Evaluating the effectiveness of staged versus simultaneous bilateral lung volume reduction surgery in patients with severe emphysema

Introduction

Emphysema is a leading cause of morbidity and mortality worldwide. Data suggest that approximately 14 million individuals in the United States are affected by emphysema (1). Chronic exposure to noxious particles or gases leads to structural changes in the lung parenchyma, including the enlargement and permanent destruction of the alveolar walls in patients with emphysema (2). These enlarged, nonfunctioning areas diminish the gas exchange surface of the lung, affecting pulmonary function and survival (3).

In patients with severe emphysema, where medical therapies offer limited benefit, surgical interventions can provide substantial improvements (4). Lung volume reduction surgery (LVRS) involves non-anatomical resection of emphysematous regions, allowing the remaining healthier lung parenchyma to expand and function more effectively. LVRS has been established as a reliable treatment that enhances lung function, exercise capacity, quality of life, and survival in selected patients with advanced emphysema (5,6).

Over the past few decades, several studies have documented the benefits of both unilateral and bilateral LVRS (7-11). Most studies suggest that bilateral LVRS leads to greater improvement in pulmonary function and functional capacity compared to the unilateral approach. However, the former is associated with a longer hospital stay and a higher incidence of complications, such as prolonged air leaks. Notably, one study found that patients who undergo bilateral LVRS experience a faster decline in forced expiratory volume in one second (FEV1) during the postoperative years than those who undergo unilateral surgery (9). Thus, despite the short-term advantages of the bilateral approach, it is important to explore the long-term outcomes of surgical alternatives.

Sequential bilateral LVRS—hereafter referred to as “staged”—may offer additional benefits over simultaneous bilateral surgery (referred to as “bilateral”), particularly given the fewer complications observed with the unilateral approach. While some studies have explored this hypothesis, no definitive conclusions have been reached. Some reported greater improvements in pulmonary function tests with bilateral LVRS, while others found no significant difference between the two approaches (12-15). Therefore, further research is necessary to determine which approach offers the most benefits for patients. Here, we aim to compare the effectiveness and safety of staged versus simultaneous bilateral LVRS in patients with severe emphysema. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-790/rc).

Methods

In this retrospective cohort study, we included patients with severe emphysema who underwent LVRS at two tertiary referral centers in the United States (Mayo Clinic Florida and Mayo Clinic Rochester) between January 2011 and June 2024. Patient selection criteria have been previously described (11). Briefly, we followed the recommendations outlined in the National Emphysema Treatment Trial for surgical selection (5). Patients underwent either bilateral or staged LVRS, depending on surgeon preference, not patient factors. The second part of the staged surgery was not planned in advance. The contralateral side was performed when the patients’ breathing function deteriorated back to baseline. There were multiple surgeons, each with their own preferences, but surgical techniques were in line with those described in the National Emphysema Treatment Trial.

We collected sociodemographic, clinical, and surgical data from medical records, including age, sex, body mass index, smoking history, comorbidities, pulmonary function tests, six-minute walk test (6MWT), and surgical complications. Data were collected and securely stored in a spreadsheet. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Mayo Clinic Florida (No. #21-006676) and individual consent for this retrospective analysis was waived. Mayo Clinic Rochester was also informed and agreed with the study.

Outcomes of interest

Functional outcomes

Pulmonary function tests [forced expiratory volume in one second (FEV1), diffusion capacity of the lungs for carbon monoxide (DLCO), residual volume (RV)] and 6MWT data were collected preoperatively and at 6-, 12-, and 24-month post-surgery, when available.

Surgical outcomes

Surgical outcomes included the duration of surgery, days with air leaks, days with chest tubes, days in the intensive care unit (ICU), total hospital length of stay, and complications such as hemothorax, transfusion requirements, pneumonia, pneumothorax requiring new chest tubes, subcutaneous emphysema, minor bleeding, and wound infections. A prolonged air leak was defined as one lasting more than 7 days. For patients discharged with chest tubes, the length of the chest tube was calculated from discharge until the tube was taken out in the clinic.

For the staged surgery outcomes, the total duration was calculated by adding the days from both the first and second surgeries, and this was compared with the bilateral LVRS group. Additionally, patients who experienced complications during either or both surgeries were classified as having that complication.

Survival outcomes

Due to uneven follow-up between the two surgical groups, we calculated the median follow-up time using the reverse Kaplan-Meier method and applied an appropriate threshold of 3 years based on the confidence interval (CI) from the median follow-up from the second surgery for the staged approach. We right-censored observations that exceeded this threshold for both approaches. Our main survival outcome was a composite of death from any cause or need for a lung transplant, evaluated in a time-to-event analysis.

Statistical analysis

Descriptive statistics were used to summarize the data. The normality of variables was assessed using visual plots and the Shapiro-Wilk test. Categorical variables were reported as counts and percentages, while continuous variables were summarized using median and interquartile range (IQR) or mean and standard deviation (SD), depending on the distribution of the data. Associations between variables were explored using Chi-squared, Fisher’s Exact, t-tests, and Mann-Whitney U tests.

To assess changes in functional outcomes before and after surgery, we used the best result from functional tests if multiple were conducted in the follow-up period. Patients with missing pre- or post-operative data were excluded from each analysis, and the number of patients for each outcome is specified in the figures showing these changes. Delta values were calculated by subtracting the baseline value from the post-operative value.

Additionally, linear mixed models were employed to assess changes in functional outcomes over time. These models account for all available data for each patient, fitting a line that best represents the changes over time. To compare the two groups, the model group changes by surgical approach (i.e., staged vs. bilateral). The models also adjust for other variables, such as the fraction of inspired oxygen (FiO₂), when analyzing the 6MWT. In these models, variables of interest were treated as fixed effects, while patients were treated as random effects. Random intercept and random slope models with linear, quadratic, or cubic time effects were fitted, with model selection based on the best Akaike and Bayesian Information Criteria.

Survival analyses were conducted using the Kaplan-Meier method, log-rank tests, and Cox-proportional hazards models. To address immortal time bias in the composite survival outcome, Cox models were calculated starting from the second surgery for the staged group. Additionally, survival curves at 5 years are also reported based on the time of the first surgery to highlight the additional benefit provided by the staged approach. No adjustment for multiplicity was made due to the exploratory nature of the analysis. All statistical analyses were conducted using R Statistical Software version 4.4.2, with statistical significance defined as P<0.05 (16).

Results

A total of 81 patients with a median age of 65 years (IQR, 61–69 years) were included in the analysis. Most patients were male (n=42, 52%) and White (n=76, 94%). The median body mass index was 25.2 kg/m² (IQR, 23.1–28.2 kg/m²), and the majority were former smokers (n=75, 93%). The most common comorbidities were hypertension (n=34, 42%) and gastroesophageal reflux disease (n=23, 28%). Baseline sociodemographic and clinical characteristics are detailed in Table 1.

Regarding the type of surgery, most patients underwent bilateral LVRS (n=60, 74%) while the remaining patients underwent the staged approach (n=21, 26%). Surgeries were performed at two sites. Sixty-eight percent of the overall cases and 86% of the staged cases were performed at one site. Two surgeons were performing surgery at this site versus 11 at the other (Table 1). For the staged group, the median time between the first and second surgeries was 20 months (IQR, 8–41 months). The only significant baseline difference between the two groups was the age at surgery: patients in the bilateral group were younger [64.5 (IQR, 60.0–68.3) years] than those with the staged approach [67.0 (IQR, 63.0–72.0) years] (P=0.03). Baseline pulmonary function tests and 6MWT were similar across both groups (Table 1).

As shown in Table 2, the average surgery duration was 154 minutes (SD: 68.7) for the bilateral LVRS group compared to 160 minutes (SD: 51.7) for both surgeries in the staged approach (P=0.73). The total length of hospital stay was similar between the bilateral LVRS group [10.9 days (SD: 8.13)] and the sum of both surgeries for the staged group [13.5 days (SD: 13.2)] (P=0.40). The average length of stay in the ICU was 2.78 days (SD: 7.62) for the bilateral group compared to 1.1 days (SD: 3.9) for staged LVRS (P=0.19).

The mean duration of air leaks after the first surgery in the staged approach (4.6 days, SD 8.36) was significantly shorter than in the bilateral group (11.0 days, SD: 15.1) (P=0.03). However, when comparing the bilateral group to the second surgery of the staged approach (7.8 days, SD 11.4) (P=0.13), or to the sum of both surgeries (12.4 days, SD: 15.7) (P=0.73), the differences were not significant. Similarly, a lower proportion of patients had prolonged air leaks after the first surgery in the staged approach (n=4, 19%) than in the bilateral LVRS group (n=25, 42%) (P=0.06). However, when comparing the bilateral group to the second surgery of the staged approach (n=7, 33%) (P=0.50), or to overall staged group (n=8, 38%) (P=0.77), the differences were not significant. 7 patients (33%) were discharged with chest tubes in the staged group versus 11 (18%) in the bilateral group (P=0.22). The only surgical complication with a significant difference between groups was subcutaneous emphysema: 33% of patients in the staged group developed it, compared to 12% in the bilateral group (P=0.041).

The median follow-up time for the entire cohort was 4.74 years (IQR, 2.05–7.95 years). For the bilateral LVRS group, the median follow-up was 6.37 years (IQR, 1.61–10.73 years). For the staged approach, the median follow-up from the first surgery was 3.85 years (IQR, 3.11–5.90 years), and from the second surgery, it was 2.12 years (IQR, 1.09–3.95 years). The 5-year overall survival for the bilateral approach was 74.3% (95% CI: 61.7–89.4%) compared to 90.0% (95% CI: 73.2–100.0%) for the staged group from the first surgery (P=0.13) (Figure 1A). The 3-year overall survival for the bilateral approach was 86.6% (95% CI: 73.2–100.0%) while for the staged group from the second surgery it was 90.0% (95% CI: 73.2–100.0%) (P=0.42) (Figure 1B). Regarding lung-transplant free survival at 3 years, for the bilateral LVRS group was 95.9% (95% CI: 90.4–100.0%) and there were no events in the unilateral approach (P=0.40).

Figure 1 Overall survival by the type of LVRS approach. (A) Overall survival comparison considering the first surgery as starting point for the staged approach. (B) Overall survival comparison considering the second surgery as starting point for the staged approach. LVRS, lung volume reduction surgery.

As shown in Figure 2A, the composite outcome at 5 years significantly favored the staged approach [90.0% (95% CI: 73.2–100.0%)] over bilateral LVRS [65.4% (95% CI: 52.1–82.1%)] (P=0.044). At 3 years, the composite outcome for the bilateral LVRS group was 82.8% (95% CI: 73.0–93.9%), while for the staged group (from the second surgery) it was 90.0% (95% CI: 73.2–100.0%) (P=0.26) (Figure 2B). In a univariable Cox-proportional hazards model (Figure 3), significant predictors of a worse composite outcome were length of hospital stay [hazard ratio (HR): 1.06, 95% CI: 1.01–1.10, P=0.01], need for transfusion during surgery (HR: 4.48, 95% CI: 1.16–17.35, P=0.03), and subcutaneous emphysema (HR: 3.72, 95% CI: 1.05–13.20, P=0.042).

Figure 2 Composite survival outcome by the type of LVRS approach. (A) Composite survival comparison considering the first surgery as starting point for the staged approach. (B) Composite survival comparison considering the second surgery as starting point for the staged approach. LVRS, lung volume reduction surgery.

Figure 3 Univariable Cox-proportional hazard models for composite outcome considering time from second surgery for the staged group. 6MWT, six-minute walk test; CI, confidence interval; DLCO%, predicted diffusion capacity of the lungs for carbon monoxide; FEV1%, predicted forced expiratory volume in one second; HR, hazard ratio; ICU, intensive care unit; LVRS, lung volume reduction surgery; RV%, predicted residual volume.

The median time interval from pre- to post-operative measurements for functional outcomes was 6 months (IQR, 3–7 months) for the bilateral LVRS group. For the staged group, the median interval from pre- to post-operative measurements for the first surgery was 6 months (IQR, 5.5–11.5 months). The total staged interval (pre-1^st surgery to post-2^nd surgery) was 22 months (IQR, 14.75–39.75 months). As shown in Figure 4A, both approaches demonstrated significant improvements in predicted FEV1%. Bilateral LVRS patients improved from 30.9% to 45.6% (P<0.001), while patients in the staged group increased from 29.1% to 40.8% after the first surgery (P<0.001) and to 43.7% after the second surgery (P<0.001). The mean delta for the bilateral approach (14.7%, SD: 13.3) was similar to that of the staged approach (14.6%, SD: 10.6) (P=0.96).

Figure 4 Pulmonary function tests before and after surgery by the type of LVRS approach. The circle indicates the mean value, and the whiskers represent the standard deviation. The mean delta values are shown on the right. (A) Changes in predicted FEV1. (B) Changes in predicted DLCO. (C) Changes in predicted RV. DLCO, diffusion capacity for carbon monoxide; FEV1, forced expiratory volume in one second; LVRS, lung volume reduction surgery; mo, months; RV, residual volume.

Regarding available data, FEV1% had the least data loss, with 53 out of 60 (88%) patients measured in the bilateral group and 16 out of 21 (76%) patients measured in the staged approach. Other outcomes had more data loss, particularly among the staged patients. Specifically, 75% and 33% of patients had measurements for DLCO%, 75% and 57% for RV%, and 65% and 29% for 6MWT in the bilateral and staged groups, respectively.

For predicted DLCO%, the bilateral approach showed a significant mean improvement, increasing from 33.9% to 42.2% (P<0.001) (Figure 4B). In contrast, the staged approach demonstrated a numerical improvement from baseline (28.1%) to after the first surgery (32.4%) (P=0.25), followed by a deterioration after the second surgery (22.9%) (P=0.14). The mean delta for the bilateral approach (8.3%, SD: 9.9) was significantly higher than for the staged approach (−5.3%, SD: 8.2) (P=0.003).

Both approaches showed a significant mean improvement in predicted RV% from baseline (Figure 4C). In the bilateral LVRS group, RV% improved from 234.0% to 159.4% (P<0.001). In the staged approach, RV% improved from 227.3% to 159.1% after the first surgery (P=0.001) and to 160.8% after the second surgery (P<0.001). Although the bilateral approach showed a greater mean delta (−74.6%, SD: 57.7) compared to the staged approach (−66.5%, SD: 49.5), the difference was not statistically significant (P=0.63).

Changes in the 6MWT based on the surgical approach are shown in Figure 5. In the bilateral LVRS group, the 6MWT improved from 298.7 to 358.9 meters after surgery (P<0.001). In the staged approach, however, the 6MWT remained relatively unchanged from baseline (330.6 meters) to after the first surgery (328.4 meters) (P=0.11) and after the second surgery (333.5 meters) (P=0.90). The bilateral approach showed a higher mean delta (60.3%, SD: 83.3) compared to the staged approach (2.9%, SD: 51.9) (P=0.046). In a linear mixed model, after adjusting for the FiO₂ during the test, the type of surgical approach was not a significant predictor of improvement in the 6MWT (Table 3).

Figure 5 Six-minute walk test before and after surgery by the type of LVRS approach. The circle indicates the mean value, and the whiskers represent the standard deviation. The mean delta values are shown on the right. LVRS, lung volume reduction surgery; mo, months.

Discussion

In this study, we compared survival, freedom from transplant, functional outcomes, and perioperative outcomes in patients undergoing staged versus bilateral LVRS. We found that the staged approach offered significant benefits in composite survival (survival and transplant-free) compared to simultaneous bilateral LVRS. This new finding challenges the longstanding belief that simultaneous bilateral LVRS should be the preferred approach, a practice handed down from the era of sternotomy LVRS.

Other notable findings included similar perioperative outcomes between the staged and single bilateral surgeries, as evidenced by similar hospital length of stay and air leak rates. Functional outcomes varied depending on the test and were influenced by missing data. DLCO and 6MWT results were lower in the staged group, while FEV1 and RV values were similar across both groups. However, it is important to consider the longer interval between measurements in the staged approach compared to the bilateral LVRS.

A major barrier to the widespread adoption of LVRS for severe emphysema is the inherent invasiveness and morbidity associated with the procedure. Although simultaneous bilateral LVRS was initially performed via median sternotomy, there has been a shift toward VATS in recent years (17). Previous studies have demonstrated that VATS provides similar survival and functional benefits as median sternotomy, with the added advantages of less patient morbidity, reduced surgical costs and shorter hospitalization (18,19). At our centers, all of the median sternotomy LVRS cases were done early in this study timeframe.

Concerns about extended hospital stays associated with staged LVRS have been raised, as bilateral LVRS was initially considered more cost-effective due to the single surgical intervention (20). However, our data showed that the total surgery duration for both bilateral and staged LVRS was comparable, and the mean length of hospitalization differed by only 2.6 days between the approaches. This contrasts with previous reports, which reported an average 6-day difference favoring the bilateral approach (12,13,15). One possible explanation for this discrepancy is that earlier studies involved different management strategies for prolonged air leaks, which often resulted in longer hospital stays (20). At our centers, stable patients are discharged with chest tubes connected to a one-way valve mechanism. Once the chest tube is taken out in the clinic, patients are given a 5-day course of antibiotics to guard against empyema. Following these management strategies, we have not seen an increased rate of readmission or secondary complications, as we previously reported (11).

Complications such as prolonged air leaks and pneumonia are commonly reported after LVRS (20). In our study, we observed a similar rate of prolonged air leaks in patients undergoing bilateral compared to staged LVRS (42% vs. 38%) and a similar rate of pneumonia (13% vs. 10%). Other complications, such as the need for transfusion during surgery, hemothorax, and wound infections, were comparable between the two groups. Thus, patients undergoing staged LVRS had similar overall complication rates than those with a bilateral approach.

Survival alone was not significantly different, but the composite outcome was statistically better in the staged cohort as measured from the first surgery. We hypothesize that the staged approach had better short-term survival due to a lower rate of post-op air leak. We assume this is particularly true when there are air leaks from both lungs rather than only one. From an earlier paper, we showed that surgery on one side results in a lower air leak rate and a shorter hospital stay compared to having surgeries on both lungs simultaneously (11). The presence of an air leak is a major risk factor for complications. A paired analysis from the National Emphysema Treatment Trial found that patients with air leaks were more likely to experience postoperative complications, develop pneumonia, and be readmitted to the ICU compared to those without air leaks (21). Although much of the survival benefit was observed within the first year (Figure 1), there also appears to be a long-term survival advantage and slower progression to lung transplant (14).

Regarding functional outcomes, we found no significant difference in exercise performance between the two surgical approaches. After adjusting for the FiO₂, both groups surpassed the threshold for clinically significant improvements (22). The literature on the pulmonary function benefits of LVRS is mixed, with some studies reporting greater improvements with bilateral approach, while others suggest more durable results for the staged approach (12-15). In our study, although the bilateral group showed greater improvements in predicted FEV1% and RV%, these differences were not statistically significant, with the only significant finding being a higher improvement in DLCO% for the bilateral group. However, this finding should be interpreted with caution, as only 7 patients (33%) in the staged approach had available DLCO% data, and these cases may not fully represent the potential improvement this approach can offer. More importantly, both approaches showed clinically meaningful improvements in RV% and FEV1% based on predefined thresholds (23,24). A key factor is the different intervals between pre- and post-surgical assessments—6 months for the bilateral approach and 22 months for the staged group. This suggests that sequential LVRS can offer more durable results, which is relevant given that emphysema is a progressive disease and pulmonary function naturally declines over time. We do not have bilateral pulmonary function tests at 12 and 24 months to verify this finding, however the reduced patient survival and higher transition to lung transplant is strongly suggestive that pulmonary function continued to decline.

Although no consensus exists regarding the optimal timing for the contralateral LVRS in a staged approach, the National Emphysema Treatment Trial data suggest low exercise capacity patients benefit more than high exercise capacity patients. Low exercise capacity was defined as a maximal workload at or below the sex-specific 40th percentile (25 Watts for women and 40 Watts for men). What this translates to in PFTs and interval length is difficult to determine. One study with a 3-month interval found no differences between staged and simultaneous bilateral LVRS, while other studies with intervals of 15–23 months reported more durable benefits in the staged approach (12,13,15). In our study, the median time between surgeries was 20 months, which may explain the long-lasting benefits observed in our population.

Limitations

As with all retrospective studies, selection bias can occur. Selection bias for the initial decision to proceed with staged versus bilateral was minimized since the surgical approach was based on surgeon preference rather than patient factors. However, there were other biases. There was a selection bias in the staged group which did not exist in the bilateral group which we call “responder bias”. Patients who responded well to unilateral LVRS presumably would be more likely to proceed to staged LVRS while the opposite is true for those who responded poorly. While this may be a good strategy to assess marginal patients, it is a selection bias in this study and may account for the better survival in the staged group. The second limitation is immortal time bias in the staged group, as all patients who underwent the first surgery, by definition, survived to the second operation. This would unfairly prolong survival time in the staged group. This bias may be less than imagined since data from our previous publication showed a 96% survival rate at 20 months for LVRS patients undergoing a unilateral procedure (11). Moreover, the survival in the staged group starting at the second surgery was still higher than the bilateral group, just not statistically significant (Figure 1B). Third, there was a high proportion of missing data, particularly for DLCO% and 6MWT assessments, which increases the level of uncertainty in the results. Thus, readers should interpret these findings with caution. Fourth, the bilateral group was nearly half sternotomies which likely negatively influenced survival. The sternotomy group had 2 (7%) deaths in the first 3 months versus 1 (3%) in the bilateral VATS group. A study has shown that sternotomy LVRS has higher morbidity than VATS but statistically similar 90-day survival outcomes (4.6% VATS vs. 5.9% sternotomy) (18). Even so, most bilateral LVRS in the modern era is performed with VATS. Finally, although the patient groups were similar in pulmonary function tests, they differed in other aspects. The patients in the staged group were significantly older on average (2.5 years) than patients in the bilateral group. This should have a negative impact on the staged group’s survival.

Conclusions

The staged approach showed higher composite survival (survival and freedom from transplant) over the bilateral approach. Survival and composite survival were higher for staged surgery as measured from the second surgery but not statistically different. Combined hospital length of stay and surgical complication rates were similar between the two groups. At the 22-month measurement interval for the staged group and 6 months for the bilateral group, the bilateral group had better DLCO and 6MWT outcomes, while FEV1 and RV assessments were similar. These findings suggest that staged LVRS may offer more advantages over simultaneous bilateral LVRS; however, this retrospective study had several inherent biases and only a prospective randomized study can confirm these findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-790/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-790/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-790/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-790/coif). S.F.B. serves as an unpaid editorial board member of Journal of Thoracic Disease from September 2024 to August 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Mayo Clinic Florida (No. #21-006676) and individual consent for this retrospective analysis was waived. Mayo Clinic Rochester was also informed and agreed with the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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