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J Thorac Cardiovasc Surg 2003;125:1294-1299
© 2003 The American Association for Thoracic Surgery
General Thoracic Surgery |
From the Division of Thoracic Surgery, Dipartimento "P. Stefanini" University "La Sapienza," Rome, Italy,a and the Division of Cardiothoracic Surgery, Washington University, St Louis, Mo.b
Received for publication May 30, 2002. Revisions requested Aug 22, 2002; revisions received Sept 12, 2002. Accepted for publication Oct 25, 2002. Address for reprints: Erino A. Rendina, MD, Department of Thoracic Surgery, II Clinica Chirurgica, Policlinico Umberto I0, 00161, Roma, Italy (E-mail: erinoangelo.rendina{at}tin.it).
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Abstract |
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Introduction |
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1 Collateral ventilation (ie, the ability of gas to move from one part of the lung to another through nonanatomic pathways) is present in the normal lung, but its importance in the distribution of ventilation is negligible because the resistance to air flow is higher in collateral channels than in the airway. Observations in postmortem emphysematous human lungs 2 demonstrated, however, that the resistance to collateral air flow in the lungs of patients with emphysema is low in comparison with that in normal lungs. This finding was confirmed by Terry and coworkers 3 in emphysematous patients, and Macklem 4 noted that collateral ventilation not only improves our understanding of the pathophysiology of airway obstruction and gas distribution in the emphysematous lung but "may also have startling therapeutic implications."
Recently, a group of researchers from Washington University 5 has proposed that the creation of direct passages between the emphysematous pulmonary parenchyma and large airways (airway bypass) could take advantage of the extensive collateral ventilation present in emphysema to provide improvement in expiratory flow and respiratory mechanics. In an ex vivo study on 12 human emphysematous lungs, Lausberg and coworkers 5 demonstrated that the forced expiratory volume in 1 second increased from an average of 245 mL at baseline to an average of 447 mL after the creation of 3 passages and to an average of 666 mL after the creation of 5 passages.
These promising experimental results encourage further research to support investigation of the feasibility and safety of the airway bypass procedure in human subjects. A crucial step in the safe performance of this procedure is to create passages through the airway wall into the lung parenchyma while avoiding injury to adjacent blood vessels.
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Methods |
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, B). The radio frequency generator (Valley Lab Force FX) was set in the blend mode at 50 W. The same procedure was then similarly repeated as required. At the end of the airway bypass, the lung was reinflated underwater to check for parenchymal air leaks. Finally, the scheduled lobectomy or transplantation was carried out. No follow-up beyond surgical intervention was required for this study. Because accurate pathologic studies in previous animal experiments, including more than 100 transbronchial passages, showed no tissue damage, pathology was not carried out in this study (Figure 1).
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Results |
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Discussion |
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6 This increase in size results from the destruction of pulmonary parenchyma (alveolar walls and interstitial tissue) and leads to a loss of elastic recoil and progressive dynamic hyperinflation of the lungs. Hyperinflation further decreases expiratory flow by compressing the small intraparenchymal airways and ultimately compromises respiratory mechanics, leading to respiratory failure. The results of lung volume reduction surgery demonstrate that the resection of areas of the lung in which hyperinflation is more severe yields an improvement in respiratory mechanics and increases expiratory flow in the residual lung. 7-9 On the basis of the concept of collateral ventilation, the group at Washington University 5 hypothesized that instead of resecting hyperinflated lung parenchyma, comparable results could be achieved by draining the air spaces, creating a direct passage between the lung and the airway. The concept of airway bypass was favorably applied in an experimental setting, in which a marked increase in forced expiratory volume in 1 second was observed. Our study was designed as the first step in the clinical application of the airway bypass procedure. The first important point in carrying out this procedure is to safely create a passage connecting segmental or subsegmental bronchi with the pulmonary parenchyma while avoiding injury to the peribronchial vessels. For this purpose, we have devised a Doppler catheter enabling detection of blood flow outside the bronchus by scanning the inner surface of the bronchial wall. This device was first used in experimental animals and proved effective in detecting pulmonary vessels. For use in human subjects, it is important that both the Doppler probe and cautery catheter can be introduced in the 2.0-mm operating channel of a 4.8-mm flexible bronchoscope, which can be easily manipulated through the endotracheal tube. The size of the bronchoscope was selected as a compromise between the width of the operating channel and the possibility to reach subsegmental bronchi, which are located more deeply in the pulmonary parenchyma and are less likely to be adjacent to pulmonary vessels. The mild bleeding seen in the 2 instances was likely due to bleeding from the parenchyma because a much larger amount of bleeding can occur if a pulmonary vessel is breached. In earlier animal research breaching of a pulmonary vessel resulted in bleeding of up to hundreds of milliliters and could result in the loss of the animal. Because the purpose of our study was specifically to ascertain that the creation of the passage was safe and no foreign material was left in place, we believe the relatively short observation period was sufficient. We also believe from this study that the location of pulmonary vessels (which are the vessels heard by the Doppler catheter) are difficult to predict without using the Doppler catheter. There was little predictability of vessel location in these segmental and subsegmental airways, making use of this device vital in avoiding contact with major vessels lying adjacent to the airway walls. As far as the question of creating the passages in segmental or subsegmental bronchi is concerned, we believe this has little relevance because both segmental and subsegmental bronchi are equally surrounded by emphysematous lung tissue, as can be seen on high-resolution computed tomographic scans. Manipulation of the of the catheters was easy in the lower lobes, whereas in the upper lobes the procedure required some training because of the unfavorable angle of the bronchoscope and the need to withdraw the Doppler catheter and introduce the cautery probe while keeping the tip of the bronchoscope stationary. All considerations about the clinical effects of the airway bypass procedure are beyond the purpose of this study; namely the effect of secretions in the patency of the passages, the best way to keep the passages steadily open, and the clinical benefit of the procedure.
Our study proved that the airway bypass procedure is safely feasible in normal human subjects, as well as in patients with emphysema requiring lung transplantation. The Doppler device used to detect pulmonary vessels is effective, and the cautery probe enables safe creation of airway bypasses. These clinical results support further investigation of the efficacy of the airway bypass procedure in patients with emphysema. In particular, animal studies with long-term follow-up are ongoing to develop the ideal stent to keep the passages open.
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Appendix: Discussion |
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I would like to make 1 comment and ask 4 questions. It is a privilege to discuss an article by such a renowned group that has made many seminal contributions in advancing the treatment of patients with emphysema.
First, did the pathologists examine the lung specimens, and, if so, what did they see at the site of the neopassages? Was there hemorrhage, and how big were the channels?
Second, it is widely known and my colleagues from Boston have shown that obstruction to air flow in emphysema occurs in the very distal airways. How many of the passages in this experiment were in the segmental airways and how many were in the subsegmental airways, and why do you surmise that this might have an effect on the trapped ventilation that occurs much more distally?
Third, is it true to conclude that this is safe and feasible when the observation period after the procedure was minutes rather than hours or days? Are there plans to carry this out in an animal model to truly show safety before attempting this in human subjects?
Fourth, if stenting the passages is the plan to keep the channels patent, we know that stenting larger airways and the esophagus for benign lesions is fraught with problems from the radial traction and occlusion from secretions. How will these issues be addressed?
Dr Rendina. At the beginning of your discussion, you mentioned a 20% rate of bleeding considering the 2 episodes occurring in the 10 patients undergoing lobectomy. The denominator should, however, be considered the 47 passages created overall and not the 10 patients undergoing lobectomy, so that this rate drops to 4.2%. Regarding pathology, we had performed accurate pathologic studies in previous animal experiments, including more than 100 transbronchial passages, and we could demonstrate that the passages were about 1.5 mm in diameter, there was no bleeding around the site of the passage, and there was no necrosis of the surrounding tissues. Therefore, we did not find it necessary to repeat pathologic examinations in this study.
Your second question refers to the pathophysiology at the basis of our work. The present study is focused only on safety and feasibility, but I will try to address the question of peripheral airway obstruction. The concept is that unless marked intrinsic small airway disease is present, the obstruction of the peripheral airways is due to the hyperinflation of the lung, and it presents mostly on expiration. Within the hyperinflated lung, collateral ventilation allows the movement of gas independently from the anatomic airways. The passages created should bypass this obstruction on expiration, while leaving inspiration unmodified. The question of creating the passages in segmental or subsegmental bronchi has little relevance because both segmental and subsegmental bronchi are equally surrounded by emphysematous lung tissue, as can be seen on high-resolution computed tomographic scans.
Concerning safety, the crucial point of this study was to demonstrate in human subjects what we had already performed in animal studies; that is, that the detection of the vessels around the bronchus was accurate and that transbronchial holes reaching into the lung parenchyma could be safely made. Therefore, we considered that a short observation time was sufficient.
As far as stents are concerned, my answer can be only speculative because stents were not used in this study. It might, however, be that the presence of a foreign body might entail further risk. I also concur with you that the secretions potentially occluding the stent can be a problem. However, one has to consider that secretions are produced by the bronchi and not by lung parenchyma. Therefore, in principle, secretions should not affect the patency of the stents when we use them in the future.
Dr Walter Klepetko (Vienna, Austria). I would like to ask 2 questions. First, were those patients who underwent lobectomy emphysematous patients?
The other question is directed to the ventilation patterns measured on the respirator. I am sure you have measured them before and after the procedure, and at least in the patients with end-stage emphysema with the indication for transplantation, there must have been an immediate and dramatic change. Can you give us some results about that?
Dr Rendina. The patients undergoing lobectomy were not severely emphysematous, with the exception of one patient. We have the preoperative spirometric data, but the postoperative spirometric data are irrelevant because the lobe in which the bypasses were done was removed. Also, the purpose of this study was not to demonstrate benefit. Patients undergoing transplantation, on the contrary, were obviously severely emphysematous. In one such patient, the free collapse was measured, and it was found to be improved; however, that was done in only one patient.
Dr Klepetko. In the transplantations, have you observed an immediate increase of the ventilation parameters? If you have such a dramatic improvement as you have been demonstrating in the experimental setting, you must have an immediate effect on the table there and you should measure that.
Dr Rendina. Yes, I answered that. This was not the purpose of this study, but free collapse in the last patient demonstrated improvement.
Dr Carlos Saldarriaga (Medellin, Colombia). Do you think this technique is feasible for endoscopic treatment of bullous emphysema?
Dr Rendina. The purpose of this procedure at the present time is not the treatment of bullae. The concept at the basis of this study is collateral ventilation and the ability to create exit pathways that are alternative to airways collapsed during expiration by the hyperinflated lung compressing from the outside.
Dr Jean Deslauriers (Sainte-Foy, Quebec, Canada). Erino, I have to congratulate you. I think you and Joel are kind of an ideal team.
I have a couple of worries about this procedure. First, concerning these stents, you have not shown the safety of the procedure. Many patients with emphysema have pulmonary hypertension to begin with. When you insert the stents, if you were to hit a vessel, it would be instant death. If you were to do a pneumothorax, it would also be instant death because these patients have no reserve.
Second, if you leave the stents in place for some days, in the patient with true emphysema who has a lot of purulent secretions and is receiving cortisone, you have inserted a foreign body. The lung moves up and down and the pulmonary artery that beats. I think you have exactly the right conditions for a catastrophic erosion that might occur within a week or 2 or 3 weeks. I would be really worried about putting in foreign bodies. Obviously the stents are going to be bigger as time goes on, so that they do not get obstructed. You said the secretions would not go in the stents, but they will because these patients are infected. They will cough. Some of this pus is going to go right outside the bronchi. These are perfect conditions for abscesses and erosions.
My second comment has to do with Dr Swanson. You are dealing with a disease that affects the periphery of the lung. It is common knowledge that emphysema is basically in the periphery of the lung and not in the center of the lung, yet you are putting these stents right where the lung is the most normal. How do you expect to treat a disease that is basically on the surface by putting these stents in the middle of the lung?
Other than that, I think the article is wonderful, and I recognize Joel's innovative ideas in the field of emphysema and his crusade to solve the problem, but I am really worried about these stents.
Dr Rendina. Thank you, Dr Deslauriers, for your comments and questions. Most of the points that you make, however, concern issues that have not been addressed in this study. I wish to remind you that stents were not used, and no follow-up beyond surgical intervention was required in this study. Nevertheless, your comments are pertinent and important with regard to the overall procedure. We share your concern about the potential danger of stents, particularly in the face of pulmonary hypertension. We have not observed problems related to the various stents that we have used in our animal experiments, although we are still in the process of developing the ideal stent. In addition, we tend to consider pulmonary hypertension as an exclusion criterion in our forthcoming clinical studies.
The occurrence of pneumothorax was also a matter of concern. We have therefore filled the chest with saline solution after creating the holes in the bronchi, and we have noticed no air leaks from the parenchyma. Therefore, this study confirmed that pneumothorax should not be expected as a complication.
The issue of secretions occluding the passage cannot be solved until the procedure undergoes clinical experimentation. There are patients with emphysema who have many secretions and others who do not or have much less. Although we tend to believe that secretions will not affect the patency of the passages, our intention is to exclude patients with extensive secretions from future clinical trials.
Last, you argue that the most destroyed areas are located at the periphery of the lung, and yet we create the passages through the bronchi in the most central part of the lung, which presumably is healthier. It is questionable whether in severe homogenous emphysema the healthier tissue is that surrounding the airway. In addition, the anatomic basis of collateral ventilation resides in the fact that air can move freely within the lung parenchyma, and therefore one passage created in a given segmental or subsegmental bronchus can, in theory, drain the whole lobe. Air-dried lung preparations confirm what can be clearly seen on any high-resolution computed tomographic scan of emphysematous lungs. The patterns of parenchymal destruction reach deep into the lung and around the airways, and in our study we could actually see destroyed lung through the passages in those patients who had emphysema.
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Footnotes |
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