selective in using this option because lung transplantation after LVRS is technically challenging and the incidence of major complications is higher than for patients who have not undergone LVRS. Severe pulmonary hypertension that develops after LVRS is a significant risk factor for mortality after lung transplantation, and the multidisciplinary committee needs to be very selective when deciding the candidacy for lung transplantation for these patients.

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MATERIALS AND METHODS

Patients

Human subject approval for this study was obtained from the University of Pittsburgh Medical Center (UPMC) Institutional Review Board (approved project number: 0001042) before obtaining data. In all patients, lung transplantation was performed using standardized techniques and our current lung protection protocol, which have been reported in detail elsewhere (19). A standardized care pathway for postoperative care was also used in all patients.

From January 2002 to December 2009, 177 primary lung transplant cases were performed for end-stage COPD/emphysema at the UPMC. Of those, 25 recipients underwent LVRS before lung transplantation. To compare the early and long-term outcomes of lung transplantation with and without prior LVRS, a retrospective, matched-cohort study was performed using the following variables for matching: preoperative diagnosis of COPD, age (±3 years), gender, procedure (double lung transplantation), and date of transplantation. Preoperative PA pressure was intentionally eliminated from variables because of the following reasons: (a) pulmonary hypertension after LVRS, which was considered to be a risk factor for poor prognosis after lung transplantation, can be a confounding variable, and (b) one of the purposes in this study was to see how the outcomes would be if the patients who underwent combined procedure of LVRS and lung transplantation had had lung transplantation alone without LVRS and without developing pulmonary hypertension. The patients who had undergone prior LVRS had more pulmonary hypertension, as indicated the PA systolic pressure, than their matched counterparts who did not undergo LVRS. All other background characteristics were similar between the two groups (Table 4).

TABLE 4

TABLE 4

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Intraoperative Details, Complications, Mortality, and Long-term Survival

Data regarding intraoperative details and postoperative complications of the lung transplantation surgery were collected from UPMC Transplant Patient Management System database, which documents all adverse outcomes via prospective data collection from patient clinical records. The requirement of blood products was expressed as a total number of units of red blood cells, packs of fresh frozen plasma, and bags of platelets required during surgery and for the first 48 hr after surgery.

Short-term complications included postoperative bleeding requiring reexploration, phrenic nerve injury, respiratory failure requiring an extended period of ventilator management (>5 days), requirement of a tracheostomy, renal insufficiency, and severe PGD requiring ECMO. Renal dysfunction was defined as severe renal insufficiency requiring either temporary or permanent dialysis treatment. PGD and acute rejection were defined and graded using the International Society for Heart and Lung Transplantation definitions (5). In our standardized care pathway, screening transbronchial biopsy after lung transplantation is performed 2 weeks after the surgery and every 2 months subsequently. Acute cellular rejection was diagnosed based on the results of transbronchial biopsy, and rejection grade A2 or greater that was treated with steroid pulse therapy was defined as acute rejection.

With our protocol, pulmonary function tests are routinely performed 1, 3, 6, and 12 months after lung transplantation and then yearly thereafter until 5 years after lung transplantation. Additional testing was performed based on clinical necessity. In this study, the peak posttransplantation FEV1.0 and 6MWT values available from the routine pulmonary function tests were used to assess of the quality of the graft. Long-term clinical outcomes were assessed by overall survival 5 years after transplantation.

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Data Analysis

Statistical analysis was performed using the StatView 5.0 software package (SAS Institute, Cary, NC). Continuous variables are expressed as mean±SD. Comparisons between groups were done using Student’s t test, whereas categorical variables were analyzed by Fisher’s exact test. The primary endpoint was posttransplantation survival. Secondary endpoints included posttransplantation allograft function and the incidence of major complications including reexploration due to bleeding, phrenic nerve injury, prolonged ventilation, requirement of tracheostomy, renal insufficiency, and severe PGD requiring ECMO. Univariate analyses and a Cox proportional hazards model were used to estimate the relationships of individual risk factors with the occurrence of mortality in the LVRS-Lung Transplant Group; risk factors for mortality with P<0.05 identified by univariate analyses were introduced into a backward stepwise regression model for multivariate analysis. We included the following in the univariate analyses: (a) preoperative factors (patient background, diagnosis, and comorbidities; variables in Table 4), (b) donor factors (age, P/F ratio, and cytomegalovirus mismatch; variables in Table 4), and (c) surgical factors (ischemic time, transfusion, and need for CPB; variables in Table 1). P<0.05 was considered statistically significant. Survival was calculated and assessed using the Kaplan–Meier method and a log-rank test, with a level of P<0.05 considered statistically significant.

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ACKNOWLEDGMENT

The authors thank Shannon L. Wyszomierski, Ph.D., for her excellent editing assistance.

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Keywords:

Lung transplant; Volume reduction surgery; Pulmonary hypertension; Complication

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