Bronchial Fenestration Improves Expiratory Flow in Emphysematous Human Lungs

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1 Bronchial Fenestration Improves Expiratory Flow in Emphysematous Human Lungs Henning F. Lausberg, MD, Kimiaki Chino, MD, G. Alexander Patterson, MD, Bryan F. Meyers, MD, Patricia D. Toeniskoetter, MD, and Joel D. Cooper, MD Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri GENERAL THORACIC Background. The crippling effects of emphysema are due in part to dynamic hyperinflation, resulting in altered respiratory mechanics, an increased work of breathing, and a pervasive sense of dyspnea. Because of the extensive collateral ventilation present in emphysematous lungs, we hypothesize that placement of stents between pulmonary parenchyma and large airways could effectively improve expiratory flow, thus reducing dynamic hyperinflation. Methods. Twelve human emphysematous lungs, removed at the time of lung transplantation, were placed in an airtight ventilation chamber with the bronchus attached to a tube traversing the chamber wall, and attached to a pneumotachometer. The chamber was evacuated to 10 cm H 2 O pressure for lung inflation. A forced expiratory maneuver was simulated by rapidly pressurizing the chamber to 20 cm H 2 O, while the expiratory volume was continuously recorded. A flexible bronchoscope was then inserted into the airway and a radiofrequency catheter (Broncus Technologies) was used to create a passage through the wall of three separate segmental bronchi into the adjacent lung parenchyma. An expandable stent, 1.5 cm in length and 3 mm in diameter, was then inserted through each passage. Expiratory volumes were then remeasured as above. In six experiments, two additional stents were then inserted and forced expiratory volumes again determined. Results. The forced expiratory volume in 1 second (FEV 1 ) increased from ml at baseline to ml after placement of three bronchopulmonary stents (p < 0.001). With two additional stents, the FEV 1 increased to ml (p < 0.001). Conclusions. Creation of extra-anatomic bronchopulmonary passages is a potential therapeutic option for emphysematous patients with marked hyperinflation and severe homogeneous pulmonary destruction. (Ann Thorac Surg 2003;75:393 8) 2003 by The Society of Thoracic Surgeons Presented at the Thirty eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28 30, Address reprint requests to Dr Cooper, One Barnes-Jewish Hospital Plaza, Suite 3108 Queeny Tower, St. Louis, MO 63110; cooperjo@msnotes.wustl.edu. Emphysema affects approximately 2 million individuals in the United States and is the fourth leading cause of death. Emphysema is anatomically defined as an irreversible increase in the size of the air spaces distal to the terminal bronchials [1]. This increase in size results from the destructive activity of neutrophil and macrophage elastase. The loss of lung tissue alters the physical properties of the lung, leading to a loss of lung elastic recoil and to progressive dynamic hyperinflation of the lungs. These changes result in an enlargement of the thorax, flattening of the diaphragm, increased work of breathing, increased dyspnea, and reduced exercise tolerance [2, 3]. The progressive loss of elastic recoil traps the patient in a state of hyperinflation in which forced effort cannot reduce the residual volume, since the force exerted to empty the lungs collapses the small airways and obstructs the outflow of gas. Progressive hyperinflation of the lungs and hyperexpansion of the chest wall also diminishes inspiratory capacity. To maintain adequate minute ventilation, the respiratory rate must increase, resulting in an increase in the work of breathing and in dyspnea. It has been repeatedly demonstrated that collateral ventilation the ability of gas to move from one part of the lung to another through nonanatomic pathways is greatly increased in emphysema, because of the extensive breakdown of alveolar walls and lobular septae [4, 5]. We hypothesize that the increased collateral ventilation can be used to bypass collapsing and obstructed small airways. We postulate that creation of noncollapsing, extraanatomic stents connecting lung parenchyma to large airways can facilitate expiration and help alleviate some of the adverse consequences of dynamic hyperinflation. Experiments were undertaken in excised human emphysematous lungs to explore the feasibility of this concept. Material and Methods Freshly explanted human lungs from recipients undergoing lung transplantation for emphysema were studied ex vivo. Patient consent was obtained. During explanta- Dr Cooper discloses that he has a financial relationship with Broncus Technologies, Inc by The Society of Thoracic Surgeons /03/$30.00 Published by Elsevier Science Inc PII S (02)

2 GENERAL THORACIC 394 LAUSBERG ET AL Ann Thorac Surg BRONCHIAL FENESTRATION IMPROVES EXPIRATORY FLOW 2003;75:393 8 Fig 1. Schematic diagram of excised lung in a ventilating chamber. The lung is inflated by reducing pressure in the chamber to 10 cm of water pressure. A forced expiratory maneuver is produced by suddenly connecting the chamber to the large drum, which has been prepressurized to 20 cm of water pressure. Airflow exiting the bronchus is measured with a pneumotachygraph. tion, the surgeon paid particular attention to avoid injury of the lungs and thus avoid air leakage from the surface during subsequent testing. The lungs were placed in ice-cold saline, taken immediately to the laboratory, and placed in an airtight ventilating chamber for measurement of forced expiratory flow and volume according to a set protocol, to be described. Figure 1 is a schematic diagram of the experimental set-up. The main bronchus was anastomosed to a segment of a polytetrafluoroethylene (PTFE) vascular prosthesis using a continuous suture. The size of the prosthesis was chosen according to the diameter of the bronchial stump. The prosthetic sleeve was advanced as far as possible over a Plexiglas tube passing through the top of the ventilating chamber, such that the end of the bronchus and the end of the Plexiglas tube were adjacent to each other. The sleeve was then tied firmly around the Plexiglas tube. The lung was tested for air leaks by manual inflation using an Ambu-bag. Identifiable leaks on the surface of the lung were closed with a linear stapling device or by application of a sealant. The lid of the chamber with the attached lung was clamped into place. The bronchial port was then attached to a heated pneumotachygraph (#8300, Hans Rudolph Inc, Kansas City, MO). Another port in the lid was used to record the pressure inside the chamber. A large-diameter ballvalved port placed in the lid of the chamber was connected by a large-bore corrugated tubing (1.5 cm internal diameter) to a 55-gallon pressurized drum, which acted as a pressure sink. The drum pressure was maintained at positive 20 cm of water pressure by means of a constant inflow of compressed air through a separate sealed inflow port. Another sealed port from the drum was attached to one end of a large-bore corrugated tubing, (1.5 cm ID), the other end of which was placed 20 cm below the surface of a water-filled cylinder. The pressure in the drum was constantly monitored and adjustment of the underwater vent made to maintain a constant 20-cm water pressure in the drum. Before initiating the forced expiratory maneuvers, the lung was expanded by adjusting the lung chamber pressure to 10 cm of water. Measurement and recording of airway pressure, chamber pressure, and inspiratory and expiratory flow and volume over time was performed with an external data acquisition device connected to a laptop computer (RSS100HR Research Pneumotachygraph system, Hans Rudolph Inc). Once the lung was fully inflated to a chamber pressure of 10 cm of water pressure, any continuing inspiratory flow through the airway represented air leakage from the surface of the lung. The lung was considered to be suitable for the experiment only if rate of air leakage was less than or equal to 400 ml/min. If this could not be achieved, the lung was discarded. After inflation of the lung to a steady-state condition, the forced expiratory maneuver was produced by sudden opening of the ball-valved port attaching the ventilating chamber to the pressurized reservoir. This raised the pressure in the ventilating chamber to 20 cm of water pressure in less than 0.4 seconds, after which the pressure in the chamber remained constant at 20 cm H 2 O. After data acquisition for 5 seconds, the valve connecting the pressure drum to the ventilating chamber was closed, the ventilating chamber again evacuated to 10 cm of water pressure, and the forced expiratory maneuver and measurements were repeated. Three measurements were obtained and the results were averaged. We created the communications between the bronchial tree and adjacent lung parenchyma at the level of the segmental or subsegmental bronchi. A standard fiberoptic bronchoscope, 4.8 mm im external diameter (BF-20D Olympus American Inc, Melville, NY) was passed through the Plexiglas cylinder attached to the bronchus and advanced into the airway. A radiofrequency catheter (Broncus Technologies Inc, Mountain View, CA) was passed down the working channel of the bronchoscope and a small hole made through the bronchial wall into the adjacent lung. The probe was withdrawn and a balloon-expandable coronary stent, 3.0 mm in diameter and 15 mm in length, was inserted through the bronchial fenestration and expanded, with the proximal end of the stent barely projecting into the airway and the distal end of the stent in the lung parenchyma. The bronchoscope was then withdrawn and the pneumotachygraph reattached to the external end of the airway port. Figure 2 is a schematic drawing of the fenestration procedure and stent insertion. The ventilating chamber was evacuated to 10 cm of water pressure and after the lung was fully inflated, the airflow into the lung was again checked to ensure that no air leakage had been created and that the airflow into the statically inflated lung was less than or equal to 400 ml/min. The forced expiratory maneuver was then performed and repeated for three consecutive trials.

3 Ann Thorac Surg LAUSBERG ET AL 2003;75:393 8 BRONCHIAL FENESTRATION IMPROVES EXPIRATORY FLOW 395 Fig 2. Technique for insertion of bronchopulmonary stents. (A) The flexible bronchoscope is inserted to the level of the segmental bronchus. (B) A radiofrequency probe inserted through the bronchoscope is used to create a hole through the bronchial wall into the adjacent lung parenchyma. (C) A balloon-expandable stent is passed down the bronchoscope and expanded with the proximal end just inside the bronchial lumen. GENERAL THORACIC In the last six experiments, after the expiratory measurements had been obtained following placement of the three stents, the bronchoscope was reinserted, and two more fenestrations were made and two additional stents were placed to give a total of five stents. The forced expiratory measurements were then repeated. The opportunity for studying a normal human lung occurred when a proposed bilateral lung transplant was converted to a single lung transplant, and the contralateral donor lung could not be used. That lung was taken to the laboratory and studied in the same fashion as the excised emphysematous lungs. After baseline determination of forced expiratory volume in the ventilation chamber, three fenestrations were made and coronary stents, 3.5 mm in diameter, were placed and expanded as for the emphysematous lungs. The measurements were then repeated. The sites chosen for the bronchopulmonary stents generally included two in the upper lobe and one in the superior segment of the lower lobe, based on the general tendency of emphysematous destruction to be greatest in the upper lobes and in the superior segments of the lower lobes. When two additional stents were inserted, one was generally placed in a basal segment of the lower lobe and the other in a previously unused segment of the upper lobe. When a right lung was used, no stents were placed in the middle lobe. A total of 12 human lungs were studied in this manner. For each forced expiratory maneuver, the expiratory flow rates were integrated electronically to produce expiratory volume for each of the first 5 seconds. The results of the three duplicate maneuvers were averaged for each experiment. Statistical analysis was calculated using one-way repeated measures analysis of variance test on ranks (SPSS Software, Chicago, IL). Statistical significance was assumed at a p value of less than Results We attempted to study 18 lungs, but in six the air leakage from the surface was less than 400 cc/min and they were not used. The data from the remaining 12 lungs form the basis for this report. In these lungs, the rate of air leakage on inflation to 10 cm of water pressure was an average Table 1. Forced Expired Volume in 1 Second Lung No. Baseline After Three Stents After Five Stents Mean SD Fig 3. Forced expiratory flow averaged from 12 lungs before and after placement of three bronchopulmonary stents.

4 GENERAL THORACIC 396 LAUSBERG ET AL Ann Thorac Surg BRONCHIAL FENESTRATION IMPROVES EXPIRATORY FLOW 2003;75:393 8 Fig 4. Cumulative expired volume averaged from 12 lungs before and after placement of three bronchopulmonary stents. of 125 cc/min (range 0 to 400 cc). Five of the last six lungs used had no air leakage whatsoever. The repeat measurements of expiratory flow and volume were very reproducible for each lung, with a mean coefficient of variation of 6% for all experiments. Table 1 shows the total forced expired volume at the end of 1 second for the 12 lungs, at baseline, after placement of three stents, and in the last 6 lungs after two additional stents were placed. Figure 3 demonstrates the forced expired flow rate over time for the average of the 12 experiments at baseline and after placement of three stents. Figure 4 shows the corresponding expiratory volume over time. The mean first second expired volume increased from 245 cc to 447 cc, or 83% (p 0.001). The five second expired volume increased from 637 cc to 1200 cc or 88% (p 0.001). In the last six experiments, two additional bronchopulmonary stents were placed, to make a total of five. For these experiments, the forced expiratory volume for the first 5 seconds is shown in Figure 5. The forced expiratory volume in 1 second increased by 101% after three stents (p 0.005) and by 155% over baseline with five stents (p 0.003). Fig 5. Cumulative forced expired volume in six lungs at baseline, after placement of three bronchopulmonary stents, and after placement of two additional stents. Fig 6. Cumulative forced expired volume in normal human lung before and after placement of three bronchopulmonary stents. Normal expiratory curve is compared with baseline curve in Figure 5, and absence of any significant change after placement of stents is noteworthy. Figure 6 illustrates the forced expiratory volume in the normal human lung studied, both before and after placement of three bronchopulmonary stents. Unlike the emphysematous lungs, this lung demonstrated a normal forced expiratory pattern, which showed no change after placement of the stents. Comment In 1930 Van Allen and colleagues [6] obstructed sublobular bronchi in canine lungs and noted no collapse distal to the obstruction. They used the term collateral inspiration to explain how gases may enter one lobule from another in the lung without resorting to known anatomical pathways [6]. Hogg and associates [4] demonstrated that resistance to collateral airflow in postmortem emphysematous human lungs was low in comparison to normal lungs. They concluded that collateral channels may be important ventilatory pathways in emphysema. Terry and coworkers [5], in 1978, studied collateral ventilation in normal subjects 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 such subjects. In contrast, however, patients with emphysema frequently had a lower resistance through collateral channels than through the airways. In an editorial accompanying the manuscript by Terry and coworkers, Macklem noted that the importance of their measurements may go far beyond the understanding of the pathophysiologic effects of airways obstruction. If it is true that the resistance to collateral flow is less than airway resistance in emphysema, as their data and the earlier data suggested by Hogg, et al in excised human lungs suggests, their results may have startling therapeutic implications [7]. Macklem noted, Although reduction in the work of breathing with the resulting improvement in dyspnea and alveolar ventilation is the most

5 Ann Thorac Surg LAUSBERG ET AL 2003;75:393 8 BRONCHIAL FENESTRATION IMPROVES EXPIRATORY FLOW important therapeutic objective in emphysema, it is very frustrating that we do not yet know how to achieve this decrease. Macklem proposed creating extraanatomic pathways between lung parenchyma and the outside of the chest by means of passageways created between the surface of the lungs and the skin. 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 (usually the upper lobe) 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 in 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. This observation, along with previous studies confirming extensive collateral ventilation in emphysematous lungs, suggested that creation of new exit pathways for the trapped gas that is present in emphysema patients might help to relieve dynamic hyperinflation and formed the basis for these ex vivo experiments with human lungs. The results confirm that creation of several, relatively small, extraanatomic communications between pulmonary parenchyma and large airways (segmental bronchi) can markedly improve forced expiratory volume in human emphysematous lungs. On inspiration, the regular airways can open, allowing inspiration through normal channels. On expiration, the new passageways provide escape pathways to bypass the collapsed small airways. Clinically, one would anticipate that the improved expiratory flow would reduce dynamic hyperinflation with resulting improvement in respiratory mechanics, increase in exercise tolerance, and alleviation of dyspnea. The benefits resulting from decreasing dynamic hyperinflation in emphysematous patients has been clearly demonstrated in patients undergoing lung volume reduction surgery [8 10]. We embarked on this study in the hopes of developing a palliative treatment for patients with homogenous severe emphysema. Such individuals are not candidates for volume reduction surgery, and this homogenous severe pattern of destruction represents the most common contraindication to volume reduction surgery. We were encouraged by the marked improvement in expiratory volumes achieved with the relatively minor intervention described in these experiments. We used all available lungs from patients undergoing lung transplantation for chronic obstructive pulmonary disease (except patients with 1 antitrypsin deficiency) without regard to preoperative pulmonary function, degree of small airway disease, or radiologic pattern of emphysematous destruction. In addition, the sites used for creation of fistulae were not preselected by evaluation of current computed tomographic scans, which were not readily available for many of these transplant patients. In actual practice, candidate selection and interventional sites would be determined in part by the assessment of high-resolution computed tomographic scans of the chest. A number of issues need to be addressed before this type of intervention can be applied clinically. The safety of the procedure must be established, especially the ability to insert bronchopulmonary stents without significant hemorrhage or production of a pneumothorax. We are working to develop the necessary technology to achieve this goal. Design of an appropriate stent to maintain patency for as long as possible will be another challenge. Patients who are candidates for this procedure need to be defined. At the outset, patients with severe homogenous emphysematous destruction who have exhausted all other available treatments would seem to be most appropriate for this type of intervention. Surgical options in the treatment of emphysema include lung transplantation and lung volume reduction surgery, both of which have limited application. Medical therapy includes exercise rehabilitation to improve the efficiency of the respiratory muscles, and the use of bronchodilators and steroids to improve expiratory flow. An improvement of 15% or more in expiratory flow rates is considered to be therapeutically significant. In this context, the improved flow rates observed in these ex vivo emphysematous lungs after a relatively simple endoscopic intervention is encouraging and warrants further exploration. The authors acknowledge the expert technical assistance provided by Kathryn Fore, Laura Martini, and Dennis Gordon. This work was supported in part by National Institutes of Health grant R01 (HL62194). References Snider G, Kleinerman J, Thurlbeck W, et al. The definition of emphysema. Report of a National Heart, Lung, and Blood Institute, Division of Lung Disease Workshop. Am Rev Respir Dis 1985;132: Rochester D, Braun N, Arora N. Respiratory muscle strength in chronic obstructive pulmonary disease. Am Rev Respir Dis 1979;119: Sharp J, Danon J, Druz W, et al. Respiratory muscle function in patients with chronic obstructive pulmonary disease: its relationship to disability and to respiratory therapy. Am Rev Respir Dis1974 ;110: Hogg JC, Macklem PT, Thurlbeck WM. The resistance of collateral channels in excised human lungs. J Clin Invest 1969;48: Terry PB, Traystman RJ, Newball HH, Batra G, Menkes HA. Collateral ventilation in man. N Engl J Med 1978;298: Van Allen CM, Lindskog GE, Richter HT. Gaseous interchange between adjacent lung lobules. Yale J Biol Med 1930;2: Macklem PT. Collateral ventilation [Editorial]. N Engl J Med 1978;298: Cooper JD, Patterson GA, Sundaresan RS, et al. Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J Thorac Cardiovasc Surg 1996;112: Sciurba FC, Rogers RM, Keenan RI, et al. Improvement in pulmonary function and elastic recoil after lung reduction surgery for diffuse emphysema. N Engl J Med 1996;334: Cassart M, Hamacher J, Verbandt Y, et al. Effects of lung volume reduction surgery for emphysema on diaphragm dimensions and configuration. Am J Respir Crit Care Med 2001;163: GENERAL THORACIC

6 GENERAL THORACIC 398 LAUSBERG ET AL Ann Thorac Surg BRONCHIAL FENESTRATION IMPROVES EXPIRATORY FLOW 2003;75:393 8 DISCUSSION DR DOUGLAS E. WOOD (Seattle, WA): That is really exciting work that you have presented. My hat is off to you and your colleagues. This is yet another potentially pioneering work in the area of surgical treatment, or I guess in this case, endoscopic treatment for emphysema. I have just a simple question. The stents that you are putting in, are those uncovered Wallstents? DR LAUSBERG: Thank you very much, Dr Wood. Yes, the stents that we used were conventional coronary stents, as I mentioned, 3 mm in diameter and 15 mm in length when fully expanded, and they were not covered; that is correct. DR WOOD: And do you have any experience yet with what happens over any period of time with these? DR LAUSBERG: Those are very preliminary data, and most of the data and most of the experience we have gained are ex vivo. However, there is some upcoming experience that shows that the stent design that we use is not ideal yet and there still needs to be a lot of work done. DR WOOD: But the stents you are using are uncovered, so the air can come through the interstices of the stent as well? DR LAUSBERG: That is correct. DR WOOD: Thank you. DR WALTER WEDER (Zurich, Switzerland): Congratulations on these exciting data. I have a question for you. You presented expiratory flow as average flow. Could you give us some information about interindividual results? Were there lungs studied that were emphysematous but did not respond, and if so, what is the explanation? DR LAUSBERG: Actually, all the lungs we chose had not bullous emphysema and not 1 antitrypsin emphysema. So the population of lungs that we used was quite homogeneous. Of course there were some interindividual changes in the flows according to the degree of emphysema in the lungs and according to the sites where we placed the stents, but in general all the data that we gained were quite homogeneous. DR DANIEL MILLER (Rochester, MN): I thought this was a very elegant study from a group that has been pioneers in the treatment of end-stage lung disease secondary to emphysema. My question is, did you try to do this without using a stent? I think that making multiple openings within terminal bronchioles may be a possible, but may close up without a stent over time. Did you explore that at all? DR LAUSBERG: Thank you very much. Yes, we tried to only puncture the bronchial wall without a stent. The problem is that in this level of the segmental bronchi, this approach doesn t work. You can really nicely observe through the bronchoscope that the holes close when you do the forced expiratory maneuver. They close down either by concentric closure or by the deeper line parenchyma being pressed against the hole. We haven t shown the results yet, but the data are very similar to the baseline data. DR STEVEN R. DEMEESTER (Los Angeles, CA): Fascinating work you are doing. I have a quick question. Did you dissect out the stents after you placed them, and was there any injury to surrounding vascular structures when you placed the stents in a blind fashion like that? DR LAUSBERG: Thank you. Yes, sir, we did examine the stents, and so far we have not experienced any injury of the vessels or the visceral pleura. However, we have some preliminary experience in an in vivo model, and there is special technology being evolved right now that helps us prevent these major injuries, damaging vessels or the pleura. DR JOSEPH LOCICERO (Chicago, IL): I want to congratulate this group. They have done outstanding work and continue to do so over the years. These results are quite spectacular. This is a wonderful adjunct to our knowledge in emphysema. Back to Doug Wood s question, these were uncovered stents. If you think about the size and length of these stents, if they were completely covered, the resistance would probably be too high to produce that same sort of result. Although you haven t had time to figure out whether or not the results with the uncovered stents will change over time, have you tried covered stents and do they get the same results? DR LAUSBERG: Yes, that is what we plan to do. Thank you.