Search

Background: Exertional breathlessness is a cardinal symptom of cardiorespiratory disease., Research Question: How does breathlessness abnormality, graded using normative reference equations during cardiopulmonary exercise testing (CPET), relate to self-reported and physiologic responses in people with chronic airflow limitation (CAL)?, Study Design and Methods: An analysis was done of people aged ≥ 40 years with CAL undergoing CPET in the Canadian Cohort Obstructive Lung Disease study. Breathlessness intensity ratings (Borg CR10 scale [0-10 category-ratio scale for breathlessness intensity rating]) were evaluated in relation to power output, rate of oxygen uptake, and minute ventilation at peak exercise, using normative reference equations as follows: (1) probability of breathlessness normality (probability of having an equal or greater Borg CR10 rating among healthy people; lower probability reflecting more severe breathlessness) and (2) presence of abnormal breathlessness (rating above the upper limit of normal). Associations with relevant participant-reported and physiologic outcomes were evaluated., Results: We included 330 participants (44% women): mean ± SD age, 64 ± 10 years (range, 40-89 years); FEV 1 /FVC, 57.3% ± 8.2%; FEV 1 , 75.6% ± 17.9% predicted. Abnormally low exercise capacity (peak rate of oxygen uptake < lower limit of normal) was present in 26%. Relative to peak power output, rate of oxygen uptake, and minute ventilation, abnormally high breathlessness was present in 26%, 25%, and 18% of participants. For all equations, abnormally high exertional breathlessness was associated with worse lung function, exercise capacity, self-reported symptom burden, physical activity, and health-related quality of life; and greater physiologic abnormalities during CPET., Interpretation: Abnormal breathlessness graded using CPET normative reference equations was associated with worse clinical, physiological, and functional outcomes in people with CAL, supporting construct validity of abnormal exertional breathlessness., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J. B. and W. C. T. report receiving institutional funding for the CanCOLD study from AstraZeneca Canada Ltd., Boehringer Ingelheim Canada Ltd., GlaxoSmithKline Canada Ltd., Merck, Novartis Pharma Canada Inc., as well as Nycomed Canada Inc. (W. C. T.), Pfizer Canada Ltd. (W. C. T.), Trudell (J. B.), and Grifolds (J. B.). None declared (P. Z. L., M. E., H. L., D. J.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular comorbidities are increasingly being recognised in early stages of chronic obstructive pulmonary disease (COPD) yet complete cardiorespiratory functional assessments of individuals with mild COPD or presenting with COPD risk factors are lacking. This paper reports on the effectiveness of the cardiocirculatory-limb muscles oxygen delivery and utilisation axis in smokers exhibiting no, or mild to moderate degrees of airflow obstruction using standardised cardiopulmonary exercise testing (CPET)., Methods: Post-bronchodilator spirometry was used to classify participants as 'ever smokers without' (n=88), with 'mild' (n=63) or 'mild-moderate' COPD (n=56). All underwent CPET with continuous concurrent monitoring of oxygen uptake (V'O 2 ) and of bioimpedance cardiac output (Qc) enabling computation of arteriovenous differences (a-vO 2 ). Mean values of Qc and a-vO 2 were mapped across set ranges of V'O 2 and Qc isolines to allow for meaningful group comparisons, at same metabolic and circulatory requirements., Results: Peak exercise capacity was significantly reduced in the 'mild-moderate COPD' as compared with the two other groups who showed similar pulmonary function and exercise capacity. Self-reported cardiovascular and skeletal muscle comorbidities were not different between groups, yet disease impact and exercise intolerance scores were three times higher in the 'mild-moderate COPD' compared with the other groups. Mapping of exercise Qc and a-vO 2 also showed a leftward shift of values in this group, indicative of a deficit in peripheral O 2 extraction even for submaximal exercise demands. Concurrent with lung hyperinflation, a distinctive blunting of exercise stroke volume expansion was also observed in this group., Conclusion: Contrary to the traditional view that cardiovascular complications were the hallmark of advanced disease, this study of early COPD spectrum showed a reduced exercise O 2 delivery and utilisation in individuals meeting spirometry criteria for stage II COPD. These findings reinforce the preventive clinical management approach to preserve peripheral muscle circulatory and oxidative capacities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Impaired exercise ventilatory efficiency (high ventilatory requirements for CO 2 [[Formula: see text]e/[Formula: see text]co 2 ]) 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]co 2 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]co 2 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]co 2 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]o 2 ([Formula: see text]o 2peak 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]co 2 ( 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]co 2 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]co 2 above the ULN was associated with greater dyspnea and low [Formula: see text]o 2peak 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.

People with chronic obstructive pulmonary disease (COPD) tend to have abnormally low levels of fat-free mass (FFM), which includes skeletal muscle mass as a central component. The purpose of this systematic review was to synthesise available evidence on the association between FFM and exercise test outcomes in COPD. MEDLINE, Cochrane Library, EMBASE, Web of Science, and Scopus were searched. Studies that evaluated exercise-related outcomes in relation to measures of FFM in COPD were included. Eighty-three studies, containing 18,770 (39% female) COPD participants, were included. Considerable heterogeneity was identified in the ways that FFM and exercise test outcomes were assessed; however, higher levels of FFM were generally associated with greater peak exercise capacity. This association was stronger for some exercise test outcomes (e.g. peak rate of oxygen consumption during incremental cycle exercise testing) than others (e.g. six-minute walking distance). This review identified heterogeneity in the methods used for measuring FFM and exercise capacity. There was, in general, a positive association between FFM and exercise capacity in COPD. There was also an identified lack of studies investigating associations between FFM and temporal physiological and perceptual responses to exercise. This review highlights the significance of FFM as a determinant of exercise capacity in COPD.

Activity-related breathlessness is the most problematic symptom of chronic obstructive pulmonary disease (COPD), arising from complex interactions between peripheral pathophysiology (both pulmonary and non-pulmonary) and central perceptual processing. To capture information on the breathlessness experienced by people with COPD, many different instruments exist, which vary in applicability depending on the purpose and context of assessment. We reviewed common breathlessness assessment instruments, providing recommendations around how to assess the severity of, or change in, breathlessness in people with COPD in daily life or in response to exercise provocation. A summary of 14 instruments for the assessment of breathlessness severity in daily life is presented, with 11/14 (79%) instruments having established minimal clinically importance differences (MCIDs) to assess and interpret breathlessness change. Instruments varied in their scope of assessment (functional impact of breathlessness or the severity of breathlessness during different activities, focal periods, or alongside other common COPD symptoms), dimensions of breathlessness assessed (uni-/multidimensional), rating scale properties and intended method of administration (self-administered versus interviewer led). Assessing breathlessness in response to an acute exercise provocation overcomes some limitations of daily life assessment, such as recall bias and lack of standardized exertional stimulus. To assess the severity of breathlessness in response to an acute exercise provocation, unidimensional or multidimensional instruments are available. Borg's 0-10 category rating scale is the most widely used instrument and has estimates for a MCID during exercise. When assessing the severity of breathlessness during exercise, measures should be taken at a standardized submaximal point, whether during laboratory-based tests like cardiopulmonary exercise testing or field-based tests, such as the 3-min constant rate stair stepping or shuttle walking tests. Recommendations are provided around which instruments to use for breathlessness assessment in daily life and in relation to exertion in people with COPD., Competing Interests: HL has no conflicts to disclose. ME was supported by unrestricted grants from the Swedish Society for Medical Research and the Swedish Research Council (Dnr 2019-02081). DJ holds a Canada Research Chair in Clinical Exercise and Respiratory Physiology (Tier 2) from the Canadian Institutes of Health Research. The authors report no other conflicts of interest in this work., (© 2021 Lewthwaite et al.)

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with abnormal skeletal muscle morphology and function. Objectives: To test the hypothesis that in vivo diaphragm muscle morphology assessed by computed tomography (CT) imaging would be associated with COPD severity, exacerbations, health status, and exercise capacity. Methods: The COPD Morphometry Study is a cross-sectional study that enrolled a clinical sample of smokers with COPD. Spirometry was performed and COPD severity was defined according to guidelines. Three-dimensional left hemidiaphragm morphology was segmented from contiguous axial CT images acquired at maximal inspiration, yielding quantitative measures of diaphragm CT density in Hounsfield units, dome height, and muscle volume. Exacerbations prompting pharmacotherapy or hospitalization in the preceding 12 months and St. George's Respiratory Questionnaire for COPD were assessed. Incremental symptom-limited cycle ergometry quantified peak oxygen uptake ([Formula: see text]o 2Peak ). Associations were adjusted for age, sex, body height, body mass index, and smoking status. Results: Among 65 smokers with COPD (75% male; [mean ± standard deviation (SD)] 56 ± 26 pack-years; forced expiratory volume in 1 second [FEV 1 ] percentage predicted 55 ± 23%), mean diaphragm CT density was 3.1 ± 10 Hounsfield units, dome height was 5.2 ± 1.3 cm, and muscle volume was 57 ± 24 cm 3 . A 1-SD decrement in the diaphragm CT density was associated with 8.3% lower FEV 1 , 3.27-fold higher odds of exacerbation history, 9.7-point higher score on the St. George's Respiratory Questionnaire for COPD, and 2.5 ml/kg/min lower [Formula: see text]o 2Peak . A 1-SD decrement in dome height was associated with 11% lower FEV 1 and 1.3 ml/kg/min lower [Formula: see text]o 2Peak . There were no associations with diaphragm volume observed. Conclusions: CT-assessed diaphragm morphology was associated with COPD severity, exacerbations, impaired health status, and exercise intolerance. The mechanisms and functional impact of lower diaphragm CT density merit investigation.

This study compared the multidimensional breathlessness response to incremental cardiopulmonary cycle exercise testing (CPET) in people with chronic obstructive pulmonary disease (COPD; n = 14, aged 69 ± 9 years, forced expiratory volume in 1-sec = 54 ± 16 % predicted) and healthy older (OA) (n = 35, aged 68 ± 5 years) and younger (YA) (n = 19, aged 28 ± 8 years) adults. Participants performed CPET and successively rated overall breathlessness intensity, unsatisfied inspiration, breathing too shallow, work/effort of breathing, and breathlessness-related unpleasantness, fear, and anxiety using the 0-10 Borg scale. At any given percent predicted peak minute ventilation, people with COPD rated all breathlessness sensations higher than OA and YAs, who were similar. Most between group differences disappeared when examined in relation to inspiratory reserve volume, except people with COPD reported higher levels of unsatisfied inspiration and breathing too shallow (vs YA), and breathlessness-related fear and anxiety (vs OA and YAs). Multidimensional ratings of breathlessness sensations during CPET provides further insight into differences in exertional symptom perceptions among people with COPD and without COPD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study describes the research and healthcare priorities of individuals living with COPD. On an online survey, individuals living with COPD assigned a percentage of funding to 22 research priorities and a percentage of time spent communicating with a healthcare provider to 24 healthcare priorities, indicating which topics were most important. For each research and healthcare priority, we examined the selection frequency of the priority and used chi-square analyses to examine differences in priority selection by quartiles of airflow obstruction (percent predicted forced expiratory volume in 1-sec (FEV 1 %predicted)) and breathlessness burden and exacerbation risk. Based on participants' responses ( N  = 148, 47% women; Mean ± Standard Deviation age = 68 ± 9 yrs) relief of breathlessness was the most often selected research (76% of respondents) and healthcare priority (61% of respondents). It was selected most often, regardless of disease severity or breathlessness burden and exacerbation risk. We found differences for disease severity and breathlessness burden and exacerbation risk in some research priorities (e.g., to improve the maximal amount of exercise of adults living with COPD in and out of the home (χ 2 (3) = 9.97, Cramer's V =.28) and healthcare priorities (e.g., increase your ability to exercise (χ 2 (3) = 9.72, Cramer's V =.27)). This study provides empirical evidence that relief of breathlessness is a top research and healthcare priority for individuals living with COPD. Future healthcare and research activities should align with the priorities of individuals with COPD to improve their care by minimizing disease/symptom burden and optimizing health-related quality of life.

This study described the participation in daily and social activities and the perceived barriers and facilitators to participation of individuals with chronic obstructive pulmonary disease (COPD). Individuals, recruited from outpatient clinics, responded to a survey on their participation in, and barriers and facilitators towards, 26 daily and social activities, divided into 3 categories: (1) physical activity and movement (PAM); (2) self-care; and (3) social engagement. For each activity, chi-square analyses were used to examine participation differences by individuals': quartiles of airflow obstruction [percent predicted forced expiratory volume in 1 second (FEV1%predicted)] and breathlessness burden and exacerbation risk. Of the 200 participants (47% women; mean ± standard deviation age = 68 ± 9 years), most wanted to increase their participation in PAM activities (range 21-75%) and significant differences were found in 5/10 PAM activities for individuals' breathlessness burden and exacerbation risk (e.g., more individuals than expected in group A (modified Medical Research Council breathlessness score <2 and 0-1 exacerbations in past 12 months) participated in regular exercise as much as they wanted (χ (9) 2 =20.43, Cramer's V =.23)). Regardless of the degree of airflow obstruction or breathlessness burden and exacerbation risk, the most common barrier to participation was breathlessness ( p <.001, η 2 p =.86) and the most common facilitator was engaging as part of their routine ( p <.001, η 2 p =.75). Individuals with COPD want to increase their participation in daily and social activities but are limited by breathlessness. Strategies to alleviate breathlessness should be identified/prioritized and incorporated into individuals' daily routines to meet their self-reported participation objectives in daily and social activities.

Objectives: To compare eccentric (ECC) and conventional concentric (CON) cycle training on quadriceps muscle strength in advanced COPD. Secondary objective was to assess functional capacity., Methods: A parallel-group, assessor-blind, randomized trial was conducted. Severe COPD patients were randomized to either an ECC (n = 13) or CON (n = 11) cycling program for 30-min, 3 times/week for 10 weeks. ECC group trained at ∼4-fold higher power than the CON group at similar relative heart rate intensity., Results: Isometric and isokinetic quadriceps peak torque improved after ECC but not CON; between group difference was significant for isometric peak muscle force (p < 0.05). Peak cycling power and endurance time increased in both groups (p < 0.05). Dyspnea at peak cycling power improved only after ECC training (p < 0.05). Sensory intensity ratings of dyspnea and leg fatigue were significantly lower (p < 0.05) during ECC compared with CON at equivalent relative heart rate intensities., Conclusions: ECC could be an effective alternative and/or adjunct modality to pulmonary rehabilitation in severely ventilatory limited COPD patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier B.V.)

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, with pulmonary and extra-pulmonary factors contributing to exercise intolerance. The primary self-reported exercise-limiting symptom may reflect the primary pathophysiological factor contributing to exercise intolerance. We compared physiological and perceptual responses at the symptom-limited peak of incremental cardiopulmonary cycle exercise testing between people with COPD reporting breathlessness (B, n = 34), leg discomfort (LD, n = 16), or a combination of B and LD (BOTH, n = 42) as their main exercise-limiting symptom(s). Despite similarly impaired health status, symptomology and peak exercise capacity, the B group had greater restrictive constraints on tidal volume expansion at end-exercise and was more likely to report unpleasant qualities of exertional breathlessness than LD and BOTH groups. In conclusion, reporting breathlessness as the primary exercise-limiting symptom indicated the presence of distinct lung pathophysiology and symptom perception during exercise in people with COPD., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to report for this work., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.

Exercise limitation is common in chronic obstructive pulmonary disease (COPD). We determined the impact of pulmonary emphysema on the physiological response to exercise independent of contemporary measures of COPD severity. Smokers 40-79 years old with COPD underwent computed tomography, pulmonary function tesing, and symptom-limited incremental exercise testing. COPD severity was quantified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) by spirometry (GOLD 1-4); and symptom burden and exacerbation risk (GOLD A-D). Emphysema severity was quantified as the percent lung volume <-950 Hounsfield units. Regression models adjusted for age, gender, body size, smoking status, airflow limitation, symptom burden and exacerbation risk. Among 67 COPD subjects (age 67 ± 8 years; 75% male; GOLD 1-4: 11%, 43%, 30%, 16%), median percent emphysema was 11%, and peak power output (PPO) was 61 ± 32 W. Higher percent emphysema independently predicted lower PPO (-24 W per 10% increment in emphysema; 95%CI -41 to -7 W). Throughout exercise, higher percent emphysema predicted 1) higher minute ventilation, ventilatory equivalent for CO 2 , and heart rate; and 2) lower oxy-hemoglobin saturation, and end-tidal PCO 2 . Independent of contemporary measures of COPD severity, the extent of pulmonary emphysema predicts lower exercise capacity, ventilatory inefficiency, impaired gas-exchange and increased heart rate response to exercise.

Rationale: A series of studies conducted approximately 40 years ago demonstrated an acute bronchodilator effect of smoked cannabis in healthy adults and adults with asthma. However, the acute effects of vaporized cannabis on airway function in adults with advanced chronic obstructive pulmonary disease (COPD) remain unknown., Objectives: To test the hypothesis that inhaled vaporized cannabis would alleviate exertional breathlessness and improve exercise endurance by enhancing static and dynamic airway function in COPD., Methods: In a randomized controlled trial of 16 adults with advanced COPD (forced expiratory volume in 1 second [FEV 1 ], mean ± SD: 36 ± 11% predicted), we compared the acute effect of 35 mg of inhaled vaporized cannabis (18.2% Δ 9 -tetrahydrocannabinol, <0.1% cannabidiol) versus 35 mg of a placebo control cannabis (CTRL; 0.33% Δ 9 -tetrahydrocannabinol, <0.99% cannabidiol) on physiological and perceptual responses during cardiopulmonary cycle endurance exercise testing; spirometry and impulse oscillometry at rest; and cognitive function, psychoactivity, and mood., Results: Compared with CTRL, cannabis had no effect on breathlessness intensity ratings during exercise at isotime (cannabis, 2.7 ± 1.2 Borg units vs. CTRL, 2.6 ± 1.3 Borg units); exercise endurance time (cannabis, 3.8 ± 1.9 min vs. CTRL, 4.2 ± 1.9 min); cardiac, metabolic, gas exchange, ventilatory, breathing pattern, and/or operating lung volume parameters at rest and during exercise; spirometry and impulse oscillometry-derived pulmonary function test parameters at rest; and cognitive function, psychoactivity, and mood., Conclusions: Single-dose inhalation of vaporized cannabis had no clinically meaningful positive or negative effect on airway function, exertional breathlessness, and exercise endurance in adults with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT03060993).

Purpose of Review: Breathlessness is a common and distressing symptom in patients with chronic obstructive pulmonary disease (COPD) and fibrotic interstitial lung disease (ILD), particularly during exercise. Effective medical management of exertional breathlessness in people living with COPD and fibrotic ILD is challenging for healthcare providers and requires an understanding of its mechanisms. Thus, in this brief review we summarize recent advances in our understanding of the pathophysiological mechanisms of exertional breathlessness in COPD and fibrotic ILD., Recent Findings: The collective results of recent physiological and clinical trials suggest that higher intensity ratings of exertional breathlessness in both COPD and fibrotic ILD compared to healthy control individuals is mechanistically linked to the awareness of greater neural respiratory drive (quantified using inspiratory muscle electromyography) needed to compensate for pathophysiological abnormalities in respiratory mechanics and pulmonary gas exchange efficiency., Summary: Any therapeutic intervention capable of decreasing intrinsic mechanical loading of the respiratory system and/or increasing pulmonary gas exchange efficiency has the potential to decrease the prevalence and severity of activity-related breathlessness and improve related clinical and patient-reported outcomes (e.g., exercise tolerance and health-related quality of life) by decreasing neural respiratory drive in people with COPD and fibrotic ILD.

The objective of the present study was to evaluate the effect of morphine on exertional breathlessness and exercise endurance in advanced chronic obstructive pulmonary disease (COPD).In a randomised crossover trial, we compared the acute effect of immediate-release oral morphine versus placebo on physiological and perceptual responses during constant-load cardiopulmonary cycle exercise testing (CPET) in 20 adults with advanced COPD and chronic breathlessness syndrome.Compared with placebo, morphine reduced exertional breathlessness at isotime by 1.2±0.4 Borg units and increased exercise endurance time by 2.5±0.9 min (both p≤0.014). During exercise at isotime, morphine decreased ventilation by 1.3±0.5 L·min -1 and breathing frequency by 2.0±0.9 breaths·min -1 (both p≤0.041). Compared with placebo, morphine decreased exertional breathlessness at isotime by ≥1 Borg unit in 11 participants (responders) and by <1 Borg unit in nine participants (non-responders). Baseline participant characteristics, including pulmonary function and cardiorespiratory fitness, were similar between responders and non-responders. A higher percentage of responders versus non-responders stopped incremental CPET due to intolerable breathlessness: 82 versus 33% (p=0.028).Immediate-release oral morphine improved exertional breathlessness and exercise endurance in some, but not all, adults with advanced COPD. The locus of symptom-limitation on laboratory-based CPET may help to identify patients most likely to benefit from morphine., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

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 (FEV 1 ) ≥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 FEV 1 z-score -0.60 ± 0.72 and FEV 1 /FVC z-score -1.56 ± 0.87 (mean ± SD)] versus controls, peak oxygen uptake (̇VO 2 ) was 21 ± 7 vs. 32 ± 9 ml/kg/min, and dyspnea/̇VO 2 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 (D L CO) 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 ̇VO 2 were D L CO% predicted (r = 0.487, p < 0.0005) and RV/TLC% (r = -0.389, p = 0.002). D L CO% predicted was also the strongest correlate of dyspnea/̇VO 2 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.

Background: The aim of this study was to evaluate the responsiveness of the 3-minute constant rate step test (3-MST) to detect the relief of exertional dyspnea (respiratory discomfort) after acute bronchodilation in COPD patients., Patients and Methods: A total of 40 patients with moderate-to-severe COPD (mean forced expiratory volume in 1 second: 45.7 (±14.7), % predicted) performed four 3-MSTs at randomly assigned stepping rates of 14, 16, 20 and 24 steps/min after inhalation of nebulized ipratropium bromide (500 µg)/salbutamol (2.5 mg) and saline placebo, which were randomized to order. Patients rated their intensity of perceived dyspnea at the end of each 3-MST using Borg 0-10 category ratio scale., Results: A total of 37 (92.5%), 36 (90%), 34 (85%) and 27 (67.5%) patients completed all 3 minutes of exercise at 14, 16, 20 and 24 steps/min under both treatment conditions, respectively. Compared with placebo, ipratropium bromide/salbutamol significantly decreased dyspnea at the end of the third minute of exercise at 14 steps/min (by 0.6±1.0 Borg 0-10 scale units, P <0.01) and 16 steps/min (by 0.7±1.3 Borg 0-10 scale units, P <0.01); however, no statically significant differences were observed between treatments at 20 and 24 steps/min (both P >0.05)., Conclusion: The 3-MST, when performed at 14 and 16 steps/min, was responsive to detect the relief of exertional dyspnea after acute bronchodilation in patients with moderate-to-severe COPD., Competing Interests: JB reports unrestricted educational grants from GSK, Pfizer, Boehringer Ingelheim (Canada) Limited and AstraZeneca, and funding for the operations of CanCOLD Longitudinal Epidemiological Study from the CIHR/Rx&D Collaborative Research Program with industry partners such as AstraZeneca Canada, Boehringer Ingelheim (Canada) Limited, GSK Canada, Merck and Novartis. DJ has received an unrestricted research grant from Boehringer Ingelheim (Canada) Limited and an education grant from AstraZeneca Canada. FM received fees for speaking at conferences sponsored by Boehringer Ingelheim (Canada) Limited, GSK, Novartis and Grifols; research grants for participating in multicenter trials sponsored by GSK, Boehringer Ingelheim (Canada) Limited, Astra Zeneca, Nycomed and Novartis and unrestricted research grants from Boehringer Ingelheim (Canada) Limited and GSK.BB, CAW-M, AH and HP report no conflicts of interest in this work.

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., (Copyright ©ERS 2016.)

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.

Context: Activity limitation and dyspnea are the dominant symptoms of chronic obstructive pulmonary disease (COPD). Traditionally, efforts to alleviate these symptoms have focused on improving ventilatory mechanics, reducing ventilatory demand, or both of these in combination. Nevertheless, many patients with COPD remain incapacitated by dyspnea and exercise intolerance despite optimal therapy., Objectives: To determine the effect of single-dose inhalation of nebulized fentanyl citrate (a μ-opioid agonist drug) on exercise tolerance and dyspnea in COPD., Methods: In a randomized, double-blind, placebo-controlled, crossover study, 12 stable patients with COPD (mean ± standard error of the mean post-β(2)-agonist forced expiratory volume in one second [FEV(1)] and FEV(1) to forced vital capacity ratio of 69% ± 4% predicted and 49% ± 3%, respectively) received either nebulized fentanyl citrate (50 mcg) or placebo on two separate days. After each treatment, patients performed pulmonary function tests and a symptom-limited constant work rate cycle exercise test at 75% of their maximum incremental work rate., Results: There were no significant postdose differences in spirometric parameters or plethysmographic lung volumes. Neither the intensity nor the unpleasantness of perceived dyspnea was, on average, significantly different at isotime (5.0 ± 0.6 minutes) or at peak exercise after treatment with fentanyl citrate vs. placebo. Compared with placebo, fentanyl citrate was associated with 1) increased exercise endurance time by 1.30 ± 0.43 minutes or 25% ± 8% (P=0.01); 2) small but consistent increases in dynamic inspiratory capacity by ∼0.10 L at isotime and at peak exercise (both P≤0.03); and 3) no concomitant change in ventilatory demand, breathing pattern, pulmonary gas exchange, and/or cardiometabolic function during exercise. The mean rate of increase in dyspnea intensity (1.2 ± 0.3 vs. 2.9 ± 0.8 Borg units/minute, P=0.03) and unpleasantness ratings (0.5 ± 0.2 vs. 2.9 ± 1.3 Borg units/minute, P=0.06) between isotime and peak exercise was less after treatment with fentanyl citrate vs. placebo., Conclusion: Single-dose inhalation of fentanyl citrate was associated with significant and potentially clinically important improvements in exercise tolerance in COPD. These improvements were accompanied by a delay in the onset of intolerable dyspnea during exercise near the limits of tolerance., (Copyright © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to evaluate the physiological basis for sex-differences in exercise-induced dyspnea in patients with mild COPD. We compared operating lung volumes, breathing pattern and dyspnea during incremental cycling in 32 men (FEV(1)=86±10% predicted) and women (FEV(1)=86±12% predicted) with mild COPD and 32 age-matched controls. There were no sex differences in dyspnea in the control group at any work-rate or ventilation (V(E)). Women with COPD had significantly greater dyspnea than men at 60 and 80 W. At 80 W, dyspnea ratings were 5.7±2.3 and 3.3±2.5 Borg units (P<0.05) and the V(E) to maximal ventilatory capacity ratio was 72% and 55% in women and men, respectively (P<0.05). Comparable increases in dynamic hyperinflation were seen in both male and female COPD groups at symptom limitation but women reached tidal volume constraints at a lower work rate and V(E) than men. Superimposing mild COPD on the normal aging effects had greater sensory consequences in women because of their naturally reduced ventilatory reserve., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The natural history of lung hyperinflation in patients with airway obstruction is unknown. In particular, little information exists about the extent of air trapping and its reversibility to bronchodilator therapy in those with mild airway obstruction. We completed a retrospective analysis of data from individuals with airway obstruction who attended our pulmonary function laboratory and had plethysmographic lung volume measurements pre- and post-bronchodilator (salbutamol). COPD was likely the predominant diagnosis but patients with asthma may have been included. We studied 2,265 subjects (61% male), age 65 ± 9 years (mean ± SD) with a post-bronchodilator FEV(1)/FVC <0.70. We examined relationships between indices of airway obstruction and lung hyperinflation, and measured responses to bronchodilation across subgroups stratified by GOLD criteria. In GOLD stage I, vital capacity (VC) and inspiratory capacity (IC) were in the normal range; pre-bronchodilator residual volume (RV), functional residual capacity (FRC) and specific airway resistance were increased to 135%, 119% and 250% of predicted, respectively. For the group as a whole, RV and FRC increased exponentially as FEV(1) decreased, while VC and IC decreased linearly. Regardless of baseline FEV(1), the most consistent improvement following bronchodilation was RV reduction, in terms of magnitude and responder rate. In conclusion, increases (above normal) in airway resistance and plethysmographic lung volumes were found in those with only minor airway obstruction. Indices of lung hyperinflation increased exponentially as airway obstruction worsened. Those with the greatest resting lung hyperinflation showed the largest bronchodilator-induced volume deflation effects. Reduced air trapping was the predominant response to acute bronchodilation across severity subgroups.

Purpose of Review: Obese individuals have impaired respiratory function relative to their normal-weight counterparts. Despite these negative effects, obesity is paradoxically associated with better survival in individuals with chronic obstructive pulmonary disease (COPD). The purpose of this review is to describe this 'obesity paradox', to discuss the effects of obesity on respiratory function, and to speculate as to whether obesity-related alterations in respiratory mechanics can influence the natural history of COPD., Recent Findings: Given the known negative effects of obesity on respiratory physiology, it is reasonable to predict that obese COPD patients would be more likely to experience greater dyspnea and exercise intolerance relative to COPD patients of normal weight. However, recent evidence suggests that obese COPD patients have similar or better dyspnea scores during exercise and do not have diminished exercise capacity. These observations may be attributable to the fact that obese COPD patients have reduced operating lung volumes and higher inspiratory capacity to total lung capacity ratios than their lean COPD counterparts., Summary: Obese patients with COPD do not appear to be at a disadvantage during exercise relative to lean COPD patients. Obesity may be associated with improved survival in COPD but specific mechanisms for this paradox remain to be elucidated.

Purpose of Review: The purpose of this review is to identify new advances in our understanding of dyspnea in patients with chronic obstructive pulmonary disease (COPD). Specifically, we highlight new scientific discoveries concerning the language of dyspnea, its underlying mechanisms and its clinical management., Recent Findings: Recent studies have confirmed that dyspnea is multidimensional and that sensory intensity and quality dimensions of the symptom are readily distinguishable by the individual. When respiratory discomfort is sufficiently unpleasant in COPD, an emotive response is evoked which encompasses feelings of fear and anxiety. Such descriptors appear to be unique to the disease state and are rarely reported in health. Recent brain imaging studies have proposed a central role of the limbic and paralimbic systems in the genesis of perceived dyspnea or its affective component. There is new indirect evidence that the elaboration of endogenous opioids may modulate dyspnea intensity during exercise in COPD. New physiological studies in COPD have provided novel insights into mechanisms of dyspnea both in early disease and in the setting of coexistent obesity., Summary: The effective management of dyspnea in COPD remains a significant challenge for caregivers but recent treatment innovations such as helium-oxygen, inhaled furosemide and breathing feedback techniques have yielded early positive results.