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Lung volume reduction surgery for the management of refractory dyspnea in chronic obstructive pulmonary disease

Shah, Asad A; D'Amico, Thomas A

Current Opinion in Supportive and Palliative Care: June 2009 - Volume 3 - Issue 2 - p 107–111
doi: 10.1097/SPC.0b013e32832ad5e1
Respiratory problems: Edited by David C. Currow and Amy P. Abernethy
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Purpose of review This review describes the role of lung volume reduction surgery (LVRS) for the management of refractory dyspnea and other debilitating conditions in patients with chronic obstructive pulmonary disease. Recent studies, including a randomized trial comparing LVRS to medical therapy, are analyzed.

Recent findings LVRS plus optimal medical therapy is superior to medical therapy alone in treating certain subsets of patients with severe emphysema. In patients with predominantly upper lobe emphysema and low-exercise capacity, LVRS not only improves symptoms of dyspnea and exercise intolerance, but also is associated with improved survival. Furthermore, LVRS has recently been shown to be superior to medical therapy in improving other quality of life parameters, such as nutritional status, sleep quality, and the frequency of chronic obstructive pulmonary disease (COPD) exacerbations in patients with severe emphysema.

Summary LVRS is an effective strategy in the treatment of properly selected patients with COPD, improving survival and quality of life, including exercise tolerance, dyspnea, oxygen requirement and functional status.

Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA

Correspondence to Thomas D'Amico, MD, Professor of Surgery, Division of Thoracic Surgery, Department of Surgery, Duke University Medical Center, Box 3496 Durham, NC 27710, USA Tel: +1 919 684 4891; fax: +1 919 684 8508; e-mail: damic001@mc.duke.edu

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Introduction

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability in the United States. Because the symptoms of COPD and severe emphysema are often refractory to conventional medical management, alternative therapies have been sought to improve quality of life. Lung volume reduction surgery (LVRS), first developed in the 1950s, involves surgically resecting the most hyperinflated portions of emphysematous lungs. The belief is that by removing the most poorly functioning areas, the remaining lung will be more functional and overall pulmonary performance will improve.

Despite this viable theory, LVRS was initially not accepted, owing to the surgical risks of the procedure. Interest in LVRS as a therapy to improve the quality of life in patients with COPD was renewed in the mid-1990s after Cooper et al.[1] reported successful results in a small series of patients with severe emphysema. This report stimulated a widespread increase in the number of LVRS procedures performed; however, results were variable. In 1996, the Healthcare Financing Administration collaborated with the National Institutes of Health to sponsor The National Emphysema Treatment Trial (NETT) to assess the safety, efficacy, and risk–benefit ratio of the procedure.

This review describes the current role of LVRS in the palliation of patients with COPD secondary to emphysema. Issues of patient selection, operative considerations, quality of life, cost, as well as emerging interventional techniques used in the management of emphysema are discussed.

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Outcomes of lung volume reduction surgery

The current role of LVRS in the treatment of emphysema is based on the results of the NETT, a multicenter, randomized controlled trial enrolling over 1000 patients that compared medical therapy alone versus medical therapy and LVRS for the treatment of emphysema. The rationale behind this trial was the uncertainty regarding the risks and benefits of LVRS, in addition to concern about the proper selection of patients for the procedure. Mortality, quality of life, cost, and patient selection were the major parameters studied.

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Early results

One of the first publications to emerge from the NETT was an interim analysis that identified groups of patients that were at a particularly high risk of death after undergoing LVRS [2]. Patients with forced expiratory volume in one second (FEV1) less than 20% of their predicted value and with either a diffusing capacity of carbon monoxide (DLCO) less than 20% of their predicted value or with homogenous distribution of emphysema based on computerized tomography (CT) scan were deemed high risk and excluded from further randomization. This group had a 30-day mortality of 16% after surgery, in comparison to the medically treated patients, who had a 30-day mortality of 0% (P < 0.001).

The NETT subsequently reported the comparative results after 24 months of follow-up, demonstrating that surgically treated patients had significant improvements in exercise capacity over medically treated patients, although mortality was similar in the two groups [3]. Subset analysis showed that patients with predominantly upper-lobe emphysema and low-exercise capacity had decreased mortality when treated surgically versus medically (risk ratio for death 0.47, P = 0.005). In contrast, patients with non-upper lobe emphysema and high exercise capacity had increased mortality when treated surgically versus medically (risk ratio for death 2.06, P = 0.02). For patients with upper lobe disease and high exercise capacity, mortality was similar; but patients in the surgery group were more likely to have improvements in maximal workload and quality of life. For patients with non-upper lobe disease and low exercise capacity, mortality and maximum workload were similar, but patients in the surgery group were more likely to have an improvement in quality of life. Thus, at 24-months of follow-up, NETT had identified a subset of emphysema patients who had a significant survival advantage when treated with LVRS. Additionally, NETT identified groups of patients who had exercise and/or quality of life improvements from LVRS, as well as a group of patients who would not benefit from it.

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Long term follow-up

Naunheim et al.[4] reported the long-term effectiveness of LVRS in the treatment of emphysema in 2006. With a median follow-up of 4.3 years, it was demonstrated that the beneficial effects LVRS were enduring and more impressive than previously realized. The LVRS group as a whole had increased overall survival compared with the medical group: 0.11 deaths per person–year in the surgically treated group versus 0.13 in the medical group (RR = 0.85; P = 0.02). There were also statistically significant improvements in exercise capacity, including relief of dyspnea and health related quality of life in the LVRS group compared with the medically treated group.

One of the goals of the study was to identify subgroups of patients that would most benefit based on anatomic location of disease predominance (upper lobe dominant vs. nonupper lobe dominant) and baseline exercise capacity (high vs. low). In the subgroup analysis, patients with upper lobe dominant emphysema and low baseline exercise capacity were the most likely to achieve the greatest benefit from LVRS. Compared with the patients treated medically, the LVRS patietnts had significant improvements in overall survival (RR = 0.57, P < 0.01), exercise capacity (P < 0.001), and quality of life (P < 0.001). Specifically, at 5 years, more than 70% of those who underwent LVRS were still alive compared with less than 50% of those treated medically. Patients with upper lobe dominant emphysema and high-exercise capacity who underwent LVRS had improvements in exercise capacity and quality of life, but no survival advantage. Patients with nonupper lobe emphysema and either high or low baseline exercise capacity had similar survival, exercise capacity, and quality of life compared with medically treated patients.

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Patient selection

LVRS should be considered for patients only after they have received maximal medical therapy and have undergone pulmonary rehabilitation [5••]. Furthermore, a chest CT and cardiopulmonary exercise testing measuring maximum work load are required to determine if a patient is likely to benefit from the procedure. Once these objectives are fulfilled, LVRS can be offered to patients who have upper lobe predominant disease, as the procedure has been shown to improve symptoms, quality of life, exercise capacity, and lung function in this group. Additionally, for patients who have low-baseline exercise capacity, LVRS also has an added mortality benefit.

In patients who have previously undergone successful LVRS but have lost the clinical benefit of the surgery, reoperation and resection of hyperinflated lung tissue has been shown to improve FEV1, forced vital capacity (FVC), residual volume (RV), 6 min walking distance, and dyspnea in one series [6•]. However, the benefits have only been proven in the short term, and the patients selected met numerous strict criteria. The long-term benefit and safety of this is yet to be seen.

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Perioperative considerations

The NETT also addressed the operative approaches, comparing median sternotomy versus video assisted thoracoscopic surgery (VATS) both in a randomized and nonrandomized setting [7]. Overall, the two approaches seem to have similar morbidity, mortality, and functional results. However, VATS resulted in a shorter recovery time than median sternotomy, as the median length of hospital stay in the randomized portion of the study was 15 days versus 9 days (P < 0.001). Additionally, more VATS patients were living independently 1 month postoperatively (87.3% VATS vs. 62.3% median sternotomy). VATS was also associated with lower total cost during the 6 months after surgery (95% confidence interval on difference, $4295–$8705; P < 0.001).

In patients with severe emphysema refractory to maximal medical management in whom bilateral LVRS is contraindicated (i.e. marked unilateral disease), unilateral LVRS may be an option. Retrospective studies have shown an increase in FEV1 up to 3 years post-surgery, with additional short-term improvements in oxygen requirements and exercise tolerance. These results are inferior to the known benefits of bilateral LVRS, but may give the clinician another option for patients with contraindications to bilateral LVRS [8•].

Lung volume reduction surgery, despite its benefits, remains a procedure with significant morbidity. In an analysis of 511 patients in the non-high risk group of NETT who underwent LVRS, 90 day operative mortality was 5.5%, with respiratory issues being the most common cause of death (43%) [9]. Major pulmonary morbidity occurred in 29.8% of patients and major cardiac morbidity occurred in 20%. The most frequent complications included reintubation (22%), arrhythmia requiring therapy (19%), and pneumonia (18%). Non-upper lobe predominant emphysema, as determined by a radiologist, was the sole predictor of operative mortality (relative odds 2.99, P = 0.009). Age, FEV1, and diffusing capacity of carbon monoxide were independent predictors of pulmonary morbidity. Age, oral steroid use at the time of surgery, and non-upper lobe predominant emphysema were independent predictors of cardiac morbidity.

The nonrandomized portion of the study demonstrated a shorter operating time in the sternotomy group, more intraoperative hypoxemia in the VATS group, increased rate of reoperation for air leak in the VATS group, and more days in the ICU in the sternotomy group. However, none of these differences occurred in the randomized portion of the trial.

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Quality of life improvent after lung volume reduction surgery

In addition to the mortality and exercise capacity benefits of LVRS demonstrated by NETT, LVRS has been shown to improve the quality of life of emphysema patients in numerous other ways. LVRS has been shown to decrease the rate of COPD exacerbations by 30% and increase the time to first COPD exacerbation [10••]. LVRS has also been proven to increase arterial oxygen concentration, decrease the need for oxygen during treadmill walking, and decrease self-reported oxygen use for up to 2 years compared with patients treated medically alone [11•]. Additionally, compared with medical therapy alone, LVRS improves total sleep time, sleep efficiency, and nocturnal oxygen saturation [12]. Significant improvements in lung function, exercise capacity, and dyspnea in LVRS patients versus medically treated patients have been demonstrated in studies outside of NETT as well [13•,14,15].

In terms of metabolism, LVRS has also been shown to improve nutritional status, insulin resistance, and glycolipidic hormone levels, all of which are negatively affected by emphysema [16•]. Additionally, LVRS decreases resting energy expenditure and oxygen consumption volume, while also increasing BMI and respiratory quotient [17]. These measures were significantly improved in patients treated with LVRS versus medical therapy, both in those with and without postoperative steroid use.

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Cost effectiveness

LVRS is a costly treatment for severe emphysema, particularly when compared with medical therapy. Given the high prevalence of the disease in the United States and the large impact widespread use of LVRS could have on the economy, the NETT contained a cost effectiveness analysis as well. In the first 12 months after randomization-to-treatment, LVRS had a higher mean total cost per patient compared with the medical group ($71 515 vs. $23 371, P < 0.001) [18]. However, as time went on, this difference shifted as total medical cost per patient in months 7–36 after treatment was significantly higher in the medically treated group ($49 628 vs. $36 199, P < 0.001).

Overall, the cost effectiveness of LVRS compared with medical therapy (observed up to 3 years) was $190 000 per quality-adjusted-life-years (QALYs), a measure of life expectancy adjusted for patient quality of life [19]. This was projected to be $53 000 at 10 years. For patients with upper-lobe predominant disease and low-exercise capacity, LVRS was more cost-effective with $98 000 per QALY at 3 years and $21 000 per QALY predicted at 10 years.

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Emerging techniques in the palliation of chronic obstructive pulmonary disease

There is variability in patient response to LVRS and recent studies have attempted to better identify which patients may be best served by LVRS. Single nucleotide polymorphisms in two genes encoding xenobiotic-metabolizing enzymes, GSTP1 and EPHX1, were shown to help predict which patients may benefit from LVRS [20•]. Further work in this area may add a genetic component to the preoperative evaluation of the patient with severe emphysema.

To decrease the morbidity and mortality that results from an operation for LVRS, recent progress has been made in trying to develop less invasive means of decreasing lung volumes. One method currently being studied involves placement of a one-way endobronchial valve. The valve can be place via bronchoscopy and prevents air from entering the diseased portion of the lung, while allowing air and secretions to exit. This, in theory, would function in a similar way as surgical removal of the emphysematous lung. Initial studies of this technique show improvements in FEV1, residual volume, forced vital capacity, and 6 min walking distance [21]. However, data showing long-term results and improvements in mortality are currently lacking. Endobronchial stents, another interventional method of decompressing hyperinflated upper lobes, are also under study.

Another method, termed biological lung volume reduction, attempts to collapse any scar-diseased portions of lungs by bronchoscopically introducing biological substances (i.e. trypsin, fibrinogen, thrombin, etc.) into hyperinflated portions of lungs [22]. Once introduced, these substances produce an inflammatory reaction that ultimately leads to a reduction in lung volume. Initial studies are small and have only short-term follow-up, but this may represent an innovative way to effectively reduce lung volume without many of the risks of LVRS.

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Conclusion

The NETT was a landmark study that proved that LVRS plus medical therapy was superior to medical therapy alone in improving both survival and quality of life in patients with low-exercise capacity and predominantly upper-lobe emphysema. Additionally, compared to medical therapy alone, LVRS has been shown to improve oxygenation, exercise capacity, performance status, sleep quality, nutritional status, metabolic status, while decreasing the number of COPD exacerbations. Emerging techniques are focusing on developing less invasive means of achieving the salutary effects of LVRS.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 145–146).

1 Cooper JD, Trulock EP, Triantafillou AN, et al. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106–116, discussion 116–119.
2 National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med 2001; 345:1075–1083.
3 Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003; 348:2059–2073.
4 Naunheim KS, Wood DE, Mohsenifar Z, et al. Long-term follow-up of patients receiving lung-volume-reduction surgery versus medical therapy for severe emphysema by the National Emphysema Treatment Trial Research Group. Ann Thorac Surg 2006; 82:431–443.
5•• Criner GJ, Sternberg AL, National Emphysema Treatment Trial Research Group. A clinician's guide to the use of lung volume reduction surgery. Proc Am Thorac Soc 2008; 5:461–467. The article provides the clinician with a clear reference as to how he or she can incorporate the results of NETT into clinical practice.
6• Tacconi F, Pompeo E, Forcella D, et al. Lung volume reduction reoperations. Ann Thorac Surg 2008; 85:1171–1177. Lung volume reduction reoperations can offer significant clinical improvement to stringently selected patients who have lost the clinical benefit achieved after lung volume reduction surgery.
7 McKenna RJ Jr, Benditt JO, DeCamp M, et al. Safety and efficacy of median sternotomy versus video-assisted thoracic surgery for lung volume reduction surgery. J Thorac Cardiovasc Surg 2004; 127:1350–1360.
8• Meyers BF, Sultan PK, Guthrie TJ, et al. Outcomes after unilateral lung volume reduction. Ann Thorac Surg 2008; 86:204–211, discussion 211–212. Unilateral lung volume reduction surgery improves pulmonary function, exercise capacity, and quality of life in patients for whom bilateral LVRS is contraindicated. Improvements are of lower magnitude than those achieved with bilateral LVRS.
9 Naunheim KS, Wood DE, Krasna MJ, et al. Predictors of operative mortality and cardiopulmonary morbidity in the National Emphysema Treatment Trial. J Thorac Cardiovasc Surg 2006; 131:43–53.
10•• Washko GR, Fan VS, Ramsey SD, et al. The effect of lung volume reduction surgery on chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008; 177:130–131. LVRS provides an approximately 30% reduction in rate of COPD exacerbations compared with a medically treated cohort. LVRS also significantly increased the time to first exacerbation compared with the medically treated cohort.
11• Snyder ML, Goss CH, Neradilek B, et al. Changes in arterial oxygenation and self-reported oxygen use after lung volume reduction surgery. Am J Respir Crit Care Med 2008; 178:339–345. LVRS increases
12 Krachman SL, Chatila W, Martin UJ, et al. Effects of lung volume reduction surgery on sleep quality and nocturnal gas exchange in patients with severe emphysema. Chest 2005; 128:3221–3228.
13• Lederer DJ, Thomashow BM, Ginsburg ME, et al. Lung-volume reduction surgery for pulmonary emphysema: improvement in body mass index, airflow obstruction, dyspnea, and exercise capacity index after 1 year. J Thorac Cardiovasc Surg 2007; 133:1412–1413. LVRS improved lung function and dyspnea in patients with predominantly upper lobe emphysema after 1 year.
14 Mineo TC, Pompeo E. Long-term results of tailored lung volume reduction surgery for severe emphysema. Clin Ter 2007; 158:127–133.
15 Miller JD, Malthaner RA, Goldsmith CH, et al. A randomized clinical trial of lung volume reduction surgery versus best medical care for patients with advanced emphysema: a two-year study from Canada. Ann Thorac Surg 2006; 81:314–320, discussion 320–321.
16• Mineo D, Ambrogi V, Frasca L, et al. Effects of lung volume reduction surgery for emphysema on glycolipidic hormones. Chest 2008; 134:30–37. LVRS significantly improves glycolipidic hormone levels and nutritional status, reduces insulin resistance, and increases physiologic utilization of substrates. LVRS also significantly improves FEV1 and reduces residual lung volume compared to respiratory rehabilitation.
17 Mineo TC, Pompeo E, Mineo D, et al. Resting energy expenditure and metabolic changes after lung volume reduction surgery for emphysema. Ann Thorac Surg 2006; 82:1205–1211.
18 Criner GJ, Sternberg AL. National Emphysema Treatment Trial: the major outcomes of lung volume reduction surgery in severe emphysema. Proc Am Thorac Soc 2008; 5:393–405.
19 Ramsey SD, Sullivan SD, Kaplan RM. Cost-effectiveness of lung volume reduction surgery. Proc Am Thorac Soc 2008; 5:406–411.
20• Hersh CP, DeMeo DL, Reilly JJ, Silverman EK. Xenobiotic metabolizing enzyme gene polymorphisms predict response to lung volume reduction surgery. Respir Res 2007; 8:59. Respone to LVRS can be predicted by variations in two genes encoding xenobiotic metabolizing enzymes, GSTP1 and EPHX1. These genetic polymorphisms may help identify the patients most likely to benefit from LVRS.
21 Wan IY, Toma TP, Geddes DM, et al. Bronchoscopic lung volume reduction for end-stage emphysema: report on the first 98 patients. Chest 2006; 129:518–526.
22 Reilly J, Washko G, Pinto-Plata V. Biological lung volume reduction: a new bronchoscopic therapy for advanced emphysema. Chest 2007; 131:1108–1113.
Keywords:

chronic obstructive pulmonary disease; emphysema; lung volume reduction surgery

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