Populations	Interventions	Comparators	Outcomes
Individuals: With upper-lobe emphysema	Interventions of interest are: Lung volume reduction surgery	Comparators of interest are: Medical management	Relevant outcomes include: Overall survival Symptoms Functional outcomes Quality of life Treatment-related mortality
Individuals: With non-upper-lobe emphysema	Interventions of interest are: Lung volume reduction surgery	Comparators of interest are: Medical management	Relevant outcomes include: Overall survival Symptoms Functional outcomes Quality of life Treatment-related mortality

Background

Emphysema

Emphysema is an anatomically defined condition characterized by destruction and enlargement of lung alveoli. It is one of the conditions considered as a chronic obstructive pulmonary disease along with chronic bronchitis and small airways disease. The pathogenesis of emphysema is primarily related to cigarette smoking leading to inflammation and recruitment of immune cells to the terminal air spaces of the lung. The resultant extracellular matrix proteolysis damages the lung. Destruction of the gas exchanging air spaces and ineffective repair of the extracellular matrix results in airspace enlargement. Emphysema can be characterized into distinct pathologic subtypes. Centriacinar emphysema is most frequently associated with cigarette smoking, is usually most prominent in the upper lobes and superior segments of the lower lobes, and is focal. Panacinar emphysema is characterized by abnormally large air spaces evenly distributed across acini in the lower lobes. It is associated with α₁-antitrypsin deficiency. Key pulmonary function parameters are the volume of the first forced expiratory volume in 1 second (FEV1) and the total volume of air exhaled during the spirometry (forced vital capacity). Airflow obstruction related to chronic obstructive pulmonary disease is characterized by the reduced ratio of forced expiratory volume in 1 second/forced vital capacity and reduction in FEV1 correlates with long-term mortality risk.^1,

Lung Volume Reduction Surgery

Lung volume reduction is a surgical treatment for patients with severe emphysema. The procedure involves the excision of peripheral emphysematous lung tissue, generally from both upper lobes.

The mechanism of clinical improvement for patients undergoing lung reduction surgery has not been firmly established. However, it is believed that mechanical factors such as elastic recoil and diaphragmatic function are improved by reducing the volume of the hyperinflated diseased lung. In addition to changes in the chest wall and respiratory mechanics, the surgery is purported to correct ventilation-perfusion mismatch and improve right ventricular filling.

Complications from the surgical procedure include death, reintubation, arrhythmias, mechanical ventilation for more than 2 days, pneumonia, wound infection, and persistent air leak.

Research on lung volume reduction surgery has focused on defining the subgroup of patients most likely to benefit from the procedure. Potential benefits of the procedure (eg, improvement in functional capacity and quality of life) must be weighed against the potential risk of the procedure (eg, the risk of postoperative mortality).

Regulatory Status

Lung volume reduction surgery is a surgical procedure and, as such, is not subject to regulation by the U.S. Food and Drug Administration.

Related Policies

• Bronchial Valves (Policy #125 in the Surgery Section)
• Outpatient Pulmonary Rehabilitation (Policy #009 in the Treatment Section)

1. Lung volume reduction surgery as a treatment for emphysema is considered medically necessary in members who meet ALL of the following criteria*:
   1. Predominantly upper lobe emphysema with hyperinflation and heterogeneity (i.e., target areas for removal)
   2. Forced expiratory volume in 1 second (FEV₁):
      1. For members who are younger than 70 years of age, the FEV₁ must be no more than 45% of the predicted value.
      2. For members who are 70 years of age or older, the FEV₁ must be no more than 45% of the predicted value and 15% or more of the predicted value.
   3. Marked restriction in activities of daily living, despite maximal medical therapy
   4. Age younger than 75 years
   5. Acceptable nutrition status (i.e., 70% to 130% of ideal body weight)
   6. Ability to participate in a vigorous pulmonary rehabilitation program
   7. No coexisting major medical problems that would significantly increase operative risk
   8. Willingness to undertake risk of morbidity and mortality associated with lung volume reduction surgery
   9. Abstinence from cigarette smoking for at least 4 months.
      
      (NOTE: * Patient selection criteria are based on the National Emphysema Treatment Trial.)
      
2. Lung volume reduction surgery is considered investigational in all other members.

• Arterial partial pressure of oxygen on room air of 45 mm Hg or more (≥30 mm Hg at elevations of ≥5000 feet [1524 meters])
• Arterial partial pressure of carbon dioxide on room air less than or equal to 60 mm Hg (≤55 mm Hg at elevations of ≥5000 feet [1524 meters])
• Postrehabilitation 6-minute walk distance of at least 140 meters, and ability to complete 3 minutes of unloaded pedaling in exercise tolerance test.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Lung Volume Reduction Surgery

Evidence for this policy consists of trials that include patients with and without upper-lobe emphysema. Results were presented for the population as a whole and subgroups of patients. While separate recommendations are provided for each subgroup of patients, all evidence is discussed in this single section.

Clinical Context and Test Purpose

The purpose of LVRS is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with upper-lobe emphysema and non-upper-lobe emphysema.

The question addressed in this policy is: Does LVRS improve the net health outcome in individuals with emphysema?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with upper-lobe emphysema and non-upper-lobe emphysema who have poor control of their condition through medical therapy.

Interventions

The therapy being considered is LVRS.

LVRS is proposed as a treatment option for patients with severe emphysema who have failed optimal medical management. The procedure involves the excision of diseased lung tissue to reduce symptoms and improve quality of life. Patients with upper-lobe and non-upper-lobe emphysema are managed by pulmonologists, thoracic surgeons, and primary care providers in an inpatient clinical setting.

Comparators

Comparators of interest include medical management, which includes bronchodilators to relax constricted airways to relieve coughing, shortness of breath, and breathing problems; inhaled corticosteroids to reduce inflammation, and antibiotics to rid bacterial infections such as bronchitis or pneumonia.

Outcomes

The general outcomes of interest are overall survival, symptoms, functional outcomes, quality of life, and treatment-related mortality. Emphysema cannot be cured. The goal of LVRS is to relieve symptoms (eg, improve dyspnea and oxygenation) and slow the progression of the disease, thereby improving quality of life.

Potential harmful outcomes are related to procedural complications: death, reintubation, arrhythmias, mechanical ventilation for more than 2 days, pneumonia, and persistent air leak.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess longer-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

The NETT (National Emphysema Treatment Trial) was a large, multicenter, prospective RCT comparing LVRS with optimal medical therapy in patients with severe emphysema. Two-year findings were published by Fishman et al (2003).^2, The trial included 1218 patients, and the analysis was an intention-to-treat, reporting on outcomes for all randomized patients. The primary outcomes included total, 30-day, and 90-day mortality and maximal exercise capacity. Secondary outcomes included pulmonary function, distance walked in 6 minutes, and self-reported health-related quality of life and general quality of life. At a preliminary analysis, 371 (30%) patients had been followed for a total of 24 months. Primary findings of the Fishman et al (2003) study are summarized in Table 1.

Table 1. National Emphysema Treatment Trial Primary Findings

Variables	90-Day Mortality, %		Total Mortality, No. Death/Total		Improvement in Exercise Capacity at 24 Months, %b		Improvement in Quality of Life at 24 Months, %c
	Med Tx	Surg Tx	Med Tx	Surg Tx	Med Tx	Surg Tx	Med Tx	Surg Tx
All patients	1.3	7.9	160/610	157/608	3	15	9	33
High-risk patientsa	28	0	30/70	42/70	2	7	0	10
ULE with low exercise capacity	3.3	2.9	51/151	26/139	0	30	10	48
ULE with high exercise capacity	0.9	2.9	39/213	34/206	3	15	11	41
Non-ULE, low exercise capacity	0	8.3	28/84	26/65	7	12	7	37
Non-ULE, high exercise capacity	0.9	10.1	27/109	14/111	3	3	12	15

Adapted from Fishman et al (2003).^2,
Med: medical; Surg: surgical; Tx: treatment; ULE: upper-lobe emphysema.

^a High risk is defined as those with a forced expiratory volume in 1 second that was ≤20% of the predicted value and either homogeneous emphysema on computed tomography or a carbon monoxide diffusion capacity that was ≤20% of the predicted value.
^bImprovement in exercise capacity in patients followed for 24 mo after randomization was defined as an increase in the maximal workload of >10 W from the patient's postrehabilitation baseline value.
^cImprovement in health-related quality of life in patients followed for 24 mo after randomization was defined as a decrease in St. George's Respiratory Questionnaire score of >8 points (on a 100-point scale) from the patient's postrehabilitation baseline score.

• Overall, LVRS increased the chance of improved exercise capacity but did not confer a survival advantage over medical therapy.
• There was a survival benefit for those patients who had both predominantly upper-lobe emphysema and low baseline exercise capacity. This survival advantage appears to be due to the very high mortality and marked progressive functional limitation of those treated medically.
• Patients considered at high-risk and those with non-upper-lobe emphysema and high baseline exercise capacity were found to be poor candidates for LVRS.

Overall, LVRS showed a mortality benefit compared with medical therapy. During follow-up, 46.5% (283/608) patients in the LVRS group and 53.1% (324/610) patients in the medical therapy group died (relative risk, 0.85; p=0.02). However, the long-term mortality benefit was limited to the subgroup of participants who had predominately upper-lobe emphysema and low exercise capacity (those found in the initial report to benefit from LVRS; relative risk, 0.57; p=0.01). Moreover, in the subgroup of patients with predominately upper-lobe emphysema and low exercise capacity (n=290), compared with medical therapy, those in the LVRS group were also more likely to have improved exercise capacity throughout 3 years of follow-up testing (p<0.01) and to have an 8-point improvement in quality of life through 4years of follow-up testing (p=0.003).

In the subgroup of patients with predominately upper-lobe emphysema and high exercise capacity (n=419), there was no survival benefit associated with LVRS, but there was a significantly greater improvement in exercise capacity over 3 years (p<0.001) and quality of life over 4 years (p=0.003). Patients with non-upper-lobe emphysema and either high or low exercise capacity did not significantly benefit from surgery with respect to mortality rates, exercise capacity, or quality of life. A limitation of the long-term follow-up study was that fewer than 80% of surviving NETT participants took part.

Sanchez et al (2010) analyzed data from the NETT, focusing on patients who met the following criteria: (1) predominantly upper-lobe emphysema and (2) a heterogeneous distribution of emphysema (non-upper-lobe emphysema) defined as a difference of at least 2 points in the severity of emphysema in any 2 zones of the lung on a 0-to-4 severity scale.^4, Of the 1218 patients enrolled in the study, 511 (42%) patients met both criteria, 261 in the LVRS group and 250 in the medical therapy group. Using Kaplan-Meier analysis, the 3-year survival rate was 81% for patients receiving LVRS and 74% for those in the medical group (p=0.05). At 5 years, the estimated survival rate was significantly higher in the LVRS group (70%) compared with the medical therapy group (60%; p=0.02). Maximal exercise capacity (another NETT primary outcome) was a mean of 49 watts in the LVRS group and 38 watts in the medical therapy group at 1 year (p<0.001). At 3 years, exercise capacity in the 2 groups was 43 watts and 38 watts, respectively, and the between-group difference was not statistically significant.

Kaplan et al (2014) reported on long-term outcomes for high-risk patients from the NETT.^5, In this subgroup of 140 randomized patients, the mortality rate was higher in the LVRS group than in the medical therapy group for the first 4.4 years but longer-term survival did not differ significantly between the 2 groups. Median survival was 2.14 years (95% confidence interval [CI], 1.20 to 4.07 years) in the LVRS group and 3.12 years (95% CI, 2.79 to 4.27 years) in the medical therapy group (p>0.05).

RCTs Other Than NETT

Miller et al (2006) published a trial evaluating data from 5 centers in Canada (Canadian Lung Volume Reduction Surgery trial).^6, Eligibility criteria included: age between 40 and 79 years; disabling dyspnea; forced expiratory volume in 1 second (FEV₁)of no more than 40% of predicted; diffusing capacity no more than 60%; and total lung capacity no more than 120% or residual volume no less than 200%. After eligibility screening, medical therapy was optimized, and patients randomized to LVRS (n=32) or continued medical therapy (n=30). The trialists had originally planned to enroll 350 subjects, but due to the low proportion of screened subjects who were eligible, recruitment stopped at only 18% (62/467) of the target. Based on intention-to-treat analysis, the overall 2-year survival rate was similar between groups: 5 (16%) of 32 patients died in the LVRS group, and 4 (13%) of 30 died in the medical therapy group (p=0.93). At 3 and 6 months, there were significantly greater improvements from baseline in FEV₁ for the LVRS group compared with the medical therapy group, but the between-group differences in FEV₁ were not significant at 12 and 24 months. This study might have been underpowered to detect differences in outcomes between groups.

Agzarian et al (2013) published long-term results of the Canadian Lung Volume Reduction Surgery trial.^7, Fifty-two (84%) of 62 randomized patients were available for follow-up 8 to 10 years posttreatment. One patient was excluded before surgery, and 9 others were lost to follow-up. The proportion of patients surviving 5 and 10 years were 46% and 7%, respectively, in the LVRS group and 25% and 0% in the control group. According to Kaplan-Meier survival analysis, median survival was 63 months in the LVRS group and 47 months in the control group (p=0.20).

Systematic Reviews

In a systematic review, Huang et al (2011) pooled analyses of patients undergoing LVRS for severe emphysema.^8, Eight RCTs (total n=1677 patients) published from 1999 to 2010 were included in the analysis. Reviewers found significantly higher odds of mortality in the medical therapy group than in the LVRS group at 3 months (odds ratio, 5.16; 95% CI, 2.84 to 9.35). They found no statistically significant difference between groups in the mortality rate at 12 months (odds ratio, 1.05; 95% CI, 0.82 to 1.33).

A 2016 Cochrane review, updating the 2006 meta-analysis, compared the effectiveness of LVRS with standard nonsurgical therapy in improving health outcomes for patients who had severe diffuse emphysema.^9,10, The search period for the update extended to April 2016. Two new trials, contributing 89 participants (Clarenbach et al [2015]^11, and Pompeo et al [2012]^12,), were identified and incorporated into the review along with long-term follow-up data from the Canadian Lung Volume Reduction Surgery and NETT trials. These additional data resulted in changes to the conclusions of the 2016 update. A summary of the updated results is presented in Table 2. Patients in the surgery group experienced lower overall mortality in the long-term (≥3 years), as well as significant improvements in FEV₁, quality of life, and exercise capacity compared with patients receiving only medical management. Patients with upper-lobe emphysema and low exercise capacity benefited most from the LVRS.

A total of 11 RCTs (1760 participants) were included in the updated review. The NETT accounted for 68% of the review participants. The odds ratio for surgery vs control was 0.76 (95% CI, 0.61 to 0.95).

Table 2. Systematic Review Results for Surgery vs Control

Overall Mortality	No. of Studies	Odds Ratio (95% CI)
Total population
3 months	5	6.2 (3.2 to 11.8)
6 months	3	4.4 (1.2 to 15.9)
12 months	3	3.6 (1.3 to 10.3)
24 months	3	1.0 (0.8 to 1.3)
≥3 years	2	0.8 (0.6 to 0.9)
Risk
High	1a	2.0 (1.0 to 3.9)
Non-high	1a	0.9 (0.6 to 1.1)
Lobe and exercise capacity
Upper-lobe, low exercise capacity	1a	0.5 (0.3 to 0.8)
Upper-lobe, high exercise capacity	1a	0.9 (0.5 to 1.5)
Non-upper-lobe, high exercise capacity	1a	0.7 (0.4 to 1.5)
Non-upper-lobe, low exercise capacity	1a	2.3 (1.1 to 4.6)
Exercise capacity		Standard Mean Difference (95% CI)
Shuttle walking distance	5	0.7 (0.4 to 1.0)
Lung function
Forced expiratory volume in 1 second	4	0.2 (0.1 to 0.3)
Quality of life
St. George's Respiratory Questionnaire	2	-13.8 (-15.7 to -11.8)

Adapted from van Agteren et al (2016).^9,
CI: confidence interval.

^a National Emphysema Treatment Trial study.

Reviewers raised a concern about the validity of using the subgroup distinctions to determine which patients would be most likely to benefit from the procedure or who would be at greatest risk of early mortality due to the low likelihood that additional studies of similar statistical power to NETT will be conducted.

Nonrandomized Comparative Studies

Decker et al (2014) reviewed data on 538 patients from the Society of Thoracic Surgeons (STS) database who received LVRS and compared these data with those of the 608 NETT participants randomized to the surgery group.^13, None of the patients in the STS database had an FEV₁ less than 20% of predicted or carbon monoxide diffusing capacity less than 20% of predicted; thus, these patients would not have been considered high-risk in the NETT. Moreover, about 10% of patients in the STS database had previous cardiothoracic surgery,and 1.5% had lung cancer, both exclusions in NETT. Overall, the mortality rate within 30 days of LVRS did not differ significantly between the STS database (5.6%) and the NETT (3.6%; p=0.113). When database findings were compared with non-high-risk NETT participants, the 30-day mortality rate was significantly higher among patients in the STS database (5.6%) than in the NETT (2.2%; p=0.005). This study was descriptive and did not propose patient selection criteria for LVRS.

Summary of Evidence
For individuals who have upper-lobe emphysema who receive LVRS, the evidence includes randomized controlled trials (RCTs) and systematic reviews of the trials. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, and treatment-related mortality. Findings from the National Emphysema Treatment Trial (NETT), a multicenter RCT, have suggested that LVRS is effective at reducing mortality and improving quality of life in select patients with severe emphysema. In subgroup analysis, LVRS offered a survival advantage only to patients not considered at high-risk who had predominately upper-lobe emphysema and low initial exercise capacity. Patients with upper-lobe emphysema, regardless of initial exercise capacity, experienced significant improvement in exercise capacity and quality of life after LVRS. Other, smaller RCTs have generally had similar findings, though they have tended to be underpowered for some outcomes and did not stratify by the distribution of emphysema. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have non-upper-lobe emphysema who receive LVRS, the evidence includes subgroup analysis of a large RCT. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, and treatment-related mortality. In the subgroup analysis of the NETT, LVRS offered a survival advantage only to patients who had predominately upper-lobe emphysema. For the subgroup with predominately non-upper-lobe emphysema, the NETT did not find significant mortality advantages or symptom improvement with LVRS. Although the NETT had positive findings for the study population as a whole, given the surgical risks, additional data are needed to confirm the net health outcome in patients with non-upper-lobe emphysema. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
American Thoracic Society and European Respiratory Society

In 2015, the American Thoracic Society and the European Respiratory Society published a joint statement on current research questions for chronic obstructive pulmonary disease.^14, The statement discussed lung volume reduction surgery and asserted that, due to the significant complications from the procedure that may result in prolonged hospital stays and morbidity, additional studies would be needed to evaluate minimally invasive techniques that might reduce complications.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in May 2020 did not identify any ongoing or unpublished trials that would likely influence this review.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Lung Volume Reduction Surgery for Severe Emphysema
Lung Volume Reduction Surgery (LVRS)
Bronchoscopic Lung Volume Reduction (BLVR)
Lung Contouring
Lung Shaving
Reduction Pneumoplasty
Volume Reduction Pneumonectomy (VRP)

References:
1. Kasper D, Fauci A, Longo D, et al. Harrison's Principles of Internal Medicine 19th Edition. McGraw-Hill Education: Chicago, IL; 2015.

2. Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. May 22 2003;348(21):2059-2073. PMID 12759479

3. Naunheim KS, Wood DE, Mohsenifar Z, et al. Long-term follow-up of patients receiving lung-volume-reduction surgery versus medical therapy for severe emphysema by the National Emphysema Treatment Trial Research Group. Ann Thorac Surg. Aug 2006;82(2):431-443. PMID 16888872

4. Sanchez PG, Kucharczuk JC, Su S, et al. National Emphysema Treatment Trial redux: accentuating the positive. J Thorac Cardiovasc Surg. Sep 2010;140(3):564-572. PMID 20723727

5. Kaplan RM, Sun Q, Naunheim KS, et al. Long-term follow-up of high-risk patients in the National Emphysema Treatment Trial. Ann Thorac Surg. Nov 2014;98(5):1782-1789. PMID 25201722

6. Miller JD, Malthaner RA, Goldsmith CH, et al. A randomized clinical trial of lung volume reduction surgery versus best medical care for patients with advanced emphysema: a two-year study from Canada. Ann Thorac Surg. Jan 2006;81(1):314-320; discussion 320-311. PMID 16368389

7. Agzarian J, Miller JD, Kosa SD, et al. Long-term survival analysis of the Canadian Lung Volume Reduction Surgery trial. Ann Thorac Surg. Oct 2013;96(4):1217-1222. PMID 23895890

8. Huang W, Wang WR, Deng B, et al. Several clinical interests regarding lung volume reduction surgery for severe emphysema: meta-analysis and systematic review of randomized controlled trials. J Cardiothorac Surg. Nov 10 2011;6:148. PMID 22074613

9. van Agteren JE, Carson KV, Tiong LU, et al. Lung volume reduction surgery for diffuse emphysema. Cochrane Database Syst Rev. Oct 14 2016;10:Cd001001. PMID 27739074

10. Tiong LU, Davies R, Gibson PG, et al. Lung volume reduction surgery for diffuse emphysema. Cochrane Database Syst Rev. Oct 18 2006(4):CD001001. PMID 17054132

11. Clarenbach CF, Sievi NA, Brock M, et al. Lung volume reduction surgery and improvement of endothelial function and blood pressure in patients with chronic obstructive pulmonary disease. a randomized controlled trial. Am J Respir Crit Care Med. Aug 1 2015;192(3):307-314. PMID 26016823

12. Pompeo E, Rogliani P, Tacconi F, et al. Randomized comparison of awake nonresectional versus nonawake resectional lung volume reduction surgery. J Thorac Cardiovasc Surg. Jan 2012;143(1):47-54, 54.e41. PMID 22056369

13. Decker MR, Leverson GE, Jaoude WA, et al. Lung volume reduction surgery since the National Emphysema Treatment Trial: study of Society of Thoracic Surgeons Database. J Thorac Cardiovasc Surg. Dec 2014;148(6):2651-2658 e2651. PMID 24631312

14. Celli BR, Decramer M, Wedzicha JA, et al. An official American Thoracic Society/European Respiratory Society statement: research questions in COPD. Eur Respir Rev. Jun 2015;24(136):159-172. PMID 26028628

15. Center for Medicare & Medicaid Services. National coverage determination (NCD) for lung volume reduction surgery (reduction pneumoplasty) (240.1). 2005; https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?NCDId=119&ncdver=3&CoverageSelection=National&KeyWord=lung+volume+reduction+surgery& KeyWordLookUp=Title&KeyWordSearchType=And&clickon=search&bc=gAAAABAAAAAAAA%3d%3d&. Accessed May 28, 2020.

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