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Original Research: COPD |

Bilateral Endoscopic Sealant Lung Volume Reduction Therapy for Advanced EmphysemaLung Sealant Volume Reduction Therapy FREE TO VIEW

Mordechai R. Kramer, MD, FCCP; Yael Refaely, MD; Nimrod Maimon, MD; Dror Rosengarten, MD; Oren Fruchter, MD
Author and Funding Information

From the Pulmonary Institute Rabin Medical Center (Drs Kramer, Rosengarten, and Fruchter), Beilinson Hospital, Petah Tikva; and the Department of Thoracic Surgery (Dr Refaely), and the Department of Pulmonary Medicine (Dr Maimon), Soroka Medical Center, Be’er Sheeva, Israel.

Correspondence to: Mordechai Kramer, MD, FCCP, Pulmonary Institute and Lung Transplantation Program, Rabin Medical Center, Beilinson Hospital, Petah Tikva 49100, Israel; e-mail: kramerm@netvision.net.il


Funding/Support: This study was supported by Aeris Therapeutics, Woburn, MA.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(5):1111-1117. doi:10.1378/chest.12-0421
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Background:  A clinical study was performed to assess the safety and efficacy of bilateral AeriSeal Emphysematous Lung Sealant System (ELS) treatment in patients with advanced emphysema out to 1 year.

Methods:  Twenty patients received treatment at four subsegments, two in each upper lobe. Ten had upper lobe disease, and 10 had homogeneous disease. Treatments were administered under moderate sedation. Efficacy was assessed at 3, 6, and 12 months.

Results:  Procedure times were short (15.2 ± 9.6 min), and hospital length of stay averaged 1.1 days. The study was successful in reaching its primary end point of a reduction at 3 months in upper lobe lung volume assessed by quantitative CT scan analysis (−895 ± 484 mL, P < .001). Treatment was associated with improvements in spirometry (ΔFEV1 at 6 months = 31.2% ± 36.6%, 12 months = 25.0% ± 33.4%), gas trapping (Δresidual volume/total lung capacity at 6 months = −7.2% ± 12.7%, 12 months = −10.9% ± 14.0%), diffusing capacity of lung for carbon monoxide (6 months = 12.7% ± 16.4%, 12 months = 12.3% ± 21.1%), symptom scores (ΔMedical Research Council dyspnea score at 6 months = median 0, range −2 to 1, 12 months = median −1, range −3 to 0), and health-related quality of life (ΔSt. George Respiratory Questionnaire at 6 months = −8.0 ± 17.2 U, 12 months = −7.0 ± 15.8 U). There was one serious procedural complication and seven all-cause significant respiratory adverse events over 17 patient-years of follow-up.

Conclusions:  Bilateral ELS treatment administered under conscious sedation in patients with advanced emphysema is associated with short procedure time and length of hospital stay and produces physiologic and functional improvement out to 1 year.

Trial registration:  ClinicalTrials.gov; No.: NCT01181466; URL: www.clinicaltrials.gov

Figures in this Article

Lung volume reduction surgery (LVRS), which was reintroduced into practice in the mid-1990s, reduces hyperinflation and improves lung function in emphysema by eliminating diseased tissue.1,2 Although LVRS produces physiologic and functional benefit in a majority of patients and was associated with improved long-term survival among patients with upper lobe disease and poor baseline functional status in the National Emphysema Treatment Trial (NETT), results showed that LVRS is also associated with significant short-term morbidity and mortality.35 As a consequence, surgical treatment of advanced emphysema is now rarely performed.

The findings of NETT fostered interest in endoscopic lung volume reduction (ELVR) as a potentially safer alternative to surgery. However, ELVR has not been widely adopted and has had limited impact on the management of patients with advanced emphysema. Results from the recently completed Endobronchial Valve for Emphysema Palliation Trial (VENT) and Exhale Airway Stents for Emphysema (EASE) trial showed that although ELVR therapy was indeed safer than LVRS, treatment was substantially less effective.6,7 Thus, the risk-benefit of ELVR for treating medically refractory emphysema remains questionable.

This report summarizes the findings of a clinical trial performed to evaluate the safety and efficacy of a tissue sealant, AeriSeal Emphysematous Lung Sealant System (ELS), for treatment of patients with advanced homogeneous and heterogeneous upper lobe predominant (ULP) emphysema. In prior studies involving patients with ULP emphysema, unilateral ELS treatment was associated with physiologic and functional benefits out to 6 months.8 The current study was performed to evaluate the safety and efficacy of bilateral ELS treatment in patients with both ULP and homogeneous emphysema out to 1 year.

Study Design

This was a single arm, prospective study performed at two academic-affiliated medical centers in Israel. All participants were nonsmokers (≥ 4 months) and had severe airflow obstruction, evidence of hyperinflation, clinical symptoms despite optimal medical management, and no prohibitive comorbid conditions. All participants signed an informed consent approved by the ethics committees at the participating institutions (Rabin Medical Center IRB protocol # 5975; Soroka Medical Center IRB protocol #4954). A detailed listing of inclusion/exclusion criteria for this study is presented online.9 A Consolidated Standards of Reporting Trials (CONSORT) diagram summarizing study events is presented in Figure 1.

Figure Jump LinkFigure 1. Consolidated Standards of Reporting Trials (CONSORT)-style flow diagram summarizing enrollment, allocation, follow-up, and data analysis for study NCT01181466. 6MWT = 6-min walk test; SAE = serious adverse event; ULP = upper lobe predominant.Grahic Jump Location

The primary study end point was change from baseline at 3-month follow-up in upper lobe lung volume assessed by quantitative analysis of CT images acquired at full lung inflation. Secondary outcome measures included FEV1, FVC, diffusing capacity for carbon monoxide (Dlco), residual volume (RV), RV/total lung capacity (TLC), Medical Research Council dyspnea score (MRCD), and St. George Respiratory Questionnaire (SGRQ) health-related quality-of-life total domain score. CT imaging was performed at baseline and at 3 and 12 months posttreatment. All other assessments were performed at baseline and 3, 6, and 12 months posttreatment.

Patient Enrollment and Retention

Study participants were recruited from the pulmonary and lung transplant clinics at Rabin Medical Center in Tel Aviv, Israel, and the Thoracic Surgery Clinic at Soroka Medical Center, Be’er Sheeva, Israel. Enrollment occurred between August 2010 and January 2011. Follow-up was completed January 2012.

Twenty patients were enrolled in the study. Ten were assessed as having homogeneous emphysema and 10 as having heterogeneous ULP emphysema. Assignment to either the heterogeneous ULP or homogenous cohort and selection of treatment sites were based on visual CT scan assessments performed by participating investigators. An independent visual assessment was performed by the sponsor’s medical team. Digital imaging and communications in medicine (DICOM) images were also forwarded to the sponsor for quantitative volumetric and densitometry assessments using commercial software (Pulmonary Workstation Plus Software; VIDA Diagnostics).

Procedure Description

ELS treatment was administered under moderate sedation either in the bronchoscopy suite (n = 17) or operating room (n = 3) without intubation. Prior to treatment, all patients were begun on a 7-day course of prophylactic antibiotics and steroids, which was previously shown to reduce acute side effects of fever, cough, chest pain, and dyspnea associated with the procedure.10

Following establishment of IV access and initiation of monitoring (peripheral oxygen saturation [Spo2], ECG, and BP), patients received IV sedatives (midazolam plus alfentanil, or propofol, per investigator preference) and topical anesthesia (1%-2% lidocaine) to achieve adequate sedation. The bronchoscope was passed into wedge position at the first site and the treatment catheter positioned 4 cm beyond the end of the scope under direct visualization. ELS treatment was prepared by mixing the sealant components (5 mL) with air (15 mL) to generate 20 mL of liquid foam. The foam was then injected rapidly through the catheter while maintaining wedge position with the bronchoscope. Immediately following injection, the catheter was removed and 30 mL of air delivered through the instrument channel of the scope to promote peripheral distribution. The scope was left in wedge position for 1 min to allow for complete polymerization of the sealant. The scope was then repositioned at the next target site and the process repeated until all sites were treated. Treatments were performed at four subsegmental sites, two in each upper lobe.

Data Analysis

Safety data were available for all 20 study patients through 1 year. Efficacy data were available for 18 of 20 patients through 1 year. No imputations were performed for missing data.

Safety was assessed in terms of serious medical events, including deaths and adverse events requiring hospitalization, through 1-year follow-up. Efficacy was assessed by comparing responses at designated follow-up time points to values measured at baseline. Values for continuous outcome variables that were normally distributed (assessed by Shapiro-Wilk test) are expressed as mean ± SDs of percentage changes and absolute changes from baseline and as median and ranges for variables not normally distributed. The significance of changes from baseline was assessed either by paired t test or Wilcoxon signed rank test as appropriate. The significance of differences across groups in categorical data were assessed by Pearson χ2 test. Correlations between continuous variables were performed by the method of Pearson.

Patient Characteristics

The majority of patients were older men (64 ± 8 years, 17 men) with significant smoking histories (34.2 ± 9.2 pack-years) and BMI values in the low-normal range (23.0 ± 4.1 kg/m2). All patients were receiving medical treatment in accordance with GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines.11 Baseline physiology confirmed severe airflow obstruction (FEV1 = 1.04 ± 0.39 L, 32.7% ± 8.7% predicted; FVC = 2.89 ± 0.85 L, 69.0% ± 14.6% predicted), hyperinflation (RV = 5.12 ± 0.98 L, 218.0% ± 43.3% predicted; TLC = 8.10 ± 1.28 L, 125.5% ± 14.4% predicted), and marked reductions from predicted baseline values in diffusing capacity (9.50 ± 2.10 mL/min/mm Hg, 26.3% ± 3.4% predicted) with no significant differences between heterogeneous and homogenous cohorts. Tissue density assessments confirmed severe destructive changes with mean density = −880 ± 16 Hounsfield units and mean heterogeneity index (equal to [% voxels in the right upper lobe + left upper lobe < cutoff]/[% voxels in the right lower lobe + left lower lobe < cutoff]) at −910 Hounsfield units of 1.80 ± 0.91 (ULP heterogeneous patients, 2.26 ± 0.79; homogeneous patients, 1.18 ± 0.19; P = .022).

Procedural Information

Target sites were selected based on visual assessment of CT images. The most severely damaged segments were identified, and one subsegment in each segment was chosen for treatment. In instances where the entire upper lobe appeared equally damaged (16 of 20 cases), treatment was performed in right bronchus 1, right bronchus 3, left bronchus 1, and left bronchus 3. All patients underwent treatment at the four target sites that had been predefined based on imaging.

The average procedure time for four-site treatment was approximately 15 min (15.2 ± 9.6 min). All treatments were completed under moderate sedation and were generally well tolerated. There was one serious procedure-related complication (see “Discussion” section). Hospital length of stay averaged slightly > 1 day (1.1 ± 2.2 days).

Efficacy Summary

Efficacy data are summarized in Table 1. At week 12, correctly formatted CT image data were available for quantitative analysis on 15 patients. ELS treatment was highly effective in reducing the volume of the targeted lobes. Four-site single-session treatment was associated with reductions in lung volume of −895 ± 484 mL. Reductions in patients with heterogeneous ULP emphysema (n = 7, −1,234 ± 395 mL) were significantly larger than those in patients with homogeneous emphysema (n = 8, −598 ± 344 mL, P = .013) at 12 weeks. Lobar reductions were durable out to 1 year in the group as a whole (−813 ± 564 mL) and in each subgroup (heterogeneous ULP = −1,235 ± 433 mL; homogeneous = −392 ± 298 mL). Representative CT images at baseline, 3, and 12 months posttreatment together with corresponding physiologic responses are shown in Figure 2 for patients with varying degrees of baseline heterogeneity.

Figure Jump LinkFigure 2. CT images along with corresponding physiologic and functional data at baseline, 12-wk follow-up, and 48-wk follow-up are presented for four study patients who display varying degrees of baseline heterogeneity assessed in terms the HI calculated at −910 Hounsfield units. A, Patient A. B, Patient B. C, Patient C. D, Patient D. Coronal images at equivalent anatomic locations along with measurements of spirometry, gas trapping, dyspnea, and respiratory-specific health-related quality of life are shown. HI = heterogeneity index; MRCD = Medical Research Council dyspnea score; RV = residual volume; SGRQ = St. George Respiratory Questionnaire; TLC = total lung capacity.Grahic Jump Location
Table Graphic Jump Location
Table 1 —Summary of Efficacy Responses to Treatment at 3, 6 and 12 mo Presented as Change From Baseline

All P values were calculated by paired t test relative to baseline except those for MRCD, which were calculated by Wilcox signed ranks test. 6MWT = 6-min walk test; Dlco = diffusing capacity of lung for carbon monoxide; MRCD = Medical Research Council dyspnea score; RV = residual volume; SGRQ = St. George Respiratory Questionnaire; TLC = total lung capacity.

The time course of changes in lung physiology, dyspnea, and quality of life responses out to 1 year are depicted in Figure 3. Improvements in most outcomes were apparent at 3 months and tended to improve further at 6 and 12 months. Improvements were observed in both heterogeneous and homogeneous patient subgroups at 48 weeks, although responses were uniformly better in patients with heterogeneous ULP disease.

Figure Jump LinkFigure 3. Time course of change in respiratory physiology, dyspnea, and quality-of-life measures out to 48 wk in the overall cohort (n = 18) and in heterogeneous ULP (n = 9) and homogeneous (n = 9) subgroups. DLco = diffusing capacity for carbon monoxide. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location

Lobar volume reduction measured by quantitative CT scan analysis correlated with improvements in spirometry and gas trapping at 12 months (n = 14, r = −0.725, P = .018 for Δupper lobe volume vs ΔFEV1; r = 0.658, P = .023 for Δupper lobe volume vs ΔRV/TLC).

Safety Summary

There were 10 all-cause events in nine patients that required hospitalization during the study. There were two deaths during follow-up. One occurred in a 76-year-old male patient with GOLD Stage IV airflow obstruction and advanced homogeneous emphysema who developed a tension pneumothorax immediately posttreatment attributed to either catheter trauma or barotrauma. The patient was intubated and stabilized, but subsequently developed nosocomial sepsis and died on study day 9. The second death, on study day 32, was due to pancreatic cancer that was not detected at screening. The remaining events included three COPD exacerbations, one upper respiratory tract infection, two pneumonia/pneumonitis, and one traumatic hand injury.

Results of this study indicate that bilateral ELS treatment performed at two subsegments in each upper lobe produces durable lung volume reduction in patients with advanced heterogeneous ULP and homogeneous emphysema that is associated with physiologic and functional benefit. Although the study is small and open label, improvements from baseline in objective, relatively effort-independent end points, including lobar volume reduction assessed by quantitative CT analysis, FEV1, Dlco, and RV/TLC ratio, indicate that ELS treatment improves respiratory physiology in patients with emphysema with hyperinflation and, secondarily, symptoms of dyspnea and quality of life. These improvements are comparable in magnitude and durability to those following LVRS reported in the NETT (NETT physiologic responses at 1 year: ΔFEV1 = 22.3% ± 33.1%; ΔFVC = 17.1% ± 28.9%; ΔRV/TLC = −12.5% ± 13.5%; ΔDlco = 11.1% ± 35.9%).3,4 Following ELS, 10 patients demonstrated clinically significant improvements in lung function (defined as an improvement from baseline ≥ 12% and 100 mL in FEV1), 11 clinically significant improvements in dyspnea (defined as ≥ 1-unit decrease in MRCD score), and eight clinically significant improvements in respiratory-specific health-related quality of life (defined as a ≥ 4-unit decline in SGRQ total domain score) 1 year after treatment. Mean improvements and responder rates at 1 year were better in patients with ULP emphysema (six of nine FEV1 responders, seven of nine MRCD responders, and five of nine SGRQ responders) than in homogeneous patients (four of nine FEV1 responders, three of nine MRCD responders, and three of nine SGRQ responders).

ELS treatment in conjunction with 7 days of antibiotics and corticosteroid prophylaxis was generally well tolerated. One patient suffered a life-threatening complication (a pneumothorax) in the periprocedural period. Life-threatening periprocedural pneumothoraces have previously been reported hours to days following lobar exclusion with endobronchial valves.12 Given that this patient did not undergo a lobar exclusion procedure, and the event was detected within minutes of completion of therapy, a similar mechanism seems unlikely here. Rather, this event was more likely due to catheter trauma or barotrauma associated with coughing during treatment. Changes in the sedation regimen and posttreatment monitoring were subsequently instituted. All other patients tolerated the procedure well and were discharged from the hospital within 3 days. Because of the small size of this trial and lack of a control group, characterization of the safety profile of sealant therapy will require further assessment in a larger randomized study.

The adverse event profile out to 1 year was generally satisfactory for this population. All patients were accounted for in follow-up. Between 12 and 48 weeks there were three respiratory events requiring hospitalization. All of these were COPD exacerbations, two at approximately 16 weeks posttreatment and one at 50 weeks posttreatment. The incidence of exacerbations requiring hospitalization during the study (0.16 events/patient-years of follow-up) compares favorably to COPD event rates reported with other therapies.6,7

The simplicity of the ELS procedure and ability to achieve sustained physiologic and functional benefits in patients with heterogeneous and homogeneous emphysema are encouraging. Procedural safety requires further assessment. Final determination of the risk/benefit ratio of this procedure awaits the results of a randomized controlled trial.

Author contributions: Dr Kramer is the guarantor of the manuscript and is responsible for the integrity and accuracy of the data.

Dr Kramer: contributed to data collection and analysis and manuscript preparation and review.

Dr Refealy: contributed to data collection and analysis and manuscript review.

Dr Maimon: contributed to data collection and analysis and manuscript review.

Dr Rosengarten: contributed to data collection and revision of the manuscript.

Dr Fruchter: contributed to data collection and analysis and manuscript review.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor, Aeris Therapeutics, provided access to the study data in the form of summary tables and assistance with image formatting for Figure 2.

Dlco

diffusing capacity of lung for carbon monoxide

ELS

AeriSeal Emphysematous Lung Sealant System

ELVR

endoscopic lung volume reduction

LVRS

lung volume reduction surgery

MRCD

Medical Research Council dyspnea score

NETT

National Emphysema Treatment Trial

RV

residual volume

SGRQ

St. George Respiratory Questionnaire

Spo2

peripheral oxygen saturation

TLC

total lung capacity

ULP

upper lobe predominant

Fessler HE, Scharf SM, Permutt S. Improvement in spirometry following lung volume reduction surgery: application of a physiologic model. Am J Respir Crit Care Med. 2002;1651:34-40. [PubMed]
 
Gelb AF, Zamel N. Lung elastic recoil in acute and chronic asthma. Curr Opin Pulm Med. 2002;81:50-53. [CrossRef] [PubMed]
 
Criner GJ, Sternberg AL. National Emphysema Treatment Trial: the major outcomes of lung volume reduction surgery in severe emphysema. Proc Am Thorac Soc. 2008;54:393-405. [CrossRef] [PubMed]
 
Fishman A, Martinez F, Naunheim K, et al; National Emphysema Treatment Trial Research Group National Emphysema Treatment Trial Research Group A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;34821:2059-2073. [CrossRef] [PubMed]
 
Naunheim KS, Wood DE, Krasna MJ, et al; National Emphysema Treatment Trial Research Group National Emphysema Treatment Trial Research Group Predictors of operative mortality and cardiopulmonary morbidity in the National Emphysema Treatment Trial. J Thorac Cardiovasc Surg. 2006;1311:43-53. [CrossRef] [PubMed]
 
Shah PL, Slebos DJ, Cardoso PF, et al; EASE trial study group EASE trial study group Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial. Lancet. 2011;3789795:997-1005. [CrossRef] [PubMed]
 
Sciurba FC, Ernst A, Herth FJ, et al; VENT Study Research Group VENT Study Research Group A randomized study of endobronchial valves for advanced emphysema. N Engl J Med. 2010;36313:1233-1244. [CrossRef] [PubMed]
 
Herth FJ, Gompelmann D, Stanzel F, et al. Treatment of advanced emphysema with emphysematous lung sealant (AeriSeal®). Respiration. 2011;821:36-45. [CrossRef] [PubMed]
 
National Institutes of Health Clinical Center. AeriSeal system for lung volume reduction in patients with advanced emphysema. NCT01181466. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2010.http://clinicaltrials.gov/ct2/show/NCT01181466. Updated October 20, 2011.
 
Herth FJ, Eberhardt R, Ingenito EP, Gompelmann D. Assessment of a novel lung sealant for performing endoscopic volume reduction therapy in patients with advanced emphysema. Expert Rev Med Devices. 2011;83:307-312. [CrossRef] [PubMed]
 
Asia Pacific COPD Roundtable GroupAsia Pacific COPD Roundtable Group Global Initiative for Chronic Obstructive Lung Disease strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: an Asia-Pacific perspective. Respirology. 2005;101:9-17. [CrossRef] [PubMed]
 
Sterman DH, Mehta AC, Wood DE, et al; IBV Valve US Pilot Trial Research Team IBV Valve US Pilot Trial Research Team A multicenter pilot study of a bronchial valve for the treatment of severe emphysema. Respiration. 2010;793:222-233. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Consolidated Standards of Reporting Trials (CONSORT)-style flow diagram summarizing enrollment, allocation, follow-up, and data analysis for study NCT01181466. 6MWT = 6-min walk test; SAE = serious adverse event; ULP = upper lobe predominant.Grahic Jump Location
Figure Jump LinkFigure 2. CT images along with corresponding physiologic and functional data at baseline, 12-wk follow-up, and 48-wk follow-up are presented for four study patients who display varying degrees of baseline heterogeneity assessed in terms the HI calculated at −910 Hounsfield units. A, Patient A. B, Patient B. C, Patient C. D, Patient D. Coronal images at equivalent anatomic locations along with measurements of spirometry, gas trapping, dyspnea, and respiratory-specific health-related quality of life are shown. HI = heterogeneity index; MRCD = Medical Research Council dyspnea score; RV = residual volume; SGRQ = St. George Respiratory Questionnaire; TLC = total lung capacity.Grahic Jump Location
Figure Jump LinkFigure 3. Time course of change in respiratory physiology, dyspnea, and quality-of-life measures out to 48 wk in the overall cohort (n = 18) and in heterogeneous ULP (n = 9) and homogeneous (n = 9) subgroups. DLco = diffusing capacity for carbon monoxide. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Summary of Efficacy Responses to Treatment at 3, 6 and 12 mo Presented as Change From Baseline

All P values were calculated by paired t test relative to baseline except those for MRCD, which were calculated by Wilcox signed ranks test. 6MWT = 6-min walk test; Dlco = diffusing capacity of lung for carbon monoxide; MRCD = Medical Research Council dyspnea score; RV = residual volume; SGRQ = St. George Respiratory Questionnaire; TLC = total lung capacity.

References

Fessler HE, Scharf SM, Permutt S. Improvement in spirometry following lung volume reduction surgery: application of a physiologic model. Am J Respir Crit Care Med. 2002;1651:34-40. [PubMed]
 
Gelb AF, Zamel N. Lung elastic recoil in acute and chronic asthma. Curr Opin Pulm Med. 2002;81:50-53. [CrossRef] [PubMed]
 
Criner GJ, Sternberg AL. National Emphysema Treatment Trial: the major outcomes of lung volume reduction surgery in severe emphysema. Proc Am Thorac Soc. 2008;54:393-405. [CrossRef] [PubMed]
 
Fishman A, Martinez F, Naunheim K, et al; National Emphysema Treatment Trial Research Group National Emphysema Treatment Trial Research Group A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;34821:2059-2073. [CrossRef] [PubMed]
 
Naunheim KS, Wood DE, Krasna MJ, et al; National Emphysema Treatment Trial Research Group National Emphysema Treatment Trial Research Group Predictors of operative mortality and cardiopulmonary morbidity in the National Emphysema Treatment Trial. J Thorac Cardiovasc Surg. 2006;1311:43-53. [CrossRef] [PubMed]
 
Shah PL, Slebos DJ, Cardoso PF, et al; EASE trial study group EASE trial study group Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial. Lancet. 2011;3789795:997-1005. [CrossRef] [PubMed]
 
Sciurba FC, Ernst A, Herth FJ, et al; VENT Study Research Group VENT Study Research Group A randomized study of endobronchial valves for advanced emphysema. N Engl J Med. 2010;36313:1233-1244. [CrossRef] [PubMed]
 
Herth FJ, Gompelmann D, Stanzel F, et al. Treatment of advanced emphysema with emphysematous lung sealant (AeriSeal®). Respiration. 2011;821:36-45. [CrossRef] [PubMed]
 
National Institutes of Health Clinical Center. AeriSeal system for lung volume reduction in patients with advanced emphysema. NCT01181466. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2010.http://clinicaltrials.gov/ct2/show/NCT01181466. Updated October 20, 2011.
 
Herth FJ, Eberhardt R, Ingenito EP, Gompelmann D. Assessment of a novel lung sealant for performing endoscopic volume reduction therapy in patients with advanced emphysema. Expert Rev Med Devices. 2011;83:307-312. [CrossRef] [PubMed]
 
Asia Pacific COPD Roundtable GroupAsia Pacific COPD Roundtable Group Global Initiative for Chronic Obstructive Lung Disease strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: an Asia-Pacific perspective. Respirology. 2005;101:9-17. [CrossRef] [PubMed]
 
Sterman DH, Mehta AC, Wood DE, et al; IBV Valve US Pilot Trial Research Team IBV Valve US Pilot Trial Research Team A multicenter pilot study of a bronchial valve for the treatment of severe emphysema. Respiration. 2010;793:222-233. [CrossRef] [PubMed]
 
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