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Background: Continuous monitoring of pulse oximetry (S pO 2 ) is recommended during the 6-min walk test (6MWT) to ensure that the lowest S pO 2 is recorded. In this case, severe exercise-induced desaturation (EID; S pO 2 < 80%) triggers walking interruption by the examiner. Our main objective was to assess the impact of this approach on 6MWT distance in patients with chronic respiratory diseases and, second, to evaluate the safety of the test without interruption due to severe EID., Methods: 6MWTs with continuous monitoring of S pO 2 were prospectively performed in subjects with chronic respiratory disease. The participants were randomly allocated to walk with or without S pO 2 real-time assessment. S pO 2 visualization during the test execution was available only in the first group, and walking interruption was requested by the examiner if S pO 2 < 80%., Results: One hundred forty-five participants were included in each group (68.6% females, 62 [52-69] y old) without differences in demographic and resting lung function parameters between them. The main respiratory conditions were COPD ( n = 101), asthma ( n = 73), pulmonary hypertension ( n = 47), and interstitial lung disease ( n = 39). The walked distance was similar comparing groups (349.5 ± 117.5 m vs 351.2 ± 105.4 m). Twenty-five subjects presented with severe EID in the group with real-time S pO 2 assessment, and 20 subjects had severe EID in the group without real-time assessment respectively (overall prevalence of 15.5%). The 23 participants who had their test interrupted by the examiner due to severe EID in the first group (2 subjects stopped by themselves due to excessive symptoms) walked a shorter distance compared to the 11 subjects with severe EID without test interruption in the second group (9 subjects stopped by themselves due to excessive symptoms): 240.6 ± 100.2 m versus 345.9 ± 73.4 m. No exercise-related serious adverse events were observed., Conclusions: Interruption driven by severe EID reduced the walked distance during the 6MWT. No serious adverse event, in turn, was observed in subjects with severe desaturation without real-time S pO 2 assessment., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2024 by Daedalus Enterprises.)

Objective: To investigate the impact of impaired pulmonary function on patient-centered outcomes after hospital discharge due to severe COVID-19 in patients without preexisting respiratory disease., Methods: This is an ongoing prospective cohort study evaluating patients (> 18 years of age) 2-6 months after hospital discharge due to severe COVID-19. Respiratory symptoms, health-related quality of life, lung function, and the six-minute walk test were assessed. A restrictive ventilatory defect was defined as TLC below the lower limit of normal, as assessed by plethysmography. Chest CT scans performed during hospitalization were scored for the presence and extent of parenchymal abnormalities., Results: At a mean follow-up of 17.2 ± 5.9 weeks after the diagnosis of COVID-19, 120 patients were assessed. Of those, 23 (19.2%) reported preexisting chronic respiratory diseases and presented with worse lung function and exertional dyspnea at the follow-up visit in comparison with their counterparts. When we excluded the 23 patients with preexisting respiratory disease plus another 2 patients without lung volume measurements, a restrictive ventilatory defect was observed in 42/95 patients (44%). This subgroup of patients (52.4% of whom were male; mean age, 53.9 ± 11.3 years) showed reduced resting gas exchange efficiency (DLCO), increased daily-life dyspnea, increased exertional dyspnea and oxygen desaturation, and reduced health-related quality of life in comparison with those without reduced TLC (50.9% of whom were male; mean age, 58.4 ± 11.3 years). Intensive care need and higher chest CT scores were associated with a subsequent restrictive ventilatory defect., Conclusions: The presence of a restrictive ventilatory defect approximately 4 months after severe COVID-19 in patients without prior respiratory comorbidities implies worse clinical outcomes.

Oscillatory ventilation detected on incremental cardiopulmonary exercise testing might be found in subjects without heart failure reporting exertional dyspnoea despite the best available therapy for their underlying cardiopulmonary disease https://bit.ly/3Tyl7bE., Competing Interests: Conflict of interest J.A. Neder is an associate editor of this journal. Conflict of interest: A. Rocha has nothing to disclose. Conflict of interest: F.F. Arbex has nothing to disclose. Conflict of interest: M.C.N. Alencar has nothing to disclose. Conflict of interest: P.A. Sperandio has nothing to disclose. Conflict of interest: D.M. Hirai has nothing to disclose. Conflict of interest: D.C. Berton is an associate editor of this journal., (Copyright ©The authors 2023.)

Background: Continuous monitoring of S pO 2 throughout the 6-min walk test (6MWT) unveiled that some patients with respiratory diseases may present values across the test lower than S pO 2 measured at the end of the test. Nevertheless, it remains unclear whether this approach improves the yield of walk-induced desaturation detection in predicting mortality and hospitalizations in patients with COPD., Methods: Four hundred twenty-one subjects (51% males) with mild-very severe COPD underwent a 6MWT with continuous measurement of S pO 2 . Exercise desaturation was defined as a fall in S pO 2 ≥ 4%. All-cause mortality was assessed up to 6 y of follow-up and the rate of hospitalizations in the year succeeding the 6MWT., Results: One hundred forty-nine subjects (35.4%) died during a mean (interquartile) follow-up of 55.5 (30.2-64.1) months. Desaturation was observed in 299/421 (71.0%). S pO 2 along the test was < end S pO 2 (88 [82-92]% vs 90 [84-93]%, P < .001). Desaturation detected only during (but not at the end of) the test was found in 81/421 (19.2%) participants. Multivariate Cox regression model adjusted for sex, body composition, FEV 1 , residual volume/total lung capacity ratio, walk distance, O 2 supplementation during the test, and comorbidities retained the presence of desaturation either at the end (1.85 [95% CI 1.02-3.36]) or only along the test (2.08 [95% CI 1.09-4.01]) as significant predictors of mortality. The rate of hospitalizations was higher in those presenting with any kind of desaturation compared to those without exercise desaturation. Logistic regression analysis revealed that walking interruption and diffusing capacity of the lung for carbon monoxide predicted desaturation observed only during the test., Conclusions: O 2 desaturation missed by end-exercise S pO 2 but exposed by measurements during the test was independently associated with all-cause mortality and hospitalizations in subjects with COPD., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

There is well established evidence that the minute ventilation ( V ' E )/carbon dioxide output ( V ' CO 2 ) relationship is relevant to a number of patient-related outcomes in COPD. In most circumstances, an increased V ' E / V ' CO 2 reflects an enlarged physiological dead space ("wasted" ventilation), although alveolar hyperventilation (largely due to increased chemosensitivity) may play an adjunct role, particularly in patients with coexistent cardiovascular disease. The V ' E / V ' CO 2 nadir, in particular, has been found to be an important predictor of dyspnoea and poor exercise tolerance, even in patients with largely preserved forced expiratory volume in 1 s. As the disease progresses, a high nadir might help to unravel the cause of disproportionate breathlessness. When analysed in association with measurements of dynamic inspiratory constraints, a high V ' E / V ' CO 2 is valuable to ascertain a role for the "lungs" in limiting dyspnoeic patients. Regardless of disease severity, cardiocirculatory (heart failure and pulmonary hypertension) and respiratory (lung fibrosis) comorbidities can further increase V ' E / V ' CO 2 A high V ' E / V ' CO 2 is a predictor of poor outcome in lung resection surgery, adding value to resting lung hyperinflation in predicting all-cause and respiratory mortality across the spectrum of disease severity. Considering its potential usefulness, the V ' E / V ' CO 2 should be valued in the clinical management of patients with COPD., Competing Interests: Conflict of interest: J.A. Neder has nothing to disclose. Conflict of interest: D.C. Berton has nothing to disclose. Conflict of interest: D.B. Philips has nothing to disclose. Conflict of interest: D.E. O'Donnell has nothing to disclose., (Copyright ©ERS 2021.)

Objective: Impaired respiratory mechanics and gas exchange may contribute to sleep disturbance in patients with COPD. We aimed to assess putative associations of different domains of lung function (airflow limitation, lung volumes, and gas exchange efficiency) with polysomnography (PSG)-derived parameters of sleep quality and architecture in COPD., Methods: We retrospectively assessed data from COPD 181 patients ≥ 40 years of age who underwent spirometry, plethysmography, and overnight PSG. Univariate and multivariate linear regression models predicted sleep efficiency (total sleep time/total recording time) and other PSG-derived parameters that reflect sleep quality., Results: The severity of COPD was widely distributed in the sample (post-bronchodilator FEV1 ranging from 25% to 128% of predicted): mild COPD (40.3%), moderate COPD (43.1%), and severe-very severe COPD (16.6%). PSG unveiled a high proportion of obstructive sleep apnea (64.1%) and significant nocturnal desaturation (mean pulse oximetry nadir = 82.2% ± 6.9%). After controlling for age, sex, BMI, apnea-hypopnea index, nocturnal desaturation, comorbidities, and psychotropic drug prescription, FEV1/FVC was associated with sleep efficiency (β = 25.366; R2 = 14%; p < 0.001), whereas DLCO predicted sleep onset latency (β = -0.314; R2 = 13%; p < 0.001) and rapid eye movement sleep time/total sleep time in % (β = 0.085; R2 = 15%; p = 0.001)., Conclusions: Pulmonary function variables reflecting severity of airflow and gas exchange impairment, adjusted for some potential confounders, were weakly related to PSG outcomes in COPD patients. The direct contribution of the pathophysiological hallmarks of COPD to objectively measured parameters of sleep quality seems to be less important than it was previously assumed.

Background: Respiratory muscle unloading through proportional assist ventilation (PAV) may enhance leg oxygen delivery, thereby speeding off-exercise oxygen uptake ( V . ⁢ O 2 ) kinetics in patients with heart failure with reduced left ventricular ejection fraction (HFrEF)., Methods: Ten male patients (HFrEF = 26 ± 9%, age 50 ± 13 years, and body mass index 25 ± 3 kg m 2 ) underwent two constant work rate tests at 80% peak of maximal cardiopulmonary exercise test to tolerance under PAV and sham ventilation. Post-exercise kinetics of V . ⁢ O 2 , vastus lateralis deoxyhemoglobin ([deoxy-Hb + Mb]) by near-infrared spectroscopy, and cardiac output (Q T ) by impedance cardiography were assessed., Results: PAV prolonged exercise tolerance compared with sham (587 ± 390 s vs. 444 ± 296 s, respectively; p = 0.01). PAV significantly accelerated V . ⁢ O 2 recovery ( τ = 56 ± 22 s vs. 77 ± 42 s; p < 0.05), being associated with a faster decline in Δ[deoxy-Hb + Mb] and Q T compared with sham ( τ = 31 ± 19 s vs. 42 ± 22 s and 39 ± 22 s vs. 78 ± 46 s, p < 0.05). Faster off-exercise decrease in Q T with PAV was related to longer exercise duration ( r = -0.76; p < 0.05)., Conclusion: PAV accelerates the recovery of central hemodynamics and muscle oxygenation in HFrEF. These beneficial effects might prove useful to improve the tolerance to repeated exercise during cardiac rehabilitation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Borghi-Silva, Goulart, Carrascosa, Oliveira, Berton, de Almeida, Nery, Arena and Neder.)

This study aimed to investigate the walking economy and possible factors influencing self-selected walking speed (SSWS) in patients with fibrotic interstitial lung disease (ILD) compared to controls. In this study, 10 patients with ILD (mean age: 63.8 ± 9.2 years, forced expiratory volume in the first second: 56 ± 7% of predicted) and 10 healthy controls underwent resting pulmonary function tests, cardiopulmonary exercise, and submaximal treadmill walking tests at different speeds. The walking economy was assessed by calculating the cost-of-transport (CoT). Dynamic stability was assessed by stride-to-stride fluctuations using video recordings. Patients with ILD showed reduced peak oxygen uptake with a tachypneic breathing pattern and significant oxygen desaturation during exercise. The CoT did not differ between the groups (p = 0.680), but dyspnea and SpO 2 were higher and lower, respectively, in patients with ILD at the same relative speeds. SSWS was reduced in ILD patients (2.6 ± 0.9 vs. 4.2 ± 0.4 km h -1 p = 0.001) and did not correspond to the energetically optimal walking speed. Dynamic stability was significantly lower in patients with ILD than in healthy controls, mainly at lower speeds. Patients with ILD presented a similar cost of transport compared to healthy controls; however, they chose lower SSWS despite higher walking energy expenditure. Although walking stability and dyspnea were negatively affected, these factors were not associated with the slower walking speed chosen by individuals with ILD.

Several shortcomings on cardiopulmonary exercise testing (CPET) interpretation have shed a negative light on the test as a clinically useful tool. For instance, the reader should recognize patterns of dysfunction based on clusters of variables rather than relying on rigid interpretative algorithms. Correct display of key graphical data is of foremost relevance: prolixity and redundancy should be avoided. Submaximal dyspnea ratings should be plotted as a function of work rate (WR) and ventilatory demand. Increased work of breathing and/or obesity may normalize peak oxygen uptake (V̇O 2 ) despite a low peak WR. Among the determinants of V̇O 2 , only heart rate is measured during non-invasive CPET. It follows that in the absence of findings suggestive of severe impairment in O 2 delivery, the boundaries between inactivity and early cardiovascular disease are blurred in individual subjects. A preserved breathing reserve should not be viewed as evidence that "the lungs" are not limiting the subject. In this context, measurements of dynamic inspiratory capacity are key to uncover abnormalities germane to exertional dyspnea. A low end-tidal partial pressure for carbon dioxide may indicate either increased "wasted" ventilation or alveolar hyperventilation; thus, direct measurements of arterial (or arterialized) PO 2 might be warranted. Differentiating a chaotic breathing pattern from the normal breath-by-breath noise might be complex if the plotted data are not adequately smoothed. A sober recognition of these limitations, associated with an interpretation report free from technicalities and convoluted terminology, is crucial to enhance the credibility of CPET in the eyes of the practicing physician., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Neder, Phillips, Marillier, Bernard, Berton and O’Donnell.)

Chronic unexplained dyspnea and exercise intolerance represent common, distressing symptoms in outpatients. Clinical history taking and physical examination are the mainstays for diagnostic evaluation. However, the cause of dyspnea may remain elusive even after comprehensive diagnostic evaluation-basic laboratory analyses; chest imaging; pulmonary function testing; and cardiac testing. At that point (and frequently before), patients are usually referred to a pulmonologist, who is expected to be the main physician to solve this conundrum. In this context, cardiopulmonary exercise testing (CPET), to assess physiological and sensory responses from rest to peak exercise, provides a unique opportunity to unmask the mechanisms of the underlying dyspnea and their interactions with a broad spectrum of disorders. However, CPET is underused in clinical practice, possibly due to operational issues (equipment costs, limited availability, and poor remuneration) and limited medical education regarding the method. To counter the latter shortcoming, we aspire to provide a pragmatic strategy for interpreting CPET results. Clustering findings of exercise response allows the characterization of patterns that permit the clinician to narrow the list of possible diagnoses rather than pinpointing a specific etiology. We present a proposal for a diagnostic workup and some illustrative cases assessed by CPET. Given that airway hyperresponsiveness and pulmonary vascular disorders, which are within the purview of pulmonology, are common causes of chronic unexplained dyspnea, we also aim to describe the role of bronchial challenge tests and the diagnostic reasoning for investigating the pulmonary circulation in this context.

Background: We evaluated the impact of thoracic radiation in patients with non-small cell lung cancer (NSCLC), considering the depletion of total lymphocytes, use or not of chemotherapy, and radiation doses in healthy lung tissue., Methods: Patients with stage III NSCLC, ECOG 0 to 2, receiving radiotherapy with or without chemotherapy were prospectively evaluated. All patients should be treated with three-dimensional radiotherapy and received biologically effective doses (BED10α/β 10) of 48 to 80 Gy. Peripheral blood lymphocyte total counts were measured at the start of radiotherapy and at 2, 6 and 12 months after radiotherapy. Along with lymphocytes, PTV and doses of 5 Gy and 20 Gy in healthy lung tissue were also evaluated as potential factors influencing overall survival (OS) and progression-free survival (PFS)., Results: A total of 46 patients were prospectively evaluated from April 2016 to August 2019, with a median follow-up of 13 months (interquartile range, 1-39 months). The median of OS of all cohort was 22,8 months (IC 95% 17,6-28,1) and the median PFS was 19,5 months (IC 95%: 14,7-24,2). Most patients received concurrent or neoadjuvant chemotherapy (43; 93.4%). No patient received adjuvant immunotherapy. The lower the lymphocyte loss at 6 months after radiotherapy (every 100 lymphocytes/mcL), the greater the chance of PFS (HR, 0.44; 95%CI, 0.25-0.77; P = 0.004) and OS (HR, 0.83; 95%CI, 0.70-0.98; P = 0.025; P = 0.025). BED was a protective factor for both PFS (HR, 0.52; 95%CI 0.33-0.83; P = 0.0006) and OS (HR, 0.73; 95%CI 0.54-0.97; P = 0.029)., Conclusions: Our results suggest that lymphocyte depletion after radiotherapy reduces tumor control and survival in patients with stage III lung cancer. Radiation doses equal or higher than 60 Gy (BED 10 72 Gy) improve PFS and OS, but they negatively affect lymphocyte counts for months, which reduces survival and the potential of immunotherapy., Key Points: SIGNIFICANT FINDINGS OF THE STUDY: Thoracic irradiation for locally advanced lung cancer depletes T lymphocytes for months. Patients whose lymphocyte loss is lower have better overall survival and progression-free survival., What This Study Adds: It is necessary to protect the lymphocyte population, as well as other organs at risk. New forms of irradiation for large fields are needed. Furthermore, could immunotherapy before chemo-radiotherapy, with a greater number of lymphocytes, bring an even better result?, (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Assessment of dyspnoea severity during incremental cardiopulmonary exercise testing (CPET) has long been hampered by the lack of reference ranges as a function of work rate (WR) and ventilation ( V' E ). This is particularly relevant to cycling, a testing modality which overtaxes the leg muscles leading to a heightened sensation of leg discomfort.Reference ranges based on dyspnoea percentiles (0-10 Borg scale) at standardised work rates and V' E were established in 275 apparently healthy subjects aged 20-85 years (131 men). They were compared with values recorded in a randomly selected "validation" sample (n=451; 224 men). Their usefulness in properly uncovering the severity of exertional dyspnoea were tested in 167 subjects under investigation for chronic dyspnoea ("testing sample") who terminated CPET due to leg discomfort (86 men).Iso-work rate and, to a lesser extent, iso- V' E reference ranges (5th-25th, 25th-50th, 50-75th and 75th-95th percentiles) increased as a function of age, being systematically higher in women (p<0.01). There were no significant differences in percentiles distribution between "reference" and "validation" samples (p>0.05). Submaximal dyspnoea-work rate scores fell within the 75th-95th or >95th percentiles in 108 out of 118 (91.5%) subjects of the "testing" sample who showed physiological abnormalities known to elicit exertional dyspnoea, i.e. ventilatory inefficiency and/or critical inspiratory constraints. In contrast, dyspnoea scores typically fell in the 5th-50th range in subjects without those abnormalities (p<0.001).This frame of reference might prove useful to uncover the severity of exertional dyspnoea in subjects who otherwise would be labelled as "non-dyspnoeic" while providing mechanistic insights into the genesis of this distressing symptom., Competing Interests: Conflict of interest: J.A. Neder has nothing to disclose. Conflict of interest: D.C. Berton has nothing to disclose. Conflict of interest: L.E. Nery has nothing to disclose. Conflict of interest: W.C. Tan reports grants from Canadian Respiratory Research Network, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Novartis, Canadian Institutes of Health Research, Respiratory Health Network of the Fonds de la recherche en santé du Québec, Merck, Nycomed, Pfizer Canada Ltd and Theratechnologies, during the conduct of the study. Conflict of interest: J. Bourbeau reports grants from CIHR, Canadian Respiratory Research Network (CRRN), Foundation of the MUHC and Aerocrine, personal fees for consultancy and lectures from Canadian Thoracic Society and CHEST, grants and personal fees for advisory board work and lectures from AstraZeneca, Boehringer Ingelheim, Grifols, GlaxoSmithKline, Novartis and Trudell, outside the submitted work. Conflict of interest: D.E. O'Donnell has nothing to disclose., (Copyright ©ERS 2020.)

The concept of critical inspiratory constraints is key to the modern understanding of exercise pathophysiology in patients with moderate-to-severe COPD https://bit.ly/2A6bCxD., Competing Interests: Conflict of interest: M. Marillier has nothing to disclose. Conflict of interest: A-C. Bernard has nothing to disclose. Conflict of interest: R. Gass has nothing to disclose. Conflict of interest: D.C. Berton has nothing to disclose. Conflict of interest: S. Verges has nothing to disclose. Conflict of interest: D.E. O'Donnell has nothing to disclose. Conflict of interest: J.A. Neder has nothing to disclose., (Copyright ©ERS 2020.)

Expiratory positive airway pressure (EPAP) is widely applicable, either as a strategy for pulmonary reexpansion, elimination of pulmonary secretion or to reduce hyperinflation. However, there is no consensus in the literature about the real benefits of EPAP in reducing dynamic hyperinflation (DH) and increasing exercise tolerance in subjects with chronic obstructive pulmonary disease (COPD). To systematically review the effects of EPAP application during the submaximal stress test on DH and exercise capacity in patients with COPD. This meta-analysis was performed from a systematic search in the PubMed, EMBASE, PeDRO, and Cochrane databases, as well as a manual search. Studies that evaluated the effect of positive expiratory pressure on DH, exercise capacity, sensation of dyspnea, respiratory rate, peripheral oxygen saturation, sense of effort in lower limbs, and heart rate were included. GRADE was used to determine the quality of evidence for each outcome. Of the 2,227 localized studies, seven studies were included. The results show that EPAP did not change DH and reduced exercise tolerance in the constant load test. EPAP caused a reduction in respiratory rate after exercise (- 2.33 bpm; 95% CI: - 4.56 to - 0.10) (very low evidence) when using a pressure level of 5 cmH 2 O. The other outcomes analyzed were not significantly altered by the use of EPAP. Our study demonstrates that the use of EPAP does not prevent the onset of DH and may reduce lower limb exercise capacity in patients with COPD. However, larger and higher-quality studies are needed to clarify the potential benefit of EPAP in this population.

Background: Expiratory flow limitation (EFL) is a key physiological abnormality in COPD. Comparing tidal-to-maximum flow-volume (F-V) loops is a simple and widely available method to assess EFL in patients with COPD. We aimed to investigate whether subjects with COPD showing significant resting tidal F-V enveloping (ie, > 50% tidal volume) would present with higher exertional operating lung volumes, which would lead to greater burden of dyspnea and poorer exercise tolerance compared to their counterparts., Methods: 37 subjects with COPD (21 males; 63.1 ± 9.2 years old; FEV 1 = 37 ± 12% predicted) and 9 paired controls (3 males; 55.9 ± 11.7 y old) performed an incremental cardiopulmonary exercise testing on a cycle ergometer. Dyspnea perception, inspiratory capacity maneuvers after 3-4 sequential tidal F-V loops, and esophageal and gastric pressures were measured during exercise., Results: Most subjects (31 of 37, 84%) presented with significant tidal F-V enveloping. Critical inspiratory constraints and upward dyspnea inflection points (as a function of both work rate and ventilation) were reached earlier in these subjects, thereby leading to poorer exercise tolerance compared to their counterparts ( P = .01). Abdominal muscle recruitment (ie, increase in gastric pressure ≥ 15%) during tidal expiration was significantly higher in the EFL+ group. However, this did not bear an influence on the operating lung volumes, inspiratory constraints, dyspnea, cardiocirculatory responses, or exercise tolerance ( P > .05)., Conclusions: Tidal F-V loop enveloping at rest should be valued as it is related to relevant clinical outcomes, such as dyspnea burden and exercise tolerance in subjects with COPD., (Copyright © 2019 by Daedalus Enterprises.)

Background: Exertional dyspnea increases when the mechanical output of the respiratory muscles becomes uncoupled from increases in neural respiratory drive. Combining measurements of inspiratory constraints and ventilatory inefficiency may better uncover the role of mechanical-ventilatory abnormalities on exertional dyspnea than the currently-recommended approach, i.e., a low breathing reserve., Methods: We determined the presence of a low breathing reserve (1-(peak ventilation (V̇E)/estimated maximal voluntary ventilation) x 100 < 15%), critical inspiratory constraints (tidal volume (VT)/exercise inspiratory capacity (IC dyn ) > 0.7) and ventilatory inefficiency (V̇E/CO 2 output (V̇CO 2 ) nadir>34) in 284 subjects (161 males) with "disproportionate dyspnea" (N = 148), "dyspnea with multiple potential causes" (N = 93) and "dyspnea without an apparent cause., Results: The agreement between breathing reserve and assessment of inspiratory constraints was only "fair" (kappa [confidence interval (CI)] = 0.264 [0.169-0.358]). Attainment of critical inspiratory constraints and an upward inflection in dyspnea ratings systematically preceded a low breathing reserve. Of note, ~55% (93/167) of subjects with normal breathing reserve showed critical inspiratory constraints despite largely preserved lung function. Regardless of the breathing reserve, subjects showing critical inspiratory constraints and/or poor ventilatory efficiency reported higher dyspnea and more impaired exercise tolerance compared to their counterparts (p < 0.05). Poor ventilatory efficiency strongly predicted a high dyspnea/work rate in subjects without critical inspiratory constraints regardless of the breathing reserve (odds ratio [95% CI] = 4.21 [2.01-6.42; p < 0.001)., Conclusion: An integrated analysis of inspiratory constraints and ventilatory inefficiency is key to uncover physiological abnormalities germane to dyspnea in clinical populations in whom the origins of this distressing symptom are uncertain., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Hyperinflation has been associated with negative cardiocirculatory consequences in patients with chronic obstructive pulmonary disease (COPD). These abnormalities are likely to worsen when the demands for O 2 increase, e.g., under the stress of exercise. Thus, pharmacologically-induced lung deflation may improve cardiopulmonary interactions and exertional cardiac output leading to higher limb muscle blood flow and oxygenation in hyperinflated patients with COPD., Methods: 20 patients (residual volume = 201.6 ± 63.6% predicted) performed endurance cardiopulmonary exercise tests (75% peak) 1 h after placebo or tiotropium/olodaterol 5/5 μg via the Respimat® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Cardiac output was assessed by signal-morphology impedance cardiography. Near-infrared spectroscopy determined quadriceps blood flow (indocyanine green dye) and intra-muscular oxygenation., Results: Tiotropium/olodaterol was associated with marked lung deflation (p < 0.01): residual volume decreased by at least 0.4 L in 14/20 patients (70%). The downward shift in the resting static lung volumes was associated with less exertional inspiratory constraints and dyspnoea thereby increasing exercise endurance by ~50%. Contrary to our premises, however, neither central and peripheral hemodynamics nor muscle oxygenation improved after active intervention compared to placebo. These results were consistent with those found in a subgroup of patients showing the largest decrements in residual volume (p < 0.05)., Conclusions: The beneficial effects of tiotropium/olodaterol on resting and operating lung volumes are not translated into enhanced cardiocirculatory responses to exertion in hyperinflated patients with COPD. Improvement in exercise tolerance after dual bronchodilation is unlikely to be mechanistically linked to higher muscle blood flow and/or O 2 delivery., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Ursodeoxycholic acid (UDCA) and its metabolites tauroursodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA) have been the subject of several pharmacological studies. The objective of this study was to develop an innovative method of quantification by HPL-tandem mass spectrometry (LC-MS/MS), with a lower cost and suitable, for application in bioequivalence studies., Methods: The procedure involved liquid-liquid extraction for quantification of UDCA/GUDCA and precipitation extraction for TUDCA, using deuterated substances as internal standards (ISs) and Phenomenex Luna 250×4.6 mm 5μ C 18 100A column. The mobile phase used was acetonitrile/ammonium acetate 30 mM (420: 580 v/v pH 7) for UDCA, acetonitrile/ammonium acetate 10 mM/ammonium hydroxide (400:600: 0.5 v/v/v pH 9) for GUDCA, and acetonitrile/ammonium acetate 10 mM (570: 430 v/v pH 7) for TUDCA. Ions were monitored by the electrospray ion source (ESI) mass spectrometer, operating in a negative ionization mode. Compound determination was performed by LC-MS/MS system using a calibration curve of 15-10,000 ng/mL for UDCA/GUDCA and 5-500 ng/mL for TUDCA. The method was developed and validated according to the Brazilian National Health Surveillance Agency (ANVISA) of Brazil norms harmonized with the main international guidelines as a prerequisite for conducting in vivo study in human volunteers., Results: The method did not present matrix effect and residual effect, showing to be selective for studied molecules, with adequate accuracy and precision. In addition, the method was considered sensitive presenting a coefficient of variation less than 20% for the lower limit of quantification of each compound., Conclusion: This method can be applied in bioequivalence studies to determine ursodiol and its metabolites reproducibly, simply, and effectively with the use of readily accessible analytical materials and instrumentation., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

AimTo investigate if cardiac/pulmonary functional tests and variables obtained from clinical practice (body mass index, dyspnea, functional class, clinical judgment of disability to perform an exercise test and previous hospitalization rate) are related to mortality in patients with overlap chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). BACKGROUND: Although the coexistence of COPD and CHF has been growingly reported, description of survival predictors considering the presence of both conditions is still scarce. METHODS: Using a cohort design, outpatients with the previous diagnosis of COPD and/or CHF that performed both spirometry and echocardiography in the same year were followed-up during a mean of 20.9±8.5 months.FindingsOf the 550 patients initially evaluated, 301 had both spirometry and echocardiography: 160 (53%) with COPD on isolation; 100 (33%) with CHF on isolation; and 41 (14%) with overlap. All groups presented similar mortality: COPD 17/160 (11%); CHF 12/100 (12%); and overlap 7/41 (17%) (P=0.73). In the overlap group (n=41), inability to exercise and hospitalization rate were the unique parameters associated with higher mortality (seven events) in univariate analyses. In conclusion, inability to exercise and hospitalization rate emerged as the unique parameters associated with mortality in our sample.

Introduction: Exercise intolerance is the most predominant symptom in patients with COPD. Nevertheless, it is unclear whether walking economy and gait variability are altered in these patients. Thus, our main objective was to compare the cost of transport and gait variability as a function of speed, including the self-selected walking speed, in subjects with COPD relative to healthy subjects., Methods: 22 subjects, 11 with COPD (FEV 1 = 45 ± 17% of predicted) and 11 age- and sex-matched healthy subjects undertook an evaluation that involved walking on a treadmill at 6 speeds (at 3.2 km/h, at a self-selected walking speed, and at 2 speeds below and 2 speeds above the self-selected walking speed) and measuring the cost of transport (the oxygen consumption normalized by mass and distance), gait variability, perceived dyspnea, and leg fatigue., Results: In subjects with COPD, the cost of transport decreased with increasing walking speed, contrary to healthy subjects, who presented a minimum at the self-selected walking speed. No difference was found in cost of transport between the experimental groups at the same absolute velocity ( P = .62). In subjects with COPD, dyspnea sensation rose above the self-selected walking speed, doubling at the maximal walking velocity ( P = .03), and gait variability was higher at low speeds., Conclusion: Subjects with COPD choose their walking speed so as to keep the dyspnea sensation tolerable and to keep gait variability and cost of transport at an acceptable level. These outcomes suggest that interventions acting on dyspnea and gait pattern may increase patients' self-selected walking speed and improve their quality of life., (Copyright © 2018 by Daedalus Enterprises.)

Background: Cardiovascular diseases play a major role in morbidity and mortality in the earlier stages of COPD. We hypothesized that systemic vascular dysfunction would be present even in patients who are currently considered at "low-risk" for negative cardiovascular outcomes, i.e., those with largely preserved FEV 1 , few exacerbations and only mild burden of respiratory symptoms (GOLD spirometric grade 1, clinical group A)., Methods: 16 patients (FEV 1  = 86 ± 13%) and 16 age- and gender-matched controls underwent measurements of: a) central arterial stiffness by pulse wave velocity, b) brachial flow-mediated dilation and c) forearm muscle oxygenation by near-infrared spectroscopy. Computed tomography quantified emphysema (% of low attenuation areas (LAA)) and airway disease., Results: Patients and controls were well matched for key clinical variables including co-morbidities burden. Thirteen patients presented with more than 5% LAA: emphysema extension was negatively related to transfer factor for carbon monoxide (TL CO ) (r = -0.63; p = .01). Compared to controls, patients had higher central arterial stiffness, lower normalized (to shear stress) flow-mediated dilation, delayed time to peak flow-mediated dilation and poorer muscle oxygenation (p < .05). TL CO and emphysema, but not airway disease, were significantly related to each of these functional abnormalities (r values ranging from 0.51 to 0.66; p < .05)., Conclusion: Systemic vascular dysfunction is present in the earlier stages of COPD, particularly in patients with greater emphysema burden and low TL CO . Regardless FEV 1 , patients showing those structural and functional abnormalities might be at higher risk of negative events thereby deserving closer follow-up for early detection of cardiovascular disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Rationale: An increased ventilatory response to exertional metabolic demand (high [Formula: see text]e/[Formula: see text]co 2 relationship) is a common finding in patients with coexistent chronic obstructive pulmonary disease and heart failure., Objectives: We aimed to determine the mechanisms underlying high [Formula: see text]e/[Formula: see text]co 2 and its impact on operating lung volumes, dyspnea, and exercise tolerance in these patients., Methods: Twenty-two ex-smokers with combined chronic obstructive pulmonary disease and heart failure with reduced left ventricular ejection fraction undertook, after careful treatment optimization, a progressive cycle exercise test with capillary (c) blood gas collection., Measurements and Main Results: Regardless of the chosen metric (increased [Formula: see text]e-[Formula: see text]co 2 slope, [Formula: see text]e/[Formula: see text]co 2 nadir, or end-exercise [Formula: see text]e/[Formula: see text]co 2 ), ventilatory inefficiency was closely related to Pc CO 2 (r values from -0.80 to -0.84; P < 0.001) but not dead space/tidal volume ratio. Ten patients consistently maintained exercise Pc CO 2 less than or equal to 35 mm Hg (hypocapnia). These patients had particularly poor ventilatory efficiency compared with patients without hypocapnia (P < 0.05). Despite the lack of between-group differences in spirometry, lung volumes, and left ventricular ejection fraction, patients with hypocapnia had lower resting Pa CO 2 and lung diffusing capacity (P < 0.01). Excessive ventilatory response in this group was associated with higher exertional Pc O 2 . The group with hypocapnia, however, had worse mechanical inspiratory constraints and higher dyspnea scores for a given work rate leading to poorer exercise tolerance compared with their counterparts (P < 0.05)., Conclusions: Heightened neural drive promoting a ventilatory response beyond that required to overcome an increased "wasted" ventilation led to hypocapnia and poor exercise ventilatory efficiency in chronic obstructive pulmonary disease-heart failure overlap. Excessive ventilation led to better arterial oxygenation but at the expense of earlier critical mechanical constraints and intolerable dyspnea.

Introduction: The application of expiratory positive airway pressure (EPAP) in patients with COPD during exercise may reduce dynamic hyperinflation, while, on the other hand, it can increase the resistive work of breathing. Therefore, we evaluated the effects of 2 intensities of EPAP during exercise on tolerance, dynamic hyperinflation, and dyspnea in subjects with moderate to very severe COPD., Methods: We performed a cross-sectional, experimental, 4-visit study. In visit 1, subjects performed symptom-limited cycling incremental cardiopulmonary exercise test (CPET). In visits 2-4, at least 48 h apart, in a randomized order, subjects performed constant CPET without EPAP, EPAP with 5 cm H 2 O (EPAP5), or EPAP with 10 cm H 2 O (EPAP10)., Results: The study included 15 non-hypoxemic subjects ranging from moderate to very severe COPD (mean FEV 1 = 35 ± 11% predicted). Increasing intensities of EPAP during constant CPET tended to cause progressive reduction in exercise tolerance ( P = .11). Of note, 10 of 15 subjects demonstrated significantly shorter average exercise duration with EPAP10 compared to the test without EPAP (-151 ± 105 s, P = .03 or -41 ± 26%). Minute ventilation increment was constrained by EPAP, secondary to a limited increase in tidal volume ( P = .01). Finally, dyspnea sensation and serial measurements of inspiratory capacity during exercise were similar when comparing the three interventions at isotime and at end-constant CPETs., Conclusions: The application of EPAP5 or EPAP10 during exercise tended to cause a progressive reduction in exercise tolerance in subjects with COPD without improvement in dyspnea or dynamic hyperinflation at equivalent exercise duration., (Copyright © 2017 by Daedalus Enterprises.)