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Background Symptoms of chronic obstructive pulmonary disease may vary throughout the day and it is important that therapeutic approaches provide 24-h symptom control. We report the results of two phase IIIb crossover studies, PT003011 and PT003012, investigating the 24-h lung function profile of GFF MDI (glycopyrrolate/formoterol fumarate 18/9.6 μg delivered using innovative co-suspension delivery technology) administered twice daily. Methods Patients with moderate-to-very severe chronic obstructive pulmonary disease received 4 weeks’ treatment with each of GFF MDI, placebo MDI, and open-label tiotropium (PT003011 only). Lung function was assessed over 24 h on day 29 of each treatment period. The primary outcome was forced expiratory volume in 1 second area under the curve from 0 to 24 h (FEV 1 AUC 0–24 ). Other outcomes included change from baseline in average daily rescue medication use over the treatment period. In addition, we conducted a post-hoc analysis of data pooled from both studies to further characterize the effect of GFF MDI on inspiratory capacity. Results GFF MDI treatment significantly increased FEV 1 AUC 0–24 versus placebo in studies PT003011 ( n = 75) and PT003012 ( n = 35) on day 29 (both studies p < 0.0001), with similar improvements in FEV 1 AUC versus placebo for hours 0–12 and 12–24. In PT003011, improvements with GFF MDI versus tiotropium in FEV 1 AUC were greater during hours 12–24 compared to 0–12 h. GFF MDI treatment also resulted in a significant reduction in rescue medication use versus placebo (−0.84 [ p <0.0001] and −1.11 [ p =0.0054] puffs/day in PT003011 and PT003012, respectively), and versus tiotropium in PT003011 (−0.44 [ p =0.017] puffs/day). A post-hoc pooled analysis showed patients treated with GFF MDI were more likely to achieve a >15% increase from baseline in inspiratory capacity than patients treated with placebo or tiotropium (72.1%, 19.0% and 47.0% of patients, respectively after the evening dose on day 29). There were no significant safety/tolerability findings. Conclusions GFF MDI significantly improved 24-h lung function versus placebo in patients with moderate-to-very severe chronic obstructive pulmonary disease, with similar benefits in the second 12-h period compared to the first, supporting twice-daily dosing of GFF MDI. Trial registration Pearl Therapeutics, Inc.; www.clinicaltrials.gov ; NCT02347072 and NCT02347085 . Registered 21 January 2015.

Objective: Investigation of the effects of preoperative physical therapy on pulmonary function and physical performance before and after upper abdominal surgery. Design: Non-blind randomized controlled trial. Setting: Tertiary public hospital and private university, São Paulo state, Brazil. Subjects: Thirty-two patients undergoing abdominal surgery. Interventions: Patients were randomly assigned to receive physical therapy, with respiratory and global exercises, 2–3 weeks before surgery (treatment group; n = 16) or await operation without engaging in practicing (control group; n = 16). After surgery, a physical therapy protocol was administered to all subjects until the seventh postoperative day. Main measures: Pulmonary function outcome variables were inspiratory and expiratory strength, respiratory muscle endurance and spirometry, and physical performance outcome variables were the functional independence measure and 6-minute walk test distance. Any postoperative pulmonary complications were recorded. Results: There were no between-group differences at randomization. In the preoperative period, patients in the intervention group had higher inspiratory strength and respiratory muscle endurance than controls (88 cmH2O versus 64 cmH2O and 28 cmH2O versus 23 cmH2O, respectively; P <0 0.05). On the seventh postoperative day, in addition to inspiratory force and respiratory muscle endurance, the intervention group showed better results than controls in the functional independence measure score (118 versus 95) and 6-minute walk test distance (368.5 m versus 223 m), all P <0 0.05. Postoperative pulmonary complications occurred in 11 patients in the control group and five in the intervention group (P = 0.03). Conclusion: Preoperative physical therapy improved pulmonary function and physical performance in the pre- and postoperative periods among patients undergoing upper abdominal surgery.

Abstract Rationale Bronchodilator therapy represents a potentially valuable therapeutic option to increase exercise tolerance and enhance lung function in mild to moderate chronic obstructive pulmonary disease (COPD). Objectives To determine effects of tiotropium on pulmonary hyperinflation and exercise tolerance in patients with symptomatic Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 and 2 COPD who experienced inspiratory capacity decrease greater than or equal to 100 ml during incremental and constant work rate treadmill exercise. Methods This 22-week, randomized, double-blind, two-period crossover study evaluated the efficacy of once-daily tiotropium bromide (18 μg) versus placebo in patients with GOLD 1 and 2 COPD. Primary endpoint was between-group (tiotropium vs. placebo) difference in inspiratory capacity at isotime (i.e., at the time the shortest test ended) during constant work rate treadmill exercise from baseline to the end of a 6-week treatment period. Key secondary endpoints included differences in exercise duration and exertional dyspnea. Safety was assessed by recording adverse events. Measurements and Main Results Study population comprised 48 patients with GOLD 1 COPD and 78 patients with GOLD 2 COPD. Resting inspiratory capacity significantly improved with tiotropium versus placebo in the overall (P < 0.0001), GOLD 1 (P = 0.0183), and GOLD 2 (P < 0.0001) groups. Isotime inspiratory capacity was significantly enhanced during exercise in the overall (P = 0.0087) and GOLD 2 (P = 0.0494) groups after tiotropium versus placebo. Tiotropium versus placebo significantly enhanced exercise duration in the GOLD 2 group (P = 0.0070) but not in the GOLD 1 or overall patient groups. In the overall group, increase in exercise duration seen with tiotropium was well correlated with the increase in isotime inspiratory capacity (r = 0.463, P < 0.0001). Conclusions Resting and exercise hyperinflation were ameliorated by bronchodilator therapy with tiotropium in the overall GOLD 1 plus 2 COPD group. Exercise tolerance was enhanced in GOLD 2, but not GOLD 1, COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01072396).

Background: Lung volume reduction surgery is a proven treatment for emphysematous patients with hyperinflation, but the precarious health of candidates has prompted development of less invasive approaches. Bronchoscopic implanted endobronchial coils, shape-memory nitinol filaments, shrink emphysematous lung tissue to restore elastic recoil and to tether airways to maintain patency. Studies have demonstrated an acceptable safety profile and improvements in lung function, exercise capacity, and quality of life out to 3 years. Volume reduction is key. However, data for longer-term survival are limited. Objective: The aim of this study was to establish the 5-year overall and transplant-free survivals of subjects whose procedure in the first randomized controlled trial, RESET, achieved clinically meaningful reduction in residual volume (RV). Methods: Patients and their primary care doctors were contacted to confirm vital status and history of additional interventions. Death certificates were acquired via the General Registry Office. Survival time was calculated for responders achieving a reduction of ≥10% in RV compared to non-responders. Results: 39 patients completed the planned bilateral sequential treatments. Six patients received unilateral implants. At 5 years, 22 patients had died. The overall survivals at 1, 2, 3, 4 and 5 years were 88.9, 88.9, 77.8, 64.4 and 50.6%, respectively. Two patients underwent lung transplantation at 52 and 59 months and were alive at 5 years. The transplant-free (TF) survivals at 1, 2, 3, 4 and 5 years were 88.9, 88.9, 77.8, 64.4 and 46.7%, respectively. Volume reduction responders (n = 18) at 3 months had a 5-year TF survival of 66.7% compared to 36.4% for non-responders (n = 22; p = 0.07). Higher baseline inspiratory capacity (HR 0.13, 95% CI 0.02–0.73; p = 0.02) and partial pressure of oxygen (pO 2 ) (HR 0.57, 95% CI 0.38–0.86; p < 0.01) values were predictive of survival for the entire cohort and were not influenced by age. Conclusions: Endobronchial coil implantation appears to confer a 5-year survival advantage for those who achieved a 10% reduction in RV at 3 months. Ongoing trials are designed to clarify the mechanisms of action of coils and to refine patient selection.

Effective treatment of chronic obstructive pulmonary disease (COPD) primarily relies on treatment delivered through inhaler devices. The effectiveness of dry powder inhalers is compromised by insufficient peak inspiratory flow (PIF). Understanding the evolution of PIF during hospitalization is crucial for optimizing inhaler selection and improving patient outcomes. A prospective monocentric observational study was conducted at Fribourg Hospital, Switzerland, from August 2022 to December 2022. PIF was assessed at hospital admission and discharge in all patients with COPD admitted to the internal medicine division. The primary outcome was the evolution of maximum PIF at a fixed medium-low resistance (R2) during hospitalization. Secondary outcomes included the variation of PIF in the intra-assessment evaluation and transitioning between sufficient and insufficient PIF. Forty-nine patients were enrolled, 61% were men and 65% experienced an acute COPD exacerbation (AECOPD). The maximum PIF for R2 increased from 64.8 ± 17.2 L/min at admission to 70.7 ± 17.9 L/min at discharge, showing a 5.9 L/min improvement (95% CI: 2.4-9.5, p < 0.01). A hospitalization >5 days in patients hospitalized for an AECOPD is associated with a higher increase in PIF (p < 0.05). In the intra-assessment measurement, we observed an increase in PIF in the successive measurements (p < 0.01). Hospitalized patients with COPD experienced a significant increase in PIF during their stay. These results appear to be independent of the reason for hospitalization but need to be confirmed with a larger sample. Nevertheless, these findings underscore the importance of regular PIF assessment and influence inhaler selection.

Purpose Respiratory muscles are known to be weakened and are a cause of reduced exercise capacity in both recipients and candidates of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Effects of inspiratory muscle training (IMT) in this patient population have not been comprehensively investigated so far. The current study was planned to investigate the effects of IMT during allo-HSCT on early transplantation-related outcomes. Methods This is a prospective, randomized controlled, double-blinded study. Thirty-eight allo-HSCT recipients, 20 of whom were allocated to the treatment group (40 % of maximal inspiratory pressure (MIP)) and 18 to the control group (5 % of MIP), received IMT for 6 weeks. Pulmonary functions, dyspnea, respiratory (MIP, maximal expiratory pressure (MEP)) and peripheral muscle strength, maximal exercise capacity using modified incremental shuttle walking test (MISWT) and submaximal exercise capacity using 6-min walking test (6-MWT), fatigue, depression, and quality of life were evaluated before and after IMT. Results The distance covered during MISWT (61.94 m) and 6-MWT (29.30 m), respiratory muscle strength (MIP 34.99 cmH 2 O, MEP 12.69 cmH 2 O), depression (−0.95), and modified Borg dyspnea scores (−0.11) showed a significant improvement in the treatment group compared to controls ( p  ≤ 0.05). Conclusions Inspiratory muscle training is a safe and effective intervention which improves respiratory muscle strength and exercise capacity and decreases depression and dyspnea in allo-HSCT recipients. These positive changes might be further enhanced by prolonging the duration of training or inclusion of more recipients with inspiratory muscle weakness. Clinical trial registration number: NCT02270346

Background Studies suggest that acute decreases in lung hyperinflation at rest improves cardiac function and increases lung vascular perfusion from decompression of a compromised heart. In those studies, changes in resting oxygen uptake induced by medications, an alternative explanation for compensatory increased cardiac function, were not explored. Methods This double-blind, multicenter, double-crossover study enrolled adults with chronic obstructive pulmonary disease, resting hyperinflation, and > 10% improvement in inspiratory capacity after 2 inhalations of budesonide/formoterol 160/4.5 μg. Metabolic, cardiac, and ventilatory function were measured 60 min pre−/post-dose at each visit. Primary endpoint was change in resting oxygen uptake for budesonide/formoterol versus placebo. Results Fifty-one patients (median age: 63 years) received treatment. Compared with placebo, budesonide/formoterol significantly increased resting oxygen uptake (mean change from baseline: 1.25 vs 11.37 mL/min; P  = 0.007) as well as tidal volume and minute ventilation. This occurred despite improvements in the inspiratory capacity, forced vital capacity, and expiratory volume in 1 s. No significant treatment differences were seen for oxygen saturation, respiratory rate, and resting dyspnea. There was a numerical increase in oxygen pulse (oxygen uptake/heart rate). Correlations between inspiratory capacity and oxygen pulse were weak. Conclusions Budesonide/formoterol treatment in resting hyperinflated patients with COPD results in significant deflation. The increase in oxygen uptake and minute ventilation at lower lung volumes, without changes in heart rate and with minimal improvement in oxygen pulse, suggests increased oxygen demand as a contributor to increased cardiac function. Trial registration ClinicalTrials.gov identifier: NCT02533505.

Background The changes in inspiratory capacity (IC) over time in chronic obstructive pulmonary disease (COPD) patients are unknown. The Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial included IC measurements. Methods IC analysis from UPLIFT® (N = 5992) was performed at 1 and 6 months, and every 6 months through 4 years. Annualized rate of decline in pre- and post-bronchodilator IC and mean differences at each time point were analyzed by mixed-effects models. The relationships between baseline IC and exacerbation rate and mortality were explored using Cox regression analysis. Results Baseline characteristics: age, 65 years; 75% men; post-bronchodilator forced expiratory volume in 1 second, 1.32 L (48% predicted); pre- and post-bronchodilator IC, 2.03 and 2.33 L. Mean IC rate of decline (mL/year) was 34 ± 2 (1.7% of baseline) and 50 ± 3 (2.1% of baseline) pre- and post-bronchodilator, respectively, without significant between-group differences. Morning pre-bronchodilator (trough) IC improved with tiotropium versus placebo: 124 mL (1 month), 103 mL (1 year), 107 mL (2 years), 98 mL (3 years), and 97 mL (4 years) (all p < 0.001). Post-bronchodilator improvements were similar between treatment groups. Lower baseline IC values were associated with reduced time to first exacerbation. For the lowest quartile (n = 1413) the values in months were 14.3 (11.7–17.0) for tiotropium and 10.3 (8.8–11.7) for controls (p < 0.01). Conclusion IC declines from approximately 34 to 50 mL/year in patients with stage II to IV COPD. Tiotropium treatment does not change the IC decline rate but provides 24-hour improvements in IC sustained over the long term. Trough IC differences suggest that tiotropium provides sustained decrease in end-expiratory lung volume.

Background Physical activity limitation is common in chronic obstructive pulmonary disease (COPD), and is associated with worse health status, and increased hospitalisation and mortality. Long-acting bronchodilators, either alone or in combination, have been shown to improve exercise intolerance. However, none of these studies were designed with physical activity as primary outcome. This study assessed the effect of indacaterol/glycopyrronium fixed dose combination (IND/GLY) 110/50 μg once daily (OD) versus placebo on lung hyperinflation (inspiratory capacity [IC]) and physical activity in patients with moderate-to-severe COPD. Methods In this multicentre, randomised, double-blind, placebo-controlled crossover study, patients received IND/GLY or placebo OD in two 21-day treatment periods (14-day washout between periods). Eligible patients were ≥40 years of age, current or ex-smokers (smoking history ≥10 pack-years), with post-salbutamol forced expiratory volume in 1 s (FEV 1 ) 40–80 % predicted, and FEV 1 :forced vital capacity <0.70. The co-primary endpoints were peak IC after 21 days and average daily activity-related energy expenditure. Key secondary endpoints were average number of steps per day and the duration of at least moderate activity per day. Peak IC and FEV 1 on Day 1, and trough IC and FEV 1 after 21 days were other secondary endpoints. Results A total of 194 patients were randomised (65.5 % male, mean age 62.8 years, mean FEV 1 61.6 % predicted), with 183 (94.3 %) completing the study. Compared with placebo, IND/GLY significantly increased peak IC after 21 days (difference 202 mL, p  < 0.0001), activity-related energy expenditure (difference 36.7 kcal/day, p  = 0.040), and the average number of steps per day (difference 358, p  = 0.029), with a trend towards an improvement in the duration of at least moderate activity (difference 4.4 min, p  = 0.264). IND/GLY was associated with statistically significant improvements versus placebo in peak IC and FEV 1 on Day 1, and trough IC and FEV 1 after 21 days. The incidence of treatment-emergent adverse events was 22.8 % with IND/GLY and 22.9 % with placebo. Conclusions In this study, compared with placebo, IND/GLY reduced hyperinflation, and, despite no patient education or lifestyle advice, improved daily physical activity levels. This suggests that IND/GLY has the potential to impact two of the main clinical concerns in the care of patients with COPD. Trial registration ClinicalTrials.gov number: NCT01996319 .

Asthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone. A 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 µg/day on budesonide/formoterol fumarate (BUD/FORM) 640/18 µg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization. A total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55-83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in ( < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods. The present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO.