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* From the Division of Cardiothoracic Surgery (Drs. Wan and Yim), The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; Department of Respiratory Medicine (Drs. Toma and Geddes), Royal Brompton Hospital, London, UK; Department of Respiratory Medicine (Drs. Snell and Williams), Alfred Hospital, Melbourne, Australia; and Cattedra di Chirugia Toracica (Dr. Venuta), University of Rome La Sapienza, Rome, Italy.
Correspondence to: Anthony P. C. Yim, MD, FCCP, Professor and Chief of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, China; e-mail: yimap{at}cuhk.edu.hk
Abstract
Objectives: To report the first multicenter experience on the treatment of end-stage emphysema using an endobronchial valve (EBV) [Emphasys EBV; Emphasys Medical; Redwood City, CA].
Design: Retrospective analysis from prospective multicenter registry.
Patients and interventions: This is a study of the use of EBVs in the treatment of end-stage emphysema at nine centers in seven countries. Ninety-eight patients with mean FEV1 of 0.9 ± 0.3 L (30.1 ± 10.7% of predicted) [± SD] and residual volume (RV) of 5.1 ± 1.3 L (244.3 ± 0.3% of predicted) were treated over a period of 20 months. Spirometry, plethysmography, and diffusing capacity of the lung for carbon monoxide (DLCO) and exercise tolerance testing were performed at 30 days and 90 days after the procedure.
Results: RV decreased by 4.9 ± 17.4% (p = 0.025), FEV1 increased by 10.7 ± 26.2% (p = 0.007), FVC increased by 9.0 ± 23.9% (p = 0.024), and 6-min walk distance increased by 23.0 + 55.3% (p = 0.001). There was a trend toward improvement in DLCO, but this did not reach statistical significance (17.2 ± 52.0%, p = 0.063). Patients treated unilaterally showed a trend toward greater improvement than those treated bilaterally. A similar trend toward improvement was observed in patients who had one entire lobe treated compared to those with just one or two bronchopulmonary segments treated. Eight patients (8.2%) had serious complications in the first 90 days, including one death (1.0%).
Conclusion: This multicenter analysis confirms that improvement in pulmonary function and exercise tolerance can be achieved in emphysematous patients using EBVs. Future efforts should be directed to determining how to select those patients who would benefit most from this procedure and the best endobronchial treatment strategy.
Key Words: bronchoscopy • emphysema • lung volume reduction • minimally invasive
Emphysema is a progressive, chronic disease that afflicted approximately 3 million people in the United States in 2001.1 The intermediate term benefit of lung volume reduction surgery (LVRS) in the management of end-stage emphysema has been defined in selected group of patients.2 LVRS has been shown to improve survival in a subset of patients with upper-lobe disease and low baseline exercise tolerance, albeit at a high cost.3 The National Emphysema Treatment trial (NETT)4 investigated the efficacy and cost-effectiveness of LVRS, and a comparison has been made with conventional medical therapy. The optimal method for surgical access for LVRS has been controversial, but the NETT results showed that video-assisted thoracoscopy (VATS) offered earlier recovery at a lower cost than median sternotomy.5 However, the trauma associated even with the less-invasive VATS approach is still considerable, as the procedure requires entry into the pleural cavity and single lung ventilation. Interim analysis of the NETT showed that patients with very low FEV1 (
20% of predicted) and a homogeneous pattern of emphysema or a diffusion capacity of the lung for carbon monoxide (DLCO) of 20% predicted were at high risk of death after LVRS.4 Even with a successful operation, patients often have to stay in the ICU, and the prolonged air leak postoperatively has been reported to be as high as 30 to 48%.5 With all of these limitations, most patients with severe emphysema are not candidates for LVRS.
The concept of removing hypoventilated and nonfunctional areas of lung and the favorable results of the NETT have led to the development of various bronchoscopic techniques to provide an alternative means of achieving the results of LVRS. Different approaches of bronchoscopic lung volume reduction have been described, including radiofrequency fenestration of the bronchial wall with stent placement,6 umbrella blockers,7 and injection of fibrin glue.8 The system used in this report (Emphasys EBV; Emphasys Medical; Redwood City, CA) is the most studied of these devices.9101112 The bronchial implants (Fig 1 ) are silicone-based, one-way valves mounted on a nitinol stent.13 The valve is intended to prevent air from entering into the isolated emphysematous segment while allowing the venting of expired gas and drainage of bronchial secretions distal to the valve. In theory, this will result in atelectasis of the isolated emphysematous lung, mimicking the results of surgical LVRS. This is the first report on the collective experience of using this device from different centers throughout the world.
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Selection of Patients
This multicenter registry was conducted at nine centers in seven countries (Table 1
). All centers received local Ethics Committee approval prior to enrolling patients into the trial. Most patients were potential candidates for LVRS, and this new procedure was offered as an alternative, investigational procedure. Standardized informed consent was obtained from each patient. The procedure was offered to them as a new and investigational procedure. All patients understood LVRS, and this remained as an option if the endobronchial treatment failed. The recruited patients did not routinely receive preprocedural pulmonary rehabilitation. The inclusion and exclusion criteria are shown in Table 2
.
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/
) scans in order to confirm the diagnosis of emphysema, to assess the severity and distribution of disease, and to rule out major comorbidities.
Physiologic Measurement:
Physiologic measurements included FEV1, FVC, residual volume (RV), and DLCO. Spirometry was used to measure FEV1 and FVC, and all spirometric data were obtained after bronchodilation. RV was measured using body plethysmography, and DLCO was measured using the single-breath hold method.
Exercise Testing:
The 6-minute walk test (6MWT) was used to assess exercise tolerance at all but one center (The Royal Brompton, London, UK), where the 6MWT was used as an alternate assessment.
Valve Targeting
The protocols in this registry allowed the clinical investigators to determine the appropriate treatment and valve targeting strategies. The investigators made these determinations based on review of the patient’s CT scans and / scans. The treatment strategies varied with respect to the following: (1) whether valves were placed in one lung (unilateral) or both lungs (bilateral); (2) a lobe was completely excluded by the valves (lobar exclusion), or at least one bronchopulmonary segment in the target lobe was not treated (nonlobar exclusion); (3) whether treatment was in an upper lobe(s) or lower lobe(s); and (4) which lobe(s) received the valves. Additional targeting variables that were not systematically captured in this study were the degree of heterogeneity and, for unilateral placement, whether the target lobe was the most destroyed lobe within the most heterogeneously destroyed lung, or the most destroyed lobe of either lung.
The criteria for valve targeting among the authors evolved over time. Some investigators believed that it was important to treat patients bilaterally based on the LVRS literature. Others took a more conservative approach by placing valves unilaterally or without complete lobar coverage. After a few centers began reporting incidences of pneumothoraces associated with complete lobar exclusion, all investigators moved to unilateral placement, some with the intent that the procedure could be staged if deemed appropriate.
Interventional Procedure
The endobronchial valve (EBV) system used in this registry consisted of an implantable valve, a delivery catheter, a loader system, and a guidewire.13 The valve implant is composed of a stent-like, self-expanding retainer made of Nitinol. The retainer is wrapped in molded silicone to provide a seal between the implant and the bronchial wall. A one-way, silicone, duckbill valve is mounted in the center of the retainer to complete the seal and to provide an escape for gas and secretions. Three sizes of implants were used in this study in order to accommodate the bronchial anatomy. Each size of implant has unique flow characteristics based on the size and geometry of the duckbill valve. At a static flow rate of 150 mL/min, the valves studied had the following resistance to flow: small valve (4.0 to 5.5 mm), 10.3 cm H2O; medium valve (5.0 to 7.0 mm), 4.7 cm H2O; and large valve (6.5 to 8.5 mm), 2.3 cm H2O. The delivery catheter facilitates placement of the EBV into the targeted bronchus. The loader system compresses and loads the EBV into the delivery catheter. The guidewire guides the delivery catheter to the target bronchus.
All procedures were performed in an operating room or bronchoscopy suite with full anesthetic capabilities. There were three anesthetic and access approaches utilized: (1) full support on a ventilator with endotracheal tube airway access by flexible bronchoscopy, (2) IV sedation and spontaneous breathing with access via flexible bronchoscopy through a bite block, or (3) rigid bronchoscopic intubation with IV sedation and spontaneous breathing partially supported by ventilation through the rigid bronchoscope. The operator located the target bronchus using flexible bronchoscopy. A flexible 0.035-inch guidewire was placed into the target bronchus at least one bronchial generation deeper than the intended target. The bronchoscope was removed while leaving the guidewire in place. The delivery catheter was advanced over the guidewire, and the valve was ejected from the delivery catheter into the targeted lobar, segmental, or subsegmental bronchus. Correct placement was subsequently confirmed with the flexible bronchoscope.
Postprocedure Care and Follow-up
Chest radiography was routinely performed within the first hour after the procedure to assess signs of atelectasis and diaphragmatic shift. A uniform method of assessing atelectasis was not done across centers. Consequently, analysis of prognostic variables for atelectasis and the affect of atelectasis or absence of atelectasis are beyond the scope of this article. Spirometry, plethysmography, DLCO, and exercise tolerance testing were performed at 30 days and 90 days after the procedure. CT scans and / scans were done at 90 days after the procedure. Patients did not routinely receive postprocedural pulmonary rehabilitation.
Statistical Analysis
Statistical analysis was performed (Intercooled Stata 8.2 for Windows; StataCorp; College Park, TX); p values were calculated using a two-tailed, Student t test for matched pairs when normality assumptions were met. For nonparametric results, the Wilcoxon signed-rank test was used. For subset analyses, analysis of variance (one way) was used when normality assumptions were met, and the Kruskal-Wallis test was used for nonparametric distributions.
Results
From April 2002 to December 2003, 98 patients were enrolled in a multicenter study. There were 20 female patients (20.4%) and 78 male patients (79.6%) being treated. Average baseline percentage of predicted values were as follows: FEV1, 30.1%; FVC, 63.8%; RV, 244.3%; total lung capacity (TLC), 128.4%; and DLCO, 32.7%. Baseline 6MWT distance was 303 m (Table 3 ). A total of 396 valves were placed (average number of valves per patient, 4.0 ± 1.6 valves, range, 1 to 8 valves). Unilateral, lobar placement was the predominant approach (49.0%) [Table 4 ]. Anatomically, valves were most commonly placed unilaterally in the right upper lobe (39.8%) followed by bilateral, upper-lobe placement (25.5%) [Table 5 ].
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There were no procedural deaths, but one patient died within the 90-day postprocedural follow-up. This was a 54-year-old man who had previously undergone a right upper lobectomy for lung cancer. His baseline pulmonary function values after 4 months of pulmonary rehabilitation were as follows: FEV1, 1.02 L (28%); FVC, 2.89 L (64%); RV, 4.22 L (199%); TLC, 7.72 L (123%); vital capacity, 3.5 L (78%); and 6MWT distance, 534 m. He was treated with five valves. Complete lobar exclusion was obtained in the right middle lobe with placement of one valve and in the left upper lobe with placement of one valve within the lingular segment, one valve in the anterior segment, and two valves in the subdivisions of the apical-posterior bronchus. The procedure was uneventful. Postoperatively, the patient remained in the hospital receiving oxygen and began a postprocedure exercise routine. Left upper lobe pneumonia developed, and IV antibiotic therapy was instituted. The pneumonia progressed to involve the left lower lobe. On day 16 after the procedure, the EBVs on the left side were removed under general anesthesia and the patient could not be extubated due to respiratory failure. Either during or immediately after the removal, a left pneumothorax developed requiring a chest tube. The pneumonia continued to progress despite multiple antibiotic therapy, and the patient died of respiratory failure on day 25.
Subset Analysis
A greater magnitude of improvement was seen in patients with lobar exclusion (FEV1 increased 14.0 ± 29.3%, p = 0.02; exercise tolerance increased 26.7 ± 58.8%, p = 0.001) [Table 8
] and in those with unilateral placement only (FEV1 increased 13.1 ± 27.5%, p = 0.006; exercise tolerance increased 33.8 ± 61.8%, p < 0.001) [Table 9
]. The greatest magnitude of benefit was found in those patients with unilateral and lobar placement (FEV1 increased 16.3 + 29.4%%, p = 0.013; exercise tolerance improved 40.6 + 68.6%, p < 0.001) [Table 10
]. Patients with baseline FEV1 < 30% had improvement in FEV1 (20.6 ± 28.1%), which was significantly greater than those patient with FEV1 > 30% (1.3 ± 20.7%; p = 0.0011) [Table 11
]. Similar findings can be observed in patients with RV > 225% of predicted in whom there was significant improvement in FEV1 (17.2 ± 28.1%) than the low-RV group (0.2 ± 15.4%; p = 0.006) [Table 12
]. The reduction in RV was also more marked for the RV > 225% group (– 11.6 ± 16.9%), vs (4.6 ± 13.7%) for the low-RV group (p = 0.0001) [Table 12].
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Medical therapy has always been the main stay of treatment for emphysema. LVRS was readvocated 10 years ago, and the most diseased part of the emphysematous lung could be resected to achieve restoration of chest wall and diaphragmatic mechanics.15 LVRS was shown to improve the exercise capacity of selected patients. Survival advantage was shown in a subset of patients with upper-lobe emphysema and low baseline exercise capacity.4 However, only a small proportion of patients could benefit from LVRS, as many of them had either severe or homogenous disease. There is clear evidence that this group of patients could not benefit from surgical LVRS. Patients often need intensive care support postoperatively and prolonged hospital stay. Other morbidities include persistent air leak and pneumonia. Attempts have been made to expand the applicability of lung volume reduction therapy with the use of nonresectional technique either by plication techniques or silicone sleeve, but not many of these devices were being adopted clinically.16 New devices and techniques were developed recently to achieve the total bronchoscopic approach of LVRS.6789 Extra-anatomic tracts for airway bypass was developed for creation of extra pathways between the lung and chest wall thus allowing the trapped air to escape with reduction in the resistance of expiratory air flow.6 These extra-anatomic tracts could be created by a radiofrequency probe being placed bronchoscopically.6 The other concept of endoscopic LVRS could be achieved by inducing volume reduction with sealants, endobronchial occluders, and EBVs.789 Many of these devices still remain in preclinical testing, with very few of them having published clinical data.7910111217 An ideal endobronchial device should be effective in achieving and maintaining volume reduction comparable to LVRS with reproducible results. The device should be easily deployable with bronchoscopic instruments, and it should not migrate while remaining easily removable. Lastly, the device should not interfere with future surgical interventions such as LVRS or lung transplantation.11
This is the first analysis of a multicenter, multitechnique cohort of endobronchial placement of one-way valve for lung volume reduction. The data indicated that the bronchoscopic placement of EBV was a safe procedure in patients with emphysema. The 90 day mortality is 1.02%, which is lower than the NETT surgical group mortality rate 7.9%.4 Significant improvement in lung function and exercise tolerance could be achieved with minimal morbidity as compared with LVRS. According to the American Thoracic Society criteria,18 45 patients (46%) had clinically significant improvement in FEV1 > 15% and 54 patients (55%) had improvement of > 15% or 50 m for the 6MWT 90 days after the procedure. The results of this registry also showed that there might be more marked beneficial effect for certain subset of patients with emphysema and that the optimal strategy of valve placement needs further study with respect to different baseline characteristics and disease distribution. Patients with worse baseline FEV1 and high RV did improve significantly more than those with better baseline values. Also, we have observed that greatest magnitude of benefit could be achieved with the strategy of unilateral and lobar exclusion. The exact underlying mechanism of this observation needs further investigation. However, this result contrasts with the findings of the LVRS as bilateral procedures were associated with better clinical outcomes and survival benefits when compared with unilateral LVRS.19 This can be explained by the fact that there is no randomized allocation of patient to either unilateral or bilateral endobronchial treatment in this study. In addition, the percentage of patients receiving lobar exclusion is higher for the unilateral group when compared with the bilateral treatment group (Table 5). Theoretically, lobar collapse is facilitated if there is potential and room for contralateral lung expansion. An interesting finding in this initial registry is that the valves do not cause a high rate of postobstructive pneumonia. This could be due to the valve feature allowing the passage of mucus and secretions, or it has been theorized that the complete obstruction of the airway (as opposed to a partial obstructive from a bronchial tumor) prevents pathogens from entering the obstructed lobe.
In this study, a variety of patient subgroups were treated with a variety of treatment strategies and this has to be standardized in the upcoming prospective trial. However, this study may better reflect how EBV therapy will be utilized in medical practice, where individual clinicians will have the option of targeting different sites, and utilizing different bronchoscopic and anesthetic approaches. Ideally, all EBVs should be implanted under local anesthesia, but the implantation of EBV at the upper lobe, in particular the apical segment, is more technically demanding.11 Prolonged manipulation under local anesthesia could lead to extreme patient discomfort. With maturation of implantation technique and modification of delivery system, this problem could be overcome.
Apart from objective pulmonary function and exercise tolerance measurements, enquiry into the quality of life of patients is of utmost importance. LVRS is a palliative procedure that helps to improve health-related quality of life (HRQOL) as being shown in the NETT.4 Other data have showed that patients receiving EBV implantation had significant improvement in HRQOL as being documented by the use of Short-Form 36 health survey 30 days and 90 days after the procedure.11 Inclusion of HRQOL or functional status assessment into future clinical trial is essential and this can be accomplished by using the Short-Form 36 health survey, the St. George Respiratory Questionnaire, and Medical Research Council dyspnea grading scale.
The development of pneumothorax might be secondary to acute lung volume loss after EBV placement. Placement of a chest drain failed to re-expand the lung, and there was no air leak from the drain indicating the absence of pressure buildup within the pleural space.11 The exact reason for its occurrence remains unclear. However, it could be due to adhesion of the nontargeted lobes to the chest wall, which can prevent them from rapidly filling up the space left by the collapsed lobe.
The accomplishment of endoscopic complete lobar exclusion did not translate directly into lobar collapse or atelectasis.12 The presence of interlobar collaterals has been described and demonstrated with the use of 133Xe ventilation scintigraphy.2021 In patients with emphysema, the collateral resistance may be reduced to an extent that can be lower than the airway resistance. This allows collateral ventilation across the lobes. The extent of these collaterals varies among different patients. In patients with high collateral resistance, atelectasis can be achieved easily after EBV placement and the ventilation mechanics improves in the same way as surgical LVRS. However, if the collateral resistance is low, the occluded bronchopulmonary segmented will remain hyperinflated during exercise and the effect of surgical LVRS can less likely be achieved. In patients with moderate collateral resistance, the dynamic hyperinflation of the occluded segments can still be reduced at higher levels of ventilation and airflow is directed to less obstructed area of lung. Hence, even without achievement of radiologic lobar collapse after EBV placement, improvement in symptoms or exercise tolerance can be observed in this group of patients.121922 The determination of the extent of collateral resistance can theoretically help us to stratify or select patients for bronchoscopic LVRS or surgical LVRS. Measurement of collateral resistance can be performed with the use of xenon scintigraphy and MRI.23 These techniques can help us to predict the efficacy of bronchoscopic lung volume reduction.
Finally, this multicenter experience confirms that improvement in pulmonary function and exercise tolerance can be achieved in emphysematous patients using EBVs. However, this is not a prospective trial with a narrowly defined target patient population and uniform treatment strategy. Standardized pulmonary rehabilitation program is going to be implemented as part of the new protocol. Future efforts should be directed to determining how to select those patients who would benefit from this procedure and the best endobronchial treatment strategy. Furthermore, we have analyzed the results up to 90 days after EBV implantation, and long term follow-up is required. This analysis, nonetheless, provides a basis for future investigation with a randomized control and longer follow-up. The preliminary conclusions of this retrospective analysis will be tested prospectively with a second-generation valve in a multicenter, randomized trial.
Footnotes
Abbreviations: 6MWT = 6-min walk test; DLCO = diffusion capacity of the lung for carbon monoxide; EBV = endobronchial valve; HRQOL = health-related quality of life; LVRS = lung volume reduction surgery; NETT = National Emphysema Treatment Trial; RV = residual volume; TLC = total lung capacity; VATS = video-assisted thoracoscopy; / = ventilation/perfusion
Dr. Yim is currently a consultant to Emphasys Medical, Redwood City, CA.
Received for publication May 5, 2005. Accepted for publication September 18, 2005.
References
This article has been cited by other articles:
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  Bronchoscopic Lung Volume Reduction for Emphysema Journal Watch (General), March 31, 2006; 2006(331): 1 - 1. [Full Text]
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 W. W. Lunn Endoscopic Lung Volume Reduction Surgery Chest, March 1, 2006; 129(3): 504 - 506. [Full Text] [PDF]
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