Effect of Bronchoscopic Lung Volume Reduction on Dynamic Hyperinflation and Exercise in Emphysema

Patients with advanced chronic obstructive pulmonary disease (COPD) frequently experience exertional breathlessness despite optimal medical therapy. In selected patients lung volume reduction surgery (LVRS) has been shown to improve mortality, exercise capacity, and quality of life (1-3). However, it is associated with significant morbidity and an early mortality rate of about 5% (1, 2). For these reasons and because the procedure poses an unacceptable risk in patients with the most severe disease (1, 4), alternatives have been sought including bronchoscopic lung volume reduction (BLVR). This involves obstructing the airways that supply the most hyperinflated, emphysematous parts of the lung. The rationale for this approach is that endobronchial obstruction should cause these areas to collapse as a result of absorption atelectasis. By reducing lung volumes, symptoms could be improved without recourse to surgery. The technique was first performed with airway blockers (5) and subsequently our group (6) and others (7, 8) have described early experience with the use of endobronchially placed valves. However, our experience suggests that lobar collapse is not necessary for clinically apparent benefit to occur and we reasoned therefore that other physiologic mechanisms must operate.

A key element in ventilatory limitation of exercise in COPD is the development of dynamic hyperinflation, in which expiratory flow limitation leads to a progressive increase in end-expiratory lung volume during exercise and consequently restricts the tidal volume that can be achieved (9). Reductions in dynamic hyperinflation have been demonstrated after treatment with bronchoclilators (10-12) and after lung volume reduction surgery or bullectomy (13). BLVR could be expected to reduce dynamic hyperinflation either by causing the worst affected areas of lung to collapse or by excluding them from ventilation. In the presence of significant atelectasis BLVR should lead to a better matching of lung and chest wall dimensions, thus increasing available vital capacity as occurs after LVRS (14). By collapsing the most compliant areas of lung this should lead to an increase in lung elastic recoil at any given lung volume, reducing airflow obstruction.

In the absence of atelectasis BLVR might still have benefits, first by reducing physiological dead space, which would improve the efficiency of ventilation, and second by reducing the dynamic hyperinflation that occurs at higher levels of ventilation by diverting airflow to less obstructed areas of lung.

Therefore the aim of the present study was to investigate the effect of endobronchial valve placement on exercise capacity in patients with emphysema and to relate this to changes in dynamic hyperinflation assessed through changes in end-expiratory lung volumes. Some of the results of these studies have been reported previously in abstract form (15).

METHODS

Patients with COPD consistent with the GOLD guidelines (16) entered the study if they had significant dyspnea despite optimal medical therapy including pulmonary rehabilitation; presented a heterogeneous pattern of disease with a target area identified by computed tomography (CT) scanning and ventilation perfusion scintigraphy (6); and were either considered too great a risk for LVRS (1, 4), or declined the surgery. The Royal Brompton Hospital (London, UK) Research Ethics Committee approved the study and patients gave their informed consent. Some data from the first eight patients in our series have been published previously (6).

Endobronchial occlusion was performed with one-way valves (Emphasys Medical, Redwood City, CA) made of nitinol and silicone (see Figures E1 and E2 in the online supplement), placed to occlude segmental bronchi leading to the most affected area of lung. All procedures were unilateral. Initially, valves were inserted on a single occasion under general anesthesia (6, 17). Subsequently some procedures were performed with sedation only and some of these were staged, with valves being inserted on two separate occasions 1 to 2 weeks apart. Measurements were made in the week preceding and 4 weeks after valve insertion had been completed. A radiologist blinded to clinical outcome assessed CT evidence of atelectasis, defined as changes in the position of interlobar fissures adjacent to the targeted area.

Quality of life was assessed on the basis of St George's Respiratory Questionnaire and the Short Form-36.

Pulmonary and Respiratory Muscle Function

Spirometry, gas transfer, and lung volumes assessed by body plethysmography were measured with a CompactLab system (Jaeger, Hoechberg, Germany). PaO^sub 2^ and PaCO^sub 2^ were measured in arterialized earlobe capillary samples. Static lung compliance was measured by an interrupter technique during a relaxed expiration from total lung capacity (TLC).

In all subjects we measured maximal static inspiratory (PI^sub max^) and expiratory (PE^sub max^) mouth pressures (18) as well as maximal sniff nasal pressure (Pn,sn) (19). When patients consented to and were able to tolerate the placement of catheter-mounted balloons, esophageal and gastric pressures were determined and transdiaphragmatic pressure was calculated (19). In these patients sniff transdiaphragmatic pressure (Pdi,sn) and the response to bilateral anterolateral magnetic phrenic nerve stimulation (Pdi,tw) were also determined (20).

Exercise Testing

Patients performed endurance cycle ergometry at 80% of the maximal workload achieved on a previous incremental test before and after BLVR, with inspiratory capacity (IC) maneuvers performed every minute to assess changes in end-expiratory lung volume. Both peak and isotime values were compared. Isotime was defined as the final 30-second period achieved on the shorter of the two tests. Leg and breathing discomfort were assessed on the basis of the Borg scale.

In some patients we recorded esophageal and gastric pressures during exercise, calculating esophageal and diaphragmatic pressure-time product (PTP) (21, 22). Further methodologic details are given in the online supplement.

Statistical Analysis

The primary end point in this study was change in cycle endurance time (T^sub lim^) 4 weeks after the procedure as a continuous variable. In addition, patients with an increase of both 60 seconds and 30% were defined a priori as "improvers." Changes from baseline were assessed using appropriate test for paired comparisons. Baseline predictors and correlates of improvement in T^sub lim^ were sought, using linear regression and then stepwise logistic regression analysis to identify which parameters had an independent effect.

RESULTS

Procedures and Complications

Nineteen subjects (16 men) were studied. Baseline characteristics are given in Table 1. Details of the procedure performed in each subject, as well as the presence of radiologic atelectasis and individual changes in cycle endurance time and resting inspiratory capacity, are given in Table E1. All but 1 patient were taking inhaled steroids, 12 were taking long-acting ß^sub 2^ agonists, 7 were taking oral theophyllines, 3 were taking regular oral prednisolone (less than 10 mg/day), 11 used a nebulizer, and 2 were receiving long-term oxygen therapy. The median (range) number of exacerbations requiring antibiotics in the preceding year was 2 (0-7).

There were no immediate complications related to the procedure itself. Two patients, both of whom had radiologic evidence of volume reduction, developed ipsilateral pneumothoraces: one at 2 days, which required intercostal drainage, and one at 4 weeks, which was small and resolved without intervention. There were no episodes of obstructive pneumonia. In five patients there was a transient worsening of symptoms consistent with an acute exacerbation in the early period after the procedure; these patients were treated with oral antibiotics. One subject developed Clostridium difficile diarrhea, presumably resulting from prophylactic antibiotic treatment, and one patient tripped at home, sustaining a rib fracture. In these patients postprocedure tests were delayed until they had recovered from these events.

Radiologic evidence of atelectasis was present in five subjects (26%). In the group as a whole there were significant improvements in airflow obstruction, lung volumes, and transfer factor for carbon monoxide (TL^sub CO^) (Table 2).

Exercise Performance

In the group overall there was a 39% improvement in mean cycle endurance exercise time from 227 (129) to 315 (195) seconds (p = 0.03), giving a mean ?T^sub lim^ of +88 (167) seconds (Figure 1). Nine patients (47%) met the 60-second and 30% increase criteria considered to represent a clinically significant benefit and were defined as improvers.

Whole group mean changes in peak and isotime exercise parameters are given in Table E2. At peak exercise, end-expiratory lung volume (EELV) was reduced from 7.60 (1.6) to 7.18 (1.7) L (p = 0.03) and at isotime from 7.47 (1.5) to 6.97 (1.7) L (p = 0.05) with nonsignificant trends toward improvement in other parameters. If patients with atelectasis were excluded, the improvement in T^sub lim^ among the remaining 14 patients was no longer significant: preprocedure, 246 (143) seconds; postprocedure, 285 (179) seconds (p = 0.2).