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Introduction: Contrary to common belief, a growing body of evidence suggests that unsatisfied inspiration (UI), an inherently uncomfortable quality of dyspnea, is experienced by ostensibly healthy adults during high-intensity exercise. Based on our understanding of the mechanisms of UI among people with chronic respiratory conditions, this analysis tested the hypothesis that the experience of UI at peak exercise in young, healthy adults reflects the combination of high ventilatory demand and critical inspiratory constraints., Methods: In a retrospective analysis design, data included 321 healthy individuals (129 females) aged 25 ± 5 yr. Data were collected during one visit to the laboratory, which included anthropometrics, spirometry, and an incremental cardiopulmonary cycling test to exhaustion. Metabolic and cardiorespiratory variables were measured at peak exercise, and qualitative descriptors of dyspnea at peak exercise were assessed using a list of 15 descriptor phrases., Results: Thirty-four percent of participants ( n = 109) reported sensations of UI at peak exercise. Compared with the non-UI group, the UI group achieved a significantly higher peak work rate (243 ± 77 vs 235 ± 69 W, P = 0.016, d = 0.10), rate of O 2 consumption (3.32 ± 1.02 vs 3.27 ± 0.96 L·min -1 , P = 0.018, d = 0.05), minute ventilation (120 ± 38 vs 116 ± 35 L·min -1 , P = 0.047, d = 0.11), and breathing frequency (50 ± 9 vs 47 ± 9 breaths per minute, P = 0.014, d = 0.33), while having a lower exercise-induced change (peak-baseline) in inspiratory capacity (0.07 ± 0.41 vs 0.20 ± 0.49 L, P = 0.023, d = 0.29). The inspiratory reserve volume to minute ventilation ratio at peak exercise was also lower in the UI versus non-UI group. Dyspnea intensity and unpleasantness ratings were significantly higher in the UI versus non-UI group at peak exercise (both P < 0.001)., Conclusions: Healthy individuals reporting UI at peak exercise have relatively greater inspiratory constraints compared with those who do not select UI., (Copyright © 2024 by the American College of Sports Medicine.)

We tested the hypothesis that increasing the respiratory control systems' arterial PCO 2 equilibrium point via induced acute metabolic alkalosis by ingestion of sodium bicarbonate (NaHCO 3 , 0.3 g/kg) would decrease the ventilatory equivalent for CO 2 (V̇ E /V̇CO 2 ) at its lowest point ("nadir") during constant-load cycle exercise testing performed at 80 % of peak power output in 18 healthy young adults. Compared to the sodium chloride (4 g) control condition, ingestion of NaHCO 3 : increased arterialized venous pH, HCO 3 - and PCO 2 at rest by 0.05 ± 0.01 units (mean ± SE), 6.4 ± 0.4 mEq/L and 4.3 ± 0.7 mmHg, respectively (all p < 0.0001); and decreased the V̇ E /V̇CO 2 nadir during exercise by 9.4 % (p < 0.0001) secondary to a 4.7 ± 1.8 L/min decrease in V̇ E (p = 0.019). In conclusion, induced acute metabolic alkalosis by ingestion of NaHCO 3 decreased the V̇ E /V̇CO 2 response to strenuous exercise in healthy adults., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.)

Purpose: This study explored if healthy adults could discriminate between different breathlessness dimensions when rated immediately one after another (successively) during symptom-limited incremental cardiopulmonary cycle exercise testing (CPET) using multiple single-item rating scales., Methods: Fifteen apparently healthy adults (60% male) aged 22 ± 2 years performed six incremental cycle CPETs separated by ≥ 48 h. During each CPET (at rest, every 2-min and at end exercise), participants rated different breathlessness sensations using the 0-10 modified Borg scale using one of six assessment protocols, randomized for order: (1) 'BREATHLESS ALL ' = breathlessness sensory intensity (SI), breathlessness unpleasantness (UN), work/effort of breathing (SQ W/E ), and unsatisfied inspiration (SQ UI ) assessed; (2) SI and UN assessed; and (3-6) SI, UN, SQ W/E , and SQ UI each assessed alone. Physiological responses to CPET were also evaluated., Results: Physiological and breathlessness responses to CPET were comparable across the six protocols, with the exception of SI rated lower at the highest submaximal power output (220 ± 56 watts) during the BREATHLESS ALL protocol (0-10 Borg units 4.2 ± 1.7) compared to SI + UN (5.2 ± 2.1, p = 0.03) and SI alone (5.1 ± 1.9, p = 0.04) protocols. Ratings of SI and SQ W/E were not significantly different when assessed in the same protocol, and were significantly higher than UN and SQ UI , which were comparable., Conclusion: In healthy younger adults, use of two separate single-item rating scales to assess breathlessness during CPET is feasible and enables the distinct sensory intensity and affective dimensions of exertional breathlessness to be assessed.

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.

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.)

We examined the impact of bariatric surgery on cardiometabolic, ventilatory and breathlessness responses to incremental cycle exercise testing in adults with class III obesity (n = 6). O 2 consumption, CO 2 production, minute ventilation (V̇) and breathing frequency were reduced during submaximal exercise after surgery. Inspiratory capacity (IC) and inspiratory reserve volume were lower at rest and any given V̇ E during exercise after surgery. In the transition from rest to peak exercise, dynamic IC decreased by 0.13 L before surgery and increased by 0.21 L after surgery. Breathlessness intensity ratings were lower during exercise at power outputs ≥75-watts after surgery (e.g., by 1.0 and 1.4 Borg 0-10 scale units at 75-watts and the highest equivalent power output of 117-watts, respectively). In contrast, bariatric surgery had no effect on breathlessness-V̇ E relationships during exercise. In conclusion, relief of exertional breathlessness following bariatric surgery could not be explained by improved dynamic breathing mechanics, but reflected the awareness of reduced metabolic and ventilatory requirements of exercise., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Understanding sex differences in the qualitative dimensions of exertional dyspnea may provide insight into why women are more affected by this symptom than men. This study explored the evolution of the qualitative dimensions of dyspnea in 70 healthy, young, physically active adults (35 M and 35 F). Participants rated the intensity of their breathing discomfort (Borg 0-10 scale) and selected phrases that best described their breathing from a standardized list (work/effort, unsatisfied inspiration, and unsatisfied expiration) throughout each stage of a symptom-limited incremental-cycle exercise test. Following exercise, participants selected phrases that described their breathing at maximal exercise from a list of 15 standardized phrases. Intensity of breathing discomfort was significantly higher in women for a given ventilation, but differences disappeared when ventilation was expressed as a percentage of maximum voluntary ventilation. The dominant qualitative descriptor in both sexes throughout exercise was increased work/effort of breathing. At peak exercise, women were significantly more likely to select the following phrases: "my breathing feels shallow," "I cannot get enough air in," "I cannot take a deep breath in," and "my breath does not go in all the way." Women adopted a more rapid and shallow breathing pattern and had significantly higher end-inspiratory lung volumes relative to total lung capacity throughout exercise relative to men. These findings suggest that men and women do not differ in their perceived quality of dyspnea during submaximal exercise, but subjective differences appear at maximal exercise and may be related, at least in part, to underlying sex differences in breathing patterns and operating lung volumes during exercise., (Copyright © 2015 the American Physiological Society.)

In a randomized cross-over study of 15 healthy men aged 20-30 years, we compared physiological and perceptual responses during treadmill and cycle exercise test protocols matched for increments in work rate - the source of increased locomotor muscle metabolic and contractile demands. The rates of O2 consumption and CO2 production were higher at the peak of treadmill versus cycle testing (p ≤ 0.05). Nevertheless, work rate, minute ventilation, tidal volume (VT), breathing frequency (fR), inspiratory capacity (IC), inspiratory reserve volume (IRV), tidal esophageal (Pes,tidal) and transdiaphragmatic pressure swings (Pdi,tidal), peak expiratory gastric pressures (Pga,peak), the root mean square of the diaphragm electromyogram (EMGdi,rms) expressed as a percentage of maximum EMGdi,rms (EMGdi,rms%max), and dyspnea ratings were similar at the peak of treadmill versus cycle testing (p > 0.05). Ratings of leg discomfort were higher at the peak of cycle versus treadmill exercise (p ≤ 0.05), even though peak O2 consumption was lower during cycling. Oxygen consumption, CO2 production, minute ventilation, fR, Pes,tidal, Pdi,tidal and Pga,peak were higher (p ≤ 0.05), while VT, IC, IRV, EMGdi,rms%max, and ratings of dyspnea and leg discomfort were similar (p > 0.05) at all or most submaximal work rates during treadmill versus cycle exercise. Our findings highlight important differences (and similarities) in physiological and perceptual responses at maximal and submaximal work rates during incremental treadmill and cycle exercise testing protocols. The lack of effect of exercise test modality on peak work rate advocates for the use of this readily available parameter to optimize training intensity determination, regardless of exercise training mode.

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.

Few therapies exist for the relief of dyspnea in restrictive lung disorders. Accumulating evidence suggests that nebulized opioids selective for the mu-receptor subtype may relieve dyspnea by modulating intrapulmonary opioid receptor activity. Our respective primary and secondary objectives were to test the hypothesis that nebulized fentanyl (a mu-opioid receptor agonist) relieves dyspnea during exercise in the presence of abnormal restrictive ventilatory constraints and to identify the physiological mechanisms of this improvement. In a randomized, double-blind, placebo-controlled crossover study, we examined the effect of 250 μg nebulized fentanyl, chest wall strapping (CWS), and their interaction on detailed physiological and perceptual responses to constant work rate cycle exercise (85% of maximum incremental work rate) in 14 healthy, fit young men. By design, CWS decreased vital capacity by ∼20% and mimicked the negative consequences of a mild restrictive lung disorder on exercise endurance time and on dyspnea, breathing pattern, dynamic operating lung volumes, and diaphragmatic electromyographic and respiratory muscle function during exercise. Compared with placebo under both unrestricted control and CWS conditions, nebulized fentanyl had no effect on exercise endurance time, integrated physiological response to exercise, sensory intensity, unpleasantness ratings of exertional dyspnea. Our results do not support a role for intrapulmonary opioids in the neuromodulation of exertional dyspnea in health nor do they provide a physiological rationale for the use of nebulized fentanyl in the management of dyspnea due to mild restrictive lung disorders, specifically those arising from abnormalities of the chest wall and not affiliated with airway inflammation., (Copyright © 2015 the American Physiological Society.)

We tested the hypothesis that neuromechanical uncoupling of the respiratory system forms the mechanistic basis of dyspnea during exercise in the setting of "abnormal" restrictive constraints on ventilation (VE). To this end, we examined the effect of chest wall strapping (CWS) sufficient to mimic a "mild" restrictive lung deficit on the interrelationships between VE, breathing pattern, dynamic operating lung volumes, esophageal electrode-balloon catheter-derived measures of the diaphragm electromyogram (EMGdi) and the transdiaphragmatic pressure time product (PTPdi), and sensory intensity and unpleasantness ratings of dyspnea during exercise. Twenty healthy men aged 25.7 ± 1.1 years (means ± SE) completed symptom-limited incremental cycle exercise tests under two randomized conditions: unrestricted control and CWS to reduce vital capacity (VC) by 21.6 ± 0.5%. Compared with control, exercise with CWS was associated with 1) an exaggerated EMGdi and PTPdi response; 2) no change in the relationship between EMGdi and each of tidal volume (expressed as a percentage of VC), inspiratory reserve volume, and PTPdi, thus indicating relative preservation of neuromechanical coupling; 3) increased sensory intensity and unpleasantness ratings of dyspnea; and 4) no change in the relationship between increasing EMGdi and each of the intensity and unpleasantness of dyspnea. In conclusion, the increased intensity and unpleasantness of dyspnea during exercise with CWS could not be readily explained by increased neuromechanical uncoupling but likely reflected the awareness of increased neural respiratory drive (EMGdi) needed to achieve any given VE during exercise in the setting of "abnormal" restrictive constraints on tidal volume expansion.

We examined the effects of dead space loading (DSL) on ventilation (V˙E), neural respiratory drive (EMGdi%max, diaphragm EMG expressed as a % of maximal EMGdi), contractile respiratory muscle effort (Pes,tidal%P(Imax), tidal esophageal pressure swing expressed as a % of maximal inspiratory Pes) and exertional dyspnea intensity ratings in 11 healthy adults with normal spirometry. Subjects completed, in random order, symptom-limited incremental cycle exercise tests under control (CTRL) and DSL (500 ml) conditions. Compared with CTRL, DSL decreased exercise tolerance by 20-25%; increased exertional dyspnea intensity ratings in direct proportion to concurrent increases in EMGdi%max, Pes,tidal%P(Imax) and V˙E; and had little/no effect on the inter-relationships between EMGdi%max, Pes,tidal%P(Imax) and V˙E during exercise. In conclusion, DSL was associated with an earlier onset of intolerable dyspnea; however, neuro-muscular and neuro-ventilatory coupling of the respiratory system remained relatively preserved during exercise in the presence of an increased external dead space. Under these circumstances, DSL-induced increases in exertional dyspnea intensity ratings reflected, at least in part, the awareness of increased neural respiratory drive, contractile respiratory muscle effort and ventilatory output., (Copyright © 2011 Elsevier B.V. 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.)

We examined the impact of human pregnancy on breathlessness intensity at matched levels of ventilation (V˙E) during isoxic hyperoxic CO₂ rebreathing and incremental cycle exercise tests in 21 healthy women in the third trimester (TM₃) and again ∼5 months post-partum (PP). Pregnancy had no significant (P > 0.05) effect on the slope or threshold of the breathlessness intensity-V˙E relationship during both exercise and rebreathing. By contrast, the slope of the breathlessness intensity-V˙E relationship was significantly higher, while the threshold of this relationship was consistently lower during rebreathing vs. exercise (both P < 0.05), regardless of pregnancy status (P > 0.05). As a result, breathlessness intensity was markedly higher at any given V˙E (e.g., by ∼4 Borg units at 40 L/min) during rebreathing vs. exercise, regardless of pregnancy status. Inter-subject variation in breathlessness intensity-V˙E slopes during exercise was not associated with inter-subject variation in breathlessness intensity-V˙E slopes during rebreathing or with increased central chemoreflex responsiveness during pregnancy (both P > 0.05). In conclusion, the intensity of perceived breathlessness for a given V˙E depends, at least in part, on the nature and source of increased central respiratory motor command output, independent of pregnancy status; and pregnancy-induced increases in activity-related breathlessness cannot be easily explained by increased central chemoreflex responsiveness., (Copyright © 2010 Elsevier B.V. All rights reserved.)

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.

We tested the hypothesis that the magnitude of the pregnancy-induced increase in exercise hyperpnea is predictable based on the level at which Pa CO2 is regulated at rest. We performed a detailed retrospective analysis of previous data from 25 healthy young women who performed exercise and rebreathing tests in the third trimester (TM(3); 36.5+/-0.2 weeks gestation; mean+/-SEM) and again 20.4+/-1.7 weeks post-partum (PP). At rest, arterialized venous blood was obtained for the estimation of Pa CO2, [H(+)] and [HCO(3)(-)]; and serum progesterone ([P(4)]) and 17beta-estradiol ([E(2)]) concentrations. Duffin's modified hyperoxic rebreathing procedure was used to evaluate changes in central ventilatory chemoreflex control characteristics at rest. Breath-by-breath ventilatory and gas exchange variables were measured at rest and during symptom-limited incremental cycle exercise tests. At rest in TM(3) compared with PP: Pa CO2, [H(+)], [HCO(3)(-)] and the central chemoreflex ventilatory recruitment threshold for Pa CO2 (VRT CO2) decreased, while ventilation (V E), [P(4)], [E(2)] and central chemoreflex sensitivity (V ES) increased (all p0.05) of changes in [P(4)], [E(2)] and V ES. In conclusion, the increased ventilatory response to exercise in pregnancy can be explained, in large part, by reductions in the respiratory control system's resting Pa CO2 equilibrium point as manifest primarily by reductions in the VRT CO2., ((c) 2010 Elsevier B.V. All rights reserved.)

Unlabelled: The aim of this study was to identify the physiological mechanisms of exertional respiratory discomfort (breathlessness) in pregnancy by comparing ventilatory (breathing pattern, airway function, operating lung volumes, oesophageal pressure (P(oes))-derived indices of respiratory mechanics) and perceptual (breathlessness intensity) responses to incremental cycle exercise in 15 young, healthy women in the third trimester (TM(3); between 34 and 38 weeks gestation) and again 4-5 months postpartum (PP). During pregnancy, resting inspiratory capacity (IC) increased (P < 0.01) and end-expiratory lung volume decreased (P < 0.001), with no associated change in total lung capacity (TLC) or static respiratory muscle strength. This permitted greater tidal volume (V(T)) expansion throughout exercise in TM(3), while preserving the relationship between contractile respiratory muscle effort (tidal P(oes) swing expressed as a percentage of maximum inspiratory pressure (P(Imax))) and thoracic volume displacement (V(T) expressed as a percentage of vital capacity) and between breathlessness and ventilation . At the highest equivalent work rate (HEWR = 128 +/- 5 W) in TM(3) compared with PP: , tidal P(oes)/P(Imax) and breathlessness intensity ratings increased by 10.2 l min(-1) (P < 0.001), 8.8%P(Imax) (P < 0.05) and 0.9 Borg units (P < 0.05), respectively. Pulmonary resistance was not increased at rest or during exercise at the HEWR in TM(3), despite marked increases in mean tidal inspiratory and expiratory flow rates, suggesting increased bronchodilatation. Dynamic mechanical constraints on V(T) expansion (P < 0.05) with associated increased breathlessness intensity ratings (P < 0.05) were observed near peak exercise in TM(3) compared with PP., In Conclusion: (1) pregnancy-induced increases in exertional breathlessness reflected the normal awareness of increased and contractile respiratory muscle effort; (2) mechanical adaptations of the respiratory system, including recruitment of resting IC and increased bronchodilatation, accommodated the increased V(T) while preserving effort-displacement and breathlessness-VE relationships; and (3) dynamic mechanical ventilatory constraints contributed to respiratory discomfort near the limits of tolerance in late gestation.

Human pregnancy is characterized by significant increases in ventilatory drive both at rest and during exercise. The increased ventilation and attendant hypocapnia of pregnancy has been attributed primarily to the stimulatory effects of female sex hormones (progesterone and estrogen) on central and peripheral chemoreflex drives to breathe. However, recent research from our laboratory suggests that hormone-mediated increases in neural (or non-chemoreflex) drives to breathe may contribute importantly to the hyperventilation of pregnancy. This review challenges traditional views of ventilatory control, and outlines an alternative hypothesis of the control of breathing during human pregnancy that is currently being tested in our laboratory. Conventional wisdom suggests that pregnancy-induced increases in central respiratory motor output command in combination with progressive thoraco-abdominal distortion may compromise the normal mechanical response of the respiratory system to exercise, increase the perception of exertional breathlessness, and curtail aerobic exercise performance in otherwise healthy pregnant women. The majority of available evidence suggests, however, that neither pregnancy nor advancing gestation are associated with reduced aerobic working capacity or increased breathlessness at any given work rate or ventilation during exhaustive weight-supported exercise.

This study examined the effects of human pregnancy and advancing gestation on the intensity of respiratory discomfort (dyspnea) during cycle exercise. Fourteen pregnant women (PG) performed a progressive cycle ergometer exercise test involving 20 W/min increases in work rate to symptom limitation and/or a heart rate of 170-175 beats/min at 19.7+/-1.2 weeks (ENTRY), 28.2+/-0.3 weeks (TM2) and 36.3+/-0.3 weeks (TM3) gestation. Eight, age-matched, sedentary non-pregnant women (CG) were also studied for comparison purposes. Measurements included dyspnea intensity (Borg scale), minute ventilation (VE), breathing pattern and other cardiorespiratory parameters. At peak exercise, neither pregnancy nor advancing gestation had an effect on dyspnea, VE, breathing pattern, oxygen uptake or work rate (p>0.05). VE was significantly greater (by 11 L/min at 100 W) in the PG at TM3 versus CG (p<0.05) at all submaximal work rates. VE also increased progressively from ENTRY to TM2 and TM3 during submaximal exercise. Dyspnea was not significantly different at any submaximal work rate in the PG at TM3 versus CG or with advancing gestation in the PG. In addition, dyspnea at a standardized exercise VE of 40 L/min was not different at TM3 versus ENTRY or in the PG at TM3 versus CG. Neither pregnancy nor advancing gestation were associated with increased respiratory discomfort during strenuous non-weight bearing cycle ergometer exercise, despite substantial increases in VE and progressive mechanical adaptations of the respiratory system to accommodate the increasing size of the gravid uterus.

This study examined the effects of aerobic conditioning during the second and third trimesters of human pregnancy on ventilatory responses to graded cycling. Previously sedentary pregnant women were assigned randomly to an exercise group (n = 14) or a nonexercising control group (n = 14). Data were collected at 15-17 weeks, 25-27 weeks and 34-36 weeks of pregnancy. Testing involved 20 W.min-1 increases in work rate to a heart rate of 170 beats.min-1 and (or) volitional fatigue. Breath-by-breath ventilatory and alveolar gas exchange measurements were compared at rest, a standard submaximal .VO2 and peak exercise. Within both groups, resting .V(E), .V(A), and V(T)/T(I) increased significantly with advancing gestation. Peak work rate, O2 pulse (.VO2/HR), .V(E), .V(A) respiratory rate, V(T)/T(I), .VO2, .VCO2, and the ventilatory threshold (T(vent)) were increased after physical conditioning. Chronic maternal exercise has no significant effect on pregnancy-induced changes in ventilation and (or) alveolar gas exchange at rest or during standard submaximal exercise. Training-induced increases in T(vent) and peak oxygen pulse support the efficacy of prenatal fitness programs to improve maternal work capacity.

Ventilatory efficiency can be evaluated using the relationship between minute ventilation (V'E) and the rate of CO2 production (V'CO2). In accordance with the modified alveolar ventilation equation, this relationship is determined by changes in dead space volume (VD) and/or the arterial CO2 tension (PaCO2) equilibrium point. In this review, we summarise the physiological factors that may account for normative ageing and pregnancy induced increases in V'E/V'CO2 during exercise. Evidence suggests that age-related increases in VD and pregnancy-related decreases in the PaCO2 equilibrium point are mechanistically linked to the increased V'E/V'CO2 during exercise. Importantly, the resultant increase in V'E/V'CO2 (ratio or slope), with normal ageing or pregnancy, remains below the critical threshold for prognostic indication in cardiopulmonary disease, is not associated with increased risk of adverse health outcomes, and does not affect the respiratory system's ability to fulfil its primary role of eliminating CO2 and maintaining arterial oxygen saturation during exercise. [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]

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. [ABSTRACT FROM AUTHOR]

Inhalation of nebulized furosemide has been shown to alleviate breathlessness provoked experimentally in health and disease; however, it remains unclear whether the efficacy of nebulized furosemide on breathlessness is dose-dependent. We tested the hypothesis that inhaled nebulized furosemide would be associated with a dose-dependent relief of breathlessness during exercise testing in the setting of abnormal restrictive constraints on tidal volume (VT) expansion. In a randomized, double-blind, crossover study, 24 healthy men aged 25.3 ± 1.2 years (mean ± SE) completed a symptom-limited constant-load cycle endurance exercise test in the setting of external thoracic restriction via chest wall strapping to reduce vital capacity by ~20% following single-dose inhalation nebulized furosemide (40 and 120mg) and 0.9% saline. Compared with 0.9% saline, neither 40 nor 120mg of inhaled nebulized furosemide had an effect on ratings of perceived breathlessness during exercise or an effect on cardiometabolic, ventilatory, breathing pattern, or dynamic operating lung volume responses during exercise. Urine production rate, the percentage of participants reporting an "urge to urinate" and the intensity of perceived "urge to urinate" were all significantly greater after inhaling the 120mg furosemide solution compared with both 0.9% saline and 40mg furosemide solutions. We concluded that, under the experimental conditions of this study, inhalation of nebulized furosemide at doses of 40 and 120mg did not alleviate breathlessness during exercise in healthy men. [ABSTRACT FROM AUTHOR]

Smokers with minor spirometric abnormalities can experience persistent activity-related dyspnea and exercise intolerance. Additional resting tests can expose heterogeneous physiological abnormalities, but their relevance and association with clinical outcomes remain uncertain. Subjects included sixty-two smokers (≥20 pack-years), with cough and/or dyspnea and minor airway obstruction [forced expiratory volume in one-second (FEV1) ≥80% predicted and >5th percentile lower limit of normal (LLN) (i.e., z-score >−1.64) using the 2012-Global Lung Function Initiative equations]. They underwent spirometry, plethysmography, oscillometry, single-breath nitrogen washout, and symptom-limited incremental cycle exercise tests. Thirty-two age-matched nonsmoking controls were also studied. Thirty-three (53%) of smokers had chronic obstructive pulmonary disease by LLN criteria. In smokers [n= 62; age 65 ± 11 years; smoking history 43 ± 19 pack-years; post-bronchodilator FEV1z-score −0.60 ± 0.72 and FEV1/FVC z-score −1.56 ± 0.87 (mean ± SD)] versus controls, peak oxygen uptake (̇VO2) was 21 ± 7 vs. 32 ± 9 ml/kg/min, and dyspnea/̇VO2slopes were elevated (bothp< 0.0001). Smokers had evidence of peripheral airway dysfunction and maldistribution of ventilation when compared to controls. In smokers versus controls: lung diffusing capacity for carbon monoxide (DLCO) was 85 ± 22 vs. 105 ± 17% predicted, and residual volume (RV)/total lung capacity (TLC) was 36 ± 8 vs. 31 ± 6% (bothp< 0.01). The strongest correlates of peak ̇VO2were DLCO% predicted (r= 0.487,p< 0.0005) and RV/TLC% (r= −0.389,p= 0.002). DLCO% predicted was also the strongest correlate of dyspnea/̇VO2slope (r= −0.352,p= 0.005). Insmokers 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. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that elastic binding of the abdomen (AB) would enhance neuromuscular efficiency of the human diaphragm during exercise. Twelve healthy non-obese men aged 24.8 ± 1.7 years (mean ± SE) completed a symptom-limited constant-load cycle endurance exercise test at 85% of their peak incremental power output with diaphragmatic electromyography (EMGdi) and respiratory pressure measurements under two randomly assigned conditions: unbound control (CTRL) and AB sufficient to increase end-expiratory gastric pressure (Pga,ee) by 5-8 cmH2O at rest. By design, AB increased Pga,ee by 6.6 ± 0.6 cmH2O at rest. Compared to CTRL, AB significantly increased the transdiaphragmatic pressure swing-to-EMGdi ratio by 85-95%during exercise, reflecting enhanced neuromuscular efficiency of the diaphragm. By contrast, AB had no effect on spirometric parameters at rest, exercise endurance time or an effect on cardiac, metabolic, ventilatory, breathing pattern, dynamic operating lung volume, and perceptual responses during exercise. In conclusion, AB was associated with isolated and acute improvements in neuromuscular efficiency of the diaphragm during exercise in healthy men. The implications of our results are that AB may be an effective means of enhancing neuromuscular efficiency of the diaphragm in clinical populations with diaphragmatic weakness/dysfunction. [ABSTRACT FROM AUTHOR]

This randomized, double-blind, crossover study examined the effects of a clothing ensemble made of a synthetic fabric promoted as having superior cooling properties ( COOL) on exercise performance and its physiological and perceptual determinants during cycle exercise in ambient laboratory conditions that mimic environmental conditions of indoor training/sporting facilities. Twenty athletes (15 men:5 women) aged 25.8 ± 1.2 years (mean ± SEM) with a maximal rate of O2 consumption of 63.7 ± 1.5 mL·kg−1·min−1 completed cycle exercise testing at 85% of their maximal incremental power output to exhaustion while wearing an ensemble consisting of a fitted long-sleeved shirt and full trousers made of either COOL or a synthetic control fabric ( CTRL). Exercise endurance time was not different under COOL versus CTRL conditions: 12.38 ± 0.98 versus 11.75 ± 1.10 min, respectively ( P > 0.05). Similarly, COOL had no effect on detailed thermoregulatory (skin and esophageal temperatures), cardiometabolic, ventilatory, and perceptual responses to exercise (all P > 0.05). In conclusion, clothing made of a synthetic fabric with purported 'cooling' properties did not improve high-intensity cycle exercise endurance in trained athletes under ambient laboratory conditions that mimic the environmental conditions of indoor training/sporting facilities. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? Does the combination of a higher neural respiratory drive and greater dynamic mechanical ventilatory constraints during exercise in healthy women versus men form the mechanistic basis of sex differences in activity-related dyspnoea?, What is the main finding and its importance? Sex differences in activity-related dyspnoea in health primarily reflected the awareness of a higher neural respiratory drive needed to achieve any given ventilation during exercise in the setting of relatively greater dynamic mechanical ventilatory constraints in women. These findings may have implications for our understanding of the mechanisms of sex differences in exertional dyspnoea in variants of health (e.g. the elderly) and in patients with cardiorespiratory disease., The purpose of this study was to elucidate the physiological mechanisms of sex differences in exertional dyspnoea. We compared detailed measures of neural respiratory motor drive [diaphragmatic EMG (EMGdi) expressed as a percentage of maximal EMGdi (EMGdi%max)], breathing pattern, operating lung volumes, dynamic respiratory mechanics [tidal oesophageal ( Poes,tidal%peak) and transdiaphragmatic pressure swings ( Pdi,tidal%peak) expressed as a percentage of their respective peak values] and sensory intensity and unpleasantness ratings of dyspnoea during symptom-limited incremental cycle exercise in healthy young women ( n = 25) and men ( n = 25). The tidal volume to forced vital capacity ratio ( VT%FVC), breathing frequency, EMGdi%max, Poes,tidal%peak, Pdi,tidal%peak and sensory intensity and unpleasantness ratings of dyspnoea were higher, while dynamic inspiratory capacity and inspiratory reserve volume were lower at a standardized absolute ventilation of 55 l min−1 during submaximal exercise in women versus men (all P < 0.05). In contrast, sex had no demonstrable effect on the inter-relationships between exercise-induced increases in VT%FVC, EMGdi%max and sensory intensity and unpleasantness ratings of dyspnoea. The results of this study suggest that sex differences in the intensity and unpleasantness of exertional dyspnoea in health are likely to reflect the awareness of a relatively higher neural respiratory motor drive (or EMGdi%max) needed to achieve any given ventilation during exercise in the setting of relatively greater dynamic mechanical constraints on VT expansion in women. [ABSTRACT FROM AUTHOR]

Abstract: 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-β2-agonist forced expiratory volume in one second [FEV1] and FEV1 to forced vital capacity ratio of 69%±4% predicted and 49%±3%, respectively) received either nebulized fentanyl citrate (50mcg) 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 ∼0.10L 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 &y& Elsevier]

To examine the effect of age-related respiratory function impairment on exertional dyspnea, we compared ventilatory and perceptual responses to incremental exercise under control (CTRL) and added dead space (DS) loading conditions in healthy fit older (55–79 years) and younger (20–39 years) men. Older individuals had higher ventilatory equivalents for CO 2 throughout exercise ( p < 0.05) suggesting greater ventilatory inefficiency but operating lung volumes were similar compared to younger individuals. With added DS compared to CTRL, both groups similarly increased tidal volume (by 0.3–0.6 L) and ventilation (by 8–13 L/min) at submaximal work rates (each p < 0.05). At peak exercise with DS, both groups failed to further increase ventilation and had small reductions in peak work rate ( p < 0.05). Increases in dyspnea intensity ratings with the addition of DS were similar at standardized submaximal work rates in older and younger groups. We conclude that, despite differences in ventilatory efficiency, the respiratory–mechanical and sensory responses to added chemostimulation during exercise were similar in fit older and younger individuals. [ABSTRACT FROM AUTHOR]

Abstract: Progressive activity-related dyspnea dominates the clinical presentation of patients afflicted by chronic obstructive and restrictive lung diseases. This symptom invariably leads to activity limitation, global skeletal muscle deconditioning and an impoverished quality of life. The effective management of exertional dyspnea remains an elusive goal but our understanding of the nature and mechanisms of this distressing symptom continues to grow. Refinements in psychophysical measurement of the sensory intensity and quality of dyspnea during laboratory clinical cardiopulmonary exercise testing (CPET) have provided new insights into causation. In this review, we focus on what is known about the physiological mechanisms of dyspnea during physical exertion in patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Although these conditions are pathologically diverse, perceptual and ventilatory responses to exercise are remarkably similar among patients with these two conditions. In both patient groups, dyspnea intensity is increased at any given ventilation compared with age-matched healthy individuals; at the limits of tolerance, most patients predominantly select qualitative descriptors that allude to perceptions of “increased respiratory effort” and “unsatisfied inspiration.” Common abnormal physiological responses to CPET across conditions include: (1) increased central respiratory drive secondary to pulmonary gas exchange and metabolic derangements, (2) abnormal “restrictive” constraints on tidal volume expansion with earlier development of critical mechanical limitation of ventilation and (3) an increasing disparity (as exercise proceeds) between the magnitude of contractile respiratory muscle effort and the thoracic volume displacement achieved. Reductionist experimental approaches that attempt to partition, or isolate, the contribution of central and multiple peripheral sensory afferent systems to activity-induced dyspnea have met with limited success. Integrative approaches which explore the possible neurophysiological mechanisms involved in the two dominant qualitative descriptors of activity-related dyspnea in both diseases may prove to be more fruitful. In this review, we present a hypothetical model for exertional dyspnea that is based on current neurophysiological constructs that have been rigorously developed to explain the origins of perceptions of “effort,” “air hunger” and the accompanying affective “distress” response. [Copyright &y& Elsevier]