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Excess exercise ventilation (high ventilation (V̇ E )/carbon dioxide output (V̇CO 2 )) contributes significantly to dyspnea and exercise intolerance since the earlier stages of chronic obstructive pulmonary disease (COPD). A selective pulmonary vasodilator (inhaled nitric oxide) has shown to increase exercise tolerance secondary to lower V̇ E /V̇CO 2 and dyspnea in this patient population. We aimed to assess whether a clinically more practical option - oral sildenafil - would be associated with similar beneficial effects. In a randomized, placebo-controlled study, twenty-four patients with mild-to-moderate COPD completed, on different days, two incremental cardiopulmonary exercise tests (CPET) one hour after sildenafil or placebo. Eleven healthy participants performed a CPET in a non-interventional visit for comparative purposes with patients when receiving placebo. Patients (FEV 1 = 69.4 ± 13.5 % predicted) showed higher ventilatory demands (V̇ E /V̇CO 2 ), worse pulmonary gas exchange, and higher dyspnea during exercise compared to controls (FEV 1 = 98.3 ±11.6 % predicted). Contrary to our expectations, however, sildenafil (50 mg; N= 15) did not change exertional V̇ E /V̇CO 2 , dead space/tidal volume ratio, operating lung volumes, dyspnea, or exercise tolerance compared to placebo (P>0.05). Due to the lack of significant beneficial effects, nine additional patients were trialed with a higher dose (100 mg). Similarly, active intervention was not associated with positive physiological or sensory effects. In conclusion, acute oral sildenafil (50 or 100 mg) failed to improve gas exchange efficiency or excess exercise ventilation in patients with predominantly moderate COPD. The current study does not endorse a therapeutic role for sildenafil to mitigate exertional dyspnea in this specific patient subpopulation. Clinical trial registry: https://ensaiosclinicos.gov.br/rg/RBR-4qhkf4 Web of Science Researcher ID: O-7665-2019., Competing Interests: Declaration of Competing Interest No authors declare conflicts of interest related to this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Activity-related dyspnea in chronic lung disease is centrally related to dynamic ( dyn ) inspiratory constraints to tidal volume expansion. Lack of reference values for exertional inspiratory reserve (IR) has limited the yield of cardiopulmonary exercise testing in exposing the underpinnings of this disabling symptom. One hundred fifty apparently healthy subjects (82 males) aged 40-85 underwent incremental cycle ergometry. Based on exercise inspiratory capacity (IC dyn ), we generated centile-based reference values for the following metrics of IR as a function of absolute ventilation: IR dyn1 ([1-(tidal volume/IC dyn )] x 100) and IR dyn2 ([1-(end-inspiratory lung volume/total lung capacity] x 100). IR dyn1 and IR dyn2 standards were typically lower in females and older subjects (p<0.05 for sex and age versus ventilation interactions). Low IR dyn1 and IR dyn2 significantly predicted the burden of exertional dyspnea in both sexes (p<0.01). Using these sex and age-adjusted limits of reference, the clinician can adequately judge the presence and severity of abnormally low inspiratory reserves in dyspneic subjects undergoing cardiopulmonary exercise testing., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest relative to this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The causes and consequences of excess exercise ventilation (EEV) in patients with fibrosing interstitial lung disease (f-ILD) were explored. Twenty-eight adults with f-ILD and 13 controls performed an incremental cardiopulmonary exercise test. EEV was defined as ventilation-carbon dioxide output (⩒E-⩒CO 2 ) slope ≥36 L/L. Patients showed lower pulmonary function and exercise capacity compared to controls. Lower DL CO was related to higher ⩒E-⩒CO 2 slope in patients (P<0.05). 13/28 patients (46.4%) showed EEV, reporting higher dyspnea scores (P=0.033). Patients with EEV showed a higher dead space (VD)/tidal volume (VT) ratio while O 2 saturation dropped to a greater extent during exercise compared to those without EEV. Higher breathing frequency and VT/inspiratory capacity ratio were observed during exercise in the former group (P<0.05). An exaggerated ventilatory response to exercise in patients with f-ILD is associated with a blunted decrease in the wasted ventilation in the physiological dead space and greater hypoxemia, prompting higher inspiratory constraints and breathlessness., Competing Interests: Declaration of Competing Interest All authors report no relationships that could be interpreted as a conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In 15 pulmonary arterial hypertension patients, the relation of functional capacity to their peripheral endothelial function and sympathaovagal modulation was studied by carrying out brachial artery ultrasound and electrocardiogram spectral analysis, respectively. The functional capacity was assessed by cardiopulmonary exercise testing and six-minute walking test. The sympathovagal modulation was correlated with the predicted peak oxygen consumption (peak VO 2 %; r = 0.692, P < 0.05), peak O 2 pulse (mL/beat; r = 0.661, P < 0.05), VE, minute ventilation, VCO 2 carbon dioxide production (VE/VCO 2 slope; r=-0.806, P < 0.01) and distance walked predicted (%6MWT; r = 0.694, P < 0.05). Moreover, there were negative correlations between parasympathetic modulation with peak VO 2 (r = 0.755, P < 0.01), peak VO 2 % (r=-0.727, P < 0.01) and peak O 2 pulse (r = 0.615, P < 0.05), %6MWT (r=-0.834, P < 0.01). Collectively these correlations indicate that parasympathetic withdrawal is crucial for improving functional capacity. This conclusion is supported by both positive and negative correlations of parasympathetic modulation with the functional capacity parameters. The sympathetic modulation predominance, although increases the cardiovascular risk, is probably crucial to facilitate the bronchodilation and the oxygen uptake., (Copyright © 2021. Published by Elsevier B.V.)

We aimed to assess detailed ventilatory and sensory responses to exercise contrasting subjects with and without PAH. 20 non-smoking patients with PAH (37.5 ± 12.1 ys; FEV 1 /FVC = 0.77 ± 0.04; mPAP by heart catheterization = 50.6 ± 18.1 mmHg) and 10 matched controls performed cycling cardiopulmonary exercise test with serial assessments of dyspnea, airway occlusion pressure during the first 0.1 s (P0.1) of tidal volume and inspiratory capacity (IC). Patients showed lower spirometric variables compared to controls. Dyspnea and ventilation (V E ) were significantly higher in patients for a given work rate. Dyspnea persisted more intense in patients even when expressed as a function of V E . Lower IC at rest (in non-hyperinflators; n = 10) or exercise-induced reduction in IC (in hyperinflators) predisposed patients to achieve earlier and at lower workloads a critical inspiratory reserve volume (IRV). At this point, there was a sudden rise in P0.1 and dyspnea perception. Attainment of a critical IRV at premature workloads leads to neuromechanical dissociation with an abrupt increment in exertional dyspnea., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Reduction in inspiratory capacity (IC) during exercise has been reported in chronic heart failure (CHF). Since inspiratory muscle dysfunction may be present to a variable degree, the assumption that IC reduction during exercise represents an increase in end-expiratory lung volume must be made with caution. This interpretation is flawed if patients develop dynamic inspiratory muscle strength reduction, i.e., progressively lower esophageal (Pes) pressures as the IC maneuvers are repeated. Sixteen CHF patients and 9 age-matched controls performed an incremental exercise test with serial IC and respiratory pressure measurements. Regardless whether IC decreased or not with exercise (N = 4 and N = 12, respectively), Pes,IC remained stable. This was confirmed by similar Pes,sniff immediately upon exercise cessation (p > .05). No association was found between changes in IC and related Pes from rest to peak exercise. Owing to the lack of dynamic inspiratory muscle weakness, non-invasive indexes of lung mechanics can be reliably obtained from exercise IC in CHF., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Interval exercise delays critical mechanical-ventilatory constraints with positive consequences on Dyspnoea and exercise tolerance in COPD. We hypothesized that those advantages of interval exercise would be partially off-set in patients showing excessive ventilation (V˙E) to metabolic demand (V˙CO 2 ). Sixteen men (FEV 1  = 42.3 ± 8.9%) performed, on different days, 30 s and 60 s bouts at 100% peak (on) interspersed by moderate exercise at 40% (off). Nine patients did not sustain exercise for 30 min irrespective of on duration. They presented with higher V˙E/V˙CO 2 nadir (35 ± 3 vs. 30 ± 5) and dead space/tidal volume (0.39 ± 0.05 vs. 0.34 ± 0.06) compared to their counterparts (p < 0.05). [Lactate], operating lung volumes and symptom burden (dyspnoea and leg effort) were also higher (p < 0.05). Unloading off decreased the metabolic-ventilatory demands, thereby allowing 7/9 patients to exercise for 30 min. Increased wasted ventilation accelerates the rate at which critical mechanical constraints and limiting dyspnoea are reached during interval exercise in patients with COPD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Inspiratory resistive loading (IRL) may have deleterious cardiocirculatory effects leading to poor peripheral perfusion in severely-hyperinflated patients with COPD. Nineteen patients (13 severely-hyperinflated with inspiratory capacity/total lung capacity ratio≤0.28) underwent calf blood flow (CBF) measurements by venous occlusion plethysmography at rest and during IRL at 60% maximal inspiratory pressure. Severely-hyperinflated patients had lower resting CBF and greater calf vascular resistance (CVR) than moderately-hyperinflated patients (p<0.05). All severely-hyperinflated patients had markedly reduced CBF (p=0.01). Opposite to our main hypothesis, however, IRL did not further reduce CBF in these patients (p>0.05). Conversely, it significantly decreased CBF and increased CVR in moderately-hyperinflated patients; in fact, end-trial CBF and CVR did not differ between the groups (p>0.05). In conclusion, marked impairments in resting appendicular blood flow in severely-hyperinflated patients with COPD were seen only after acute IRL in less hyperinflated patients. These findings set the stage for studies investigating the effects of lung deflation on peripheral hemodynamics in patients with severe hyperinflation., (Copyright © 2016 Elsevier B.V. All rights reserved.)