Bronchoscopic procedures for emphysema treatment

European Journal of Cardio-thoracic Surgery 29 (2006) 281—287 www.elsevier.com/locate/ejcts

Review

Bronchoscopic procedures for emphysema treatment Federico Venuta *, Erino A. Rendina, Tiziano De Giacomo, Marco Anile, Daniele Diso, Claudio Andreetti, Francesco Pugliese, Giorgio F. Coloni ` di Roma ‘‘La Sapienza’’, Cattedra di Chirurgia Toracica, Policlinico Umberto I, V.le del Policlinico, 00100 Rome, Italy Universita Received 19 July 2005; received in revised form 28 November 2005; accepted 5 December 2005

Summary Emphysema is a debilitating lung disease continuing to be a major source of morbidity and mortality in the developed countries. Medical treatment is the mainstay of therapy and consists of smoking cessation, pulmonary rehabilitation, administration of bronchodilators and, when indicated, steroids and supplemental oxygen. Various surgical procedures have been promoted in the past to relieve dyspnoea and improve quality of life in patients with advanced emphysema; whilst early results were often encouraging, a sustained objective functional improvement was rarely achieved and most of those procedures were progressively abandoned. Despite controversies, LVRS has been shown to be beneficial to selected patients with end-stage emphysema when medical therapy has failed. There is no doubt that LVRS allows a significative functional improvement in a selected group of patients; however, it still carries a substantial morbidity, even if mortality is low at the centres with the larger experience. Patients with a most advanced functional deterioration show a higher surgical mortality and less impressive functional results, suggesting that LVRS should be considered more carefully in these situations. Bronchoscopic alternatives to the surgical approach have been recently proposed and some of them may play an important role in the future; in particular, the airway bypass and bronchoscopic lung volume reduction with one-way valves are certainly one step beyond on their way to clinical application. We hereby report the initial experimental and clinical experience with these new treatment options. # 2006 Published by Elsevier B.V. Keywords: Lung volume reduction; Emphysema; Bronchoscopy

1. Introduction Emphysema is a debilitating lung disease continuing to be a major source of morbidity and mortality in the developed countries. Estimates suggest that as many as two million people are affected in the United States; many of them develop severe dyspnoea and subsequent deterioration in quality of life [1—4]. Emphysema is characterized by permanent and anatomically irreversible enlargement of air spaces distal to the terminal bronchiole, accompanied by destruction of their walls, and without obvious fibrosis [5]. This definition is probably the only concept about emphysema that has not been modified over the last 50 years. In fact, the clinical approach along with the therapeutic policy have been progressively changed to reach the current state. Medical treatment is the mainstay of therapy and consists of smoking cessation, pulmonary rehabilitation, administration of bronchodilators and, when indicated, steroids and supplemental oxygen.

* Corresponding author. Tel.: +39 06 4461971; fax: +39 06 49970735. E-mail addresses: [email protected], [email protected] (F. Venuta). 1010-7940/$ — see front matter # 2006 Published by Elsevier B.V. doi:10.1016/j.ejcts.2005.12.009

From the functional point of view, a considerable degree of emphysema is suspected when the forced expiratory volume in 1 s (FEV1) is significantly decreased, the total lung capacity (TLC) and residual volume (RV) are increased and single breath carbon monoxide diffusion capacity (DLCO) is reduced. The regional severity of emphysema within each lung or between both lungs may significantly vary; heterogeneity refers to the regional variation of severity of emphysema throughout the parenchyma. Patients having ‘target areas’ of severe emphysema among areas of relatively mild or moderate disease are said to possess a high degree of heterogeneity. Heterogeneity may exist within the same lobe, between different lobes of the same lung or between the two lungs. When the emphysematous destruction is diffused throughout the lungs with all regions similarly affected, the disease is defined homogeneous. Heterogeneity can be assessed with chest radiographs, computed tomography and lung scans [6]. Major pathophysiological consequences of this disease can be attributed to a loss of elastic recoil resulting in static and dynamic hyperinflation. The loss of elasticity results in a progressive enlargement of the lung and thoracic diameters; the rib cage expands to an abnormal position and the diaphragm becomes flattened. This results in severely impaired respiratory mechanics with consequent dyspnoea;

282

F. Venuta et al. / European Journal of Cardio-thoracic Surgery 29 (2006) 281—287

the work of breathing is markedly increased and the amount of air moved in and out of the chest with each breath is quite limited. The main symptom for patients with severe emphysema is shortness of breath during minimal physical activity. Despite all the available therapies, the course of the disease is progressively disabling with a significant increase in morbidity and mortality. Over the past 50 years, many investigators have attempted to determine which factors influence survival of patients with COPD: when the FEV1 is lower than 30% of the predicted value, less than 50% of patients will survive for 3 years [7,8] notwithstanding optimal medical therapy; thus, medical treatment certainly shows some limitations in the most advanced phases of the disease. Various surgical procedures have been promoted in the past to relieve dyspnoea and improve quality of life in patients with advanced emphysema [9,10]; whilst early results were often encouraging, a sustained objective functional improvement was rarely achieved and most of those procedures were progressively abandoned. Bullectomy is the only operation that has stood the test of time. Lung transplantation and lung volume reduction surgery (LVRS) are now established treatment modalities in selected patients. Despite controversies, LVRS has been shown to be beneficial to selected patients with end-stage emphysema when medical therapy has failed [11,12]. This operation was rescued and popularized by Cooper et al. in 1995 [13] and progressively gained worldwide acceptance. The basic principle of this procedure is that removal of the most diseased parts of the hyperinflated lungs helps to remodel and restore the chest wall and diaphragmatic mechanics during respiration. There is no doubt that LVRS allows a significative functional improvement in a selected group of patients; however, it still carries a substantial morbidity, even if mortality is low at the centres with the larger experience [14]. Patients with a most advanced functional deterioration show a higher surgical mortality and less impressive functional results, suggesting that LVRS should be considered more carefully in these situations [15]. In particular, patients with very low FEV1 and either homogeneous emphysema or a very low DLCO are at high risk of death, and the most recently published data have indicated that patients with non-upper lobe disease have a higher operative mortality. Bronchoscopic alternatives to the surgical approach have been recently proposed and some of them may play an important role in the future; in particular, the airway bypass and bronchoscopic lung volume reduction (BLVR) with oneway valves are certainly one step beyond on their way to clinical application.

2. Airway bypass This endoscopic procedure is based on the concept of ‘collateral ventilation’, first described by Van Allen et al. in 1930 [16]. Collateral ventilation is defined as the ability of gas to move from one part of the lung to another through nonanatomical pathways. Originally, it was used the term ‘collateral respiration’ to explain how gases may enter one lobule from another without resorting to known anatomical pathways. Hogg et al. [17] demonstrated that resistance to

collateral airflow in post-mortem emphysematous human lungs was low in comparison to normal lungs, concluding that collateral channels may be important ventilatory pathways in emphysema. Terry et al. [18] studied collateral ventilation in normal and emphysematous subjects. In young normal persons they found that resistance to collateral ventilation is high at functional residual capacity and they concluded that there was a negligible role for collateral channels in the distribution of ventilation in these subjects. However, patients with emphysema had lower resistance through collateral channels than through the airways. Thus, collateral ventilation is present in normal lungs but it does not play an important role; in emphysematous lungs the destruction of alveolar septa creates a preferential route for collateral airflow. Gunnarsson et al. [19] looked in detail at patients with COPD undergoing general anaesthesia; they described significantly less atelectasis and shunt when compared to the population with normal lungs. Three levels of collateral ventilation have been described in human lungs. Kohn first described intra-alaveolar pores over a century ago [20]; in 1955, Lambert [21] described accessory bronchiolar—alveolar connections; interbronchial channels were described by Martin in dogs, and have been subsequently verified in humans [22]. Morrell et al. [23] discovered that segmental collateral ventilation occurred to a much greater extent in the emphysematous lung than in the normal lung. Utilizing careful dissection techniques and selective lobar intubation, Hogg et al. [17] noted complete upper/lower lobe fissures in only three out of eight normal lungs and one of eight emphysematous lungs, with substantial flow across the incomplete fissures. Rosenberg and Lyons [24] examined 13 isolated lungs from patients with various diseases, including one patient with emphysema and pneumonia with significant crosslobar flow; their microscopic analysis of the regions adjacent to the fissures where interlobar collateral flow had been seen demonstrated lobar/alveolar pores, potentially variants of the pores of Kohn. Such interlobar flow and communications were not observed in paediatric lungs. It has been speculated that pathologic collaterals may represent inflammatory or sheer force damage between airways and the parenchyma and serve to even out areas on inhomogeneity [23]. Macklem [25] suggested that creating extra-anatomic pathways through the chest wall, between the surface of the lung and the skin, might alleviate hyperinflation and improve respiratory mechanics; in fact, ‘bypassing’ the small obstructed airways should allow trapped gas to exit from the hyperinflated emphysematous lung. The extensive collateral ventilation present in emphysematous lungs can be demonstrated at the time of lung volume reduction surgery. The portion of the lung to be removed remains distended after suspension of ventilation to that lung. Compression of the lung will not significantly deflate the lobe because of the collapse of the small airways. However, a 1 mm puncture on the surface of the lung will lead to rapid collapse of the lobe because of the extensive collateral ventilation from other parts of the lobe to the lobule that has been punctured [26]. The procedure proposed by Macklem was certainly a great idea; however, it could create some problems of acceptance and management in the clinical setting.

F. Venuta et al. / European Journal of Cardio-thoracic Surgery 29 (2006) 281—287

The concept of bypassing the small obstructed airways was recently rescued and simplified by the group of the Washington University in St. Louis [26]. They proposed that the creation of artificial communications between lung parenchyma and segmental bronchi would facilitate lung deflation and improve expiratory airflow and respiratory mechanics. In fact, on inspiration the regular airways can open, allowing air passage through normal channels; on expiration, the new passageways provide escape pathways bypassing the obstructed small airways. This procedure should be particularly indicated for patients with a homogeneous distribution of the disease to maximize expiratory deflation. The airway bypass procedure has been initially performed by bronchoscopically puncturing the wall of segmental bronchi with a radiofrequency catheter and inserting a specially designed stent to keep open the internal bronchopulmonary communications. The first step to evaluate the potential for this procedure was performed in the laboratories of the Washington University School of Medicine in St. Louis [26]. A specially designed ventilation chamber was prepared to evaluate the improvement obtained by creating airway bypass in emphysematous lungs resected for lung transplantation. Twelve lungs were closed in the chamber and connected to a pneumotachygraph to measure the airflow. The baseline FEV1 was measured and then flows were measured again after creation of stented passages. As a result of this study, the FEV1 increased from an average of 245 ml at baseline to 447 ml after the creation of three stented passages in each lung and to 666 ml after six stented passages. The experimental procedure was repeated in normal lungs harvested but not used for lung transplantation: after three stented holes the FEV1 did not differ from baseline, confirming that the modifications in emphysematous lungs and probably the presence of collateral ventilation were the base of the modifications observed in the first part of the experiment. The improved flow rates observed in this simple ex vivo model with emphysematous lungs were encouraging and warranted further exploration. The second step has been designed to assess safety of the procedure and ability to avoid injury to the adjacent blood vessels. A specially designed Doppler probe (Bronchus Technologies, Inc., Mountain View, CA, USA) was used to map the extrabronchial vessel distribution [27]. This probe can be introduced through the operating channel of the flexible bronchoscope and used to scan from the inner surface of the bronchus the bronchial and pulmonary vessels located outside it. A preliminary safety study was performed in patients undergoing lobectomy for lung cancer and lung transplantation for emphysema. In this group of patients, after selecting the target site, the Doppler probe was withdrawn and a radiofrequency catheter was advanced to create a passage through the bronchial wall into the lung parenchyma. Twenty-nine passages were performed in the lobectomy patients with only two episodes of mild bleeding, and 18 passages in patients with emphysema undergoing lung transplantation. No major complications were observed. Further laboratory observations and preliminary clinical work (personal unpublished data) subsequently demonstrated that the new pathways progressively close within

283

2—3 weeks after the procedure, and that stents derived from intracoronary devices can prolong patency only for a limited period of time. The radiofrequency probe has the disadvantage of injuring adjacent tissue because of the radial spread of heat and of penetrating too deeply, with potential haemorrhage and pneumothorax. For this reason the technique was subsequently simplified [28]. Once the appropriate site within the airway was identified, the Doppler probe was exchanged for a 22-gauge transbronchial needle that was advanced through the bronchial wall to create a small passage into the lung parenchyma. Aspiration through the needle was performed as it was slowly withdrawn out of the bronchial wall. An angioplasty catheter with an expandable balloon diameter of 2.5 mm and a length of 30 mm was then inserted into the fenestration and dilated. A 3 mm long  3 mm wide balloon expandable stainless steel stent covered with a sleeve of silicone rubber was placed into the dilated passage. To avoid, or at least delay obstruction by granulation tissue, mitomycin C (concentration 1 mg/ml) was delivered over the stent. This is an anti-inflammatory and antifibrotic agent that has been reported to be useful in the treatment of airway stenosis [29]. Four episodes of minor and brief bleeding occurred during stent placement. These were treated with diluted topical epinephrine solution and resolved without incident. Also, one pneumothorax and one episode of leucopoenia developed. Control stents, without drug application, were all occluded at the first week bronchoscopic follow-up. In contrast, mitomycin C-treated stents had a prolongation of patency, and the duration of stent patency was also associated with the number of once-weekly topical mitomycin application, reaching 20 weeks for dogs treated for 9 weeks with topical application of the drug. A combined needle-and-balloon device has subsequently been developed to overcome the disadvantages encountered with the separate needle and balloon devices used in this study. To further improve patency avoiding multiple drug instillations within the airway a drug eluting stent has been proposed and experimented in an animal model. One hundred and seven controlled release Paclitaxel stents have been implanted in dogs and compared with 50 control stents with no impregnation; the follow-up at 12 weeks demonstrated that 65% of the Paclitaxel stents were patent while no control stent was patent [30]. The experimental studies previously reported [27,28] demonstrate that the creation of bronchial fenestration is feasible and safe in normal and severely emphysematous lungs. However, this information will certainly require pilot clinical studies and trials to be confirmed. The functional improvement probably can last only until the new passageways stay open; the use of anti-inflammatory, antifibrotic or antiblastic agents topically instilled or stent-eluted may significantly contribute to prolong patency; this will probably bring this procedure in the clinical arena after testing in multicentre trials which are not yet available in the international literature. However, based on the physiological principles on which the procedure is based (the need of a wide collateral ventilation), we can postulate that in the future the best indication for airway bypass should be homogeneous emphysema with chronic respiratory failure.

284

F. Venuta et al. / European Journal of Cardio-thoracic Surgery 29 (2006) 281—287

3. Bronchoscopic lung volume reduction with one-way valves The airway bypass is not the only endoscopic procedure proposed to improve symptoms and quality of life in patients with emphysema. Other procedures have been described both experimentally and in selected clinical settings with the use of occlusive stents, synthetic sealants and unidirectional valves [31—35]. These procedures were all designed to reduce hyperinflation and obtain atelectasis of the most destroyed functionless parts of the emphysematous lungs (heterogeneous emphysema). They have been evaluated to find safe alternatives to LVRS, especially for patients with the most advanced disease; this group of patients, as mentioned before, showed a higher surgical mortality suggesting that LVRS may not be suitable for all of them. It has been postulated that blocking an airway supplying the most over-inflated emphysematous parts of the lung could cause atelectasis of these regions and contribute to alleviate symptoms. This has been experimentally demonstrated by Ingenito et al. in 2001 [35]. They studied three groups of sheep with papaine-induced emphysema and compared the effectiveness of surgical lung volume reduction, bronchoscopic lung volume reduction performed by occluding lung segments with a synthetic sealant and a sham procedure that was a simple bronchoscopy. The results of this experimental work showed that with this model, bronchoscopic lung volume reduction could produce the same functional results as LVRS. Instead of sealants, other authors have used endobronchial devices working as one-way valves. These devices allow air to exit from the lung parenchyma but not to enter and should also allow a sufficient clearance of bronchial secretions. There are basically two devices under clinical evaluation: the Spiration umbrella and the Emphasys one-way valve (Fig. 1). These devices are placed in the segmental or subsegmental bronchi to obtain lobar exclusion. The goal of the procedure is deflation of the target area in patients with heterogeneous emphysema, mimicking surgical lung volume reduction. The Umbrella Implantable Intrabronchial Valve (IBVIM) (Spiration, Inc., Redmond, WA, USA) is a one-way valve designed for placement in the bronchi via flexible bronchoscopy. The valve is made of nitinol (nickel—titanium) framework with five anchors that seat distally, engaging the airway without perforation, and providing stability. The proximal portion is made up of six support stents that expand radially. These struts are covered by a synthetic polymer, forming an umbrella shape that conforms to the airway wall. The flexible membrane and struts allow conformation to the airways to improve sealing with minimal pressure on the mucosa. The valve is designed to limit airflow distally, but the membrane and support stents allow mucociliary clearance, air and mucous to flow proximally past the valve in order to allow decompression of collateral ventilation and to reduce the hazards of mucous impaction and obstruction pneumonia. The valve design includes a proximal centre rod that allows repositioning or removal if required. This device is currently under evaluation in a North American multicentre trial, but yet no clinical data are available in the literature.

Fig. 1. First-generation endobronchial valve (EBV) designed to both control and redirect airflow.

The Emphasys endobronchial valve (EBV) (Emphasys, Redwood City, CA, USA) is an endobronchial prosthesis designed to control and redirect airflow. It is a one-way, polymer, duckbill valve that is mounted inside a stainless steel cylinder which is attached to a nickel—titanium (nitinol) self-expanding retainer. It prevents air entering the target lung but allows air and mucous to exit. The EBV is provided in three sizes, each intended for a different range of target bronchial lumen diameters: 4.0—5.5 mm (inner—outer diameter), 5.0—7.0 mm and 6.5—8.5 mm; the valve is 10 mm long. These valves are usually placed in the operating room, with the patient intubated under intravenous anaesthesia (Propofol infusion) and spontaneous assisted ventilation. After the patient is intubated, the flexible bronchoscope is advanced into the endotracheal tube and the target bronchia are chosen. They correspond to the most hyperinflated part of the lung affected by heterogeneous emphysema. The valves are usually placed in the segmental bronchi, but subsegmental orifices can also be stented to obtain complete lobar occlusion. A guide wire is inserted through the operating channel of the bronchoscope and left in place while the bronchoscope is withdrawn; a flexible delivery catheter is guided to the target bronchus by the guide wire. Local anaesthesia is generously administered before inserting the valves to prevent coughing. The fiberoptic bronchoscope is reinserted after the advancement of the delivery catheter; the tip of the delivery catheter containing the valve is pushed with a gentle rotation in the selected bronchial orifice, and the valve is delivered. Fiberoptic bronchoscopy performed

F. Venuta et al. / European Journal of Cardio-thoracic Surgery 29 (2006) 281—287

Fig. 2. Zephyr new-generation endobronchial valve.

after removal of the delivery catheter confirms the correct placement of the valve. Gentle suction through the bronchoscope ensures the correct opening of the valve to allow deflation of the lung and clearance of secretions. The valves can be removed easily if placement is not satisfactory using a rat-tooth grasper through the working channel of the bronchoscope. The EBV can be clearly seen at chest X-ray. The first generation of EBV have been extensively employed in several prospective, non-randomized, single centre longitudinal pilot studies to evaluate safety and short-term efficacy with promising results in a selected group of patients with heterogeneous end-stage emphysema (Table 1). A new generation of EBV is ready and is currently under evaluation in a multicentre prospective trial: the Zephyr endobronchial valve (Fig. 2). This new valve is a device incorporating a one-way valve supported by a stent-like selfexpanding retainer that secures the EBV in place during all physiological conditions, including coughing. The retainer is a self-expanding tubular mesh structure that is cut from nitinol (nickel—titanium) superelastic alloy tubing and processed to its final expanded dimensions. It is covered with silicone in order to create a seal between the implant and the bronchial

285

wall; the silicone membrane is formed integrally with the struts of the self-expanding retainer component. When the EBV is delivered into the target bronchus, the retainer expands to contact the walls of the lumen. Also, this valve has been designed to allow air to be vented from the isolated lung segment while preventing air from refilling the isolated lung area during inspiration: it vents during expiration and closes when flow is reversed during inhalation. The Zephyr EBV is provided in two sizes: the EBV 4.0, designed for bronchial lumens with diameters of 4.0—7.0 mm, and the Zephyr EBV 5.5, designed for bronchial lumens with diameters of 5.5—8.5 mm. The previous version of the device, as mentioned before, was provided in three different sizes for the same overall treatable lumen diameter range of 4.0—8.5 mm. The Zephyr valve can be easily seen at chest X-ray (Fig. 3). The performance of the valve is different according to the type of valve (first generation vs second generation of EBV), and to the size of the device itself. In other words, the cracking pressure, and thus flow resistance, was higher for the EBV of the first generation when compared to the Zephyr valve. On the other side, within the two different models of valves, flow resistance is lower for valves of the larger diameter. In other words, air expiratory flow is much higher for large valves of the second generation. A flexible delivery catheter is used also to place this second-generation EBV valve to the targeted bronchial lumen. The catheter is constructed of a flexible stainless steel and polymer composite shaft. It has an actuation handle on the proximal hand and a retractable polymer housing for containing the compressed Zephyr EBV on the distal end. A bronchial diameter measurement gauge made of flexible polymer is attached to the proximal end of the distal housing.

Table 1 Worldwide experience with bronchoscopic lung volume reduction Authors Yim et al. [39]

Toma et al. [37]

Venuta et al. [40]

Snell et al. [36]

No. pts Valves/pts

21 4

8 3

13 4

10 6.7

FEV1 pre (l) FEV1 1 month (l) p value

0.73 0.84 ns

0.79 1.06 0.028

0.75 1.1 0.01

0.72 0.74 ns

RV pre (l) RV 1 month (l) p value

4.98 4.85 ns

6.82 NA NA

5.3 4.8 0.01

4.2 4.2 ns

TLC pre (l) TLC 1 month (l) p value

7.03 6.5 ns

NA NA NA

7.9 7.1 0.04

6.81 6.72 ns

DLCO pre DLCO 1 month p value

8.00 9.18 ns

3.05 3.92 0.01

33% 45% 0.01

7.47 8.26 0.04

FVC pre (l) FVC 1 month (l) p value

1.94 2.12 ns

NA NA NA

1.86 2.3 ns

2.33 2.34 ns

6MWT pre (m) 6MWT post (m) p value

251.6 306.3 0.01

NA NA ns

223 375 0.005

340 346 ns

FEV1: forced expiratory volume in 1 s; RV: residual volume; TLC: total lung capacity; DLCO: carbon monoxide diffusion in the lung; FVC: forced vital capacity; 6MWT: 6-min walking test. NA: not available; ns: not statistically significative; No. pts: number of patients; valves/pts: mean number of valves per patients.

286

F. Venuta et al. / European Journal of Cardio-thoracic Surgery 29 (2006) 281—287

Fig. 3. Chest X-ray showing the Zephyr EBV in place in the right upper lobe.

This measurement gauge allows the user to visually (bronchoscopically) measure the diameter of the bronchial lumen prior to device deployment to verify that the size gauge of the valve is appropriate for the target lumen. The measurement gauge consists of two sets of flexible gauges. On the delivery catheter for the Zephyr EBV 4.0, the larger gauge spans a 7 mm diameter and the smaller gauge spans a 4 mm diameter, indicating the maximum and minimum treatable bronchial diameters, respectively, for this size of device. On the delivery catheter for the Zephyr EBV 5.5, the two gauges are sized to span diameters of 8.5 and 5.5 mm. The EBV is compressed into the retractable distal housing by the operator using a specifically designed EBV loader system. The loaded catheter is advanced to the target location and the valve is deployed by actuating the deployment handle, which retracts the distal housing and releases the EBV. The delivery catheter is designed to be inserted through a 2.8 mm diameter working channel of a flexible bronchoscope. Thus, this new generation of valves can be placed under local anaesthesia since the deployment manoeuvre is much simpler. After a series of animal experiments, more than 100 patients have been treated so far in pilot studies performed at several centres worldwide, with selection criteria similar to those for LVRS (Table 1). The inclusion criteria in these pilot studies were similar to those for surgical lung volume reduction: heterogeneous emphysema, FEV1 less than 30%, DLCO higher than 20%, no pulmonary hypertension, no hypercapnia. Heterogeneous emphysema was chosen since this type of disease shows less collateral ventilation than the homogeneous one; thus, it should be easier to achieve volume reduction and even atelectasis. The first 10 patients treated with a first-generation type of EBV were reported by Snell et al. [36]. They demonstrated that that type of bronchoscopic prosthesis could be safely and reliably placed into the human bronchi; however, symptomatic improvement

was observed only in four patients, with no major change in radiographic findings, lung function, or 6-min walk distance at 1 month, although gas transfer improved from 7.47  2.0 ml/(min mmHg) to 8.26  2.6 ml/(min mmHg) and nuclear upper lobe perfusion fell from 32  10% to 27  9%. Toma et al. [37] subsequently reported on eight patients undergoing unilateral volume reduction with a second generation of EBV. Five patients had emphysema judged too severe for volume reduction surgery and three refused the operation. After valve placement there was a 34% increase in FEV1 and 29% difference in DLCO; CTscans showed a substantial reduction in regional volume in four of the eight patients. The same group also reported that in a subgroup of patients in whom invasive measurements were performed, improvement in exercise capacity was associated with a reduction of lung compliance and isotime oesophageal pressure—time product [38]. Other two series of patients treated with EBV have been reported [39,40] with encouraging functional results. Along with the functional improvement (Table 1) there was also a subjective improvement benefit reported by most of the patients, even if a dyspnoea score was not available in all the series. Overall, all patients tolerated the treatment well. Between three and five valves were placed in the target lobe and most of them received unilateral treatment. It has been demonstrated that the procedure can be safely performed with encouraging shortterm results. Up to now the data available for this technique are still extremely limited and the follow-up is too short to be compared with other therapies. In our experience [40] with the first generation of EBV valves, we have observed one contralateral and two bilateral pneumothorax out of 17 treatments (two-staged bilateral); this complication has been experienced also by other authors [39]. However, with the second generation of EBV valves (five patients, unpublished data) we have not observed this complication any more. Three of our patients showed granulation tissue obstructing one or more of the valves; this complication occurred with the first-generation valves 6 months after placement. One patient had pneumonia in the non-treated lobe; this complication was easily managed with the administration of broad-spectrum antibiotics. The functional improvement was statistically significant; in particular FEV1 markedly improved and the residual volume decreased: at 3 months more than 50% of the patients still show at least a 30% functional improvement; most of them required less supplemental oxygen and 7 out of 15 were able to stop it. We were not able to observe a complete atelectasis of the lobe where valves where implanted, even if it has been described by other authors; however, in most of the patients, the shape of the chest was redesigned. Exercise tolerance was also improved and remained stable after 3 months of follow up. Contralateral BLVR could be attempted to obtain a second functional improvement when pulmonary function tests start to deteriorate again, as it is done for LVRS [41]. A contralateral BLVR was performed in two of our patients, but neither was required for functional reasons: both patients had pneumothorax on the contralateral side and valves were placed with the aim of stopping the air leak; this result was easily obtained, along with further functional improvement. With more experience, simultaneous bilateral insertion of the valves could be attempted. One of the advantages of the

F. Venuta et al. / European Journal of Cardio-thoracic Surgery 29 (2006) 281—287

endobronchial lung volume reduction is that the procedure can be reversed and other treatments tried if necessary. The short-term results with BLVR are encouraging, but long-term follow-up is certainly required, as well as multicentre trials, to evaluate the therapeutic potential of this procedure. Even if it is certainly too early to speculate about the potential clinical implications of these new techniques, we can postulate that airway bypass could be indicated for patients with homogeneous emphysema while BLVR with one-way valves should be indicated for patients with an heterogeneous distribution of the disease. However, it could be more likely that in the future both systems could be employed in each patients to optimize results.

References [1] Feinleib M, Rosenberg H, Collins J, Delozier JE, Pokras R, Chevarley FM. Trends in COPD morbidity and mortality in the United States. Am Rev Respir Dis 1989;140(Suppl.):S9—18. [2] Guyatt G. Measuring health status in chronic airflow limitation. Eur Respir J 1988;1:560—4. [3] Higgins M, Keller J. Trends in COPD morbidity and mortality in Tecumseh, Michigan. Am Rev Respir Dis 1989;140(Suppl.):S42—8. [4] McSweeney A, Grant I, Heaton R, Adams KM, Timmes RM. Life quality of patients with chronic obstructive pulmonary disease. Arch Intern Med 1982;142:473—8. [5] Russi EW, De Wever W, Decramer M. Surgery for emphysema: medical aspects. In: Verleden GM, Van Raemdonck D, Leryt T, Demedts M, editors. Surgery for non neoplastic disorders of the chest a clinical update European Respiratory Society monograph 29, vol. 9. 2004. p. 129—38. [6] Stone RM, Gierada DS. Radiology of pulmonary emphysema and lung volume reduction surgery. Semin Thorac Cardiovasc Surg 1996;8:61—82. [7] Anthonisen NR, Wright EC, Hodgkin JE, IPPB Trial Group. Prognosis in chronic obstructive pulmonary disease. Am Rev Respir Dis 1986;133: 14—20. [8] Ries AL, Kaplan RM, Limberg TM, Prewitt L. Effects of pulmonary rehabilitation on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann Intern Med 1995;122: 823—32. [9] Cooper JD. The history of surgical procedures for emphysema. Ann Thorac Surg 1997;63:312—9. [10] Deslauriers J. History of surgery for emphysema. Semin Thorac Cardiovasc Surg 1996;8:43—51. [11] Yusen RD, Lefrak SS, Gierada DS, Davis GE, Meyers BF, Patterson GA, Cooper JD. A prospective evaluation of lung volume reduction surgery in 200 consecutive patients. Chest 2003;123:1026—37. [12] Ciccone AM, Meyers BF, Guthrie TJ, Davis GE, Yunes RD, Lefrak SS, Patterson GA, Cooper JD. Long term outcome of bilateral lung volume reduction in 250 consecutive patients with emphysema. J Thorac Cardiovasc Surg 2003;125:513—25. [13] Cooper JD, Trulock EP, Triantafillou AN, Patterson GA, Pohl MS, Deloney PA, Sundaresan RS, Roper CL. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995;109:106—19. [14] Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, Winmann G, Wood DE, National Emphysema Treatment Trial Research Group. A randomized trial comparing lung volume reduction surgery with medical therapy for emphysema. N Engl J Med 2003;348:2059—73. [15] National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung volume reduction surgery. N Engl J Med 2001; 345:1075—83. [16] Van Allen CM, Lindskog GE, Richter HT. Gaseous interchange between adjacent lung lobules. Yale J Biol Med 1930;2:297—300.

287

[17] Hogg JC, Macklem PT, Thurlbeck WM. The resistance of collateral channels in excised human lungs. J Clin Invest 1969;48:421—31. [18] Terry PB, Traystman RJ, Newball HH, Batra G, Menkes HA. Collateral ventilation in man. N Engl J Med 1978;298:10—5. [19] Gunnarsson L, Tokics L, Lundquist H, Brismar B, Strandberg A, Berg B, Hedenstierna G. Chronic obstructive pulmonary disease and anaesthesia: formation of atelectasis and gas exchange impairment. Eur Respir J 1991;4:1106—16. [20] Cordingley JL. Pores of Kohn. Thorax 1972; 27:433—41. [21] Lambert MW. Accessory bronchoalveolar communications. J Pathol Bacteriol 1955;70:311—4. [22] Mitzner W. Collateral ventilation. In: Crystal RG, editor. The lung: scientific foundations. New York, NY: Raven Press; 1991. p. 1053—63. [23] Morrell NW, Wignall BK, Biggs T, Seed WA. Collateral ventilation and gas exchange in emphysema. Am J Respir Crit Care Med 1994;150:635—41. [24] Rosenberg DF, Lyons HA. Collateral ventilation in excised human lungs. Respiration 1979;37:125—34. [25] Macklem PT. Collateral ventilation. N Engl J Med 1978;298:49—50. [26] Lausberg HF, Chino K, Patterson GA, Meyers BM, Toeniskoetter PD, Cooper JD. Bronchial fenestration improves expiratory flow in emphysematous human lungs. Ann Thorac Surg 2003;75:393—8. [27] Rendina EA, De Giacomo T, Venuta F, Coloni GF, Meyers BF, Patterson GA, Cooper JD. Feasibility and safety of the airway bypass procedure for patients with emphysema. J Thorac Cardiovasc Surg 2003;125:1294—9. [28] Choong CK, Haddad FJ, Gee EJ, Cooper JD. Feasibility and safety of airway bypass stent placement and influence of topical mitomycin C on stent patency. J Thorac Cardiovasc Surg 2005;129:632—8. [29] Correa AJ, Reinisch L, Sanders DL, Huang S, Deriso W, Dunacavage JA, Garrett CG. Inhibition of subglottic stenosis with mitomycin C in a canine model. Ann Otol Rhinol Laryngol 1999;108:1053—60. [30] Choong CK, Phan L, Massetti P, Haddad FJ, Roschak EJ, Cooper JD. Patency of airway bypass stents is prolonged with use of drug eluting stents. American Association for Thoracic Surgery 85th Annual Meeting, April 10— 13, 2005, San Francisco, CA. Paper F20, p. 160. [31] Snell GI, Smith GA, Silovers AJ. Bronchoscopic volume reduction: a pilot study. ACCP Meeting 2001; Paper 25. [32] Ingenito EP, Berger RJ, Henderson AC, Reilly JJ, Tsai L, Hoffman A. Bronchoscopic volume reduction using tissue engineering principles. Am J Respir Crit Care Med 2003;167:771—8. [33] Sabanhatan S, Richardson J, Pieri-Davies S. Bronchoscopic lung volume reduction. J Cardiovasc Surg 2003;44:101—8. [34] Fann JI, Berry GJ, Burden TA. Bronchoscopic approach to lung volume reduction using a valve device. J Bronchol 2003;10:253—9. [35] Ingenito EP, Reilly JJ, Mentzer SJ, Swanson SJ, Vin R, Keuhn H, Berger RL, Hoffman A. Bronchoscopic volume reduction: a safe and effective alternative to surgical therapy for emphysema. Am J Respir Crit Care Med 2001;164:295—301. [36] Snell GI, Halsworth L, Borrill ZL, Thomson KR, Kalff V, Smith JA, Williams TJ. The potential for bronchoscopic lung volume reduction using bronchial prosthesis: a pilot study. Chest 2001;124:1073—80. [37] Toma TP, Hopkinson NS, Hiller J, Hansell DM, Morgan C, Goldstraw PG, POlkey MI, Geddes DM. Bronchoscopic volume reduction with valve implants in patients with severe emphysema. Lancet 2003;361:931—3. [38] Hopkinsons NS, Toma TP, Hansell DM, Goldstraw P, Maxham J, Geddes DM, Polkey MI. Effect of bronchoscopic lung volume reduction on dynamic hyperinflation and exercise in emphysema. Am J Crit Care Med 2005; 171:423—4. [39] Yim AP, Hwong TM, Lee TW, Li WW, Lam S, Yeung TK, Hui DS, Ko FW, Sihoe AD, Thung KH, Arifi AA. Early results of endoscopic lung volume reduction for emphysema. J Thorac Cardiovasc Surg 2004;127:1564—73. [40] Venuta F, De Giacomo T, Rendina EA, Ciccone AM, Diso D, Perrone A, Parola D, Anile M, Coloni GF. Bronchoscopic lung volume reduction with one way valves in patients with emphysema. Ann Thorac Surg 2005; 79:411—7. [41] Soon SY, Saidi G, Ong ML, Syed A, Codispoti M, Walker WS. Sequential VATS lung volume reduction surgery: prolongation of benefits derived after the initial operation. Eur J Cardiothorac Surg 2003;24:149—53.