Identification of Three Exercise-induced Mortality Risk Factors in Patients with COPD

The survival rate of chronic obstructive pulmonary disease (COPD) patients with severely reduced exercise capacity is extremely low. We recently identified three life-threatening pathophysiological conditions during cardiopulmonary exercise testing (CPET): (1) exercise-induced hypoxemia, (2) sympathetic overactivity, and (3) progressive respiratory acidosis at low-intensity exercise. The present prospective observation study aimed to determine whether these parameters constitute risk factors of mortality in moderate-to-very severe COPD. Ninety-six COPD patients were followed-up, monthly, for > 3 years. Subsequently, spirometry and CPET were performed to examine parameters of exercise-induced hypoxemia ([PaO2 slope, mmHg/L.min(-1)] = Decrease in PaO2/Delta VO2 (Difference in Delta VO2 between at rest and at peak exercise)), progression of acidosis ([Delta pH/Delta VO2/L.min(-1)] = Decrease in pH/Delta VO2), and sympathetic overactivity ([Delta norepinephrine(NE)/Delta VO2, ng/mL/L.min(-1)] = increase in NE/Delta VO2). Univariate analysis revealed a significant association between the three conditions with increased mortality. Kaplan-Meier analysis showed that the quartile combining the steepest PaO2 slope (<=-55 mmHg/Delta VO2 [L/min]), steepest decrease in arterial blood pH (<= -1.72/Delta VO2 [L/min]), and most rapid increase in plasma NE level (>= 5.2 ng/Delta VO2 [L/min]) during incremental exercise was associated with higher all-cause mortality. These conditions showed cumulative effects on COPD patients' survival. Multivariate analyses revealed that these three life-threatening factors are also independent predictors of mortality based on age, heart rate and PaO2 at rest, body mass index, and forced expiratory volume in 1 s. Thus, these new exercise-induced mortality risk factors may lead to more efficient pulmonary rehabilitation programs for COPD patients based on patient-specific exercise-induced pathophysiological profiles.