Metabolic and cardiorespiratory effects of decreasing lung hyperinflation with budesonide/formoterol in COPD: a randomized, double-crossover, placebo-controlled, multicenter trial.

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.

Long-acting bronchodilators improve exercise capacity in COPD patients: a systematic review and meta-analysis.

Background: We carried out a systematic review and meta-analysis with the aim to evaluate the efficacy of longacting bronchodilators on exercise capacity in COPD patients. Methods: The endpoints were the efficacy of long-acting bronchodilators (altogether, and by single classes) vs. placebo in modifying endurance time (ET), inspiratory capacity (IC) and dyspnea during exercise, taking into consideration the outcomes according to different patients' inclusion criteria and exercise methodology. Results: Twenty-two studies were deemed eligible for analysis. Weighted mean increase in ET resulted of 67 s (95% CI ranges from 55 to 79). For isotime IC and dyspnea during exercise, weighted improvements were 195 ml (162­229), and − 0.41 units (− 0.56 to − 0.27), respectively. The increase in trough IC was 157 ml (138­175). We found a trend in favour of LAMA compared to LABA in terms of ET. In the 11 studies which reported a value of functional residual capacity > 120% as inclusion criterion, weighted mean increase in endurance time was 94 s (65 to 123); however we did not find any significant correlation between ET and mean trough IC (P: 0.593). The improvement of ET in the 5 studies using walking as exercise methodology resulted of 58 s (− 4 to 121). Conclusions: Long-acting bronchodilators improve exercise capacity in COPD. The main effect of long-acting bronchodilators seems to be a increase of basal IC rather than a modification of dynamic hyperinflation during exercise. The efficacy in terms of endurance time seems higher in studies which enrolled patients with hyperinflation, with a similar efficacy on walking or cycling.

Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD.

Two replicate, double-blind, 6-week, incomplete-crossover studies (MORACTO 1 and 2) assessed the effects of tiotropium/olodaterol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease.For each patient, four of five treatments were administered once daily for 6 weeks, with a 21-day washout between treatments: tiotropium/olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg, olodaterol 5 µg or placebo, all via the Respimat inhaler. Primary outcomes were inspiratory capacity prior to exercise and exercise endurance time during constant work-rate cycle ergometry to symptom limitation at 75% of peak incremental work rate after 6 weeks (2 h post-dose).295 and 291 patients were treated in MORACTO 1 and 2, respectively. Tiotropium/olodaterol 2.5/5 and 5/5 µg provided significant improvements in inspiratory capacity versus placebo and monotherapies (p<0.0001), and significant improvements in exercise endurance time versus placebo (p<0.0001). Intensity of breathing discomfort was reduced following both doses of tiotropium/olodaterol versus placebo (p<0.0001).Once-daily tiotropium/olodaterol yielded improvements in lung hyperinflation versus placebo and statistically significant improvements versus monotherapies. Tiotropium/olodaterol also showed improvements in dyspnoea and exercise tolerance versus placebo but not consistently versus monotherapies.

24-h bronchodilation and inspiratory capacity improvements with glycopyrrolate/formoterol fumarate via co-suspension delivery technology in COPD.

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 (FEV1AUC0-24). 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 FEV1AUC0-24 versus placebo in studies PT003011 (n = 75) and PT003012 (n = 35) on day 29 (both studies p < 0.0001), with similar improvements in FEV1AUC versus placebo for hours 0-12 and 12-24. In PT003011, improvements with GFF MDI versus tiotropium in FEV1AUC 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.

Parasternal intercostal muscle activity during methacholine-induced bronchoconstriction.

NEW FINDINGS: What is the central question of this study? The parasternal intercostal electromyogram (EMGpara) is known to provide an accurate, non-invasive index of respiratory load-capacity balance. Although relationships between EMGpara and both airflow obstruction and hyperinflation have been shown, the independent contribution of each factor has not been examined. What is the main finding and its importance? Reductions in airway calibre and inspiratory capacity along with increases in EMGpara were induced via methacholine challenge. A strong inverse relationship was observed between EMGpara and airway obstruction, with no influence of inspiratory capacity. These data suggest that EMGpara is more strongly influenced by airway calibre than by changes in end-expiratory lung volume during airway challenge testing. Neural respiratory drive, measured via the parasternal intercostal electromyogram (EMGpara), provides a non-invasive index of the load-capacity balance of the respiratory muscle pump. Previous studies in patients with obstructive lung disease have shown strong relationships between EMGpara and the extent of both airflow obstruction and hyperinflation. The relative influence of the two factors has not, however, been described. Airflow obstruction was induced via methacholine challenge testing in 25 adult humans. Forced expiratory volume in 1 s (FEV1 ) and surface EMGpara during tidal breathing were measured after each dose, with 20 of the participants also undergoing measurements of inspiratory capacity (IC) at each stage. Linear mixed model analysis was used to assess dose-wise changes in FEV1 and EMGpara, and thereafter to determine the influence of changes in FEV1 and IC on change in EMGpara. Median (interquartile range) FEV1 decreased significantly [from 96.00 (80.00-122.30) to 67.80 (37.98-92.27)% predicted, P < 0.0001] and EMGpara increased significantly [from 5.37 (2.25-8.92) to 6.27 (3.37-19.60) µV, P < 0.0001] from baseline to end of test. Linear mixed model analysis showed a significant interaction between methacholine dose and induced change in EMGpara, with an increase in EMGpara of 0.24 (95% confidence interval 0.11-0.37) µV per methacholine dose2 . Change in FEV1 further influenced this relationship [increase in slope of 0.002 (0.004-0.001) µV dose-2 per % predicted fall in FEV1 , P = 0.011], but not with change in IC. These data suggest that bronchoconstriction exerts a more potent influence on levels of EMGpara than changes in end-expiratory lung volume during methacholine challenge.

Multivariate Analysis of Effects of Asthmatic Patient Respiratory Profiles on the In Vitro Performance of a Reservoir Multidose and a Capsule-Based Dry Powder Inhaler.

PURPOSE: The aim of this work was to evaluate the effect of two different dry powder inhalers, of the NGI induction port and Alberta throat and of the actual inspiratory profiles of asthmatic patients on in-vitro drug inhalation performances. METHODS: The two devices considered were a reservoir multidose and a capsule-based inhaler. The formulation used to test the inhalers was a combination of formoterol fumarate and beclomethasone dipropionate. A breath simulator was used to mimic inhalatory patterns previously determined in vivo. A multivariate approach was adopted to estimate the significance of the effect of the investigated variables in the explored domain. RESULTS: Breath simulator was a useful tool to mimic in vitro the in vivo inspiratory profiles of asthmatic patients. The type of throat coupled with the impactor did not affect the aerodynamic distribution of the investigated formulation. However, the type of inhaler and inspiratory profiles affected the respirable dose of drugs. CONCLUSIONS: The multivariate statistical approach demonstrated that the multidose inhaler, released efficiently a high fine particle mass independently from the inspiratory profiles adopted. Differently, the single dose capsule inhaler, showed a significant decrease of fine particle mass of both drugs when the device was activated using the minimum inspiratory volume (592 mL).

Effects of indacaterol/glycopyrronium (QVA149) on lung hyperinflation and physical activity in patients with moderate to severe COPD: a randomised, placebo-controlled, crossover study (The MOVE Study).

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 (FEV1) 40-80 % predicted, and FEV1: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 FEV1 on Day 1, and trough IC and FEV1 after 21 days were other secondary endpoints. RESULTS: A total of 194 patients were randomised (65.5 % male, mean age 62.8 years, mean FEV1 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 FEV1 on Day 1, and trough IC and FEV1 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 .

Effects of long-acting bronchodilators and prednisolone on inspiratory lung function parameters in stable COPD.

BACKGROUND: In chronic obstructive pulmonary disease (COPD), there is a poor correlation between forced expiratory volume in 1 s (FEV1) and dyspnea following bronchodilator use. Better correlations have been observed between inspiratory lung function parameters (ILPs) and dyspnea, which drives our interest in ILPs. However, the acute and prolonged effects of long-acting bronchodilators and oral corticosteroids on ILPs have not been well investigated. Therefore, the aim of this study was to investigate the effects of these treatments on the ILPs, FEV1, dyspnea (visual analog scale (VAS)) and clinical COPD questionnaire (CCQ). METHODS: Twenty-eight stable COPD patients had their ILPs and FEV1 measured both before and 2 h after the use of a single dose of 18 mcg bronchodilator tiotropium and 50 mcg salmeterol. Thereafter, the patients were randomized to 2 weeks of treatment with 30 mg oral prednisolone once daily or oral placebo in combination with daily treatment with these two bronchodilators. Four weeks after the cessation of the randomized treatment, the ILPs and FEV1 were again measured. After each intervention, any change in the VAS score was assessed. RESULTS: With both bronchodilators, significant improvements in ILPs were demonstrated (p < 0.005), with the exception of changes in ILPs inspiratory capacity (IC) and forced inspiratory flow at 50% of the vital capacity (FIF50) after tiotropium inhalation. After 2 weeks of treatment with prednisolone, significant differences were found for ILP forced inspiratory volume in 1 s (FIV1) and FEV1 compared with placebo. These differences were no longer present 4 weeks after the cessation of prednisolone. Significant relationships between ILPs and VAS scores were only found after 2 weeks of treatment with prednisolone or placebo. CONCLUSIONS: After a single dose of long-acting bronchodilator salmeterol, significant improvements are observed in all ILPs and in FIV1 and PIF after tiotropium. Two weeks of oral corticosteroid treatment improved the FIV1 and FEV1. The dyspnea VAS score was only significantly correlated with the ILPs after 2 weeks of oral corticosteroid treatment.

Indacaterol improves lung hyperinflation and physical activity in patients with moderate chronic obstructive pulmonary disease--a randomized, multicenter, double-blind, placebo-controlled study.

BACKGROUND: Indacaterol is a long-acting beta-2 agonist for once-daily treatment of COPD. We evaluated the effects of indacaterol 150 µg on lung hyperinflation compared with placebo and open-label tiotropium 18 µg. We measured physical activity during treatment with indacaterol 150 µg and matched placebo. METHODS: We performed a randomized, three-period, cross-over study (21 days of treatment separated by two wash-out periods of 13 days) with indacaterol 150 µg or matching placebo and tiotropium 18 µg. Lung function was assessed by body plethysmography and spirometry. Physical activity was measured for one week by a multisensory armband at the end of both treatment periods with indacaterol/matched placebo. The primary endpoint was peak inspiratory capacity at the end of each treatment period. RESULTS: 129 patients (mean age, 61 years; mean post-bronchodilator FEV1, 64%), were randomized and 110 patients completed the study. Peak inspiratory capacity was 0.22 L greater with Indacaterol at day 21 compared to placebo (p < 0.001). Similar results were observed for tiotropium. Both bronchodilators also significantly improved other parameters of lung hyperinflation compared with placebo. All parameters of physical activity were significantly increased during treatment with indacaterol versus placebo. CONCLUSIONS: Indacaterol 150 µg improved lung hyperinflation in patients with moderate COPD, which was associated with an increase of physical activity. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT01012765.

Efficacy and safety of once daily triamcinolone acetonide aqueous nasal spray in adults with non-allergic and allergic rhinitis.

BACKGROUND: The efficacy of corticosteroid has not been thoroughly studied in the treatment of non-allergic rhinitis. This study was designed to compare the efficacy of nasal corticosteroid in patients with allergic rhinitis (AR), and non-allergic rhinitis (NAR). METHODS: The efficacy of triamcinolone acetonide nasal spray (TANS) on total nasal symptom scores (TNSS), and nasal peak inspiratory flow rate (nPIFR) was studied in a six-week parallel-group trial of NAR (n: 25), and AR (n: 16) patients. Health-related quality of life (HRQoL) and Epworth Sleepiness Scale (ESS) were also analysed. RESULTS: The TNSSs, and symptom scores of conjunctivitis, snoring, and postnasal drainage were significantly improved in both groups, after two and six weeks of treatment. In contrast to AR, patients with NAR had statistically significant improvement in nasal obstruction, and postnasal drainage beginning from two weeks of the treatment. nPIFR slightly increased in both groups. Scores of generic (SF-36), rhinitis specific (MiniRQLQ) and ESS questionnaires generally improved better in AR than NAR. TANS was well-tolerated in AR and NAR groups with minor adverse events including headache, nasal burning, and bitter mouth taste. CONCLUSIONS: Our study disproved the idea of ineffectiveness of corticosteroid treatment in NAR, and showed that triamcinolone acetate may be an alternative drug in the treatment of NAR.

Longitudinal inspiratory capacity changes in chronic obstructive pulmonary disease.

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.

Randomized controlled trial of a breath-activated nebulizer in patients with exacerbation of COPD.

BACKGROUND: Exacerbations of COPD (ECOPD) are characterized by increased dyspnea due to dynamic pulmonary hyperinflation. This study sought to determine whether the AeroEclipse II breath-activated nebulizer (BAN) would produce greater bronchodilator responses than a continuous flow small-volume nebulizer (SVN) in patients with ECOPD. METHODS: Prospective randomized controlled trial. Forty patients with ECOPD were recruited to participate in the trial. The primary study outcomes were inspiratory capacity (IC) and dyspnea via the Borg scale. Subjects were randomized to receive bronchodilator from either a BAN or a continuous flow SVN. Subjects in both groups received 2.5 mg albuterol sulfate and 0.5 mg ipratropium bromide by nebulizer every 4 hours, and 2.5 mg albuterol every 2 hours as needed. Approximately 2 hours after the subject's 6th scheduled nebulizer treatment, IC, dyspnea, and respiratory frequency measurements were repeated. RESULTS: Both groups received an equal number of nebulizer treatments over the study period (BAN 6.25 ± 0.55, control 6.2 ± 0.7, P = .80). Following completion of the study protocol the BAN group had a higher IC than the SVN group (1.83 ± 0.65 L vs 1.42 ± 0.49 L, P = .03, respectively). The change in IC was higher in the BAN group (0.33 ± 0.31 L than in the SVN group (0.15 ± 0.19 L, P = .03). The BAN group also had a lower respiratory rate (19 ± 3.3 breaths/min vs 22 ± 5.3 breaths/min, P = .03, respectively). There was no difference in resting dyspnea as measured with the Borg scale (BAN 3.3 ± 2.1, SVN 3.5 ± 2.4, P = .69) or stay (BAN 4.6 ± 2.6 d, SVN 5.7 ± 2.8 d, P = .21). CONCLUSIONS: In this cohort of patients with ECOPD, a BAN was more effective in reducing lung hyperinflation and respiratory frequency than a continuous-flow SVN.

Effect of heliox on heart rate kinetics and dynamic hyperinflation during high-intensity exercise in COPD.

Respiratory mechanical abnormalities in patients with chronic obstructive pulmonary disease (COPD) may impair cardiodynamic responses and slow down heart rate (HR) kinetics compared with normal resulting in reduced convective oxygen delivery during exercise. We reasoned that heliox breathing (79% helium-21% oxygen) and the attendant reduction of operating lung volumes should accelerate HR kinetics in the transition from rest to high-intensity exercise. Eleven male ambulatory patients with clinically stable COPD undertook constant work-rate cycle testing at 80% of each individuals' maximum work capacity while breathing room air (RA) or heliox (HX), randomly. Mean response time (MRT) for HR and dynamic end-expiratory lung volume (EELV) were measured. Resting EELV was not affected by HX breathing, while exercise EELV decreased significantly by 0.23 L at isotime during HX breathing compared with RA. During HX breathing, MRT for HR significantly accelerated (p = 0.002) by an average of 20 s (i.e., 17%). Speeded MRT for HR correlated with indices of reduced lung hyperinflation, such as EELV at isotime (r = 0.88, p = 0.03), and with improved exercise endurance time (r = -0.64, p = 0.03). The results confirm that HX-induced reduction of dynamic lung hyperinflation is associated with consistent improvement in indices of cardio-circulatory function such as HR kinetics in the rest-to-exercise transition in COPD patients.

Comparison of nasal sound spectral analysis and peak nasal inspiratory flow before and after decongestion in patients with nasal obstruction.

OBJECTIVES: We compared the results of nasal sound spectral analysis (NSSA) with the results of peak nasal inspiratory flow (PNIF) testing and use of a visual analog scale in patients with allergic rhinitis with nasal obstruction. METHODS: We performed NSSA and PNIF testing on 38 patients with allergic rhinitis and 35 healthy subjects. A diagnostic decongestion test was performed on the patients (not on the control subjects). Twenty minutes after decongestant was sprayed into the nostrils, NSSA and PNIF testing were performed again. RESULTS: There was a significant difference in the PNIF values and the nasal inspiratory sound intensities before and after decongestion (p < 0.001). There was a correlation between the NSSA results at the frequency range of 2 to 4 kHz and the PNIF results. The calculated cutoffs between normal and pathological values were 14.8 dB (2 to 4 kHz) for NSSA and 116 +/- 14.1 L/min for PNIF testing. No significant differences were computed between NSSA and PNIF testing in terms of sensitivity (0.71 versus 0.76) or specificity (0.74 versus 0.80). CONCLUSIONS: Use of NSSA and PNIF testing together for assessment of nasal obstruction in allergic rhinitis provides clinical relevance in that it allows a fair degree of reliability. Such testing can be performed as a surrogate for rhinomanometry.

Effect of indacaterol on dynamic lung hyperinflation and breathlessness in hyperinflated patients with COPD.

Indacaterol is a novel, inhaled once-daily ultra long-acting ß2-agonist for the treatment of COPD. This randomised, double-blind, placebo-controlled, two-period crossover study evaluated the effect of two-week treatment with indacaterol 300 µg on peak and isotime exercise inspiratory capacity (IC) in patients with COPD. Patients (40-80 years) with post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 70%, percent predicted FEV1 ≥ 40% and ≤ 80%, smoking history ≥ 20 pack-years and functional residual capacity > 120% of predicted normal were randomised to receive indacaterol 300 µg or placebo once-daily via a single-dose dry powder inhaler. Following 14 days of treatment, IC at peak and isotime during constant-load (80% of maximum workload) cycle ergometry was analysed using linear mixed-effects models. Safety and tolerability were also monitored. Twenty-seven patients (67% male; mean age, 61.3 years) were randomised; 24 completed the study. On Day 14, indacaterol showed statistically significant improvements over placebo in peak (317 mL [95% CI: 118-517]; p < 0.01) and isotime IC (268 mL [95% CI: 104-432]; p < 0.01). Statistically significant improvements were observed with indacaterol versus placebo on Day 14 for the following secondary endpoints: resting IC, trough FEV1, dyspnoea (BDI/TDI and Borg CR10 scale at isotime) and exercise endurance time. Indacaterol was well tolerated, with no serious adverse events or deaths. In conclusion, indacaterol 300 µg administered once-daily showed a clinically relevant increase in IC after 14 days of treatment, reflecting a reduction in dynamic hyperinflation.

Neuromodulatory effect of endogenous opioids on the intensity and unpleasantness of breathlessness during resistive load breathing in COPD.

BACKGROUND: Endogenous opioids are naturally occurring peptides released by the brain in response to noxious stimuli. Although these naturally occurring peptides modulate pain, it is unknown whether endogenous opioids affect the perception of breathlessness associated with a specific respiratory challenge. The hypothesis is that intravenous administration of naloxone, used to block opioid signaling and inhibit neural pathways, will increase ratings of breathlessness during resistive load breathing (RLB) in patients with chronic obstructive pulmonary disease (COPD). METHODS: Fourteen patients with COPD (age, 64 ± 9 years) inspired through resistances during practice sessions to identify an individualized target load that caused ratings of intensity and/or unpleasantness of breathlessness ≥ 50 mm on a 100 mm visual analog scale. At two intervention visits, serum beta-endorphins were measured, naloxone (10 mg/25 ml) or normal saline (25 ml) was administered intravenously, and patients rated the two dimensions of breathlessness each minute during RLB. RESULTS: Patient ratings of intensity (p = 0.0004) and unpleasantness (p = 0.024) of breathlessness were higher with naloxone compared with normal saline. Eleven patients (79%) reported that it was easier to breathe during RLB with normal saline (p = 0.025). RLB led to significant increases in serum beta-endorphin immunoreactivity and decreases in inspiratory capacity. There were no significant differences in physiological responses between interventions. CONCLUSIONS: Endogenous opioids modulate the intensity and the unpleasantness of breathlessness in patients with COPD. Differences in breathlessness ratings between interventions were clinically relevant based on the patients' global assessment.

Deterioration of Nighttime Respiratory Mechanics in COPD: Impact of Bronchodilator Therapy.

BACKGROUND: COPD is associated with nighttime respiratory symptoms, poor sleep quality, and increased risk of nocturnal death. Overnight deterioration of inspiratory capacity (IC) and FEV1 have been documented previously. However, the precise nature of this deterioration and mechanisms by which evening bronchodilation may mitigate this occurrence have not been studied. RESEARCH QUESTION: What is the effect of evening dosing of dual, long-acting bronchodilation on detailed nocturnal respiratory mechanics and inspiratory neural drive (IND)? STUDY DESIGN AND METHODS: A double-blind, randomized, placebo-controlled crossover study assessed the effects of evening long-acting bronchodilation (aclidinium bromide/formoterol fumarate dihydrate: 400/12 µg) or placebo on morning trough IC (12 h after the dose; primary outcome) and serial overnight measurements of spirometry, dynamic respiratory mechanics, and IND (secondary outcomes). Twenty participants with COPD (moderate/severe airway obstruction and lung hyperinflation) underwent serial measurements of IC, spirometry, breathing pattern, esophageal and transdiaphragmatic pressures, and diaphragm electromyography (diaphragmatic electromyography as a percentage of maximum; IND) at 6 time points from 0 to 12 h after the dose and compared with sleeping IND. RESULTS: Compared with placebo, evening bronchodilation was not associated with increased morning trough IC 12 h after the dose (P = .48); however, nadir IC (lowest IC, independent of time), peak IC, area under the curve for 12 h after the dose, and IC for 10 h after the dose were improved (P < .05). During placebo, total airways resistance, lung hyperinflation, IND, and tidal esophageal and transdiaphragmatic pressure swings all increased significantly overnight compared with baseline evening values; however, each of these parameters improved with bronchodilator treatment (P < .05) with no change in ventilation or breathing pattern. INTERPRETATION: Respiratory mechanics significantly deteriorated at night during placebo. Although the morning trough IC was unchanged, evening bronchodilator treatment was associated consistently with sustained overnight improvements in dynamic respiratory mechanics and inspiratory neural drive compared with placebo CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02429765.

Respiratory safety pharmacology: concurrent validation of volume, rate, time, flow and ratio variables in conscious male Sprague-Dawley rats.

This study compares basic respiratory variables (rate, tidal and minute volumes) with time-, flow- and ratio-derived parameters obtained using head-out plethysmography in rats following administration of reference drugs (isotonic saline, 2.0 mL/kg, IV; albuterol, 400 µg/kg, inhalation; methacholine, 136 µg/kg, IV; and remifentanil, 14 µg/kg, IV) to identify respiratory variables with superior sensitivity. Paired t-tests by block-period, and analysis of covariance (ANCOVA) with baseline as covariate and a posteriori pair-wise comparisons using Dunnett's test were used. Variations in respiratory parameters observed over time justify the use of a control group in any respiratory safety pharmacology study for inter-groups comparison. Handling-, and slumbering-, induced perturbations were minimal. The system was sensitive and specific to detect changes in respiratory variables related to pharmacologically-induced bronchodilation, bronchoconstriction and central respiratory depression. The standard variables (respiratory rate, tidal and minute volumes) confirmed to be the cornerstone of respiratory safety pharmacology to detect pharmacological changes. Flow-derived parameters appeared as highly valuable complement for interpretation of respiratory response, whereas time- and ratio-derived parameters presented limited added value during interpretation.

Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate Improves Inspiratory Capacity in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap.

Purpose: 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 ß2 agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone. Methods: 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. Results: 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 (p < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods. Conclusion: 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.