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Ann Thorac Surg 2002;73:1587-1593
© 2002 The Society of Thoracic Surgeons
a Division of Pulmonary Transplantation, The University of Pittsburgh Medical Center, West Penn Allegheny Health System, Pittsburgh, Pennsylvania, USA
b Division of Cardiothoracic Surgery, The University of Pittsburgh Medical Center, West Penn Allegheny Health System, Pittsburgh, Pennsylvania, USA
c Division of Cardiothoracic Surgery, West Penn Allegheny Health System, Pittsburgh, Pennsylvania, USA
Accepted for publication December 3, 2001.
* Address reprint requests to Dr Zenati, Division of Cardiothoracic Surgery, 200 Lothrop St, C-700, Pittsburgh, PA, USA
e-mail: zenatim{at}msx.upmc.edu
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Abstract |
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Methods. We compared the postoperative and long-term outcomes of a sequential procedure cohort to a matched cohort to assess the possible added post-transplant morbidity.
Results. Fifteen patients who underwent sequential LVRS (including 11 unilateral LVRS, 4 bilateral LVRS) and lung transplantation (ipsilateral in 7 and contralateral in 8) on average 28.1 ± 17.2 months (median, 27.4 months; range, 3.7 to 61.7 months) later were assessed. No significant differences were noted in pretransplant demographics, post-transplant variables, longitudinal spirometric indices, or survival. A trend toward a lower pretransplant arterial carbon dioxide tension was apparent in the sequential procedure cohort. Group analysis revealed a significant increase in the number of patients requiring transfusion and in the total number of units transfused in patients undergoing ispsilateral transplantation after LVRS; a significant increase in the length of intensive care unit stay; and a trend toward an increase in the duration of hospital stay in patients undergoing lung transplantation within 18 months of LVRS.
Conclusions. In appropriate candidates, LVRS bridged the time to transplantation by an average of 28.1 ± 17.2 months (median, 27.4 months; range, 3.7 to 61.7 months) without significantly increasing post-transplant morbidity or mortality. Furthermore, bilateral LVRS bridged the time to transplantation to a greater extent than unilateral LVRS (34.9 ± 29.8 months; median, 32.1 months versus 25.4 ± 16.3 months; median, 22.3 months; p = 0.23).
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Introduction |
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Lung volume reduction surgery (LVRS) is a possible alternative treatment to LTx for patients with nonuniform emphysema. The LVRS has been demonstrated to result in decreased lung hyperinflation, increased elastic recoil and forced expiratory volume in 1 second (FEV1), reduced intrathoracic pressures, improved right ventricular systolic functioning, and symptomatic relief in dyspneic patients [3, 4]. Whether LVRS is a temporizing therapy, serving as a bridge to transplantation [5, 6] or an alternative therapy [6–8] with comparable outcomes, is controversial. We have previously published that approximately 47.4% of patients with emphysema referred for evaluation by the Lung Transplant Program at the University of Pittsburgh were candidates for both LVRS and LTx, whereas 23.1% were candidates for LTx but not for LVRS. An additional 22.1% were declined as potential candidates for either procedure, whereas 7.4% were denied LTx but were offered LVRS as their only surgical intervention [7]. Lung volume reduction surgery has been suggested to palliate patients with end-stage emphysema, as an alternate to LTx, in up to 75% of selected patients after 32 months of follow-up [9]. The LVRS and LTx are still evolving therapies and the optimal intervention and timing remain to be determined. We hypothesized that LVRS may serve as a bridge to LTx for selected candidates with end-stage emphysema, without significant increases in post-transplantation morbidity and comparable longitudinal spirometry and survival after sequential procedures.
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Material and methods |
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Individuals in the matched LTx cohort were extrapolated from the University of Pittsburgh Lung Transplant Registry and matched using the following criteria: preoperative diagnosis of emphysema, age (±3 years), gender (M/F), procedure (right single LTx, left single LTx, or double LTx), and date of transplantation. If more than one suitable candidate was found, an individual was selected by matching the date of transplantation to ensure similar postoperative management strategies. No patient in either cohort was transplanted before 1991. This protocol was approved by the Institutional Review Board.
Surgical technique
All lung reduction procedures were performed with continuous electrocardiographic monitoring, central venous line insertion, radial artery access, continuous end-tidal arterial carbon dioxide tension monitoring and oximetry. All patients received an epidural catheter to facilitate intraoperative anesthesia and provide postoperative pain management. The airway was intubated with a left-sided double lumen endotracheal tube. The most severely affected hemithorax, as determined by computed tomographic scanning and single photon emission computed tomography perfusion imaging, was placed in a nondependent, lateral decubitus position. If both hemithoraces demonstrated an equal degree of parenchymal destruction, either a bilateral approach with sequential thoracoscopic LVRS was performed, or bilateral LVRS was achieved through a median sternotomy.
Three to five ports were used to facilitate access with the thoracoscope inserted into the pleural space through the seventh or eighth intercostal space at the mid to posterior axillary line. In 8 of 15 (53.3%) patients undergoing LVRS, a combination of endostapler resection with sparing use of neodymium:yttrium-aluminum garnet laser was used; the latter being used predominantly near the pulmonary hilum and at angles difficult to access with the endostapler. Endostapler resection was the preferred method in 7 of 15 (46.7%) patients, using either a 30-mm (US Surgical Corp, Norwalk, CT) or a 60-mm (Ethicon Endo-Surgery, Cincinnati, OH) stapler depending on the extent of resection required. The staple line was buttressed with bovine pericardial strips for added enforcement. The extent of the resection was determined by preoperative perfusion studies, with a goal of reducing the volume of lung by 25%. Strips of tissue were resected along the basal and superior segments of the lower lobes and along the minor fissure, as well as anteriorly and posteriorly in the region of the upper lobe. Episodic lung inflation was performed to facilitate evaluation of the extent of surgical resection and to avoid over-resection. At procedure completion, three chest tubes were placed in the pleural space through the intercostal access ports and placed on -10 cm H20 suction. No pleural abrasion or pleurectomy was performed. The lungs were ventilated to limit peak airway pressures while ensuring adequate tidal volume.
Study design
We compared the postoperative and long-term outcomes of the LVRS-LTx cohort to the age-, gender-, procedure-, and transplant time-matched (LTx) cohort, obtained from the University of Pittsburgh Lung Transplant Registry, to assess for possible additional post-transplant morbidity.
Retrospective chart reviews were performed for all patients to ascertain demographic data (age at LVRS, type of LVRS, age at LTx, type of LTx, organ ischemia time, mean pretransplant pulmonary artery pressure, pulmonary vascular resistance, pulmonary capillary wedge pressure, cardiac output, pretransplant lung function and arterial carbon dioxide tension, as well as pretransplant body mass index, oxygen requirement, New York Heart Association classification, and smoking history. To assess for potential added post-transplant morbidity with sequential procedures, we collected and compared post-transplantation outcomes including the number of units of packed red blood cells required in the first 24 hours after LTx, the number of patients requiring transfusion, the length of intubation, length of intensive care unit (ICU) stay and hospital stay, arterial oxygen dioxide tension/fractional concentration of oxygen ratio at the time of ICU admission and at 24 hours, rates of reintubation, the development of ischemia reperfusion injury and atrial fibrillation, the requirement for and duration of extracorporeal membrane oxygenation (ECMO), and 30-day mortality. Longitudinal spirometry was reviewed for all surviving patients at 1, 2, and 3 years after transplantation and compared between the two cohorts. Group analyses were conducted in the LVRS-LTx chort to compare patients undergoing transplantation ipsilateral and contralateral to the site of initial LVRS. Similarly, early and late outcomes were analyzed based on the time interval between LVRS and LTx, with an early cohort defined by undergoing LTx within 18 months before LVRS.
Statistical analysis
Comparisons between the pretransplant demographic variables and post-transplant outcomes were performed using 
2 testing for proportions and the Mann Whitney U test for continuous data. A Kaplan-Meier survival curve was generated and the log rank test was performed to assess post-transplant mortality. A p value of 0.05 or less was considered significant. All data are expressed as mean ± standard deviation, with the median and range specified for data, which were not normally distributed.
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Results |
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1-antitrypsin deficiency. Transplant procedures included 12 left and 2 right single lung allografts and 1 double lung transplant in each cohort.
Pretransplant demographics
Preoperative variables demonstrated a mean age of 56.2 ± 7.2 years in the LVRS-LTx cohort compared to 56.6 ± 5.5 years in the LTx cohort. Nine of 15 patients (60%) in each cohort were men, and 2 of 15 (13.3%) in each cohort had 1-antitrypsin deficiency emphysema. There were no significant differences in mean pretransplant oxygen requirements, smoking history, New York Heart Association classification, prednisone use, or cold ischemia time between the LVRSLTx and LTx cohorts. Furthermore, no apparent differences were noted in pretransplant FEV1, FEV1/forced vital capacity ratio, or diffusing capacity of the lung for carbon monoxide. Hemodynamic data demonstrated no statistically significant difference in mean pretransplant pulmonary artery pressure, pulmonary vascular resistance, and cardiac output between the matched cohorts (Table 1).
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After transplant, patients in the sequential procedure cohort were extubated after an average of 4.2 ± 8.8 days (median, 1 day; range, 1 to 34 days) compared to 3.3 ± 6.5 days (median, 1 day; range, 1 to 26 days) (p = 0.76) in the LTx cohort. The mean length of stay in the ICU was 5.9 ± 9.8 days (median, 2 days; range, 1 to 34 days) versus 5.8 ± 7.2 days (median, 3 days; range, 2 to 26 days) (p = 0.23) and the average duration of hospitalization was 41.1 ± 54.4 days (median, 22 days; range, 10 to 203 days) versus 26.9 ± 23.1 days (median, 21 day; range, 10 to 90 days) (p = 0.95) in the LVRS-LTx and LTx cohorts, respectively. The length of intubation and length of ICU stay were not significantly different (6.0 ± 12.3 days; median, 1 day versus 2.6 ± 4.2 days; median, 1 day; p = 0.56 and 6.9 ± 12.1 days; median, 2 days versus 5.1 ± 8.0 days; median, 2 days; p = 0.82); however, a nonsignificant trend toward a longer duration of hospitalization was apparent (50.0 ± 69.4 days; median, 26 days versus 33.3 ± 40.4 days; median, 15 days; p = 0.45) with the ipsilateral compared to the contralateral approach. When analyzed according to the interval of time between LVRS and LTx, although the early sequential procedure cohort demonstrated a similar duration of intubation (4.3 ± 5.9 days; median, 1.5 days versus 4.2 ± 9.9 days; median, 1 day; p = 0.51) compared to the late sequential procedure group, a statistically significant increase in the length of ICU stay (9.0 ± 10.7 days; median, 4 days versus 4.8 ± 9.7 days; median, 2 days; p = 0.02) and a nonsignificant trend toward longer duration of hospitalization (56.7 ± 48.7 days; median, 42 days versus 35.4 ± 57.4 days; median, 12 days; p = 0.12) were noted.
Postoperative complications
Radiographic ischemia reperfusion injury was noted in 5 of 15 (30.0%) patients in the sequential procedure cohort compared to 6 of 15 (40.0%) patients in the LTx cohort (p = 0.70). In 3 individuals in the former cohort, ischemia reperfusion injury was of sufficient severity to warrant ECMO intervention, and 2 individuals in the LTx cohort required ECMO support. The average duration of ECMO support was 4.0 ± 3.6 days (median, 3 days) in the LVRS-LTx cohort and 4.5 ± 2.1 day (median, 4.5 days) in the LTx cohort (p = 0.77). Two patients in each cohort developed postoperative supraventricular dysrhythmias (p = 0.99). No differences were noted in the requirement for reintubation (1 of 15 versus 2 of 15 patients, p = 0.54) or in 30-day mortality (2 of 15 versus 2 of 15 patients, p = 0.99) between the LVRS-LTx and LTx cohorts, respectively.
Postoperative complications in the LVRS-LTx cohort included four episodes of early acute rejection, one episode of Serratia marcescens pneumonia, one deep venous thrombosis and one fatal saddle embolism, a paralytic ileus, and one endobronchial airway anastomotic complication of bronchial stenosis. In the LTx cohort there was one episode of early acute rejection, an episode of Cytomegalovirus pneumonitis, an episode of vocal cord palsy, two hemothoraces, and one episode of renal insufficiency.
Spirometry
After an average of 34 months of post-transplant follow-up, longitudinal spirometry revealed a nonsignificant decline in post-transplant FEV1 and forced vital capacity at 2 years (1.36 ± 0.52 L versus 1.60 ± 0.42 L, p = 0.23 and 2.43 ± 0.50 L versus 2.78 ± 0.76 L, p = 0.42), which was sustained at 3 years after transplant (1.09 ± 0.47 L versus 1.43 ± 0.27 L, p = 0.20 and 1.95 ± 0.73 L versus 2.70 ± 0.48 L, p = 0.06) in both the LVRS-LTx and LTx cohorts (Fig 1).
Similar trends were apparent in forced expiratory flow at 25% to 75%. A further analysis revealed that there were no statistically significant differences in the rates of acute rejection per 100 patient days of survival (0.78 ± 1.84 versus 0.19 ± 0.23, p = 0.09) or the frequency of development of obliterative bronchiolitis (4 of 15 versus 4 of 15 patients, p = 0.99) between LVRS-LTx and LTx cohorts.
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Comment |
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We have previously demonstrated that thoracoscopic LVRS can palliate patients with end-stage chronic obstructive pulmonary disease, as an alternate to LTx, in up to 75% of selected patients with up to 32 months of follow-up, although sustainable benefits remain to be demonstrated [9]. Bavaria and co-workers [6] showed that 77.4% of patients (24 of 31 patients) with end-stage chronic obstructive pulmonary disease who underwent LVRS were able to be deactivated from the lung transplant waiting list after 6 months of follow-up. Subsequently however, 4 patients (16.7%) experienced significant clinical and physiologic deterioration necessitating relisting for LTx. Of these, half of the patients were successfully transplanted without significant morbidity or mortality. Clearly we can conclude that LVRS and LTx need not be considered mutually exclusive procedures.
In this matched, retrospective cohort study, we sought to determine whether additional postoperative morbidity was associated with LTx in patients who underwent previous LVRS. In our cohort of 15 patients, whom underwent sequential LVRS and LTx, no significant differences were noted in New York Heart Association classification, smoking history, oxygen requirements, or hemodynamic data between the matched cohorts. The mean FEV1, forced vital capacity, and diffusing capacity of the lung for carbon monoxide were not significantly different between the cohorts. A trend toward a lower pretransplant arterial carbon dioxide tension and body mass index was apparent in the sequential procedure cohort. The former has been proposed previously by Wisser and colleagues [17] and suggests that LVRS results in decreased dead space and may optimize patient condition before transplantation. However, the nonsignificant trend toward a lower body mass index in the LVRS-LTx cohort compared to the LTx cohort is contrary to that of Wisser and associates [17]. The mean corticosteroid dose cannot be implicated as the cause, as it did not differ significantly between the cohorts. Similar attention to nutrition and rehabilitation was endorsed before transplantation in both groups.
Importantly, no significant differences were noted in transfusion requirements, length of intubation, ICU stay, and hospitalization between the LVRS-LTx and LTx cohorts. A nonsignificant trend toward increased transfusion requirements was apparent in the sequential procedure cohort, with 6 of 15 patients in the LVRS-LTx cohort and 3 of 15 patients in the LTx cohort requiring transfusions (p = 0.23). Although the requirement for transfusions could be attributed solely to the presence of adhesions in the former group, the occurrence of postoperative hemothoraces and adhesions contributed to the need for transfusions in the latter group. Group analyses revealed that both the number of units required and the number of patients requiring transfusions were statistically significantly increased in patients undergoing transplantation ipsilateral to the site of prior LVRS. The presence of adhesions alone accounted for the increase in transfusion requirements. Adhesions were most commonly located adjacent to the diaphragm and anteriorly in the location of wedge resections performed in the region of the anterior segment of the upper lobe.
The length of intubation and length of ICU stay, although not significantly different overall, revealed a nonsignificant trend toward a longer duration of hospitalization with the ipsilateral compared to the contralateral approach. Subsequent group analyses demonstrated a similar duration of intubation in the early sequential procedure group to the late sequential procedure group, but a statistically significant increase in the length of ICU stay and a nonsignificant trend toward a longer duration of hospitalization, suggesting that delayed complications, not immediate postoperative complications, contributed to the increased length of ICU and hospital stay. Furthermore, previous LVRS did not significantly increase the development of ischemia reperfusion injury, the requirement for ECMO, the duration of ECMO support, or the occurrence of postoperative atrial dysrhythmias. Similarly, no differences were noted in the requirement for reintubation or in 30-day mortality between the matched cohorts.
The requirement for ECMO was 20% in the LVRS-LTx cohort and 13.3% in the LTx cohort. The former is slightly higher than the 15% incidence in the perioperative period published previously [18] and may be a reflection of the small sample size, a tendency toward early initiation of ECMO, or premorbid patient characteristics. The ECMO therapy was initiated either in the operating room or within the first 10 hours postoperatively, suggesting an institutional bias toward the early initiation of ECMO. Criteria for the initiation of ECMO therapy included severe hypoxemia despite maximum ventilatory support and 100% supplemental fractional inspired oxygen, decreased static lung compliance, and diffuse radiographic infiltrates. The range of decline in the arterial oxygen dioxide tension/fractional concentration of oxygen ratio within the first 24 hours postoperatively was between 52% and 89%. No single preoperative predictive variable of the subsequent requirement for ECMO could be identified. No patient in the LVRS-LTx cohort who developed primary graft failure had an elevation in arterial carbon dioxide tension beyond 55 mm Hg or a panacinar pattern of emphysema. One patient demonstrated a marginal cardiac output of 3.7 L/min, a further patient had a diffusing capacity of the lung for carbon monoxide of 16% of predicted, whereas the final patient appeared to be severely malnourished with a body mass index of 18.4 kg/m2.
No significant differences were noted between the cohorts in FEV1 for up to 3 years after transplantation, with the mean FEV1 in the sequential procedure cohort being lower than that in the LTx cohort. Similar nonsignificant trends were apparent with the forced vital capacity and forced expiratory flow at 25% to 75%. A further analysis of the rates of development of acute and chronic rejection after transplant revealed that there were no significant differences between the two cohorts in the frequency and severity of episodes of clinically significant acute rejection or the time to development of obliterative bronchiolitis between the groups, although there was a trend toward more frequent episodes of rejection in the LVRS-LTx group. It would be difficult to implicate that the trend represents a loss of pulmonary reserve secondary to resected tissue as the objective of LVRS is to resect the most diseased portions of lung and improve ventilation to the relatively more preserved regions. The latter may be attributed to the continued destruction of lung parenchyma after LVRS, together with concomitant declines in expiratory flow rates due to acute and chronic rejection. The trend toward and significance of the decrease in pulmonary reserve would require a larger sample size and further study for clarification.
After an average follow-up period of 34 months, no differences in long-term survival were noted for the LVRS-LTx and LTx cohorts with an average post-transplant survival of 31.8 months at study completion. The LVRS bridged the time to transplantation by an average of 28.1 ± 17.2 months (median, 27.4 months; range, 3.7 to 61.7 months) without significantly increasing post-transplant morbidity or mortality. Furthermore, bilateral LVRS bridged the time to transplantation to a greater extent than unilateral LVRS (34.9 ± 29.8 months, median, 32.1 months versus 25.4 ± 16.3 months, median, 22.3 months; p = 0.23). Whether LVRS or LTx or sequential procedures will be endorsed for a particular patient in the future will depend on the elucidation of preoperative indices that will optimize patient-procedure selection and will require more accurate delineation of measures of both immediate and delayed postoperative complications and long-term outcomes. To this end, we could find no evidence that previous LVRS adversely affected the post-transplant course compared to a match cohort with end-stage emphysema.
Lung volume reduction surgery and LTx are still evolving therapies. The optimal intervention and timing remain to be determined. Further data are clearly required to best stratify patients to the procedure that is most likely to offer the best opportunity for survival and the most favorable quality of life. If the risk-to-benefit ratio associated with LVRS is low for selected patients with end-stage emphysema and there is no significant added perioperative morbidity associated with sequential procedures, one could argue for more liberal criteria for LVRS to delay the early and late mortality associated with LTx in appropriate candidates. This strategy may provide definitive therapy for some patients, and act as a bridge to transplantation for others, thereby permitting better rationalization of the scarce donor organ pool to sicker patients for whom transplant may offer their only chance for survival and thereby decrease the attendant waiting period. Perhaps in the future, staged unilateral lung volume reduction procedures may provide both improved functional status and symptomatic relief without significant added postoperative morbidity while delaying the imminent mortality risk associated with transplantation. Whether LVRS will serve as a definitive therapeutic option with sustainable results in selected patients with emphysema remains controversial. However, in the case of nonresponders or those experiencing a lack of sustained response, our study demonstrates that LVRS may serve as a bridge to LTx with significant increases in the number of patients requiring transfusions and the number of units transfused after ipsilateral sequential procedures and significant increases in the length of ICU stay and a trend toward increased duration of hospitalization in individuals undergoing sequential procedures within an 18-month period. The trend toward and significance of decreased pulmonary reserve and the effect of the combination of previous unilateral or bilateral LVRS and subsequent ipsilateral or contralateral transplantation requires a larger sample size and further study for clarification. At present, the optimal management strategy for patients with end-stage lung disease failing medical management eludes clinicians and remains to be disclosed by the results of large, prospective clinical trials assessing the morbidity and mortality associated with individual interventions and subsequently the role of sequential procedures.10111213141516
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