Michele R. Schaeffer

Physiological mechanisms of sex differences in exertional dyspnoea: role of neural respiratory motor drive

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.

Effects of hyperoxia on dyspnoea and exercise endurance in fibrotic interstitial lung disease

Dyspnoea is a major source of distress and is the hallmark symptom of patients with interstitial lung disease (ILD). Supplemental oxygen may alleviate dyspnoea by attenuating arterial oxygen desaturation, increasing oxygen delivery and reducing the drive to breathe; however, previous studies show conflicting results on the effectiveness of supplemental oxygen on dyspnoea and exercise performance in ILD [1–6]. Methodological factors in these studies likely led to underestimation of the potential magnitude of improvement, including an insufficient fraction of inspired oxygen (FIO2) and/or the use of self-paced walking tests and incremental cycle tests rather than constant-load exercise protocols [3–8]. Dyspnoea was also either not evaluated or only evaluated at peak exercise [1, 3–6], which is insensitive to change compared to more clinically relevant submaximal exercise [8]. Finally, some studies were retrospective and did not include a blinded room-air exercise trial, making it difficult to rule out the potential placebo effect [4, 5]. The purpose of this study was to determine the effects of hyperoxia on exercise endurance as well as the intensity and qualitative dimensions of exertional dyspnoea in patients with fibrotic ILD. Hyperoxia significantly improves exertional dyspnoea and exercise tolerance in patients with fibrotic ILD http://ow.ly/WbHf309VwcM

Exertional hypoxemia is more severe in fibrotic interstitial lung disease than in COPD: Exertional hypoxemia in ILD and COPD

Despite its clinical and prognostic significance, few studies have evaluated the severity of exertional oxygen desaturation in fibrotic interstitial lung disease (ILD). Our objectives were to identify clinical and physiological variables that predict the extent of exertional oxygen desaturation in fibrotic ILD and to quantify the severity of desaturation compared to chronic obstructive pulmonary disease (COPD).

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.

Physiological and perceptual responses to incremental exercise testing in healthy men: effect of exercise test modality.

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.

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.

The effects of age and sex on mechanical ventilatory constraint and dyspnea during exercise in healthy humans

We examined the effects of age, sex, and their interaction on mechanical ventilatory constraint and dyspnea during exercise in 22 older (age = 68 ± 1 yr; n = 12 women) and 22 younger (age = 25 ± 1 y, n = 11 women) subjects. During submaximal exercise, older subjects had higher end-inspiratory (EILV) and end-expiratory (EELV) lung volumes than younger subjects (both P < 0.05). During maximal exercise, older subjects had similar EILV ( P > 0.05) but higher EELV than younger subjects ( P < 0.05). No sex differences in EILV or EELV were observed. We noted that women had a higher work of breathing (Wb) for a given minute ventilation (V̇e) ≥65 l/min than men ( P < 0.05) and older subjects had a higher Wb for a given V̇e ≥60 l/min ( P < 0.05). No sex or age differences in Wb were present at any submaximal relative V̇e. At absolute exercise intensities, older women experienced expiratory flow limitation (EFL) more frequently than older men ( P < 0.05), and older subjects were more likely to experience EFL than younger subjects ( P < 0.05). At relative exercise intensities, women and older individuals experienced EFL more frequently than men and younger individuals, respectively (both P < 0.05). There were significant effects of age, sex, and their interaction on dyspnea intensity during exercise at absolute, but not relative, intensities (all P < 0.05). Across subjects, dyspnea at 80 W was significantly correlated with indexes of mechanical ventilatory constraint (all P < 0.05). Collectively, our findings suggest age and sex have significant impacts on Wb, operating lung volumes, EFL, and dyspnea during exercise. Moreover, it appears that mechanical ventilatory constraint may partially explain sex differences in exertional dyspnea in older individuals. NEW & NOTEWORTHY We found that age and sex have a significant effect on mechanical ventilatory constraint and the perception of dyspnea during exercise. We also observed that the perception of exertional dyspnea is associated with indexes of mechanical ventilatory constraint. Collectively, our results suggest that the combined influences of age and biological sex on mechanical ventilatory constraint during exercise contributes, in part, to the increased perception of dyspnea during exercise in older women.

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.

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. Neural respiratory drive is a strong independent predictor of dyspnoea in patients with fibrotic ILD http://ow.ly/MXjd30hcabH

Supplemental oxygen and dypsnoea in interstitial lung disease: absence of evidence is not evidence of absence

It is with great interest that we read the recent systematic review by Bell et al. [1] concerning the effects of oxygen therapy on dyspnoea and exercise capacity in patients with interstitial lung disease (ILD). The authors report that, while supplemental oxygen increases exercise capacity, it does not improve dyspnoea. Overall, this is a well-executed systematic review that accurately reflects the current literature; however, we believe the conclusion regarding the lack of benefit of supplemental oxygen on dyspnoea in ILD is misleading. This opinion is not based on the quality of the systematic review, but rather on the quality of the existing literature that was evaluated. We base our opinion on two important lines of evidence. First, previous studies that have evaluated the effect of supplemental oxygen on exertional dyspnoea in ILD patients only report peak or end-exercise dyspnoea ratings, thereby ignoring important clinically and physiologically relevant changes occurring at submaximal exercise intensities. Secondly, the exercise testing modalities employed are variable, such as self-paced walk tests [2–5] or incremental cycle exercise tests [6], which are often insensitive to changes in dyspnoea. An additional concern relates to the measures in place to reduce experimental bias, as the authors have addressed. Indeed, the only study included in their review that showed a beneficial effect of oxygen on dyspnoea did not have an appropriate control condition [5], making it impossible to rule out the placebo effect. Previous methodological flaws led to erroneous conclusions on the effects of oxygen on exertional dyspnoea in ILD http://ow.ly/Y48d30dCMk9