Development of a Bronchial Valve for Treatment of Severe Emphysema

The impetus for intrabronchial treatment of emphysema came from the experiences with lung volume reduction surgery (LVRS).

Introduction

The impetus for intrabronchial treatment of emphysema came from the experiences with lung volume reduction surgery (LVRS). LVRS improves survival, function, exercise capacity, and quality of life in selected patients with severe chronic obstructive pulmonary disease (COPD) and emphysema [1, 2]. The mechanisms of action of LVRS are thought to be a combination of factors including chest cage mechanics, respiratory muscle function, and improved elastic recoil of the lung [3, 4].

The results with LVRS brought attention to the potential of alternative treatments for emphysema. Endobronchial occlusion with a plug or valve was one consideration, and research and development was started by multiple groups in the late 1990’s. The IBV® Valve (Spiration, Inc., Redmond, WA) is an implantable device, designed as a one-way valve, which is placed by flexible bronchoscopy. The valve obstructs airflow into targeted segments, yet allows passage of distal air and mucus. The concept was to redirect ventilation away from more diseased lung tissue, change the volume of the treated lobe, or decrease dynamic hyperinflation. We review the development of the valve, pre-clinical testing, and selected results from treatment in human subjects. Details regarding the initial results of the prospective multicenter trial have been published [5].

IBV® Valve design

Figure 1: The IBV™ Valve appearance and nomenclature

The valve is an implantable, self-expanding device (Figure 1) and the frame is made of nitinol. The five distal prongs provide stability and anchoring. The proximal portion is made up of six support struts that are covered by a thin polymer membrane. The membrane covered struts form an umbrella shape that allows conformation and sealing with the airway with minimal pressure on the mucosa. The valve is designed to limit distal airflow, yet the membrane and struts compress to allow air and mucus to flow out of the occluded segment around the umbrella. The valve design includes a central rod that allows removal if needed.

Valve placement

Figure 2: Catheter loaded with compressed valve extending from the flexible bronchoscope. The tip of the valve removal rod is seated against the tip of the deployment stabilization rod.

The valve is deployed via flexible bronchoscopy using a catheter delivery system. The catheter system is supplied in a sterile tray with the valve in a loading housing. The loading housing allows compression of the valve into the 2.2 mm flexible delivery catheter (Figure 2). The catheter has a flexible internal rod which stabilizes the valve while the outer sheath of the catheter is withdrawn to release the valve (Figure 2). This feature allows the operator to accurately place the valve in the tapering airways under direct vision. The catheter size requires using a flexible bronchoscope with a working channel of 2.6 mm or greater. There was concern that the larger bronchoscope would not be able to access all the segmental airways desired for treatment but this concern was unfounded [5].

IBV™ Valve Research and Development

Figure 3: One of many prototype designs of IBV™ Valve

At the 2002 World Congress for Bronchology, prototype designs (Figure 3) and data from initial studies with swine were presented on valve placement and removal [6]. These studies used 4 healthy swine (52±18 Kg) and a total of 17 valves. Four days after placement, all valves were evaluated using bronchoscopic and fluoroscopic techniques, then the chest was opened to obtain visual confirmation of volume reduction. One valve in each animal was easily removed and replaced under direct bronchoscopic and surgical observation.

Animal studies continued, and by early 2003 over 2000 valves had been manufactured and over 500 valves implanted with effective isolation of lung segments. Studies regarding lung volume reduction, valve removal, anchoring, and airway sizing were performed [7-10]. Additional experiments to test the removal design over time were performed with a total of 366 valves in 14 dogs and 14 sheep and at multiple time periods up to 12 months [11]. The devices were successfully removed using common biopsy forceps. Bronchoscopic observations of airways were done immediately after removal and in follow up procedures. After removal of 208 devices, all distal airways were patent. During removal, localized bleeding and tissue irritation were minimal and follow-up observations of removal sites showed healthy airways. Less than 5% of removal attempts were unsuccessful due to hyperplastic tissue impeding access. The animal studies indicated the design allowed for potential removal up to 12 months after placement.

A device placed in an airway may increase the risk of infection, and experiments were performed in a healthy canine model to evaluate this risk [12]. To evaluate the incidence of bacterial colonization or infection, 16 dogs were implanted with valves. All animals were carefully evaluated for any sign of respiratory infection. Four animals were terminated at time points of 1, 3, 6 and 13 months. At necropsy, cultures were obtained from each lobe treated with valves and control areas. A total of 196 valves were placed and there was no clinical evidence of infection at necropsy or dissection. Screening cultures showed only 5 samples with low level positive at 1+ (Gram neg., Neisseria, Staph. and Diptheroid species) and one with 2+ (Gram neg. species) from a total of 114 samples. These positive cultures were judged to represent colonization, suggesting a minimal impact of the valve on the airway’s clearance mechanisms.

Engineering studies have been performed in parallel with animal studies to evaluate factors such as device fatigue, biocompatibility, radial forces, and corrosion [13]. This testing included ex-vivo models and has shown that the valve would not fail due to fatigue during the expected life span of patients with severe emphysema [13].

Human studies

Based on the favorable pre-clinical data, a prospective multicenter trial in patients with severe upper-lobe emphysema was initiated. The results with the initial 30 subjects were presented [14, 15] and published [5]. Patients had severe to very severe airflow obstruction with air-trapping, thoracic hyperinflation, and a reduced DLCO. Therapy generally consisted of bilateral occlusion of all upper lobe segments except for the lingula, with placement of valves into segmental and/or subsegmental airways. Airways were sized with a calibrated balloon. Valve diameter sizes were 4mm, 5mm, 6mm, and 7mm.

Valves were deployed in all planned segments or subsegments, followed by a final visual inspection. Patients had a chest x-ray following the procedure and at each follow-up visit for a year. The anchor system has been robust with no valves expectorated and all valves accounted for by chest x-ray.

Twenty-eight patients were followed for at least 6 months after valve placement. There were no episodes of pneumothorax and no deaths. Evidence of efficacy was documented in disease-specific health status by the St.George’s Respiratory Questionnaire (SGRQ). There were significant changes in the SGRQ scores at all post-procedure time points compared to the pre-procedure baseline (Table 3). The mean change at 6 months was –6.8 + 14.3 points. Fifty two percent of the patients had a clinically meaningful response (SGRQ score improved by at least -4 points) at 6 months after valve implantation. Other measures, such as lung volumes, FEV1, and DLCO before and after valve implantation did not show statistically significant changes. The statistically significant improvement occurred in disease-specific health status.

Table 1. Health related quality of life, FEV1, and 6MWD changes and proportion responding.

The trial was continued in the United States to evaluate other treatment algorithms and testing methods and results after 75 subjects were presented at two forums in 2006 [16, 17]. 520 valves were implanted at 9 US centers over a 27 month period between January 2004 and April 2006. Patient follow-up ranged from 1 to 12 months. There continued to be no device migration and no device erosion. The effectiveness results were similar to those published with the initial 30 subjects (Table 1) with significant and sustained improvement in disease-specific health status. A subset analysis for safety identified 46 subjects with reduced complications and retained efficacy. This subset (group A) was compared to 29 others (group B). The factors identified for improved safety were no added treatment of the lingular segment of the left upper-lobe, fewer segments treated, 5.7 vs. 7.0, and age less than 75 years and these results are shown in Table 2. The 90 day serious complications were 1 bronchospasm and 1 COPD flare in the A group and 2 bronchospasm and 1 death with pneumothorax in group B. The analysis concluded that the IBV™ valve has acceptable safety and efficacy results for proceeding with a randomized trial using the criteria for group A.

Table 2: Complications after procedures (90 days) for Group A and Group B. See text for definitions of Group A and Group B.

Discussion and Conclusion

An early hypothesis for bronchial valve therapy was to mimic surgical lung volume reduction by promoting lobar atelectasis in treated lobes. Achievement of this goal has been sporadic in published reports [18], and our experience is similar. We have found only about 5% of subjects will have lobar atelectasis after treatment. Although segmental or lobar atelectasis was common in our animal studies, this appears harder to achieve in patients with end-stage emphysema, potentially due to collateral ventilation pathways. In addition, lobar atelectasis is associated with an increased rate of complications so we believe that promoting lobar atelectasis is no longer the goal of valve therapy.

The majority of our subjects reported improvement. There are several possible explanations for the improvement without lung volume reduction. Valve treatment could reduce volume in the treated lobe while increasing volume in untreated lobes and if these are proportional, there will be no change in total lung volume. This intra-lobar shift may not be detected by pulmonary function testing in the standard fashion. Another explanation may be that most of the benefit of valves occurs with physical activity. This valve effect could be largely due to blocking dynamic hyperinflation [19]. Bronchial occlusion may mitigate dynamic hyperinflation during activity and improve symptoms without showing consistent improvement in resting pulmonary function tests.

Targeted endobronchial occlusion of upper lobe segments in patients with emphysema can be achieved with high success and low morbidity, and may provide palliation of symptoms for a majority of subjects. Endobronchial therapies for emphysema may create treatment options for patients not currently considered candidates for LVRS, and may offer less morbidity and mortality for LVRS candidates.

Disclosure Statement

Steven C. Springmeyer, MD
Employee, patents, and stock holder: Spiration, Inc.

Douglas E. Wood, MD
Research Support, Consulting Fees, Scientific Advisory Board: Spiration, Inc

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