Lung volume reduction surgery

Current Problems in

Surgery Volume 37

Number 4 April 2000

Lung Volume Reduction Surgery Joseph B. Shrager, MD Assistant Professor of Surgery University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

Larry R. Kaiser, MD Eliason Professor of Surgery Chief, Section of General Thoracic Surgery University of Pennsylvania School of Medicine Philadelphia, Pennsylvania with

Jeffrey D. Edelman, MD Assistant Professor of Medicine Pulmonary and Critical Care Division Oregon Health Sciences University Portland, Oregon

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Current Problems in

Sur Volume 37

ry Number 4 April 2000

Lung Volume Reduction Surgery Foreword

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In Brief

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Biographic Information Introduction

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The History of Lung Volume ReductionSurgery

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Early Procedures Operations for Giant Bullae The Introduction of Lung Volume Reduction Surgery The Recent Reintroduction of Lung Volume Reduction Surgery

Current PathophysiologicConcepts Adjunctive and Alternative Therapies to Lung Volume Reduction Surgery Medical Therapy Lung Transplantation

Patient Selection for Operation pCO 2 Inspiratory Resistance Heterogeneous Disease Nutritional Status 6-Minute Walk Distance Contradictory Data Lung Volume Reduction Surgery versus Lung Transplantation

Surgical Technique Median Sternotomy Video-assisted Thoracic Surgery

Resultsof Lung Volume Reduction Surgery Curr Probl Surg, April 2000

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270 274 275 276 283 283 283 285 287 288 288 289 290 290 297 298 255

Ongoing Controversies Surgical Technique Duration of Benefit and Survival Benefit Mechanism of Improvement Costs

Current Status of LungVolume ReductionSurgery NETT Objectives NETT Eligibility Criteria NETT Accrual of Patients Other Randomized Trials

References

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301 301 304 305 306 306 309 309 310 310 311

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Foreword The idea of reducing lung volume in patients with severe emphysema at first seems unwise, until one considers that the operation is designed to resect diseased tissue, thereby providing more room for the remaining normal lung to expand. The concept was first proposed almost 50 years ago but was not established in medical practice, only to be reconsidered in the middle of the last decade as a possible therapeutic procedure and also as a bridge to lung transplantation. In this issue of Current Problems in Surgery, Drs Shrager, Kaiser, and Edelman from the University of Pennsylvania School of Medicine present a timely monograph on this topic. Their excellent review covers the historic background of the procedure, the pathophysiologic concepts on which the operation is based, the difficult process of patient selection, and the important considerations of surgical technique. The monograph is very well written and illustrated, and the bibliography is thorough. Importantly, the authors discuss the controversies associated with the operation, and they address the challenges faced by surgeons when evaluating new operative procedures through prospective randomized trials.

Samuel A. Wells, Jr, MD Editor in Chief

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In Brief Lung volume reduction surgery (LVRS) is an operation that was proposed initially in the 1950s as a surgical treatment for patients with severe emphysema, a disease for which there were at that time, and still remain, few viable therapeutic options. Otto Brantigan postulated that, by removing some portion of the hyperexpanded and poorly functioning lung tissue, the elastic recoil of the remaining tissue would be improved, resulting in increased expiratory airflow, and furthermore that the respiratory muscles would be allowed to operate at less of a mechanical disadvantage because of the reduction in hyperinflation, resulting in increased inspiratory force. Despite subjective clinical improvement in most survivors, the high mortality rate in this early series and the failure to document improvement in an objective way resulted in the abandonment of the procedure. In 1995, Joel Cooper revived the operation on the basis of the experience with patients who had undergone lung transplantation. This experience indicated that patients with severe emphysema could be maintained safely on single lung ventilation during operation and that the chest wall and diaphragmatic configuration in patients with emphysema were remarkably plastic, with significant resolution of hyperexpansion after the replacement of the enlarged, emphysematous lung with the smaller transplanted organ. The increased experience managing patients with emphysema that resulted from the advent of lung transplantation clearly increased the comfort level of the use of LVRS in the modem era. Cooper's initial report of 20 patients undergoing LVRS with no deaths and dramatic improvements in pulmonary function led to enthusiastic application of the procedure around the United States and the world. In the time since this revival of LVRS, a large amount of experience has been gained with the procedure. A variety of published, uncontrolled case series have confirmed significant improvements in expiratory flows, inspiratory muscle function, and dyspnea after LVRS in selected patients with severe emphysema. Although there is now little doubt that a subgroup of patients benefits from the operation when it is performed in centers equipped to care for this challenging patient cohort, many questions remain, The ongoing areas of controversy are wide ranging. Chief among them is the issue of patient selection. Certainly there are patients with emphysema that is too far advanced to benefit from the operation, but there are conflicting data about how to identify these patients precisely. Criteria 258

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identifying cutoff points, such as a particular pCO 2 level or distance covered during a 6-minute walk, are supported by the data of some groups, but not those of others. There has been an evolving consensus that patients with heterogeneous disease (ie, areas of lung that demonstrate more severe emphysema that can serve as "target areas" for resection and other areas with relatively preserved lung) are the ideal candidates. However, several groups have reported improvement in the conditions of patients with homogeneous emphysema as well. Most authorities now feel that patients with predominant emphysema derive greater benefit from the procedure with less morbidity than those patients with major components of chronic bronchitis. Advances in the understanding of the physiologic mechanisms of improvement after the procedure will, it is hoped, lead to more accurate methods of patient selection. Although a number of basic principles have been established by the early experience, important questions regarding surgical technique also remain unresolved. Laser resection has been abandoned. It has become clear that prolonged air leaks, in most cases, can be avoided by the use of staple-line buttressing. Much has been learned about the intraoperative and postoperative management of patients with emphysema, leading to an emphasis on early extubation and an avoidance of suction on tboracostomy tubes. Objective data are just now becoming available, however, that compare the thoracoscopic and median sternotomy approaches. Opinion remains the dominant mode of discourse on this point. We have not even begun to address seriously the complex issue of what quantity of resected lung tissue is optimal in each patient. Because the procedure has only been performed for a few years, there are limited data available regarding the duration of benefit conferred by LVRS. Early reports on this issue suggest that improvements may peak after approximately 2 years and fall off thereafter. This begs the question of a potential survival benefit, but this critical question can only be resolved finally by a prospective, randomized clinical trial. On the basis of these ongoing areas of controversy and, certainly, the fact that this operation has had the misfortune of being promulgated in an era of strict cost containment, 2 prospective, randomized clinical trials of LVRS have been organized in the United States and 1 prospective, randomized clinical trial has been organized in Canada: The main US trial represents an unprecedented arrangement between the National Institutes of Health (National Heart Lung and Blood Institute) and the Health Care Financing Administration. The National Emphysema Treatment Trial (NETT) deems that LVRS is an experimental procedure and, as such, will not be covered for reimbursement by Medicare. Most private insurers Curr Probl Surg, April 2000

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have followed suit and are currently denying coverage for the procedure. The NETT has been organized to evaluate rigorously many of the benefits of LVRS that are suggested by the early uncontrolled studies, while addressing many of the remaining unresolved issues. Its goal for accrual of the required 2500 patients is July 2002, with an anticipated reporting date of January 2003. Early recruitment efforts, unfortunately, have been significantly slower than anticipated. In the meantime, patients who wish to undergo LVRS must be randomized to the surgical arm of the NETT (or that of the Canadian or New England Blue Cross trials), must be covered by one of the few insurers who have continued to pay for the procedure, or must be sufficiently wealthy to cover the costs of the operation themselves. This leaves most of the patients with severe emphysema who might be candidates for the procedure in the unfortunate position of having to hope that the ongoing trials will corroborate the benefits of LVRS before it is too late for them.

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Joseph B. Shrager, MD, is a graduate of Amherst College and Harvard Medical School. He obtained his general surgical training at the Hospital of the University of Pennsylvania and his thoracic surgical training at Massachusetts General Hospital before returning to the University of Pennsylvania where he is currently Assistant Professor of Surgery in General Thoracic Surgery. Lung volume reduction surgery is among Dr Shrager's clinical and basic research interests. His laboratory work focuses on the respiratory muscles and on the role of respiratory muscle adaptation in lung volume reduction surgery. This work is currently supported by an Edward D. Churchill Research Award from the American Association for Thoracic Surgery.

Larry R. Kaiser, MD, is the Eldridge L. Eliason Professor of Surgery and Chief of General .... j ~ ~ ~.~ Thoracic Surgery at the University of Pennsylvania School of Medicine and the Hospital of the University of Pennsylvania. He obtained his undergraduate degrees in chemistry in 1973 and his medical degree in 1977, both from Tulane University. After the completion of his general surgery residency and a fellowship in surgical oncology at the University of California at Los Angeles, he pursued further training in thoracic and cardiovascular surgery at the University of Toronto. His entire career has focused on general thoracic surgery, starting with his first faculty appointment at Memorial Sloan-Kettering Cancer Center/Cornell Medical College in 1985. In 1988 he moved along with Joel Cooper, MD, to Washington University in St Louis. He was recruited to the University of Pennsylvania in 1991 and was promoted to Professor of Surgery in 1996. Dr Kaiser's special interests include malignant mesothelioma, lung cancer, and mediastinal tumors.

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Lung Volume Reduction Surgery --

ung volume reduction surgery (LVRS) is an operation that was initially proposed and abandoned in the late 1950s but was revived recently as a surgical treatment for patients with severe emphysema, a disease for which there are few other viable therapeutic options. It appears that by excising surgically a portion of the diseased lung tissue, the elastic recoil of the remaining lung is improved (resulting in increased expiratory airflow) and the respiratory muscles are allowed to operate at less of a mechanical disadvantage (resulting in increased inspiratory force and decreased dyspnea). Although a substantial amount of experience has been gained with the procedure, and although there is now little doubt that a subgroup of patients benefit from the operation when it is performed in centers that are equipped to care for this challenging patient cohort, a wide variety of questions remains to be answered. These areas of conl~'oversy include issues as far ranging as patient selection, surgical technique, durability and extent of benefit, and basic questions that surround the physiologic mechanisms of the beneficial effects. The National Emphysema Treatment Trial (NETT) and other prospective, randomized clinical trials have been organized to address many of these outstanding issues. It is hoped that these studies will confirm the many reports that document the benefits to be gained from LVRS and will help to guide the application of this operation in the future. In this monograph, we provide a comprehensive discussion of LVRS. We begin by reviewing the history of surgery for emphysema and the initial attempts at LVRS, as well as detailing the more recent reintroduction of the operation. We then explore the pathophysiologic rationale for LVRS. Traditional medical therapies for emphysema and the surgical option of lung transplantation are reviewed to provide an understanding of the treatments that "compete" with LVRS. Patient selection, perhaps the most critical issue surrounding LVRS, is covered, followed by a presentation of the surgical details of the performance of tung volume reduction by both the median sternotomy and video-assisted thoracoscopic approaches. Finally, we present the published results of LVRS before concluding with a discussion of the current status of the operation in the setting of the ongoing multicenter prospective, randomized clinical trials.

The History of LungVolume Reduction Surgery A number of operations have been proposed to treat patients with emphysema during the course of the 20th century. Although a few of 262

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these operations were based on sound physiologic principles, all had been abandoned before the recent re:introduction of LVRS because of either poor, or at best unpredictable, results.

Early Procedures Costochondrectomy 1 was the first such procedure (1918) and ironically that which is closest in concept to volume reduction. One could consider this procedure to be a "volume reduction in reverse." The German surgeon Freundl resected 4 to 6 costal cartilages on 1 or both sides based on the concept that, by decreasing the compliance of the thoracic cage, he would be allowing the hyperinflated lungs to enlarge further. This may have improved elastic recoil of the lung but likely did the opposite to the chest wall. Nevertheless, he reported relief of dyspnea and improved vital capacity. Thoracoplasty 2 and phrenicectomy3 were clearly misbegotten procedures that were used to reduce the volume of the thoracic cavity and likely worsened dyspnea. Procedures that were used in an attempt to restore the curvature of the diaphragm such as abdominal belting 4 and the creation of pneumoperitoneum5 had advocates in the 1920s and 1930s. Although the goal was laudable and it is possible that these procedures actually improved diaphragmatic: function, they were both impractical and produced variable clinical result~s. A variety of complex operations were devised to disrupt the autonomic nervous innervation of the lung and airways. 6'7 It was hoped that this might decrease bronchoconstriction, reduce mucous secretion, increase pulmonary circulation, or decrease hypoxic respiratory drive, but there is no good evidence that any of these goals were achieved. Nakayama 8 performed his glomectomy procedure, whereby the carotid body was ablated unilaterally or bilaterally, on at least 3914 patients, and he reported good results. Controlled studies, however, showed that the procedure is no better than a sham operation. 9

Operations for Giant gullae The first operations on the lung itself in the treatment of emphysema were introduced for localized bullous, rather than diffuse, disease. We are referring to the presence of giant bullous disease, a situation in which a portion of the lung becomes greatly hyperinflated because of the destruction of alveolar septa and by virtue of this hyperinflation compresses the adjacent lung tissue. Often these individuals have relatively normal lung parenchyma that is being compressed. Head and Avery 1~ adapted Monaldi's 11 intracavitary drainage procedure (originally described for the eurr Probl Surg, April 2000

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treatment of giant lung abscesses) to the treatment of giant bullae. In this procedure, the bulla is decompressed by placing a tube directly into it and allowing it to collapse. The tube remains in place until such time as the air leak ceases. This decompression of the bulla allows for the expansion of the adjacent lung parenchyma, improving the mechanics and gas exchange. Tube decompression of a giant bulla has stood the test of time and continues to be used on an occasional basis in many centers, usually when the patient is judged not to be a candidate for thoracotomy. Most authorities, however, favor actual bullectomy in the setting of a giant bulla with adjacent, more normal lung parenchyma. This procedure, which first became popular in the 1950s, lz was actually the first procedure to use resection of pulmonary tissue in patients with hyperexpanded lungs. This was a counterintuitive concept, considering that one was removing lung tissue in a patient who seemingly needs more lung tissue, not less. Although this remains the procedure of choice for patients with giant bullous disease, it is the patient population with diffuse emphysema that presents significantly greater challenges for treatment and relief of symptoms, and this is the much larger group. Many patients with diffuse emphysema have some component of bullous disease, but these are usually small, multiple bullae instead of a single giant one. Compression of adjacent "normal" lung tissue is not the issue in patients with diffuse emphysema, because they do not have any "normal" lung tissue.

The Introduction of Lung VolumeReductionSurgery Brantigan and colleagues 13-15were the first to attempt therapeutic resection of pulmonary parenchyma in patients with diffuse, nonbullous emphysema. They noted that all areas of the lungs were not involved equally by the pathologic process and that those areas with the greatest amount of destruction were essentially functionless in terms of gas exchange. Furthermore, they noted that the circumferential pull holding the bronchioles open (Fig 1) is significantly impaired in the markedly hyperinflated, emphysematous lung that is essentially "stuffed" into an undersized thoracic cavity (Fig 2). Brantigan and colleagues designed their operation of lung reduction to remove functionless lung tissue that was only contributing to volume. To the volume reduction they added a denervation procedure by lysing vagal nerve branches and branches from the sympathetic system. A reduction in the lung volume was accomplished by resecting or plicating areas of the lung that were "most useless as respiratory tissue." Their goal was to reduce the lung volume such that it would match the size of the pleural cavity on full expiration. 264

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Fig 1. A, Brantigan's concept of how the elastic fibers of the lung and the normal negative intrapbural pressure act together to cause a circumferential pull on small bronchi, holding them open. B, In emphysema, the fibers and the negative pressure are eclch reduced or lost, resulting in loss of the circumferential pull, and reduced bronchial luminal diameter. (F'om Brantigan OC, Mueller E. Surgical treatment of pulmonary emphysema. Am Surg 1957;23:789-804, By permission.) Curr Probl Surg, April 2000

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Fig 2. Brantigan's concept of how a hyperinflated, emphysematouslung is effectively stuffed into an undersized thoracic cavity. (From Brantigan OC, Kress MB, Mueller EA. The surgical approach to pulmonary emphysema.Dis Chest 1961; 39:485-501. By permission.)

Brantigan and colleagues 1315 postulated that by reducing the lung volume, one could (1) restore the radial traction on the terminal bronchioles and thereby reduce expiratory airflow obstruction, (2) elevate the diaphragm to a more normal anatomic position and contour and thereby improve its function, and (3) ameliorate hyperexpansion of the rib cage and thereby improve intercostal muscle function. Starting in 1950, Brantigan and colleagues 13-1s evaluated 89 patients with emphysema who he felt were potential candidates for surgical treatment. The evaluation included chest radiographs with tomograms, fluoroscopy of the chest, bronchoscopy, bronchography, angiocardiography, right heart and pulmonary artery catheterization, and measurement of vital capacity, maximal breathing capacity, and expiratory flow rate. Of the 89 patients, 56 patients underwent operation. No patient was refused 266

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b e c a u s e the disease was too severe; rather, patients were refused because they were judged to have disease that was not severe enough. Patients ranged in age from 16 to 73 years, with an average age of 58 years. Most of the patients (90%) were men with an average duration of symptoms of 70 months (range, 12-192 months). Patients underwent unilateral operations as a rule, but 14 patients had staged, bilateral procedures. Nine patients (16%) died in the postoperative period after the first operation, with no deaths occurring after the second operation. Three patients showed no improvement, but 30 patients (71%) who underwent unilateral operations were improved. Twelve of 14 patients (85%) undergoing bilateral operations were improved. Two of the deaths were din~ctly attributable to technical problems involving the inability to manage a large air leak. It is remarkable that this number is as low as 2, remembering that these operations were performed in the era before stapling devices, when lung tissue to be resected was clamped and excised, and the cut edge was sutured closed. Often at the conclusion of the procedure 1 hour or more would be spent solely in an attempt to seal the air leaks that occurred within the pulmonary parenchyma. When lung volume was reduced too much and there was not enough parenchyma to fill and obliterate the space, the air leaks persisted, ultimately resulting in the patients' deaths. Two patients died because they were left with insufficient lung tissue to sustain gas exchange. Of great interest is that 2 patients died "on the hottest day of summer in 1953." Although we have come to take air conditioning for granted, this was not so in the 1950s. Brantigan recognized that a bilateral operation was the procedure of choice but noted that some patients achieved such significant improvement in their symptoms that they chose to forgo a second operation. He did not report on pulmonary function measurements, but he did say that these were performed on some patients. These procedures were performed during the infancy of pulmonary function studies, and the tests were not readily available and were not well validated. He based his determination of improvement on the patients' reports and the increase in ventilation of the lung noted by the presence of breath sounds that were formerly absent. He understood that the patient with other pulmonary disease in addition to emphysema posed difficult problems and an increased risk for surgery, but if the associated disease did not occupy much volume it could be excised as part of the volume reduction procedure. As such, he recognized that a patient with a lung cancer and emphysema could undergo a lobectomy and potentially be less dyspneic after the operation because ventilation is iraproved. Curr Probl Surg, April 2000

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Brantigan had occasion to follow many of his postoperative patients long-term, and he noted that the improvement realized with the lung volume reduction persisted for as long as 8 years after operation. In his experience, no patient who experienced improvement lost what he had gained. Obviously, these observations were based on the surgeon's subjective impression and not on rigorous pulmonary function measurements. However, this surgeon was clearly ahead of his time and took on patients for operation who were significant operative risks long before we had sophisticated ventilators or even monitoring capability. The operations were tried at several other centers, often with far less success, 16translated as higher mortality rates, and mostly were abandoned by the early 1960s. In 1965, Knudson and Gaensler 17 reviewed the history of surgery for emphysema and had significant reservations about Brantigan's operation, thus further contributing to the decline in popularity of the procedure. The problem of massive air leaks could not be addressed effectively. In 1989, Dahan and colleagues 18 presented data from 10 patients who underwent reduction in lung volume where he sought to define the selection criteria for operation on the basis of hemodynamic data. He used the concept of dynamic expiratory compression of venous and pulmonary arterial flow and suggested that it might be possible to predict who would have significant improvement and who would continue to experience deterioration. Five of the 10 patients experienced improvement after a unilateral procedure, and all had a high compression index before the operation.

The RecentReintroductionof Lung Volume ReductionSurgery The current era of LVRS began with the pioneering work of Cooper and colleagues ~9 at Washington University in St Louis, Missouri. Having accumulated the world's largest experience with lung transplantation, they had been thinking about the problems related to end-stage lung disease for a number of years and were particularly interested in end-stage emphysema. This interest was related in no small part to the fact that there were so many patients with emphysema who were potential candidates for lung transplantation and, unfortunately, so few donors. The double lung transplantation that they had devised and performed successfully in a small number of patients who required replacement of both lungs proved to be problematic with respect to airway healing and the mandatory use of cardiopulmonary bypass. The concept of single lung replacement in patients with emphysema evolved from the difficulties with the en-bloc double lung replacement procedure and a recognition that older patients likely could not tolerate a procedure of such mag268

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nitude. Cooper and colleagues felt that a single lung, albeit somewhat oversized for a particular recipient, would be sufficient and predicted correctly that differences in airway resistance between the newly transplanted lung and the remaining native lung would not result in dramatic over-inflation of the native lung. They successfully implanted a single lung in a 62-year-old man with emphysema who did well, and they began to offer single lung transplantation preferentially to older patients with emphysema. From a functional standpoint, the patients with single lung transplants did quite well--not as well as those patients with emphysema who received bilateral lung transplants, but better than would be expected. Cooper and colleagues reasoned that either those patients who received 2 lungs were not able to exercise at their full capacity or that those patients who received 1 lung were performing better than could be accounted for by the function of the transplanted lung alone. It had been noted previously that the bony hemithorax, ,expanded by the native emphysematous lung, would reconfigure to the smaller, transplanted lung within several weeks. The seminal observation made by Cooper and colleagues was that the contralateral, nontransplanted side changed as well. Whether because of the shift in the mediastinum toward the transplanted side or to the reconfiguration of the bony hemkhorax, the contralateral hemidiaphragm was noted to have assumed a more normal position and contour. They postulated that a volume reduction of sorts was occurring on the contralateral side that was leading to improved elastic recoil and better diaphragmatic excursion and theIeby more effective respiration. So, single lung recipients were actually behaving more like bilateral lung recipients because of changes occurring passively on the nontransplanted side. Cooper and colleagues 19began evaluating patients with emphysema and attempted to determine who might benefit most from a volume reduction procedure. The initial patients were screened very carefully. Those selected then underwent at least 6 week,~ of supervised pulmonary rehabilitation before operation, All credit must go to Dr Cooper who was wilting to resurrect Brantigan's operation but did so only after careful, meticulous planning and thought. The report of his initial 20 patients that was presented at the meeting of the American Association for Thoracic Surgery in New York in 1994 created tremendous excitement. 19 The procedure was performed by way of a median stemotomy, and 20% to 30% of the volume of each lung was resected with a linear stapler. To minimize postoperative air leaks, strips of bovine pericardium were used to buttress the staple tines. There were no postoperative deaths, and no patient required ventilatory assistance in the postoperative period. The mean forced expiratory volume Curr Probl Surg, April 2000

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in 1 second (FEV1) improved by 82% in this initial group of patients; reductions in total lung capacity, residual volume, and trapped gas also were highly statistically significant. Patients noted a marked relief in dyspnea and noted improved quality of life and exercise tolerance. A number of groups around the world began performing this procedure on the basis of these exciting initial results. Many groups noted results similar to those reported by Cooper and colleagues, and these will be reviewed later in this monograph. Many other groups (primarily in centers with little experience in dealing with patients with severe emphysema) had significantly worse results. A Current Procedural Terminology (CPT 9) code was established for LVRS, and over a 1-year period almost 800 patients were reported to Medicare with the use of this code. The mortality rate for this group approached 30%, causing significant concern on the part of the Health Care Financing Administration (HCFA). Many other patients were undergoing the procedure, but it was being coded as bullectomy or wedge excisions, and these could not be tracked as easily. After further investigation and a determination by HCFA that the procedure was investigational, a decision was made to suspend reimbursement for the procedure in January 1996, pending further study.

Current PathophysiologicConcepts Emphysema is best defined in anatomic terms and is recognized pathologically as enlargement of alveoli and destruction of their walls, causing them to become confluent and to form grossly oversized air spaces. Emphysema is further characterized as having an absence of obvious fibrosis, thereby differentiating it from primary fibrotic processes that can enlarge the airspaces. Centriacinar emphysema, the pattern most frequently associated with smoking, most commonly involves the upper lobes and the superior segments of the lower lobes and may be quite focal. Panacinar emphysema more often affects the basilar segments and is usually encountered in patients with o~-1-antitrypsin deficiency. Although the distinction can be murky, emphysema is usually distinguished from chronic bronchitis (the other form of chronic obstructive pulmonary disease [COPD]). In so-called "pure" emphysema, the airflow obstruction results from disease of the lung parenchyma and produces the classic "pink puffer." In predominant chronic bronchitis, obstruction results from intrinsic disease of the airways and is seen clinically as the "blue bloater." Certainly, most patients have a combination of these 2 forms of COPD, demonstrating variable degrees of both airway and alveolar disease. Because airway narrowing that results from the structural abnormalities of emphysema fits nicely into the conceptual 270

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Fig 3. Photomicrograph shows a small airway in the normal lung (A) versus the loss of tethering of small airways in emphysema [B). The picture in Fig 3, B results from anatomic loss of interstitial tissue and physiologic loss of elastic recoil. (l:rom Lamb D. Pai'hology. In: Calverley P, Pride N, editors. Chronic obstructive pulmonary disease. London: Chapman & I--rail; 1995. p 9-34. By permission.)

framework of how LVRS might be effective (whereas it is difficult to conceptualize how airflow obstruction that results from intrinsic narrowing of the airways [such as that seen in chronic bronchitis] might benefit from LVRS), interest has recently been rekindled in distinguishing the respective roles of emphysema and chronic bronchitis in the clinical syndrome of COPD. Most groups have sought to apply LVRS to patients in whom COPD is predominantly of the emphysema type. This discussion therefore focuses on emphysema over chronic bronchitis. Both centriacinar and panacinar emphysema are associated with loss of elastin, and possibly collagen, in the lung tissue, a~Elastin is a rubber-like polymer that is the principal component of the elastic fibers that make up a large part of the extracellular matrix of the lung. From elastin, the lung derives the important elastic properties that help determine static lung volumes, that are responsible for pas~sive exhalation, and that are critical to maintaining patent airways (Fig 3). According to the most widely held theory of the pathogenesis of emphysema (the proteinase-antiproteinase hypothesis), patients with emphysema have an imbalance between proteinases and antiproteinases in favor of the former. The proteinases are derived from inflammatory cells that, in smokers, are particularly abundant. The antiproteinases, particularly a-1antitrypsin, are normally abundant in the lung but may be reduced in persons with emphysema. With an imbalance of elastases over antielastases and collagenases over anticollagenases, the lung elastin and/or collagen are thought to be reduced, resulting in emphysema. Interestingly, the prinCurr Probl Surg, April 2000

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cipal animal model of emphysema (elastase-induced emphysema) is created by introducing elastase intratracheally. Expiratory airflow obstruction occurs late in the course of the disease and is reflected most accurately in decrements of the FEV r With loss of elastin, a number of elastic properties that are important to normal airflow are compromised. First, the elastic recoil of the lung, which in normal patients renders quiet exhalation a passive process, is greatly diininished in severe emphysema. In addition to reducing the driving pressure that favors exhalation, this loss of elastic recoil allows progressive overexpansion of the lung with increasing residual volume and total lung capacity. Furthermore, the loss of elastin results in a dramatic loss of mechanical support of the small airways. 21 In normal patients, these airways, 2 mm or less in diameter, are held open by intact surrounding lung parenchyma that provides radial traction at points where alveolar septa attach to hronchioles. In patients with emphysema, loss of these attachments that result from the destruction of the extracellular matrix of elastin and collagen is thought to cause airway narrowing (Fig 3). In addition to having fewer alveolar wall attachments, emphysematous lungs are also thought to exert less radial force on the few remaining attachments because the hyperexpanded lung is crowded into a relatively undersized thorax and therefore is less able to create outwardly directed forces (Figs 1 and 2). In addition to changes in the airways themselves, airflow limitation in emphysema is thought to result from compromise of the respiratory muscles in these patients. 22 Hyperexpansion of the lung pushes the diaphragm in a caudad direction. The curvature of the diaphragm is thereby reduced, forcing its muscle fibers to operate at shorter-than-normal lengths. Although controversialY ,~4 many physicians believe that this causes a decrement in the diaphragm's ability to generate negative intrathoracic pressure. The accessory muscles of respiration and intercostal muscles are similarly, but probably less markedly, forced to operate at an unfavorable position on their length-tension curves. The diaphragm's zone of apposition to the lower ribs decreases in size, reversing the effect of diaphragmatic contraction on the lower rib cage from causing expansion, thereby aiding inspiration, to creating an expiratory force. The overall elastic recoil of the thoracic cage, which is normally directed outward, becomes directed inward because of its overdistension, creating an "'inspiratory elastic load" and further decreasing the efficiency of breathing: Finally, these disadvantaged muscles must work constantly against an increased load created by the increased airflow resistance, such that the overall work of breathing is increased. It has been demonstrated recently that the diaphragm of patients with emphysema adapts to this chronically loaded 272

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condition by altering its expression of myosin heavy-chain isoforms towards those with slow-twitch, nonfatiguing characteristics. 2s Emphysema also has deleterious effects on cardiac function. Limitation of cardiac filling by the hyperinflated lung has been demonstrated, such that during exercise the left and/or right ventricles may be compressed, with an elevation of the pulmonary capillary wedge pressure, z6 The essential concept of LVRS is that, by resecting some amount of emphysematous lung, these pathophysiologic changes demonstrated by patients with emphysema could be impacted positively. Removing the most diseased lung tissue should allow expansion of the remaining tissue to fill the thoracic cavity, thereby increasing the elastic recoil of that remaining tissue. This would theoretically increase the radially directed forces on the small airways, improving their pathologic narrowing, and increase the driving force for exhalation. The combination of these effects should be to decrease expiratory airway resistance and to increase airflow. Reducing the overall lung volume should also improve the performance of the diaphragm and perhaps the other respiratory muscles of patients with emphysema. The diaphragm would be allowed to return towards its normal curvature (Fig 4) and thereby theoretically move more air with each inspiratory sweep. The diaphragm and the other respiratory muscles' resting lengths would be returned towards the normal optimal length, and their mechanical disadvantage would be reduced. The abnormal load imposed on the inspiratory muscles by the reversal of chest wall recoil, which occurs because of hyperexpansion, would also be expected to improve. Because dyspnea in COPD is closely related to respiratory muscle function, 27 these alterations in respiratory muscle physiologic condition might be anticipated to improve dyspnea. Additional anticipated therapeutic affects of the procedure may include decreased ventilation/perfusion mismatch and improved cardiovascular hemodynamics. If resection is targeted to the most severely affected areas (those with retention of inspired gas and the least perfusion), hypercarbia may be improved. At the same time, shunting in adjacent, atalectatic regions may be reduced, thereby improving hypoxia. With regard to the heart, it is possible that fight and/or left heart function might be improved after LVRS as a result of recruitment of hypoperfused pulmonary capillaries and reduction of pulmonary a~ery pressures or by virtue of increased systemic venous return that results from a reduction in intrathoracic pressures. The published results with LVRS to date suggest that many, if not all, of these anticipated beneficial effects are accomplished in properly selected patients. Curr Probl Surg, April 2000

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A

B Fig 4. Preoperative (A) and postoperative (B) posteroanterior and lateral chest radiographs. Note the hyperexpanslonand depressed,flattened diaphragms on the preoperative films and the reversalof these changes on the postoperative films.

Adjunctive and Alternative Therapies to Lung Volume Reduction Surgery The management of patients with advanced emphysema requires familiarity with the potential benefits and limitations of tile available medical and surgical options. Given the indolent course of emphysema and the inherent reserve of the respiratory system, a substantial amount of lung function is often lost before patients seek medical attention. Medical ther274

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apy may reduce symptoms, slow disease progression, and improve survival, but it can do little to restore lost lung function and does not halt the slow downhill course of the disease. Surgical treatment offers the only significant hope for patients who have lost so much pulmonary function that they consider their severe dyspnea and limited lifestyle unacceptable after exhaustion of the available medical interventions. In addition to LVRS, lung transplantation may be considered for patients with advanced emphysema but differs dramatically from LVRS in its availability, risks, and functional outcomes.

Medical Therapy Smoking cessation and treatment of hypoxia are the only 2 medical interventions associated with improved disease course and survival. 28-3l The severity of airflow obstruction (as assessed by the postbronchodilator FEV1) is an important predictor of prognosis. When this value falls below 30% of the predicted normal value, the survival rate is approximately 87% at 1 year, 72% at 2 years, and 59% at 3 years. 32 Smoking cessation reduces the rate of decline in FEV v Continuous supplemental oxygen is indicated for all patients with resting PaO 2 of 55 mmHg or less or oxygen saturation less than 88%. For patients with secondary polycythemia, cor pulmonale, or pulmonary hypertension, continuous oxygen is indicated when the PaO 2 is 59 mmHg or less or oxygen saturation is 89% or less. The need for supplemental oxygen must also be addressed during sleep and exertion.33 Additional therapeutic goals include relief of airflow obstruction, improvement in exercise tolerance, reduction of symptoms, and improved quality of life. Bronchodilating agents (inhaled ~-agonists and/or ipratropium) represent first-line pharmacologic therapy. Administration by metered-dose inhaler with a spacer leads to adequate drug delivery while minimizing systemic side effects. If symptoms persist, longer-acting agents, such as inhaled salmeterol or extended-release theophylline, may be added to this regimen. Although systemic corticosteroids are indicated for the treatment of acute exacerbations, chronic steroid therapy plays a limited role in the management of emphysema. Approximately 10% of patients may exhibit improvement, and it is therefore important to document a response. 34 Systemic corticosteroids are associated with significant side effects, and patients whose condition fails to respond should not receive chronic therapy. The dosage in responders should be tapered to the lowest possible level. The role of inhaled corticosteroids in the treatment of emphysema is a subject of ongoing investigation. Pulmonary rehabilitation consists of aerobic and resistive exercise trainCurr Probl Surg, April 2000

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ing, education, breathing retraining, energy conservation techniques, nutrition, and psychosocial support. 35 Although effects on survival and pulmonary function have not been demonstrated, pulmonary rehabilitation results in improved exercise performance and reduced symptomsJ 6 The role of pulmonary rehabilitation in preparing patients for LVRS or lung transplantation has not been studied, although significantly reduced exercise tolerance has been associated with greater risk for postoperative complications in patients who undergo LVRS or lung resection for c a n c e r 37,38

Assessment, treatment, and prevention of comorbid conditions associated with advanced emphysema are also essential. Weight loss is common in advanced emphysema, and poor nutritional status is associated with decreased physical performance, respiratory muscle function, and overall survival. Nutritional supplementation to achieve weight gain can lead to improvement in these parameters. 39 Cachexia or significant unplanned weight loss should only be attributed to advanced emphysema after other causes have been excluded. Patients who are postmenopausal or nutritionally compromised or who have a history of chronic steroid use should also be evaluated for osteoporosis. All patients should receive vaccination against influenza and pneumococcus. Review and, if necessary, adjustment of medical therapy is an essential component in the evaluation of candidates for LVRS. Patients and physicians must assess how much improvement may be gained from optimal treatment, including pulmonary rehabilitation, before proceeding with operation. Patients undergoing LVRS should be on a stable regimen, and operation should be delayed for patients who experience an acute decline from their baseline at the time of or just before operation. Given the elective nature of this procedure, any factors that may adversely affect the outcome must be addressed before LVRS. It should be emphasized that none of the described medical therapies for emphysema can halt the progressive loss of pulmonary function characteristic of the disease, and patients tend to progress despite these medical interventions. When the disease has progressed to a degree that the patient's quality of life has become unbearable, the surgical options of LVRS or lung transplantation may be considered in appropriate candidates.

Lung Transplantation A small subset of patients with far-advanced emphysema may be candidates for lung transplantation, and this subset may overlap with those candidates being considered for LVRS. Lung transplantation was first 276

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attempted in 1963; but, despite multiple attempts over the ensuing 2 decades, long-term survival after lung transplantation was not achieved until 1983. 4~ Successful bilateral lung transplantation for emphysema was first achieved in 1986, and successful single lung transplantation for emphysema was first achieved in 1988. 42,43 Since then, more than 9000 lung transplantation procedures have been performed worldwide, with a current rate of approximately 1200 procedures per year. Approximately 45% of all lung transplantations have been performed for patients with COPD. 44 Patient Selection for Operation. Transplantation may be offered when further medical or other surgical therapy is unavailable or inadvisable, when the expected survival is limited, and when significant comorbid medical conditions are absent. Typical age limits are 65 years and under for single lung transplantation and 60 years and under for bilateral lung transplantation.45 Patients must be ambulatory, abstinent from smoking, and able to participate in a pulmonary rehabilitation program. Transplantation for emphysema may be considered when the postbronchodilator FEV 1 is below 25% of predicted or significant hypercapnia (PaCO 2 >55 mmHg), hypoxemia, or secondary pulmonary hypertension are present. A rapid decline may prompt being listed at an earlier time. Comorbid conditions likely to increase the risk or limit the survival may preclude transplantation. Absolute contraindications include significant renal, hepatic, or cardiac dysfunction; severe coronary artery disease; progressive neuromuscular disease; recent active malignancy (excluding basal or squamous cell skin carcinoma); and HIV or active hepatitis infection (Hepatitis B with positive antigen or Hepatitis C with histologic evidence of liver disease). Symptomatic osteoporosis; severe musculoskeletal disease, high-dose corticosteroid use (above 20 mg prednisone daily), ventilator dependence, severe deconditioning, poor nutritional status (<70% of ideal body weight), morbid obesity (> 130% ideal body weight), significant psychiatric illness or psychosocial problems, active substance abuse within 6 months, active mycobacteria or fungal infection, or other poorly controlled chronic medical conditions are additional relative contraindications.45 Specific listing criteria and evaluation protocols may vary between centers. Pulmonary function testing, chest radiography, quantitative ventilation perfusion and/or computed tomography (CT) scanning are used to assess disease severity and distribution. An assessment of the disease distribution is useful in the determination of which lung should be replaced in the setring of single lung transplantation and the evaluation of the patient simultaneously for LVRS. Exercise testing or 6-minute walk testing determines the Curr Probl Surg, April 2000

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overall conditioning and oxygen requirements. Echocardiography, radionuclide scanning, and right and left heart catheterization may be performed to assess for pulmonary hypertension, cardiac dysfunction, and coronary artery disease. Additional testing includes the assessment of hepatic and renal function, lipid profile, viral serologies, blood and tissue typing, measurement of preformed anti-human leukocyte antibodies, bone densitometry, PPD and anergy testing, and age-appropriate screening for malignancy. Patients who meet center-specific criteria are placed on the waiting list. In the United States, where allocation is based on time accrued on the list, the median waiting time is 1.5 years. In 1997, 928 lung transplantation procedures were performed for all indications, including emphysema, in the United States, and 1876 patients were added to the waiting list. 46 Technical Aspects: Single versus Bilateral Procedures. Single lung transplantation is the procedure most conunonly performed for emphysema, and it is accomplished with posterolateral thoracotomy or anterolateral muscle-sparing thoracotomy. Ventilation and perfusion of the native lung during implantation usually permits adequate gas exchange and blood flow. After explantation of the native lung, the allograft is implanted by establishing 3 anastomotic connections. Single lung transplantation for emphysema (Fig 5) creates unique physiologic constraints. Perfusion is preferentially distributed to the allograft because of its lower pulmonary vascular resistance in comparison to the native lung. The combination of increased airflow resistance and elevated static compliance in the native lung predisposes to hyperinflation of the native lung, particularly in the setting of mechanical ventilation. In most cases, these relationships do not significantly compromise allograft function or gas exchange. However, when allograft dysfunction necessitates prolonged mechanical ventilation, the compliance differential between native and transplanted lungs is magnified; and marked hyperinflation of the native lung may compromise ventilation of the allograft, leading to hypoxemia, hypercapnia, and hemodynamic compromise. This complication may be managed with the use of independent lung ventilation. 43,47,48 Bilateral lung transplantation is performed with a transverse thoracosternotomy incision or bilateral anterior thoracotomy or anterolateral musclesparing thoracotomy incisions. Transplantation is accomplished by a bilateral sequential technique with ventilation and perfusion of 1 native lung during implantation of the first allograft followed by ventilation and perfusion of the first allograft to permit implantation of the second allograft. The presence of severe pulmonary hypertension and/or inability to tolerate single lung ventilation or perfusion necessitates the use of cardiopulmonary bypass. In reported series, 0% to 2% of single lung trans278

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Fig 5. Chest radiograph o~:a 50-year-old man 7 months after uncomplicated right single lung transplantation for emphysema. The native left lung is hyperinflated with a shift of the mediastinum to the right side.

plantation procedures and 3% to 20% of bilateral lung transplantation procedures performed for emphysema required cardiopulmonary bypass. 49-5~The choice of single or bilateral lung transplantation is based on patient age, physiologic considerations, donor organ availability, functional outcomes, and survival. Single lung transplantation accounts for over 75 % of lung transplantation procedures performed for emphysema,a4 Single lung transplantation is a technically and physiologically less demanding procedure and is therefore preferred for older and more tenuous patients. This procedure permits 2 recipients to benefit from a single donor, thereby maximizing the use of scarce lung allografts. Outcomes after Lung Transplantation for Emphysema. Both single and bilateral lung transplantation produce significant improvement in FEV1, gas exchange, and exercise tolerance (Fig 6). The FEV 1 is usually slightly greater than 50% of predicted after single lung transplantation Curr Probl Surg, April 2000

279

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Fig 6. Comparison of changes in FEV1 (A) and 6.minute walk distance (8) after single lung transplantation [SLT), bilateral lung transplantation (BLT), and bilateral LVRS. Although bilateral lung transplantation results in a much greater increase in FEV~ than does single lung transplantation, improvements in the 6minute walk distance are similar. Both single lung transplantation and bilateral lung transplantation produce greater improvements in FEV1 and the 6-minute walk distance than does bilateral LVRS. It is the morbidity rate, long-term mortality rate, and limited availability of transplantation that suggest the need for an alternative surgical approach, such as LVRS, to emphysema. Pre, Preoperative values with 6MWT performed after 12 weeks of pulmonary rehabilitation; Post, postoperative values obtained 3 to 6 months after surgery. (From Edelman JD, Kotloff RM. Surgical approaches to advancod emphysema. Respir Care Clin N Am 1998;4:513-39. By permission.) 280

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and normal or nearly normal after bilateral lung transplantation. Despite this difference in lung function, 6-minute walk distances are only slightly greater after bilateral procedures than after unilateral procedures. Maximum oxygen uptake measured by cardiopulmonary exercise tests ranges from 40% to 60% of predicted, with no significant difference between single and bilateral transplant recipients. Reduction in exercise tolerance is not related to ventilatory or gas-exchange factors but more likely to cardiovascular limitations, deconditioning, and skeletal muscle dysfunction because of steroids, cyclosporine, and chronic illness) 2-59 The overall, 1-, 3-, and 5-year survival rates after transplantation for emphysema are 81%, 63%, and 42%, respectively. 46 Experience and outcomes may vary between centers, and 3-year survival rates exceeding 80% have been reported. 58 Beyond the first year, bilateral lung transplantation appears to confer over single lung transplantation a survival advantage that reaches statistical significance after 3 years. 44 The greater functional reserve afforded by the bilateral procedure may permit recipients to better tolerate the detrimental impact of chronic rejection. In addition, differences in age, severity of illness, and accompanying comorbidity between single and bilateral transplant recipients may also contribute to the difference in survival rates. Complications. Despite careful recipient selection and donor management, complications after lung transplantation are common. Within the perioperative period, infection, primary allograft dysfunction, and surgical complications contribute to the mortality rate. Infection that results from the requisite immunosuppression is the most common cause of death during the first year and remains a significant cause of death in subsequent years. Chronic rejection, however, is the major limitation to long-term survival. 44 Chronic rejection manifests as bronchiolitis obliterans, a fibroproliferative process that affects the small airways and leads to a progressive decline in airflow. In contrast to acute rejection, chronic rejection frequently fails to respond to manipulation of the immunosuppressive therapy. Lung transplantation mandates life-long immunosuppressive therapy. In addition to increasing the risk for infection, this regimen is associated with the development or potentiation of hyperglycemia, hypertension, hyperlipidemia, coronary artery disease, osteoporosis, chronic renal insufficiency, and increased risk for malignancy.

Lung Transplantation and Lung Volume Reduction Surgery. The change in lung function and exercise tolerance after transplantation is much more dramatic than that observed after LVRS (Fig 6). However, LVRS is associated with a lower perioperative mortality rate and avoids the added risks of immunosuppression and rejection. Although the availabiliCurr Probl Surg, April 2000

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ty of lung transplants is limited by the scarcity of donor organs, LVRS is potentially available to a much greater number of patients. Selection criteria for LVRS are less stringent than those for lung transplantation. Patients over age 65 years who are not candidates for transplantation may still undergo LVRS. Although poor functional status, active cigarette smoking, high-dose steroid use, and significant coronary artery disease may preclude both procedures, other comorbid medical conditions may be considered contraindications to transplantation but not LVRS. The severity of emphysema may determine the choice of procedure. Although LVRS may be offered to patients with an FEV~ of less than 45% predicted, lung transplantation is generally not considered until the FEV~ falls below 25% of predicted. More advanced disease with an FEV~ of less than 15% of predicted or severe homogeneous distribution may warrant transplantation rather than LVRS. The presence of significant pulmonary hypertension or severe chronic bronchitis precludes LVRS but not transplantation. Some patients may be considered simultaneously for both LVRS and transplantation. In this setting, LVRS may improve function sufficiently to permit patients to tolerate the prolonged waiting period until donor organs become available or to actually defer transplantation altogether.6~ Patients who experience ongoing deterioration after LVRS may then undergo transplantation. If lung function deteriorates after transplantation, options are much more limited. The 1-year survival rate after retransplantation is below 50%; because of this high risk, retransplantation is rarely considered.62 Occasionally, progressive hyperinflation of the native lung may compromise allograft function. After exclusion of other causes of late graft dysfunction (eg, bronchiolitis obliterans, anastomotic stenosis, infection), volume reduction of the native lung has been reported to be of benefit.63,64 To summarize, then, smoking cessation and oxygen therapy for patients with hypoxia may improve survival rates for patients with emphysema, but other medical therapies are palliative and do not dramatically impact the downward course of the disease. When selected patients reach a point of severely limited lifestyle because of their dyspnea, they may consider LVRS or lung transplantation. Transplantation, because of the apparently higher perioperative and long-term morbidity, is generally considered only in patients who are felt to be poor candidates for LVRS or in those patients whose pulmonary dysfunction is so severe that only transplantation is likely to improve their condition sufficiently to make an impact on their quality of life. LVRS in well-selected cases, on the other hand, may serve as a "bridge to transplantation" or to obviate the need for transplantation entirely. 282

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Patient Selection for Operation Cooper and colleagues 19 reported refusing 80% of the patients who were referred for LVRS. It is likely that their stringent patient selection criteria were in large part responsible for their excellent early results. Conversely, the anecdotal, unpublished mortality rates of up to 50% at some institutions possibly were due, in part, to poor patient selection. This mirrors the early experience with lung transplantation where perhaps the primary factor that led to success was the recognition of which patients were the best patients. This remains a critical area of controversy, and one in which the NETT hopefully will contribute useful information. Many groups have expressed opinions about the indications and contraindications for LVRS and about which patients are most likely to benefit from the procedure without providing any objective data to support these opinions. Criteria that have been suggested range from specific numeric recommendations (eg, FEV 1 above and pulmonary artery pressures below a certain level) to more subjective evaluations of, for example, a patient's anxiety level (which many groups have suggested predicts a difficult postoperative course). A reasonable distillation of these many criteria according to what little data are available and the application of common sense can be found in Table 1, which lists the inclusion and exclusion criteria used by the NETT.

pCO 2 A few studies have specifically addressed the question of patient selection. Szekely and colleagues 38 reviewed the preoperative characteristics of the first 47 patients who underwent bilateral LVRS by median sternotomy at Massachusetts General Hospital and identified both PaCO 2 greater than 45 mmHg and an inability to walk more than 200 m on the 6-minute walk test after a pulmonary rehabilitation program to be highly predictive of death and of a hospital stay of greater than 21 days. Ferguson and colleagues 65 have also noted increased early death in patients with either preoperative higher resting dead space ventilation/total ventilation ratio (median, 53 in nonsurvivors vs 43 in survivors) or higher resting PaCO 2 (median, 52 vs 40).

Inspiratory Resistance Ingenito and colleagues 66 measured lung resistance during inspiration, static recoil pressure at total lung capacity, static lung compliance, expiratory flow rates, and lung volumes in 29 patients before LVRS in an attempt to find a reliable means of identifying patients most likely to benefit from the operation. The technique used for LVRS differed slightly in Curr Probl Surg, April 2000

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TABLE 1. Inclusion and exclusion criteria for the NETi" Inclusion criteria History and physical examination consistent with emphysema Nonsmoker (tobacco products) for 4 months before initial interview and a nonsmoker throughout screening Postbronchodilator total lung compliance, _>110% predicted Postbronchedilator RV, ->220% predicted Postbronchodilator FEVl, _<45% of predicted; if age _>70 years, postbronchodilator FEV~, _>15% of predicted FEV1 postbronchedilator increase, _<30%or _<300 mL Carbon dioxide diffusion in the lungs, _<70%of predicted HRCT scan evidence of moderate to severe, bilateral, heterogeneous emphysema, or moderate to severe, bilateral, homogeneous emphysema (if emphysema is homogeneous, additional physiologic criteria may be required) Approval for surgery by cardiologist if any of the following findings are noted before randomization (approval must be obtained before randomization): Unstable angina Left ventricular ejection fraction, <45% Dobutamine-radioactive nuclide cardiac scan indication of coronary artery disease or ventricular dysfunction Premature ventricular beats/rain (does not apply during exercise testing), >5 Cardiac rhythm, other than sinus or premature atrial contractions, during resting electrocardiography S3 gallop on physical examination Approval for surgery by pulmonary physician and thoracic surgeon in consultation with the anesthesiologist, after rehabilitation, and just before randomization Signed consent for screening and patient registry Signed consent for pulmonary rehabilitation Signed consent for randomization to treatment Exclusion cgteria BMI as of randomization, >31.1 kg/m 2 (male patients) or >32.3 kg/m 2 (female patients) Unplanned weight loss, >10% of usual weight within 90 days before initial interview or before randomization Resting PaCO2, >60 mmHg (55 mmHg in Denver); or PaO2 (room air), <50 mmHg (40 mmHg in Denver) Pulmonary hypertension (mean P~, _>35 mmHg; or peak systolic P~, _>45mmHg) Recurrent infections with sputum, >3 T (>45 mL) per day Previous laser or LVRS Pleural or interstitial disease that precludes surgery Giant bulla (_>89the volume of the lung in which the bulla is located) Clinically significant bronchiectasis Pulmonary nodule requiring surgery Previous coronary artery bypass surgery Myocardial infarction within 6 months of interview and ejection #action, <45% Congestive heart failure within 6 months of interview and ejection fraction, <45% Uncontrolled hypertension (systolic, >200 mmHg; or diastolic, >110 mmHg) History of exercise-related syncope Resting bradycardia (<50 beats/min), frequent multifocal premature ventricular contractions, or complex ventricular arrhythmia or sustained supraventricular tachycardia Other cardiac dysrhythmia that, in the judgment of the supervising physician, might pose a risk to the patient during exercise testing or training

284

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Oxygen requirement exceeding 6 L/min to keep saturation at _>90%during an oxygen titration assessment 6-Minute walk distance, <140 m during postrehabilitation 6-minute walk test Evidence of systemic disease or neoplasia that is expected to compromise survival over the duration of the trial Any disease or condition that may interfere with the completion of tests, therapy, or follow-up Inability to complete successfully any of the screening or baseline data collection procedures Plasma cotinine measured during the prerehabilitation assessments and during the postrehabilitation assessments in patients who are not using nicotine products; patients not using nicotine products who test positive for nicotine (plasma cotinine, >13.7 ng/mL) at any time For patients who are still using nicotine products, but who are reported to be nonsmokers, measurement of arterial carboxyhemoglobin during the prerehabilitation and postrehabilitation assessments to confirm their status as nonsmokers; patients who test positive for carboxyhemoglobin (>2.5% of total hemoglobin) at any time NEFF, National EmphysemaTreatmentTrial; FEV,forced expiratoryvolume; RV, residual volume; HRCT,high-resolution computedtomography;LVRS,lung volume reduction surgery.

that unilateral sequential plication-type procedures were performed, with the first procedure separated from the second procedure by a period of time ranging from 8 weeks to 8 months. Univariate analysis from this relatively small group showed that only preoperative inspiratory lung resistance correlated with a change in the postoperative FEV 1. This finding was confirmed with multivariate analysis as well. An inspiratory resistance of 10 cm of water per liter per second had a sensitivity of 88% and a specificity of 92% in identifying patients who were likely to benefit from LVRS. Thus it seems that patients with lower inspiratory resistance are likely to respond best to lung volume reduction. This would seem to confirm the clinical impression that this is an operation for patients with emphysema (pink puffers) rather than patients with predominant chronic bronchitis (blue bloaters).

HeterogeneousDisease McKenna and coUeagues67 reviewed a group of 154 patients who underwent bilateral video-assisted thoracoscopic surgery (VATS) LVRS, looking for predictors of optimal clinical outcome as measured by improvement in the FEV 1 and dyspnea scale. These investigators found that an upper-lobe heterogeneous pattern of emphysema on CT and/or nuclear scan was the best predictor of good outcome, whereas preoperative FEV v residual volume, total lung capacity, diffusing capacity, and arterial blood gases had no association with the outcome. They did find that patients on 4 L or more of oxygen had slightly less improvement than others. Several other groups have also supported the concept of heterogeneous emphysema as a predictor of outcome. Maki and colleagues 6s looked simCurr Probl Surg, April 2000

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ply at the preoperative chest radiographic findings as a predictor of outcome and concluded that this study alone, when evaluated by an experienced observer, may be sufficient for initial screening. Significant heterogeneity (as seen on the plain radiograph) and lung compression were highly predictive of a favorable functional outcome. In another study, CT scans were reviewed retrospectively by blinded reviewers and graded for heterogeneity. This study found that the patients whose conditions were "markedly heterogeneous" had an increase in FEV 1 of 81%, whereas the group with "moderately heterogeneous" conditions improved by only 44%. Notably, however, even those patients with homogeneous emphysema improved significantly, although less, with an increase in FEV 1 of 34%. 69 With the 6-minute walk test as the outcome measure, patients at the University of Pennsylvania were also shown to have a better outcome if they had apical localization of emphysema, 7~ and the Washington University group reported similar data. 7~ Jamadar and colleagues 72 evaluated ventilation/perfusion scans with single-photon emission tomography as a predictor for outcome after LVRS. An emphysema index (extent x severity) for the upper and lower halves of the lung and an emphysema index ratio for upper to lower lung were calculated. The mean perfusion emphysema index ratio differed significantly between those patients who undergo LVRS and those who are excluded from LVRS because of a lack of apical disease as assessed by chest CT. There was a moderate correlation between the perfusion emphysema index ratio and changes in FEV 1 at 3, 6, and 12 months. Patients who were selected to undergo LVRS had more severe apical hypoperfusion than patients who were excluded from LVRS on the basis of their chest CT findings. Weder and colleagues 73 reported on the long-term follow-up of 91 patients who were assessed prospectively after bilateral, video-assisted LVRS. Early improvement in the FEV~ was best in the heterogeneous group, but the decline in function was similar in those patients with homogeneous and heterogeneous disease. The improvement lasted for more than 24 months in both groups. How does one best evaluate heterogeneity versus homogeneity? Thurnheer and colleagues TM compared the assessment of heterogeneity with perfusion lung scans versus chest CT scans. Whereas it has been the experience of our group that the perfusion lung scan predicts areas of nonfunction quite well (Fig 7), Thurnheer and colleagues found that the functional improvement after LVRS was more closely correlated with the heterogeneity estimated by chest CT. In 16 of 22 patients in whom the chest CT indicated a homogeneous emphysema distribution, 286

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POSTERIOR

I

Fig 7. Lung perfusion scan from a patient who would be considered ideal for LVRS because of the severely diminished perfusion at the apices and relatively normal perfusion at the bases. These data, along with radiographs, can help the surgeon target the resection to the areas of worst disease.

the perfusion lung scan showed either intermediate or markedly heterogeneous perfusion.

Nutritional Status We have been impressed that nutritional status also has a significant impact on patient outcome, especially in the early postoperative period. Patients who have lost a substantial amount of weight, especially women, are not good candidates for operation; unless they can demonstrate weight gain during the period of pulmonary rehabilitation, they probably should not be offered operation. Mazolewski and colleagues75prospectively studied 51 patients who underwent video-assisted thoracoscopic LVRS and measured body mass index (BMI) and a variety of serum nutritional Curr Probl Surg, April 2 0 0 0

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indices including albumin, transferrin, total protein, and cholesterol both before and after the operation. These investigators identified 27 of their patients (53%) with below normal BMI before operation, but serum nutritional indices were similar between abnormal BMI and the normal BMI groups. Postoperative nutritional indices were significantly lower in the low BMI group, and 26% of this group required prolonged ventilator support compared with only 4% of the patients with normal BMI before operation. It follows that the hospital length of stay was significantly longer in the low preoperative BMI group. Thus they concluded that BMI is an accurate determinant of nutritional status in this patient population and that preoperative repletion of nutritional deficiencies, if possible, likely is beneficial in reducing postoperative morbidity.

6-Minute Walk Distance Several groups have suggested that patients who are so compromised that they cannot cover 600 feet in the 6-minute walk test are poor candidates for operation. These patients should be assessed carefully after pulmonary rehabilitation. If they are able to increase their 6-minute walk distance significantly, they may be candidates for operation. Some of these patients, however, have such significant muscle wasting that they are unable to improve the distance walked, and these patients appear to have a high perioperative mortality rate.

Contradictory Data Despite the substantial data that there are, in fact, categories of patients who would seem to do better (or worse) after LVRS, several investigators have specifically highlighted the benefits of the operation in patients whom most would exclude from consideration for surgery. Argenziano and colleagues 76 report that in "high risk" groups (including patients with a pCO 2 of greater than 55 mmHg, a steroid requirement of greater than 10 mg of prednisone per day, an FEV 1 of less than 500 mL, and an inability to complete pulmonary rehabilitation), there was no difference in the mortality rate or functional results compared with a more standard group of patients. Eugene and colleagues 77 performed primarily unilateral LVRS in 44 patients with an FEV 1 of less than 500 mL and also reported results comparable to those in series excluding patients with this degree of pulmonary dysfunction. O'Brien and colleagues 78 evaluated the outcome in a small group of patients with a resting PaCO 2 of greater than 45 mmHg and compared them to a group with PaCO 2 of less than 45 mmHg. The patients with hypercapnia were more impaired before operation in all physiologic and 288

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quality of life variables, but both groups had similar improvement after operation, and there was no difference in the mortality rate between the 2 groups. They concluded that hypercapnia alone should not exclude patients from consideration for LVRS. It should be noted here that most investigators have continued to observe an increased mortality rate among patients with carbon dioxide retention and are wary of performing operation in these patients.

Lung Volume ReductionSurgery versus Lung Transplantation Because patients who are candidates for LVRS may also be considered for lung transplantation, the potentially competing roles of these procedures is another issue that bears investigation. Zenati and colleagues61 performed 35 LVRS procedures in 40 patients who had been accepted for both LVRS and transplantation. This group found that 66% of patients could be removed from the transplantation list because of their degree of improvement. Of the remaining 10 patients, 7 patients were bridged to lung transplantation and survived that procedure after LVRS. The authors concluded that LVRS is an alternative to lung transplantation in selected candidates. The difficulty remains in selecting which candidates should have which procedure. Aside from the data on heterogeneity of emphysema, then, there have been a variety of often conflicting recommendations regarding patient selection for LVRS. One of the major roles of the NETT will be to sort out these issues, but there are those who question whether such a large-scale randomized trial is absolutely necessary to define which patients are most likely to benefit from this procedure. The Data Safety and Monitoring Board of the NETT specifically have been asked to look at the group of patients who fulfill characteristics thought by the NETT investigators to be associated with the best outcome. These include heterogeneity of disease, pCO 2 less than 45 mmHg, residual v o l u m e greater than 200% predicted, and FEV~ greater than 15% and less than 30% predicted. It is hoped by the investigators that, if this group shows a significant benefit over the medical group even at an interim analysis, patients meeting some or all of these criteria could be pulled out of the NETT study and offered the operation as a Medicare covered benefit. In summary, there are several physiologic parameters that must be considered in selecting patients for LVRS. Perhaps the most important factor, and one that may be assessed reasonably well on the plain chest radiograph, is the presence of hyperinflated lungs with areas of parenchyma with little or no perfusion that allow for volume reduction without the Curr Probl Surg, April 2000

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removal of functional lung tissue. The NETT is designed to allow for an assessment of this and the variety of other physiologic variables that we have reviewed here and for which significant controversy remains.

Surgical Technique Median Sternotorny Pain management and the ability to cough effectively is particularly important in these patients. Before the operation, a thoracic epidural catheter is placed for postoperative analgesia because extubation is planned immediately at the conclusion of the procedure. The induction of anesthesia is a crucial and often dangerous time for patients with severe emphysema. Occasionally, the condition of a patient will deteriorate rapidly with the onset of positive-pressure ventilation, and one should ascertain rapidly whether this is from a self-controlled positive end-expiratory pressure (auto-PEEP) phenomenon or a tension pneumothorax. Because of the tenuous nature of the pulmonary parenchyma in these patients, rupture from positive-pressure ventilation with an ongoing air leak rapidly results in tension physiology and hemodynamic collapse if not rapidly recognized. Any increase in peak airway pressures noted by the anesthesiologist at the time of induction and institution of positive pressure ventilation calls for immediate assessment. The surgeon should always be present at the time of induction when a patient with severe emphysema is anesthetized. The inspiratory:expiratory ratio often needs to be decreased in these patients because a longer expiratory phase usually is necessary to prevent the auto-PEEP phenomenon. It is extremely important to work with an anesthesiologist who is experienced in the care of thoracic surgical patients when these operations are undertaken. Ideally, the anesthesiologist should have experience in the perioperative management of lung transplant patients. Fiberoptic bronchoscopy is performed through a single-lumen endotracheal tube to exclude unexpected malignancy or active infection that would preclude proceeding with the operation. A sputum sample or bronchial washing is sent for microbiologic examination at this time even if there is not an impressive amount of secretions. These intraoperative cultures often prove useful in guiding initial antimicrobial therapy if the patient develops an infiltrate in the early postoperative period. A double-lumen left endobronchial tube is then placed. These are not the patients in whom difficulty with intubation is well tolerated, and the less manipulation the better. The double-lumen tube position is checked with a pediatric bronchoscope to assure that the bronchial lumen is in the left main stem bronchus. 290

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A median sternotomy is performed with complete division of the bone from the sternal notch to the xyphoid process. The skin incision is kept somewhat shorter, from approximately the angle of Louis to 3 cm above the xiphosternal junction, with elevation of flaps to expose the full extent of the bone incision. Care is taken throughout the procedure to handle the sternum gently. Electrocautery is used judiciously for control of bleeding, mainly on specific bleeding points, to preserve the sternal blood supply and to preserve the periosteum. The sternal edges are protected with laparotomy pads to avoid damage from the retractor. Furthermore, the retractor is spread slowly to allow progressive relaxation of attached soft tissues and cartilage, avoiding sternal and rib fractures. We have found these maneuvers useful in minimizing sternal complications, which can range from nuisance "clicks" to the rare case (1 in our experience with over 200 LVRS procedures) of mediastinitis. Certainly, these patients are at high risk for problems with sternal healing because of their significant work of breathing and the stress that this places on the sternal closure. Emphysema is a recognized risk factor for sternal infection after cardiac surgical procedures. Unilateral ventilation to the side opposite that to be operated on first (generally the side with the most severe disease as demonstrated on preoperative studies) is begun before the skin incision is made. This provides more time for the lung to deflate, keeping in mind that the most severely diseased areas with the least perfusion remain inflated longer because of the lack of reabsorption atelectasis. Usually by the time the chest is entered, the areas with the most perfusion are well deflated, and the most severely diseased area (usually the apex) remains inflated. The sternal edge on the side of interest is elevated with a sternal retractor (either a hemisternal retractor or a standard sternal retractor can be used). The pleural reflection is bluntly dissected off the anterior chest wall for a width of approximately 5 cm along the entire length of the incision. This maneuver facilitates identification and careful avoidance of injury to the phrenic nerve. The pleura is then carefully opened, exposing the lung. It is at the upper end of the pleural incision that the phrenic nerve is most at risk and must be most assiduously identified and avoided; electrocautery should not be used during the incision of this portion of pleura. Furthermore, care must be taken not to apply overly excessive retraction on the nerve. Finally, if pleural adhesions are encountered superiorly and medially, lysis must be performed with great care because of the location of the nerve. Damage to the phrenic nerve is disastrous and must be avoided. Sternal retraction is gradually increased until sufficient room has been Curr Probl Surg, April 2000

291

created to insert a hand into the thorax. Many of the patients have scattered areas of filmy adhesions, presumably the result of past inflammatory processes. Taking care not to tear any adhesions that may be present, the surgeon carefully retracts the lung, and the adhesions (which are often vascular) are divided with the electrocautery as they are encountered. Over-vigorous retraction and at times even standard retraction at this point may cause the lung to tear, rather than the adhesion, and this may result in a prolonged postoperative air leak. On rare occasions, we have encountered severe, dense adhesions that had not been anticipated before the operation and that caused us to abort the procedure on that side. Attempting to lyse dense adhesions may lead to prolonged air leaks and additional postoperative complications, so prudent judgment must be exercised in these situations. We do not, as a routine, incise the inferior pulmonary ligament, although we acknowledge that other surgeons do this as a rule. Especially on the left side, this requires significant retraction on the heart, which usually is not well tolerated. The benefit of incising the inferior pulmonary ligament remains unclear. Once the lung is fully mobilized, the areas for resection are chosen. Ideally, a single, large oblique strip of tissue from the upper lobe (in the ideal patient who has upper lobe-predominant disease) can be resected with several firings of the stapler, creating a single continuous staple line from the most caudad portion of the upper lobe to the extreme apex (Fig 8). The concept here is a reshaping of the lung with this single large strip, not multiple wedge excisions from various locations. It is possible to take more parenchyma with this single large, linear oblique strip than with multiple wedge excisions. It is difficult to get a significant amount of additional parenchyma from the same lobe once this strip is taken, so the total amount to be taken should be accomplished with this single staple line. Filling the hemithorax with saline solution and rotating the table slightly to the side of interest floats the lung well up into the operative field, making resection easier. The target areas of lung to be resected (ie, those with the most severe disease and thus with the least perfusion) usually remain inflated and sometimes must be deflated to obtain enough visualization and room to insert a stapler. Once the portion of lung is deflated simply by incising into the area, resection proceeds much more expeditiously and without undo manipulation of the lung. We have found that even minimal manipulation of these emphysematous lungs often results in some degree of hemorrhage within the manipulated lung parenchyma. This may interfere significantly with postoperative oxygenation. The lung in the area where the disease appears to be most severe is grasped with either a Duvall 292

Curr Probl Surg, April 2000

of I

Oblique strips /

J

/

/

Fig 8. Sketch of a standard apical wedge resection performed in the typical patient with primarily apica) disease. Thiswould be carried out bilaterally. (From Kaiser LR.Atlas of general thoracic surgery. St Louis: Mosby; 1995. p 149. By permission.)

clamp or ring forceps (lung not to be resected is left undisturbed), and the staple line is begun beneath the clamps. The stapler we favor is a linear 80-ram device with 4.8-ram staples, and we use 0.35 mm polytetrafluoroethylene (PTFE) inserts or bovine pericardial strips for buttressing the staple lines in the hopes of minimizing postoperative air leaks (Figs 9 and 10). We are careful that, as the staple line is created, the stapler is placed exactly at the "crotch" created by the previous stapler; we suspect that some postoperative air leaks occur at points where staple lines cross. In patients who have disease that, by ventilation/perfusion scan, is not localized primarily to the apices, we attempt to target the areas of resection to the areas of the least perfusion, often resecting portions of the middle or lower lobes. In patients who have minimal function in the fight upper lobe, we occasionally perform a formal fight upper lobectomy. How much parenchyma to remove cannot be quantitated easily, but an average of 20% to 30% of the volume on each side is targeted. More is removed, certainly, in hemithoraces that contain more diseased lung, and less is removed in hemithoraces that contain less severely diseased lung. If too much is resected, postoperative oxygenation may be affected, CaLlSCurr Probl Surg, April 2000

293

Apical

Stapled lun parenchyma wi! strips of bovir pericardiu

Fig 9. Sketch of the appearance of the lung after resection with reinforcement of staple lines with bovine pericardium or PTFE. We currently try to create a single, long, U-shaped staple line rather than 2 staple lines as pictured here. (From Kaiser LR. Arias of general thoracic surgery. St Louis: Mosby; 1995. p 151. By permission.)

ing significant difficulties, ff too little is resected, one fails to accomplish the intent of the operative procedure. These patients carry too high a risk not to accomplish what one sets out to do, which is to reduce the lung volume by resecting nonfunctional lung parenchyma. The "correct" amount of tissue to be resected is better ascertained after significant experience with the operation on the part of the operating surgeon. Certainly, the resection should result in a residual apical space when the lung in reinflated, ff no such space is visible after the initial reinflation, more tissue should be resected to achieve an optimal resection. It is safe to say that early in one's experience the most likely outcome is the resection of too little parenchyma. Most of us probably fail by resecting too little, rather than too much. Once the resection is completed, the lung is gently re-expanded while the staple line is submerged in saline solution and evaluated for air leaks. We are extremely careful to keep peak inspiratory pressures less than 25 cm water at the time of lung re-expansion and from this point forward 294

Curr Probl Surg, April 2000

Fig 10. Intraoperative photograph of apical resection through median sternotomy with a continuous buttressed staple line. (From Cooper JD, PattersonA. Lung volume reduction surgery for severe emphysema. Chest Surg Clin N Am 1995;5:815-31. By permission.)

during the procedure. Ideally, no air leaks are identified at this time. Occasionally, leaks occur adjacent to the buttressed staple line, and in fact this may be the most common site for air leaks. As the lung is re-expanded, the parenchyma near the fixed buttressed staple line tends to tear (thus the importance of gentle re-expansion). Small leaks are tolerated, if found, because attempts to repair them often lead to worsening air leaks. The rare large air leak sometimes may be repaired by restapling the area or occasionally with judicious suture placement that incorporates strips of buttress material. Needless to say, and as Brantigan and Mueller ~3 noted, the emphysematous parenchyma is not a particularly hospitable environment for suture placement. This type of situation is an ideal one for a tissue adhesive. Once tissue adhesives are available, they should be able to stop any and all of these leaks. A pleural tent may be constructed by the development of an extrapleural plane at the apex and the mobilization of the apical pleura for a distance posteriorly. This brings the parietal pleural surface into apposition with the visceral pleural and may lead to earlier sealing of a parenchymal air leak. By this "dynamic thoracoplasty," the tent will be compressed as the lung expands; but if the lung does not expand completely, the extrapleural space will fill in with fluid to obliterate the residual apical Curr Probl Surg, April 2000

295

space. We rarely use this technique, but others use it routinely on all cases of lung volume reduction. Generally a single no. 28 chest tube is placed from the midline and directed into the pleural space and left to water seal with no suction applied. The avoidance of suction on the chest tubes in the postoperative period may lead to earlier closure of parenchymal air leaks, and water seal drainage is the management technique of choice as long as the lung remains fully or near-fully inflated. If the air leak is of such magnitude that there is greater than an approximately 10% pneumothorax on the first postoperative chest radiograph, then minimal suction (10 cm water) should be applied. In most cases, water-seal drainage alone is all that is required because these emphysematous lungs have a tendency to remain inflated and because all efforts are made to avoid significant air leaks at the time of the surgical procedure. Once the procedure on the first side is completed, we check an arterial blood gas while the patient is being ventilated with both lungs. If severe hypercarbia (pCO2 > 60 mmHg in patients with no preoperative carbon dioxide retention) is identified, we ventilate both lungs for several minutes to reduce this toward normal before reinstituting single lung ventilation. The opposite lung is then collapsed, and the procedure is repeated. Peak pressures on the previously operated lung that is now being ventilated are kept at a minimum. At the termination of the procedure, the sternum is closed with 3 wires in the manubrium, and no less than 4 others in the body of the sternum. These are secured tightly without tearing through the sternum. A Robiscek-type weave with the sternal wires may be necessary in some patients with fragile sternums. This situation is often found in older women. A wire is woven longitudinally around each costal cartilage, going from superior to inferior and back; transverse wires are then placed around the longitudinal wire struts. This results in a more secure sternal closure when the bone quality is poor. As a routine, the patient is awakened in the operating room, and the endotracheal tube is removed. Usually, this can be accomplished promptly, but it sometimes requires up to 1 hour of waiting for the narcotics to be metabolized and for the carbon dioxide to be blown off. Rarely are formal "extubation criteria" met by these patients before extubation is accomplished; yet if the analgesic is adequate, successful extubation can almost always be achieved despite an elevated pCO2 and inspiratory pressures or tidal volumes that do not meet classic criteria. This further underscores the importance of the epidural analgesia. We avoid the use of long-acting narcotics in the epidural infusion and rely on local anesthetic alone, if possible. Narcotic may be added to the 296

Curr Probl Surg, April 2000

infusion later, if necessary. Epidural narcotics often cause respiratory depression and somnolence in these patients. Control of pain is particularly important in the early postoperative period so that the patient may cough effectively to clear secretions. Mucous plugging can have disastrous consequences in these borderline patients. Secretions may be thick and tenuous; if the patient has any difficulty clearing secretions, we do not hesitate to place a minitracheostomy to facilitate suctioning. This device comes as a self-contained kit and is placed through the cricothyroid membrane where it remains in place until such time as the patient is able to manage secretions without it. Therapeutic bronchoscopy should be performed whenever there is any question that a mucous Plug may be present in the proximal airways. Patients should be instructed in the use of the incentive spirometer, and postural drainage and chest physiotherapy should be used when indicated. Bronchospasm must also be managed aggressively, usually with inhaled bronchodilators, but parenteral steroids may be required to break an acute exacerbation. A rapid tapering schedule should be used. Patients should be up and walking with help on postoperative day 1, and intermittent compression stockings should be worn as prophylaxis for deep venous thrombosis. Chest tubes should be removed as soon as air leaks cease and drainage is less than 200 mL over 24 hours. These patients require close observation and physiologic monitoring for the first 2 to 3 postoperative days. Continuous electrocardiographic monitoring and oxygen saturation monitoring should be used in the early postoperative period. Whether the patient receives care in the surgical intensive care unit or in the recovery room on the first postoperative night depends on the individual institution, but admitting patients to a regular nursing unit is not optimal for the first night.

Video-assistedThoracicSurgery After the initial report of LVRS through median sternotomy, a number of surgeons reasoned that perhaps the procedure could be performed with less morbidity with a VATS approach. This would involve a bilateral VATS procedure, and there were those who supported doing both sides under the same anesthetic and others who favored operating on 1 side and bringing the patient back for operation on the other side in 2 to 3 months. We currently perform both sides under the same anesthetic. The goal of the operation remains the same whether the procedure is performed by median sternotomy or VATS (ie, to reduce the volume of pulmonary parenchyma by excising nonfunctioning areas that are not contributing significantly to gas exchange). Curr Probl Surg, April 2000

297

The VATS procedure may either be performed with the patient in the lateral decubitus position (in which case the patient must be completely repositioned before operating the other side) or in the supine position, with the arms positioned over the head. The initial incision made is aligned with the anterior superior iliac spine and is placed in approximately the sixth intercostal space. This incision is used for placement of the videothoracoscope. Two additional incisions are made to allow for additional instruments, including graspers and linear staplers. For the placement of a grasping instrument, we make another incision anterior and superior to the first incision that is aligned just posterior to the lateral border of the pectoralis major muscle. The third incision is made at the same level as, but anterior to, the first incision and is used for stapler placement. Some surgeons prefer to make a small inframammary incision for the insertion of the stapler and removal of the excised parenchyma. Just as with the median sternotomy approach, we attempt to excise a large oblique strip of lung parenchyma, most commonly from the upper lobe, proceeding from inferior to superior at the apex. The most efficient excision of lung tissue is obtained with this first strip; therefore it should be well placed to achieve the desired amount. If desired, a pleural tent may be brought down through the VATS approach as well. Staple lines should be inspected thoroughly to assure hemostasis before closure, and air leaks should be assessed. Epidural analgesia is also used with a VATS excision. Single lung ventilation is used during the parenchymal excision, and as soon as 1 side has been completed, double lung ventilation is restored for a few minutes while the incisions are closed and the patient's condition is allowed to stabilize. Usually there has been some increase in the PaCO 2 that needs to be blown off by a period of ventilation on 2 lungs. The contralateral lung is then collapsed, and excision of nonfunctioning areas is carried out as on the first side. The most involved side should be completed first. If dense adhesions are encountered, it may be necessary to convert to an open procedure. We prefer to use a vertical axillary musclesparing thoracotomy incision to accomplish this. Great care should be taken to avoid tearing the fragile lung parenchyma in patients with emphysema; this can be more difficult when working with a VATS approach. The patient is treated after the operation exactly as if he or she had undergone LVRS by median sternotomy.

Results of Lung Volume Reduction Surgery The significant limitations of medical treatment and transplantation for severe emphysema led to the rapid application of LVRS to this desperate patient population shortly after Cooper and colleagues ~9 presented their 298

Curr Probl Surg, April 2000

initial encouraging data. The surgical approaches used, as well as the indications for the procedure, have been highly variable among institutions. Undoubtedly, institutions with poor results did not rush to publication. An examination of the published series of LVRS (Table 2), 61'76'79-96 however, provides convincing evidence of the efficacy of the procedure, with acceptable morbidity and mortality rates, in properly selected patients. It is important to point out that these results have been achieved almost exclusively at large institutions with the resources, both institutional and professional, to sustain the highest level of specialized care for patients with this disease. Collating data from all of the series listed in Table 2 that used stapled, bilateral LVRS (weighted according to the number of patients in each study), the mean increase in FEV 1 obtained is 52%. The residual volume decreased a mean of 28% in those studies that measured this parameter, and the 6-minute walk test increased an average of 25%. These beneficial effects were achieved with a mean operative mortality rate of 6.0% and a 15-day length of stay. The reproducibility of the data from study to study is impressive. Apart from these objective improvements in pulmonary function parameters, most of these studies have also documented an equally important, although more difficult to validate scientifically, improvement in the quality of life and sensation of dyspnea after LVRS. We mention here only a few of the reports that attempt to evaluate these more subjective postoperative improvements that occur in conjunction with objective improvements in pulmonary function. On a quality-of-life survey, Daniel and colleagues 88 found that 79% of patients expressed marked improvement in their lifestyle, with 17% of patients expressing some improvement. Only 4% of patients felt that their condition was worse than before the operation. Bousamra and colleagues 94 noted a significant improvement in dyspnea score from 0.83 to 2.4 and moderate or major improvement in a dyspnea index in 18 of 42 surviving patients, with mild improvement in 15 patients. O'Brien and colleagues78 found a dramatic improvement in a perceived overall quality-of-life score (P < .001). A few issues have been fairly well settled by those early reports listed in Table 2. For example, it is clear from the data in the table that the objective improvement in pulmonary function is more substantial in patients who undergo bilateral than unilateral LVRS. Furthermore, stapled resection has been demonstrated to be more effective than laser resection. In a randomized controlled clinical trial, 82 stapled resection resulted in a greater improvement in FEV~ than laser treatment without the problem of delayed pneumothoraces encountered in 18% of the patients who underCurt Probl Surg, April 2000

299

TABLE 2. Published results of LVRS

Study Eugene et al 7~ Wakabayashi 8~ Keenan et al s~ McKenna et als2 Naunheim et al ~ McKenna et al ~ Bingisser et al ~5 Cooper et al B6 Miller et a187 Daniel et al ~ Miller et a189 Argenziano et a176 Zenati et a161 Kotloff et a190 Swansonet a191. Wisser et a192 O'Brien et al TM Bagley et a193 Bousamra et a194 Date et a195 Demertzis et a196

Patients (n) 28 443 57 39 50 79 20 150 100 26 53 85 30 120 32 54 46 55 37 39 25

Preoperative FEV1 (% predicted) 0.68 -0,82 0.70 0.73 0.69 0.80 0.70 0.60 0,73 0.56 0.55 0.64 0.73 0.68 -0.70 0.70 0.68 0.74 0.96

(--) (25) (30) (--) (26) (25) (28) (25) (19) (25) (--) (23) (22) (--) (23) (24) (27) (28) (26) (--) (--)

Preoperative RV (% predicted) 5.07 -5.10 5.40 5.13 4.80 5.80 5.91 5.50 6.10 -4.00 5.62 4.95 --4.73 3.94 ----

(--) (197) (239) (--) (235) (--) (250) (283) (290) (--) (--) (265) (--) (317) (237) (192) (201) (280)

Preoperative 6-mln walk (ft) --754 -864 -1608 1125 1106 -785 589 904 1008 --797 774 913 1083 753

Studies that used laser techniques solely and studies that used apparently overlapping series of patients have been excluded. RV, Residual volume. *Used novel plication technique. tExcept i patient.

went laser treatment. Furthermore, it is now generally agreed that it is important to make every effort to extubate these patients immediately after the procedure to avoid exacerbating the problem of prolonged air leaks. Most groups also feel that avoiding suction on chest tubes is helpful in avoiding air leaks, and many groups now discharge patients with Heimlich valves in place if the lung remains fully or close to fully expanded despite ongoing air leakage. Although a few such issues have been settled and although on the basis of the published data most thoracic surgeons and pulmonologists would agree that there is a role for LVRS in the management of selected patients with emphysema, perhaps more questions have been raised than have been answered. Remaining areas of controversy, aside from the critical issue of patient selection, which has been discussed previously, include issues of surgical technique and approach, the duration of benefit, the question of a survival benefit, and the mechanism of the benefit. 300

Curr Probl Surg, April 2 0 0 0

Technique Unilateral; VATS Unilateral; VATS Unilateral; VATS Unilateral; VATS Unilateral; VATS Bilateral; VATS Bilateral; VATS Bilateral; open Bilateral; open Bilateral; open Both; open

Mortality rate (%)

Length of stay

Increased FEV x (d)

Decreased RV (%)

Increased 6-rnin walk (%)

0

--

34

12

5.6

18

26

12

---

5.3

17

27

16

14

2.5

13

33

--

--

4.0

13

35

33

20

1.0

11

52

--

--

0

15

37

24

39

5.0

15

51

28

17

5.2

--

97

--

104

3.8

14

40

30

--

5.2

--

97

--

104

Both; open

7.1

17

61

--

62

Both; both

0

18

54

24

12

10

20

41

26

26

0

7

29

--

--

9.8

12

40

31

--

8.7

--

20

22

26

Bilateral; both Both; both Both; both Bilateral; both Bilateral; ope nt

5.0

18

27

25

17

Both; open

6.7

16

59

--

32

Bilateral; open Both; open

0

--

41

21

16

0

--

50

34

90

Ongoing Controversies

Surgical Technique Laser resection has been abandoned on the basis of the published data by essentially all groups. The issue of bilateral versus unilateral resection is more complex. Authors who have specifically addressed this issue 97'98 have found that spirometric indices are improved more dramatically after the bilateral versus the unilateral procedure, but one group found that there was a higher 1-year mortality rate among the unilateral patients whereas the other investigators found 1-year survival rates to be equivalent. Although there are no good data that early morbidity and mortality rates are different after the unilateral procedure, some groups still argue that the unilateral procedure may be the procedure of choice in the most severely compromised patients. We favor the unilateral procedure only in patients with clear "target zones" (ie, heterogeneous disease) on only one side or in those patients with a clear contraindication to LVRS (such as previous thoracotomy) on 1 side. How much tissue to excise on one or Curr Probl Surg, April 2000

301

both sides is another, altogether different, issue that is likely to remain unresolved. Certainly, the optimal resection volume is different in each patient and will be nearly impossible to quantify. The issue of staple-line buttressing is also controversial. Cooper and colleagues, 86 after recognizing in their first group of patients the significant problem with air leaks, adopted a technique of buttressing the staple lines with bovine pericardium. They reported anecdotally that this virtually eliminated the intraoperative air leaks at the staple lines that were associated with prolonged postoperative leaks. Most surgeons went on to adopt this technique or the alternative use of PTFE strips in a similar manner. A prospective, randomized study of LVRS operations performed with or without bovine pericardial buttressing demonstrated that those patients with buttressing had chest tubes removed 2.5 days sooner and were discharged 2.8 days sooner as a result. Cost analysis, however, showed that the cost of the bovine pericardium offset the money saved by the shorter hospital stay.99 Other groups have noted localized infections anecdotally at buttressed staple lines in patients who undergo lung transplantation after LVRS. Most groups continue to buttress with one of the available materials, however. One of the most controversial areas in the technical realm is the question of whether a median sternotomy or thoracoscopic (VATS) approach is most appropriate. A cursory examination of Table 2 suggests that both the median sternotomy and VATS approaches are reasonable, and each has its advocates. A retrospective study from our institution reviewed 80 patients who underwent bilateral LVRS by median sternotomy and 40 patients who underwent bilateral LVRS by VATS and found that there were similar improvements in pulmonary function and exercise capacity, regardless of the approach. There was a lower incidence of respiratory failure that required reintubation in the VATS group and a trend, which did not reach statistical significance, favoring VATS with regard to the inhospital mortality rate. 9~ In patients older than 65 years, there was a significant increase in the in-hospital mortality rate in the sternotomy group. From a later study published by our group, 1~176 encompassing both our early and more recent experience, slightly different conclusions can be drawn regarding VATS versus median sternotomy. There were no significant differences found between the patients who underwent VATS and the patients who underwent median sternotomy with regard to the length of stay, chest tube duration, or Heimlich valve requirement. Operating times were significantly longer for the VATS group (largely reflecting the necessity of repositioning the patient between sides). Blood loss was greater for the median sternotomy group. Most importantly, with a probability value of less than .05 as the level of significance, the patients who underwent 302

Curr Probl Surg, April 2000

median sternotomy had significantly longer intensive care unit stays, more days intubated, more respiratory complications, and more postoperative tracheostomy placements. However, when only the most recent one half of median sternotomy cases were included in the analysis, only the number of intensive care unit days and the number of respiratory complications reached statistical significance. Furthermore, the mean age of the patients who underwent median sternotomy was 4.6 years greater than that of the patients who underwent VATS, and, as established in the earlier publication, 9~ there is a significantly greater mortality rate after LVRS by median sternotomy versus VATS in patients over age 65 years. Another group has addressed the issue of LVRS by median sternotomy versus VATS by direct retrospective comparison. 1~ This study also demonstrated that the VATS approach takes longer, but that there was a significantly longer intensive care unit stay in the median sternotomy group. Trends that did not reach statistical significance included more ventilator days, air leak days, and total hospital days in the median sternotomy group. Costs were increased in the median sternotomy group. Again, the sternotomies were performed primarily early in this group's experience, clouding the analysis of the data to some extent. Returning to Table 2, we can review the available literature to provide further information about the issue of VATS versus median sternotomy approaches. Focusing on the 2 studies that reported only bilateral VATS operations and the 4 studies that reported only bilateral open operations, we find that (1) the improvement in pulmonary function after median sternotomy may be slightly greater than that after VATS (average increase in FEV v 58% vs 49%), (2) the weighted average mortality rate with VATS is 1% whereas that with median sternotomy is 4.4%, and (3) the length of stay for VATS averages 12 days versus 15 days with median sternotomy. Of course, these data are merely suggestive and contain all the flaws mentioned earlier in the discussion of the direct comparison studies, plus several others. In this setting, in which there are no perfect data available to recommend one approach over the other, several clinical impressions continue to drive our tendency to perform many of our LVRS procedures with median sternotomy. First, we feel that we are better able to visualize and therefore more precisely resect the areas of lung most involved by the emphysematous process during procedures conducted through a median sternotomy. Second, we feel that the VATS procedure, because of the limited "jaw" opening of currently available endoscopic staplers, tends to result in resection of less than the optimal amount of pulmonary tissue (compounding the natural tendency to perform too conservative a resection). Third, the median sternotomy approach allows us greater flexibility Curr Probl Surg, April 2000

303

in the performance of the procedure. For example, this approach allows the performance of a right upper lobectomy in patients in whom there is virtually no functional parenchyma remaining in this lobe. The data suggesting an increased mortality rate by the median sternotomy approach in patients over age 65 years have altered our approach to these patients. In elderly patients and in others who appear to be more severely compromised by a variety of clinical criteria (but who nevertheless remain candidates for the procedure), we currently favor a VATS approach.

Duration of Benefit and Survival Benefit Although there are few in our field who do not recognize that at least a subgroup of patients with emphysema benefit from LVRS, the duration of benefit and the question of a survival benefit are unsettled. Some of the longest term results currently available are from Cooper and colleages, 86 whose 24-month data on their initial 20 patients demonstrates essentially preserved improvement. It is also mentioned anecdotally that 5 of the initial patients who have been followed 3 or more years continue to show a sustained benefit. Gelb and colleaguesl~ also reported a cohort of patients with physiologic testing 2 years after the operation. These investigators found that, although a physiologic benefit of the operation persisted at 24 months, the benefits peaked at 6 months after operation and gradually declined thereafter. Greater numbers and data at points farther out from the procedure will need to be presented to confirm this report. Regarding survival, it remains unclear whether LVRS will have an impact, and this is an issue that only a randomized, controlled trial (such as the NETT) can answer definitively. Even if the progressive deterioration of lung function known to occur with emphysema continues (which is almost certain to be the case), it is possible that "setting back the clock" by LVRS will result in a survival benefit. The actuarial survival rate of 92% reported by Cooper and colleagues86 at 24 months compares favorably to the anticipated death rate for patients with this degree of emphysema, but as they has noted, selection bias could certainly account for this finding. The most direct attempt to address the issue of a survival benefit short of a randomized, controlled trial has again been carried out by Cooper's group. Meyers and colleagues 1~ retrospectively compared the survival of 22 LVRS candidates who met the criteria for the operation (but were denied operation as a result of withdrawal of Medicare funding for the procedure) with 65 concurrently selected patients who did undergo LVRS. Patients denied operation experienced the expected, progressive worsening of pulmonary function, whereas patients who underwent LVRS experienced significant improvements, The absolute survival rate 304

Curt Probl Surg, April 2000

for the 2 groups was 82% for patients who underwent LVRS and 64% for patients who did not undergo operation, with a mean follow-up of 976 and 867 days, respectively. There were, however, no significant differences between the actuarial survival curves at 12 or 36 months.

Mechanism of Improvement Several putative mechanisms of action whereby LVRS may exert its ameliorative effects on pulmonary function and dyspnea have been proposed and investigated. Chief among them are the theories that (1) LVRS increases the elastic recoil of the lung and that (2) LVRS increases respiratory muscle efficiency and favorably alters the chest wall geometry. In an animal model, LVRS in rabbits with elastase-induced emphysema has resulted in decreased lung compliance, decreased airway resistance, and increased flows. 1~ In rats with elastase-induced emphysema, our group has obtained preliminary data that demonstrates a restoration of the normal diaphragmatic length-tension relationship after LVRS (unpublished data). We are not aware of other studies of the physiologic mechanisms of LVRS in experimental animals. In humans, evidence accumulated early in the experience that confirmed the lung elastic recoil hypothesis, and a good deal of information has been presented more recently in support of improvements in muscle and chest wall mechanics. Significant immediate and sustained increases in lung elastic recoill~176 and airway conductance1~ were demonstrated first after LVRS. These findings suggest that after the removal of lung tissue, the remaining lung does provide increased transmission and generation of driving pressure and increased stability of the airways because of increased lung elastic recoil. In addition to improving lung elastic recoil, LVRS has now also been demonstrated to improve the performance of the respiratory muscles in humans. Maximal inspiratory pressures that can be generated are increased significantly after LVRS. The maximal inspiratory mouth pressure, the most widely applied method of determining global inspiratory strength, was increased by 52% in one study, t~ The maximal transdiaphragmatic pressure that can be generated by a patient against a partially occluded shutter (which reflects the force of diaphragmatic contraction) improved in another study to 92 from 67 cm water after LVRS. a~ In 2 other reports, transdiaphragmatic pressure generated by bilateral supramaximal phrenic nerve stimulation increased from 7 to 15 cm water 1~ and 17 to 26 cm water, H~ respectively. All other measures of respiratory muscle strength in these studies also improved significantly. Curr Probl Surg, April 2000

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There is a postulated improvement in the inspiratory elastic load imposed by the chest wall in emphysema. This reversal of the normal recoil of the chest wall by hyperexpansion, such that it exerts a load on the inspiratory muscles, has also been shown to be improved after LVRS. m One would expect the overall effect of the improvement in respiratory muscle function and chest wall mechanics after LVRS to be a decrease in the work of breathing, which translates to the patient as a decreased sensation of dyspnea. The mechanical work of breathing has, in fact, been measured before and after LVRS. Tschernko and colleagues ~1~ documented a fall from 1.93 J/L before operation to a low of 0.65 J/L after operation (P < .005). The pressure-time product, perhaps an even better measure of respiratory muscle oxygen consumption and thus work, also decreases 22% after LVRS. ~1~ There is less evidence in support of mechanisms of action of LVRS other than improved elastic recoil of the lung and improved efficiency of respiratory muscle function. With regard to proposed improvements in pulmonary vascular hemodynamics, 1 study found that 24 hours after LVRS, both pulmonary artery pressure and pulmonary capillary wedge pressure were decreased significantly. ~3 Another study found that, although pulmonary artery pressures were unchanged after LVRS both at rest and during exercise, pulmonary capillary wedge pressure during exercise was decreased significantly after the procedure and that cardiac index both at rest and during exercise was increased significantly, u4 The initial study that demonstrated increased elastic recoil after LVRS also demonstrated that the fractional change in right ventricular area, a measure of right ventricular systolic function, is increased significantly by LVRS. 1~

Costs Little has been written addressing the issue of the cost-effectiveness of LVRS. This void has stimulated the Canadian Lung Volume Reduction Study Group to emphasize the cost-benefit analysis in their randomized study of the operation. One study has documented the medical center and physician charges incurred in a single academic institution, u5 This group found that charges were related to length of stay, with a median total charge of $26,669 (27% for physician services) and a median total reimbursement of $25,047. Only assessment of these data relative to outcomes data can allow determination of cost-effectiveness.

Current Status of Lung Volume Reduction Surgery The initial response after the reintroduction of LVRS was extremely enthusiastic within the thoracic surgical and pulmonary medical commu306

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nities. This was natural, given the absence of other effective therapeutic options for these patients, their dismal prognosis without intervention of some type, and the elegant physiologic rationale for the operation. As a result, the procedure was rapidly and widely applied to patients who were probably in many cases poorly selected and at institutions that had little previous experience caring for patients with advanced emphysema. The impressive published reports detailed earlier notwithstanding, anecdotal experiences circulated by word of mouth with mortality rates of up to 50% in some centers in which only a handful of cases were treated. It must be taken at face value that most surgeons did not rush out and publish their experience if they had a high mortality rate with the procedure. It must also be kept in mind that the performance of LVRS involves much more than performing the surgical procedure itself, which, in reality, is relatively straightforward. The expertise of an experienced pulmonologist who is interested and committed to taking care of patients with advanced lung disease is absolutely essential, as is the availability of experienced consultants from other disciplines such as infectious disease and rehabilitation medicine. The postoperative management of these patients presents significantly greater challenges than the intraoperative management, and it is likely that, in centers with a high mortality rate, it was at least partially the postoperative care that was lacking. In addition, there is no substitute for the experience that one gains after taking care of many of these patients, especially as that experience relates to selecting appropriate patients for operation. The significant morbidity and mortality rates that seem to have resulted during this period of early, aggressive application of LVRS (and, arguably, purely economic interests as well) led the HCFA to halt Medicare payments for the procedure in December 1995. The HCFA requested an assessment of LVRS by the Center for Health Care Technology (CHCT) of the Agency for Health Care Policy and Research. The CHCT requested data on treated patients and received it from 27 institutions (including many that had not published their results) on a total of 2800 patients. On the basis of its analysis of these data, the CHCT reported that "it cannot reasonably be concluded at this time that the objective data permit a logical and a scientifically defensible conclusion regarding the risks and benefits of LVRS as currently provided," and, furthermore, that "a prospective trial of LVRS under uniform protocol requirements with comprehensive long-term postoperative follow-up data is both ethically and scientifically essential. ''116 Shortly, thereafter, the HCFA and the National Heart, Lung, and Blood Institute organized the randomized, controlled clinical trial of the proceCurr Probl Surg, April 2000

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dure known as the NETT, which is currently accruing patients. Other governmental and private insurers followed suit, with the subsequent organization of randomized trials by the Canadian Lung Volume Reduction Study Group and New England Blue Cross. The organization of the NETT has created significant legal and economic obstacles to performing LVRS. For Medicare beneficiaries, mostly people over the age of 65 years but also a number of people on long-term disability, the only way to undergo LVRS is to enter the NETT and be randomized to the surgical arm. The only other option is to pay for the procedure out of pocket, and a number of centers offer a single rate that covers the hospitalization and the professional fees. For patients not eligible for Medicare, it is also quite unlikely that one would be able to choose LVRS, although a number of private insurers (including several large health maintenance organizations) offer the procedure as a covered benefit. This is actually quite an interesting observation that deserves some explanation. Despite the ruling on the part of the HCFA to deny coverage for LVRS because the procedure was felt to be investigational, a number of for-profit health maintenance organizations and nonprofit third-party carriers examined the published data and made a decision to cover the procedure on the basis of these data. Suffice it to say, these organizations examined the same data that were available to the HCFA, which took a different course. The HCFA decision may have been influenced greatly by the notion that this procedure could be the "next coronary artery bypass" and that millions of people would be clamoring for the operation. As it turns out, this is unlikely because fewer than 1 patient in 10 with emphysema actually is a candidate for the procedure. The fact that all of the published studies that were detailed earlier show dramatic and similar improvements in pulmonary function after LVRS appears quite convincing. Furthermore, these improvements have been shown to correlate with reproducible changes in measurable physiologic variables that correspond to the theoretic conception of how a volume-reduction procedure might work. It must be acknowledged, however, as pointed out by numerous critics, that multiple data points from follow-up visits are missing. Also, all of these clinical studies are uncontrolled, and data have accumulated over 3 years at most. Finally, many centers that have performed LVRS have not reported their data (ie, there is a selection bias in the reported cases). The NETT will, it is hoped, serve to confirm the finding of a benefit after LVRS in a more scientifically rigorous fashion, while addressing the multitude of completely unanswered questions surrounding the procedure, which 308

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we have highlighted. A major question that remains unanswered is how long the benefits obtained from the procedure will last. From the data available, the organizers of the NETT have attempted to distill what would appear to be reasonable indications for the procedure, preoperative studies, preoperative preparation, and surgical approaches. 11v Although many would object to some of the exclusion criteria and other aspects of the trial, the current status of LVRS can be at least in large part summarized by reviewing the plan for the NETT. Patients will be randomized to medical therapy alone versus medical therapy plus LVRS. Both VATS LVRS and LVRS by median sternotomy will be included in the trial. All patients will undergo at least 5 weeks of preoperative pulmonary rehabilitation and 8 weeks of postoperative pup monary rehabilitation. Although the amount of tissue to be removed is left to the discretion of the surgeon, only stapled excision of tissue is permitted, and tissue buttressing of the staple lines is optional.

N E'I-FObjectives The 2 primary objectives of the trial are to determine whether LVRS, added to maximal medical therapy, improves survival and whether it increases exercise capacity as measured by maximum exercise capacity on a stationary bicycle. Secondary outcome measures have been chosen to learn more about the potential benefits of LVRS, to explore proposed mechanisms of improvement, and to refine the selection criteria. These include measurements of quality of life and utility (by questionnaire), pup monary function, pulmonary mechanics, and gas exchange. Additional secondary outcome measures include oxygen requirement, 6-minute walk distance, and right ventricular function. Additional listed objectives include the determination of those patients who benefit most and those at highest risk, the determination of the durability of the benefits, and the evaluation of the cost-effectiveness.

NEI-F Eligibility Criteria The inclusion and exclusion criteria for the NETT are outlined briefly and are summarized in Table 1. The patients must have the clinical diagnosis of emphysema and have quit smoking at least 4 months before the initial assessment. Pulmonary function values before the bronchodilator must be total lung compliance greater than 110% predicted, residual volume greater than 220%, FEVj less than 45% (>15% if over age 69 years), carbon dioxide diffusion in the lungs of less than 70%, and a postbronchodilator increase in FEV 1 not exceeding 30%. The PaO 2 must be greater than 45 mmHg on room air, and the PaCO 2 must be less than 60 mmHg. Curt Probl Surg, April 2000

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The oxygen saturation must be 90% on no more than 6 L/rain of supplemental oxygen. The mean pulmonary artery pressure must be below 35 mmHg, and the peak pressure must be below 45 mmHg. After pulmonary rehabilitation, patients must be able to achieve a 140-meter 6-minute walk distance. The chest CT scan must demonstrate, by application of a complex radiologic grading schema, bilateral emphysema of at least moderate severity. Patients with both heterogeneous and homogeneous emphysema will be enrolled, but the additional criteria that must be met for a patient with homogeneous emphysema to gain entry into the study are rather stringent. Essentially any cardiac abnormality discovered by history or routine electrocardiography, echocardiography, stress thallium imaging, or fight heart catheterization must be evaluated by a cardiologist. Specific cardiac exclusion criteria include prior coronary artery bypass grafting, recent myocardial infarction or congestive heart failure with an ejection fraction less than 45%, and a variety of dysrhythmias. Patients are excluded from consideration for entry into the trial if they do not meet certain body mass criteria or have lost weight immediately before their evaluation. Furthermore, patients with giant bullae, bronchiectasis, or a pulmonary nodule or who previously have undergone volume reduction are excluded.

NET[ Accrual of Patients The goal of the NETT, as it was originally designed, was to accrue 4500 patients over 4.5 years with a 6-month closeout period. Accrual has been slower than anticipated, and the total accrual goal has been revised to 2500 patients to be on study by July 2002. Reasons for the slower-thanexpected accrual include an inability to travel long distances to study centers, protocol testing requirements that are difficult for this group of patients to meet, an overestimation of the true number of eligible candidates, the lack o f information about the trial on the part of primary care and specialty physicians, and a desire on the part of some individuals to avoid randomization. An aggressive marketing campaign targeted to several potential audiences is about to begin that hopefully will improve the accrual onto the protocol and allow the trial to b e completed by the expected date.

Other Randomized Trials The New England Blue Cross and Canadian Trials are in many respects similar to the NETT. The Canadian Trial 118 was organized by 12 chest surgery units at university hospitals in Canada. The major differences 310

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from the NETT are (1) the use of only median stemotomy as the surgical approach and (2) the use of a health-related quality-of-life index as the primary outcome measure, rather than survival and maximum exercise capacity. This trial began in July 1997, and the reporting of results was initially anticipated by December 2001. As of October 1999, only 38 of an anticipated 350 patients had been randomized. The New England Blue Cross trial involves centers mainly in Massachusetts and differs from the other studies in that all patients who were randomized will be offered LVRS. The initial randomization assigns patients to either best medical therapy or LVRS. Patients in the medical arm are observed for 6 months when repeat study parameters are measured, and patients are then crossed over to the surgery arm. This trial will not address survival differences between a surgical and nonsurgical arm but is designed to study the short-term differences in survival rates and quality of life. Seemingly, this trial should be more attractive to patients because no matter what group they are randomized to initially, all patients will be offered LVRS.

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