Treatment of patients with chronic obstructive pulmonary disease (COPD) traditionally has been the task of the internal medicine physician. Global Initiative for Chronic Obstructive Lung Disease recommendations for treatment of COPD include the use of bronchodilators, anti-inflammatory agents, oxygen therapy, aids to assist with smoking cessation, and pulmonary rehabilitation.¹ While pharmacotherapy improves lung function, symptoms, quality of life, and exacerbation rates in COPD, no medical therapies have been shown to improve emphysema, where the primary abnormality is destruction of alveoli with loss of elastic recoil, and subsequent lung hyperinflation. The National Emphysema Treatment Trial (NETT), a large multicenter randomized clinical trial to evaluate the effectiveness of lung volume reduction surgery (LVRS) for the treatment of emphysema, suggested that surgical lung volume reduction, which directly addresses the problem of lung hyperinflation through resection of the most damaged tissue, should be considered for selected patients with emphysema. The findings of this trial, while applicable to a defined subset of COPD patients with advanced upper lobe predominant (ULP) emphysema and reduced exercise capacity, clearly indicate that LVRS can affect lung physiology, symptoms, and even mortality for this disease.²

LVRS alters respiratory physiology in several ways—accordingly, posttreatment improvement is multifactorial.^3–10 As originally proposed by Brantigan and Mueller in the 1950s¹¹ and convincingly demonstrated by Fessler and Permutt,⁴ LVRS partially normalizes the mechanical relationship between the hyperinflated emphysematous lung and the surrounding chest wall by increasing the vital capacity and isovolume transpulmonary recoil pressures. Moreover, by reducing the overall size of the hyperinflated lung, LVRS produces space within the less compliant chest cavity for the remaining lung to expand and function.

While this “resizing” process appears to be the primary mechanism responsible for improvements after lung reduction, other factors play a role. Increased recoil pressures cause an increase in airway conductance in a subset of patients, presumably by raising airway isovolume transmural pressures and increasing airway dimensions.^12,13 The reduction in lung size after LVRS normalizes diaphragmatic and chest wall dimensions and improves ventilatory capacity by shortening the operating length over which the respiratory muscles contract.^8–10 In a smaller number of patients, temporary improvements in oxygenation have been observed as a result of local changes in lung impedance that act to normalize ventilation/perfusion matching. LVRS also may improve dynamic lung mechanics by eliminating lung zones with the longest expiratory time constants, not only reducing the tendency for gas trapping and dynamic hyperinflation during exercise but also increasing the inspiratory capacity.¹⁴ Emerging evidence further indicates that the benefits of LVRS go beyond primary respiratory effects; LVRS may in fact improve the compromised cardiac function that is a common comorbidity in this population.^15–17

Although LVRS provides a treatment option for many patients with advanced emphysema, it is a major procedure performed in a sick population and is associated with substantial morbidity and mortality. Procedural (90-day) mortality was 5.5% in NETT. In that trial, serious complications were observed in 59% of patients (i.e., respiratory failure, prolonged air leak, pneumonia, and cardiac morbidity).¹⁸ Furthermore, when expressed in terms of quality-adjusted life-years, LVRS is more expensive than other currently accepted surgical interventions that improve quality of life for individuals with end-stage disease, such as coronary artery bypass grafting, cardiac transplantation, and lung transplantation.¹⁹ Due to the risks and costs associated with LVRS, fewer than 200 procedures are estimated to be performed annually in the United States,²⁰ and as a result, a great deal of effort has been spent to devise safer, less invasive, and less costly alternatives. Several different approaches have been and are being tested in clinical trials in the United States and elsewhere. Initial results suggest that the physiologic basis for symptomatic improvement after “nonsurgical lung volume reduction” may not be the same for each of these new methods and may, in fact, be distinct from the effect of LVRS itself. In this chapter, we summarize the technology, methodology, published experiences, and limitations of each approach (Table 101-1).

The work of Fessler and colleagues⁴ and Ingenito and colleagues⁶ has shown that lung volume reduction therapy improves respiratory function in emphysema primarily by reducing the size of the hyperinflated lung within the rigid chest cavity. Thus, any process that eliminates areas of hyperinflated lung could potentially achieve the same effect as surgical resection. A variety of nonsurgical techniques have been developed in an attempt to accomplish this including primarily, one-way valves, endobronchial coils, tissue sealants, thermal airway ablation, and airway bypass.

One-way Valve Devices

Lung volume reduction, in principle, could be accomplished by placing a device in a proximal airway, thereby impeding distal gas flow. Theoretically, gas “trapped” beyond the obstructing device would eventually be absorbed and the lung would collapse. Endobronchial plugs and blockers were the original method developed to promote resorption atelectasis.^21,22 However, the high rate of postobstructive pneumonia, pneumothoraces, and device migration led to their abandonment. One-way valves are an evolution of this concept. They are deployed in the proximal airway through a flexible bronchoscope. Once positioned, these devices are designed to block air from entering the target area during inhalation, while allowing gas to escape during exhalation, leading to volume reduction by promoting progressive deflation and atelectasis in distal emphysematous lung. These valves also allow drainage of mucus, reducing the potential for postobstructive pneumonia.

Two one-way valve systems have been developed, both intended primarily for treatment of heterogeneous ULP emphysema: the endobronchial valve (EBV) and the intrabronchial valve (IBV). The EBV, manufactured by Pulmonx (formerly Emphasys Medical), is designed with a nitinol skeleton and a silicone body with a “duckbill” valve on the proximal end. Originally deployed over a guide wire, the most recent version – the Zephyr® EBV (Fig. 101-1) – is deployed through the working channel of a bronchoscope under direct vision. The deployment catheter also functions as a sizing mechanism so that the valve which best fits the bronchus can be chosen. Several studies,^23–26 including a randomized controlled trial,²⁷ have investigated the use of these valves in patients with severe heterogeneous emphysema.

In a retrospective analysis from a prospective multicenter registry, Wan et al.²⁶ reported the experience of the first 98 patients treated with EBVs (Emphasys EBV). In the registry, four valves were delivered on average per patient using several different treatment strategies—unilateral (predominant approach) versus bilateral, lobar versus nonlobar exclusion, upper lobe (most common) versus lower lobe. There were modest but statistically significant improvements in residual volume (RV: −350 ± 970 mL, −4.9 ± 17.4%, p = 0.025), forced expiratory volume in 1 second (FEV₁: +60 ± 210 mL, 10.7 ± 26.2%, p = 0.007), forced vital capacity (FVC: +120 ± 470 mL, 9.0 ± 23.9%, p = 0.024), and 6-minute walk distance (6MWD: +36.9 ± 90 m, p <0.001) at 90-day follow-up. Patients with lobar exclusion and unilateral treatment had the greatest benefit. Eight patients (8.2%; one death) had serious complications, the majority of which were pneumothoraces thought secondary to lung volume changes rather than iatrogenic injury. Thirty patients had other complications including COPD exacerbations and pneumonia in nontreated lobes. Importantly, postobstructive pneumonia was not seen as with the earlier generation endobronchial plug devices.

The Endobronchial Valve for Emphysema Palliation Trial (VENT) ²⁷ was a multicenter, prospective, randomized controlled trial designed to evaluate the safety and efficacy of unilateral EBV therapy with the newer Zephyr® valves (deployed through an internal bronchoscope channel rather than over guidewire). Three hundred and twenty-one patients were randomized to EBV therapy (n = 220) or optimal medical care (control, n = 101). Patients in the EBV group underwent unilateral and unilobar treatment with the aim of completely isolating the target—most diseased lobe (upper in 76.6% of patients). Again, four valves, on average, were placed per patient. At 6 months, there was a 34.5 mL increase (95% CI 10.8 to 58.3) in FEV₁ in the EBV group compared with a 25.4 mL decrease (95% CI −48.3 to −2.6) in the control group (p = 0.002 for between-group difference). The 6MWD increased by 9.3 m (95% CI −0.5 to 19.1) in the EBV group and decreased by 10.7 m (95% CI –29.6 to 8.1) in the control group (p = 0.02 for between-group difference). Functional outcomes were not as good as those in the multicenter registry. There were also modest (not clinically significant) improvements in disease-specific quality of life (measured by the St. George’s Respiratory Questionnaire, SGRQ) and dyspnea (measured by the Modified Medical Research Council scale, mMRC). Further analysis revealed greatest benefit in patients with computed tomographic (CT) complete fissures (i.e., absent interlobar collaterals), complete lobar isolation, and greater emphysema heterogeneity and paralleled findings in the European VENT cohort.²⁸ At 6 months, there was a trend toward more major complications in the EBV versus control group (6.1% vs. 1.2%, respectively, p = 0.08), though this was less apparent between 6 and 12 months (4.7% vs. 4.6%). The most common adverse events (AEs) in the EBV group included postobstructive pneumonia, hemoptysis, and pneumothorax. Severe COPD exacerbations were significantly more common in the EBV group than the control group during the first 90 days, but there was no difference in severe exacerbations after 90 days. At 6 months, 67/194 (34.5%) patients with CT imaging were found to have evidence of valve malposition.

A smaller, longitudinal, single-center study²⁹ of 40 patients with a median follow-up of 32 months (up to 5 years) suggested a lasting benefit of EBV treatment. While 40% of patients died during the follow-up, no deaths were procedure-related and this proportion can be contrasted with a projected mortality rate in excess of 40% at 5 years in patients with similar COPD severity.³⁰ There were statistically and clinically significant improvements in FEV₁, 6MWD, and dyspnea score that persisted out to 5 years.

The second type of one-way valve – Spiration IBV® Valve (Olympus Corp., formerly Spiration, Inc.; Fig. 101-2) – has an umbrella design in which an elastomeric covering is stretched over a nitinol wire frame that anchors the device in place. Air (and mucus) can escape from the lung around the edges of the flexible covering as the umbrella-shaped frame partially collapses, but is prevented from flowing in the forward direction. As with the EBV, the IBV can be deployed through the working channel of a flexible bronchoscope under direct visualization and is designed for placement in segmental or subsegmental bronchi. A calibrated balloon is used to determine the valve with the best fit for the target airway.

A number of studies have shown the ability of IBVs to improve perceived quality of life though associated improvements in anatomic lung inflation patterns are variably affected and physiological measures remain unchanged. Moreover, it remains unclear as to the percentage of patients who actually receive benefit or the persistence of treatment. In an initial safety evaluation, Wood et al.³¹ reported the results of a multicenter, prospective, open-enrollment cohort study of 30 patients with severe to very severe airflow obstruction, hyperinflation, and ULP emphysema who underwent bilateral upper lobe treatment with IBVs. A mean of 6.5 valves were placed per patient. The procedure was well tolerated with few reported in-hospital or 30-day AEs and no late complications attributed to the valves. While the trial was not designed to assess effectiveness, there was a measurable improvement in SGRQ (mean change from baseline to 6 months: −6.8 ± 14.3 points, p = 0.05 with 52% of patients exceeding the minimal clinically important difference [MCID] of at least a 4-point decrease in SGRQ³²) with no significant change in physiologic or exercise outcomes. In another study of 57 subjects with ULP emphysema who had paired CT assessments both prior to treatment and either 1, 3, or 6 months after bilateral upper lobe IBV treatment, Coxson and colleagues³³ further associated such changes in SGRQ with changes in regional lung volume and speculated that the improved disease-specific quality of life might be due to increased ventilation and perfusion of the untreated/less-diseased nonupper lobes.

A larger, multicenter, prospective, open-enrollment case series³⁴ of 91 patients with ULP emphysema who underwent bilateral IBV treatment (mean of 6.7 valves placed per patient) also had similar findings with >50% of patients demonstrating a clinically significant improvement in SGRQ at 1, 3, 6, and 12 months following device placement (no change in FEV₁ or 6MWD). In this larger study, seven patients had device-related serious adverse events (SAEs) in the first 3 months. Pneumothorax was the most common complication particularly when all segments within a lobe were occluded and 16 patients required valve removal (44 valves total; for pneumonia, bronchospasm, recurrent COPD exacerbations, or pneumothorax). There were no occurrences of valve migration or erosion.

In two subsequent multicenter, sham bronchoscopy-controlled trials of IBV treatment (first 73 patients, reported; ³⁵ second 277 patients, completed) SGRQ again improved, though there were fewer responders. In the first study, 73 patients with ULP emphysema were randomized to IBV placement (n = 37) versus sham bronchoscopy (n = 36). To avoid complete occlusion of the upper lobes, lobar atelectasis, and potential pneumothorax, one segment (or subsegment) of the right upper lobe and the lingula were left untreated. A mean number of 7.3 valves were placed per patient in the treatment group. At 3 months, there were 8 (24%) responders (composite endpoint: ≥4-point improvement in SGRQ and lobar volume shift measured by CT with a decrease in upper lobe volume and a volume increase of ≥7.5% in nontreated lobes) in the treatment group versus none in the sham group (p = 0.002). In the treatment group, upper lobe volume decreased by 7.3 ± 9.0% and lower lobe volume increased by 6.7 ± 14.5%; these volume shifts persisted at 6 months. At 3 months, both groups had statistically significant mean improvements in SGRQ compared to baseline (treatment: −4.3 ± 16.2 points, control: −3.6 ± 10.7 points; there was no difference between groups, p = 0.8), though mean change in SGRQ only exceed the MCID in the treatment group. At 6 months, treated patients had further improvement in SGRQ (mean change from baseline: −10.9 ± 18.2 points). There were no significant improvements in pulmonary function tests, dyspnea, or exercise capacity. There were also no differences in procedural AEs or hospital length of stay between groups, indicating that as a whole, IBV treatment appeared safe, though effective in only a subset of patients.