The main finding of this study was that V̇E/V̇CO2 intercept was consistently correlated with worsening LH and increasing airflow limitation in COPD. V̇E/V̇CO2 intercept could be a useful index for ventilatory inefficiency during incremental exercise in COPD.
V̇E/V̇CO2 relationship was analyzed according to the V̇E/V̇CO2 ratio vs. time plot . For healthy subjects who can tolerate high levels of exercise, the V̇E/V̇CO2 nadir and V̇E/V̇CO2 ratio at the anaerobic threshold were usually very similar . Abnormalities in the V̇E/V̇CO2 relationship were present across the spectrum of COPD severity. The V̇E/V̇CO2 nadir showed superior test-retest reliability compared to the V̇E/V̇CO2 slope in COPD patients . Increases both in V̇E/V̇CO2 nadir and slope were associated with lower maximal exercise capacity in COPD patients [24, 25]. A retrospective study with a large range of resting pulmonary function (FEV1 = 12–148% predicted) showed an increased V̇E/V̇CO2 slope in mild-moderate COPD but a decreased slope in advanced stage in comparison to control. As for V̇E/V̇CO2 nadir, there was no significant difference in different stages. However, the V̇E/V̇CO2 intercept was higher across all stages of COPD . In our study, compared to control, COPDstages1−2 had a higher slope and nadir, while patients with more advanced stages (COPDstages3−4) had a lower slope and a stable nadir (i.e., with no significant change compared to COPDstages1−2). The V̇E/V̇CO2 intercept increased from COPDstages1−2 to COPDstages3−4. In advanced-stage COPD, the stable V̇E/V̇CO2 nadir likely reflected the opposite changes in the V̇E/V̇CO2 slope and intercept.
There was mounting evidence that ventilatory inefficiency parameters were powerful prognostic predictors in COPD patients with comorbidity. A retrospective study in 145 COPD patients undergoing surgery for non-small cell cancer showed that V̇E/V̇CO2 slope > 34 predicted mortality after lung resection surgery . As for the V̇E/V̇CO2 nadir, Neder et al. reported that the nadir > 34 in combination with resting hyperinflation predicted mortality in COPD . Importantly, a series of studies demonstrated that the V̇E/V̇CO2 intercept (cutoff values ranging from 2.64–4.07 L/min) might discriminate COPD from heart failure [28, 29].
Ventilatory inefficiency increases ventilatory demand and exercise capacity limitation due to expiratory flow limitation that enhances dynamic hyperinflation. Two other independent studies showed correlations between the V̇E/V̇CO2 nadir and emphysema severity on high-resolution computed tomography scans in COPD patients with largely preserved FEV1 [30, 31]. Static LH caused by reduction of elastic recoil due to emphysema in COPD and development of expiratory flow limitation promoted progressive air trapping with an increase in the EELV and a decrease in IC. RV was also increased in emphysema/COPD because of both loss of elastic recoil and premature closure of the small airways [32–34]. In expiratory flow-limited patients, EELV was a continuous dynamic variable, which depended on expiratory duration and breathing pattern. DH referred to this temporary and variable increase in EELV. DH was a consequence as ventilation increases and expiratory duration decreases, there was not enough time to allow EELV to decline to its baseline resting value during exercise .
Studies reported both static hyperinflation and the degree of dynamic lung hyperinflation were associated with the development of dyspnea and exercise intolerance in COPD patients [36, 37]. Assuming stability of TLC, the resting IC and inspiratory reserve (IRV) showed the operating position of VT relative to TLC. The smaller the resting IC, the shorter the exercise time before VT reached plateau and dyspnea abruptly escalates . A four-year longitudinal study reported that significant reductions in peak V̇O2 and V̇E were related to a decrease in resting IC . Both IC/TLC and RV/TLC in patients with COPD reflected not only the degree of lung static hyperinflation but also the functional reserve. IC/TLC was also found to be a valuable and independent predictor of all-cause and respiratory mortality in COPD compared with that of the BODE (body mass index, airflow obstruction, dyspnea, exercise performance) index . The present study showed V̇E/V̇CO2 intercept exhibited better correlated with rest IC/TLC (r=-0.574, p < 0.001) and RV/TLC (r = 0.588, p < 0.001) than V̇E/V̇CO2 nadir .with peak IC/TLC (r=-0.350, p = 0.004) and RV/TLC (r = 0.431, p < 0.001) while V̇E/V̇CO2 slope had no correlation with static LH parameters.
The EELV progressively increases while IC decreases were associated with dyspnea and exercise intolerance in COPD during exercise . Serial measurements of IC to detect its changes had been reported to be a classic way to identify dynamic hyperinflation [36, 37, 42]. However, the study participates had to be familiar with the maneuvers, and IC measurements also had to be standardized by researchers . Nevertheless, dynamic IC measurement was not recommended for ramp-pattern protocols where VT cannot steadily proceed to perform IC maneuver. However, the ramp-pattern protocol was a widely used for incremental test . Elevated EELV can substantially constrain the expansion of VT at higher exercise intensities. It followed that COPD patients reached a VT plateau and a similar minimal inspiratory reserve volume. Chuang et al. investigated peak VT/TLC as a convenient new marker of DH and the cutoff value was 0.27 . The present results showed among ventilatory inefficiency parameters (slope, nadir and intercept), only V̇E/V̇CO2 intercept exhibited better correlated with peak VT/TLC (r=-0.585, p < 0.001) than V̇E/V̇CO2 nadir with peak VT/TLC (r=-0.503, p < 0.001) and V̇E/V̇CO2 slope with peak VT/TLC (r=-0.148, p = 0.232). To our knowledge, this is the first study to describe the relationship between ventilatory inefficiency and DH. Interestingly, the V̇E/V̇CO2 intercept was better correlated with worsening pulmonary airflow limitation, FEV1/FVC (r=-0.629, p < 0.001) and FEV1% predicted (r=-0.606, p < 0.001), than with the other ventilator inefficiency parameters.
A limitation of our study is the modest number of subjects. We believe that the increased ventilatory inefficiency associated with LH might be more pronounced in patients with more advanced COPD. However, in the absence of a true criterion test for ventilatory inefficiency during exercise, we relied on a cluster of variables that were indirect markers of pulmonary gas-exchange disturbances. We also recognize that variables related to disease phenotypes and test factors (e.g., duration) affect the different strategies to reflect ventilatory inefficiency.