A Double-blind Placebo-controlled Crossover Study to Assess the Effects of Bronchodilation on Dyspnea, Ventilatory Responses, and Exercise Tolerance in Adults With Cystic Fibrosis

BACKGROUND

Exertional dyspnea is a symptom that reduces quality of life and is associated with reduced exercise tolerance in individuals with cystic fibrosis (CF). Lung hyperinflation has been suggested to be an important factor contributing to dyspnea in CF. Dynamic hyperinflation during exercise testing has been reported in up to 58% of CF patients with mild-to-moderate CF lung disease and is associated with reduced exercise tolerance and increased exertional dyspnea.

Dynamic lung hyperinflation also occurs in chronic obstructive pulmonary disease (COPD) and is believed to be a major cause of exertional dyspnea and exercise limitation. Bronchodilator use in COPD has been shown to reduce lung hyperinflation and improve exertional dyspnea and exercise tolerance; however, there is limited data available in CF despite the pathophysiological similarities between these conditions. Although a majority of individuals six years and older with CF are prescribed bronchodilators, evidence to support the chronic use of bronchodilators has been insufficient.

Unlike acute bronchodilator reversibility testing during routine spirometry, cardiopulmonary exercise testing (CPET) is a highly sensitive and reproducible tool to assess the efficacy of bronchodilators in CF. CPET can be used to identify significant physiological abnormalities even in patients with mild CF lung disease with relatively normal spirometry. Compared to healthy age-matched controls during exercise, adults with mild-to-moderate CF have: greater exertional dyspnea; higher ventilatory requirements; earlier constraints on tidal volume expansion; increased operating lung volumes; an earlier onset of unpleasant dyspnea descriptors (i.e. unsatisfied inspiration); and are more likely to experience "chest tightness". All of these abnormalities are, in theory, amenable to change following bronchodilator therapy.

Very few studies have evaluated the effects of short-acting bronchodilators on exercise in CF using CPET. In these studies, despite improvements in forced expiratory volume in one second (FEV1), short-acting β2-agonists (SABA) failed to show any effect on maximal exercise parameters including workload, oxygen uptake, dyspnea, and leg discomfort ratings. Unfortunately, these studies used incremental exercise tests and focused on peak dyspnea responses, which are often unresponsive to most pharmacological and non-pharmacological interventions. A more clinically and physiologically relevant protocol is to use constant work rate exercise tests and to evaluate dyspnea at standardized submaximal exercise times. This approach has been highly effective in showing beneficial effects of bronchodilators in COPD. Accordingly, the purpose of this study is to evaluate the acute effects of SABA on sensory, physiological, and exercise performance outcomes in adults with CF. We hypothesize that SABA will reduce dyspnea intensity ratings and ventilatory limitations, delay the onset of unpleasant dyspnea descriptors, and will improve exercise performance compared to placebo. These findings would support future guideline recommendations for the use of SABAs to improve dyspnea and exercise tolerance in patients with CF.