Chronic obstructive pulmonary diseases (COPD) are

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1 Review : Out on a Limb Without a NETT JAMES P. UTZ, M.D., ROLF D. HUBMAYR, M.D., AND CLAUDE DESCHAMPS, M.D. Lung volume reduction surgery (LVRS) has recently been rediscovered and offers the potential of improving the quality of life of patients with advanced emphysema. In this article, we discuss the historical and contemporary versions of LVRS. Although initial enthusiasm has been substantial, existing data seem insufficient to demonstrate the safety and efficacy of the procedure in comparison with conventional medical therapy. Fundamental questions remain regarding the long-term effects of an operation versus medical therapy, the optimal selection criteria, the best measures of efficacy, the mechanisms of improvement, the cost-effectiveness of the procedure, and the optimal surgical technique. Until such questions are answered, advising patients about the best management of their emphysema will be difficult. The National Emphysema Treatment Trial will address many of these issues and should be embraced by both health-care providers and patients. Mayo Clin Proc 1998;73: CABG = coronary artery bypass grafting; COPD = chronic obstructive pulmonary diseases; FEV S = forced expiratory volume in 1 second; FRC = functional residual capacity; HCFA = Health Care Financing Administration; LOS = length of stay; LVRS = lung volume reduction surgery; NETT = National Emphysema Treatment Trial; RV = residual volume; TLC = total lung capacity; VATS = video-assisted thoracoscopy Chronic obstructive pulmonary diseases (COPD) are characterized by reduced maximal expiratory flow and include various disease entities such as chronic obstructive bronchitis, asthmatic bronchitis, and emphysema. At least 14 million people in the United States suffer from COPD, and the prevalence of this syndrome seems to be increasing. 13 As many as 2 million people suffer from emphysema, and the overall death rate for emphysema in the United States has been estimated at 20,000 per year. 46 Medical management of COPD typically includes bronchodilators and anti-inflammatory agents and, when appropriate, smoking cessation intervention, oxygen, mucolytic drugs, antibiotics, pulmonary exercise rehabilitation, and α,-antitrypsin replacement therapy in deficient patients. 4 These treatment modalities are often used without regard for the specific underlying pathologic condition. Frequently, the quality of life of patients with severe endstage emphysema is unaltered by these interventions. Until the advent of transplantation, surgical interventions for end-stage emphysema, such as glomectomy, phrenic crush, and initial attempts of volume reduction, had been abandoned as unproven, ineffective, or harmful. 7 8 Resection of From the Division of Pulmonary and Critical Care Medicine and Internal Medicine (J.P.U., R.D.H.) and Division of Thoracic and Cardiovascular Surgery (CD.), Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. J. P. Utz, Division of Pulmonary and Critical Care Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MIM giant bullae has been performed for many years, but most patients with end-stage emphysema do not have manifestation of the giant bulla syndrome, which is characterized by a single air space occupying at least one-third of the hemithorax, compressing normal lung. Although emphysema has become the most frequent indication for singlelung transplantation, the scarcity of donor organs, patient's age, comorbidity, and expense eliminate transplantation as a viable treatment option in many instances For accompanying editorial, see page 603 In light of the prevalence of COPD, the economic burden, and the devastating effect on the quality of life of patients, the widespread interest and enthusiasm created by Cooper's 1995 report on lung volume reduction surgery (LVRS) are not surprising. Cooper and colleagues 14 described their initial experience with LVRS in 20 patients with severe emphysema. LVRS resulted in substantial improvements in lung function, as reflected in a higher forced expiratory volume in 1 second (FEV,) and reduced total lung capacity (TLC) and residual volume (RV). Of more importance, these patients reported less dyspnea, improved exercise tolerance, and enhanced quality of life. All patients survived the operation. Since that time, further experience has been accumulated by many groups. Despite this experience, Medicare has suspended reimbursement for this procedure. In this review, we critically assess the available literature and discuss a compelling need for a randomized trial that compares LVRS with conventional Mayo Clin Proc 1998;73: Mayo Foundation for Medical Education and Research

2 Mayo Clin Proc, June 1998, Vol 73 medical therapy for patients with moderate to severe emphysema. MEDICARE REFUSES TO REIMBURSE LVRS Fueled by abstract presentations at national meetings,15 the preliminary report by Cooper and colleagues,14 several reports of laser LVRS,1618 and intense patient interest, LVRS programs proliferated. This explosion of programs occurred during a period when minimal information was available to assess the safety and efficacy of LVRS. "Howto" seminars were organized by proponents of the procedure and were attended by a multitude of physicians and support personnel. Initially, Medicare reimbursed LVRS on a billing technicality. Because no CPT (current procedural terminology) code existed for the new procedure, it was typically billed as "multiple wedge resections" or "excision-plication of bullae." Strategies for "successful coding" were prepared in booklet form by surgical supply companies (Reimbursement Guidelines, Bio-Vascular, Inc., 2575 University Avenue, St. Paul, MN ) and were distributed at LVRS seminars. Because no national Medicare reimbursement policy existed for LVRS, funding decisions were ultimately the responsibility of regional carriers. This approach led to regional variability in coverage for LVRS. As interest in LVRS intensified, "cautionary voices" raised concern about long-term efficacy, safety, incomplete follow-up data, selection criteria, and optimal technique.1928 In December 1995, two independent assessments led to a nationwide Health Care Financing Administration (HCFA) policy not to reimburse LVRS. First, a National Heart, Lung, and Blood Institute workshop held in September 1995 urged more systematic study of selection criteria and long-term efficacy of the procedure. Second, a study prepared by the Federal Agency for Health Care Policy and Research declared that the current data on the risks and benefits of LVRS were too inconclusive to recommend unrestricted Medicare funding. These two assessments were published only recently Because a substantial proportion of patients who wanted to undergo LVRS were in the Medicare age-group or subject to Medicare coverage, this policy substantially restricted access to the procedure. The decision by the HCFA to deny coverage for LVRS has been viewed as a mistake by some investigators,31 and many patients have strongly objected to the Medicare coverage policy. Other investigators have advocated clinical trials to evaluate LVRS before more widespread dissemination of the proced u r e 19,22,23,25,26,28-30,32,33 I n r e s p o n s e ; t h e H CFA and National Institutes of Health decided to sponsor a large multicenter trial, with the goal of assessing the safety and efficacy of 553 LVRS when added to maximal medical therapy. The resultant National Emphysema Treatment Trial (NETT) began in early HISTORY OF LVRS FOR EMPHYSEMA Because one of the hallmarks of severe emphysema is hyperinflation, attempts have been made either to reduce lung volume by compressive means or to enlarge the chest cavity.8 Pneumoperitoneum, abdominal belts, phrenic paralysis, and thoracoplasty represented efforts to compress the hyperinflated lung; costochondrectomy was used to increase the size of the chest cavity. In the late 1950s, Brantigan and associates3436 pioneered an entirely different operation. They proposed that the removal of lung tissue would increase the circumferential pull on small airways and thereby relieve bronchial obstruction and dyspnea. Although many of their patients reported symptomatic benefit, they made no attempt to document improvements in lung function. Because of this and a 16% perioperative mortality rate, the Brantigan procedure was not widely accepted, and the concept was viewed as ill-conceived by leading authorities of that time.37 Resection of giant bullae associated with emphysema has diminished dyspnea in selected patients, but giant bullae do not manifest in most patients.8,38 39 Limited interest in Brantigan's ideas persisted. In 1977, Delarue and colleagues40 reported a surgical series of 47 patients with emphysema. They characterized emphysema as either focal or multifocal, with or without space occupation. Because they found it difficult preoperatively to distinguish bullae from more diffuse "cotton candy" changes, they resected lung in patients without giant bullae. The perioperative mortality rate was 21%, and 45% of patients had long-term improvement. Objective testing was not provided to support the claim of improved pulmonary function. In 1980, a French group headed by Debesse41 theorized that the removal of the worst areas of diffusely emphysematous lung might result in a benefit similar to the removal of a single lesion in patients with the giant bullae syndrome. Based on their experience in 10 patients with giant bullae, Debesse and colleagues described a new syndrome of "emphysematous cardiac tamponade." These patients had experienced minimal improvements in spirometry but significant increases in cardiac output and characteristic changes in the pulmonary artery pressure waveform. Between 1985 and 1987, Dahan and coworkers42 tested Debesse's theory by performing operations on 10 patients with diffuse emphysema who exhibited the hemodynamic changes described in Debesse's article. The operation was coined "intervention chirurgicale de reduction du volume pulmonaire," which translates to "lung volume reduction

3 554 surgery." Five patients had subjective improvement, with increases in FEVj from 10 to 62%. In 1992, Crosa-Dorado and associates 43 published a description of a surgical suturing technique for excision of bullae or sectors of the lung destroyed by emphysema. This technique was performed in 76 patients during an 11- year period and was described as "lung remodeling" in patients with diffuse disease, a concept similar to Brantigan's. No outcome data were presented. In 1991, Wakabayashi and colleagues 16 described a technique of unilateral thoracoscopy and laser shrinkage of target areas of emphysema. Hundreds of patients underwent this procedure, and improvement was reported. Follow-up in these and other series was incomplete, however, and thus assessment of efficacy is impossible. 17,4447 The contemporary version of LVRS by surgical resection technique has been championed by Cooper and coworkers. 14 Their experience grew from observations made in patients undergoing lung transplantation for COPD. 48 Initial LVRS techniques were performed in 1993, information began to be disseminated at national meetings in 1994, and the first peer-reviewed manuscript was published in January According to this report on the first 20 patients, LVRS by median sternotomy produced an impressive 82% improvement in FEV, 6 months postoperatively. THE MODERN LVRS ERA (1993 TO 1997) Patient Characteristics Typically, patients who have undergone LVRS in recent years have suffered from end-stage emphysema. Such patients exhibit severe obstruction and hyperinflation, have a reduced diffusing capacity for carbon monoxide, and are limited by severe dyspnea at rest or with mild exertion. Historically, indications and exclusion criteria for the procedure have reflected physiologic reasoning and anecdotal experience, and these criteria have varied from center to center. "Typical" criteria are outlined in Table 1. Inclusion criteria have often limited the procedure to patients younger than 75 years of age who have an FEVj of less than 40% of predicted and a TLC greater than 120% of predicted. Pulmonary hypertension, left ventricular dysfunction, hypercapnia, and other serious comorbidities have all been considered relative exclusion criteria. The regional distribution of emphysema has received substantial emphasis as an important selection criterion. The distribution of emphysema is usually assessed with computed tomography because it guides the surgeon to "target areas" of more extensive disease. The prevailing viewpoint is that patients with upper lobe-predominant emphysema are better surgical candidates than are those with a more homogeneous distribution of disease Table 1. "Typical" Patient Selection Criteria for Lung Volume Reduction Surgery* Inclusion criteria Age younger than 75 yr Presence of severe obstruction after bronchodilator, FEVj <40% of predicted Presence of hyperinflation total lung capacity >120% as measured by plethysmography Presence of emphysema Moderate to severe decrease in the health-related quality of of life Absence of severe pulmonary hypertension mean pulmonary artery pressure <35 mm Hg or systolic pulmonary artery pressure <45 mm Hg Preserved alveolar ventilation PaC0 2 <50 mm Hg Adequate rehabilitation potential completion of a 6-wk exercise-rehabilitation program Compliance with prescribed medical regimen Exclusion criteria Significant comorbidity nonrespiratory illness with an expected 5-yr mortality >50% Malignancy Organ failure End-stage cardiopulmonary impairment 6-minute walk <400 feet Ventilator dependence Inability to cope with the psychologic stress of the evaluation process and treatment Severe depression Anxiety disorder Active chemical dependence during the past 12 mo Conditions associated with increased surgical risk or in which benefit from LVRS is not anticipated Severe coronary artery disease Previous thoracic operation or pleurodesis Chest wall deformity Corticosteroid dependence or corticosteroid-responsive hyperreactive airways disease (or both) Airways disease with copious purulent secretions or frequent lower respiratory tract infections (or both) Regular tobacco use within the past 6 mo; any tobacco use within the past 3 mo *FEVj = forced expiratory volume in 1 second; PaC0 2 = partial arterial pressure of carbon dioxide; LVRS = lung volume reduction surgery. Outcome Pulmonary Function Tests. Most LVRS case series focus on changes in FEV, as an important surrogate outcome variable and report short-term improvements ranging from 30 to 99% of baseline ' 54 ' " 64 (Table 2). In almost all the reports, follow-up is incomplete and brief; thus, the results are potentially biased. Furthermore, patients can have remarkable improvements in exercise performance despite minimal changes in FEV r Initial estimates of doubling the FEVj by means of an operation have not withstood the "test of time." The first interim report by Cooper and colleagues 61 indicated a 99%

4 555 Reference Table 2. Summary of Studies of Short-Term Increases in Forced Expiratory Volume in 1 Second* Increase in FEV, Median sternotomy bilateral stapling Cooper et al, Cooper et al, Cooper et al, Daniel et al, Miller et al, Kotloffetal, Bagley et al, VATS bilateral stapling Gelb et al, Brenner et al, Bingisser et al, Follow-up (mo) 3 to 10 (mean, 6) 1 to 15 (mean, 6.4) to to 3 3 Patients followed up/ total patientsf (no.) 8/8 20/20 101/127$ 17/26 25/ /55 18/18 103/122/ 20/25 *FEV, = forced expiratory volume in 1 second; VATS = video-assisted thoracoscopy. f Deaths not excluded unless indicated. $Follow-up data in 101 of 127 survivors at 6 mo. Follow-up data in 81% of survivors (median sternotomy arm). AJnpaired data. H"Mean" was inconsistent throughout article: 36%, 33%, and 38% seem to be actual possible change in mean FEV based on information in abstract, Table 2, and discussion. increase in the FEV, (range, 64 to 200%) in eight patients who underwent bilateral LVRS by median sternotomy. Follow-up ranged from 3 to 10 months, with a mean of 6 months. In 1995, these investigators detailed results of the first 20 patients. 14 The short-term increase in FEV, was 82%. Follow-up ranged from 1 to 15 months (mean, 6.4). In addition to the improved FEV,, reductions in TLC, RV, and trapped gas were noted, and most patients experienced improvements in quality of life and exercise tolerance. 14 A follow-up report in 1996 stated that 6 months postoperatively the FEV, of 37 patients was 67% higher than that of the entire group of 84 patients preoperatively. 66 A more recent update by Cooper and coworkers 54 on the first 150 bilateral staple LVRS procedures indicated a mean improvement in FEV, of 51% at 6 months. Follow-up was available in 101 of 127 survivors at 6 months. Other investigators have reported 3- to 6-month data (with varying completeness of follow-up data) on patients who have undergone bilateral staple LVRS by median sternotomy, and mean improvements in FEV, ranged from 30 to 49% 55,58,62,65 R esu i ts f or bilateral staple LVRS by videoassisted thoracoscopy (VATS) are similar Whether improvements in pulmonary mechanics after LVRS can be sustained or whether LVRS is followed by an accelerated decline in function is unclear. Gelb and associates 67 reported 1-year follow-up data on 10 patients in whom bilateral stapling LVRS was performed by thoracoscopic technique. The preoperative mean FEV, was 0.71 L, the 6-month postoperative FEV, mean was 1.19 L, and the 1-year postoperative mean FEV, was 0.95 L. This yields a 68% mean improvement in the FEV, at 6 months and 34% at 12 months, suggesting that a substantial degradation of the benefit from LVRS may be noted as early as 1 year postoperatively. 67 DiMango and colleagues 68 reported their 1-year followup data on 13 patients, a select sample of a much larger group. Their mean FEV, was L at baseline, increased to 0.94 L 6 months after LVRS, and decreased to L at 12 months. This corresponds to a mean improvement in the FEV, of 54% at 6 months and 37% at 12 months. This study also suggests that the improvement in FEV, may decrease substantially as early as 6 to 12 months postoperatively. Roué and coworkers 69 reported long-term results in 13 patients who had undergone LVRS by various techniques, including median sternotomy and thoracoscopic approaches. Of 13 patients, 11 had a unilateral procedure. Approximately 30% of these patients had an FEV, increase of at least 20% at 2 years, but no patient had an FEV, change of at least 20% at 4 years. Cooper and associates recently presented 30-month follow-up data on the first 20 patients who had been subjects in the initial report in Despite minor differences in the reported baseline pulmonary function values between the two case series, the FEV, at 30 months was still 50% greater than preoperatively. Nevertheless, the 30-

5 556 month value declined from 69% above baseline at 6 months and 60% above baseline at 12 months. A similar conclusion can be reached from larger subsequent case series from the Washington University group70 and from more recent data from other centers Effects on Supplemental Oxygen Dependence ("Oxygen Liberation"). Ascertaining the rate of oxygen liberation due to LVRS on the basis of a review of the published literature is difficult. In many of the reports, follow-up is incomplete, and thus the rates of oxygen liberation may be seriously overestimated. Many patients who refuse to return for follow-up are probably doing poorly. The literature is also unclear whether preoperative and postoperative rates of oxygen use are based on careful oxygen titration studies; postoperative oxygen use is frequently self-reported. Many studies fail to distinguish between oxygen use at rest and that during exertion, and some reports consider a reduction in the oxygen flow rate postoperatively to be a substantial gain. Claims of oxygen liberation are typically based on 3- to 6month follow-up evaluations; whether this benefit can be sustained remains unclear. Keenan and colleagues73 reported their experience with 67 patients undergoing unilateral LVRS (staple in 57 and laser in 10) and noted that 80% used supplemental oxygen during exertion and that 62% used it continuously preoperatively. A 3-month follow-up assessment of 40 of 53 oxygen-dependent patients who had undergone LVRS suggested that 17% no longer required oxygen. Naunheim and coworkers74 reported follow-up information on 25 of 50 patients after LVRS; 84% used oxygen continuously or during exertion preoperatively. Of 21 patients, 10 (48%) had discontinued use of oxygen at the 3-month follow-up. No criteria for the change in oxygen therapy were provided. Daniel and associates58 reported follow-up data on 17 of 26 patients 3 months after bilateral LVRS by median sternotomy. They found no significant difference in the partial arterial pressure of oxygen or partial arterial pressure of carbon dioxide in the patients in whom follow-up data were available; however, they paradoxically reported that seven patients required oxygen continuously preoperatively and that only one required oxygen continuously postoperatively. McKenna and colleagues57 reported their experience with 166 patients undergoing either unilateral or bilateral LVRS by thoracoscopic staple technique and had short-term physiologic follow-up data on 139 of 161 survivors. In the unilateral group, 18 of 50 patients (36%) who used preoperative oxygen (unknown whether continuously or during exertion) no longer used oxygen at 6 months, and in the bilateral group, 30 of 44 patients (68%) who used preoperative oxygen were no longer using oxygen at 6 months. Whether this discontinuance of use of oxygen was related to a postoperative oxygen titration is unknown. Eu- Mayo Clin Proe, June 1998, Vol 73 gene and coworkers75 reported their experience with 28 patients who underwent combined single-lung LVRS by laser and staple technique and found that the need for oxygen (at rest or during exertion not specified) was eliminated in 5 of 23 patients who were using oxygen preoperatively (22%). Cooper and associates54 reported that, in a group of 150 patients undergoing LVRS by median sternotomy staple technique, postoperative physiologic data at 6 months were available in 101 patients. Ofthat subpopulation of patients, 52% had been using oxygen at rest preoperatively, and 16% were using it postoperatively; 92% were using oxygen during exertion preoperatively, and 44% were using oxygen during exertion postoperatively. More recent evidence from another group also suggests that LVRS may have limited effects on gas exchange.76 Effects on Exogenous Corticosteroid Dependence ("Corticosteroid Liberation"). The report by Cooper and colleagues54 of 150 patients undergoing bilateral LVRS by median sternotomy staple technique indicated that follow-up data were available in 56 of 76 patients eligible for follow-up at 1 year. Corticosteroid-dependency rates were as follows: preoperatively, 53%; 6 months postoperatively, 17%; and 1 year postoperatively, 19%. McKenna and coworkers57 reported a 54% corticosteroid liberation rate in 51 patients who underwent unilateral LVRS by thoracoscopic staple technique and an 85% rate of corticosteroid liberation in patients who underwent bilateral LVRS by thoracoscopic staple technique. These data are difficult to interpret because no consensus exists on the benefit of corticosteroids for emphysema. At best, only 10% of patients with emphysema have short-term improvements in lung function with use of highdose corticosteroids, and symptoms referable to dosing changes tend to reflect central nervous system side effects rather than changes in cardiopulmonary performance.77 Morbidity and Mortality. Most large case series report 30- to 90-day mortality rates of 4 to 10% Long-term survival rates are surprisingly difficult to ascertain based on the literature. McKenna and associates57 reported a 10% 1-year mortality rate in a group of 166 patients undergoing LVRS and a 17% 1-year mortality rate in a subgroup of those patients. Cooper and colleagues54 reported a 7% 1-year mortality rate in a group of 150 patients who underwent LVRS and an 8% mortality rate at 2 years; however, median follow-up in this case series was only 13 months. Argenziano and coworkers80 reported a 17% 1-year mortality rate in 85 patients after LVRS by means of several different techniques. Petureau and associates81 reported their experience in abstract form; of 18 patients who underwent LVRS, 5- and 8-year survival rates were 50% and 36%, respectively. Published mortality figures for LVRS may underestimate the mortality rates at many centers where this procedure is performed. HCFA analyzed 711 Medicare

6 557 Table 3. Summary of Studies Reporting Morbidity Rates After Lung Volume Reduction Surgery* Reference Complication Cooper et al 54 (N = 150) McKenna et al 57 (N = 166) Miller et al 56 (N = 53) Naunheim et al 74 (N = 50) Keenan et al 73 (N = 57) Argenziano et al 80 (N = 85) Elpern et al 95 (N = 52) Air leak >7 days Reintubationventilation Tracheostomy Reoperation Pneumonia Empyema Dysrhythmia Gastrointestinal Cerebrovascular event Other neurologic event Myocardial infarction or cardiac arrest * = not reported. claims for LVRS from October 1995 through January 1997, and a strikingly high mortality rate of 26% was noted by January During that 12- to 15-month period, the hospital readmission rate was high, and the need for longterm care in conventional or rehabilitation hospital facilities was frequent. 82 Some investigators have estimated that late mortality from LVRS may be close to 50%, at least at some institutions. 53 Uncertainty about the natural history of COPD is considerable, and thus putting LVRS mortality figures into appropriate context is difficult. Prior data suggest that medically managed patients with COPD have a 5-year survival rate of 40 to 60%. 83 ~ 94 How closely these estimates apply to the subset of patients with COPD whose disease is predominantly related to emphysema is unclear. Surgical morbidity figures are difficult to ascertain because some centers are more rigorous in reporting the "lesser" complications of LVRS than are others. The most common complications of staple LVRS performed by either open or thoracoscopic techniques are outlined in Table ,73,74,80,95 p er sistent air leak (for more than 7 days) is the most commonly reported complication and occurs in 30 to 54% of patients. Patients are usually extubated on the operating table in order to reduce the risk of barotrauma, but reintubation is necessary in 5 to i7% w Tracheostomy has been necessary in as many as 13% of patients, 56 and reoperation has been necessary in as many as 16%. 74 Although diagnostic criteria are not explicitly stated, postoperative pneumonia has been reported in 4 to 17% of patients Postoperative dysrhythmia has been reported in 7 to 21% of patients in some series or not mentioned in others Six series reported gastrointestinal complications, including cecal perforation, prolonged ileus, colitis, and peptic ulcer disease Postoperative stroke has been reported, and "transient" unspecified neurologic events occurred in up to 19% of patients in one series. 56 Myocardial infarction or cardiac arrest has been noted in other series The mean length of stay (LOS) for patients undergoing LVRS ranges from 13 to 22 days. The LOS distribution is skewed because a few patients require prolonged hospitalization (more than 100 days) The mean LOS tends to decrease with experience At some centers, the use of the Heimlich valve has been helpful in reducing LOS in selected patients with prolonged air leak. 96 Dismissal to intermediate care or rehabilitation hospitals has been reported in 21 to 29% of patients PERSISTENT QUESTIONS Do Highly Significant Group Mean Changes in FEV, Tell the Whole Story? In large population studies concerned primarily with cardiovascular risk factors, the FEV ( proved to be a surprisingly strong predictor of life expectancy. Such associations provide minimal insight into mechanisms but are of interest in the context of the literature on LVRS. Group mean improvements in FEVj imply that at least a fraction of patients are helped by LVRS. This reasoning is consistent with anecdotal clinical experience, but important questions remain unanswered. Who benefits, and who is harmed? Are there better surrogate outcome variables that more closely reflect the mechanisms through which an operation improves respiratory system function? Argenziano and associates 80 reported a 71.1 ± 66.9% improvement in FEVj in patients with a preoperative FEV, of less than 500 ml and a 53.1 ± 63.4% improvement in patients whose preoperative FEV was 500 ml or greater.

7 558 Clearly, on the basis of this standard deviation, some patients have done extraordinarily well with regard to the change in FEVj, whereas others have derived no benefit or may have become worse. The Cooper group reported the 6-month follow-up data for 37 of 84 patients, indicating a mean improvement in the FEVj of 64% (unpaired data); however, significant variance was noted in the FEVj results (Fig. I).66 Almost 30% of their patients had an FEVj change of less than 25%. Keenan and coworkers73 reported similar findings. Although a 27% mean improvement in FEVj was noted in 40 of 53 patients eligible for follow-up at 3 months (unilateral thoracoscopic staple or combined staple-laser LVRS), the histogram of FEVj changes presented in their article illustrates that 38% of patients had an FEVj improvement of less than 20% and that 15% of patients had a postoperative FEV, lower than the preoperative value by 0 to -20% (Fig. 2). These and other data suggest heterogeneity in treatment response.97 Who Benefits From and Who Is Harmed by Surgery? As with any new procedure, selection criteria were needed, and these were based largely on assumptions about disease mechanisms. As clinical experience accumulated, the criteria were modified. To date, however, their validity has not been tested in a prospective manner. "Typical" inclusion and exclusion criteria for LVRS, as they have evolved over time, are shown in Table 1. In most large programs, only 20% of patients with COPD who were assessed for LVRS were advised to undergo the procedure.98 Smaller programs seem to have been less restrictive. Many investigators agree that the optimal selection criteria for patients undergoing LVRS have yet to be established Numerous anecdotal experiences have described good outcome in patients who are considered high risk based on conventional criteria. Argenziano and associates80 reported short-term improvements in pulmonary function, exercise capacity, and dyspnea in patients with hypercapnia (partial arterial pressure of carbon dioxide greater than 55 mm Hg), corticosteroid dependence (greater than 10 mg of prednisone per day), low preoperative FEVj values (less than 500 ml), and severe exercise limitation that prevented them from completing a preoperative pulmonary rehabilitation program. Other investigators have also reported improvements in patients with carbon dioxide retention and very low preoperative FEV, values On average, however, patients with an increased carbon dioxide level (45 mm Hg or greater) who walk less than 200 m during the 6-minute walk test seem to do worse.101 Whether minimal FEVj or carbon monoxide diffusing capacity values exist that predict a poor outcome is unknown. Some investigators believe that a high iulll. < % Increase in FEV, >100 Fig. 1. Distribution of percent increase in forced expiratory volume in 1 second (FEV^ preoperatively in comparison with 6 months postoperatively (N = 37). (From Yusen and associates.66 By permission.) preoperative TLC (greater than 130%) correlates with a better outcome.97 Most surgeons consider that topographic heterogeneity in emphysema is a prerequisite for a satisfactory surgical outcome.4960 Patients with uniformly emphysematous (and destroyed) lungs are thought to be much worse candidates for LVRS than are those with predominant upper lobe disease.56 Although some physiologic underpinning exists to support this viewpoint, the predictive value of emphysema distribution analyses has not been formally tested in a prospective manner. For example, improvement has been demonstrated in a small series of patients with a deficiency of aj-antitrypsin who had predominant lower lobe disease.102 Morphologic heterogeneity issues have recently been examined retrospectively, and, although patients with more heterogeneous disease tend to have higher mean changes in FEVj, some patients with more homogeneous disease have clearly experienced significant changes in expiratory flow after LVRS Traditionally, these patients have been excluded from consideration for LVRS. Unfortunately, no validated algorithm is available to determine the amount and scale of topographic heterogeneity in lung structure, and the number of surgical patients with socalled homogeneous disease is not large enough to facilitate meaningful conclusions. Finally, it is possible that current surgical approaches, which are particularly suited for patients with upper lobe disease, have not been sufficiently modified to accommodate alternative emphysema distribution patterns. Similar uncertainty surrounds other exclusion criteria such as pulmonary hypertension,53' advanced age, and pulmonary rehabilitation performance standards Although most surgeons have adhered to

8 an age limit of 75 years, others have performed LVRS successfully in octogenarians Echocardiographic estimations of pulmonary artery pressures have limited accuracy,106 but subjecting all candidates for LVRS to right heart catheterization does not seem feasible. Some investigators believe strongly that pulmonary rehabilitation must be an essential component of the preoperative and postoperative care of these patients and that patients must achieve certain performance milestones before they should be considered surgical candidates Others have not consistently used pulmonary rehabilitation23 57,73 (or have not used rehabilitation at all) but have demonstrated similar surgical outcomes.107 Even ventilator-dependent patients have undergone LVRS and were consequently liberated from machine support Although coronary disease is clearly a risk factor for surgical morbidity and mortality, Miller and colleagues109 performed combined coronary artery bypass grafting (CABG) and LVRS in several patients, and results were good. Although reasonable patient selection criteria must be established with any new procedure, these criteria must be rigorously validated or discarded. As one investigator pointed out, what one knows as "truth" does not always withstand the test of time.27 It was "known" that single-lung transplantation was contraindicated in patients with emphysema because of theoretical concerns about resultant unfavorable ventilation-perfusion relationships. Kotloff27 correctly points out that single-lung transplantation is now the procedure of choice for transplantation in this group of patients. What Is Known About the Mechanisms of Improvement After LVRS? Any debate about patient selection criteria and surrogate outcome measures must begin with an appraisal of the physiologic mechanisms of emphysema and the potential effects of LVRS on these mechanisms. Viewed in simple mechanical terms, the emphysematous destruction of lung tissue causes a loss of elastic recoil. This loss of recoil has several important consequences.110 First, airways tethered to lung parenchyma lose their support; thus, their diameter at any specific lung volume is reduced. This mechanism contributes to the increase in specific airway resistance and reduced maximal expiratory flow. Second, the volume at which lungs and chest cavity operate increases because the outward recoil of the chest wall is opposed to a lesser extent by the inward recoil of the lungs and because reduced expiratory flows cause dynamic hyperinflation. In turn, dynamic hyperinflation has important consequences on respiratory muscle activity and energetics and undoubtedly affects hemodynamics. Operating at high volumes not only places the inspiratory muscles at a mechanical disadvantage but also increases their elastic load from inadver a <u ç 8 <* i % change in FEV1 >60 Fig. 2. Histogram demonstrating range of improvement in postoperative forced expiratory volume in 1 second (FEVt) in patients at 3-month assessment. (From Keenan and associates.73 By permission.) tent positive end-expiratory pressure. Compounding the mechanical consequences of emphysema are the impaired gas exchange function of the lung and the propensity for cardiovascular exercise limitation. Ventilation-perfusion (V/Q) mismatch, through its effect on physiologic dead space, increases the ventilatory requirement of patients unless, or until, the ventilatory control system begins to tolerate hypercapnia. Hypoxemia complicating V/Q mismatch, hypoventilation, or sleep-related disordered breathing, in turn, promotes pulmonary vasoconstriction, pulmonary hypertension, cor pulmonale, and right heart failure. The success of LVRS in selected patients implies that these patients were limited by mechanical constraints on the respiratory system. Of note, the loss of gas exchange surface from lung resection does not aggravate the problem, a further emphasis of the intimate relationship between mechanical impairment and gas exchange function. If one accepts the theory that hyperinflation is a key to patients' disability, then the first step in understanding LVRS is to contemplate its effect on the volume range over which patients breathe during the activities of daily living. Unlike ambulatory monitoring of blood pressure or electrocardiography, the technology needed to determine lung volume measurements in the ambulatory setting is not available. We can only make inferences from pulmonary function laboratory-based assessments of the static lung volume subdivisions, including the TLC, functional residual capacity (FRC) (the end-expired lung volume measured during quiet breathing through a mouthpiece), and RV. Mechanisms by Which LVRS Alters the Lung Volume Subdivisions. In contrast to a young healthy person in whom airways close at RV, in a patient with emphysema, RV is determined by the rate at which obstructed lung units

9 560 can empty relative to the patient's ability to sustain an expiratory effort."1 Because of the more complex determinants of RV, predicting the effects of LVRS on minimal lung volume is difficult. In the most simple case, the reduction in RV is in direct proportion to the amount of lung tissue surgically removed. The clinical literature supports this insofar as bilateral staple procedures result in greater RV reductions than do unilateral VATS or laser procedures In patients with emphysema, TLC is determined largely by the mechanical properties of the chest wall and the ability of inspiratory muscles to displace it. In contrast to normal lung, the retractive force of the emphysematous lung is so low that it does not constitute an appreciable load on the inspiratory muscles to impede their shortening. Evidence supporting this viewpoint was provided by Sharp and colleagues.113 They inflated the lungs of anesthetized patients with emphysema, who had received paralytic agents, by using a super syringe to volumes exceeding TLC (measured during a maximal inspiratory effort during wakefulness) by greater than 1 L. After LVRS, the smaller remaining lung exerts a greater retractive force; isovolume recoil pressure (recoil pressure at the same absolute thoracic cavity volume) must increase. As pointed out by Fessier and associates,114 the greater retractive force is an added load on the inspiratory muscles; hence, TLC decreases. Unless there is profound muscle weakness, however, TLC is expected to decrease substantially less than RV; individual units of the remaining lung tissue can easily be stretched to a length exceeding their maximal lengths preoperatively. As a result, the vital capacity of patients with emphysema increases after LVRS. The clinical literature on LVRS supports predictions by Fessier and colleagues, at least qualitatively. Although similar reasoning may be applied to predict the changes in relaxation volume, the influence of an operation on dynamically determined FRC necessitates knowledge of the effects of LVRS on ventilatory requirement and expiratory mechanics.115 In brief, predicting the effects of LVRS on TLC, RV, and vital capacity may not be sufficient for predicting surgical outcome in individual patients, and changes in these variables would not necessarily be valid surrogate measures of clinical benefit. This situation is further compounded by uncertainty about lung and chest wall remodeling after LVRS and difficulties in characterizing the mechanical properties of the lung tissue removed relative to the properties of the remaining emphysematous tissue. Mechanisms by Which LVRS Alters Maximal Expiratory Flow. Lung recoil is an important determinant of maximal expiratory flow. An intervention (LVRS) that increases isovolume pressure should therefore also increase isovolume flow. The extent to which this happens depends on the mechanical properties of the conducting airways. Stiff, narrow, and fibrotic airways of patients with bronchitis or asthma may not respond to increases in recoil; intrinsically normal airways of patients with emphysema may respond dramatically.116 These predictions of classic mechanics theory have held up qualitatively in the LVRS literature, but their role in individual decision making remains to be defined "8 Incorporation of lung recoil and isovolume pressure flow measurements into the preoperative screening and patient selection process cannot be recommended without further study. In view of the heterogeneity of lung mechanical properties in patients with emphysema, a concern is that esophageal balloon pressure measurements from a single site could yield misleading information. Furthermore, very small changes in recoil pressure that may be beyond the resolution of the technique could have major effects on maximal flow. In brief, the precision of lung recoil and airway compliance measurements as selection criteria may be insufficient to justify their use despite the strong mechanistic underpinning of the arguments. Mechanics by Which LVRS Alters Respiratory Muscle Function. Hyperinflation places the inspiratory muscles at a mechanical disadvantage and thereby contributes in large measure to the disability of patients with emphysema. " 9 In light of the effect of LVRS on RV and FRC, the observation that maximal transdiaphragmatic and airway occlusion pressures increase after an operation should be no surprise Whether muscle remodeling (resulting from unloading and altered use) contributes to improved function is unknown. The available literature does not clarify the role of inspiratory muscle testing in patient selection. Mechanisms by Which LVRS Alters Exercise Performance. The exercise capacity of patients with emphysema is thought to be determined by the mechanical constraints placed on maximal ventilation.123 Therefore, improvements in lung mechanics may explain the longer 6-minute walk distances, increased maximal workloads, and higher maximal oxygen uptake values, all of which have been reported after LVRS." The role of cardiovascular adaptations and altered heart-lung interactions in this process is unclear. Most patients with severe emphysema have mild to moderate pulmonary hypertension, which may contribute to their exercise limitation.126 Anecdotal reports suggest that resting pulmonary artery pressure increases slightly after LVRS (Scharf S. Personal communication). This factor makes it less appealing to link the improved exercise performance to unloading of the right side of the heart. An untested hypothesis links the reduced exercise performance of patients with COPD to an inadequate venous return (Hyatt RE. Personal communica-

10 tion). The displaced contracting diaphragm may impede flow through the vena cava, an outcome offering a potential mechanism for cardiovascular exercise limitation that could be amenable to surgical treatment. Because the effects of exercise on right ventricular dimensions remain to be defined, no data have addressed this reasoning. Will a Better Understanding of How LVRS Works Result in Better Patient Selection Criteria? Key in understanding emphysema and the potential effect of LVRS on the disability caused by emphysema is an appreciation for the intimate relationships among lung recoil, compliance, volume, flow, inspiratory muscle pressure output, blood gas tensions, pulmonary artery pressure, dyspnea, and exercise performance. All these variables contain some information about most of the other variables. We suspect that treating each as single independent patient selection criterion rather than considering them in aggregate will confuse more than illuminate matters. The focus should be on pattern recognition, which must be founded on established physiologic principles. What Is the Best Procedure for LVRS? Various techniques are available for performing LVRS. Laser ablation of pulmonary tissue is still promoted by some investigators,44 but most have abandoned this procedure "2 In the only randomized study comparing laser ablation with surgical stapling, McKenna and colleagues59 compared unilateral stapled lung reduction with unilateral laser bullectomy for diffuse emphysema. They found a significantly higher incidence of delayed pneumothorax in the laser group, a significantly higher increase in the FEVj at 6 months in the staple group, and a higher rate of oxygen liberation in the staple group. They concluded that unilateral stapled lung reduction is superior to unilateral laser bullectomy. Surgeons who use a sternotomy route for lung reduction stapling generally perform bilateral reductions, and surgeons who perform staple lung reduction by VATS have used both unilateral and bilateral approaches Bilateral procedures tend to result in greater improvements in lung function, but unilateral stapling may have a role in selected patients No consensus exists whether stapling by VATS or stapling by median sternotomy is superior. Some investigators have suggested that this depends on surgeon preference.53 Several nonrandomized studies have suggested that equivalent results are achieved with staple reduction by VATS and staple reduction by median sternotomy The use of buttressing materials has been promoted by some investigators for decreasing the incidence of pro- 561 longed air leak after a staple reduction surgical procedure. Some investigators have promoted the use of porcine pericardial strips,48 whereas others have used polytetrafluoroethylene (Teflon) sleeves and polydioxanone ribbon.134 Some investigators, however, have challenged the need for these buttressing products, which increase the cost of the procedure Stammberger and coworkers135 performed bilateral LVRS by VATS without buttressing material in 42 patients. The median hospital stay (12 days), median chest tube drainage time (8 days), and rate of prolonged air leak greater than 7 days (50%) compared favorably with that reported by other investigators using buttressing material. These investigators concluded that the buttressing material did not seem to offer obvious advantage when they compared their results with those of other investigators in a nonrandomized fashion. Furukawa and colleagues136 reported similar findings. They performed staple LVRS by median sternotomy in 15 patients. Each patient's right or left lung was randomized to receive pericardial buttressing on one side and no buttressing on the other. With respect to the mean duration of air leak, buttressing with pericardial strips did not seem to offer a substantial advantage. Other investigators have described particular suturing techniques in an attempt to decrease the frequency and duration of air leaks in surgical patients with severe emphysema How Much Lung Should Be Resected and How Is It Measured? The stated goal of LVRS by staple technique is to remove 20 to 30% of each lung.14 Exactly how this number was adopted is unclear. Even if this number is accepted on faith, measuring the resected lung volume intraoperatively is difficult if not impossible. The resected lung tissue is sometimes weighed, but at the time of operation, there is no way of knowing the specific density of the lung removed relative to that of the remaining lung. What Is the Cost-Effectiveness of LVRS in Comparison With Conventional Medical Therapy? The cost-effectiveness of LVRS has not been defined. Albert and colleagues139 calculated the costs for 23 consecutive patients undergoing LVRS at their institution and found that the median charge was $26,669 (range, $20,032 to $75,561). They further estimated that, if only 10%ofUS patients with emphysema were candidates for LVRS, the expense for operations would exceed $4.6 billion. Elpern and coworkers95 estimated a mean charge of $30,976 (range, $11,712 to $121,829) for LVRS at their institution. Whether the initial expense of an operation would result in fewer dollars being spent for outpatient clinic visits, hospitalizations, medications, oxygen, and other expenses asso-