Treatment of patients with chronic obstructive pulmonary disease (COPD) traditionally has been the task of the internal medicine physician. Current American Thoracic Society and World Health Organization 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 The National Emphysema Treatment Trial, a large multicenter randomized clinical trial to evaluate the effectiveness of lung volume-reduction surgery (LVRS) for the treatment of emphysema, has mandated a change in this traditional thinking. The findings of this trial, while applicable only to a defined subset of COPD patients with advanced upper lobe predominant disease and reduced exercise capacity, clearly indicate that LVRS can affect lung physiology, symptoms, and even mortality for this disease.²

Although the results of this trial have provided a new treatment option for many patients with advanced emphysema, LVRS nevertheless is associated with substantial morbidity and mortality. Even when performed by experienced physicians at tertiary referral centers, LVRS is associated with a 5% 90-day mortality rate and a 30–40% incidence of complications, including respiratory failure, prolonged air leak, pneumonia, cardiac arrhythmia, and gastrointestinal complications.³ 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 transplantation⁴ (Table 89-1).

PHYSIOLOGIC BASIS FOR IMPROVEMENT AFTER LUNG VOLUME REDUCTION

LVRS alters respiratory physiology in several ways, and improvements after treatment result from a combination of these distinct effects.^5–9 As originally proposed by Brantigan and Mueller in the 1950s¹⁰ and convincingly demonstrated by Fessler and colleagues,¹³ LVRS partially normalizes the mechanical relationship between the hyperinflated emphysematous lung and surrounding chest wall by increasing the vital capacity and isovolume transpulmonary recoil pressures. This "resizing" process appears to be the primary mechanism responsible for physiologic 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.¹¹ 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. 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.¹²

Alternatives to LVRS are being developed to provide safer, less invasive, and less costly ways of reducing residual volume relative to total lung capacity.^11,13–15 Several different approaches 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 89-2).

NONSURGICAL METHODS FOR LUNG VOLUME REDUCTION

Proximally Obstructing Devices

The work of Fessler and colleagues¹³ and Ingenito and colleagues⁸ 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. It is possible, however, to reduce lung size by means other than surgical resection. Any process that eliminates areas of hyperinflated lung would achieve the same effect. Thus lung volume reduction, in principle, could be accomplished by placing a device in the proximal airway to impede gas flow to lung distal to the obstruction. Theoretically, gas "trapped" beyond the obstruction eventually would be absorbed, and the lung would remain collapsed as long as the airway was obstructed.

Sabanathan and colleagues tested this concept by placing a silicone balloon designed for vessel occlusion in the lung and later placing a hospital-manufactured stainless steel stent containing a biocompatible sponge to maintain the occlusion. The device was placed under anesthesia using a rigid bronchoscope in one or more segments of the bilateral upper lobes of eight patients with end-stage emphysema. Five patients experienced subjective improvement. Four had improved dyspnea scores and measured walking distances. One had a reduction in lung volume measured by helium dilution. Periprocedure complications included an expectorated balloon in one patient and bilateral tension pneumothoraces with cardiac arrest in another.¹⁶

Watanabe and colleagues also tested this concept using a rigid bronchoscope to place a silicone plug designed to obstruct airways, reduce airflow, and cause collapse of target areas of the lung.¹⁷ This device, called theEndoscopic Watanabe Spigot (EWS), is constructed of biocompatible materials and is deployed in a fashion similar to a Dumon stent.¹⁸ Toma and colleagues used the EWS in 23 patients with emphysema to treat persistent pneumothorax. Two patients developed upper lobe collapse. Complications included pneumonia in two patients and dyspnea in one.¹⁹ Watanabe reported another case using the EWS device in which a pneumothorax occurred after treating a giant bulla in a patient with emphysema.¹⁷

One-Way Valve Devices

The early experience with proximally obstructing devices was disappointing. The limited effectiveness of these devices for lung volume reduction, as well as the incidence of posttreatment pneumothoraces, pointed to the presence of a design flaw. Specifically, the proximally obstructing devices did not effectively eliminate ventilation to the distal lung. This failure was thought to result from incomplete blockage of the proximal airway or, more likely, from flow through the extensive collateral ventilation pathways that exist within and between the lobes in emphysematous lung.²⁰ Collateral ventilation could, paradoxically, lead to hyperinflation of the lung distal to the occlusion as a result of persistent inflow through collateral ventilation pathways together with increased outflow resistance through normal airway channels after device placement.

To overcome this problem, two companies (Emphasys Medical, Inc., and Spiration, Inc.) developed one-way valve devices for endobronchial deployment to produce targeted collapse of segmental regions of lung. These one-way valve designs are less likely to be associated with paradoxical hyperinflation and pneumothorax because any pressure buildup in areas of lung distal to the valves should be relieved by flow of gas through the one-way valve out into the central airways. The Emphasys Endobronchial Valve (Fig. 89-1A ) consists of a silicone duckbill one-way valve with a self-expanding Nitinol stent retainer. The device is inserted into a segmental or subsegmental bronchus via a delivery system that can be positioned over a guidewire placed using a flexible or rigid bronchoscope under anesthesia.

The Emphasys device has been placed in over 100 patients worldwide with limited morbidity (8%) and mortality (1%), although responses have been quite variable. Toma and colleagues reported their experience in eight patients with severe heterogeneous emphysema (baseline FEV₁ 18.4–35.7% of predicted, D_LCO 24.8–51.4% of predicted) who were not candidates for or had refused LVRS. Valves were placed in all the subsegments of one upper lobe in each patient. Four patients showed radiographic evidence of volume reduction in the treated lobe. After 4 weeks, the group as a whole had significant improvements in forced expiratory volume in 1 second (FEV₁: 0.79–1.06 L, p = 0.025) and D_LCO (3.05–3.92 mL/min/mm Hg). The largest changes were seen in patients with radiographic evidence of volume reduction. There were no significant changes in residual volume (RV), total lung capacity (TLC), shuttle walk distance, or St. George's Respiratory Questionnaire score. Two patients developed pneumothoraces, three had COPD exacerbations, and one had a transient increase in cough.²²Objective improvements in lung function appeared to decrease with time. Initial increases in FEV₁ and D_LCO recorded at 1 week declined by 25–50% at 30 days.²³ Improvements in symptom and health quality-of-life scores persisted in several patients despite declining spirometry, suggesting that spirometry alone may not be the best indicator of response to treatment.

Venuta and colleagues recently reported their experience using this system in a cohort of 13 patients with advanced heterogeneous emphysema.³ Two to six valves per patient were placed using bronchoscopic guidance after general anesthesia and intubation. Valves were inserted into preselected segmental airways with the intent of producing lobar collapse. Median postprocedure hospitalization time was 6 days. Improvement was noted in a subset of physiologic parameters. FEV₁ was improved from baseline (median 0.75 L) at 1 (median 1.1 L) and 3 (median 1 L) months' follow-up, but forced vital capacity (FVC) and RV:TLC ratio did no change after treatment. Six complications were reported, including bilateral pneumothoraces in two patients, unilateral pneumothorax in one, pneumonia in one, and bronchospasm in two.

Snell and colleagues reported their experience with the Emphasys valve in 10 patients with severe heterogeneous upper-lobe emphysema (FEV₁ 18–50% of predicted; D_LCO 21–28% of predicted) who were considered candidates for LVRS. Four to eleven valves were placed in subsegments of the upper lobes bilaterally. After 30 days, significant changes were seen in D_LCO (7.47–8.26 mL/min/mm Hg, p = 0.04) and upper lobe perfusion by technetium-99m scan (32–27%, p = 0.02). No significant changes were seen in FEV₁, RV, TLC, 6-minute walking distance, Medical Research Council (MRC) dyspnea score, or blood gases. Of note, very little volume reduction was detectable radiographically in any patient. One patient had a pneumothorax, one developed pneumonia, and two had COPD exacerbations.²⁴

Several abstracts have been published reporting similar results by Germonpré and colleagues,²⁵ Venuta and colleagues,²⁶ and Zuhlke.²⁷ Overall results to date indicate that procedures involving the Emphasys valve have been well tolerated. Although only a subset of patients has demonstrated spirometric improvements and evidence of lung volume reduction, a higher percentage of patients has demonstrated improvements in exercise capacity, health-related quality of life, and symptoms. Emphasys is now conducting a larger multicenter randomized controlled trial to examine the efficacy of its device, characterize mechanisms of improvement, and better define patient selection criteria.

The device manufactured by Spiration (see Fig. 89-1B ) has a different design but works in a similar fashion to the Emphasys valve. The Spiration intrabronchial valve is an umbrella-shaped device consisting of a polyurethane membrane on a Nitinol frame. Unlike the Emphasys valve, which is placed using a guidewire, the Spiration valve is deployed via a delivery catheter that can be inserted directly through the instrument channel of a bronchoscope. When deployed, the umbrella opens and secures itself against the bronchial wall. The design produces unidirectional gas flow out of the subtended region of lung and should function similar to the Emphasys device. In an animal study of six healthy dogs, placement of seven to eight Spiration valves into the upper lobes resulted in a 13% mean reduction in TLC after 3 months.²⁸ Subsequent studies in swine confirmed volume reduction and demonstrated that valves could be removed easily and safely.²⁹ Human trials of the Spiration device are currently under way.

Both valve systems have the advantage of being removable should complications arise either during placement or as a consequence of airway damage or postobstructive pathology over time. The devices also can be replaced in the event of mechanical failure or repositioned in response to changes resulting from progression of disease.

The major limitation of these valve devices appears to be their lack of ability to produce sustained physiologic improvement in most patients. This is likely because of two factors: (1) the extensive collateral ventilation that exists in the emphysematous lung permitting substantial gas flow around the valves, which prevents effective collapse, and (2) the high closing volume and abnormal area-transmural pressure relationship of peripheral airways in the emphysematous lung that can result in obstruction of conducting pathways peripheral to an endobronchial valve, rendering the valve completely ineffective in achieving unidirectional emptying.

It should be noted that some patients seem to have substantial improvements after treatment, and a reduction in symptoms using these valves does not appear to require demonstrable reductions in lung volume.

Tissue Engineering Principles

In contrast to the device-oriented approaches just described, Aeris Therapeutics (Woburn, MA) has developed a bronchoscopic lung volume-reduction (BLVR) system that uses a series of biologically active reagents to promote collapse and scar formation in diseased areas of lung. The reagents are delivered into subsegmental bronchi through a flexible bronchoscope. Three 10-mL injections are administered at each treatment site within the lung to produce initial collapse and initiate a biologic response that leads to volume reduction. The final injection is delivered through a dual-lumen catheter and produces in situ polymerization of a fibrin-based hydrogel. The gel is impregnated with two biopolymers that promote permanent remodeling of the collapsed area, leading to volume reduction over a period of approximately 8 weeks through the controlled modulation of myofibroblast differentiation and proliferation. This approach has the potential advantage of being less affected by collateral ventilation because it does not necessarily rely on elimination of ventilation to produce volume reduction. However, once administered, the effects of treatment are irreversible.

In nonclinical animal studies, Ingenito and colleagues demonstrated that the Aeris system produces safe and effective reductions in lung volume. Using an experimental model of emphysema in sheep, significant reductions in TLC (3.63–3.01 L, p = 0.02) and RV (1.43–0.63 L, p = 0.002) were observed 4 weeks after treatment (Fig. 89-2) without evidence of local or systemic toxicity.³⁰ Tsai and colleagues reported the application of the BLVR system in a bullous model of sheep emphysema to explore its utility in markedly heterogeneous disease that more closely resembles human emphysema. The authors observed statistically significant improvement in the RV:TLC ratio (0.46–0.33, p = 0.01) that was not seen in the sham BLVR system group. An example of the responses observed in this study is shown in Fig. 89-3, in which a large bullous lesion seen on CT scan was reduced after BLVR system placement. One animal developed a fever after treatment. There were no other complications, and no abscesses were seen at necropsy.³¹

Aeris has recently completed phase I testing of its BLVR system in humans with heterogeneous upper lobe disease. Initial results in a small cohort of six patients have been promising. Safety testing in the first three patients involving subsegmental treatment at two sites in one lung demonstrated the procedure to be safe. All patients were discharged on posttreatment day 1, and no serious complications were observed. Initial efficacy testing in a separate cohort of three patients who received treatment at four subsegmental sites in one lung demonstrated improvements in spirometry at 1 (FEV₁ = +4%, FVC = 16%) and 2 months (FEV₁ = +11%, FVC = +20%), with corresponding reductions in dyspnea scores and lung volumes (RV at 2 months = –10%).

Although this approach appears promising, durability of response after BLVR system implementation has not been assessed, and initial results require confirmation in larger clinical trials.

RADIOFREQUENCY ABLATION TO PRODUCE PARALLEL SHUNT FENESTRATION CHANNELS WITHIN THE LUNG

Broncus Technologies is developing a novel alternative bronchoscopic approach for the treatment of advanced emphysema. Instead of attempting to collapse damaged regions of lung with a device or biologic agent, the Broncus airway bypass procedure attempts to create shunt pathways from damaged lung parenchyma into the central airways using a radiofrequency ablation (RFA) catheter (Fig. 89-4). This approach is designed to bypass the small, collapsible airways in the damaged emphysematous lung by creating low-impedance pathways into the central airways, resulting in more effective emptying. Rather than altering the static component of gas trapping, the Broncus approach alters the dynamic component of gas trapping that results from premature airway closure, the volume of which is equal to the closing transmural airway pressure multiplied by lung compliance.^7,13 Although measurements in patients with emphysema suggest that this component of RV averaged over the entire lung is not large (the transmural airway pressure at which collapse occurs and expiratory flows go to zero is usually less than 2 cm H₂O), in a specific area of marked damage, this effect can be large. Thus, altering local closing volume using this approach could, in theory, have a large beneficial physiologic effect.¹¹ The clinical application of this approach, however, is significantly more complicated than any of the previously described bronchoscopic approaches for treating advanced emphysema. First, endobronchial ultrasound is used to locate pulmonary vascular structures within the treatment area to avoid damaging them during application of radiofrequency energy. Next, the RFA catheter is used to burn a passageway through a nonvascularized region of the bronchial wall into the target region of damaged lung, creating the shunt pathway. Finally, a stent is placed in the newly created shunt pathway to help maintain patency.

Lausberg and colleagues reported the use of the Broncus procedure in isolated human emphysematous lungs and found 83–155% improvement in FEV₁ using an apparatus designed to simulate forced expiratory maneuvers.³² Rendina and colleagues reported the feasibility and safety of the procedure in 10 patients undergoing lobectomy for neoplasm and 5 patients undergoing lung transplant. After the chest was opened and full control of the pulmonary vessels and bronchus was obtained, one to five airway bypasses per patient were created using the RFA catheter passed through a flexible bronchoscope. There were two instances of minor bleeding (20 mL) treated with suction and topical epinephrine.³³ To date, there are no published data on longer-term outcomes or functional changes after this procedure.

While innovative and physiologically sound, this approach has several limitations. First, the complexity of the procedure may limit its use to experienced interventionalists who have surgical backup and to thoracic surgeons. At the very least, specialized training and equipment will be required to perform this procedure safely, which may limit its use to tertiary care centers. A second challenge is development of a method for maintaining patency of the RFA shunt pathways. RFA damage to the lung is associated with significant scarring and tissue contraction. The tendency for these pathways to close and the ability to successfully modulate closure will be critical determinants of the long-term effectiveness of this procedure.

MECHANISMS OF SYMPTOMATIC AND FUNCTIONAL IMPROVEMENT AFTER ENDOSCOPIC LUNG VOLUME REDUCTION

Preliminary results from clinical trials involving some of the methods described earlier are now available and indicate that these bronchoscopic approaches to lung volume reduction may well improve lung function through distinct physiologic mechanisms that do not necessarily involve or require a reduction in static lung volumes.

Although only a minority of patients treated with endobronchial valves (EBVs) has demonstrated measurable reductions in lung volume, presumably because of extensive collateral ventilation within the emphysematous lung, a much larger fraction of patients has benefited clinically from the procedure. Six-minute walk distances and walking oxygen saturation values have improved in the majority of studies, suggesting that EBV placement may alter regional time constants for filling and emptying of different lung regions. By selectively impeding gas flow into severely abnormal areas, these valves can reduce dynamic hyperinflation during exercise, an effect that may not be reflected in changes in spirometry but could improve exercise capacity and ventilation/perfusion matching. Furthermore, although the primary mechanism responsible for improvement in respiratory function after LVRS appears to be relief of restrictive physiology through lung-chest wall resizing, increases in FEV₁ can result from changes in regional expiratory time constants caused by small reductions in the size of overly compliant zones and concomitant expansion of adjacent less compliant regions. The net effect of such a response could be an overall improvement in FEV₁ without an accompanying change in RV or RV/TLC ratio. Responses of this type have been observed after EBV therapy. Clearly, more detailed physiologic information is required to fully understand the basis for responses to EBV treatment and is likely to be forthcoming on completion of ongoing clinical trials.

Early clinical results using tissue engineering-based BLVR suggest that this approach may produce physiologic responses that more closely resemble those of conventional lung volume reduction. Theoretically, this approach should be less compromised by the effects of collateral ventilation because it collapses at the parenchymal level. This notion is supported by early clinical findings showing more consistent responses with hydrogel BLVR than observed with EBV therapy.

Clinical experiences using RFA to create fenestrations are not yet available, although nonclinical studies attest to the physiologic soundness of this approach. Clinical trials are ongoing.

SUMMARY

A number of novel bronchoscopic approaches for producing lung volume-reduction treatment for advanced emphysema are currently being developed and evaluated in clinical trials. EBV systems (Emphasys Medical, Inc., and Spiration, Inc.) are the simplest and most direct. Testing in humans has shown these valves to be relatively safe, and it is likely that they will be the first of the nonsurgical systems available on the market for widespread use by pulmonologists and interventionalists. Their principal limitation may be lack of effectiveness owing to the inherent design limitation of attempting to use an endobronchial blocking device to produce collapse in the presence of extensive collateral ventilation. Nevertheless, preliminary studies suggest that a subset of treated patients may benefit from this approach. Ongoing larger studies will be important to identify appropriate selection criteria for patients who may benefit.

The application of biologic reagents to remodel and shrink regions of emphysema (Aeris Therapeutics, Inc.) has been shown to produce effective lung volume reduction in nonclinical studies involving large animal models of experimental emphysema. Initial results in patients have been promising. This approach has the appeal of being the simplest to perform, and its physiologic effectiveness is not limited by the presence of collateral ventilation. Clinical results to date demonstrate that the procedure has been well tolerated and is physiologically effective, but long-term results are not yet available.

An airway bypass procedure that uses RFA to generate shunt pathways through damaged areas of lung (Broncus Technologies, Inc.) is also being evaluated. Nonclinical studies in isolated lungs confirm the scientific soundness of this approach, and intraoperative studies suggest that it is feasible. However, the procedure is somewhat complex to perform in patients because it requires specialized equipment and training, and its clinical safety and effectiveness will need to be evaluated in clinical trials.

All the technologies summarized here have potential benefits as well as limitations. Although it is not yet clear how each will function in the clinic, it is anticipated that pulmonologists, interventionalists, and surgeons will have a variety of new procedures for treatment of emphysema in the next few years. It is likely that at least some of these methods will prove clinically useful and help to reduce the medical and financial burden associated with treating patients with advanced emphysema.

EDITOR'S COMMENT

Procedure-oriented approaches to the treatment of emphysema have revolutionized not only the treatment of emphysema, but also our concepts of the disease. Even so-called "negative" studies of novel therapies will likely provide important insights into the physiology of emphysema.

–SJM

REFERENCES