Qualitative dimensions of exertional dyspnea in fibrotic interstitial lung disease.

Unsatisfied inspiration is commonly reported during exercise by patients with interstitial lung disease (ILD). However, the physiological basis of perceived dyspnea quality in this population has not been evaluated. We examined the relationship between dyspnea quality and indices of ventilatory-mechanical limitations during exercise in patients with fibrotic ILD. Sixteen fibrotic ILD patients (12 male) with a median age of 64 years (range 49-81), FVC 71%-predicted (51-100), and DLCO 47%-predicted (27-77) performed incremental and constant work-rate cycle exercise tests to exhaustion. Ventilatory responses were recorded at rest, throughout exercise, and at peak exercise. Dyspnea quality was serially assessed using a 4-item list from which participants selected the phrase that best described their breathing compared to rest. Increased work/effort was the dominant descriptor of dyspnea throughout exercise, but with increased selection of unsatisfied inspiration following the inflection point of tidal volume relative to ventilation. Delaying or preventing ILD patients from reaching a critically reduced IRV may have implications for symptom management.

Neurophysiological mechanisms of exertional dyspnoea in fibrotic interstitial lung disease.

Our understanding of the mechanisms of dyspnoea in fibrotic interstitial lung disease (ILD) is incomplete. The aims of this study were two-fold: 1) to determine whether dyspnoea intensity is better predicted by neural respiratory drive (NRD) or neuromechanical uncoupling (NMU) of the respiratory system in fibrotic ILD, and 2) to examine the effect of breathing 60% oxygen on NRD, NMU and dyspnoea ratings.Fourteen patients with fibrotic ILD were included. Visit 1 comprised a familiarisation incremental cycle exercise test, Visit 2 comprised a normoxic incremental cycling test to address Aim 1, and Visits 3 and 4 consisted of constant-load cycling while breathing room air or 60% oxygen to address Aim 2. Diaphragmatic electromyography (EMGdi) was used as a surrogate of NRD. NMU was calculated as the ratio between EMGdi (%max) and tidal volume (%vital capacity).On adjusted analysis, NMU and its constituents were all significantly associated with dyspnoea ratings during incremental cycling, with EMGdi having the strongest correlation. The between-treatment change in dyspnoea ratings during constant load cycling was only correlated with change in exercise endurance time and NMU.Dyspnoea more strongly reflected the level of EMGdi than NMU in fibrotic ILD. However, the improvement in dyspnoea with 60% oxygen was better predicted by improvements in NMU.

Sex differences in respiratory muscle activation patterns during high-intensity exercise in healthy humans.

Although women experience greater ventilatory constraints and have a higher work of breathing during exercise, they are less susceptible to diaphragm fatigue compared to men. The mechanisms for diaphragmatic fatigue resistance in women is unknown but may be related to sex differences in respiratory muscle recruitment. Accordingly, the purpose of this study was to determine if electromyography (EMG) of the diaphragm (EMGdi) and extra-diaphragmatic inspiratory muscles differ between sexes during exercise. Forty subjects (21M:19F) completed a constant load cycling test at 85% of maximum work rate until exhaustion, while instrumented with an oesophageal electrode catheter to measure EMGdi and surface electrodes to measure EMG of the sternocleidomastoid (EMGscm) and scalene (EMGsca) muscles. No sex difference in EMGdi was observed at any measurement time. However, EMGscm and EMGsca were higher throughout all submaximal exercise times in women (p<0.01). These results suggest greater reliance on the extra-diaphragmatic inspiratory muscles in women relative to men, which may serve as a strategy to minimize diaphragmatic fatigue.

Effects of inspiratory muscle training on respiratory muscle electromyography and dyspnea during exercise in healthy men.

Inspiratory muscle training (IMT) has consistently been shown to reduce exertional dyspnea in health and disease; however, the physiological mechanisms remain poorly understood. A growing body of literature suggests that dyspnea intensity can be explained largely by an awareness of increased neural respiratory drive, as measured indirectly using diaphragmatic electromyography (EMGdi). Accordingly, we sought to determine whether improvements in dyspnea following IMT can be explained by decreases in inspiratory muscle electromyography (EMG) activity. Twenty-five young, healthy, recreationally active men completed a detailed familiarization visit followed by two maximal incremental cycle exercise tests separated by 5 wk of randomly assigned pressure threshold IMT or sham control (SC) training. The IMT group (n = 12) performed 30 inspiratory efforts twice daily against a 30-repetition maximum intensity. The SC group (n = 13) performed a daily bout of 60 inspiratory efforts against 10% maximal inspiratory pressure (MIP), with no weekly adjustments. Dyspnea intensity was measured throughout exercise using the modified 0-10 Borg scale. Sternocleidomastoid and scalene EMG was measured using surface electrodes, whereas EMGdi was measured using a multipair esophageal electrode catheter. IMT significantly improved MIP (pre: -138 ± 45 vs. post: -160 ± 43 cmH2O, P < 0.01), whereas the SC intervention did not. Dyspnea was significantly reduced at the highest equivalent work rate (pre: 7.6 ± 2.5 vs. post: 6.8 ± 2.9 Borg units, P < 0.05), but not in the SC group, with no between-group interaction effects. There were no significant differences in respiratory muscle EMG during exercise in either group. Improvements in dyspnea intensity ratings following IMT in healthy humans cannot be explained by changes in the electrical activity of the inspiratory muscles.NEW & NOTEWORTHY Exertional dyspnea intensity is thought to reflect an increased awareness of neural respiratory drive, which is measured indirectly using diaphragmatic electromyography (EMGdi). We examined the effects of inspiratory muscle training (IMT) on dyspnea, EMGdi, and EMG of accessory inspiratory muscles. IMT significantly reduced submaximal dyspnea intensity ratings but did not change EMG of any inspiratory muscles. Improvements in exertional dyspnea following IMT may be the result of nonphysiological factors or physiological adaptations unrelated to neural respiratory drive.

Qualitative dimensions of exertional dyspnea in adults with cystic fibrosis.

No studies of cystic fibrosis (CF) have systematically characterized the evolution of the qualitative dimensions of exertional dyspnea. Adults with CF (n = 25) and control individuals matched for sex, age, and body mass index (n = 25) underwent cardiopulmonary cycle exercise testing with a detailed evaluation of ventilatory and dyspnea responses. The qualitative dimensions of dyspnea were examined during each exercise stage by having subjects select phrases that best described their breathing (i.e., "work/effort," "unsatisfied inspiration," and "unsatisfied expiration"). Subjects also selected phrases that described the quality of their breathing at peak exercise using an established 15-item questionnaire, which was then clustered into different categories. Subjects with CF had greater ventilatory requirements, higher end-inspiratory and end-expiratory lung volumes (% total lung capacity), and an earlier inflection/plateau in tidal volume during exercise compared with control subjects. Increased work/effort was the dominant qualitative descriptor in both groups throughout exercise. Unsatisfied inspiration was selected by 48% of subjects with CF and 40% of controls at some point during exercise. The onset of unsatisfied inspiration in these subjects occurred at a significantly lower relative exercise intensity in subjects with CF vs. controls (72 ± 21 vs. 94 ± 11% Wmax, P < 0.01). Chest tightness was the only qualitative descriptor cluster that was selected more frequently by subjects with CF vs. controls (36 vs. 0%, respectively, P < 0.05) at peak exercise. Therapeutic interventions that reduce ventilatory requirements and improve lung volumes may delay the onset of distressing sensations such as unsatisfied inspiration and chest tightness in adults with CF.

Cardiorespiratory and sensory responses to exercise in adults with mild cystic fibrosis.

The purpose of this study was to evaluate cardiorespiratory fitness and reasons for exercise curtailment in a contemporary adult cystic fibrosis (CF) cohort with mild lung disease. Adults with mild CF (n = 19, forced expiratory volume in 1 s = 95 ± 17% predicted) were age-, sex-, ethnicity-, and body mass index-matched to healthy controls (n = 19) and underwent a detailed cardiopulmonary cycle exercise test. While CF subjects had a reduced peak oxygen uptake compared with controls, the values were normal when expressed as %predicted in 14/19 (74%) of subjects. Both groups demonstrated a normal cardiovascular limitation to exercise and stopped exercise primarily because of leg fatigue. Despite not being exercise-limited by respiratory factors, there was some evidence of ventilatory abnormalities as patients with mild CF had increased end-inspiratory lung volumes and reached an inflection/plateau in tidal volume relative to minute ventilation at lower exercise intensities compared with controls. Subjects with CF were not more likely to demonstrate expiratory flow limitation compared with controls and did not have evidence of dynamic hyperinflation during exercise. Despite increased end-inspiratory lung volumes and an earlier tidal volume inflection/plateau, CF subjects did not experience higher levels of dyspnea. In an exploratory analysis, a significant inverse correlation was observed between sweat chloride and peak work rate. Adult CF subjects with relatively well preserved spirometry have normal exercise performance relative to reference values and are primarily limited by nonrespiratory factors. However, ventilatory abnormalities were detected even in this mild CF cohort and should be evaluated in future therapeutic trials focused on disease-modifying therapies in mild CF.

Sex differences in the intensity and qualitative dimensions of exertional dyspnea in physically active young adults.

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.

Heliox breathing equally influences respiratory mechanics and cycling performance in trained males and females.

In this study we tested the hypothesis that inspiring a low-density gas mixture (helium-oxygen; HeO2) would minimize mechanical ventilatory constraints and preferentially increase exercise performance in females relative to males. Trained male (n = 11, 31 yr) and female (n = 10, 26 yr) cyclists performed an incremental cycle test to exhaustion to determine maximal aerobic capacity (V̇o2max; male = 61, female = 56 ml·kg(-1)·min(-1)). A randomized, single-blinded crossover design was used for two experimental days where subjects completed a 5-km cycling time trial breathing humidified compressed room air or HeO2 (21% O2:balance He). Subjects were instrumented with an esophageal balloon for the assessment of respiratory mechanics. During the time trial, we assessed the ability of HeO2 to alleviate mechanical ventilatory constraints in three ways: 1) expiratory flow limitation, 2) utilization of ventilatory capacity, and 3) the work of breathing. We found that HeO2 significantly reduced the work of breathing, increased the size of the maximal flow-volume envelope, and reduced the fractional utilization of the maximal ventilatory capacity equally between men and women. The primary finding of this study was that inspiring HeO2 was associated with a statistically significant performance improvement of 0.7% (3.2 s) for males and 1.5% (8.1 s) for females (P < 0.05); however, there were no sex differences with respect to improvement in time trial performance (P > 0.05). Our results suggest that the extent of sex-based differences in airway anatomy, work of breathing, and expiratory flow limitation is not great enough to differentially affect whole body exercise performance.

Physiological mechanisms of dyspnea relief following ivacaftor in cystic fibrosis: a case report.

Ivacaftor is a novel oral pharmacologic agent that specifically targets the genetic defect of cystic fibrosis (CF) by augmenting chloride conductance through the CF transmembrane regulator (CFTR) protein. For individuals with CF and at least one copy of the G551D gating mutation, improvements in sweat chloride, nutritional parameters, lung function, respiratory symptoms, and exercise tolerance (i.e., 6-min walk distance) are attained within 2 weeks of initiating ivacaftor. However, there are no reports detailing the physiological and sensory implications of these improvements and their underlying mechanisms. We performed detailed cardiopulmonary exercise testing pre- and post-initiation of ivacaftor in a 27-year old male with CF (CFTR genotype F508del/G551D) and chronic airflow obstruction (FEV1/FVC=0.44). An improvement of FEV1 (by 16%) following ivacaftor was accompanied by clinically significant improvements in exercise capacity (by 14%) and exertional dyspnea (by up to 5 Borg scale units). These improvements were attributable, at least in part, to favorable alterations in the ventilatory response to exercise, including improvements in breathing patterns (e.g., increased tidal volume and reduced breathing frequency) and dynamic operating lung volumes (e.g., increased inspiratory reserve volume and inspiratory capacity) and decreases in dynamic mechanical ventilatory constraints.

Cardiorespiratory and sensory responses to exercise in well-controlled asthmatics.

OBJECTIVES: The purpose of this study was to evaluate detailed ventilatory, cardiovascular and sensory responses to cycle exercise in sedentary patients with well-controlled asthma and healthy controls. METHODS: Subjects included sedentary patients meeting criteria for well-controlled asthma (n = 14), and healthy age- and activity-matched controls (n = 14). Visit 1 included screening for eligibility, medical history, anthropometrics, physical activity assessment, and pre- and post-bronchodilator spirometry. Visit 2 included spirometry and a symptom limited incremental cycle exercise test. Detailed ventilatory, cardiovascular and sensory responses were measured at rest and throughout exercise. RESULTS: Asthmatics and controls were well matched for age, body mass index and physical activity levels. Baseline forced expiratory volume in 1 second (FEV(1)) was similar between asthmatics and controls (98 ± 10 versus 95 ± 9% predicted, respectively, p > 0.05). No significant differences were observed between asthmatics and controls for maximal oxygen uptake (31.8 ± 5.6 versus 30.6 ± 5.9 ml/kg/min, respectively, p > 0.05) and power output (134 ± 35 versus 144 ± 32 W, respectively, p > 0.05). Minute ventilation (V(E)) relative to maximum voluntary ventilation (V(E)/MVV) was similar between groups at maximal exercise with no subjects showing evidence of ventilatory limitation. Asthmatics and controls achieved similar age-predicted maximum heart rates (92 ± 7 versus 93 ± 8% predicted, respectively, p > 0.05). Ratings of perceived breathing discomfort and leg fatigue were not different between groups throughout exercise. CONCLUSIONS: The results of this study indicate that sedentary patients with well-controlled asthma have preserved sensory and cardiorespiratory responses to exercise with no evidence of exercise impairment or ventilatory limitation.

Effects of an aging pulmonary system on expiratory flow limitation and dyspnoea during exercise in healthy women.

Aging related changes in pulmonary function may make older women (OW) more susceptible to expiratory flow limitation (EFL) and lead to higher dyspnoea ratings during exercise relative to young women (YW). Accordingly, the purpose of this study was to compare sensory responses and EFL susceptibility and magnitude in 8 YW (29 ± 7 years) and 8 healthy OW (64 ± 3 years) matched for percentage-predicted forced vital capacity (% predicted FVC) and % predicted forced expiratory volume in 1 s. EFL was calculated as the percent overlap between tidal flow-volume loops during maximal exercise and the maximal expiratory flow-volume (MEFV) curve. Peak oxygen consumption (V'O(2peak)) was lower in the OW compared to the YW (29.4 ± 3.6 vs. 49.1 ± 8.9 ml kg(-1) min(-1), P < 0.05) as was maximal ventilation (73.7 ± 18.4 vs. 108.7 ± 14.1 l min(-1), P < 0.05). EFL at maximal exercise was present in 2 of 8 YW and in 5 of 8 OW. There were no significant differences in the magnitude of EFL between OW (23 ± 24, range: 0-69 %EFL) and YW (9 ± 18, range: 0-46 %EFL, P = 0.21). The magnitude of EFL in OW was inversely related to % predicted FVC (r = -0.69, P = 0.06), but this relationships was not observed in the YW (r = -0.23, P = 0.59). The OW consistently reported greater dyspnoea and leg discomfort for any given absolute work rate, but not when work was expressed as a percentage of maximum. Reduced ventilatory and exercise capacities may cause OW to be more susceptible to EFL during exercise and experience greater dyspnoea relative to YW for a standardized physical task.

Determinants of expiratory flow limitation in healthy women during exercise.

PURPOSE: Expiratory flow limitation (EFL) can occur in healthy young women during exercise. We questioned whether the occurrence and severity of EFL were related to aerobic fitness or anatomical factors. METHODS: Twenty-two healthy young (<40 yr) women performed a progressive cycle test to exhaustion. The subjects' maximum expiratory flow-volume curve was compiled from several effort-graded vital capacity maneuvers before and after exercise. The maximum expiratory flow-volume curve, along with inspiratory capacity maneuvers, was used to determine lung volumes and expiratory flows and to quantify EFL. To determine relative airway size, we used a ratio sensitive to both airway size and lung volume, called the dysanapsis ratio. The subjects were partitioned into two groups based upon the appearance of >5% EFL. RESULTS: Ten subjects showed EFL during exercise. Forced vital capacities (4.4 ± 0.4 vs 3.7 ± 0.4 L, P < 0.001) and forced expiratory flows for any given lung volume were significantly larger in the non-expiratory flow-limited (NEFL) group. The NEFL group's dysanapsis ratio was significantly larger than that of the EFL group (0.27 ± 0.06 vs 0.21 ± 0.04, respectively, P < 0.05), indicating larger airways in the NEFL group. There was no difference between the NEFL and EFL groups with respect to maximal aerobic capacity (50.8 ± 10.0 vs 46.7 ± 5.9 mL·kg(-1)·min(-1), respectively, P = 0.264). At peak exercise, the NEFL group had a significantly higher end-expiratory lung volume than the EFL group (40.1% ± 4.8% vs 33.7% ± 5.7% FVC, respectively, P < 0.05). CONCLUSIONS: We conclude that EFL in women can largely be explained by anatomical factors that influence the capacity to generate flow and volume during exercise rather than fitness per se.