Neurophysiology of Exertional Dyspnea in Interstitial Lung Disease and Pulmonary Vascular Disease: Final Common Pathways
Dyspnea is an important symptom that negatively impacts quality of life and results in functional limitation and disability. The overarching objective of this thesis was to explore mechanisms of chronic activity-related dyspnea in diverse patient groups with: 1) restrictive (interstitial lung disease [ILD]), and 2) pulmonary thromboembolic vascular disorders (post-pulmonary embolism [PE] syndrome). The first study examined mechanisms of dyspnea in patients with ILD in comparison to healthy control participants. Dyspnea intensity increased in ILD patients during constant work rate exercise in association with a sharp increase in inspiratory neural drive (IND) (diaphragm activation) from a high resting value of 16.66±6.52% to 60.04±12.52% of maximum (r=0.798, p<0.001). To further evaluate the strength of this association, we attempted to manipulate the independent variable (IND) and conducted a randomized double-blind placebo-controlled crossover study comparing the effect of inhaled fentanyl vs placebo on dyspnea and IND during exercise. At standardized exercise time, Borg dyspnea intensity ratings with fentanyl vs placebo were 4.1±1.2 vs 3.8±1.2, respectively (p=0.174), and IND responses were also similar; pulmonary gas exchange and respiratory mechanical responses to exercise were unaltered by fentanyl. We concluded that the strong correlation between dyspnea and IND during exercise in ILD was not modified by inhaled opiates, at least under these experimental conditions. The second study examined the relationship between dyspnea and IND during incremental exercise in patients with post-PE syndrome in comparison with matched healthy participants. Dyspnea and IND were higher at submaximal work rates vs control, and dyspnea was strongly correlated with increased IND (r=0.630, p<0.001) in the post-PE group. In addition, ventilatory inefficiency (assessed by ventilatory equivalent for CO2 [VE/VCO2]) was consistently higher in the post-PE group (VE/VCO2 nadir: 33.27±4.99 vs 27.15±2.44, p=0.002). The results suggested that increased chemo-stimulation, linked to high physiological dead space (and relatively reduced pulmonary blood perfusion), was an important contributor to increased IND and attendant dyspnea following remote PE. Collectively, these studies extend our knowledge of the neurophysiology of exertional dyspnea in novel and diverse clinical populations. In particular, they highlight the central role of amplified IND – a major therapeutic target for dyspnea relief.