Common Mechanisms of Dyspnea in Chronic Interstitial and Obstructive Lung Disorders.

RATIONALE: The mechanisms underlying dyspnea in interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) are unknown. OBJECTIVES: To examine whether the relationship between inspiratory neural drive to the diaphragm and exertional dyspnea intensity is different in ILD and COPD, given the marked differences in static respiratory mechanics between these conditions. METHODS: We compared sensory-mechanical relationships in patients with ILD, patients with COPD, and healthy control subjects (n = 16 each) during incremental cycle exercise with diaphragmatic electromyography (EMGdi) and respiratory pressure measurements. MEASUREMENTS AND MAIN RESULTS: In patients with mild to moderate ILD or COPD with similarly reduced inspiratory capacity, the peak oxygen uptake, work rate, and ventilation were lower (P < 0.05) than in healthy control subjects. EMGdi expressed as a percentage of the maximum (EMGdi/EMGdi,max), respiratory effort (esophageal pressure expressed as percentage of the maximum), and ventilation were higher (P < 0.05) at rest and during exercise in both patients with ILD and patients with COPD than in control subjects. Each of these measurements was similar in the ILD and COPD groups. A Vt inflection and critically reduced inspiratory reserve volume occurred at a lower (P < 0.05) ventilation in the ILD and COPD groups than in control subjects. Patients with ILD had greater diaphragmatic activity, whereas patients with COPD had greater expiratory muscle activity. The relationship between dyspnea intensity and EMGdi/EMGdi,max during exercise was similar in all three groups. In ILD and COPD, descriptors alluding to inspiratory difficulty were selected more frequently, with a greater disparity between EMGdi/EMGdi,max and Vt. CONCLUSIONS: Disease-specific differences in mechanics and respiratory muscle activity did not influence the key association between dyspnea intensity and inspiratory neural drive to the diaphragm.

Resting Physiological Correlates of Reduced Exercise Capacity in Smokers with Mild Airway Obstruction.

Smokers with minor spirometric abnormalities can experience persistent activity-related dyspnea and exercise intolerance. Additional resting tests can expose heterogeneous physiological abnormalities, but their relevance and association with clinical outcomes remain uncertain. Subjects included sixty-two smokers (≥20 pack-years), with cough and/or dyspnea and minor airway obstruction [forced expiratory volume in one-second (FEV1) ≥80% predicted and >5th percentile lower limit of normal (LLN) (i.e., z-score >-1.64) using the 2012-Global Lung Function Initiative equations]. They underwent spirometry, plethysmography, oscillometry, single-breath nitrogen washout, and symptom-limited incremental cycle exercise tests. Thirty-two age-matched nonsmoking controls were also studied. Thirty-three (53%) of smokers had chronic obstructive pulmonary disease by LLN criteria. In smokers [n = 62; age 65 ± 11 years; smoking history 43 ± 19 pack-years; post-bronchodilator FEV1 z-score -0.60 ± 0.72 and FEV1/FVC z-score -1.56 ± 0.87 (mean ± SD)] versus controls, peak oxygen uptake (̇VO2) was 21 ± 7 vs. 32 ± 9 ml/kg/min, and dyspnea/̇VO2 slopes were elevated (both p < 0.0001). Smokers had evidence of peripheral airway dysfunction and maldistribution of ventilation when compared to controls. In smokers versus controls: lung diffusing capacity for carbon monoxide (DLCO) was 85 ± 22 vs. 105 ± 17% predicted, and residual volume (RV)/total lung capacity (TLC) was 36 ± 8 vs. 31 ± 6% (both p < 0.01). The strongest correlates of peak ̇VO2 were DLCO% predicted (r = 0.487, p < 0.0005) and RV/TLC% (r = -0.389, p = 0.002). DLCO% predicted was also the strongest correlate of dyspnea/̇VO2 slope (r = -0.352, p = 0.005). In smokers with mild airway obstruction, associations between resting tests of mechanics and pulmonary gas exchange and exercise performance parameters were weak, albeit consistent. Among these, DLCO showed the strongest association with important outcomes such as dyspnea and exercise intolerance measured during standardized incremental exercise tests.

Mechanisms of exertional dyspnoea in symptomatic smokers without COPD.

Dyspnoea and activity limitation can occur in smokers who do not meet spirometric criteria for chronic obstructive pulmonary disease (COPD) but the underlying mechanisms are unknown.Detailed pulmonary function tests and sensory-mechanical relationships during incremental exercise with respiratory pressure measurements and diaphragmatic electromyography (EMGdi) were compared in 20 smokers without spirometric COPD and 20 age-matched healthy controls.Smokers (mean±sd post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity 75±4%, mean±sd FEV1 104±14% predicted) had greater activity-related dyspnoea, poorer health status and lower physical activity than controls. Smokers had peripheral airway dysfunction: higher phase-III nitrogen slopes (3.8±1.8 versus 2.6±1.1%·L(-1)) and airway resistance (difference between airway resistance measured at 5 Hz and 20 Hz 19±11 versus 12±7% at 5 Hz) than controls (p<0.05). Smokers had significantly (p<0.05) lower peak oxygen uptake (78±40 versus 107±45% predicted) and ventilation (61±26 versus 97±29 L·min(-1)). Exercise ventilatory requirements, operating lung volumes and cardio-circulatory responses were similar. However, submaximal dyspnoea ratings, resistive and total work of breathing were increased in smokers compared with controls (p<0.05); diaphragmatic effort (transdiaphragmatic pressure/maximumal transdiaphragmatic pressure) and fractional inspiratory neural drive to the diaphragm (EMGdi/maximal EMGdi) were also increased (p<0.05) mainly reflecting the reduced denominator.Symptomatic smokers at risk for COPD had greater exertional dyspnoea and lower exercise tolerance compared with healthy controls in association with greater airways resistance, contractile diaphragmatic effort and fractional inspiratory neural drive to the diaphragm.

Pulmonary Gas Exchange Abnormalities in Mild Chronic Obstructive Pulmonary Disease. Implications for Dyspnea and Exercise Intolerance.

RATIONALE: Several studies in mild chronic obstructive pulmonary disease (COPD) have shown a higher than normal ventilatory equivalent for carbon dioxide ([Formula: see text]e/[Formula: see text]co2) during exercise. Our objective was to examine pulmonary gas exchange abnormalities and the mechanisms of high [Formula: see text]e/[Formula: see text]co2 in mild COPD and its impact on dyspnea and exercise intolerance. METHODS: Twenty-two subjects (11 patients with GOLD [Global Initiative for Chronic Obstructive Lung Disease] grade 1B COPD, 11 age-matched healthy control subjects) undertook physiological testing and a symptom-limited incremental cycle exercise test with arterial blood gas collection. MEASUREMENTS AND MAIN RESULTS: Patients (post-bronchodilator FEV1: 94 ± 10% predicted; mean ± SD) had evidence of peripheral airway dysfunction and reduced peak oxygen uptake compared with control subjects (80 ± 18 vs. 113 ± 24% predicted; P<0.05). Arterial blood gases were within the normal range and effective alveolar ventilation was not significantly different from control subjects throughout exercise. The alveolar-arterial O2 tension gradient was elevated at rest and throughout exercise in COPD (P<0.05). [Formula: see text]e/[Formula: see text]co2, dead space to tidal volume ratio (Vd/Vt), and arterial to end-tidal CO2 difference were all higher (P<0.05) in patients with COPD than in control subjects during exercise. In patients with COPD versus control subjects, there was significant dynamic hyperinflation and greater tidal volume constraints (P<0.05). Standardized dyspnea intensity ratings were also higher (P<0.05) in patients with COPD versus control subjects in association with higher ventilatory requirements. Within all subjects, Vd/Vt correlated with the [Formula: see text]e/[Formula: see text]co2 ratio during submaximal exercise (r=0.780, P<0.001). CONCLUSIONS: High Vd/Vt was the most consistent gas exchange abnormality in smokers with only mild spirometric abnormalities. Compensatory increases in minute ventilation during exercise maintained alveolar ventilation and arterial blood gas homeostasis but at the expense of earlier dynamic mechanical constraints, greater dyspnea, and exercise intolerance in mild COPD.

Exercise Ventilatory Inefficiency Adds to Lung Function in Predicting Mortality in COPD.

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.

Ventilation Distribution Heterogeneity at Rest as a Marker of Exercise Impairment in Mild-to-Advanced COPD.

The difference between total lung capacity (TLC) by body plethysmography and alveolar volume (VA) from the single-breath lung diffusing capacity measurement provides an index of ventilation distribution inequalities in COPD. The relevance of these abnormalities to dyspnea and exercise intolerance across the continuum of disease severity remains unknown. Two-hundred and seventy-six COPD patients distributed across GOLD grades 1 to 4 and 67 healthy controls were evaluated. The "poorly communicating fraction" (PCF) of the TLC was estimated as the ratio (%) of TLC to VA. Healthy subjects showed significantly lower PCF values compared to GOLD grades 1 to 4 (10 ± 3% vs. 17 ± 8% vs. 27 ± 10% vs. 37 ± 10% vs. 56 ± 11%, respectively; p < 0.05). Pulmonary gas exchange impairment, mechanical ventilatory constraints and ventilation-corrected dyspnea scores worsened across PCF tertiles (p < 0.05). Of note, GOLD grades 1 and 2 patients with the highest PCF values had pronounced exercise ventilatory inefficiency and dyspnea as a limiting symptom. In fact, dyspnea was a significant contributor to exercise limitation only in those with "moderate" or "extensive" PCF (p < 0.05). A receiver operating characteristics curve analysis revealed that PCF was a better predictor of severely reduced maximal exercise capacity than traditional pulmonary function indexes including FEV1 (area under the curve (95% confidence interval) = 0.85 (0.81-0.89), best cutoff = 33.4%; p < 0.01). In conclusion, PCF is a readily available functional marker of gas exchange and mechanical abnormalities relevant to dyspnea and exercise intolerance across the COPD grades.

Does exercise test modality influence dyspnoea perception in obese patients with COPD?

The purpose of this study was to investigate whether differences in physiological responses to weight-bearing (walking) and weight-supported (cycle) exercise influence dyspnoea perception in obese chronic obstructive pulmonary disease (COPD) patients, where such discrepancies are probably exaggerated. We compared metabolic, ventilatory and perceptual responses during incremental treadmill and cycle exercise using a matched linearised rise in work rate in 18 (10 males and eight females) obese (mean ± sd body mass index 36.4 ± 5.0 kg·m(-2)) patients with COPD (forced expiratory volume in 1 s 60 ± 11% predicted). Compared with cycle testing, treadmill testing was associated with a significantly higher oxygen uptake, lower ventilatory equivalent for oxygen and greater oxyhaemoglobin desaturation at a given work rate (p<0.01). Cycle testing was associated with a higher respiratory exchange ratio (p<0.01), earlier ventilatory threshold (p<0.01) and greater peak leg discomfort ratings (p=0.01). Ventilation, breathing pattern and operating lung volumes were similar between tests, as were dyspnoea/work rate and dyspnoea/ventilation relationships. Despite significant between-test differences in physiological responses, ventilation, operating lung volumes and dyspnoea intensity were similar at any given external power output during incremental walking and cycling exercise in obese COPD patients. These data provide evidence that either exercise modality can be selected for reliable evaluation of exertional dyspnoea in this population in research and clinical settings.

Mechanisms of exercise intolerance in global initiative for chronic obstructive lung disease grade 1 COPD.

The purpose of this study was to determine if a dissociation existed between respiratory drive, as estimated by diaphragmatic electromyography (EMGdi), and its pressure-generating capacity during exercise in mild chronic obstructive pulmonary disease (COPD) and whether this, if present, had negative sensory consequences. Subjects meeting spirometric criteria for mild COPD (n=16) and age and sex-matched controls (n=16) underwent detailed pulmonary function testing and a symptom limited cycle test while detailed ventilatory, sensory and respiratory mechanical responses were measured. Compared with controls, subjects with mild COPD had greater ventilatory requirements throughout submaximal exercise. At the highest equivalent work rate of 60 W, they had a significantly higher: total work of breathing (32±17 versus 16±7 J·min(-1); p<0.01); EMGdi (37.3±17.3 versus 17.9±11.7% of maximum; p<0.001); and EMGdi to transdiaphragmatic pressure ratio (0.87±0.38 versus 0.52±0.27; p<0.01). Dyspnoea-ventilation slopes were significantly higher in mild COPD than controls (0.17±0.12 versus 0.10±0.05; p<0.05). However, absolute dyspnoea ratings reached significant levels only at high levels of ventilation. Increased respiratory effort and work of breathing, and a wider dissociation between diaphragmatic activation and pressure-generating capacity were found at standardised work rates in subjects with mild COPD compared with controls. Despite these mechanical and neuromuscular abnormalities, significant dyspnoea was only experienced at higher work rates.

Does the respiratory system limit exercise in mild chronic obstructive pulmonary disease?

RATIONALE: It is not known if abnormal dynamic respiratory mechanics actually limit exercise in patients with mild chronic obstructive pulmonary disease (COPD). We reasoned that failure to increase peak ventilation and Vt in response to dead space (DS) loading during exercise would indicate true ventilatory limitation to exercise in mild COPD. OBJECTIVES: To compare the effects of DS loading during exercise on ventilation, breathing pattern, operating lung volumes, and dyspnea intensity in subjects with mild symptomatic COPD and age- and sex-matched healthy control subjects. METHODS: Twenty subjects with Global Initiative for Chronic Obstructive Lung Disease stage I COPD and 20 healthy subjects completed two symptom-limited incremental cycle exercise tests, in randomized order: unloaded control and added DS of 0.6 L. MEASUREMENTS AND MAIN RESULTS: Peak oxygen uptake and ventilation were significantly lower in COPD than in health by 36% and 41%, respectively. With added DS compared with control, both groups had small decreases in peak work rate and no significant increase in peak ventilation. In health, peak Vt and end-inspiratory lung volume increased significantly with DS. In contrast, the COPD group failed to increase peak end-inspiratory lung volume and had a significantly smaller increase in peak Vt during DS. At 60 W, a 50% smaller increase in Vt (P < 0.001) in response to added DS in COPD compared with health was associated with a greater increase in dyspnea intensity (P = 0.0005). CONCLUSIONS: These results show that the respiratory system reached or approached its physiologic limit in mild COPD at a lower peak work rate and ventilation than in healthy participants. Clinical trial registered with www.clinicaltrials.gov (NCT 00975403).

Impact of pulmonary rehabilitation on the major dimensions of dyspnea in COPD.

The evaluation of dyspnea and its responsiveness to therapy in COPD should consider the multidimensional nature of this symptom in each of its sensory-perceptual (intensity, quality), affective and impact domains. To gain new insights into mechanisms of dyspnea relief following pulmonary rehabilitation (PR), we examined effects on the major domains of dyspnea and their interaction with physiological training effects. This randomized, controlled study was conducted in 48 subjects with COPD. Subjects received either 8-weeks of PR or usual care (CTRL). Pre- and post-intervention assessments included: sensory-perceptual (i.e., exertional dyspnea intensity, dyspnea descriptors at end-exercise), affective (i.e., intensity of breathing-related anxiety during exercise, COPD self-efficacy, walking self-efficacy) and impact (i.e., activity-related dyspnea measured by the Baseline/Transition Dyspnea Index, Chronic Respiratory Questionnaire dyspnea component, St. George's Respiratory Disease Questionnaire activity component) domains of dyspnea; functional performance (i.e., 6-minute walk, endurance shuttle walk); pulmonary function; and physiological measurements during constant work rate cycle exercise at 75% of the peak incremental work rate. Forty-one subjects completed the study: PR (n = 17) and CTRL (n = 24) groups were well matched for age, sex, body size and pulmonary function. There were no significant between-group differences in pre- to post-intervention changes in pulmonary function or physiological parameters during exercise. After PR versus CTRL, significant improvements were found in the affective and impact domains but not in the sensory-perceptual domain of dyspnea. In conclusion, clinically meaningful improvements in the affective and impact domains of dyspnea occurred in response to PR in the absence of consistent physiological training effects.

Physiological effects of roflumilast at rest and during exercise in COPD.

The purpose of this study was to investigate the effects of 500 µg roflumilast, taken once daily for 12 weeks, on airway physiology during rest and exercise in patients with moderate-to-severe chronic obstructive pulmonary disease. This randomised, double-blind, placebo-controlled, parallel-group study was conducted in 250 patients with a post-bronchodilator forced expiratory volume in 1 s (FEV(1)) of 30-80% predicted and a functional residual capacity of ≥ 120% pred. Pre- and post-bronchodilator spirometry and body plethysmography, and pre-bronchodilator constant work rate cycle exercise at 75% of peak work rate were evaluated. Exercise measurements included ventilation, breathing pattern, inspiratory capacity (IC) and arterial oxygen saturation measured by pulse oximetry (S(p,O(2))). Compared with placebo, 12 weeks of treatment with roflumilast was associated with: small but progressive increases in pre- and post-bronchodilator FEV(1) and FEV(1)/forced vital capacity; small decreases in specific airway resistance; and no significant changes in resting vital capacity, IC or measurements of lung hyperinflation. There was no treatment effect on exercise endurance time. At a standardised exercise time after roflumilast, compared with placebo, IC increased by 0.12 L (p = 0.008) and S(p,O(2)) increased by 0.7% (p = 0.020); peak ventilation increased by 1.9 L · min(-1) (p = 0.014). Roflumilast treatment was associated with progressive improvement of airway function but not lung hyperinflation. Newly described non-bronchodilator effects of roflumilast included small but consistent improvements in air trapping and S(p,O(2)) during exercise.

Does dynamic hyperinflation contribute to dyspnoea during exercise in patients with COPD?

Dynamic hyperinflation (DH) during exercise occurs in most but not all patients with advanced chronic obstructive pulmonary disease (COPD). It is not known whether the presence or absence of DH has implications for dyspnoea and exercise tolerance. Therefore, we compared detailed ventilatory and sensory responses to exercise in hyperinflators and nonhyperinflators with moderate-to-severe COPD. Nonhyperinflators (n=65) were retrospectively identified from a sample of 427 patients and case-matched to a group of hyperinflators (n=65) based on sex, age, body mass index and % predicted forced expiratory volume in 1 s. Resting pulmonary function and constant work rate cycle exercise responses were compared. Hyperinflators decreased inspiratory capacity (IC) from rest to peak exercise by 0.46±0.24 L whereas the nonhyperinflators increased IC by 0.10±0.15 L (p<0.0001). There were no significant group differences in endurance time (9.11±5.98 versus 8.87±5.24 min) or dyspnoea intensity for any given time or ventilation. An inflection in tidal volume versus ventilation occurred in the majority of nonhyperinflators (n=61) and hyperinflators (n=62) at a similar time and ventilation. Mechanical constraints on tidal volume expansion and the attendant rise in dyspnoea intensity were similar in both groups. Dyspnoea intensity during exercise was associated with progressive mechanical constraints on tidal volume expansion regardless of the presence of DH.

Evolution of dyspnea during exercise in chronic obstructive pulmonary disease: impact of critical volume constraints.

RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) primarily describe their exertional dyspnea using descriptors alluding to increased effort or work of breathing and unsatisfied inspiration or inspiratory difficulty. OBJECTIVES: The purpose of this study was to examine the impact of changes in dynamic respiratory mechanics during incremental (INCR) and high-intensity constant work-rate (CWR) cycle exercise on the evolution of dyspnea intensity and its major qualitative dimensions in patients with moderate-to-severe COPD. METHODS: Sixteen subjects with COPD performed symptom-limited INCR and CWR cycle exercise tests. Measurements included dyspnea intensity and qualitative descriptors, breathing pattern, operating lung volumes, and esophageal pressure (Pes). MEASUREMENTS AND MAIN RESULTS: During both exercise tests, there was an inflection in the relation between tidal volume (Vt) and ventilation. This inflection occurred significantly earlier in time during CWR versus INCR exercise but at a similar ventilation, Vt, and tidal Pes swing. Beyond this inflection, there was no further change in Vt despite a continued increase in ventilation and tidal Pes. During both tests, "work and effort" was the dominant dyspnea descriptor selected up to the inflection point, whereas after this point dyspnea intensity and the selection frequency of "unsatisfied inspiration" rose sharply. CONCLUSIONS: Regardless of the exercise test protocol, the inflection (or plateau) in the Vt response marked the point where dyspnea intensity rose abruptly and there was a transition in the dominant qualitative descriptor choice from "work and effort" to "unsatisfied inspiration." Intensity and quality of dyspnea evolve separately and are strongly influenced by mechanical constraints on Vt expansion during exercise in COPD.

Components of the COPD Assessment Test (CAT) associated with a diagnosis of COPD in a random population sample.

The aim of this study was to determine if components of the COPD Assessment Test (CAT), a validated health status impairment instrument, had additional utility in identifying patients at risk for COPD in whom spirometry testing is appropriate. This study was part of the Canadian Obstructive Lung Disease prevalence study. Consenting participants ≥ 40 years of age were identified by random digit dialing. Smoking history, 8-item CAT scores, and post-bronchodilator spirometry were recorded for each. Stepwise logistic regression analysis was used to identify variables related to the presence of airway obstruction and a final logistic model was developed which best predicted COPD in this sample. Of the 801 individuals approached, 532 were included: 51 (9.6%) had COPD, the majority (92%) of whom fit GOLD I or II severity criteria. Items that correlated significantly with a COPD diagnosis included the CAT total score (p = 0.01) and its breathlessness (p < 0.0001) and phlegm (p = 0.001) components. The final logistic model included: age (<55 or ≥55 years), smoking status (current, former, never) and the CAT breathlessness score (ordinal scale 0-5). The area under the receiver-operating characteristic curve for this model was 0.77, sensitivity was 77.6%, specificity was 64.9% and the positive likelihood ratio was 2.21. In summary, the triad of smoking history, age at least 55 years and the presence of exertional breathlessness were key elements of a simple model which had reliable measurement properties when tested in a random population. This may help identify patients at risk for COPD for whom spirometry testing is recommended.

Physiological predictors of morbidity and mortality in COPD: the relative importance of reduced inspiratory capacity and inspiratory muscle strength.

Low resting inspiratory capacity (IC) and low maximal inspiratory pressure (MIP) have previously been linked to exertional dyspnea, exercise limitation, and poor survival in chronic obstructive pulmonary disease (COPD). The interaction and relative contributions of these two related variables to important clinical outcomes are unknown. The objective of the current study was to examine the interaction between resting IC and MIP (both % predicted), exertional dyspnea, exercise capacity, and long-term survival in patients with COPD. Two hundred and eighty-five patients with mild to advanced COPD completed standard lung function testing and a cycle cardiopulmonary exercise test. Multiple regression determined predictors of the exertional dyspnea-ventilation slope and peak oxygen uptake (V̇o2peak). Cox regression determined predictors of 10-year mortality. IC was associated with the dyspnea-ventilation slope (standardized ß = -0.42, P < 0.001), whereas MIP was excluded from the regression model (P = 0.918). IC and MIP were included in the final model to predict V̇o2peak. However, the standardized ß was greater for IC (0.43) than MIP (0.22). After adjusting for age, sex, body mass index, cardiovascular risk, airflow obstruction, and diffusing capacity, resting IC was independently associated with 10-year all-cause mortality (hazard ratio = 1.25, confidence interval5%-95% = 1.16-1.34, P < 0.001), whereas MIP was excluded from the final model (all P = 0.829). Low resting IC was consistently linked to heightened dyspnea intensity, low V̇o2peak, and worse survival in COPD even after accounting for airway obstruction, inspiratory muscle strength, and diffusing capacity. These results support the use of resting IC as an important physiological biomarker closely linked to key clinical outcomes in COPD.NEW & NOTEWORTHY To our knowledge, this study is the first to show an independent association between low resting inspiratory capacity (IC) and, severe exertional dyspnea, exercise limitation, and increased mortality risk, after accounting for the severity of airway obstruction, inspiratory muscle strength, and diffusing capacity. These results support the use of resting IC as an important independent physiological biomarker closely linked to key clinical outcomes in COPD.

Effects of obesity on perceptual and mechanical responses to bronchoconstriction in asthma.

RATIONALE: The influence of obesity on the perception of respiratory discomfort during acute bronchoconstriction in asthma is unknown. OBJECTIVES: We hypothesized that the respiratory impairment associated with an increased body mass index (BMI) would predispose to greater perceived symptom intensity during acute airway narrowing. We therefore compared relationships between induced changes in dyspnea intensity and lung function during methacholine (MCh) bronchoprovocation in obese (OBA) and normal-weight (NWA) individuals with asthma of mild to moderate severity. METHODS: High-dose MCh challenge tests to a maximum 50% decrease in FEV(1) were conducted in 51 NWA (BMI, 18.5-24.9 kg/m(2); 29% male) and 45 OBA (BMI, 30.1-51.4 kg/m(2); 33% male) between 20 and 60 years of age. Serial spirometry, inspiratory capacity (IC), plethysmographic end-expiratory lung volume (EELV) and dyspnea intensity using the Borg scale were measured throughout bronchoprovocation. MEASUREMENTS AND MAIN RESULTS: Spirometry and airway sensitivity were similar in both groups; baseline EELV was lower (P < 0.0005) and IC was higher (P = 0.007) in OBA compared with NWA. From baseline to PC(20), EELV increased more in OBA (20% predicted) than NWA (13% predicted) (P = 0.008) with concomitant greater reductions in IC (P < 0.0005). Dyspnea ratings were not different for a given FEV(1) or IC across groups. By mixed effects regression analysis, relationships between induced dyspnea and changes in lung function parameters were not influenced by BMI, sex, or their interaction. CONCLUSIONS: Perceptual responses to MCh-induced bronchoconstriction and lung hyperinflation were similar in obese and normal-weight individuals with asthma despite significant group differences in baseline lung volumes.

Qualitative Components of Dyspnea during Incremental Exercise across the COPD Continuum.

INTRODUCTION: Evaluation of the intensity and quality of activity-related dyspnea is potentially useful in people with chronic obstructive pulmonary disease (COPD). The present study sought to examine associations between qualitative dyspnea descriptors, dyspnea intensity ratings, dynamic respiratory mechanics, and exercise capacity during cardiopulmonary exercise testing (CPET) in COPD and healthy controls. METHODS: In this cross-sectional study, 261 patients with mild-to-very severe COPD (forced expiratory volume in 1 s, 62 ± 25%pred) and 94 age-matched controls (forced expiratory volume in 1 s, 114 ± 14%pred) completed an incremental cycle CPET to determine peak oxygen uptake (V˙O2peak). Throughout exercise, expired gases, operating lung volumes, and dyspnea intensity were assessed. At peak exercise, dyspnea quality was assessed using a modified 15-item questionnaire. RESULTS: Logistic regression analysis revealed that among 15 dyspnea descriptors, only those alluding to the cluster "unsatisfied inspiration" were consistently associated with an increased likelihood for both critical inspiratory mechanical constraint (end-inspiratory lung volume/total lung capacity ratio ≥0.9) during exercise and reduced exercise capacity (V˙O2peak < lower limit of normal) in COPD (odds ratio (95% confidence interval), 3.26 (1.40-7.60) and 3.04 (1.24-7.45), respectively; both, P < 0.05). Thus, patients reporting "unsatisfied inspiration" (n = 177 (68%)) had an increased relative frequency of critical inspiratory mechanical constraint and low exercise capacity compared with those who did not select this descriptor, regardless of COPD severity or peak dyspnea intensity scores. CONCLUSIONS: In patients with COPD, regardless of disease severity, reporting descriptors in the unsatisfied inspiration cluster complemented traditional assessments of dyspnea during CPET and helped identify patients with critical mechanical abnormalities germane to exercise intolerance.

Combined effects of obesity and chronic obstructive pulmonary disease on dyspnea and exercise tolerance.

RATIONALE: Severity of lung hyperinflation is known to influence the extent of dyspnea and exercise intolerance among patients with chronic obstructive pulmonary disease (COPD) with similar degrees of airway obstruction. Lung volume components are consistently affected by body mass index (BMI) in health and in disease. OBJECTIVES: To explore the complex interactions between obesity, lung hyperinflation, dyspnea, and exercise performance in COPD. METHODS: We compared dyspnea intensity ratings and ventilatory responses (breathing pattern, operating lung volumes, and gas exchange) during symptom-limited incremental cycle exercise in well-characterized groups of 18 obese (mean BMI +/- SD, 35 +/- 4 kg/m(2)) and 18 normal-weight (mean BMI +/- SD, 22 +/- 2 kg/m(2)) patients with moderate to severe COPD. MEASUREMENTS AND MAIN RESULTS: Groups were well matched for FEV(1) (mean 49% predicted) and diffusing capacity (means >70% predicted), but resting lung hyperinflation (end-expiratory lung volume [EELV]) was significantly reduced in association with increasing BMI (P < 0.005). In the obese patients, peak symptom-limited oxygen uptake was increased (P < 0.01) and dyspnea ratings at a standardized ventilation were decreased (P < 0.01) compared with normal-weight patients. Ratings of dyspnea intensity at a standardized ventilation during exercise correlated well with the concurrent dynamic EELV/total lung capacity (TLC) ratio (r = 0.68; P < 0.00001) and with the resting EELV/TLC (r = 0.67; P < 0.00001). CONCLUSIONS: The combined mechanical effects of obesity and COPD reduced operating lung volumes at rest and throughout exercise with favorable influences on dyspnea perception and peak oxygen uptake during cycle ergometry.

Effect of obesity on constant workrate exercise in hyperinflated men with COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and a high body mass index (BMI) can both affect pulmonary volumes as well as exercise tolerance, but their combined effect on these outcomes is not well known. The aim of this study was to investigate the effects of increased BMI during constant workrate cycle ergometry in patients with COPD. METHODS: Men with COPD and hyperinflation were divided according to World Health Organization BMI classification: 84 normal BMI (NBMI), 130 overweight (OW) and 64 obese (OB). Patients underwent spirometric and lung volumes assessment and an incremental cycling exercise test. This was followed by a constant workrate exercise test (CET) at 75% of peak capacity. Inspiratory capacity and Borg dyspnea scores were measured at baseline, during and at the end of CET. RESULTS AND DISCUSSION: FEV1 % predicted was not different across BMI classes. Total lung capacity and functional residual capacity were significantly lower in OB and OW compared to NBMI patients. Peak VO2 in L x min(-1) was significantly higher in OB and OW patients than in NBMI patients. CET time was not different across BMI classes (p = 0.11). Changes in lung volumes and dyspnea during CET were not different between BMI categories. CONCLUSIONS: OB and OW patients with COPD had a higher peak VO2 than their lean counterparts. Endurance time, dyspnea and changes in lung volumes during CET were similar between BMI categories.