Bronchodilator's Effects on Exertional Dyspnoea in Pulmonary Arterial Hypertension
Status:
Withdrawn
Trial end date:
2019-02-01
Target enrollment:
Participant gender:
Summary
Activity-related dyspnoea appears to be the earliest and the most frequent complaint for
which patients with PAH seek medical attention. This symptom progresses relentlessly with
time leading invariably to avoidance of activity with consequent skeletal muscle
deconditioning and an impoverished quality of life. Unfortunately, effective management of
this disabling symptom awaits a better understanding of its underlying physiology. Our team
has recently showed that PAH patients may exhibit reduced expiratory flows at low lung
volumes at spirometry (namely instantaneous forced expiratory flows measured after 50% and
75% of the FVC has been exhaled [FEF50% and FEF75%] lower than predicted), despite a
preserved forced expiratory volume in 1 second/forced vital capacity ratio (FEV1/FVC) .
Several studies have shown that such a finding ("small airway disease") could be common in
certain PAH cohorts, have either related it to incidental descriptions of airway wall
thickening with lymphocytic infiltration in PAH or proposed several other speculative
explanatory mechanisms, either biological or mechanical. Whatever its cause, reduced
expiratory flows at low lung volumes imply that the operating tidal volume (VT) range becomes
closer than normally to residual volume (RV) mostly through an increase in RV (elevated
residual volume/total lung capacity ratio, RV/TLC). The reduced difference between forced and
tidal expiratory flows promotes dynamic lung hyperinflation [i.e., a progressive increase in
end-expiratory lung volume (EELV)] under conditions of increased ventilatory demand. Dynamic
lung hyperinflation (DH) is well known to have serious sensory consequences, i.e., increase
in dyspnoea intensity, as clearly shown in patients with chronic obstructive pulmonary
disease and chronic heart failure. The aim of this study is to evaluate whether
administration of inhaled BDs (β2-agonist and/or anticholinergic), as add-ons to
vasodilators, would be beneficial to PAH patients by reducing and/or delaying the rate of
onset of DH, thus ameliorating the exertional symptoms in patients with stable PAH undergoing
high-intensity constant work-rate (CWR) cycle endurance test.
This is a randomised double-blind placebo-controlled crossover study. Design: 5 visits; V1:
screening, familiarization, incremental cardiopulmonary exercise testing (CPET); V2: constant
work-rate (CWR-CPET); V3, V4 and V5: CWR-CPET after intervention, in a random order: Placebo
(P), Ipratropium Bromide (IB), Ipratropium Bromide + Salbutamol (IB+SALB).