Emphysema is a debilitating lung disease with a significant

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1 Bronchoscopic Lung-Volume Reduction With One-Way Valves in Patients With Heterogenous Emphysema Federico Venuta, MD, Tiziano de Giacomo, MD, Erino A. Rendina, MD, Anna Maria Ciccone, MD, Daniele Diso, MD, Alessandro Perrone, MD, Daniela Parola, MD, Marco Anile, MD, and Giorgio F. Coloni, MD Departments of Thoracic Surgery and Pulmonology, University of Rome La Sapienza, Rome, Italy GENERAL THORACIC Background. We evaluated the feasibility and shortterm functional outcome after bronchoscopic lung-volume reduction performed with one-way valves in patients with severe heterogeneous emphysema. Methods. Thirteen patients entered this pilot study. Endobronchial one-way valves were placed in the segmental bronchi supplying the most hyperinflated parts of the emphysematous lungs to allow lung deflation, reduce lung volume, and alleviate symptoms. The valves and delivery catheter were inserted under intravenous anesthesia and spontaneous assisted ventilation, with visual control through a flexible bronchoscope. We performed unilateral bronchoscopic lung-volume reduction in 11 patients and staged bilateral procedures in 2. Preoperative median forced expiratory volume in 1 second (FEV 1 ) was 0.75 L/s (22%), residual volume was 5.3 L (233%), total lung capacity, 7.9 L (123%); intrathoracic gas volume, 6.5 L (176%); and 6-minute walk test, 223 meters. All patients required supplemental oxygen at rest (1.4 L/min). The median preoperative Medical Research Council (MRC) scale dyspnea score was 4. Results. Six complications occurred in 3 patients: two bilateral and one contralateral pneumothorax, one pneumonia, and two episodes of bronchospasm. Functional results at 1 and 3 months showed a significant improvement in FEV 1, residual volume, and 6-minute walk test; 43% of the patients were able to completely stop supplemental oxygen. The posttreatment MRC median dyspnea score at 1 and 3 months was 2. Bronchoscopic follow up at 1 and 3 months showed that the valves were correctly in place with no granulation. Conclusions. Bronchoscopic lung-volume reduction with one-way valves can be performed with acceptable short-term safety and worthwhile functional benefits. (Ann Thorac Surg 2005;79:411 7) 2005 by The Society of Thoracic Surgeons Emphysema is a debilitating lung disease with a significant morbidity and mortality that affects 2 million people in the United States[1 3]. The medical treatment currently available clearly shows some limitations in the most advanced phases of the disease. For this reason, a number of surgical procedures are currently performed to improve quality of life and survival. According to the characteristics of the disease and the clinical status of the patients they include bullectomy [4], lung transplantation [5], and more recently, surgical lung-volume reduction (LVRS) [6, 7]. 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 centers with the larger experience [8]. 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 [9]. Bronchoscopic alternatives to the surgical approach Accepted for publication July 19, Address reprint requests to Dr Venuta, University of Rome La Sapienza, Department of Thoracic Surgery, Policlinico Umberto I, V.le del Policlinico, Rome, Italy; sofed@libero.it. have been recently proposed [10 12]; in particular, bronchoscopic lung-volume reduction (BLVR) with one-way valves has been attempted in the experimental laboratory [13] and in selected clinical settings [14, 15]. The one-way valve allows air to be vented from the isolated lung segment during normal expiration and prevents air from refilling the lung during inspiration. It has been postulated that the placement of these valves in the segmental bronchi could functionally isolate the airway that supplies the most hyperinflated parts of the emphysematous lungs, favoring deflation and even atelectasis, and thus mimicking LVRS in its contribution to alleviate symptoms. We report our initial clinical experience with this newly developed endoscopic procedure. Material and Methods We conducted a prospective, nonrandomized, singlecenter longitudinal study to evaluate the safety and short-term efficacy of BLVR performed by placing oneway endobronchial valves (Emphasys, Redwood City, CA) in the bronchi supplying the most hyperinflated parts of the emphysematous lungs. Thirteen patients ( by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 GENERAL THORACIC 412 VENUTA ET AL Ann Thorac Surg LUNG VOLUME REDUCTION 2005;79:411 7 Table 1. Patient Criteria for the Bronchoscopic Lung- Volume-Reduction Study Inclusion criteria Heterogeneous emphysema FEV 1 35% RV 180% Age between 35 and 75 years Exclusion criteria Homogeneous emphysema Currently smoking Presence of isolated bulla Paco 2 50 mm Hg Dlco 20% Productive cough Small airway disease Dlco carbon monxide diffusion in the lung; FEV 1 forced expiratory volume in 1 second; Paco 2 partial arterial pressure of carbon dioxide; RV residual volume. men, 1 woman; median age, 56 years; range, 32 to 71) entered this pilot study during a 14-month period. Patient Selection The protocol was approved by the ethical committee of the University of Rome La Sapienza. Most of the patients were borderline candidates for LVRS. All patients knew of the surgical LVR procedure and understood it, or it was explained to them. Bronchial LVR was offered to them as a new investigational procedure that possibly was an alternative to LVRS. They understood that LVRS could remain an option, if indicated, should the bronchoscopic procedure fail. All patients that were given a choice of therapy did not decline this procedure when it was offered, although it was stressed that it was experimental. Four patients formally refused any surgical approach (either LVRS or transplantation). Formal informed consent was obtained from each patient. We performed unilateral BLVR in 11 and staged bilateral BLVR in 2 (15 treatments). The inclusion and exclusion criteria are listed in Table 1. Critical selection criteria were marked hyperinflation and regional variations in the distribution of emphysema to provide target areas of useless lung ( surgical heterogeneous emphysema) to be excluded from ventilation with one-way valves. Almost all patients had one or more lobes clearly more compromised than the rest of the lung, which is why complete lobar occlusion was undertaken in all of the patients. In 2 patients, a small area of the posterior segment of the right upper lobe was less destroyed than the rest of the lobe, but it was occluded to prevent collateral ventilation refilling of the surrounding areas. All patients received optimal medical treatment at the time of inclusion and no changes were made in their medications during the study period. They had been under long-term rehabilitation before the procedure, but a specific program was not designed for this study. All patients required supplemental oxygen. The preoperative functional variables of the patients enrolled in this study are reported in Table 2. The stratification of patients according to forced expiratory volume in 1 second (FEV 1 ) is reported in Figure 1. The on-site evaluation process included a physical examination, pulmonary function tests performed with body plethysmography, carbon monoxide diffusion (Dlco) measurement and reversibility test, arterial blood gas analysis, exercise tolerance measured with the 6-minute walk test (6MWT), chest roentgenogram, computed tomography scan, perfusion lung scan, and transthoracic echocardiogram. The degree of dyspnea was Table 2. Preoperative Functional Variables of Study Patients Preoperative h 1 Month 3 Months p Value FEV 1 (L/sec) 0.75 ( ) 0.95 ( ) 1.1 ( ) 1 ( ) 0.01 FEV 1 (%) 22 (15 52) 33 (17 68) 30 (18 63) 29 (18 58) 0.01 RV (L) 5.3 ( ) 4.5 ( ) 4.8 ( ) 4.5 ( ) 0.01 RV (%) 233 ( ) 196 ( ) 207 ( ) 207 ( ) 0.01 ITGV (L) 6.5 (4 8.1) 5 (3 6.6) 5.6 ( ) 5.5 ( ) ITGV (%) 176 ( ) 146 ( ) 159 ( ) 153 ( ) TLC (L) 7.9 ( ) 7 ( ) 7.1 ( ) 7 (5 8.7) 0.04 TLC (%) 123 (86 134) 106 (87 138) 109 (87 133) 110 (88 129) 0.04 FVC (L) 1.86 (1.2 3) 1.8 ( ) 2.3 ( ) 2.1 ( ) 1 FVC (%) 47 (35 63) 51 (42 73) 57 (41 82) 57 (34 66) 1 Dlco (%) 33 (27 76) 26 (12 49) 45 (21 47) 50 (30 89) 0.01 Suppl. O 2 (L/m) 1.4 (0 3) 0 (0 3) 0 (0 3) 0 (0 3) PaO 2 (mm Hg) 77 (55 100) 76 (62 89) 71 (58 102) 74 (56 136) 0.57 Paco 2 (mm Hg) 43 (27 46) 38 (30 46) 40 (34 50) 40 (35 48) MWT (m) 223 ( ) ( ) 410 ( ) MRC Scale 4 (3 5) 3.5 (1 5) 2 (1 4) 2 (1 4) Dlco carbon monxide diffusion in the lung; FEV 1 forced expiratory volume in 1 second; FVC forced vital capacity; ITGV intrathoracic gas volume; MRC medical research council; Paco 2 partial arterial pressure of carbon dioxide; Pao 2 partial arterial pressure of oxygen; RV residual volume; 6MWT (m) 6-minute walk test (meters); TLC total lung capacity.

3 Ann Thorac Surg VENUTA ET AL 2005;79:411 7 LUNG VOLUME REDUCTION 413 GENERAL THORACIC Fig 1. Stratification of patients according to forced expiratory volume in 1 second (FEV 1 ). A measured by the Medical Research Council (MRC) dyspnea grading system. Arterial blood gas analysis and chest roentgenogram were performed again 24 hours after the procedure, and after 1 and 3 months; spirometry was performed 24 to 72 hours after the procedure and repeated after 1 and 3 months. The MRC score was also recorded at these time points. Fiberoptic bronchoscopy was repeated after 1 and 3 months. The Emphasys endobronchial valve (EBV) is an endobronchial prosthesis designed to both control and redirect airflow. The EBV is a one-way, polymer, duckbill valve that is mounted inside a stainless steel cylinder which is attached to a nickel-titanium (nitilol) selfexpanding retainer (Fig 2A). 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 to 5.5 mm (inner outer diameter), 5.0 to 7.0 mm, and 6.5 to 8.5 mm; the valve is 10 mm long. All the procedures were performed in the operating room with the patient intubated (tracheal tube size 8 or 9) under intravenous anesthesia (propofol infusion) and spontaneous assisted ventilation. Local anesthesia (lydocaine 2%) was generously administered before inserting the valves to prevent coughing. Operative Technique for Valve Placement After the patient is intubated, the flexible bronchoscope is advanced into the endotracheal tube and the target bronchi are chosen. The valves are usually placed in the segmental bronchi, but subsegmental orifices can also be stented to obtain complete lobar occlusion. A guidewire is inserted through the operating channel of the bronchoscope and left in place while the bronchoscope is withdrawn; a flexible delivery catheter (Fig 2B) is guided to the targeted bronchus by the guidewire. 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 after removal of the delivery catheter confirms the correct placement of B Fig 2. (A) One-way valves specifically designed for bronchoscopic lung-volume reduction. (B) Newly designed delivery catheter for one-way valve deployment. the valve. Gentle suction through the bronchoscope ensures the correct opening of the valve to allow deflation of the lung and clearance of secretions. No fluoroscopy is required. The valves can be removed easily if placement is not satisfactory using a rat-tooth grasper through the working channel of the bronchoscope. Statistical Analysis In view of the limited number of observations, all descriptive statistics were expressed as median and range. The Wilcoxon signed rank test was used to assess the significance of differences between the medians of the variables measured at the different time points during follow-up. A p value of less than 0.05 was considered to indicate statistical significance. Results Fifty-nine valves were placed (median 4 per patient; range 2 to 6); the devices were placed in the right upper lobe in 6 treatments (40%), in the right upper and middle lobe in 1 (7%), in the left upper lobe in 3 (20%), and in the right and left lower lobes in 3 (20%) and 2 (13%) cases, respectively. The median operative time was 45 minutes (range 20 to 95 minutes). No intraoperative complications were observed. All patients were extubated immediately after the procedure and returned to the ward. The median post-

4 GENERAL THORACIC 414 VENUTA ET AL Ann Thorac Surg LUNG VOLUME REDUCTION 2005;79:411 7 operative stay was 6 days (range 2 to 110). No deaths occurred. We observed 6 complications in 3 patients (23% of the patients, 20% of the treatments; 0.46 complications per patient). One contralateral pneumothorax developed 15 days postprocedure while the patient was at home. Two bilateral simultaneous pneumothoraces occurred 2 and 7 days postprocedure, one of which occurred during spirometry. This patient was intubated, admitted to the intensive care unit, and required prolonged hospitalization. Both patients with bilateral pneumothorax had diffuse bronchospasm that required the intravenous infusion of bronchodilators immediately after the procedure. One patient had pneumonia in the lobe adjacent to that where valves were inserted (valves were in the right upper and middle lobe and pneumonia was in the right inferior lobe). The 3-month functional evaluation was available in all but 2 patients (for logistic reasons). No significant modification was noted of the functional variables measured 24 to 48 hours after the procedure. Functional results at 1 month and 3 months showed a significant improvement in terms of FEV 1 and a decrease of residual volume (Table 2). Total lung capacity and intrathoracic gas volume decreased, and the 6MWT was significantly improved as well as Dlco. Overall, all the patients showed an improvement of the MRC dyspnea score at 30 days and 3 months, indicating a significant reduction in symptoms. Most of the patients (67%) required less supplemental oxygen and 6 (46%) were able to stop it. The partial arterial pressures of oxygen and carbon dioxide remained stable, although these values were obtained with less supplemental oxygen. The 2 patients that showed bilateral pneumothorax improved their FEV 1 from 0.6 L/s (22%) to 1.4 L/s (44%) and from 0.7 L/s (29%) to 1.2 L/s (45%). At 3 months, 3 patients showed an FEV 1 improvement of 50% or more, 3 were at 30% or more, one was 20% or more, 2 were at 10% or more, and 2 had spirometric values similar to preoperative measurements No granulation tissue was present at fiberoptic bronchoscopy performed after 1 and 3 months (Fig 3). Chest roentgenograms confirmed that all the valves were correctly in place (Fig 4). Fig 3. Endoscopic view of the one-way endobronchial valve. Surgery may not be required in the future to perform lung volume-reduction, because similar results could be achieved with deflation and atelectasis of the target areas obtained with bronchoscopic procedures. Some new options have been recently described [10 15, 19, 20] and they could play an important role in the future. The group at the Washington University School of Medicine in St. Louis [10] recently proposed that the creation of artificial communications between the lung parenchyma and segmental bronchi would facilitate lung deflation and improve expiratory air flow and respiratory mechanics. This can be safely achieved bronchoscopically by puncturing the wall of segmental bronchi and inserting a stent to create internal bronchopulmonary communications. This procedure would be ideal for patients with homogeneous emphysema, in which collateral ventilation allows a preferential route for airflow with a more uniform expiratory deflation of the lung. Comment Surgical lung-volume reduction (LVRS) can now be considered an effective palliation for a selected group of patients with advanced emphysema [6, 7]. It provides improved pulmonary function, quality of life, and exercise tolerance [16, 17] with an accepted mortality of 5% to 10% [18]. Morbidity has still an impact, with a significant percentage of patients showing prolonged air leaks [16, 18]. LVRS is not always indicated, however. In fact, patients with the most advanced disease show a higher mortality and achieve less favorable results, suggesting caution in patients with low FEV 1 and either homogeneous emphysema or a very low Dlco [9]. Lower-lobe emphysema is predictive of a less favorable functional improvement [8]. Fig 4. Chest roentgenogram shows the one-way endobronchial valves placed in the segmental orifices of the right upper lobe.

5 Ann Thorac Surg VENUTA ET AL 2005;79:411 7 LUNG VOLUME REDUCTION Fig 5. Chest roentgenograms of a patient that underwent bilateral, staged bronchoscopic lung-volume reduction (A) before bilateral treatment and (B) after bilateral treatment. 415 Patients with heterogeneous emphysema may not be suitable for this procedure. For this specific subset of patients, BLVR with one-way valves could represent a useful option [14, 15, 20]. This procedure allows deflation of the target areas, thus reducing the volume of the lung and improving mechanics. We did not, however, observe the complete collapse of the target lobe in our early experience, probably because of the presence of a certain degree of interlobar collateral ventilation that allows airflow between lobes when fissures are incomplete. However, the shape of the chest was redesigned after the procedure (Fig 5) in most of the patients. A few complications have been observed, of which bilateral tension pneumothorax was certainly the most serious. Ipsilateral pneumothorax was probably caused by a tear in the remodeling lung owing to acute volume loss secondary to valve placement. Concomitant pleural adhesions were always visible after the onset of pneumothorax and probably contributed to limit the sliding movements of the parenchyma that did not rise up to occupy the space. The diffuse bronchospasm showed by 2 patients could have contributed to the onset of pneumothorax; in one of them, the onset was certainly facilitated by the expiratory maneuvers during spirometry, as already mentioned. The treatment of this complication required the placement of multiple chest tubes, with prolonged air leaks and hospitalization. In both patients that showed contralateral pneumothorax (bilateral in one case) valves were placed also on that side to facilitate closure of the air leak, which was achieved shortly thereafter. This could be a useful indication to valve placement in the future and certainly requires further investigation. Incidentally, the patients with bilateral pneumothorax showed the best functional results (from 22% predicted to 44% and from 29% to 45%). Overall, the valves were well tolerated and bronchoscopic controls did not show any mucous plugs or granulation tissue around the valve. The functional improvement was statistically significant. In particular, FEV 1 markedly improved and residual volume decreased: at 3 months, more than 50% of the patients still show at least a 30% functional improvement and most of the patients required less supplemental oxygen and 6 (46%) were able to stop it. Exercise tolerance was also improved and remained stable after 3 months of follow-up. Patients were so satisfied that most of them are now willing to receive treatment on the contralateral side, but lung morphology will not allow it in all of them. Contralateral BLVR could be attempted to obtain a second functional improvement when pulmonary function tests start again to deteriorate. We performed a second treatment on the contralateral side only in two 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 as mentioned. The results of this pilot study demonstrate that bronchoscopic lung volume reduction can be safely performed with encouraging short-term results; long term follow up is mandatory as well as randomized control studies. This procedure may be considered in the future in conjunction with other similar bronchoscopic options such as airway bypass, according to the characteristics of the distribution of emphysema in the different areas of the lung. GENERAL THORACIC

6 GENERAL THORACIC 416 VENUTA ET AL Ann Thorac Surg LUNG VOLUME REDUCTION 2005;79:411 7 This clinical study was sponsored by Emphasys Medical, Redwood City, CA. References 1. American Lung Association. Facts about emphysema. New York: American Lung Association Anthonisen NR, Wright EC, Hodgkin JE (IPPB trial group). Prognosis in chronic obstructive pulmonary disease. Am Rev Respir Dis 1986;133: 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: De Giacomo T, Rendina EA, Venuta F, et al. Bullectomy is comparable to lung volume reduction in patients with endstage emphysema. Eur J Cardiothorac Surg 2002;22: Cassivi SD, Meyers BF, Battafarano RJ, et al. Thirteen-year experience in lung transplantation for emphysema. Ann Thorac Surg 2002;74: Cooper JD, Patterson GA, Sundaresan S, et al. Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J Thorac Cardiovasc Surg 1996;112: Block KE, Georgosen CL, Russi EW, Weder W. Gain and subsequent loss of lung function after lung volume reduction surgery in cases of severe emphysema with different morphologic patterns. J Thorac Cardiovasc Surg 2002;123: Fishman A, Martinez F, Naunheim K, et al, 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: National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med 2001;345: Lausberg HF, Chino K, Patterson GA, Meyers BF, Toeniskotter PD, Cooper JD. Bronchial fenestration improves expiratory flow in emphysema human lungs. Ann Thorac Surg 2003;75: Rendina EA, De Giacomo T, Venuta F, et al. Feasibility and safety of the airway bypass procedure for emphysema. J Thorac Cardiovasc Surg 2003;125: 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: Fann JI, Berry GJ, Burdon TA. Bronchoscopic approach to lung volume reduction using a valve device. J Bronchol 2003;10: Toma TP, Hopkinson NS, Hiller J, et al. Bronchoscopic volume reduction with valve implants in patients with severe emphysema. Lancet 2003;361: 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 2003;124: Ciccone AM, Meyers BF, Guthrie TJ, et al. Long-term outcome of bilateral lung volume reduction in 250 consecutive patients with emphysema. J Thorac Cardiovasc Surg 2003; 125: Fujimoto T, Teschler H, Hillejan L, Zaboura G, Stamatis G. Long-term results of lung volume reduction surgery. Eur J Cardiothorac Surg 2002;21: Wood DE. Results of lung volume reduction surgery for emphysema. Chest Surg Clin N Am 2003;13: Sabanathan S, Richardson J, Pieri-Davies S. Bronchoscopic lung volume reduction. J Thorac Cardiovasc Surg (Torino) 2003;44: Yim AP, Hwong TM, Lee TW, et al. Early results of endoscopic lung volume reduction for emphysema. J Thorac Cardiovasc Surg 2004;127: INVITED COMMENTARY Lung volume reduction surgery (LVRS) for emphysema has been the greatest advancement in general thoracic surgery since the development of lung transplantation 20 years ago, providing valuable palliation of the symptoms of end-stage emphysema in select patients. However, a minority of emphysema patients are candidates for LVRS and before realizing the symptomatic improvement, patients must navigate the minefield of surgical morbidity and mortality that can frequently extend the period of convalescence. Even while LVRS was being validated in the recently completed National Emphysema Treatment Trial, surgical and pulmonary investigators and biotechnology companies have been developing innovative strategies to try to mimic the effect of surgical lung reduction less invasively and with less risk. Surgeons with expertise in video-assisted thoracic surgery (VATS) quickly adapted VATS techniques to accomplish LVRS. But thinking even more radically, interventional bronchoscopists, including both thoracic surgeons and pulmonologists, considered whether emphysema palliation might be accomplished endoscopically, possibly becoming an outpatient procedure with minimal risk at much less cost. Some surgeons see this possibility as a threat; concerned that interventional pulmonologists will replace surgical LVRS with endoscopic therapy perhaps, even if LVRS is better. Other surgeons, such as Venuta and colleagues, embrace the prospect of endoscopic management of emphysema and are clear leaders in the development and investigation of these new technologies. They do not see the development of endoscopic lung reduction as a threat to a thoracic surgical procedure, but as an opportunity to benefit a wider spectrum of symptomatic patients who may not be candidates for surgical LVRS or who may be able to achieve palliation with less recovery and less risk. Bronchoscopic lung volume reduction, if successful, may have a significant impact on the shortcomings of LVRS. An endoscopic approach may open emphysema palliation to many more patients, bothbecause the difference in treatment physiology may broaden the indications to patients not currently considered for LVRS, and the decreased invasiveness may make the procedures more acceptable to patients who are disabled by emphysema, but skeptical or cautious about undergoing em by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur