Publication of the National Emphysema Treatment Trial (NETT) in 2003 established lung volume reduction surgery (LVRS) as a viable treatment of select patients with moderate to severe emphysema, and the only intervention since the availability of ambulatory supplemental oxygen to improve survival. Despite these findings, surgical treatment has been underused in part because of concern for high morbidity and mortality. This article reviews recent literature generated since the original NETT publication, focusing on physiologic implications of LVRS, recent data regarding the safety and durability of LVRS, and patient selection and extension of NETT criteria to other patient populations.
Key points
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LVRS may enact clinical benefit through improvements in chest wall asynchrony, increased maximum inspiratory pressure, and reduction in inflammatory mediators.
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Recent data demonstrate that LVRS may be performed safely with 6-month mortality of 0% to 1.5% and durable functional improvements.
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Initial investigation suggests LVRS may benefit an expanded patient population, including carefully selected patients with homogenous emphysema and low DLCO.
Introduction: the National Emphysema Treatment Trial
Initial publication of the National Emphysema Treatment Trial (NETT) results in 2003 offered significant level I evidence in support of surgical therapy for the management of patients with severe emphysema. , This landmark prospective multicenter trial randomized a total of 1218 patients to either lung volume reduction surgery (LVRS) or medical management, marking a notable departure from the small, heterogeneous, single-center case series that comprised most of the existing data. At the time of publication, NETT participants had a mean follow-up of 29 months and investigators reported on a range of outcomes including short- and long-term survival, maximal exercise performance, lung function, and quality of life.
Key study findings facilitated risk stratification and the ability to identify patients most likely to benefit from surgery. Based on 30-day surgical mortality, high-risk individuals were defined by forced expiratory volume in 1 second (FEV1) less than or equal to 20% predicted and a diffusion capacity for carbon monoxide (DLCO) less than or equal to 20% predicted, or a homogenous distribution of emphysema. This subgroup was ultimately excluded from undergoing LVRS because they experienced an unacceptably high 30-day mortality rate of 16%. After removing these patients, statistically significant improvements in 6-minute-walk distance, FEV1% predicted, maximal exercise capacity, and disease-specific and general quality of life were found for non-high-risk patients who underwent LVRS as compared with medical therapy. Furthermore, in the subset of patients with upper-lobe-predominant emphysema and low exercise capacity, the surgery group had lower total mortality and improved exercise capacity and health-related quality of life at 24-month follow-up. Unfortunately, these benefits failed to persist for all study participants. Although patients with high exercise capacity did have a statistically significant improvement in exercise capacity and health-related quality of life, surgery did not offer a survival benefit in this group. Furthermore, there was no surgical advantage in survival, exercise capacity, or health-related quality of life for patients with non-upper-lobe-predominant disease. In addition, analysis of postoperative outcomes suggested that only non-upper-lobe-predominant emphysema was predictive of increased operative mortality.
Aside from supplemental oxygen, LVRS is one of few available therapies proven to improve survival in select patients with emphysema. Together with updated results from 2006, findings from NETT solidified surgery in the management algorithm of patients suffering from moderate to severe emphysema. Applying NETT inclusion and exclusion criteria to examine an academic medical center’s pulmonary function laboratory database and radiology archive, Akuthota and colleagues estimated 15% of emphysema patients could benefit from LVRS. Yet despite these data, widespread adoption of LVRS remains meager. Although a precise rationale remains elusive, the cause of this marked underuse is likely multifactorial and includes limited access to approved surgical centers and pulmonary rehabilitation programs and confusion on behalf of medical providers regarding patient candidacy for surgery. LVRS may also be falsely perceived as overly complicated and costly. Because NETT was a single payer (Centers for Medicare and Medicaid Services) trial, cost-effective analyses were feasible and enlightening. Using actual data from 3 and 5 years of clinical follow-up, NETT investigators showed Incremental Cost Effective Ratios for the upper-lobe-predominant emphysema patients that were comparable with Incremental Cost Effective Ratios used to support implantable defibrillators or heart transplantation. For example, the cost-effectiveness ratio for LVRS as compared with medical therapy for upper-lobe-predominant disease was reported as $77,000 per quality-adjusted life year gained at 5 years versus $65,0000 for heart transplantation. More troubling, perhaps, is a misconception that the prohibitive postoperative outcomes from the high-risk group apply more broadly to all patients with emphysema, creating a stigma of surgery as an excessively risky endeavor.
These fears have spurred innovation; recent years have seen development of less invasive means of lung volume reduction and important advancements in the understanding of disease characteristics and postoperative outcomes. In this article we highlight some of the salient research performed on LVRS published after the NETT in 2003, focusing on three important areas of investigation: (1) physiologic implications of LVRS, (2) recent data regarding the safety and durability of LVRS, and (3) patient selection and extension of NETT criteria to other patient populations.
Physiologic implications of lung volume reduction surgery
Lung volume reduction has proven effective in promoting enhanced exercise capacity, lung function, and quality of life for select patients with emphysema. , Although surgery was the first available means of volume reduction, less invasive strategies including endobronchial valves, coils, and sclerosing agents are under investigation. Regardless of the technical execution, reducing lung volume is thought to combat the primary physiologic derangements of emphysema: airflow obstruction, asynchrony, and hyperinflation. The primary mechanism was believed to be via increased elastic recoil pressure coupled with decreased airway resistance resultant from surgical resection of diseased lung. , In addition, resection of heterogenous lung parenchyma may counteract the effect of hyperinflation, providing decreased work of breathing and improved alveolar gas exchange. However, recent investigation offers more sophisticated insight into the physiologic implications of lung volume reduction.
Emphysema results in diaphragmatic flattening, negatively impacting ventilatory mechanics through asynchronous chest movement and recruitment of abdominal musculature. Furthermore, older studies suggest correlation between chest wall asynchrony, airflow obstruction, and breathlessness. , As such, Zoumot and colleagues proposed improvements in chest wall asynchrony as an advantageous outcome of LVR. The authors conducted a single-institution prospective trial and randomized 26 patients under evaluation for LVR to either surgical or bronchoscopic LVR or sham treatment, using novel optoelectronic plethysmography generated three-dimensional volume measurements to assess chest wall asynchrony. Patients in the LVR group had statistically significant improvement in exercise capacity, quality of life, lung function, and radiographic evidence of decreased lung volume. The authors report high baseline levels of asynchrony in both groups. However, LVR patients had significantly greater improvement in asynchrony 3 months post-treatment, suggesting that this may correlate with symptomatic improvement.
Beyond asynchrony, recent investigation corroborates a long-term impact of LVRS on respiratory musculature. Using prospectively collected data from the NETT, Criner and colleagues performed a retrospective analysis comparing pretreatment maximum inspiratory pressure (MIP) in patients who underwent LVRS versus medical management with MIP up to 36 months post-treatment. Patients in the LVRS group had significantly greater increase in MIP (19.8% compared with 3.2%) at 12 months. The improvement in MIP for patients who underwent LVRS peaked at 12 months but remained statistically significant at the 36-month follow-up. Male participants and those age 65 to 70 years had greater increase in MIP at all timepoints compared with their counterparts who received medical therapy. In accordance with original NETT findings, patients with upper-lobe-predominant disease and low exercise capacity also demonstrated sustained improvement in MIP at 24 months. The authors report an inverse relationship between MIP and noninvasive markers of dynamic hyperinflation, and propose that LVRS may promote clinical improvement by restoring optimal length-tension ratio of inspiratory musculature. This work builds on prior smaller studies suggesting a relationship between LVRS and improvement in MIP. ,
Distinct from mechanical changes, LVRS may also impact inflammatory mediators associated with emphysema. Low-grade chronic inflammation likely plays an important role in the pathophysiology of emphysema; preponderance of leukocytes and deranged production of inflammatory mediators including increased tumor necrosis factor-α (TNF-α) and decreased α 1 -antitrypsin (α 1 -AT) have been reported. With this in mind, Mineo and colleagues proposed that LVRS reduced inflammatory mediators by removing emphysematous parenchyma. In a case-control study, the authors measured levels of inflammatory mediators and α 1 -AT from 54 patients with severe emphysema (assigned to LVRS or standard respiratory rehabilitation program) and 25 healthy control subjects. Gene expression levels of protease-antiprotease and inflammatory mediators were also assessed from specimens in surgical patients. After 12 months, patients assigned to LVRS had significantly decreased levels of inflammatory mediators including TNF-α (−22.2%) and increased α 1 -AT (+27%) when compared with respiratory rehabilitation. Gene expression analysis revealed protease hyperactivity and predominant inflammation in diseased specimens, suggesting that surgery reduced the inflammatory burden by removing sites where these mediators were most heavily produced. Furthermore, study findings support a significant correlation between reduction in TNF-α, augmentation of α 1 -AT, and decrease in residual volume (RV).
Better understanding of the relationship between LVRS, respiratory mechanics, and distribution of disease may improve the ability to select patients most likely to benefit from surgery. To this effect, Washko and colleagues examined a subset of the NETT study population who underwent preoperative thoracic high-resolution computed tomographic (CT) scanning. Physiologic measures of lung recoil and inspiratory resistance were also measured but found not to be significantly associated with improvement in surgical outcomes, namely FEV1 or maximal exercise capacity after surgery. In contrast, preoperative CT assessment of the emphysema burden and ratio of upper to lower lobe disease demonstrated a weak, albeit statistically significant, association with improvement in FEV1 and exercise capacity postoperatively. Building on this foundation, recent radiographic advancements allow greater sophistication in quantifying the emphysema burden and distribution. An automated system can calculate the upper to lower zone ratio of low attenuation areas to facilitate selection of surgical candidates and target areas of resection. Although conventional CT remains the most commonly used radiographic assessment of surgical candidacy, dual-energy CT and dynamic MRI may offer important functional information to facilitate optional patient selection. ,
Examining surgical safety and durability
Despite the NETT results demonstrating significant postoperative benefits and survival advantage for select patient populations, controversy persists regarding use of LVRS. Much of the debate stems from concern for unacceptably high surgical morbidity and mortality. Indeed, the 2003 NETT publication reported a sobering 90-day mortality of 5.5% for non-high-risk surgical patients compared with 1.5% following medical management. This trepidation undoubtedly contributed to a marked decline in patients undergoing LVRS over the past decade in the United States and internationally. , However, long-term results from the original NETT publication and subsequent institutional data reinforce surgery as a safe treatment option in the setting of appropriate patient selection ( Table 1 ).
| Authors, Year of Publication | Study Design | Study Size | Procedural Morbidity and Mortality | Long-Term Outcomes |
|---|---|---|---|---|
| Naunheim et al, 2006 | Updated results from NETT (randomized controlled trial) | 1218 |
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| Agzarian et al, 2013 | Retrospective observational analysis of patients randomized in the Canadian Lung Volume Reduction Surgery trial | 62 |
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| Ginsburg et al, 2016 | Retrospective, single institution | 91 |
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| van Agteren et al, 2016 | Meta-analysis | 1760 |
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| Lim et al, 2020 | Re-evaluation of NETT data using longitudinal data methodology | 1218 |
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