Low resting diffusion capacity, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease

Abstract

The mechanisms linking reduced diffusing capacity of the lung for carbon monoxide (DlCO) to dyspnea and exercise intolerance across the chronic obstructive pulmonary disease (COPD) continuum are poorly understood. COPD progression generally involves both DlCO decline and worsening respiratory mechanics, and their relative contribution to dyspnea has not been determined. In a retrospective analysis of 300 COPD patients who completed symptom-limited incremental cardiopulmonary exercise tests, we tested the association between peak oxygen-uptake (V̇o2), DlCO, and other resting physiological measures. Then, we stratified the sample into tertiles of forced expiratory volume in 1 s (FEV1) and inspiratory capacity (IC) and compared dyspnea ratings, pulmonary gas exchange, and respiratory mechanics during exercise in groups with normal and low DlCO [i.e., <lower limit of normal (LLN)] using Global Lung Function Initiative reference values. DlCO was associated with peak V̇o2 ( P = 0.006), peak work-rate ( P = 0.005), and dyspnea/V̇o2 slope ( P < 0.001) after adjustment for other independent variables (airway obstruction and hyperinflation). Within FEV1 and IC tertiles, peak V̇o2 and work rate were lower ( P < 0.05) in low versus normal DlCO groups. Across all tertiles, low DlCO groups had higher dyspnea ratings, greater ventilatory inefficiency and arterial oxygen desaturation, and showed greater mechanical volume constraints at a lower ventilation during exercise than the normal DlCO group (all P < 0.05). After accounting for baseline resting respiratory mechanical abnormalities, DlCO<LLN was consistently associated with greater dyspnea and poorer exercise performance compared with preserved DlCO. The higher dyspnea ratings and earlier exercise termination in low DlCO groups were linked to significantly greater pulmonary gas exchange abnormalities, higher ventilatory demand, and associated accelerated dynamic mechanical constraints. NEW & NOTEWORTHY Our study demonstrated that chronic obstructive pulmonary disease patients with diffusing capacity of the lung for carbon monoxide (DlCO) less than the lower limit of normal had greater pulmonary gas exchange abnormalities, which resulted in higher ventilatory demand and greater dynamic mechanical constraints at lower ventilation during exercise. This, in turn, led to greater exertional dyspnea and exercise intolerance compared with patients with normal DlCO.

Measurement and Interpretation of Exercise Ventilatory Efficiency

“…In healthy individuals, the V E /V CO 2 corresponding to the nadir and the V E /V CO 2 at anaerobic threshold are often similar (Figure 2; Sun et al, 2002). The nadir V E /V CO 2 increases progressively with age and is abnormally high in cardiocirculatory and respiratory disease (Sun et al, 2002;Ingle et al, 2012;Elbehairy et al, 2015Elbehairy et al, , 2019Neder et al, 2015;Phillips et al, 2019). Although the nadir V E /V CO 2 is highly reproducible, it may over-estimate ventilatory inefficiency in individuals with poor exercise tolerance and an excessively short test duration during CPET (Neder et al, 2001).…”

“…Airflow limitation, secondary to dynamic respiratory mechanical abnormalities, is generally considered the primary cause of exertional dyspnea in COPD. However, emerging research has suggested that ventilatory inefficiency is also a key contributor to dyspnea and exercise intolerance in patients with COPD (Neder et al, 2015;Elbehairy et al, 2019). In a study examining patients with mild COPD, arterial blood gas-derived dead space and V E /V CO 2 (slope, nadir, and y-intercept) were consistently elevated during exercise while P a CO 2 and alveolar ventilation were similar to age-matched healthy controls (Elbehairy et al, 2015).…”

Clinical Utility of Measuring Inspiratory Neural Drive During Cardiopulmonary Exercise Testing (CPET)

“…These resting differences are exaggerated throughout exercise, with decreased exercise endurance, increased IND, and increased dyspnea in smokers-at-risk and mild COPD vs. health (108,129). This increased dyspnea has recently been linked to ventilatory inefficiency causing premature mechanical constraint, with individuals with DLCO lower than the lower limit of normal (LLN) experiencing a higher ventilatory requirement and thus greater dyspnea and exercise intolerance than patients with DLCO > LLN despite equivalent spirometry (130). This topic is covered in greater detail in the accompanying review by (104).…”

Ventilatory inefficiency during graded exercise in COPD: A pragmatic approach

“…We hypothesized that the new approach would prevent bias during ηV ′ E evaluation owing to ventilatory constraints, characteristic of more severe COPD (III/IV), as previously suggested for the V ′ E ‐ V ′CO 2 slope (Neder et al., 2015). Furthermore, as the severity of airflow limitation increases and lung diffusion capacity decreases in the progression from early COPD to more advanced disease (Elbehairy et al, 2019), we should find a linear reduction in ηV ′ E throughout these clinical stages.…”