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Rationale: It is increasingly recognized that adults with preserved ratio impaired spirometry (PRISm) are prone to increased morbidity. However, the underlying pathophysiological mechanisms are unknown. Objectives: Evaluate the mechanisms of increased dyspnea and reduced exercise capacity in PRISm. Methods: We completed a cross-sectional analysis of the CanCOLD (Canadian Cohort Obstructive Lung Disease) population-based study. We compared physiological responses in 59 participants meeting PRISm spirometric criteria (post-bronchodilator FEV1 < 80% predicted and FEV1/FVC ⩾ 0.7), 264 control participants, and 170 ever-smokers with chronic obstructive pulmonary disease (COPD), at rest and during cardiopulmonary exercise testing. Measurements and Main Results: Individuals with PRISm had lower total lung, vital, and inspiratory capacities than healthy controls (all P < 0.05) and minimal small airway, pulmonary gas exchange, and radiographic parenchymal lung abnormalities. Compared with healthy controls, individuals with PRISm had higher dyspnea/ V ˙ o2 ratio at peak exercise (4.0 ± 2.2 vs. 2.9 ± 1.9 Borg units/L/min; P < 0.001) and lower V ˙ o2peak (74 ± 22% predicted vs. 96 ± 25% predicted; P < 0.001). At standardized submaximal work rates, individuals with PRISm had greater Vt/inspiratory capacity (Vt%IC; P < 0.001), reflecting inspiratory mechanical constraint. In contrast to participants with PRISm, those with COPD had characteristic small airways dysfunction, dynamic hyperinflation, and pulmonary gas exchange abnormalities. Despite these physiological differences among the three groups, the relationship between increasing dyspnea and Vt%IC during cardiopulmonary exercise testing was similar. Resting IC significantly correlated with V ˙ o2peak (r = 0.65; P < 0.001) in the entire sample, even after adjusting for airflow limitation, gas trapping, and diffusing capacity. Conclusions: In individuals with PRISm, lower exercise capacity and higher exertional dyspnea than healthy controls were mainly explained by lower resting lung volumes and earlier onset of dynamic inspiratory mechanical constraints at relatively low work rates. Clinical trial registered with (NCT00920348). [ABSTRACT FROM AUTHOR]

Rationale: Ventilatory demand-capacity imbalance, as inferred based on a low ventilatory reserve, is currently assessed only at peak cardiopulmonary exercise testing (CPET). Peak ventilatory reserve, however, is poorly sensitive to the submaximal, dynamic mechanical ventilatory abnormalities that are key to dyspnea genesis and exercise intolerance. Objectives: After establishing sex- and age-corrected norms for dynamic ventilatory reserve at progressively higher work rates, we compared peak and dynamic ventilatory reserve for their ability to expose increased exertional dyspnea and poor exercise tolerance in mild to very severe chronic obstructive pulmonary disease (COPD). Methods: We analyzed resting functional and incremental CPET data from 275 controls (130 men, aged 19-85 yr) and 359 Global Initiative for Chronic Obstructive Lung Disease patients with stage 1-4 obstruction (203 men) who were prospectively recruited for previous ethically approved studies in three research centers. In addition to peak and dynamic ventilatory reserve (12[ventilation / estimated maximal voluntary ventilation]3100), operating lung volumes and dyspnea scores (0-10 on the Borg scale) were obtained. Results: Dynamic ventilatory reserve was asymmetrically distributed in controls; thus, we calculated its centile distribution at every 20 W. The lower limit of normal (lower than the fifth centile) was consistently lower in women and older subjects. Peak and dynamic ventilatory reserve disagreed significantly in indicating an abnormally low test result in patients: whereas approximately 50% of those with a normal peak ventilatory reserve showed a reduced dynamic ventilatory reserve, the opposite was found in approximately 15% (P,0.001). Irrespective of peak ventilatory reserve and COPD severity, patients who had a dynamic ventilatory reserve below the lower limit of normal at an isowork rate of 40W had greater ventilatory requirements, prompting earlier attainment of critically low inspiratory reserve. Consequently, they reported higher dyspnea scores, showing poorer exercise tolerance compared with those with preserved dynamic ventilatory reserve. Conversely, patients with preserved dynamic ventilatory reserve but reduced peak ventilatory reserve reported the lowest dyspnea scores, showing the best exercise tolerance. Conclusions: Reduced submaximal dynamic ventilatory reserve, even in the setting of preserved peak ventilatory reserve, is a powerful predictor of exertional dyspnea and exercise intolerance in COPD. This new parameter of ventilatory demand-capacity mismatch may enhance the yield of clinical CPET in the investigation of activity-related breathlessness in individual patients with COPD and other prevalent cardiopulmonary diseases. [ABSTRACT FROM AUTHOR]

Individuals with COPD and preserved ratio impaired spirometry (PRISm) findings in clinical settings have an increased risk of cardiovascular disease (CVD). Do individuals with mild to moderate or worse COPD and PRISm findings in community settings have a higher prevalence and incidence of CVD compared with individuals with normal spirometry findings? Can CVD risk scores be improved when impaired spirometry is added? The analysis was embedded in the Canadian Cohort Obstructive Lung Disease (CanCOLD). Prevalence of CVD (ischemic heart disease [IHD] and heart failure [HF]) and their incidence over 6.3 years were compared between groups with impaired and normal spirometry findings using logistic regression and Cox models, respectively, adjusting for covariables. Discrimination of the pooled cohort equations (PCE) and Framingham risk score (FRS) in predicting CVD were assessed with and without impaired spirometry. Participants (n = 1,561) included 726 people with normal spirometry findings and 835 people with impaired spirometry findings (COPD Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1 disease, n = 408; GOLD stage ≥ 2, n = 331; PRISm findings, n = 96). Rates of undiagnosed COPD were 84% in GOLD stage 1 and 58% in GOLD stage ≥ 2 groups. Prevalence of CVD (IHD or HF) was significantly higher among individuals with impaired spirometry findings and COPD compared with those with normal spirometry findings, with ORs of 1.66 (95% CI, 1.13-2.43; P =.01∗) (∗ indicates statistical significane with P <.05) and 1.55 (95% CI, 1.04-2.31; P =.033∗), respectively. Prevalence of CVD was significantly higher in participants having PRISm findings and COPD GOLD stage ≥ 2, but not GOLD stage 1. CVD incidence was significantly higher, with hazard ratios of 2.07 (95% CI, 1.10-3.91; P =.024∗) for the impaired spirometry group and 2.09 (95% CI, 1.10-3.98; P =.024∗) for the COPD group compared to individuals with normal spirometry findings. The difference was significantly higher among individuals with COPD GOLD stage ≥ 2, but not GOLD stage 1. The discrimination for predicting CVD was low and limited when impaired spirometry findings were added to either risk score. Individuals with impaired spirometry findings, especially those with moderate or worse COPD and PRISm findings, have increased comorbid CVD compared with their peers with normal spirometry findings, and having COPD increases the risk of CVD developing. [ABSTRACT FROM AUTHOR]

This document is a reply to a comment made by Dr. Jankowich on a recent publication that studied adults with preserved ratio impaired spirometry (PRISm). The study found a strong physiological link between the spirometry pattern of PRISm and activity-related dyspnea and exercise limitation. The authors explored the potential physiological basis of low resting vital capacity (VC) and inspiratory capacity (IC) in patients with PRISm but found inconclusive results. The study also compared PRISm with chronic obstructive pulmonary disease (COPD) and found that PRISm had a distinctive pattern of lower IC and reduced operating lung volumes. The role of smoking in the pathophysiology of PRISm was also examined, but no significant differences were found between ever-smokers and never-smokers with PRISm. The authors suggest that future studies are needed to better understand the management of individuals with PRISm, regardless of smoking history. [Extracted from the article]

In people with COPD, pulmonary gas-exchange efficiency may be impaired because of abnormal alveolar ventilation (V˙A), capillary perfusion (Q˙c), or both. Both have been reported in early and mild stages of the disease. Such derangements often accompany significant clinical consequences such as activity-related dyspnea and exercise intolerance. Although much attention has been paid to pharmacologic treatment of mechanical abnormalities in COPD (eg, bronchodilators to deflate the lungs), increasing neurochemical afferent activity, secondary to gas-exchange inefficiency, has remained elusive as a therapeutic target. Hence, in this invited review, we first summarize how dyspnea, leading to poor exercise tolerance in COPD, may be explained by an increased venous admixture resulting from low V˙A/Q˙c, or wasted ventilation related to high V˙A/Q˙c, or both. We review the conflicting evidence supporting current treatments for gas-exchange inefficiency and exercise tolerance that act primarily on V˙A (bronchodilators, antiinflammatory medications) or Q˙c (oral and inhaled vasodilators, almitrine, and supplemental oxygen). Finally, to address the current knowledge and health care gaps, we propose two independent clinical research foci that may lead to a better understanding of the role of pulmonary gas-exchange inefficiency and activity-related dyspnea in COPD: (1) enhanced and deeper phenotyping of patients with COPD with V˙A/Q˙c abnormalities and (2) evaluation of existing and novel pharmacologic treatments to improve gas-exchange inefficiency, exertional dyspnea, and exercise tolerance across the spectrum of COPD severity. [ABSTRACT FROM AUTHOR]

Rationale: Impaired exercise ventilatory efficiency (high ventilatory requirements for CO2 [[Formula: see text]e/[Formula: see text]co2]) provides an indication of pulmonary gas exchange abnormalities in chronic obstructive pulmonary disease (COPD). Objectives: To determine 1) the association between high [Formula: see text]e/[Formula: see text]co2 and clinical outcomes (dyspnea and exercise capacity) and its relationship to lung function and structural radiographic abnormalities; and 2) its prevalence in a large population-based cohort. Methods: Participants were recruited randomly from the population and underwent clinical evaluation, pulmonary function, cardiopulmonary exercise testing, and chest computed tomography. Impaired exercise ventilatory efficiency was defined by a nadir [Formula: see text]e/[Formula: see text]co2 above the upper limit of normal (ULN), using population-based normative values. Measurements and Main Results: Participants included 445 never-smokers, 381 ever-smokers without airflow obstruction, 224 with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 COPD, and 200 with GOLD 2-4 COPD. Participants with [Formula: see text]e/[Formula: see text]co2 above the ULN were more likely to have activity-related dyspnea (Medical Research Council dyspnea scale ⩾ 2; odds ratio [5-95% confidence intervals], 1.77 [1.31 to 2.39]) and abnormally low peak [Formula: see text]o2 ([Formula: see text]o2peak below the lower limit of normal; odds ratio, 4.58 [3.06 to 6.86]). The Kco had a stronger correlation with nadir [Formula: see text]e/[Formula: see text]co2 (r = -0.38; P < 0.001) than other relevant lung function and computed tomography metrics. The prevalence of [Formula: see text]e/[Formula: see text]co2 above the ULN was 24% in COPD (similar in GOLD 1 and 2 through 4), which was greater than in never-smokers (13%) and ever-smokers (12%). Conclusions: [Formula: see text]e/[Formula: see text]co2 above the ULN was associated with greater dyspnea and low [Formula: see text]o2peak and was present in 24% of all participants with COPD, regardless of GOLD stage. The results show the importance of recognizing impaired exercise ventilatory efficiency as a potential contributor to dyspnea and exercise limitation, even in mild COPD. [ABSTRACT FROM AUTHOR]

Patients with mild chronic obstructive pulmonary disease (COPD) and lower resting diffusing capacity for carbon monoxide (DLCO) often report troublesome dyspnea during exercise although the mechanisms are not clear. We postulated that in such individuals, exertional dyspnea is linked to relatively high inspiratory neural drive (IND) due, in part, to the effects of reduced ventilatory efficiency. This cross-sectional study included 28 patients with GOLD I COPD stratified into two groups with (n = 15) and without (n = 13) DLCO less than the lower limit of normal (2 (V̇E/V̇CO2), and respiratory mechanics during incremental cycle exercise in the three groups. Spirometry and resting lung volumes were similar between COPD groups. During exercise, dyspnea, IND and V̇E/V̇CO2 were higher at equivalent work rates (WR) in the DLCOCOCOCOE/V̇CO2 at a given work rate. Higher ventilatory requirements in the DLCO

Background: The Global Initiative for Obstructive Lung Disease (GOLD) does not promote diffusing capacity for carbon monoxide (Dlco) values in the evaluation of COPD. In GOLD spirometric stage I COPD patients, the clinical and prognostic impact of a low Dlco has not been explored.Research Question: Could a Dlco threshold help define an increased risk of death and a different clinical presentation in these patients?Study Design and Methods: GOLD stage I COPD patients (n = 360) were enrolled and followed over 109 ± 50 months. Age, sex, pack-years' history, BMI, dyspnea, lung function measurements, exercise capacity, BODE index, and history of exacerbations were recorded. A cutoff value for Dlco was identified for all-cause mortality and the clinical and physiological characteristics of patients above and below the threshold compared. Cox regression analysis explored the predictive power of that cutoff value for all-cause mortality.Results: A Dlco cutoff value of <60% predicted was associated with all-cause mortality (Dlco ≥ 60%: 9% vs Dlco < 60%: 23%, P = .01). At a same FEV1% predicted and Charlson score, patients with Dlco < 60% had lower BMI, more dyspnea, lower inspiratory capacity (IC)/total lung capacity (TLC) ratio, lower 6-min walk distance (6MWD), and higher BODE. Cox multiple regression analysis confirmed that after adjusting for age, sex, pack-years history, smoking status, and BMI, a Dlco < 60% is associated with all-cause mortality (hazard ratio [HR], 95% CI = 3.37, 1.35-8.39; P = .009) INTERPRETATION: In GOLD I COPD patients, a Dlco < 60% predicted is associated with increased risk of death and worse clinical presentation. What the cause(s) of this association are and whether they can be treated need to be determined. [ABSTRACT FROM AUTHOR]

Background and objective: The combination of both reduced resting diffusing capacity of the lung for carbon monoxide (DLCO) and ventilatory efficiency (increased ventilatory requirement for CO2 clearance [V˙E/V˙CO2]) has been linked to exertional dyspnoea and exercise intolerance in chronic obstructive pulmonary disease (COPD) but the underlying mechanisms are poorly understood. The current study examined if low resting DLCO and higher exercise ventilatory requirements were associated with earlier critical dynamic mechanical constraints, dyspnoea and exercise limitation in patients with mild COPD. Methods: In this retrospective analysis, we compared V˙E/V˙CO2, dynamic inspiratory reserve volume (IRV), dyspnoea and exercise capacity in groups of patients with Global Initiative for Chronic Obstructive Lung Disease stage 1 COPD with (1) a resting DLCO at or greater than the lower limit of normal (≥LLN; Global Lung Function Initiative reference equations [n = 44]) or (2) below the

There is growing recognition that a sizable fraction of COPD patients with forced expiratory volume in one second (FEV1)/forced vital capacity ratio below the lower limit of normal but preserved FEV 1 reports out-of-proportion dyspnea relative to the severity of airflow limitation. Most physicians, however, assume that patients' breathlessness is unlikely to reflect the negative physiological consequences of COPD vis-à-vis FEV1 normalcy. This concise review integrates the findings of recent studies which uncovered the key pathophysiological features shared by these patients: poor pulmonary gas exchange efficiency (increased "wasted" ventilation) and gas trapping. These abnormalities are associated with two well-known causes of exertional dyspnea: heightened ventilation relative to metabolic demand and critically low inspiratory reserves, respectively. From a clinical standpoint, a low diffusion capacity associated with increased residual volume (RV) and/or RV/total lung capacity ratio might uncover these disturbances, identifying the subset of patients in whom exertional dyspnea is causally related to "mild" COPD. [ABSTRACT FROM AUTHOR]

Background: Physiologic and symptom responses at the ventilatory threshold (Tvent) during incremental cardiopulmonary exercise testing (CPET) can provide important prognostic information.Research Question: This study aimed to develop an updated normative reference set for physiologic and symptom responses at Tvent during cycle CPET (primary aim) and to evaluate previously recommended reference equations from a 1985 study for predicting Tvent responses (secondary aim).Study Design and Methods: Participants were adults 40 to 80 years of age who were free of clinically relevant disease from the Canadian Cohort Obstructive Lung Disease. Rate of oxygen consumption (V˙O2) at Tvent was identified by two independent raters; physiologic and symptom responses corresponding to V˙O2 at Tvent were identified by linear interpolation. Reference ranges (5th-95th percentiles) for responses at Tvent were calculated according to participant sex and age for 29 and eight variables, respectively. Prediction models were developed for nine variables (oxygen pulse, V˙O2, rate of CO2 production, minute ventilation, tidal volume, inspiratory capacity, end-inspiratory lung volume [in liters and as percentage of total lung capacity], and end-expiratory lung volume) using quantile regression, estimating the 5th (lower limit of normal), 50th (normal), and 95th (upper limit of normal) percentiles based on readily available participant characteristics. The two one-sided test of equivalence for paired samples evaluated the measured and 1985-predicted V˙O2 at Tvent for equivalence.Results: Reference ranges and equations were developed based on 96 participants (49% men) with a mean ± SD age of 63 ± 9 years. Mean V˙O2 at Tvent was 50% of measured V˙O2 peak; the normal range was 33% to 66%. The 1985 reference equations overpredicted V˙O2 at Tvent: mean difference in men, -0.17 L/min (95% CI, -0.25 to -0.09 L/min); mean difference in women, -0.19 L/min (95% CI, -0.27 to -0.12 L/min).Interpretation: A contemporary reference set of CPET responses at Tvent from Canadian adults 40 to 80 years of age is presented that differs from the previously recommended and often used reference set from 1985.Trial Registry: ClinicalTrials.gov; No.: NCT00920348; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: COPD is associated with nighttime respiratory symptoms, poor sleep quality, and increased risk of nocturnal death. Overnight deterioration of inspiratory capacity (IC) and FEV1 have been documented previously. However, the precise nature of this deterioration and mechanisms by which evening bronchodilation may mitigate this occurrence have not been studied.Research Question: What is the effect of evening dosing of dual, long-acting bronchodilation on detailed nocturnal respiratory mechanics and inspiratory neural drive (IND)?Study Design and Methods: A double-blind, randomized, placebo-controlled crossover study assessed the effects of evening long-acting bronchodilation (aclidinium bromide/formoterol fumarate dihydrate: 400/12 μg) or placebo on morning trough IC (12 h after the dose; primary outcome) and serial overnight measurements of spirometry, dynamic respiratory mechanics, and IND (secondary outcomes). Twenty participants with COPD (moderate/severe airway obstruction and lung hyperinflation) underwent serial measurements of IC, spirometry, breathing pattern, esophageal and transdiaphragmatic pressures, and diaphragm electromyography (diaphragmatic electromyography as a percentage of maximum; IND) at 6 time points from 0 to 12 h after the dose and compared with sleeping IND.Results: Compared with placebo, evening bronchodilation was not associated with increased morning trough IC 12 h after the dose (P = .48); however, nadir IC (lowest IC, independent of time), peak IC, area under the curve for 12 h after the dose, and IC for 10 h after the dose were improved (P < .05). During placebo, total airways resistance, lung hyperinflation, IND, and tidal esophageal and transdiaphragmatic pressure swings all increased significantly overnight compared with baseline evening values; however, each of these parameters improved with bronchodilator treatment (P < .05) with no change in ventilation or breathing pattern.Interpretation: Respiratory mechanics significantly deteriorated at night during placebo. Although the morning trough IC was unchanged, evening bronchodilator treatment was associated consistently with sustained overnight improvements in dynamic respiratory mechanics and inspiratory neural drive compared with placebo CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02429765. [ABSTRACT FROM AUTHOR]

Introduction: Respiratory-related morbidity and mortality were evaluated in relation to incident prescription oral synthetic cannabinoid (nabilone, dronabinol) use among older adults with chronic obstructive pulmonary disease (COPD).Methods: This was a retrospective, population-based, data-linkage cohort study, analysing health administrative data from Ontario, Canada, from 2006 to 2016. We identified individuals aged 66 years and older with COPD, using a highly specific, validated algorithm, excluding individuals with malignancy and those receiving palliative care (n=185 876 after exclusions). An equivalent number (2106 in each group) of new cannabinoid users (defined as individuals dispensed either nabilone or dronabinol, with no dispensing for either drug in the year previous) and controls (defined as new users of a non-cannabinoid drug) were matched on 36 relevant covariates, using propensity scoring methods. Cox proportional hazard regression was used.Results: Rate of hospitalisation for COPD or pneumonia was not significantly different between new cannabinoid users and controls (HR 0.87; 95% CI 0.61-1.24). However, significantly higher rates of all-cause mortality occurred among new cannabinoid users compared with controls (HR 1.64; 95% CI 1.14-2.39). Individuals receiving higher-dose cannabinoids relative to controls were observed to experience both increased rates of hospitalisation for COPD and pneumonia (HR 2.78; 95% CI 1.17-7.09) and all-cause mortality (HR 3.31; 95% CI 1.30-9.51).Conclusions: New cannabinoid use was associated with elevated rates of adverse outcomes among older adults with COPD. Although further research is needed to confirm these observations, our findings should be considered in decisions to use cannabinoids among older adults with COPD. [ABSTRACT FROM AUTHOR]

Background: Up-to-date normative reference sets for cardiopulmonary exercise testing (CPET) are important to aid in the accurate interpretation of CPET in clinical or research settings.Research Question: This study aimed to (1) develop and externally validate a contemporary reference set for peak CPET responses in Canadian adults identified with population-based sampling; and (2) evaluate previously recommended reference equations for predicting peak CPET responses.Study Design and Methods: Participants were healthy adults who were ≥40 years old from the Canadian Cohort Obstructive Lung Disease who completed an incremental cycle CPET. Prediction models for peak CPET responses were estimated from readily available participant characteristics (age, sex, height, body mass) with the use of quantile regression. External validation was performed with a second convenience sample of healthy adults. Peak CPET parameters that were measured and predicted in the validation cohort were assessed for equivalence (two one-sided tests of equivalence for paired-samples and level of agreement (Bland-Altman analyses). Two one-sided tests of equivalence for paired samples assessed differences between responses in the derivation cohort using previously recommended reference equations.Results: Normative reference ranges (5th-95th percentiles) for 28 peak CPET parameters and prediction models for 8 peak CPET parameters were based on 173 participants (47% male) who were 64 ± 10 years old. In the validation cohort (n = 84), peak CPET responses that were predicted with the newly generated models were equivalent to the measured values. Peak cardiac parameters predicted by the previously recommended reference equations by Jones and colleagues and Hansen and colleagues were significantly higher.Interpretation: This study provides reference ranges and prediction models for peak cardiac, ventilatory, operating lung volume, gas exchange, and symptom responses to incremental CPET and presents the most comprehensive reference set to date in Canadian adults who were ≥40 years old to be identified with population-based sampling. [ABSTRACT FROM AUTHOR]

The article describes how forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio discordance relates to functional outcomes relevant to subjects' daily functioning. Topics include the fixed FEV1/FVC ratio cutoff can result in over diagnosis of Chronic obstructive pulmonary disease (COPD) in older individuals; and a discordant FEV1/FVC ratio should be individually interpreted in light of clinical data.

Background and objective: Lack of consensus on diagnosis of ACO limits our understanding of the impact, management and outcomes of ACO. The present observational study aims to describe the prevalence, clinical characteristics and course of individuals with ACO based on various definitions used in clinical practice. Methods: We included individuals with COPD from the prospective, multisite CanCOLD study and defined subjects with ACO using seven definitions commonly used in the literature. Results: Data including questionnaires, lung function and CT scans were analysed from 522 individuals with COPD who were randomly recruited from the population. Among them, 264 fulfilled at least one of the seven definitions of ACO. Prevalence of ACO varied from 3.8% to 31%. Regardless of the definition, individuals with ACO had worse outcomes (lung function and higher percentage of fast decliners, symptoms and exacerbations, health‐related quality of life and comorbidities) than the remaining patients with COPD. Conversely, patients with non‐ACO had higher emphysema and bronchiolitis scores. The three definitions that included atopy and/or physician diagnosis of asthma identified subjects who differed significantly from patients with COPD. The two ACO definitions with post‐bronchodilator reversibility were concordant with COPD and were the least stable, with less than 50% of the patients from each group maintaining reversibility over visits. Conclusion: Atopy and physician‐diagnosed asthma are more distinguishing characteristics to identify ACO. This finding needs to be validated using measures of airway inflammation and other specific biomarkers. [ABSTRACT FROM AUTHOR]

Rationale: Although opioids are frequently prescribed in chronic obstructive pulmonary disease (COPD), there is poor understanding regarding which individuals will experience pulmonary harm upon exposure.Objectives: We sought to identify patient characteristics and opioid drug properties predictive of opioid-related adverse pulmonary events among older adults with chronic COPD.Methods: A retrospective, population-based, cohort study design was used, analyzing Ontario heath administrative data. Individuals aged 66 years and older, with validated, physician-diagnosed COPD receiving a new opioid drug were included. Adverse pulmonary events (defined as an emergency room visit, hospitalization, or death related to either COPD or pneumonia) occurring within 30 days following new opioid receipt were considered. Multivariable-adjusted, cause-specific hazard modeling was used to identify predictors of adverse pulmonary events.Results: Out of 169,517 older adults with COPD receiving a new opioid, 4,861 (2.9%) experienced an adverse pulmonary event within 30 days. Factors independently predisposing to adverse pulmonary events included older age (≥85 yr old: hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.26-1.49), long-term-care home residence (HR, 1.32; 95% CI, 1.21-1.44), severe COPD exacerbation within the preceding year (HR, 2.96; 95% CI, 2.77-3.17), comorbidities (including non-COPD lung disease [HR, 1.16; 95% CI, 1.09-1.23], congestive heart failure [HR, 1.22; 95% CI, 1.14-1.30], sleep disorder [HR, 1.22; 95% CI, 1.15-1.30], and dementia [HR, 1.14; 95% CI, 1.05-1.24]); other psychoactive medication receipt, including benzodiazepines (HR, 1.27; 95% CI, 1.19-1.35) and serotonergic antidepressants (HR, 1.10; 95% CI, 1.03-1.19), and receipt of an opioid-only agent (HR, 1.35; 95% CI, 1.26-1.46). Factors that independently protected from adverse pulmonary events included female sex (HR, 0.78; 95% CI, 0.73-0.82), surgery within the preceding year (HR, 0.70; 95% CI, 0.64-0.77), and musculoskeletal disease (HR, 0.75; 95% CI, 0.70-0.80). No significant associations were observed between adverse pulmonary events and opioid half-life duration or opioid daily dosage.Conclusions: Patient and opioid drug factors predictive of opioid-related adverse pulmonary events among older adults with COPD were identified, which may assist with safer opioid prescribing. [ABSTRACT FROM AUTHOR]

Background: Exertional dyspnea is a cardinal feature of chronic obstructive pulmonary disease (COPD) and a major cause of activity limitation. Although dual bronchodilation is more effective than bronchodilator monotherapy at improving resting pulmonary function, it is unclear to which extent this translates into superior relief of exertional dyspnea. Methods: We conducted a randomized controlled, double-blind, cross-over trial comparing indacaterol 110 µg/glycopyrronium 50 µg once daily (OD) with tiotropium 50 µg OD in patients with moderate to severe COPD and resting hyperinflation (functional residual capacity >120% of predicted value). The primary outcome was Borg dyspnea score at the end of a 3-min constant speed shuttle test after 3 weeks of treatment. Secondary outcomes included changes in Borg dyspnea score after the first dose of study medication, expiratory flows and lung volumes. Statistical analysis was conducted using a cross-over analysis of variance model with repeated measurements. Results: A total of 50 patients with COPD and a mean forced expiratory volume in 1 s of 54 ± 11% (mean ± SEM) predicted participated in the cross-over phase of the trial. Compared with baseline, there was a decrease in dyspnea after the first dose of medication with indacaterol/glycopyrronium [mean −1.00, 95% confidence interval (CI) −1.49 to −0.52] but not with tiotropium alone (mean −0.36, 95% CI −0.81 to 0.08). The reduction in dyspnea after the first dose was statistically significant between the two treatments (mean difference of −0.64, 95% CI −1.11 to −0.17). Despite indacaterol/glycopyrronium providing further bronchodilation and lung deflation throughout the trial, the reduction in dyspnea was not sustained at 3 weeks of treatment (mean between-treatment difference at 3 weeks of 0.09, 95% CI −0.44 to 0.61). Conclusion: In comparison with bronchodilator monotherapy, indacaterol/glycopyrronium provided greater immediate exertional dyspnea relief, although this difference was not sustained after 3 weeks of therapy despite evidence of further bronchodilation and lung deflation. The reviews of this paper are available via the supplemental material section. [ABSTRACT FROM AUTHOR]

Background: Exercise tolerance is an important endpoint in chronic obstructive pulmonary disease (COPD) clinical trials. Little is known about the comparative measurement properties of constant work rate cycle ergometry (CWRCE) and the endurance shuttle walking test (ESWT). The objective of this sub-analysis of the TORRACTO® study was to directly compare the endurance measurement properties of CWRCE and ESWT in patients with COPD in a multicentre, multinational setting. We predicted that both tests would be similarly reliable, but that the ESWT would be more responsive to bronchodilation than CWRCE. Methods: This analysis included 151 patients who performed CWRCE and ESWT at baseline and week 6 after receiving once-daily placebo, tiotropium/olodaterol (T/O) 2.5/5 μg or T/O 5/5 μg. Reproducibility was assessed by comparing their respective performance at baseline and week 6 in the placebo group. Responsiveness to bronchodilation was assessed by comparing endurance time at week 6 with T/O with baseline values and placebo. The locus of symptom limitation and end-exercise Borg scales for breathing and leg discomfort for both tests were also analysed. Results: The intraclass correlation coefficients for CWRCE and ESWT were 0.56 [95% confidence interval (CI) 0.37–0.71] and 0.75 (95% CI 0.63–0.84). More patients were limited by breathing discomfort during the ESWT than during CWRCE, whereas more patients were limited by leg discomfort or breathing/leg discomfort during CWRCE than the ESWT (p <0.0001). Both tests were responsive to bronchodilator treatment: there was a 19% increase in endurance time from baseline at week 6 (p = 0.0006) assessed with CWRCE, and a 20% increase in endurance time assessed with ESWT (p = 0.0013). Conclusions: Both exercise tests performed well in a multicentre clinical trial. Although the locus of symptom limitation differed between the two tests, both were reliable and responsive to bronchodilation. For future clinical trials, the choice of test should depend on the study requirements. ClinicalTrials.gov identifier: NCT01525615. The reviews of this paper are available via the supplemental material section. [ABSTRACT FROM AUTHOR]

BACKGROUND: Severe exertional dyspnea is a commonly reported symptom in patients with COPD, especially in the advanced stages. Our objective was to assess the preliminary impact of comprehensive, individualized management provided by a specialized tertiary center clinic on exertional dyspnea and patient-centered outcomes in patients with advanced COPD. METHODS: This retrospective analysis included 45 subjects with COPD who were evaluated in a newly established dyspnea clinic over 3 years. Those with severe exertional dyspnea (Medical Research Council dyspnea score of >4/5), despite optimal disease-targeted therapy were eligible for referral. We used the revised Edmonton Symptom Assessment System (ESAS-r) to assess symptoms. Responders were defined as those whose change from baseline to 2-months met the minimum clinically important difference of <=1 in ESAS-r score for shortness of breath. RESULTS: Subjects (mean = SD age 70 = 7 years) had an average FEV1 of 36 = 18% predicted and a Medical Research Council dyspnea score of 4.7 = 0.4. Responses to the intervention were variable and mean change in the ESAS-r score for shortness of breath in the total group was =0.32 = 3.39, P = .53. Forty-seven percent of the subjects were identified as responders, and 42, 40, 40, and 33% met the minimum clinically important difference for improvement in ESAS-r scores for tiredness, anxiety, well-being, and depression, respectively. Responders had fewer emergency department annual visits in the 2 years after their first clinic visit compared with nonresponders (mean = SD, 1.38 = 1.63 vs 4.45 = 5.52, P = .034). CONCLUSIONS: Although the impact of our specialized advanced dyspnea clinic was variable, as evaluated by the ESAS-r, it provided measurable additional clinically important benefit to almost half of the subjects with advanced COPD and severe refractory dyspnea. [ABSTRACT FROM AUTHOR]

Introduction: Heart failure (HF) with reduced ejection fraction and chronic obstructive pulmonary disease (COPD) frequently coexist, particularly in the elderly. Given their rising prevalence and the contemporary trend to longer life expectancy, overlapping HF-COPD will become a major cause of morbidity and mortality in the next decade. Areas covered: Drawing on current clinical and physiological constructs, the consequences of negative cardiopulmonary interactions on the interpretation of pulmonary function and cardiopulmonary exercise tests in HF-COPD are discussed. Although those interactions may create challenges for the diagnosis and assessment of disease stability, they provide a valuable conceptual framework to rationalize HF-COPD treatment. The impact of COPD or HF on the pharmacological treatment of HF or COPD, respectively, is then comprehensively discussed. Authors finalize by outlining how the non-pharmacological treatment (i.e. rehabilitation and exercise reconditioning) can be tailored to the specific needs of patients with HF-COPD. Expert commentary: Randomized clinical trials testing the efficacy and safety of new medications for HF or COPD should include a sizeable fraction of patients with these coexistent pathologies. Multidisciplinary clinics involving cardiologists and respirologists trained in both diseases (with access to unified cardiorespiratory rehabilitation programs) are paramount to decrease the humanitarian and social burden of HF-COPD. [ABSTRACT FROM AUTHOR]

Background: Synthetic oral cannabinoids (nabilone and dronabinol) may have adverse respiratory effects. Our purpose was to describe the scope, pattern, and patient characteristics associated with incident off-label synthetic oral cannabinoid use among older adults with chronic obstructive pulmonary disease (COPD) compared to older adults without COPD. Methods: This was a retrospective, population-based, cohort study using Ontario, Canada, heath administrative data. Individuals aged 66 years or older were included, and physician-diagnosed COPD was identified using a previously validated, highly specific algorithm. Incident off-label oral cannabinoid use was examined between April 1, 2005 and March 31, 2015. Descriptive statistics were used to describe drug use patterns. Multiple logistic regression was used to identify patient characteristics associated with incident drug use. Results: There were 172,282 older adults with COPD and 1,068,256 older adults without COPD identified between April 1, 2005 and March 31, 2015. Incident synthetic oral cannabinoid use during this period occurred with significantly greater (p < 0.001) frequency among older adults with COPD (0.6%) versus older adults without COPD (0.3%). Compared to those without COPD, older adults with COPD used synthetic cannabinoids for significantly longer durations and more frequently at higher doses. Conclusions: Although incident off-label oral cannabinoid use was relatively low among all older Ontarian adults, this drug class was used with greater frequency and more often in potentially concerning ways among older adults with COPD. These findings raise possible safety concerns, but further research on the respiratory safety of oral cannabinoids among individuals with COPD is needed. [ABSTRACT FROM AUTHOR]

Background: COPD increases susceptibility to sleep disturbances, which may in turn predispose to increased respiratory symptoms. The objective of this study was to evaluate, in a population-based sample, the relationship between subjective sleep quality and risk of COPD exacerbations.Methods: Data were obtained from the Canadian Cohort Obstructive Lung Disease (CanCOLD) study. Participants with COPD who had completed 18 months of follow-up were included. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI) and a three-factor analysis. Symptom-based (dyspnea or sputum change ≥ 48 h) and event-based (symptoms plus medication or unscheduled health services use) exacerbations were assessed. Association of PSQI with exacerbation rate was assessed by using negative binomial regression. Exacerbation-free survival was also assessed.Results: A total of 480 participants with COPD were studied, including 185 with one or more exacerbations during follow-up and 203 with poor baseline sleep quality (PSQI score > 5). Participants with subsequent symptom-based exacerbations had higher median baseline PSQI scores than those without (6.0 [interquartile range, 3.0-8.0] vs 5.0 [interquartile range, 2.0-7.0]; P = .01), and they were more likely to have baseline PSQI scores > 5 (50.3% vs 37.3%; P = .01). Higher PSQI scores were associated with increased symptom-based exacerbation risk (adjusted rate ratio, 1.09; 95% CI, 1.01-1.18; P = .02) and event-based exacerbation risk (adjusted rate ratio, 1.10; 95% CI, 1.00-1.21; P = .048). The association occurred mainly in those with undiagnosed COPD. Strongest associations were with Factor 3 (sleep disturbances and daytime dysfunction). Time to symptom-based exacerbation was shorter in participants with poor sleep quality (adjusted hazard ratio, 1.49; 95% CI, 1.09-2.03).Conclusions: Higher baseline PSQI scores were associated with increased risk of COPD exacerbation over 18 months' prospective follow-up. [ABSTRACT FROM AUTHOR]

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 (VO2), 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., CO was associated with peak VO2 (P = 0.006), peak work-rate (P = 0.005), and dyspnea/VO2 slope (P < 0.001) after adjustment for other independent variables (airway obstruction and hyperinflation). Within FEV1 and IC tertiles, peak VO2 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, DLCOCO. 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. [ABSTRACT FROM AUTHOR]

Background: FVC may underestimate the slow vital capacity (SVC) due to early closure of the small airways at low lung volumes in the forced maneuver. It remains unclear whether using SVC instead of FVC in the FEV1/vital capacity (VC) ratio increases the yield of spirometry in detecting airflow limitation or, alternatively, leads to a false-positive finding for obstruction.Methods: This study included 13,893 adult outpatients with FEV1/FVC and total lung capacity at or above the lower limit of normal. A cluster of clinical and physiological variables defined the probability of airway disease and dysfunction, respectively.Results: The prevalence of "discordance" (preserved FEV1/FVC but low FEV1/SVC) was 20.4%: discordant subjects had lower mid-expiratory flows, higher airway resistance, worse gas trapping, and ventilation distribution abnormalities than "concordant" subjects (both ratios preserved) (P < .05). Regardless of sex, age < 60 years, BMI > 30 kg/m2, and FEV1 > 70% predicted were associated with discordance (P < .001). Discordant subjects with preserved FEV1/FVC but low FEV1/SVC were four times more likely to be diagnosed with an obstructive airway disease by a respirologist compared with those with preserved FEV1/SVC and FEV1/FVC. The only exception was in the elderly subgroup with discordance (age > 70 years): only 10% of these subjects were subsequently diagnosed with an airway disease (P > .05).Conclusions: Using SVC instead of FVC in the FEV1/VC ratio enhances the yield of spirometry in detecting mild airflow obstruction in younger and obese subjects. The FEV1/SVC ratio, however, should be used with caution in elderly subjects with preserved FEV1/FVC because a low value may represent a false-positive finding for airflow limitation. [ABSTRACT FROM AUTHOR]

Smoking and physical inactivity are important preventable causes of disability and early death worldwide. Reduced exercise tolerance has been described in smokers, even in those who do not fulfill the extant physiological criteria for chronic obstructive pulmonary disease (COPD) and are not particularly sedentary. In this context, it is widely accepted that exercise capacity depends on complex cardio-pulmonary interactions which support oxygen (O2) delivery to muscle mitochondria. Although peripheral muscular factors, O2 transport disturbances (including the effects of increased carboxyhemoglobin) and autonomic nervous system unbalance have been emphasized, other derangements have been more recently described, including early microscopic emphysema, pulmonary microvascular disease, ventilatory and gas exchange inefficiency, and left ventricular diastolic dysfunction. Using an integrative physiological approach, the present review summarizes the recent advances in knowledge on the effects of smoking on the lung-heart-muscle axis under the stress of exercise. Special attention is given to the mechanisms connecting physiological abnormalities such as early cardio-pulmonary derangements, inadequate oxygen delivery and utilization, and generalized bioenergetic disturbances at the muscular level with the negative sensations (sense of heightened muscle effort and breathlessness) that may decrease the tolerance of smokers to physical exercise. A deeper understanding of the systemic effects of smoking in subjects who did not (yet) show evidences of COPD and ischemic heart disease – two devastating smoking related diseases – might prove instrumental to fight their ever-growing burden. [ABSTRACT FROM AUTHOR]

Supervised exercise training (EXT) as part of pulmonary rehabilitation is arguably the most effective intervention for improving exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). In the current review, we focus on the physiological rationale for EXT and the expected physiological benefits that can be achieved in patients who can be exposed to sufficiently high training stimuli. Thus, after a brief consideration of the mechanisms of exercise limitation and their sensory consequences, we expose the potential beneficial effects of EXT on respiratory mechanical and peripheral muscular adaptations to exercise. The available evidence indicates that changes in exertional ventilation, breathing pattern, operating lung volumes and static respiratory muscle strength after EXT are modest and often inconsistent. Inspiratory muscle training may have a role in patients showing inspiratory weakness pre-rehabilitation. Beneficial changes in peripheral muscles can be seen in those who can tolerate higher training intensity, particularly using combined resistance and dynamic (including interval) exercise. It should be recognised, however, that it might not be feasible to reach meaningful physiological training effects in many frail elderly patients with advanced respiratory mechanical and pulmonary gas exchange derangements with serious co-morbidities (such as cardiac and peripheral vascular disease). These potential shortcomings should not discourage the use of pulmonary rehabilitation as an effective strategy to improve patients' capacity to tolerate physical activity. Currently, the greatest challenge is to develop effective strategies to ensure that these important gains in functional capacity are translated into sustained increases in daily physical activity for patients with COPD. [ABSTRACT FROM AUTHOR]

Background: The COPD Assessment Test (CAT) is a valid disease-specific questionnaire measuring health status. However, knowledge concerning its use regarding patient and disease characteristics remains limited. Our main objective was to assess the degree to which the CAT score varies and can discriminate between specific patient population groups.Methods: The Canadian Cohort Obstructive Lung Disease (CanCOLD) is a random-sampled, population-based, multicenter, prospective cohort that includes subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] classifications 1 to 3). The CAT questionnaire was administered at three visits (baseline, 1.5 years, and 3 years). The CAT total score was determined for sex, age groups, smoking status, GOLD classification, exacerbations, and comorbidities.Results: A total of 716 subjects with COPD were included in the analysis. The majority of subjects (72.5%) were not previously diagnosed with COPD. The mean FEV1/FVC ratio was 61.1 ± 8.1%, with a mean FEV1 % predicted of 82.3 ± 19.3%. The mean CAT scores were 5.8 ± 5.0, 9.6 ± 6.7, and 16.1 ± 10.0 for GOLD 1, 2, and 3+ classifications, respectively. Higher CAT scores were observed in women, current smokers, ever-smokers, and subjects with a previous diagnosis of COPD. The CAT was also able to distinguish between subjects who experience exacerbations vs those who had no exacerbation.Conclusions: These results suggest that the CAT, originally designed for use in clinically symptomatic patients with COPD, can also be used in individuals with mild airflow obstruction and newly diagnosed COPD. In addition, the CAT was able to discriminate between sexes and subjects who experience frequent and infrequent exacerbations.Trial Registry: ClinicalTrials.gov; No.: NCT00920348; Study ID No.: IRO-93326. [ABSTRACT FROM AUTHOR]

Dyspnoea (perceived breathing discomfort) is the most common symptom experienced by patients with chronic obstructive pulmonary disease (COPD) and is associated with progressive physical inactivity and poor quality of life. Exertional dyspnoea ratings in COPD have been shown to consistently correlate with a number of physiological ratios that ultimately point to demand/capacity imbalance of the dynamic respiratory system.[1] These include ventilatory output, tidal oesophageal pressure and tidal diaphragmatic electromyography (EMG) (all expressed relative to respective maxima). Studies using bronchodilators or inspiratory muscle training (IMT) to relive dyspnoea have confirmed the importance of high IND in dyspnoea causation in COPD. [Extracted from the article]

Among patients with chronic obstructive pulmonary disease (COPD), those with the lowest maximal inspiratory pressures experience greater breathing discomfort (dyspnea) during exercise. In such individuals, inspiratory muscle training (IMT) may be associated with improvement of dyspnea, but the mechanisms for this are poorly understood. Therefore, we aimed to identify physiological mechanisms of improvement in dyspnea and exercise endurance following inspiratory muscle training (IMT) in patients with COPD and low maximal inspiratory pressure (Pimax). The effects of 8 wk of controlled IMT on respiratory muscle function, dyspnea, respiratory mechanics, and diaphragm electromyography (EMGdi) during constant work rate cycle exercise were evaluated in patients with activity-related dyspnea (baseline dyspnea index <9). Subjects were randomized to either IMT or a sham training control group (n = 10 each). Twenty subjects (FEV1 = 47 ± 19% predicted; Pimax  = −59 ± 14 cmH2O; cycle ergometer peak work rate = 47 ± 21% predicted) completed the study; groups had comparable baseline lung function, respiratory muscle strength, activity-related dyspnea, and exercise capacity. IMT, compared with control, was associated with greater increases in inspiratory muscle strength and endurance, with attendant improvements in exertional dyspnea and exercise endurance time (all P < 0.05). After IMT, EMGdi expressed relative to its maximum (EMGdi/EMGdimax) decreased (P < 0.05) with no significant change in ventilation, tidal inspiratory pressures, breathing pattern, or operating lung volumes during exercise. In conclusion, IMT improved inspiratory muscle strength and endurance in mechanically compromised patients with COPD and low Pimax. The attendant reduction in EMGdi/EMGdimax helped explain the decrease in perceived respiratory discomfort despite sustained high ventilation and intrinsic mechanical loading over a longer exercise duration. NEW & NOTEWORTHY In patients with COPD and low maximal inspiratory pressures, inspiratory muscle training (IMT) may be associated with improvement of dyspnea, but the mechanisms for this are poorly understood. This study showed that 8 wk of home-based, partially supervised IMT improved respiratory muscle strength and endurance, dyspnea, and exercise endurance. Dyspnea relief occurred in conjunction with a reduced activation of the diaphragm relative to maximum in the absence of significant changes in ventilation, breathing pattern, and operating lung volumes. [ABSTRACT FROM AUTHOR]

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 (Tlim3′-8′). There is, however, no simple method to select a work rate which is consistently associated with Tlim3′-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 (CWR50%⇐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 Tlim3′-8′ in 23/26 (88%) “high-endurance” patients; conversely, decreasing exercise intensity to 50% slowed those responses leading to Tlim3′-8′ in 5/6 (83%) “high-endurance” patients. Repeating the tests at higher (60%) or lower (80%) intensities fail to consistently produce Tlim3′-8′ in “low-” and “high-endurance”, respectively (p > 0.05). Compared to a fixed work rate at 75%, CWR50%⇐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 (CWR50%⇐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. [ABSTRACT FROM AUTHOR]

Background: We carried out a systematic review and meta-analysis with the aim to evaluate the efficacy of longacting bronchodilators on exercise capacity in COPD patients. Methods: The endpoints were the efficacy of long-acting bronchodilators (altogether, and by single classes) vs. placebo in modifying endurance time (ET), inspiratory capacity (IC) and dyspnea during exercise, taking into consideration the outcomes according to different patients’ inclusion criteria and exercise methodology. Results: Twenty-two studies were deemed eligible for analysis. Weighted mean increase in ET resulted of 67 s (95% CI ranges from 55 to 79). For isotime IC and dyspnea during exercise, weighted improvements were 195 ml (162–229), and − 0.41 units (− 0.56 to − 0.27), respectively. The increase in trough IC was 157 ml (138–175). We found a trend in favour of LAMA compared to LABA in terms of ET. In the 11 studies which reported a value of functional residual capacity > 120% as inclusion criterion, weighted mean increase in endurance time was 94 s (65 to 123); however we did not find any significant correlation between ET and mean trough IC (P: 0.593). The improvement of ET in the 5 studies using walking as exercise methodology resulted of 58 s (− 4 to 121). Conclusions: Long-acting bronchodilators improve exercise capacity in COPD. The main effect of long-acting bronchodilators seems to be a increase of basal IC rather than a modification of dynamic hyperinflation during exercise. The efficacy in terms of endurance time seems higher in studies which enrolled patients with hyperinflation, with a similar efficacy on walking or cycling. [ABSTRACT FROM AUTHOR]

This randomized, double-blind, crossover study examined the physiological rationale for using a dual long-acting bronchodilator (umeclidinium/vilanterol (UME/VIL)) versus its muscarinic-antagonist component (UME) as treatment for dyspnea and exercise intolerance in moderate COPD. After each 4-week treatment period, subjects performed pulmonary function and symptom-limited constant-work rate cycling tests with diaphragm electromyogram (EMGdi), esophageal (Pes), gastric (Pga) and transdiaphragmatic (Pdi) pressure measurements. Fourteen subjects completed the study. Both treatments improved spirometry and airway resistance. UME/VIL had larger increases in FEV 1 (+0.14 ± 0.23 L, p < 0.05) but no added reduction in lung hyperinflation compared with UME. Isotime during exercise after UME/VIL versus UME (p < 0.05): “unpleasantness of breathing” fell 0.8 ± 1.3 Borg units; mean expiratory flow and ventilation increased; Pdi and Pga decreased. There were no treatment differences in endurance time, breathing pattern, operating lung volumes, inspiratory neural drive (EMGdi) or respiratory muscle effort (Pes swings) during exercise. UME/VIL compared with UME was associated with reduced breathing unpleasantness reflecting improved airway and respiratory muscle function during exercise. [ABSTRACT FROM AUTHOR]

Low inspiratory capacity (IC), chronic dyspnea, and reduced exercise capacity are inextricably linked and are independent predictors of increased mortality in chronic obstructive pulmonary disease. It is no surprise, therefore, that a major goal of management is to improve IC by reducing lung hyperinflation to improve respiratory symptoms and health-related quality of life. The negative effects of lung hyperinflation on respiratory muscle and cardiocirculatory function during exercise are now well established. Moreover, there is growing appreciation that a key mechanism of exertional dyspnea in chronic obstructive pulmonary disease is critical mechanical constraints on tidal volume expansion during exercise when resting IC is reduced. Further evidence for the importance of lung hyperinflation comes from multiple studies, which have reported the clinical benefits of therapeutic interventions that reduce lung hyperinflation and increase IC. A reduced IC in obstructive pulmonary disease is further eroded by exercise and contributes to ventilatory limitation and dyspnea. It is an important outcome for both clinical and research studies. [ABSTRACT FROM AUTHOR]

There is growing evidence that emphysema on thoracic computed tomography (CT) is associated with poor exercise tolerance in COPD patients with only mild-to-moderate airflow obstruction. We hypothesized that an excessive ventilatory response to exercise (ventilatory inefficiency) would underlie these abnormalities. In a prospective study, 19 patients (FEV1 = 82 ± 13%, 12 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1) and 26 controls underwent an incremental exercise test. Ventilatory inefficiency was assessed by the ventilation (E)/CO2 output (CO2) nadir. Pulmonary blood flow (PBF) in a submaximal test was calculated by inert gas rebreathing. Emphysema was quantified as % of attenuation areas below 950 HU. Patients typically presented with centrilobular emphysema (76.8 ± 10.1% of total emphysema) in the upper lobes (upper/total lung ratio = 0.82 ± 0.04). They had lower peak oxygen uptake (O2), higher E/ CO2 nadir, and greater dyspnea scores than controls (p < 0.05). Lower peak O2 and worse dyspnea were found in patients with higher E/ CO2 nadirs (≥30). Patients had blunted increases in PBF from rest to iso- O2 exercise (p < 0.05). Higher E/ CO2 nadir in COPD was associated with emphysema severity (r = 0.63) which, in turn, was related to reduced lung diffusing capacity (r = −0.72) and blunted changes in PBF from rest to exercise (r = −0.69) (p < 0.01). Ventilation "wasted" in emphysematous areas is associated with impaired exercise ventilatory efficiency in mild-to-moderate COPD. Exercise ventilatory inefficiency links structure (emphysema) and function (DLCO) to a key clinical outcome (poor exercise tolerance) in COPD patients with only modest spirometric abnormalities. [ABSTRACT FROM AUTHOR]

Background: Some patients with COPD report frequent acute exacerbations (AECOPD) of the disease (FE), whereas others suffer them infrequently (IE). Because the current diagnosis of exacerbation relies on patient's perception of increased symptoms (mostly dyspnoea), we hypothesised that dyspnoea perception might be different in COPD patients with FE (≥2 exacerbations or 1 hospitalisation due to AECOPD in the previous year) or IE (≤1 exacerbation in the previous year), AECOPD being defined by the institution antibiotics and/or steroids treatment, or hospital admission.Objective: To test the hypothesis that dyspnoea perception is increased in FE and/or decreased in IE with COPD.Methods: We compared the perception of dyspnoea (Borg scale), mouth occlusion pressure 0.1 s after the onset of inspiration (P0.1) and ventilatory response to hypercapnia (ΔVE/ΔPETCO2) in 34 clinically stable COPD patients with FE (n=14) or IE (n=20), with similar age, gender, body mass index and degree of airflow limitation. As a reference, we studied a group of age-matched healthy volunteers (n=10) with normal spirometry.Results: At rest, P0.1 was higher in FE than IE and controls (p<0.01). Compared with controls, the ventilatory response to hypercapnia was equally blunted both in FE and IE (p<0.001). Despite similar spirometry, during rebreathing peak Borg score and ΔBorg were higher (p<0.01) in FE and lower (p<0.01) in IE, than in controls.Conclusions: Dyspnoea perception during CO2 rebreathing is enhanced in FE and blunted in IE. These differences may contribute to the differential rate of reported exacerbations in FE and IE.Trial Registration Number: NCT02113839. [ABSTRACT FROM AUTHOR]

Background: Thoracic computed tomography (CT) scans are widely performed in clinical practice, often leading to detection of airway or parenchymal abnormalities in asymptomatic or minimally symptomatic individuals. However, clinical relevance of CT abnormalities is uncertain in the general population. Methods: We evaluated data from 1361 participants aged ≥40 years from a Canadian prospective cohort comprising 408 healthy never-smokers, 502 healthy ever-smokers, and 451 individuals with spirometric evidence of chronic obstructive pulmonary disease (COPD) who had thoracic CT scans. CT images of subjects were visually scored for respiratory bronchiolitis(RB), emphysema(E), bronchial-wall thickening(BWT), expiratory air-trapping(AT), and bronchiectasis(B). Multivariable logistic regression models were used to assess associations of CT features with respiratory symptoms, dyspnea, health status as determined by COPD assessment test, and risk of clinically significant exacerbations during 12 months follow-up. Results: About 11% of life-time never-smokers demonstrated emphysema on CT scans. Prevalence increased to 30% among smokers with normal lung function and 36%, 50%, and 57% among individuals with mild, moderate or severe/very severe COPD, respectively. Presence of emphysema on CT was associated with chronic cough (OR,2.11; 95%CI,1.4–3.18); chronic phlegm production (OR,1.87; 95% CI,1.27–2.76); wheeze (OR,1.61; 95% CI,1.05–2.48); dyspnoea (OR,2.90; 95% CI,1.41–5.98); CAT score≥10(OR,2.17; 95%CI,1.42–3.30) and risk of ≥2 exacerbations over 12 months (OR,2.17; 95% CI, 1.42–3.0). Conclusions: Burden of thoracic CT abnormalities is high among Canadians ≥40 years of age, including never-smokers and smokers with normal lung function. Detection of emphysema on CT scans is associated with pulmonary symptoms and increased risk of exacerbations, independent of smoking or lung function. [ABSTRACT FROM AUTHOR]

Heart failure, a prevalent and disabling co-morbidity of COPD, may impair cardiac output and muscle blood flow thereby contributing to exercise intolerance. To investigate the role of impaired central and peripheral hemodynamics in limiting exercise tolerance in COPD-heart failure overlap, cycle ergometer exercise tests at 20% and 80% peak work rate were performed by overlap (FEV1 = 56.9 ± 15.9% predicted, ejection fraction = 32.5 ± 6.9%; N = 16), FEV1-matched COPD (N = 16), ejection fraction-matched heart failure patients (N = 15) and controls (N = 12). Differences (Δ) in cardiac output (impedance cardiography) and vastus lateralis blood flow (indocyanine green) and deoxygenation (near-infrared spectroscopy) between work rates were expressed relative to concurrent changes in muscle metabolic demands (ΔO2 uptake). Overlap patients had approximately 30% lower endurance exercise tolerance than COPD and heart failure (p < 0.05). ΔBlood flow was closely proportional to Δcardiac output in all groups (r = 0.89–0.98; p < 0.01). Overlap showed the largest impairments in Δcardiac output/ΔO2 uptake and Δblood flow/ΔO2 uptake (p < 0.05). Systemic arterial oxygenation, however, was preserved in overlap compared to COPD. Blunted limb perfusion was related to greater muscle deoxygenation and lactate concentration in overlap (r = 0.78 and r = 0.73, respectively; p < 0.05). ΔBlood flow/ΔO2 uptake was related to time to exercise intolerance only in overlap and heart failure (p < 0.01). In conclusion, COPD and heart failure add to decrease exercising cardiac output and skeletal muscle perfusion to a greater extent than that expected by heart failure alone. Treatment strategies that increase muscle O2 delivery and/or decrease O2 demand may be particularly helpful to improve exercise tolerance in COPD patients presenting heart failure as co-morbidity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease ( COPD) is a common and often progressive inflammatory disease of the airways, alveoli and microvasculature that is both preventable and treatable. It is well established that smokers with mild airway obstruction, as spirometrically defined, represent the vast majority of patients with COPD, yet this population has not been extensively studied. An insidious preclinical course means that mild COPD is both underdiagnosed and undertreated. In this context, recent studies have confirmed that even patients with mild COPD can have extensive physiological impairment, which contributes to poor perceived health status compared with non-smoking healthy controls. This review describes the heterogeneous pathophysiology that can exist in COPD patients with only mild airway obstruction on spirometry. It exposes the compensatory adaptations that develop in such patients to ensure that the respiratory system fulfils its primary task of maintaining adequate pulmonary gas exchange for the prevailing metabolic demand. It demonstrates that adaptations such as increased inspiratory neural drive to the diaphragm due to combined effects of increased mechanical loading and chemostimulation underscore the increased dyspnoea and exercise intolerance in this population. Finally, based on available evidence, we present what we believe is a sound physiological rationale for earlier diagnosis in this population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

The article discusses a study which aims to differentiate the physiologic measurements of patients with chronic bronchitis (CB) who fit the grade 1B criteria of the Global Initiative for Chronic Obstructive Lung Disease (GLOBE), and non-CB at rest and exercise. Topics discussed include the use of modified Medical Research Council dyspnea scale or COPD Assessment Test (CAT) score, and cardiopulmonary exercise test, and pulmonary and small-airway functions in both groups.

Central cardiorespiratory and gas exchange limitations imposed by chronic obstructive pulmonary disease (COPD) impair ambulatory skeletal muscle oxygenation during whole body exercise. This investigation tested the hypothesis that peripheral factors per se contribute to impaired contracting lower limb muscle oxygenation in COPD patients. Submaximal neuromuscular electrical stimulation (NMES; 30, 40, and 50 mA at 50 Hz) of the quadriceps femoris was employed to evaluate contracting skeletal muscle oxygenation while minimizing the influence of COPD-related central cardiorespiratory constraints. Fractional O2 extraction was estimated by near-infrared spectroscopy (deoxyhemoglobin/myoglobin concentration; deoxy-[Hb/Mb]), and torque output was measured by isokinetic dynamometry in 15 nonhypoxemic patients with moderate-to-severe COPD (SpO2 = 94 ± 2%; FEV1 ± 46.4 ± 10.1%; GOLD II and III) and in 10 age- and gender-matched sedentary controls. COPD patients had lower leg muscle mass than controls (LMM = 8.0 ± 0.7 kg vs. 8.9 ± 1.0 kg, respectively; P < 0.05) and produced relatively lower absolute and LMM-normalized torque across the range of NMES intensities (P < 0.05 for all). Despite producing less torque, COPD patients had similar deoxy-[Hb/Mb] amplitudes at 30 and 40 mA (P > 0.05 for both) and higher deoxy-[Hb/Mb] amplitude at 50 mA (P < 0.05). Further analysis indicated that COPD patients required greater fractional O2 extraction to produce torque (i.e., ↑ Δdeoxy-[Hb/Mb]/torque) relative to controls (P < 0.05 for 40 and 50 mA) and as a function of NMES intensity (P < 0.05 for all). The present data obtained during submaximal NMES of small muscle mass indicate that peripheral abnormalities contribute mechanistically to impaired contracting skeletal muscle oxygenation in nonhypoxemic, moderate-to-severe COPD patients. [ABSTRACT FROM AUTHOR]

The article highlights developments in understanding and management of dyspnea, which mostly came from findings disclosed by studies on patients with chronic obstructive pulmonary disease (COPD). Topics discussed include the influence of obesity with increased prevalence of dyspnea, the effectiveness of using optimal exercise modality to evaluate intensity of dyspnea and new medications and rehabilitation strategies addressing the symptom.

Chronic obstructive pulmonary disease (COPD) is a common and often progressive inflammatory disease of the airways that is both preventable and treatable. It is well established that those with mild-to-moderate disease severity represent the majority of patients with COPD, yet this subpopulation is relatively under-studied. Because of an insidious pre-clinical phase, COPD is both under-diagnosed and under-treated. Recent studies have confirmed that even patients with mild, grade 1 COPD [i.e. those with a reduced forced expiratory volume in one second (FEV 1)/forced vital capacity ratio but normal FEV 1], have measurable physiological impairment with increased morbidity and a higher risk of mortality compared with non-smoking healthy controls. Beyond the imperative of smoking cessation—the pivotal intervention in all COPD stages—the role of pharmacotherapy for prevention of disease progression has yet to be established. The main objective of this review is to provide a concise overview of the heterogeneous pathophysiology of COPD with only mild airway obstruction on spirometry and obstacles for early diagnosis. We emphasize that the absence of sufficiently powered trials involving a large number of patients precludes definitive recommendations in support of (or against) long-term pharmacological treatment in mild COPD. Despite these limitations, we present a rationale for earlier pharmacological intervention derived from recent physiological studies performed in symptomatic patients with mild COPD. [ABSTRACT FROM AUTHOR]

Patients with chronic obstructive pulmonary disease (COPD) are progressively limited in their ability to undertake normal everyday activities by a combination of exertional dyspnoea and peripheral muscle weakness. COPD is characterised by expiratory flow limitation, resulting in air trapping and lung hyperinflation. Hyperinflation increases acutely under conditions such as exercise or exacerbations, with an accompanying sharp increase in the intensity of dyspnoea to distressing and intolerable levels. Air trapping, causing increased lung hyperinflation, can be present even in milder COPD during everyday activities. The resulting activity-related dyspnoea leads to a vicious spiral of activity avoidance, physical deconditioning, and reduced quality of life, and has implications for the early development of co- morbidities such as cardiovascular disease. Various strategies exist to reduce hyperinflation, notably long-acting bronchodilator treatment (via reduction in flow limitation and improved lung emptying) and an exercise programme (via decreased respiratory rate, reducing ventilatory demand), or their combination. Optimal bronchodilation can reduce exertional dyspnoea and increase a patient's ability to exercise, and improves the chance of successful outcome of a pulmonary rehabilitation programme. There should be a lower threshold for initiating treatments appropriate to the stage of the disease, such as long-acting bronchodilators and an exercise programme for patients with mild-to-moderate disease who experience persistent dyspnoea. [ABSTRACT FROM AUTHOR]

The article provides information on a study which examined responses to symptom-limited cycle exercise in chronic obstructive pulmonary disease (COPD) patients to determine the interrelationship among disease severity, inspiratory capacity (IC), breathing pattern and dyspnea. Factors compared include spirometry, plethysmographic lung volumes, and responses to constant work rate (CWR) cycle exercise. It concludes that progressive reduction of resting IC was associated with dyspnea increase.

In many parts of the world, the prevalence of obesity is increasing at an alarming rate. The association between obesity, multiple comorbidities, and increased mortality is now firmly established in many epidemiological studies. However, the link between obesity and exercise intolerance is less well studied and is the focus of this paper. Although exercise limitation is likely to be multifactorial in obesity, it is widely believed that the respiratory mechanical constraints and the attendant dyspnea are important contributors. In this paper, we examined the evidence that critical ventilatory constraint is a proximate source of exercise limitation in individuals withmild-to-moderate obesity. We first reviewed existing information on exercise performance, including ventilatory and perceptual response patterns, in obese individuals who are otherwise healthy. We then considered the impact of obesity in patients with preexisting respiratory mechanical abnormalities due to chronic obstructive pulmonary disease (COPD), with particular reference to the effect on dyspnea and exercise performance. Our main conclusion, based on the existing and rather sparse literature on the subject, is that abnormalities of dynamic respiratory mechanics are not likely to be the dominant source of dyspnea and exercise intolerance in otherwise healthy individuals or in patients with COPD with mild-to-moderate obesity. [ABSTRACT FROM AUTHOR]