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Combining measurements of impaired lung mechanics (inspiratory constraints) with an index of increased respiratory stimuli to metabolic demand (poor ventilatory efficiency) might enhance the ability of cardiopulmonary exercise testing (CPET) in exposing a mechanistic role for ventilation on exertional dyspnea in COPD. In addition to the standard approach to suggest ventilatory limitation to exercise - a low breathing reserve (1-(peak ventilation (V̇E)/maximal voluntary ventilation × 100 < 20%) - we assessed the presence of critical inspiratory constraints (end-inspiratory lung volume (EILV)/total lung capacity (TLC) ≥ 0.9) and ventilatory inefficiency (V̇E/CO 2 output (V̇CO 2 ) nadir > 34) in 288 patients with mild to very severe COPD (FEV 1 ranging from 18 to 121% predicted). We found that ∼50% of the patients with preserved breathing reserve developed critical inspiratory constraints. A low breathing reserve was weakly related to a lower peak O 2 uptake (V̇O 2 ) and/or a higher dyspnea burden; for instance, patients with low breathing reserve but without critical inspiratory constraints had similar dyspnea and peak V̇O 2 than those with preserved breathing reserve ( p  > 0.05). In contrast, critical inspiratory constraints and ventilatory inefficiency were strongly associated with a negative outcome (likelihood ratio = 42.3 and 47.7, respectively; p  < 0.001). A multiple logistic regression analysis revealed that only EILV/TLC ≥ 0.9 and V̇E/V̇CO 2 nadir >34 predicted a severely reduced peak V̇O 2 due to a high dyspnea burden ( p  < 0.001). Measurements of dynamic mechanical constraints and ventilatory inefficiency during incremental CPET are key to determine the impact of COPD on dyspnea and exercise tolerance across the spectrum of disease severity.

Time to exercise limitation (Tlim) in response to constant work rate (CWR) is sensitive to interventions in chronic obstructive pulmonary disease (COPD). This is particularly true when the pre-intervention test lasts between 3 and 8 min (Tlim 3'-8' ). There is, however, no simple method to select a work rate which is consistently associated with Tlim 3'-8' across the spectrum of COPD severity. We assessed 59 GOLD stages II-IV patients who initially cycled to Tlim at 75% peak. In case of short (<3 min, low-endurance) or long (>8 min, high-endurance) tests, patients exercised after 60 min at 50% or 90%, respectively (CWR 50%⇐75%⇒90% ). Critical mechanical constraints and limiting dyspnea at 75% were reached within the desired timeframe in 27 "mid-endurance" patients (46%). Increasing work rate intensity to 90% hastened the mechanical-ventilatory responses leading to Tlim 3'-8' in 23/26 (88%) "high-endurance" patients; conversely, decreasing exercise intensity to 50% slowed those responses leading to Tlim 3'-8' in 5/6 (83%) "high-endurance" patients. Repeating the tests at higher (60%) or lower (80%) intensities fail to consistently produce Tlim 3'-8' in "low-" and "high-endurance", respectively (p > 0.05). Compared to a fixed work rate at 75%, CWR 50%⇐75%⇒90% significantly decreased Tlim's coefficient of variation; consequently, the required N to detect 100 s or 33% improvement in Tlim decreased from 82 to 26 and 41 to 14, respectively. This simplified approach to individualized work rate adjustment (CWR 50%⇐75%⇒90% ) might allow greater sensitivity in evaluating interventional efficacy in improving respiratory mechanics and exercise tolerance while simultaneously reducing sample size requirements in patients with COPD.

Systolic heart failure is a common and disabling co-morbidity of chronic obstructive pulmonary disease (COPD) which may increase exercise ventilation due to heightened neural drive and/or impaired pulmonary gas exchange efficiency. The influence of heart failure on exercise ventilation, however, remains poorly characterized in COPD. In a prospective study, 98 patients with moderate to very severe COPD [41 with coexisting heart failure; 'overlap' (left ventricular ejection fraction < 50%)] underwent an incremental cardiopulmonary exercise test (CPET). Compared to COPD, overlap had lower peak exercise capacity despite higher FEV 1 . Overlap showed lower operating lung volumes, greater ventilatory inefficiency and larger decrements in end-tidal CO 2 (PETCO 2 ) (P < 0.05). These results were consistent with those found in FEV 1 -matched patients. Larger areas under receiver operating characteristic curves to discriminate overlap from COPD were found for ventilation ([Formula: see text]E)-CO 2 output [Formula: see text]CO 2 ) intercept, [Formula: see text]E-[Formula: see text]CO 2 slope, peak [Formula: see text]E/[Formula: see text]CO 2 ratio and peak PETCO 2 . Multiple logistic regression analysis revealed that [Formula: see text]CO 2 intercept ≤ 3.5 L/minute [odds ratios (95% CI) = 7.69 (2.61-22.65), P < 0.001] plus [Formula: see text]E-[Formula: see text]CO 2 slope ≥ 34 [2.18 (0.73-6.50), P = 0.14] or peak [Formula: see text]E/[Formula: see text]CO 2 ratio ≥ 37 [5.35 (1.96-14.59), P = 0.001] plus peak PETCO 2 ≤ 31 mmHg [5.73 (1.42-23.15), P = 0.01] were indicative of overlapping. Heart failure increases the ventilatory response to metabolic demand in COPD. Variables reflecting excessive ventilation might prove useful to assist clinical interpretation of CPET responses in COPD patients presenting heart failure as co-morbidity.

Severity of resting functional impairment only partially predicts the increased risk of death in chronic obstructive pulmonary disease (COPD). Increased ventilation during exercise is associated with markers of disease progression and poor prognosis, including emphysema extension and pulmonary vascular impairment. Whether excess exercise ventilation would add to resting lung function in predicting mortality in COPD, however, is currently unknown. After an incremental cardiopulmonary exercise test, 288 patients (forced expiratory volume in one second ranging from 18% to 148% predicted) were followed for a median (interquartile range) of 57 (47) months. Increases in the lowest (nadir) ventilation to CO2 output (VCO2) ratio determined excess exercise ventilation. Seventy-seven patients (26.7%) died during follow-up: 30/77 (38.9%) deaths were due to respiratory causes. Deceased patients were older, leaner, had a greater co-morbidity burden (Charlson Index) and reported more daily life dyspnea. Moreover, they had poorer lung function and exercise tolerance (p < 0.05). A logistic regression analysis revealed that ventilation/VCO2 nadir was the only exercise variable that added to age, body mass index, Charlson Index and resting inspiratory capacity (IC)/total lung capacity (TLC) ratio to predict all-cause and respiratory mortality (p < 0.001). Kaplan-Meier analyses showed that survival time was particularly reduced when ventilation/VCO2 nadir > 34 was associated with IC/TLC ≤ 0.34 or IC/TLC ≤ 0.31 for all-cause and respiratory mortality, respectively (p < 0.001). Excess exercise ventilation is an independent prognostic marker across the spectrum of COPD severity. Physiological abnormalities beyond traditional airway dysfunction and lung mechanics are relevant in determining the course of the disease.