Advances in lung-volume-reduction surgery and lung transplantation may offer improved quality of life to patients with advanced chronic obstructive pulmonary disease.

photoThe term chronic obstructive pulmonary disease (COPD) refers to a spectrum of chronic pulmonary conditions characterized by shortness of breath, coughing, sputum production, airflow limitations, and impaired gas exchange. Most patients with COPD have either chronic bronchitis or emphysema. COPD is estimated to affect at least 15 million US residents, and it is the fourth leading cause of death in the United States.1 Among the principal causes of death, only COPD continues to have a growing death rate (increasing by more than 20% in the past decade).2

Successful management of COPD is predicated on the ability to slow disease progression, prevent infection, and treat reversible symptoms. If the extent of disease is not completely irreversible (end stage), its progression can be slowed through smoking cessation, reduction of exposure to environmental or occupational irritants, and therapy with supplemental oxygen. Several agents are available for the management of reversible bronchospasm associated with COPD. These include theophylline, b2-agonists, corticosteroids, anticholinergic agents, and mucolytic agents. Management of COPD is, therefore, a complex process that often requires multiple medications, multiple dosing regimens, supplemental oxygen, lifestyle changes, and frequent physician visits. The cornerstone of medical management is compliance, without which therapy may be ineffective and quality of life may be suboptimal.

Despite advances in medical therapy, a significant number of patients with advanced COPD face a miserable existence and are at risk for death. This subgroup includes patients who have a forced expiratory volume in one second (FEV1) of less than 45% of the predicted value and who remain symptomatic despite smoking cessation, optimal drug therapy, use of supplemental oxygen, and pulmonary rehabilitation. Once the FEV1 falls below 30% of the predicted value, the 5-year death rate approaches 60%.2 For patients with advanced COPD, surgical options include lung-volume–reduction surgery (LVRS) and lung transplantation. The goal of surgical therapy of COPD is to prolong life by preventing secondary complications, to relieve dyspnea, and to enhance quality of life by improving functional status.

LVRS Historical Perspective
In the 1950s, Brantigan and Mueller3 reported their experience with resecting the most diseased 20% to 30% of emphysematous lung tissue, coupled with radical hilar nerve stripping, in a small sample of patients. They postulated that resection of peripheral lung in patients with severe COPD would increase lung recoil and, therefore, increase radical traction on peripheral bronchioles, thereby reducing airflow obstruction and relieving dyspnea. Brantigan and Mueller’s procedure did produce clinical improvements in pulmonary function, but the mortality rate was high and the procedure was soon abandoned.

Today, improvements in surgical techniques have rekindled interest in the surgical treatment of COPD. Between 1991 (when Wakabayashi et al4 began reporting success using laser bullectomy for patients with diffuse bullous emphysema) and 1995 (when Medicare stopped reimbursing for LVRS), the number of surgical procedures increased at an almost exponential rate. The biggest spur to surgical intervention came when Cooper et al5 presented data from 20 patients who had undergone bilateral LVRS. The operations were done through a median sternotomy and employed a linear stapling device fitted with strips of bovine pericardium to minimize air leakage through the staple holes. These investigators reported no early or late mortality, and the procedure produced a mean improvement in FEV1 of 82%, a rise in mean room-air Pao2 from 64 to 70 mm Hg, and a mean increase of 122 m in the 6-minute walking test, as well as improvements in dyspnea and quality-of-life scores.

The positive outcomes seen in the series by Cooper et al5 sent a wave of excitement through the medical and surgical communities that continues to this day. Although many centers have been performing LVRS and aggressively marketing the procedure to patients, only a few have systematically collected data that would help assess any criteria or outcomes. As a result, perhaps thousands of patients have now undergone a major thoracic procedure about which little is actually known. Questions about LVRS still exist, particularly those concerning associated morbidity and mortality, the durability of improvements in lung function, the characterization of patients who benefit most from the procedure, and the ultimate effect of the procedure on mortality in comparison with conventional medical therapy.

LVRS Surgical Approaches
A variety of surgical approaches to LVRS have been described. These include median sternotomy with bilateral stapling lung resection, video-assisted thoracoscopic surgery (VATS) performed unilaterally or bilaterally with stapling lung resection, and unilateral VATS with laser ablation of emphysematous tissue.

With either median sternotomy or VATS with stapling resection, excision of lung tissue has been based on preoperative targeting of the worst areas of emphysematous lung using preoperative high-resolution CT scanning or quantitative lung-perfusion scanning. Ultimately, direct visualization during the operation determines the extent of resection (which is accompanied by the use of an automatic stapling device). Bovine pericardium strips, biological fibrin glues, and TeflonĀ® reinforcement patches have all been used to buttress staple lines in order to decrease the number and magnitude of postoperative air leaks.

Laser therapy for LVRS is applied either in direct contact with the lung surface or as a beam directed at the lung from a distance. Proponents of laser ablation argue that no functional lung is damaged by the process; however, the procedure is capable of ablating emphysematous tissue only at the lung surface. Laser-induced inflammatory responses in nonresected lung tissue have, so far, precluded simultaneous bilateral applications.

Once resection has been completed, extubation is done as quickly as possible to decrease the incidence of postoperative air leaks and pneumonia. Conventional postoperative care includes liberal use of bronchodilators, placement of epidural catheters for analgesic administration, avoidance of excessive systemic narcotics to prevent respiratory depression, early ambulation, and avoiding the connection of chest tubes to wall suction (which could increase the magnitude of postoperative air leaks).6

• Better elastic recoil improves tethering of the airways,

• ventilation-perfusion mismatching is corrected via expansion of compressed atelectatic lung,

• the diaphragm is unflattened and the efficiency of respiratory musculature improves, and

• the cardiac tamponade effect is reduced.

TABLE 1. Possible mechanisms of benefits from lung- volume– reduction surgery. Adapted with permission from Chest.2

Mechanism of LVRS Benefits
Improvements in pulmonary function after LVRS have been attributed to at least four possible mechanisms: enhanced elastic recoil, correction of ventilation-perfusion mismatching, improved efficiency of the respiratory musculature, and improved right ventricular filling (Table 1).2 It is likely that one or more mechanisms may be involved, to varying degrees. The amount and characteristics of the removed and remaining portions of lung will largely determine each patient’s physiologic response. Hence, patients who have compressed lungs could be expected to have increased elastic recoil and improved compliance after surgery, whereas those who have mainly emphysematous lung tissue would probably see little change in overall respiratory mechanics.7 By the same token, if areas of low ventilation with preserved perfusion are removed and areas of equal ventilation and perfusion remain, oxygenation would be expected to improve.

Primary Objectives
Comparison of the effects of medical therapy alone with those of medical therapy plus LVRS on
• survival rates and
• exercise capacity.

Secondary Objectives
Comparison of the effects of medical therapy alone with those of medical therapy plus LVRS on
• quality of life and patient symptoms and
• FEV1, 6-minute walking test, and gas exchange.

Other Objectives Determination of
• optimum operative approach,
• which patients benefit most and least from the surgery,
• durability of effects, and
• cost-effectiveness

TABLE 2. Objectives of the National Emphysema Treatment Trial; FEV1=forced expiratory volume in 1 second and LVRS= lung-volume– reduction surgery. Adapted with permission from Postgraduate Medicine.6

The National Emphysema Treatment Trial
The National Institutes of Health and the Health Care Financing Administration are jointly sponsoring the ongoing National Emphysema Treatment Trial (NETT). This trial began enrolling patients in 1997; its target enrollment is 4,700 patients over a 5-year period.6 Objectives of the NETT and patient selection criteria for it are shown in Table 2. The primary goal of the trial is to compare, in patients with severe COPD, the survival rates and exercise capacity of subjects who receive medical therapy alone and subjects who receive medical therapy plus LVRS. It is hoped that the results of this trial will shed a clearer light on the efficacy and safety of LVRS for severe COPD.

Transplantation surgery
The first attempts at single-lung transplantation for COPD were reported in 1970.8 These early attempts failed because of the development of severe early graft dysfunction, which resulted in edematous consolidation of the allograft and hyperinflation of the native lung.6 Severe ventilation-perfusion abnormalities ensued, and investigators concluded, at the time, that unilateral lung replacement was impossible for patients with advanced COPD because of the propensity for unilateral native-lung air trapping. Double-lung transplantation for patients with COPD was performed successfully in the 1980s, and interest in the procedure for this patient group was rekindled.9

In the early 1990s, single-lung transplantation was again attempted, and it was accomplished successfully. Currently, single-lung transplantation is preferred to double-lung transplantation for most COPD patients because it affords more effective use of a limited supply of donor organs. Furthermore, the single-lung procedure is less rigorous than a bilateral procedure, and in the absence of acute allograft failure, hyperinflation and overdistension of the native lung occur only rarely.10 These problems are less likely to develop if the donor lung is oversized and the allograft is placed within the right hemithorax.6

In general, lung recipients have clinically and physiologically severe pulmonary parenchymal or vascular disease that is unresponsive to medical therapy.11 These patients have significant limitations in their activities of daily life and a limited life expectancy (1 to 2 years). The potential recipient should have adequate cardiac function without significant coronary artery disease, should be ambulatory with rehabilitation, and should have adequate nutritional status and a satisfactory emotional support system.11-14 Some selection criteria may be considered controversial.

Posttransplantation Management
Early postoperative care focuses on ventilatory support and weaning, fluid and hemodynamic management, immunosuppression, detection of early rejection, and prevention or treatment of infection. As the patient recuperates, the emphasis shifts toward regulating the medical regimen, establishing the routine for postoperative monitoring, and continuing postoperative rehabilitation and education.13

All patients are intubated postoperatively and cared for in a cardiothoracic surgery intensive care unit. Most patients can be managed with a standard single-lumen endotracheal tube, which is preferable for pulmonary toilet. Differential lung ventilation may occasionally be useful. After single-lung transplantation for emphysema, positive-pressure ventilation may result in hyperinflation of the native lung, with a subsequent mediastinal shift.15

Immunosuppression is begun preoperatively with loading doses of azathioprine and cyclosporine.15,16 Before the transplanted lung is reperfused, intravenous methylprednisolone (10 mg per kg of body weight) is given by the anesthesiologist.15 Postoperative immunosuppression is continued with triple therapy, initially using intravenous azathioprine, cyclosporine, and corticosteroids.16 Cyclosporine levels are observed daily and the dosage is adjusted accordingly. Oral preparations of these drugs are used as soon as reliable gastrointestinal absorption occurs. Some programs have favored withholding corticosteroids for the first postoperative week because of concerns about bronchial healing, but there is no evidence that the use of cortico-steroids in the period immediately after surgery has a deleterious effect on bronchial anastomosis.15

All patients initially use radial and pulmonary artery pressure monitoring for optimal hemodynamic management. A newly transplanted lung is extremely sensitive to volume overload due to disruption of the lymphatics. Extreme care is taken to minimize intravenous fluid overload in the early postoperative period. Low-dose dopamine therapy and the careful use of other inotropic agents may help support the hemodynamics of these dry patients.15 Pulmonary edema may be experienced within the first 24 hours after transplantation; therefore, diuretics and fluid restriction are balanced with the maintenance of adequate arterial pressure and renal output.

Immediate alimentation is given to lung-transplant patients who are nutritionally depleted. Postoperative paralytic ileus is common; consequently, patients usually require parenteral nutrition.

Functional Results
After transplantation, pulmonary function is markedly improved. Postoperatively, dyspnea at rest is abolished in most patients, and dyspnea on exertion is significantly diminished. Usually, supplemental oxygen is no longer required, and exercise tolerance is markedly improved. The use of single versus bilateral lung replacement greatly affects the extent and time course of improvement.16 Patients who receive bilateral lung replacement have significantly better pulmonary function than those treated with single-lung transplantation. Diffusion capacity is approximately 75% of the predicted value after bilateral lung transplantation and approximately 60% after single-lung transplantation.17

Trulock17 evaluated lung function 6 months after single-lung transplantation. Patients with double-lung transplants had normal pulmonary function, but those with single-lung transplants had residual obstructive abnormalities. Hemodynamic values and right-heart function improved more rapidly after single-lung transplantation in patients with pulmonary hypertension. No significant difference in most exercise-testing parameters has been demonstrated between the two groups, however, despite the significant difference in pulmonary function. This may be due to chronic muscle deconditioning and an accompanying abnormal cardiovascular response to exercise.

The Registry of the International Society for Heart and Lung Transplantation has compiled data from 124 multinational lung transplantation centers.18 New and follow-up data were recorded for all known transplant centers, and a directory of these centers was developed. Univariate survival analysis was performed with Kaplan-Meier statistics, and a subset of the data underwent multivariate logistic regression. As of February 7, 1996, a total of 5,039 lung transplantations (3,194 single-lung and 1,845 double-lung transplantations) had been reported to the registry. Actuarial survival rates at 1, 2, 3, and 6 years were 84%, 60%, 57%, and 38%, respectively, for single-lung transplantation and 84%, 62%, 58%, and 48%, for double-lung transplantation. There was no significant difference seen in actuarial survival when comparing single-lung and double-lung transplantation.18

Additional risk factors for lung transplantation have been reported since that time. Several of the risk factors before the 1-year mark (preoperative ventilator support, congenital heart disease, idiopathic pulmonary fibrosis, and older recipient age) are no longer significant 3 years after surgery. Other risk factors, including prior transplantation and underlying primary pulmonary hypertension, continue to pose long-term risks. A new independent risk factor for 3-year mortality has also been identified: nonwhite recipient race.18

Emerging Technologies
Emerging technologies related to lung transplantation include new immunosuppressive approaches such as

• donor-recipient chimerism (the coexistence of donor cells in recipient tissues, resulting in an enhanced state of tolerance);

• further development of monoclonal antibodies using newly discovered gene transfers (human leukocyte antigen-B7 and the luciferase reporter gene);

• intervention at the endothelial-cell–blood interface on a cellular level (by developing specific antibodies directed against the endothelial cell adhesion molecule leukocyte function associated antigen and the intercellular adhesion molecule); and

• what would be, perhaps, the ultimate expansion of the donor pool: xenotransplantation using transgenic pigs. Transgenic animal technology offers a solution to the problem of early hyperacute rejection because a gene transfected at the time of egg fertilization is present in all cells of a selected transgenic animal line.19

Recently, transgenic mice and pigs that expressed the human complement regulatory proteins decay accelerating factor and protectin were fostered.19 Hearts from these animals were resistant to complement activation and deposition when perfused with human plasma. The implications of such research are truly astounding. If transgenic pigs that express molecules that prevent hyperacute rejection can be generated, then the future of lung transplantation holds great promise.

Conclusion
LVRS and lung transplantation may offer hope for improved quality of life and prolonged life in selected patients with severe COPD. With refinements in surgical technique has come a renewed interest in using these surgical modalities as a therapeutic adjunct to medical therapy. Whether combined-modality treatment offers improvements in outcome over medical therapy alone remains to be determined. Results of the NETT will, one hopes, more fully elucidate the therapeutic value of LVRS, and future prospective trials will define the role of lung transplantation in patients with severe COPD.

John D. Zoidis, MD, is a contributing writer for RT Magazine.

References
1. Higgins MW. Epidemiology of obstructive pulmonary disease. In: Casaburi R, Petty TL, eds. Principles and Practice of Pulmonary Rehabilitation. Philadelphia: WB Saunders; 1993:10-17.

2. Fein AM. Lung volume reduction surgery. Answering the crucial questions. Chest. 1998;113:S277-S282.

3. Brantigan OC, Mueller E. Surgical treatment of pulmonary emphysema. Am Surg. 1957;23:789-804.

4. Wakabayashi A, Brenner M, Kayaleh RA, et al. Thorascopic carbon dioxide laser treatment of bullous emphysema. Lancet. 1991;337:881-883.

5. Cooper JD, Trulock EP, Triantafillou AN, et al. Bilateral pneumonectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg. 1995;109:106-119.

6. O’Brien GM, Criner GJ. Surgery for severe COPD. Lung volume reduction and lung transplantation. Postgrad Med. 1998;103:179-180,183-186,192-194,199-200.

7. Sciurba FC, Rogers RM, Keenan RJ, et al. Improvement in pulmonary function and elastic recoil after lung reduction surgery for diffuse emphysema. N Engl J Med. 1996;334:1095-1099.

8. Stevens PM, Johnson PC, Bell RL, et al. Regional ventilation and perfusion after lung transplantation in experimental and human emphysema. N Engl J Med. 1970;282:245.

9. Cooper JD, Patterson GA, Grossman R, et al. Double-lung transplant for advanced chronic obstructive lung disease. Am Rev Respir Dis. 1989;139:303-307.

10. Levine SM, Anzueto A, Gibbons WJ, et al. Graft position and pulmonary function after single-lung transplantation for obstructive lung disease. Chest. 1993;103:444-448.

11. Garg K, Zamora MR, Tuder R, Armstrong JD II, Lynch DA. Lung transplantation: indications, donor and recipient selection, and imaging of complications. Radiographics. 1996;16:355-367.

12. Peters SG, McDougal JC, Scott JP, Midthun DE, Jowsey SG. Lung transplantation: selection of patients and analysis of outcome. Mayo Clin Proc. 1997;72:85-88.

13. Trulock EP. Lung transplantation. Am J Respir Crit Care Med. 1997;155:789-818.

14. Lynch JP, Trulock EP. Recipient selection. Seminars in Respiratory and Critical Care Medicine. 1996;17:109-117.

15. Wood DE, Raghu G. Lung transplantation. Part II. Postoperative management and results. West J Med. 1997;166:45-55.

16. Davis DR, Pasque MK. Pulmonary transplantation. Ann Surg. 1995;221:14-28.

17. Trulock EP. Lung transplantation. Annu Rev Med. 1992;43:1-8.

18. Hosenpud JD, Novick RJ, Bennett LE, Keck BM, Fiol B, Daily OP. The Registry of the International Society for Heart and Lung Transplantation: thirteenth official report—1996. J Heart Lung Transplant. 1996;15:655-674.

19. Brown JM, Grover FL. The future of lung transplantation. Seminars in Respiratory and Critical Care Medicine. 1996;17:207-209.