The Neuromechanical Mechanisms of Exertional Dyspnea Across the Continuum of Chronic Obstructive Pulmonary Disease (COPD) Severity
Rationale: Patients with chronic obstructive pulmonary disease (COPD) have burdensome exertional dyspnea (breathlessness) during exercise, which is associated with an elevated inspiratory neural drive (IND). The neurophysiologic mechanisms of dyspnea across the continuum of disease severity remain incompletely understood. Objectives: The main objectives of this thesis were to 1) determine the contribution of an isolated reduction in the diffusing capacity for carbon monoxide (DLCO) to elevated IND and dyspnea during exercise in mild COPD, and 2) to determine the role of critical inspiratory constraints in elevated IND, neuromechanical dissociation (NMD), and dyspnea intensity and quality during exercise across the continuum of COPD. General Methods: All studies included resting pulmonary function testing, and cycle cardiopulmonary exercise testing (CPET). During CPET, physiologic parameters including ventilatory requirements, pulmonary gas exchange, breathing pattern, and operating lung volumes, and perceptual parameters of dyspnea intensity and quality, were evaluated. All studies used an esophageal catheter during CPET to measure diaphragm activation as a surrogate of IND. General Results: 1) Patients with mild COPD and an isolated reduction in DLCO have an elevated IND and dyspnea compared with patients with a preserved DLCO and similar resting lung mechanics. This was associated with reduced ventilatory efficiency (i.e., a high ventilation relative to carbon dioxide production, V̇E¬/V̇CO2). Acute administration of inhaled nitric oxide, a pulmonary vasodilator, reduced physiologic dead space and V̇E¬/V̇CO2, which was associated with reduced IND and dyspnea compared with placebo. 2) IND was progressively elevated from mild to severe COPD, which was associated with earlier attainment of critical inspiratory constraints and NMD, greater dyspnea intensity, a greater frequency of reporting “unsatisfied inspiration”. Conclusions: This thesis has shown that patients with mild COPD have elevated dyspnea and IND that is associated with a low DLCO¬, independent of the effects of respiratory mechanics. We have also shown that the attainment of critical inspiratory constraints has important implications for neuromechanical dissociation, dyspnea intensity, and quality across the continuum of COPD. The findings of this thesis have added to our understanding of the neurophysiology of dyspnea across the continuum of COPD severity.