Physiological Characterization of Preserved Ratio Impaired Spirometry in the CanCOLD Study: Implications for Exertional Dyspnea and Exercise Intolerance.

Rationale: It is increasingly recognized that adults with preserved ratio impaired spirometry (PRISm) are prone to increased morbidity. However, the underlying pathophysiological mechanisms are unknown. Objectives: Evaluate the mechanisms of increased dyspnea and reduced exercise capacity in PRISm. Methods: We completed a cross-sectional analysis of the CanCOLD (Canadian Cohort Obstructive Lung Disease) population-based study. We compared physiological responses in 59 participants meeting PRISm spirometric criteria (post-bronchodilator FEV1 < 80% predicted and FEV1/FVC ⩾ 0.7), 264 control participants, and 170 ever-smokers with chronic obstructive pulmonary disease (COPD), at rest and during cardiopulmonary exercise testing. Measurements and Main Results: Individuals with PRISm had lower total lung, vital, and inspiratory capacities than healthy controls (all P < 0.05) and minimal small airway, pulmonary gas exchange, and radiographic parenchymal lung abnormalities. Compared with healthy controls, individuals with PRISm had higher dyspnea/[Formula: see text]o2 ratio at peak exercise (4.0 ± 2.2 vs. 2.9 ± 1.9 Borg units/L/min; P < 0.001) and lower [Formula: see text]o2peak (74 ± 22% predicted vs. 96 ± 25% predicted; P < 0.001). At standardized submaximal work rates, individuals with PRISm had greater Vt/inspiratory capacity (Vt%IC; P < 0.001), reflecting inspiratory mechanical constraint. In contrast to participants with PRISm, those with COPD had characteristic small airways dysfunction, dynamic hyperinflation, and pulmonary gas exchange abnormalities. Despite these physiological differences among the three groups, the relationship between increasing dyspnea and Vt%IC during cardiopulmonary exercise testing was similar. Resting IC significantly correlated with [Formula: see text]o2peak (r = 0.65; P < 0.001) in the entire sample, even after adjusting for airflow limitation, gas trapping, and diffusing capacity. Conclusions: In individuals with PRISm, lower exercise capacity and higher exertional dyspnea than healthy controls were mainly explained by lower resting lung volumes and earlier onset of dynamic inspiratory mechanical constraints at relatively low work rates. Clinical trial registered with www.clinicaltrials.gov (NCT00920348).

Beyond Spirometry: Linking Wasted Ventilation to Exertional Dyspnea in the Initial Stages of COPD.

Exertional dyspnea, a key complaint of patients with chronic obstructive pulmonary disease (COPD), ultimately reflects an increased inspiratory neural drive to breathe. In non-hypoxemic patients with largely preserved lung mechanics - as those in the initial stages of the disease - the heightened inspiratory neural drive is strongly associated with an exaggerated ventilatory response to metabolic demand. Several lines of evidence indicate that the so-called excess ventilation (high ventilation-CO2 output relationship) primarily reflects poor gas exchange efficiency, namely increased physiological dead space. Pulmonary function tests estimating the extension of the wasted ventilation and selected cardiopulmonary exercise testing variables can, therefore, shed unique light on the genesis of patients' out-of-proportion dyspnea. After a succinct overview of the basis of gas exchange efficiency in health and inefficiency in COPD, we discuss how wasted ventilation translates into exertional dyspnea in individual patients. We then outline what is currently known about the structural basis of wasted ventilation in "minor/trivial" COPD vis-à-vis the contribution of emphysema versus a potential impairment in lung perfusion across non-emphysematous lung. After summarizing some unanswered questions on the field, we propose that functional imaging be amalgamated with pulmonary function tests beyond spirometry to improve our understanding of this deeply neglected cause of exertional dyspnea. Advances in the field will depend on our ability to develop robust platforms for deeply phenotyping (structurally and functionally), the dyspneic patients showing unordinary high wasted ventilation despite relatively preserved FEV1.

Impaired Ventilatory Efficiency, Dyspnea, and Exercise Intolerance in Chronic Obstructive Pulmonary Disease: Results from the CanCOLD Study.

Rationale: Impaired exercise ventilatory efficiency (high ventilatory requirements for CO2 [[Formula: see text]e/[Formula: see text]co2]) provides an indication of pulmonary gas exchange abnormalities in chronic obstructive pulmonary disease (COPD). Objectives: To determine 1) the association between high [Formula: see text]e/[Formula: see text]co2 and clinical outcomes (dyspnea and exercise capacity) and its relationship to lung function and structural radiographic abnormalities; and 2) its prevalence in a large population-based cohort. Methods: Participants were recruited randomly from the population and underwent clinical evaluation, pulmonary function, cardiopulmonary exercise testing, and chest computed tomography. Impaired exercise ventilatory efficiency was defined by a nadir [Formula: see text]e/[Formula: see text]co2 above the upper limit of normal (ULN), using population-based normative values. Measurements and Main Results: Participants included 445 never-smokers, 381 ever-smokers without airflow obstruction, 224 with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 COPD, and 200 with GOLD 2-4 COPD. Participants with [Formula: see text]e/[Formula: see text]co2 above the ULN were more likely to have activity-related dyspnea (Medical Research Council dyspnea scale ⩾ 2; odds ratio [5-95% confidence intervals], 1.77 [1.31 to 2.39]) and abnormally low peak [Formula: see text]o2 ([Formula: see text]o2peak below the lower limit of normal; odds ratio, 4.58 [3.06 to 6.86]). The Kco had a stronger correlation with nadir [Formula: see text]e/[Formula: see text]co2 (r = -0.38; P < 0.001) than other relevant lung function and computed tomography metrics. The prevalence of [Formula: see text]e/[Formula: see text]co2 above the ULN was 24% in COPD (similar in GOLD 1 and 2 through 4), which was greater than in never-smokers (13%) and ever-smokers (12%). Conclusions: [Formula: see text]e/[Formula: see text]co2 above the ULN was associated with greater dyspnea and low [Formula: see text]o2peak and was present in 24% of all participants with COPD, regardless of GOLD stage. The results show the importance of recognizing impaired exercise ventilatory efficiency as a potential contributor to dyspnea and exercise limitation, even in mild COPD.

Pulmonary Vascular Volume by Quantitative CT in Dyspneic Smokers with Minor Emphysema.

Reduced lung diffusing capacity for carbon monoxide (DLCO) at rest and increased ventilation (⩒E)-carbon dioxide output (⩒CO2) during exercise are frequent findings in dyspneic smokers with largely preserved FEV1. It remains unclear whether low DLCO and high ⩒E-⩒CO2 are mere reflections of alveolar destruction (i.e. emphysema) or impaired pulmonary perfusion in non-emphysematous tissue contributes to these functional abnormalities. Sixty-four smokers (41 males, FEV1= 84 ± 13%predicted) underwent pulmonary function tests, an incremental exercise test, and quantitative chest computed tomography. Total pulmonary vascular volume (TPVV) was calculated for the entire segmented vascular tree (VIDA Vision™). Using the median % low attenuation area (-950 HU), participants were dichotomized into "Trace" or "Mild" emphysema (E), each group classified into preserved versus reduced DLCO. Within each emphysema subgroup, participants with abnormally low DLCO showed lower TPVV, higher ⩒E-⩒CO2, and exertional dyspnea than those with preserved DLCO (p < 0.05). TPVV (r = 0.34; p = 0.01), but not emphysema (r = -0.05; p = 0.67), correlated with lower DLCO after adjusting for age and height. Despite lower emphysema burden, Trace-E participants with reduced DLCO had lower TPVV, higher dyspnea, and lower peak work rate than the Mild-E with preserved DLCO (p < 0.05). Interestingly, TPVV (but not emphysema) correlated inversely with both dyspnea-work rate (r = -0.36, p = 0.004) and dyspnea-⩒E slopes (r = -0.40, p = 0.001). Reduced pulmonary vascular volume adjusted by emphysema extent is associated with low DLCO and heightened exertional ventilation in dyspneic smokers with minor emphysema. Impaired perfusion of non-emphysematous regions of the lungs has greater functional and clinical consequences than hitherto assumed in these subjects.

Exertional dyspnoea in patients with mild-to-severe chronic obstructive pulmonary disease: neuromechanical mechanisms.

In patients with chronic obstructive pulmonary disease (COPD), exertional dyspnoea generally arises when there is imbalance between ventilatory demand and capacity, but the neurophysiological mechanisms are unclear. We therefore determined if disparity between elevated inspiratory neural drive (IND) and tidal volume (VT ) responses (neuromechanical dissociation) impacted dyspnoea intensity and quality during exercise, across the COPD severity spectrum. In this two-centre, cross-sectional observational study, 89 participants with COPD divided into tertiles of FEV1 %predicted (Tertile 1 = FEV1 = 87 ± 9%, Tertile 2 = 60 ± 9%, Tertile 3 = 32 ± 8%) and 18 non-smoking controls, completed a symptom-limited cardiopulmonary exercise test (CPET) with measurement of IND by diaphragm electromyography (EMGdi (%max)). The association between increasing dyspnoea intensity and EMGdi (%max) during CPET was strong (r = 0.730, P < 0.001) and not different between the four groups who showed marked heterogeneity in pulmonary gas exchange and mechanical abnormalities. Significant inspiratory constraints (tidal volume/inspiratory capacity (VT /IC) ≥ 70%) and onset of neuromechanical dissociation (EMGdi (%max):VT /IC > 0.75) occurred at progressively lower minute ventilation ( V ̇ E ${\dot{V}}_{{\rm{E}}}$ ) from Control to Tertile 3. Lower resting IC meant earlier onset of neuromechanical dissociation, heightened dyspnoea intensity and greater propensity (93% in Tertile 3) to select qualitative descriptors of 'unsatisfied inspiration'. We concluded that, regardless of marked variation in mechanical and pulmonary gas exchange abnormalities in our study sample, exertional dyspnoea intensity was linked to the magnitude of EMGdi (%max). Moreover, onset of critical inspiratory constraints and attendant neuromechanical dissociation amplified dyspnoea intensity at higher exercise intensities. Simple measurements of IC and breathing pattern during CPET provide useful insights into mechanisms of dyspnoea and exercise intolerance in individuals with COPD. KEY POINTS: Dyspnoea during exercise is a common and troublesome symptom reported by patients with chronic obstructive pulmonary disease (COPD) and is linked to an elevated inspiratory neural drive (IND). The precise mechanisms of elevated IND and dyspnoea across the continuum of airflow obstruction severity in COPD remains unclear. The present study sought to determine the mechanisms of elevated IND (by diaphragm EMG, EMGdi (%max)) and dyspnoea during cardiopulmonary exercise testing (CPET) across the continuum of COPD severity. There was a strong association between increasing dyspnoea intensity and EMGdi (%max) during CPET across the COPD continuum despite significant heterogeneity in underlying pulmonary gas exchange and respiratory mechanical impairments. Critical inspiratory constraints occurred at progressively lower ventilation during exercise with worsening severity of COPD. This was associated with the progressively lower resting inspiratory capacity with worsening disease severity. Earlier critical inspiratory constraint was associated with earlier neuromechanical dissociation and greater likelihood of reporting the sensation of 'unsatisfied inspiration'.

Excess ventilation and exertional dyspnoea in heart failure and pulmonary hypertension.

Increased ventilation relative to metabolic demands, indicating alveolar hyperventilation and/or increased physiological dead space (excess ventilation), is a key cause of exertional dyspnoea. Excess ventilation has assumed a prominent role in the functional assessment of patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction, pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). We herein provide the key pieces of information to the caring physician to 1) gain unique insights into the seeds of patients' shortness of breath and 2) develop a rationale for therapeutically lessening excess ventilation to mitigate this distressing symptom. Reduced bulk oxygen transfer induced by cardiac output limitation and/or right ventricle-pulmonary arterial uncoupling increase neurochemical afferent stimulation and (largely chemo-) receptor sensitivity, leading to alveolar hyperventilation in HFrEF, PAH and small-vessel, distal CTEPH. As such, interventions geared to improve central haemodynamics and/or reduce chemosensitivity have been particularly effective in lessening their excess ventilation. In contrast, 1) high filling pressures in HFpEF and 2) impaired lung perfusion leading to ventilation/perfusion mismatch in proximal CTEPH conspire to increase physiological dead space. Accordingly, 1) decreasing pulmonary capillary pressures and 2) mechanically unclogging larger pulmonary vessels (pulmonary endarterectomy and balloon pulmonary angioplasty) have been associated with larger decrements in excess ventilation. Exercise training has a strong beneficial effect across diseases. Addressing some major unanswered questions on the link of excess ventilation with exertional dyspnoea under the modulating influence of pharmacological and nonpharmacological interventions might prove instrumental to alleviate the devastating consequences of these prevalent diseases.

Inhaled nitric oxide does not improve maximal oxygen consumption in endurance trained and untrained healthy individuals.

PURPOSE: Previous work suggests that endurance-trained athletes have superior pulmonary vasculature function as compared to untrained individuals, which may contribute to their greater maximal oxygen uptake ([Formula: see text]O2max). Inhaled nitric oxide (iNO) reduces pulmonary vascular resistance in healthy individuals, which could translate into greater cardiac output and improved [Formula: see text]O2max, particularly in untrained individuals. The purpose of the study was to examine whether iNO improved [Formula: see text]O2max in endurance trained and untrained individuals. METHODS: Sixteen endurance-trained and sixteen untrained individuals with normal lung function completed this randomized double-blind cross-over study over four sessions. Experimental cardiopulmonary exercise tests were completed while breathing either normoxia (placebo) or 40 ppm of iNO, on separate days (order randomized). On an additional day, echocardiography was used to determine pulmonary artery systolic pressure at rest and during sub-maximal exercise (60 Watts) while participants breathed normoxia or iNO. RESULTS: Right ventricular systolic pressure was significantly reduced by iNO during exercise (Placebo: 34 ± 7 vs. iNO: 32 ± 7; p = 0.04). [Formula: see text]O2max was greater in the endurance trained group (Untrained: 3.1 ± 0.7 vs. Endurance: 4.3 ± 0.9 L min-1; p < 0.01), however, there was no effect of condition (p = 0.79) and no group by condition interaction (p = 0.68). Peak cardiac output was also unchanged by iNO in either group. CONCLUSION: Despite a reduction in right ventricular systolic pressure, the lack of change in [Formula: see text]O2max with iNO suggests that the pulmonary vasculature does not limit [Formula: see text]O2max in young healthy individuals, regardless of fitness level.

Compensatory responses to increased mechanical abnormalities in COPD during sleep.

PURPOSE: To assess whether night-time increases in mechanical loading negatively impact respiratory muscle function in COPD and whether compensatory increases in inspiratory neural drive (IND) are adequate to stabilize ventilatory output and arterial oxygen saturation, especially during sleep when wakefulness drive is withdrawn. METHODS: 21 patients with moderate-to-severe COPD and 20 age-/sex-matched healthy controls (CTRL) participated in a prospective, cross-sectional, one-night study to assess the impact of COPD on serial awake, supine inspiratory capacity (IC) measurements and continuous dynamic respiratory muscle function (esophageal manometry) and IND (diaphragm electromyography, EMGdi) in supine sleep. RESULTS: Supine inspiratory effort and EMGdi were consistently twice as high in COPD versus CTRL (p < 0.05). Despite overnight increases in awake total airways resistance and dynamic lung hyperinflation in COPD (p < 0.05; not in CTRL), elevated awake EMGdi and respiratory effort were unaltered in COPD overnight. At sleep onset (non-rapid eye movement sleep, N2), EMGdi was decreased versus wakefulness in COPD (- 43 ± 36%; p < 0.05) while unaffected in CTRL (p = 0.11); however, respiratory effort and arterial oxygen saturation (SpO2) were unchanged. Similarly, in rapid eye movement (stage R), sleep EMGdi was decreased (- 38 ± 32%, p < 0.05) versus wakefulness in COPD, with preserved respiratory effort and minor (2%) reduction in SpO2. CONCLUSIONS: Despite progressive mechanical loading overnight and marked decreases in wakefulness drive, inspiratory effort and SpO2 were well maintained during sleep in COPD. Preserved high inspiratory effort during sleep, despite reduced EMGdi, suggests continued (or increased) efferent activation of extra-diaphragmatic muscles, even in stage R sleep. CLINICAL TRIAL INFORMATION: The COPD data reported herein were secondary data (Placebo arm only) obtained through the following Clinical Trial: "Effect of Aclidinium/Formoterol on Nighttime Lung Function and Morning Symptoms in Chronic Obstructive Pulmonary Disease" ( https://clinicaltrials.gov/ct2/show/NCT02429765 ; NCT02429765).

Inhaled nitric oxide improves ventilatory efficiency and exercise capacity in patients with mild COPD: A randomized-control cross-over trial.

KEY POINTS: Patients with mild chronic obstructive pulmonary disease (COPD) have an elevated ventilatory equivalent to CO2 production ( V̇E / V̇CO2 ) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. Despite emerging evidence that mild COPD is associated with pulmonary microvascular dysfunction, limited research has focused on experimentally modulating the pulmonary microvasculature during exercise in mild COPD. The present study sought to examine the effect of inhaled nitric oxide (iNO), a selective pulmonary vasodilator, on V̇E / V̇CO2 , dyspnoea and exercise capacity in patients with mild COPD. Experimental iNO increased peak oxygen uptake in mild COPD, secondary to reduced V̇E / V̇CO2 and dyspnoea. This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD. ABSTRACT: Patients with mild chronic obstructive pulmonary disease (COPD) have an exaggerated ventilatory response to exercise, contributing to dyspnoea and exercise intolerance. Previous research in mild COPD has demonstrated an elevated ventilatory equivalent to CO2 production ( V̇E / V̇CO2 ) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. The present study tested the hypothesis that inhaled nitric oxide (iNO), a selective pulmonary vasodilator, would lower V̇E / V̇CO2 and dyspnoea, and improve exercise capacity in patients with mild COPD. In this multigroup randomized-control cross-over study, 15 patients with mild COPD (FEV1  =  89 ± 11% predicted) and 15 healthy controls completed symptom-limited cardiopulmonary exercise tests while breathing normoxic gas or 40 ppm iNO. Compared with placebo, iNO significantly increased peak oxygen uptake (1.80 ± 0.14 vs. 1.53 ± 0.10 L·min-1 , P < 0.001) in COPD, whereas no effect was observed in controls. At an equivalent work rate of 60 W, iNO reduced V̇E / V̇CO2 by 3.8 ± 4.2 units (P = 0.002) and dyspnoea by 1.1 ± 1.2 Borg units (P < 0.001) in COPD, whereas no effect was observed in controls. Operating lung volumes and oxygen saturation were unaffected by iNO in both groups. iNO increased peak oxygen uptake in COPD, secondary to reduced V̇E / V̇CO2 and dyspnoea. These data suggest that mild COPD patients demonstrate pulmonary microvascular dysfunction that contributes to increased V̇E / V̇CO2 , dyspnoea and exercise intolerance. This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD.

Reduced exercise tolerance in mild chronic obstructive pulmonary disease: The contribution of combined abnormalities of diffusing capacity for carbon monoxide and ventilatory efficiency.

BACKGROUND AND OBJECTIVE: The combination of both reduced resting diffusing capacity of the lung for carbon monoxide (DLCO ) and ventilatory efficiency (increased ventilatory requirement for CO2 clearance [V˙E /V˙CO2 ]) has been linked to exertional dyspnoea and exercise intolerance in chronic obstructive pulmonary disease (COPD) but the underlying mechanisms are poorly understood. The current study examined if low resting DLCO and higher exercise ventilatory requirements were associated with earlier critical dynamic mechanical constraints, dyspnoea and exercise limitation in patients with mild COPD. METHODS: In this retrospective analysis, we compared V˙E /V˙CO2 , dynamic inspiratory reserve volume (IRV), dyspnoea and exercise capacity in groups of patients with Global Initiative for Chronic Obstructive Lung Disease stage 1 COPD with (1) a resting DLCO at or greater than the lower limit of normal (≥LLN; Global Lung Function Initiative reference equations [n = 44]) or (2) below the

Blunted sympathetic neurovascular transduction is associated to the severity of obstructive sleep apnea.

PURPOSE: Obstructive sleep apnea (OSA) is a common disorder (~ 4%) that augments sympathetic nerve activity (SNA) and elevates blood pressure. The relationship between sympathetic vasomotor outflow and vascular responsiveness, termed sympathetic neurovascular transduction (sNVT), has been sparsely characterized in patients with OSA. Therefore, we sought to quantify spontaneous sympathetic bursts and related changes in diastolic pressure. METHODS: Twelve participants with variable severities of OSA were recruited. We collected muscle sympathetic nerve activity (MSNA) (microneurography) and beat-by-beat diastolic pressure (finger photoplethysmography) during normoxia (FiO2 = 0.21) and hyperoxia (FiO2 = 1.0) to decrease MSNA burst frequency. MSNA burst sequences (i.e. singlets, doublets, triplets and quadruplets) were identified and coupled to changes in diastolic pressure over 15 cardiac cycles as an index of sNVT. sNVT slope for each individual was calculated from the slope of the relationship between peak responses in outcome plotted against normalized burst amplitude. RESULTS: sNVT slope was unchanged during hyperoxia compared to normoxia (normoxia 0.0024 ± 0.0011 Δ mmHg total activity [a.u.]-1 vs. hyperoxia 0.0029 ± 0.00098 Δ mmHg total activity [a.u.]-1; p = 0.14). sNVT slope was inversely associated with burst frequency during hyperoxia (r = -0.58; p = 0.04), but not normoxia (r = -0.11; p = 0.71). sNVT slope was inversely associated with the apnea-hypopnea index (AHI) (r = -0.62; p = 0.030), but not after age was considered. CONCLUSIONS: We have demonstrated that the prevailing MSNA frequency is unmatched to the level of sNVT, and this can be altered by acute hyperoxia.

Mechanisms of Exertional Dyspnea in Patients with Mild COPD and a Low Resting DLCO.

Patients with mild chronic obstructive pulmonary disease (COPD) and lower resting diffusing capacity for carbon monoxide (DLCO) often report troublesome dyspnea during exercise although the mechanisms are not clear. We postulated that in such individuals, exertional dyspnea is linked to relatively high inspiratory neural drive (IND) due, in part, to the effects of reduced ventilatory efficiency. This cross-sectional study included 28 patients with GOLD I COPD stratified into two groups with (n = 15) and without (n = 13) DLCO less than the lower limit of normal (

Cardiac rehabilitation in the paediatric Fontan population: development of a home-based high-intensity interval training programme.

INTRODUCTION: We evaluated the safety and feasibility of high-intensity interval training via a novel telemedicine ergometer (MedBIKE™) in children with Fontan physiology. METHODS: The MedBIKE™ is a custom telemedicine ergometer, incorporating a video game platform and live feed of patient video/audio, electrocardiography, pulse oximetry, and power output, for remote medical supervision and modulation of work. There were three study phases: (I) exercise workload comparison between the MedBIKE™ and a standard cardiopulmonary exercise ergometer in 10 healthy adults. (II) In-hospital safety, feasibility, and user experience (via questionnaire) assessment of a MedBIKE™ high-intensity interval training protocol in children with Fontan physiology. (III) Eight-week home-based high-intensity interval trial programme in two participants with Fontan physiology. RESULTS: There was good agreement in oxygen consumption during graded exercise at matched work rates between the cardiopulmonary exercise ergometer and MedBIKE™ (1.1 ± 0.5 L/minute versus 1.1 ± 0.5 L/minute, p = 0.44). Ten youth with Fontan physiology (11.5 ± 1.8 years old) completed a MedBIKE™ high-intensity interval training session with no adverse events. The participants found the MedBIKE™ to be enjoyable and easy to navigate. In two participants, the 8-week home-based protocol was tolerated well with completion of 23/24 (96%) and 24/24 (100%) of sessions, respectively, and no adverse events across the 47 sessions in total. CONCLUSION: The MedBIKE™ resulted in similar physiological responses as compared to a cardiopulmonary exercise test ergometer and the high-intensity interval training protocol was safe, feasible, and enjoyable in youth with Fontan physiology. A randomised-controlled trial of a home-based high-intensity interval training exercise intervention using the MedBIKE™ will next be undertaken.

Ventilatory responses in males and females during graded exercise with and without thoracic load carriage.

PURPOSE AND METHODS: To compare the effects of thoracic load carriage on the ventilatory and perceptual responses to graded exercise, 14 pairs of height-matched, physically active males and females completed randomly ordered modified Balke treadmill exercise tests with and without a correctly sized and fitted 20.4 kg backpack and work clothing. Subjects walked at 1.56 m.s- 1 while grade was increased by 2% every 2 min until exhaustion. Ventilatory responses were measured with open circuit spirometry and perceptual responses were evaluated using the modified Borg scale. Inspiratory capacity maneuvers were performed to calculate operating lung volumes. RESULTS: Despite height matching, males had significantly greater lung volumes and peak oxygen uptake ([Formula: see text]O2peak). Peak [Formula: see text]O2 and ventilation ([Formula: see text]E) were lower (p < 0.05) for all subjects under load. Throughout exercise, the ventilatory equivalents for [Formula: see text]O2 and carbon dioxide production were significantly higher in females, independent of condition. At similar relative submaximal intensities (%[Formula: see text]O2peak), there was no difference in [Formula: see text]E between conditions in either group, however, all subjects adopted a rapid and shallow breathing pattern under load with decreased tidal volume secondary to lower end-inspiratory lung volume. The relative changes in breathing pattern and operating lung volume between unloaded and loaded conditions were similar between males and females. Females reported significantly higher dyspnea ratings for a given [Formula: see text]E compared to males; however, the relationship between dyspnea and [Formula: see text]E was unaffected by load carriage. CONCLUSION: The relative response patterns for ventilatory and perceptual responses to graded exercise with thoracic loading were similar in males and females.

The carotid chemoreceptor contributes to the elevated arterial stiffness and vasoconstrictor outflow in chronic obstructive pulmonary disease.

KEY POINTS: The reason(s) for the increased central arterial stiffness in chronic obstructive pulmonary disease (COPD) are not well understood. In this study, we inhibited the carotid chemoreceptor with both low-dose dopamine and hyperoxia, and observed a decrease in central arterial stiffness and muscle sympathetic nervous activity in COPD patients, while no change was observed in age- and risk-matched controls. Carotid chemoreceptor inhibition increased vascular conductance, secondary to reduced arterial blood pressure in COPD patients. Findings from the current study suggest that elevated carotid chemoreceptor activity may contribute to the increased arterial stiffness typically observed in COPD patients. ABSTRACT: Chronic obstructive pulmonary disease (COPD) patients have increased central arterial stiffness and muscle sympathetic nervous activity (MSNA), both of which contribute to cardiovascular (CV) dysfunction and increased CV risk. Previous work suggests that COPD patients have elevated carotid chemoreceptor (CC) activity/sensitivity, which may contribute to the elevated MSNA and arterial stiffness. Accordingly, the effect of CC inhibition on central arterial stiffness, MSNA and CV function at rest in COPD patients was examined in a randomized placebo-controlled study. Thirteen mild-moderate COPD patients (forced expired volume in 1 s (FEV1 ) predicted ± SD: 83 ± 18%) and 13 age- and risk-matched controls completed resting CV function measurements with either i.v. saline or i.v. dopamine (2 µg kg-1  min-1 ) while breathing normoxic or hyperoxic air (100% O2 ). On a separate day, a subset of COPD patients and controls completed MSNA measurements while breathing normoxic or hyperoxic air. Arterial stiffness was determined by pulse-wave velocity (PWV) and MSNA was measured by microneurography. Brachial blood flow was determined using Doppler ultrasound, cardiac output was estimated by impedance cardiography, and vascular conductance was calculated as flow/mean arterial pressure (MAP). CC inhibition with dopamine decreased central and peripheral PWV, and MAP (P < 0.05) while increasing vascular conductance in COPD. No change in CV function was observed with dopamine in controls. CC inhibition with hyperoxia decreased peripheral PWV and MSNA (P < 0.05) in COPD, while no change was observed in controls. CC inhibition decreased PWV and MSNA, and improved vascular conductance in COPD, suggesting that tonic CC activity is elevated at rest and contributes to the elevated arterial stiffness in COPD.

Ventilatory responses to prolonged exercise with heavy load carriage.

PURPOSE: The purpose of this experiment was to study breathing pattern and operating lung volume during 45 min of exercise with a heavy backpack (25 kg) and examine the effect of this exercise on respiratory muscle strength. METHODS: Fifteen males completed randomly ordered graded exercise tests on a treadmill with and without a correctly sized and fitted 25 kg pack. Subsequently, each subject completed, in random order, on separate days, 45 min of treadmill walking with and without the pack. Oxygen demand was matched between conditions (loaded: 3.01 ± 0.11 and unloaded 3.02 ± 0.11 L min(-1)). RESULTS: With load, breathing frequency (f B) and minute ventilation increased by 21.7 and 15.1 % (P < 0.05), respectively, while tidal volume (V T) and end-inspiratory lung volume (EILV) were reduced by 6.3 and 6.4% (P < 0.05), respectively, compared to unloaded. Following loaded exercise, maximal inspiratory pressure decreased by 6.7% (P < 0.05) with no change in maximal expiratory pressure. No changes in maximal inspiratory or expiratory pressures were observed following unloaded exercise. Despite equivalent oxygen demand, perceived exercise stress and breathing discomfort was higher (P < 0.05) in the loaded condition. CONCLUSIONS: The mechanical disadvantage placed on the respiratory system during exercise with a heavy pack led to compensatory changes in breathing pattern and EILV, and a reduction in maximal inspiratory pressure post-exercise. We suggest that in an attempt to minimize the work of breathing, subjects adopted a shallow and frequent breathing pattern. However, this pattern increased deadspace and minute ventilation, which likely contributed to altered perceptions of exercise stress and breathing discomfort.

The impact of thoracic load carriage up to 45 kg on the cardiopulmonary response to exercise.

PURPOSE: The purposes of this experiment were to, first, document the effect of 45-kg thoracic loading on peak exercise responses and, second, the effects of systematic increases in thoracic load on physiological responses to submaximal treadmill walking at a standardized speed and grade. METHODS: On separate days, 19 males (age 27 ± 5 years, height 180.0 ± 7.4 cm, mass 86.9 ± 15.1 kg) completed randomly ordered graded exercise tests to exhaustion in loaded (45 kg) and unloaded conditions. On a third day, each subject completed four randomly ordered, 10-min bouts of treadmill walking at 1.34 m s(-1) and 4 % grade in the following conditions: unloaded, and with backpacks weighted to 15, 30, and 45 kg. RESULTS: With 45-kg thoracic loading, absolute oxygen consumption ([Formula: see text]), minute ventilation, power output, and test duration were significantly decreased at peak exercise. End-inspiratory lung volume and tidal volume were significantly reduced with no changes in end-expiratory lung volume, breathing frequency, and the respiratory exchange ratio. Peak end-tidal carbon dioxide and the ratio of alveolar ventilation to carbon dioxide production were similar between conditions. The reductions in peak physiological responses were greater than expected based on previous research with lighter loads. During submaximal treadmill exercise, [Formula: see text] increased (P < 0.05) by 11.0 (unloaded to 15 kg), 14.5 (15-30 kg), and 18.0 % (30-45 kg) showing that the increase in exercise [Formula: see text] was not proportional to load mass. CONCLUSION: These results provide further insight into the specificity of physiological responses to different types of load carriage.

Reduced tidal volume-inflection point and elevated operating lung volumes during exercise in females with well-controlled asthma.

INTRODUCTION: Individuals with asthma breathe at higher operating lung volumes during exercise compared with healthy individuals, which contributes to increased exertional dyspnoea. In health, females are more likely to develop exertional dyspnoea than males at a given workload or ventilation, and therefore, it is possible that females with asthma may develop disproportional dyspnoea on exertion. The purpose of this study was to compare operating lung volume and dyspnoea responses during exercise in females with and without asthma. METHODS: Sixteen female controls and 16 females with asthma were recruited for the study along with 16 male controls and 16 males with asthma as a comparison group. Asthma was confirmed using American Thoracic Society criteria. Participants completed a cycle ergometry cardiopulmonary exercise test to volitional exhaustion. Inspiratory capacity manoeuvres were performed to estimate inspiratory reserve volume (IRV) and dyspnoea was evaluated using the Modified Borg Scale. RESULTS: Females with asthma exhibited elevated dyspnoea during submaximal exercise compared with female controls (p<0.05). Females with asthma obtained a similar IRV and dyspnoea at peak exercise compared with healthy females despite lower ventilatory demand, suggesting mechanical constraint to tidal volume (VT) expansion. VT-inflection point was observed at significantly lower ventilation and V̇O2 in females with asthma compared with female controls. Forced expired volume in 1 s was significantly associated with VT-inflection point in females with asthma (R2=0.401; p<0.01) but not female controls (R2=0.002; p=0.88). CONCLUSION: These results suggest that females with asthma are more prone to experience exertional dyspnoea, secondary to dynamic mechanical constraints during submaximal exercise when compared with females without asthma.

Physiological underpinnings of exertional dyspnoea in mild fibrosing interstitial lung disease.

The functional disturbances driving "out-of-proportion" dyspnoea in patients with fibrosing interstitial lung disease (f-ILD) showing only mild restrictive abnormalities remain poorly understood. Eighteen patients (10 with idiopathic pulmonary fibrosis) showing preserved spirometry and mildly reduced total lung capacity (≥70% predicted) and 18 controls underwent an incremental cardiopulmonary exercise test with measurements of operating lung volumes and Borg dyspnoea scores. Patients' lower exercise tolerance was associated with higher ventilation (V̇E)/carbon dioxide (V̇CO2) compared with controls (V̇E/V̇CO2 nadir=35 ± 3 versus 29 ± 2; p < 0.001). Patients showed higher tidal volume/inspiratory capacity and lower inspiratory reserve volume at a given exercise intensity, reporting higher dyspnoea scores as a function of both work rate and V̇E. Steeper dyspnoea-work rate slopes were associated with lower lung diffusing capacity, higher V̇E/V̇CO2, and lower peak O2 uptake (p < 0.05). Heightened ventilatory demands in the setting of progressively lower capacity for tidal volume expansion on exertion largely explain higher-than-expected dyspnoea in f-ILD patients with largely preserved dynamic and "static" lung volumes at rest.

Systemic Determinants of Exercise Intolerance in Patients With Fibrotic Interstitial Lung Disease and Severely Impaired DLCO.

BACKGROUND: The precise mechanisms driving poor exercise tolerance in patients with fibrotic interstitial lung diseases (fibrotic ILDs) showing a severe impairment in single-breath lung diffusing capacity for carbon monoxide (DLCO < 40% predicted) are not fully understood. Rather than only reflecting impaired O2 transfer, a severely impaired DLCO may signal deranged integrative physiologic adjustments to exercise that jointly increase the burden of exertional symptoms in fibrotic ILD. METHODS: Sixty-seven subjects (46 with idiopathic pulmonary fibrosis, 24 showing DLCO < 40%) and 22 controls underwent pulmonary function tests and an incremental cardiopulmonary exercise test with serial measurements of operating lung volumes and 0-10 Borg dyspnea and leg discomfort scores. RESULTS: Subjects from the DLCO < 40% group showed lower spirometric values, more severe restriction, and lower alveolar volume and transfer coefficient compared to controls and participants with less impaired DLCO (P < .05). Peak work rate was ∼45% (vs controls) and ∼20% (vs DLCO > 40%) lower in the former group, being associated with lower (and flatter) O2 pulse, an earlier lactate (anaerobic) threshold, heightened submaximal ventilation, and lower SpO2 . Moreover, critically high inspiratory constrains were reached at lower exercise intensities in the DLCO < 40% group (P < .05). In association with the greatest leg discomfort scores, they reported the highest dyspnea scores at a given work rate. Between-group differences lessened or disappeared when dyspnea intensity was related to indexes of increased demand-capacity imbalance, that is, decreasing submaximal, dynamic ventilatory reserve, and inspiratory reserve volume/total lung capacity (P > .05). CONCLUSIONS: A severely reduced DLCO in fibrotic ILD signals multiple interconnected derangements (cardiovascular impairment, an early shift to anaerobic metabolism, excess ventilation, inspiratory constraints, and hypoxemia) that ultimately lead to limiting respiratory (dyspnea) and peripheral (leg discomfort) symptoms. DLCO < 40%, therefore, might help in clinical decision-making to indicate the patient with fibrotic ILD who might derive particular benefit from pharmacologic and non-pharmacologic interventions aimed at lessening these systemic abnormalities.