Mechanical Ventilatory Constraints Research Articles

Effects of Obesity and Sex on Ventilatory Constraints during a Cardiopulmonary Exercise Test in Children.

Ventilatory constraints are common during exercise in children, but the effects of obesity and sex are unclear. The purpose of this study was to investigate the effects of obesity and sex on ventilatory constraints (i.e., expiratory flow limitation (EFL) and dynamic hyperinflation) during a maximal exercise test in children. Thirty-four 8- to 12-yr-old children without obesity (18 females) and 54 with obesity (23 females) completed pulmonary function testing and maximal cardiopulmonary exercise tests. EFL was calculated as the overlap between tidal flow-volume loops during exercise and maximal expiratory flow-volume loops. Dynamic hyperinflation was calculated as the change in inspiratory capacity from rest to exercise. Maximal minute ventilation was not different between children with and without obesity. Average end-inspiratory lung volumes (EILV) and end-expiratory lung volumes (EELV) were significantly lower during exercise in children with obesity (EILV: 68.8% ± 0.7% TLC; EELV: 41.2% ± 0.5% TLC) compared with children without obesity (EILV: 73.7% ± 0.8% TLC; EELV: 44.8% ± 0.6% TLC; P < 0.001). Throughout exercise, children with obesity experienced more EFL and dynamic hyperinflation compared with those without obesity ( P < 0.001). Also, males experienced more EFL and dynamic hyperinflation throughout exercise compared with females ( P < 0.001). At maximal exercise, the prevalence of EFL was similar in males with and without obesity; however, the prevalence of EFL in females was significantly different, with 57% of females with obesity experiencing EFL compared with 17% of females without obesity ( P < 0.05). At maximal exercise, 44% of children with obesity experienced dynamic hyperinflation compared with 12% of children without obesity ( P = 0.002). Obesity in children increases the risk of developing mechanical ventilatory constraints such as dynamic hyperinflation and EFL. Sex differences were apparent with males experiencing more ventilatory constraints compared with females.

Ventilatory Limitation in Patients with HFpEF and Obesity: The Balance Between Increased Ventilatory Demand vs. Reduced Ventilatory Capacity

Study Objective: Patients with heart failure with preserved ejection fraction (HFpEF) have an increased ventilatory demand during exertion. Whether ventilatory capacity can meet this increased demand is unknown, especially in those with obesity. Hypothesis: We hypothesized that ventilatory capacity would be reduced in patients with HFpEF due to age- and obesity-related mechanical ventilatory constraints. Methodology: Body composition (DEXA) and pulmonary function were measured in 20 patients with invasively confirmed HFpEF (69±6yr; 9M/11W). Cardiorespiratory responses, breathing mechanics, and arterial blood gases were measured at rest, during exercise at 20 W, and at peak exercise. Based upon inspection of resting forced vital capacity (FVC, L) values, the patients were grouped into those with an FVC&lt;3L (n=12; 2M/10W) and those with an FVC&gt;3.8L (n=8; 7M/1W). Differences between the two groups were compared using independent t-tests. Comparisons were not made between conditions (rest, 20W, &amp; peak exercise). Results: Percent body fat was greater in the FVC&lt;3L group (51% vs. 38%, p&lt;0.01). Ventilatory demand (V̇ E /V̇CO 2 ) was equally elevated in both groups at rest and during exercise. FVC was 2 L less in the FVC&lt;3L group (79±14 vs. 100±13 %predicted) and maximal voluntary ventilation was approximately 50 L/min less (p&lt;0.01). All lung volume subdivisions (L) were significantly lower in the FVC&lt;3L group at rest and during exercise (p&lt;0.05). End expiratory lung volume (L) was higher during exercise in both groups as many of the patients had expiratory flow limitation at rest and during exercise (&gt;50% V T at peak exercise). End inspiratory lung volume (L) approached 90% of total lung capacity in both groups, thus V T (%FVC) expansion was limited in both groups. The FVC&lt;3L group was not able to increase V̇ E (L/min) enough to lower arterial CO 2 at peak exercise as much as the FVC&gt;3.8L group (40±4 vs 35±3; p&lt;0.05). Peak V̇O 2 (%predicted) was approximately 22% less (p&lt;0.05) in the FVC&lt;3L group. Ratings of perceived breathlessness and unpleasantness were higher in the FVC&lt;3L group at 20 W (p&lt;0.05). Conclusion: Ventilatory capacity is limited in patients with HFpEF and obesity; this is particularly true for patients who have a small or reduced FVC. We propose that quantifying ventilatory limitations in patients with HFpEF is critical to establishing whether they can meet the challenges of an elevated ventilatory demand and whether these limitations may play a role in provoking exertional dyspnea and exercise intolerance. This research was supported by the National Institutes of Health (1P01HL137630), King Foundation, Cain Foundation, and Texas Health Presbyterian Hospital Dallas. B.N. Balmain is supported by an American Heart Association Fellowship (grant number: 826064). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Evidence of ventilatory constraints during exercise in hypermobile Ehlers-Danlos syndrome.

Hypermobile Ehlers-Danlos syndrome (hEDS) is a connective tissue disorder with many different symptoms such as pain, fatigue, dysautonomia, or respiratory symptoms. Among the respiratory manifestations described, the most frequent are exertional dyspnea and breathing difficulties. Mechanical ventilatory constraints during exercise could participate in these respiratory manifestations. The objective of this study was to explore the response of pulmonary flow-volume loops to exercise in patients with hEDS and to look for dynamic hyperinflation and expiratory flow limitation during exercise. For this purpose, breathing pattern and tidal exercise flow-volume loops were recorded at two workloads (30% and 80% of the peak power output) of a constant load exercise test. Twelve patients were included (11 women, mean age 41 ± 14years). The results showed a decrease (p = 0.028) in the inspiratory capacity (from 3.12 ± 0.49L to 2.97 ± 0.52L), an increase (p = 0.025) in the end-expiratory lung volume (from 0.73 ± 0.68L to 0.88 ± 0.66L, i.e., from EELV comprising 17 ± 12% to 21 ± 12% of forced vital capacity) between the two workloads in favor of dynamic hyperinflation, and half of the patients had expiratory flow limitations. This exploratory study provides evidence for mechanical ventilatory constraints during exercise in patients with hEDS, which may induce discomfort during exercise and could contribute to the respiratory symptomatology. This study is part of a larger clinical trial (ID: NCT04680793, December 2020).

Sex differences in the ventilatory responses to exercise in mild to moderate obesity

New Findings What is the central question of the study? What are the sex differences in ventilatory responses during exercise in adults with obesity? What is the main finding and its importance? Tidal volume and expiratory flows are lower in females when compared with males at higher levels of ventilation despite small increases in end‐expiratory lung volumes. Since dyspnoea on exertion is a frequent complaint, particularly in females with obesity, careful attention should be paid to unpleasant respiratory symptoms and mechanical ventilatory constraints while prescribing exercise. Obesity is associated with altered ventilatory responses, which may be exacerbated in females due to the functional consequences of sex‐related morphological differences in the respiratory system. This study examined sex differences in ventilatory responses during exercise in adults with obesity. Healthy adults with obesity (n = 73; 48 females) underwent pulmonary function testing, underwater weighing, magnetic resonance imaging (MRI), a graded exercise test to exhaustion, and two constant work rate exercise tests; one at a fixed work rate (60 W for females and 105 W for males) and one at a relative intensity (50% of peak oxygen uptake, V˙O2peak). Metabolic, respiratory and perceptual responses were assessed during exercise. Compared with males, females used a smaller proportion of their ventilatory capacity at peak exercise (69.13 ± 14.49 vs. 77.41 ± 17.06% maximum voluntary ventilation, P = 0.0374). Females also utilized a smaller proportion of their forced vital capacity (FVC) at peak exercise (tidal volume: 48.51 ± 9.29 vs. 54.12 ± 10.43%FVC, P = 0.0218). End‐expiratory lung volumes were 2–4% higher in females compared with males during exercise (P < 0.05), while end‐inspiratory lung volumes were similar. Since the males were initiating inspiration from a lower lung volume, they experienced greater expiratory flow limitation during exercise. Ratings of perceived breathlessness during exercise were similar between females and males at comparable levels of ventilation. In summary, sex differences in the manifestations of obesity‐related mechanical ventilatory constraints were observed. Since dyspnoea on exertion is a common complaint in patients with obesity, particularly in females, exercise prescriptions should be tailored with the goal of minimizing unpleasant respiratory sensations.

Adipose Tissue Inflammation and Pulmonary Dysfunction in Obesity.

Obesity is a chronic disease caused by an excess of adipose tissue that may impair health by altering the functionality of various organs, including the lungs. Excessive deposition of fat in the abdominal area can lead to abnormal positioning of the diaphragm and consequent reduction in lung volume, leading to a heightened demand for ventilation and increased exposure to respiratory diseases, such as chronic obstructive pulmonary disease, asthma, and obstructive sleep apnoea. In addition to mechanical ventilatory constraints, excess fat and ectopic deposition in visceral depots can lead to adipose tissue dysfunction, which promotes metabolic disorders. An altered adipokine-secretion profile from dysfunctional adipose tissue in morbid obesity fosters systemic, low-grade inflammation, impairing pulmonary immune response and promoting airway hyperresponsiveness. A potential target of these adipokines could be the NLRP3 inflammasome, a critical component of the innate immune system, the harmful pro-inflammatory effect of which affects both adipose and lung tissue in obesity. In this review, we will investigate the crosstalk between adipose tissue and the lung in obesity, highlighting the main inflammatory mediators and novel therapeutic targets in preventing pulmonary dysfunction.

Sex, gender and the pulmonary physiology of exercise.

In this review, we detail how the pulmonary system's response to exercise is impacted by both sex and gender in healthy humans across the lifespan. First, the rationale for why sex and gender differences should be considered is explored, and then anatomical differences are highlighted, namely that females typically have smaller lungs and airways than males. Thereafter, we describe how these anatomical differences can impact functional aspects such as respiratory muscle energetics and activation, mechanical ventilatory constraints, diaphragm fatigue, and pulmonary gas exchange in healthy adults and children. Finally, we detail how gender can impact the pulmonary response to exercise.

Ventilatory efficiency in athletes, asthma and obesity.

During submaximal exercise, minute ventilation (V' E) increases in proportion to metabolic rate (i.e. carbon dioxide production (V' CO2 )) to maintain arterial blood gas homeostasis. The ratio V' E/V' CO2 , commonly termed ventilatory efficiency, is a useful tool to evaluate exercise responses in healthy individuals and patients with chronic disease. Emerging research has shown abnormal ventilatory responses to exercise (either elevated or blunted V' E/V' CO2 ) in some chronic respiratory and cardiovascular conditions. This review will briefly provide an overview of the physiology of ventilatory efficiency, before describing the ventilatory responses to exercise in healthy trained endurance athletes, patients with asthma, and patients with obesity. During submaximal exercise, the V' E/V' CO2 response is generally normal in endurance-trained individuals, patients with asthma and patients with obesity. However, in endurance-trained individuals, asthmatics who demonstrate exercise induced-bronchoconstriction, and morbidly obese individuals, the V' E/V' CO2 can be blunted at maximal exercise, likely because of mechanical ventilatory constraint.

Ventilatory inefficiency during graded exercise in COPD: A pragmatic approach.

The current approach to measuring ventilatory (in)efficiency (V'E -V'CO2 slope, nadir and intercept) presents critical drawbacks in the evaluation of COPD subjects, owing mainly to mechanical ventilatory constraints. Thus, we aimed to compare the current approach with a new method we have developed for ventilatory efficiency calculation. The new procedure was based on measuring the amount of CO2 cleared by the lungs (V'CO2 , L/min) plotted against a predefined range of increase in minute ventilation (V'E ) (ten-fold increase based on semilog scale) during incremental exercise to symptom-limited maximum tolerance. This value was compared to a hypothetical predicted maximum CO2 output at the predicted maximal voluntary ventilation, defining ventilatory efficiency (ηV'E , %). The results were used to compare 30 subjects with COPD (II-IV Global Initiative for Chronic Obstructive Lung Disease, GOLD) and 10 non-COPD smokers, to establish the best discriminative physiological variable for disease severity through logistic multinomial regression. The new approach was more sensitive to progressive deterioration of airway obstruction, resulting in worse ηV'E as lung function worsens throughout the GOLD panel (ηV'E (%), p<.001), when compared with V'E -V'CO2 slope (p=.715) or V'E -V'CO2 nadir (p=.070), besides showing the best model based on the logistic regression approach. Although requiring more complex calculations compared to the current procedure, the new approach is highly sensitive to true ventilatory/gas-exchange deterioration, even throughout more severe pulmonary lung function in COPD subjects.

Respiratory and cardiopulmonary limitations to aerobic exercise capacity in adults born preterm.

Adults born preterm, regardless of whether they develop bronchopulmonary dysplasia, have underdeveloped respiratory and cardiopulmonary systems. The resulting impaired respiratory and cardiopulmonary systems are inadequate for the challenges imposed by aerobic exercise, which is exacerbated by the presence of bronchopulmonary dysplasia. Thus the respiratory and cardiopulmonary systems of these preterm individuals may be the most influential contributors to the significantly lower aerobic exercise capacity compared with their term born counterparts. The precise underlying cause(s) of the lower aerobic exercise capacity in adults born preterm is not entirely known but could be a number of interrelated parameters including mechanical ventilatory constraints, impaired pulmonary gas exchange efficiency, and excessive cardiopulmonary pressures. Likewise, additional aspects, such as impaired cardiovascular function and altered muscle bioenergetics, may play additional roles in limiting aerobic exercise capacity. Whether or not all or some of these aspects are present in adults born preterm and precisely how they may contribute to the lower aerobic exercise capacity are only beginning to be systematically explored. The purpose of this mini-review is to outline what is currently known about the respiratory and cardiopulmonary limitations during exercise in this population and to identify key areas where additional knowledge will help to advance this area. Additionally, where possible, we highlight the similarities and differences between obstructive lung disease resulting from preterm birth and chronic obstructive pulmonary disease (COPD) as the physiology and pathophysiology of these two forms of obstructive lung disease may not be identical.

Sex Differences in the Pulmonary System Influence the Integrative Response to Exercise.

Healthy women have proportionally smaller lungs and airways compared with height-matched men. These anatomical sex-based differences result in greater mechanical ventilatory constraints and may influence the integrative response to exercise. Our review will examine this hypothesis in healthy humans in the context of dynamic whole-body exercise.

Manipulation of mechanical ventilatory constraint during moderate intensity exercise does not influence dyspnoea in healthy older men and women.

The perceived intensity of exertional breathlessness (i.e. dyspnoea) is higher in older women than in older men, possibly as a result of sex-differences in respiratory system morphology. During exercise at a given absolute intensity or minute ventilation, older women have a greater degree of mechanical ventilatory constraint (i.e. work of breathing and expiratory flow limitation) than their male counterparts, which may lead to a greater perceived intensity of dyspnoea. Using a single-blind randomized study design, we experimentally manipulated the magnitude of mechanical ventilatory constraint during moderate-intensity exercise at ventilatory threshold in healthy older men and women. We found that changes in the magnitude of mechanical ventilatory constraint within the physiological range had no effect on dyspnoea in healthy older adults. When older men and women perform moderate intensity exercise, mechanical ventilatory constraint does not contribute significantly to the sensation of dyspnoea. We aimed to determine the effect of manipulating mechanical ventilatory constraint during submaximal exercise on dyspnoea in older men and women. Eighteen healthy subjects (aged 60-80years; nine men and nine women) completed two days of testing. On day1, subjects were assessed for pulmonary function and performed a maximal incremental cycle exercise test. On day2, subjects performed three 6-min bouts of cycling at ventilatory threshold, in a single-blind randomized manner, while breathing: (i) normoxic helium-oxygen (HEL) to reduce the work of breathing (Wb ) and alleviate expiratory flow limitation (EFL); (ii) through an inspiratory resistance (RES) of ∼5 cmH2 OL-1 s-1 to increase Wb ; and (iii) ambient air as a control (CON). Oesophageal pressure, diaphragm electromyography, and sensory responses (category-ratio 10 Borg scale) were monitored throughout exercise. During the HEL condition, there was a significant decrease in Wb (men: -21±6%, women: -17±10%) relative to CON (both P<0.01). Moreover, if EFL was present during CON (four men and five women), it was alleviated during HEL. Conversely, during the RES condition, Wb (men: 42±19%, women: 50±16%) significantly increased relative to CON (both P<0.01). There was no main effect of sex on Wb (P=0.59). Across conditions, women reported significantly higher dyspnoea intensity than men (2.9±0.9vs. 1.9±0.8 Borg scale units, P<0.05). Despite significant differences in the degree of mechanical ventilatory constraint between conditions, the intensity of dyspnoea was unaffected, independent of sex (P=0.46). When older men and women perform moderate intensity exercise, mechanical ventilatory constraint does not contribute significantly to the sensation of dyspnoea.

Experimentally Manipulating Mechanical Ventilatory Constraint During Exercise Does Not Influence Dyspnea in Older Men and Women

During exercise at a standardized metabolic work load, the perception of dyspnea is higher in older women than older men, which is thought to be related to sex-differences in mechanical ventilatory constraint; however, this hypothesis has yet to be experimentally tested. PURPOSE: To determine the effect of manipulating the magnitude of mechanical ventilatory constraint during submaximal exercise on dyspnea in older men and women. METHODS: Thirteen healthy subjects (60-80 y; n=7 women) completed two days of testing. On Day 1, subjects performed pulmonary function testing and a maximal incremental cycle exercise test. On Day 2, esophageal pressure (Pes) and diaphragm electromyography (EMGdi) were recorded during three constant load cycle exercise tests (6 min each) at ventilatory threshold (VTh). Constant load exercise tests were performed under three conditions in a single blind, randomized, counterbalanced fashion: i) breathing normoxic helium-oxygen gas (HeO2) to reduce the work of breathing (W b ) and alleviate expiratory flow limitation (EFL); ii) inspiratory resistance (RES) of 5 cmH2O·l-1·s-1 to increase W b ; and iii) control (CON) breathing room air. During exercise on Day 2, Pes-derived measures of Wb, EMGdi, and EFL were assessed. RESULTS: During the HeO2 condition, there was a significant decrease in Wb (men=-20±4%, women= -16±5%) and EMGdi (men= -11±7%, women= -9±7%) relative to CON (both p<0.01). Moreover, if EFL was present during the CON condition (n=3 men, n=5 women), it was alleviated during HeO2. Conversely, during the RES condition, there was a significant increase in Wb (men= 34±11%, women= 50±12%) and EMGdi (men=32±15%, women= 23±12%) relative to CON (both p<0.01). The effect of condition on Wb and EMGdi was not significantly different between the sexes (both p>0.05). Across conditions, women reported significantly higher levels of dyspnea than men (3.3±0.4 vs. 1.9±0.4 Borg units, p<0.05). However, despite significant differences in the degree of mechanical ventilatory constraint between conditions, there was no effect of condition on the perception of dyspnea intensity, regardless of sex (p=0.46). CONCLUSION: Our results suggest that during short bouts of exercise at VTh, sex-differences in dyspnea in older adults are not related to sex-differences in mechanical ventilatory constraint.

Premature birth affects the degree of airway dysanapsis and mechanical ventilatory constraints

What is the central question of this study? Adult survivors of preterm birth without (PRE) and with bronchopulmonary dysplasia (BPD) have airflow obstruction at rest and significant mechanical ventilatory constraints during exercise compared with those born at full term (CON). Do PRE/BPD have smaller airways, indexed via the dysanapsis ratio, than CON? What is the main finding and its importance? The dysanapsis ratio was significantly smaller in BPD and PRE compared with CON, with BPD having the smallest dysanapsis ratio. These data suggest that airflow obstruction in PRE and BPD might be because of smaller airways than CON. Adult survivors of very preterm birth (≤32weeks gestational age) without (PRE) and with bronchopulmonary dysplasia (BPD) have obstructive lung disease as evidenced by reduced expiratory airflow at rest and have significant mechanical ventilatory constraints during exercise. Airflow obstruction, in any conditions, could be attributable to several factors, including small airways. PRE and/or BPD could have smaller airways than their counterparts born at full term (CON) owing to a greater degree of dysanaptic airway development during the pre- and/or postnatal period. Thus, the purpose of the present study was to compare the dysanapsis ratio (DR), as an index of airway size, between PRE, BPD and CON. To do so, we calculated DR in PRE (n=21), BPD (n=14) and CON (n=34) individuals and examined flow-volume loops at rest and during submaximal exercise. The DR, using multiple estimates of static recoil pressure, was significantly smaller in PRE and BPD (0.16±0.05 and 0.10±0.03a.u.) compared with CON (0.22±0.04a.u.; both P<0.001) and smallest in BPD (P<0.001). The DR was significantly correlated with peak expiratory airflow at rest (r=0.42; P<0.001) and the extent of expiratory flow limitation during exercise (r=0.60; P<0.001). Our findings suggest that PRE/BPD might have anatomically smaller airways than CON, which might help to explain their lower expiratory airflow rate at rest and during exercise and further our understanding of the consequences of preterm birth and neonatal O2 therapy.

Cardiopulmonary Exercise Testing in Pulmonary Hypertension.

Cardiopulmonary exercise testing allows the assessment of the integrative cardiopulmonary response to exercise and is a useful tool to assess the underlying pathophysiologic mechanisms leading to exercise intolerance. Patients with pulmonary hypertension often face a considerable delay in diagnosis due to the rarity of the disease and nonspecific symptoms of dyspnea, fatigue, and exercise limitation. Cardiopulmonary exercise testing may be suggestive of pulmonary hypertension in patients with evidence of both circulatory impairment and ventilatory inefficiency. Other factors, such as mechanical ventilatory constraints from dynamic hyperinflation and peripheral muscle dysfunction, contribute to the profound dyspnea during exercise experienced by many patients with pulmonary hypertension. In patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension, several exercise variables, such as low peak [Formula: see text]o2, high Vd/Vt, and high [Formula: see text]e/[Formula: see text]co2, have proven to be useful in establishing the severity of functional impairment, predicting prognosis, and assessing the efficacy of interventions.

Does Exercise Ventilatory Inefficiency Predict Poor Outcome in Heart Failure Patients With COPD?

To investigate whether the opposite effects of heart failure (HF) and chronic obstructive pulmonary disease (COPD) on exercise ventilatory inefficiency (minute ventilation [(Equation is included in full-text article.)E]-carbon dioxide output [(Equation is included in full-text article.)CO2] relationship) would negatively impact its prognostic relevance. After treatment optimization and an incremental cardiopulmonary exercise test, 30 male patients with HF-COPD (forced expiratory volume in 1 second [FEV1] = 57% ± 17% predicted, ejection fraction = 35% ± 6%) were prospectively followed up during 412 ± 261 days for major cardiac events. Fourteen patients (46%) had a negative outcome. Patients who had an event had lower echocardiographically determined right ventricular fractional area change (RVFAC), greater ventilatory inefficiency (higher (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 nadir), and lower end-tidal CO2 (PETCO2) (all P < .05). Multivariate Cox models revealed that (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 nadir >36, ΔPETCO2(PEAK-REST)≥2 mm Hg, and PETCO2PEAK≤33 mm Hg added prognostic value to RVFAC≤45%. Kaplan-Meyer analyses showed that although 18% of patients with RVFAC>45% had a major cardiac event after 1 year, no patient with RVFAC>45% and (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 nadir ≤36 (or PETCO2PEAK>33 mm Hg) had a negative event. Conversely, although 69% of patients with RVFAC≤45% had a major cardiac event after 1 year, all patients with RVFAC≤45% and ΔPETCO2(PEAK-REST)≥2 mm Hg had a negative event. Ventilatory inefficiency remains a powerful prognostic marker in HF despite the presence of mechanical ventilatory constraints induced by COPD. If these preliminary findings are confirmed in larger studies, optimal thresholds for outcome prediction are likely greater than those traditionally recommended for HF patients without COPD.

Revisiting dysanapsis: sex-based differences in airways and the mechanics of breathing during exercise.

What is the topic of this review? This review focuses on sex-based differences in the anatomy of the respiratory system, which manifest in mechanical ventilatory constraints and potentially alter the integrative response to exercise. What advances does it highlight? Recent evidence indicates that women have smaller conducting airways than men, even when matched for lung size. Consequently, women are more likely to experience mechanical ventilatory constraints to exercise hyperpnoea. Furthermore, at a given ventilation, women have a higher work and oxygen cost of breathing, both of which may lead to differences in the whole-body integrative response to dynamic exercise. Our understanding of the human ventilatory response to exercise is largely based on a historical body of literature focused primarily on male rather than female research subjects. In recent years, important sex-based differences in the anatomy of the human respiratory system have been identified; for a given lung size, women appear to have smaller-diameter conducting airways than men. The presence of such inherent differences in the tracheobronchial tree greatly affects the mechanics of airflow generation, especially during conditions of high ventilation rates, such as exercise. Data from a growing number of studies suggest that women may be more susceptible to respiratory system limitations during exercise than their male counterparts. Specifically, women are more likely to experience expiratory flow limitation and exercise-induced arterial hypoxaemia and have a higher metabolic cost of breathing for a given ventilation. Collectively, the available evidence suggests that sex differences in the ventilatory response to exercise are present and may have important ramifications for the integrated response to exercise; however, several fundamental questions remain unanswered.

Advanced Mechanical Ventilatory Constraints During Incremental Exercise in Class III Obese Male Subjects.

We investigated the role of mechanical ventilatory constraints in obese class III subjects during incremental exercise. We examined 14 control subjects (body mass index [BMI], 23.6 ± 3.2 kg/m(2)), 15 obese class II subjects (BMI, 37.2 ± 4.5 kg/m(2)), and 17 obese class III subjects (BMI, 53.4 ± 6.8 kg/m(2)). All subjects performed pulmonary function tests and maximal inspiratory pressure at rest, ventilatory parameters, flow-volume loops, and rated perceived exertion and breathlessness during exercise. All subjects had normal pulmonary function. Obesity resulted in increased minute ventilation for a given submaximal work rate, although minute ventilation during peak exercise was lowest in the obese class III subjects. End-expiratory lung volume was significantly lower in the obese subjects at rest and during exercise at the ventilatory threshold but not during peak exercise. During heavy-to-peak exercise, the obese subjects increased their end-expiratory lung volume, whereas the control group continued to decrease this parameter. Compared with controls, end-inspiratory lung volume was significantly lower in obese class II subjects and obese class III subjects at rest and at the ventilatory threshold but not during peak exercise. At maximal exercise, obese class III subjects had a greater end-inspiratory lung volume than obese class II subjects and controls. Obese class III subjects displayed a greater expiratory air flow limitation at rest, at the ventilatory threshold, and during peak exercise than both controls and obese class II subjects. Mechanical ventilatory constraints increase progressively with degrees of obesity, contributing to exercise limitation in obese subjects.

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.

Ventilation Distribution Heterogeneity at Rest as a Marker of Exercise Impairment in Mild-to-Advanced COPD

The difference between total lung capacity (TLC) by body plethysmography and alveolar volume (VA) from the single-breath lung diffusing capacity measurement provides an index of ventilation distribution inequalities in COPD. The relevance of these abnormalities to dyspnea and exercise intolerance across the continuum of disease severity remains unknown. Two-hundred and seventy-six COPD patients distributed across GOLD grades 1 to 4 and 67 healthy controls were evaluated. The “poorly communicating fraction” (PCF) of the TLC was estimated as the ratio (%) of TLC to VA. Healthy subjects showed significantly lower PCF values compared to GOLD grades 1 to 4 (10 ± 3% vs. 17 ± 8% vs. 27 ± 10% vs. 37 ± 10% vs. 56 ± 11%, respectively; p < 0.05). Pulmonary gas exchange impairment, mechanical ventilatory constraints and ventilation-corrected dyspnea scores worsened across PCF tertiles (p < 0.05). Of note, GOLD grades 1 and 2 patients with the highest PCF values had pronounced exercise ventilatory inefficiency and dyspnea as a limiting symptom. In fact, dyspnea was a significant contributor to exercise limitation only in those with “moderate” or “extensive” PCF (p < 0.05). A receiver operating characteristics curve analysis revealed that PCF was a better predictor of severely reduced maximal exercise capacity than traditional pulmonary function indexes including FEV1 (area under the curve (95% confidence interval) = 0.85 (0.81–0.89), best cutoff = 33.4%; p < 0.01). In conclusion, PCF is a readily available functional marker of gas exchange and mechanical abnormalities relevant to dyspnea and exercise intolerance across the COPD grades.