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A reappraisal of inspiratory capacity in chronic obstructive pulmonary disease: clinical correlates and role of long-acting muscarinic antagonists and long-acting β2 agonists
Abstract
Introduction:
In patients with chronic obstructive pulmonary disease (COPD), static and dynamic hyperinflation, together with expiratory flow limitation and gas exchange abnormalities, is one of the major causes of dyspnea, decreased exercise performance and ventilatory failure. An increase in functional residual capacity (FRC) is accompanied by a decrease in inspiratory capacity (IC), which is a volume readily available, repeatable, and simple to measure with any spirometer. Changes in IC and FRC after bronchodilation, contrary to changes in FEV1, have been closely associated with improvements in dyspnea and exercise performance. We systematically searched PubMed and Embase databases for clinical trials that assessed the effects of dual bronchodilation on inspiratory capacity in patients with COPD.
Areas covered:
Despite their pivotal role in COPD, IC and static volumes have rarely been considered as primary outcomes in randomized clinical trials assessing the efficacy of bronchodilators. Available studies on dual bronchodilation have shown a significant and persistent positive impact on IC focusing mainly on patients with moderate-to-severe COPD, whereas dynamic hyperinflation is also present at milder disease stages.
Expert opinion:
This narrative review discusses the pathophysiological and clinical importance of measuring IC in patients with COPD and how IC can be modified by maximizing bronchodilation combining long-acting muscarinic antagonists and long-acting β2 agonists.
A rise in the disinfection of spaces occurred as a result of the COVID-19 pandemic as well as an increase in people wearing facial coverings. Hydrogen peroxide was among the recommended disinfectants for use against the virus. Previous studies have investigated the emissions of hydrogen peroxide associated with the disinfection of spaces and masks; however, those studies did not focus on the emitted byproducts from these processes. Here, we simulate the disinfection of an indoor space with H2O2 while a person wearing a face mask is present in the space by using an environmental chamber with a thermal manikin wearing a face mask over its breathing zone. We injected hydrogen peroxide to disinfect the space and utilized a chemical ionization mass spectrometer (CIMS) to measure the primary disinfectant (H2O2) and a Vocus proton transfer reaction time-of-flight mass spectrometer (Vocus PTR-ToF-MS) to measure the byproducts from disinfection, comparing concentrations inside the chamber and behind the mask. Concentrations of the primary disinfectant and the byproducts inside the chamber and behind the mask remained elevated above background levels for 2–4 h after disinfection, indicating the possibility of extended exposure, especially when continuing to wear the mask. Overall, our results point toward the time-dependent impact of masks on concentrations of disinfectants and their byproducts and a need for regular mask change following exposure to high concentrations of chemical compounds.
Flow rate dependence of inhaled bronchodilators
Since its introduction in the clinical practice, body plethysmography has assisted pneumologists in the diagnosis of respiratory diseases and patients’ follow-up, by providing easy assessment of absolute lung volumes and airway resistance. In the last decade, emerging evidence suggested that estimation of alveolar pressure by electronically-compensated plethysmographs may contain information concerning the mechanics of the respiratory system which goes beyond those provided by the simple value of airway resistance or conductance. Indeed, the systematic study of expiratory alveolar pressure-flow loops produced during spontaneous breathing at rest has shown that the marked expansion of expiratory loops in chronic obstructive pulmonary disease patients mainly reflects the presence of tidal expiratory flow-limitation. The presence of this phenomenon can be accurately predicted on the basis of loop-derived parameters. Finally, we present results suggesting that plethysmographic alveolar pressure may be used to estimate non-invasively intrinsic positive end-expiratory pressure (PEEPi) in spontaneously breathing patients, a task which previously could be only accomplished by introducing a balloon-tipped catheter in the esophagus.
Background
Our aim was to describe: 1) lung deposition and inspiratory flow rate; 2) main characteristics of inhaler devices in chronic obstructive pulmonary disease (COPD).
Methods
A systematic literature review (SLR) was conducted to analyze the features and results of inhaler devices in COPD patients. These devices included pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and a soft mist inhaler (SMI). Inclusion and exclusion criteria were established, as well as search strategies (Medline, Embase, and the Cochrane Library up to April 2019). In vitro and in vivo studies were included. Two reviewers selected articles, collected and analyzed data independently. Narrative searches complemented the SLR. We discussed the results of the reviews in a nominal group meeting and agreed on various general principles and recommendations.
Results
The SLR included 71 articles, some were of low–moderate quality, and there was great variability regarding populations and outcomes. Lung deposition rates varied across devices: 8%–53% for pMDIs, 7%-69% for DPIs, and 39%–67% for the SMI. The aerosol exit velocity was high with pMDIs (more than 3 m/s), while it is much slower (0.84–0.72 m/s) with the SMI. In general, pMDIs produce large-sized particles (1.22–8 μm), DPIs produce medium-sized particles (1.8–4.8 µm), and 60% of the particles reach an aerodynamic diameter <5 μm with the SMI. All inhalation devices reach central and peripheral lung regions, but the SMI distribution pattern might be better compared with pMDIs. DPIs’ intrinsic resistance is higher than that of pMDIs and SMI, which are relatively similar and low. Depending on the DPI, the minimum flow inspiratory rate required was 30 L/min. pMDIs and SMI did not require a high inspiratory flow rate.
Conclusion
Lung deposition and inspiratory flow rate are key factors when selecting an inhalation device in COPD patients.
Metered dose inhalers (MDIs) are one of the most common device types for delivering inhaled therapies. However, there are several technical challenges in development and drug delivery of these medications. In particular, suspension-based MDIs are susceptible to suspension heterogeneity, in vitro drug–drug interactions, and patient handling errors, which may all affect drug delivery. To overcome these challenges, new formulation approaches are required. The AerosphereTM inhaler, formulated using co-suspension delivery technology, combines drug crystals with porous phospholipid particles to create stable, homogenous suspensions that dissolve once they reach the airways. Two combination therapies using this technology have been developed for the treatment of COPD: glycopyrrolate/formoterol fumarate (GFF MDI; dual combination) and budesonide/glycopyrrolate/formoterol fumarate (BGF MDI; triple combination). Here, we review the evidence with a focus on studies assessing dose delivery, lung deposition, and effects on airway geometry. In vitro assessments have demonstrated that the Aerosphere inhaler provides consistent dose delivery, even in the presence of simulated patient handling errors. Combination therapies delivered with this technology also show a consistent fine particle fraction (FPF) and an optimal particle size distribution for delivery to the central and peripheral airways even when multiple drugs are delivered via the same inhaler. Studies using gamma scintigraphy and functional respiratory imaging have demonstrated that GFF MDI is effectively deposited in the central and peripheral airways, and provides clinically meaningful benefits on airway volume and resistance throughout the lung. Overall, studies suggest that the Aerosphere inhaler, formulated using co-suspension delivery technology, may offer advantages over traditional formulations, including consistent delivery of multiple components across patient handling conditions, optimal particle size and FPF, and effective delivery to the central and peripheral airways. Future studies may provide additional evidence to further characterize the clinical benefits of these technical improvements in MDI drug delivery.
One of the most debilitating symptoms of chronic obstructive pulmonary disease (COPD) is breathlessness, which leads to avoidance of physical activities in daily living and hastens clinical deterioration. Treatment of patients with COPD with inhaled long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination therapy improves airflow limitation, reduces breathlessness compared with LAMA or LABA monotherapies, and improves health status and quality of life. A large clinical trial programme focusing on the effects of tiotropium/olodaterol combination therapy demonstrated that this LAMA/LABA combination improves lung function and reduces hyperinflation (assessed by serial inspiratory capacity measurements) compared with either tiotropium alone or placebo in patients with COPD. Tiotropium/olodaterol also increases exercise endurance capacity and improves patient perception of the intensity of breathlessness compared with placebo. In this narrative review, we focus on the relationship between improving symptoms during activity, the ability to remain active in daily life and how this may impact quality of life. We consider the benefits of therapy optimisation by means of dual bronchodilation with tiotropium/olodaterol, and present new data from meta-analyses/pooled analyses showing that tiotropium/olodaterol improves inspiratory capacity compared with placebo and tiotropium and improves exercise endurance time compared with placebo after 6 weeks of treatment. We also discuss the importance of taking a holistic approach to improving physical activity, including pulmonary rehabilitation and exercise programmes in parallel with bronchodilator therapy and psychological programmes to support behaviour change.
This study identified the effects of pursed-lip breathing (PLB), forward trunk lean posture (FTLP), and combined PLB and FTLP on total and compartmental lung volumes, and ventilation in patients with chronic obstructive pulmonary disease (COPD). Sixteen patients with mild to moderate COPD performed 2 breathing patterns of quiet breathing (QB) and PLB during FTLP and upright posture (UP). The total and compartmental lung volumes and ventilation of these 4 tasks (QB-UP, PLB-UP, QB-FTLP, PLB-FTLP) were evaluated using optoelectronic plethysmography. Two-way repeated measures ANOVA was used to identify the effect of PLB, FTLP, and combined strategies on total and compartmental lung volumes and ventilation. End-expiratory lung volume of ribcage compartment was significantly lower in PLB-UP than QB-UP and those with FTLP (P < .05). End-inspiratory lung volume (EILV) and end-inspiratory lung volume of ribcage compartment were significantly greater during PLB-FTLP and PLB-UP than those of QB (P < .05). PLB significantly and positively changed end-expiratory lung volume of abdominal compartment (EELVAB ) end-expiratory lung volume, EILVAB, tidal volume of pulmonary ribcage, tidal volume of abdomen, and ventilation than QB (P < .05). UP significantly increased tidal volume of pulmonary ribcage, tidal volume of abdomen, and ventilation and decreased EELVAB, end-expiratory lung volume, and EILVAB than FTLP (P < .05). In conclusion, combined PLB with UP or FTLP demonstrates a positive change in total and compartmental lung volumes in patients with mild to moderate COPD.
Background
The six-minute pegboard and ring test (6-PBRT) has been used to evaluate functional capacity of the upper limbs in stable chronic obstructive pulmonary disease (COPD) patients. To the best of our knowledge, no studies have evaluated dynamic hyperinflation (DH) during exercise with upper limbs in the hospital setting. The aim of this study was to evaluate physiological responses and DH induced by 6-PBRT in hospitalized patients with acute exacerbation of COPD (AECOPD).
Methods
A cross-sectional study was conducted in a tertiary hospital enrolling patients who were hospitalized due to AECOPD. All included participants underwent an evaluation of lung function and 6-PBRT when they reached minimum clinical criteria. Ventilatory and hemodynamics parameters were monitored during 6-PBRT and until 6 minutes of rest after the test. Symptoms of dyspnea and upper limb fatigue were also measured.
Results
Eighteen patients (71.3±5.1 years) with a mean FEV1 of 43.2±18.3% were included in the study (11 females). Prevalence of DH after 6-PBRT was 50% (considering the drop of 150 ml or 10% of inspiratory capacity, immediately after the end of the test). There was a significant increase in respiratory rate, minute volume, dyspnea, and upper limb fatigue after the end of 6-PBRT (p<0.05). Dyspnea recovered more precociously than the perception of fatigue, being reestablished within four minutes of rest. An increase in heart rate, systolic and diastolic blood pressures was also induced by 6-PBRT (p<0.05), requiring 6 minutes of recovery to return to baseline. No adverse events were observed during 6-PBRT. We concluded that 6-PBRT induces physiological changes during its execution, at safe levels, requiring a maximum of 6 minutes for recovery. Finally, the test proved to be safe and applicable for patients hospitalized due to AECOPD.
The majority of smokers with chronic obstructive pulmonary disease (COPD) have mild airflow limitation as determined by simple spirometry. Although small airway dysfunction is the hallmark of COPD, many studies attest to complex heterogeneous physiological impairments beyond increased airway resistance. These impairments are related to inflammation of lung parenchyma and its microvasculature, which is obscured by simple spirometry. Recent studies using advanced radiological imaging have highlighted significant structural abnormalities in smokers with relatively preserved spirometry. These important studies have generated considerable interest and have reinforced the pressing need to better understand the physiological consequences of various morphological abnormalities, and their impact on the clinical outcomes and natural history of COPD. The overarching objective of this review is to provide a concise overview of the importance and utility of cardiopulmonary exercise testing (CPET) in clinical and research settings. CPET uniquely allows evaluation of integrated abnormalities of the respiratory, cardio-circulatory, metabolic, peripheral muscle and neurosensory systems during increases in physiologic stress. This brief review examines the results of recent studies in mild COPD that have uncovered consistent derangements in pulmonary gas exchange and development of “restrictive” dynamic mechanics that together contribute to exercise intolerance. We examine the evidence that compensatory increases in inspiratory neural drive from respiratory control centers are required during exercise in mild COPD to maintain ventilation commensurate with increasing metabolic demand. The ultimate clinical consequences of this high inspiratory neural drive are earlier onset of critical respiratory mechanical constraints and increased perceived respiratory discomfort at relatively low exercise intensities.
Background
Bronchoscopic lung volume reduction techniques are minor invasive treatment modalities for severely hyperinflated emphysema patients. The severity of static lung hyperinflation determines eligibility and success rate for these treatments. However, it is not exactly known what parameter should be used to optimally reflect hyperinflation. Commonly used parameters are residual volume (RV) and the RV/Total lung capacity (TLC) ratio. Other parameters reflecting hyperinflation are Inspiratory Capacity/TLC and forced vital capacity.Objectives
To define which of these function parameters is the most optimal reflection of hyperinflationin in relation to patient-related outcomes.Methods
In a retrospective cohort study, data from measurements during baseline visits of eight studies were pooled. Primary outcomes were RV/TLC ratio and RV as percentage of predicted (RV%pred), both measured by bodyplethysmography, compared to the patient-related outcome variables: 6-min walk distance (6MWD), the St. George’s Respiratory Questionnaire (SGRQ), and the modified Medical Research Council (mMRC).ResultsTwo hundred seventy-four COPD patients (mean age 59 years; 66% female), FEV1 0.74 ± 0.28 L, RV 4.94 ± 1.06 L, 6MWD of 339 ± 95 m, were included in the analysis. Significant correlations (all p < 0.01) were found between RV%pred and 6MWD (r = − 0.358), SGRQ (r = 0.184), and mMRC (r = 0.228). Also, there was a significant correlation between RV/TLC ratio and 6MWD (r = − 0.563), SGRQ (r = 0.289) and mMRC (r = 0.354). Linear regression analyses showed that RV/TLC ratio was a better predictor of patient outcomes than RV%pred.Conclusion
This study demonstrates that both RV/TLC ratio and RV%pred are relevant indicators of hyperinflation in patients with severe emphysema in relation to patient-related outcomes. RV/TLC ratio is more strongly related to the patient-related outcomes than RV%pred.
Bronchodilators remain the cornerstone of the treatment of airway disorders such as asthma and chronic obstructive pulmonary disease (COPD). There is therefore considerable interest in understanding how to optimize the use of our existing classes of bronchodilator and in identifying novel classes of bronchodilator drugs. However, new classes of bronchodilator have proved challenging to develop because many of these have no better efficacy than existing classes of bronchodilator and often have unacceptable safety profiles. Recent research has shown that optimization of bronchodilation occurs when both arms of the autonomic nervous system are affected through antagonism of muscarinic receptors to reduce the influence of parasympathetic innervation of the lung and through stimulation of β2-adrenoceptors (β2-ARs) on airway smooth muscle with β2-AR-selective agonists to mimic the sympathetic influence on the lung. This is currently achieved by use of fixed-dose combinations of inhaled long-acting β2-adrenoceptor agonists (LABAs) and long-acting muscarinic acetylcholine receptor antagonists (LAMAs). Due to the distinct mechanisms of action of LAMAs and LABAs, the additive/synergistic effects of using these drug classes together has been extensively investigated. More recently, so-called "triple inhalers" containing fixed-dose combinations of both classes of bronchodilator (dual bronchodilation) and an inhaled corticosteroid in the same inhaler have been developed. Furthermore, a number of so-called "bifunctional drugs" having two different primary pharmacological actions in the same molecule are under development. This review discusses recent advancements in knowledge on bronchodilators and bifunctional drugs for the treatment of asthma and COPD. SIGNIFICANCE STATEMENT: Since our last review in 2012, there has been considerable research to identify novel classes of bronchodilator drugs, to further understand how to optimize the use of the existing classes of bronchodilator, and to better understand the role of bifunctional drugs in the treatment of asthma and chronic obstructive pulmonary disease.
Dyspnea is the most common symptom experienced by patients with chronic obstructive pulmonary disease (COPD). To avoid exertional dyspnea, many patients adopt a sedentary lifestyle which predictably leads to extensive skeletal muscle deconditioning, social isolation, and its negative psychological sequalae. This “dyspnea spiral” is well documented and it is no surprise that alleviation of this distressing symptom has become a key objective highlighted across COPD guidelines. In reality, this important goal is often difficult to achieve, and successful symptom management awaits a clearer understanding of the underlying mechanisms of dyspnea and how these can be therapeutically manipulated for the patients’ benefit. Current theoretical constructs of the origins of activity-related dyspnea generally endorse the classical demand–capacity imbalance theory. Thus, it is believed that disruption of the normally harmonious relationship between inspiratory neural drive (IND) to breathe and the simultaneous dynamic response of the respiratory system fundamentally shapes the expression of respiratory discomfort in COPD. Sadly, the symptom of dyspnea cannot be eliminated in patients with advanced COPD with relatively fixed pathophysiological impairment. However, there is evidence that effective symptom palliation is possible for many. Interventions that reduce IND, without compromising alveolar ventilation (VA), or that improve respiratory mechanics and muscle function, or that address the affective dimension, achieve measurable benefits. A common final pathway of dyspnea relief and improved exercise tolerance across the range of therapeutic interventions (bronchodilators, exercise training, ambulatory oxygen, inspiratory muscle training, and opiate medications) is reduced neuromechanical dissociation of the respiratory system. These interventions, singly and in combination, partially restore more harmonious matching of excessive IND to ventilatory output achieved. In this review we propose, on the basis of a thorough review of the recent literature, that effective dyspnea amelioration requires combined interventions and a structured multidisciplinary approach, carefully tailored to meet the specific needs of the individual.
The airway epithelium stretches and relaxes during the normal respiratory cycle, and hyperventilation exaggerates this effect, resulting in changes in lung physiology. In fact, stretching of the airways influences lung function and the secretion of airway mediators, which in turn may cause a potentially injurious inflammatory response. This aim of the present narrative review was to illustrate the current evidence on the importance of mechanical stress in the pathophysiology of lung diseases with a particular focus on chronic obstructive pulmonary disease (COPD) and to discuss how this may influence pharmacological treatment strategies. Overall, treatment selection should be tailored to counterpart the effects of mechanical stress, which influences inflammation both in asthma and COPD. The most suitable treatment approach between a long-acting β 2-agonists/long-acting antimuscarinic-agonist (LABA/LAMA) alone or with the addition of inhaled corticosteroids should be determined based on the underlying mechanism of inflammation. Noteworthy, the anti-inflammatory effects of the glycopyrronium/indacaterol combination on hyperinflation and mucociliary clearance may decrease the rate of COPD exacerbations, and it may synergistically improve bronchodilation with a double action on both the cyclic adenosine monophosphate (cAMP) and the acetylcholine pathways.
Background and objective
FEV1 is the gold standard for assessment of COPD. We compared efficacy of FEV1, inspiratory capacity (IC), and IC to total lung capacity (TLC) ratio in the evaluation of COPD and their association with exacerbation.
Methods
We analyzed the association of dyspnea severity, quality of life status, and lung function with lung function measurements and exacerbation risk in 982 patients enrolled in the Korea COPD Subgroup Registry and Subtype Research study. Exacerbation and longitudinal lung function change were evaluated in 3 years’ follow-up.
Results
The FEV1, IC, and IC to TLC ratio showed comparable negative correlations with dyspnea severity and quality of life status, and positive correlation with exercise capacity. In patients with >2 events/year, annual rate of change in FEV1 and IC tended to decline more rapidly in those with FEV1 <50% than in those with FEV1 >50% (−14.46±19.40 mL/year vs 12.29±9.24 mL/year, P=0.213; −4.75±17.28 mL/year vs −78.05±34.16 mL/year, P=0.056 for FEV1 and IC, respectively), without significance.
Conclusion
Longitudinal changes in IC and FEV1 were not significantly associated with exacerbation risk.
The 3-min constant speed shuttle test (CSST) was used to examine the effect of tiotropium/olodaterol compared with tiotropium at reducing activity-related breathlessness in patients with chronic obstructive pulmonary disease (COPD).
This was a randomised, double-blind, two-period crossover study including COPD patients with moderate to severe pulmonary impairment, lung hyperinflation at rest and a Mahler Baseline Dyspnoea Index <8. Patients received 6 weeks of tiotropium/olodaterol 5/5 µg and tiotropium 5 µg in a randomised order with a 3-week washout period. The speed for the 3-min CSST was determined for each patient such that an intensity of breathing discomfort ≥4 (“somewhat severe”) on the modified Borg scale was reached at the end of a completed 3-min CSST.
After 6 weeks, there was a decrease in the intensity of breathlessness (Borg dyspnoea score) at the end of the 3-min CSST from baseline with both tiotropium (mean –0.968, 95% CI −1.238– −0.698; n=100) and tiotropium/olodaterol (mean −1.325, 95% CI −1.594– −1.056; n=101). The decrease in breathlessness was statistically significantly greater with tiotropium/olodaterol versus tiotropium (treatment difference −0.357, 95% CI −0.661– −0.053; p=0.0217).
Tiotropium/olodaterol reduced activity-related breathlessness more than tiotropium in dyspnoeic patients with moderate to severe COPD exhibiting lung hyperinflation.
Objectives:
In patients with chronic obstructive pulmonary disease (COPD), the inspiratory capacity-to-total lung capacity (IC/TLC) ratio has been found to be correlated with mortality and a reduced exercise capacity. Pulmonary rehabilitation (PR) is known to improve the exercise capacity and respiratory functions of patients with COPD. Our study aims to examine the impact of PR on the IC/TLC ratio in patients with COPD.
Materials and methods:
We included a total of 122 patients with COPD who received PR therapy twice a week over a period of 8 weeks in an outpatient clinic.
Results:
Patients' mean age was 62.5 (±8.2), and 15 patients (12.3%) were female. Post-PR FEV1, TLCO, and pO2 values, and the 6mWD, dyspnea, and quality-of-life (QoL) scores indicated a statistically significant improvement (p<0.05 for all). Patients were grouped as follows: patients with IC/TLC >0.25 as Group 1 and IC/TLC ≤0.25 as Group 2. Both groups exhibited a significantly increased post-PR 6 mWT distance (375-420, 336-400 meters) with no difference between the groups. We observed a significantly increased FEV1% in both groups after the PR (p=0.007, 0.004). Again, QoL questionnaires and Modified Medical Research Council scores significantly improved for both groups (p<0.001). Although no post-PR IC/TLC improvement was detected in patients with good prognosis, we identified an IC/TLC improvement in the poor prognosis group (Group 2) (p=0.002).
Conclusion:
COPD patients with IC/TLC ≤0.25 benefit from the PR just as those COPD patients with IC/TLC >0.25.
Background
Functional respiratory imaging (FRI) uses high-resolution computed tomography (HRCT) scans to assess changes in airway volume and resistance.
Patients and methods
In this randomized, double-blind, 2-week, crossover, Phase IIIB study, patients with moderate-to-severe COPD received twice-daily glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler (GFF MDI, 18/9.6 μg) and placebo MDI, formulated using innovative co-suspension delivery technology. Co-primary endpoints included the following: specific image-based airway volume (siVaw) and specific image-based airway resistance (siRaw) at Day 15, measured using FRI. Secondary and other endpoints included the following: change from baseline in post-dose forced expiratory volume in 1 second (FEV1) and inspiratory capacity (IC; spirometry) and ratio to baseline in post-dose functional residual capacity (FRC) and residual volume (RV; body plethysmography).
Results
Twenty patients (46–78 years of age) were randomized and treated; of whom 19 completed the study. GFF MDI treatment increased siVaw by 75% and reduced siRaw by 71% vs placebo MDI (both P<0.0001). Image-based airway volume (iVaw) and image-based airway resistance (iRaw), without adjusting for lobe volume, demonstrated corresponding findings to the co-primary endpoint, as lobe volumes did not change with either treatment. Approximately 48% of the delivered dose of glycopyrronium and formoterol fumarate was estimated to be deposited in the lungs. Compared with placebo, GFF MDI treatment improved post-dose FEV1 and IC (443 mL and 454 mL, respectively; both P<0.001) and reduced FRC and RV (13% and 22%, respectively; both P<0.0001). There were no significant safety findings.
Conclusion
GFF MDI demonstrated significant, clinically meaningful benefits on FRI-based airway volume and resistance in patients with moderate-to-severe COPD. Benefits were associated with improvements in FEV1, IC, and hyperinflation.
Clinical trial registration
ClinicalTrials.gov: NCT2643082.
Plethysmographic alveolar pressure-flow (Palv–F) loops contain potentially relevant information about the pathophysiology of chronic obstructive pulmonary disease (COPD), but no quantitative analysis of these loops during spontaneous breathing has ever been performed. The area of the loop’s inspiratory (Ains) and expiratory portion (Aexp), and the difference between the end-expiratory and end-inspiratory alveolar pressure (ΔPalv) were measured in 20 young, 20 elderly healthy subjects, and 130 stable COPD patients. Ains and ΔPalv increased by 55 and 78% from young to elderly subjects, and by 107 and 122% from elderly subjects to COPD patients, reflecting changes in mechanical heterogeneity, lung-units recruitment/derecruitment, and possibly air trapping occurring with aging and/or obstructive disease. Aexp increased by 38% from young to elderly subjects, and by 198% from elderly subjects to COPD patients, consistent with the additional contribution of tidal expiratory flow-limitation, which occurs only in COPD patients and affects Aexp only. In COPD patients, Aexp and ΔPalv showed a significant negative correlation with VC, FEV1, IC, and a significant positive correlation with RV/TLC. The results suggest that the analysis of plethysmographic Palv–F loops provides an insight of the pathophysiological factors, especially tidal expiratory flow-limitation, that affect lung function in COPD patients.
Background
Severe exacerbations and mortality are major outcomes in COPD, and risk factors for these events are actively searched for. Several predictors of mortality have been identified in COPD. The inspiratory capacity/total lung capacity (IC/TLC) ratio has been shown to be a strong predictor of all cause and respiratory mortality in patients with COPD. The major objectives of this study were to analyze which clinical parameters, including lung volumes, were the best predictors of the 5-year cumulative risk of hospital admissions or death and the 5-year risk of exacerbations, in stable COPD patients.
Methods
This study retrospectively reviewed data from 98 stable COPD patients, consecutively recruited in 2012. Forced expiratory volume in 1 s (FEV1), modified Medical Research Council dyspnea scale, exacerbation history (ExH), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 groups, and lung volumes were reviewed. Five years later, this population was evaluated for cumulative exacerbations, hospital admissions, and mortality. All the population, and GOLD group D separately, were analyzed.
Results
The cumulative 5-year combined risk of hospital admission or death was significantly predicted by the ExH and the IC/TLC ratio. Analyzing separately group D, FEV1 was the only predictor of this outcome. The frequency of exacerbations in the previous year was the best predictor of future cumulative 5-year risk of subsequent exacerbations, both for the total population and the GOLD D group.
Conclusion
ExH and IC/TLC ratio were the best predictors of the most severe outcomes in COPD (admissions or mortality), independently of COPD severity. FEV1 was the only predictor of the cumulative 5-year combined risk of hospital admission or death in the GOLD D group. ExH was the best predictor of 5-year cumulative future risk of exacerbations. Besides FEV1 and ExH, the IC/TLC ratio can be a useful predictor of severe outcomes in COPD.
Background:
The TORRACTO®study evaluated the effects of tiotropium/olodaterol versus placebo on endurance time during constant work-rate cycling and constant speed shuttle walking in patients with chronic obstructive pulmonary disease (COPD) after 12 weeks of treatment.
Methods:
The effects of once-daily tiotropium/olodaterol (2.5/5 and 5/5 μg) on endurance time during constant work-rate cycle ergometry (CWRCE) after 6 and 12 weeks of treatment were compared with placebo in patients with COPD in a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Endurance time during the endurance shuttle walk test (ESWT) after 6 and 12 weeks of treatment was also evaluated in a subset of patients.
Results:
A total of 404 patients received treatment, with 165 participating in the ESWT substudy. A statistically significant improvement in endurance time during CWRCE was observed after 12 weeks (primary endpoint) with tiotropium/olodaterol 5/5 µg [14% ( p = 0.02)] but not with tiotropium/olodaterol 2.5/5 µg [9% ( p = 0.14)] versus placebo. In the ESWT substudy, a trend to improvement in endurance time during ESWT after 12 weeks (key secondary endpoint) was observed with tiotropium/olodaterol 5/5 µg [21% ( p = 0.055)] and tiotropium/olodaterol 2.5/5 µg [21% ( p = 0.056)] versus placebo.
Conclusion:
Tiotropium/olodaterol 5/5 µg improved endurance time during cycle ergometry versus placebo, with a strong tendency to also improve walking endurance time. [ ClinicalTrials.gov identifier: NCT01525615.].
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 (162–229), and − 0.41 units (− 0.56 to − 0.27), respectively. The increase in trough IC was 157 ml (138–175). 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.
This multicentre, randomised, double-blind, placebo-controlled, two-period crossover study assessed the effect of umeclidinium/vilanterol (UMEC/VI) on exercise capacity in patients with chronic obstructive pulmonary disease (COPD) using the endurance shuttle walk test (ESWT).
Patients were randomised 1:1 to one of two treatment sequences: 1) UMEC/VI 62.5/25 µg followed by placebo or 2) placebo followed by UMEC/VI 62.5/25 µg. Each treatment was taken once daily for 12 weeks. The primary end-point was 3-h post-dose exercise endurance time (EET) at week 12. Secondary end-points included trough forced expiratory volume in 1 s (FEV1) and 3-h post-dose functional residual capacity (FRC), both at week 12. COPD Assessment Test (CAT) score at week 12 was also assessed.
UMEC/VI treatment did not result in a statistically significant improvement in EET change from baseline at week 12 versus placebo (p=0.790). However, improvements were observed in trough FEV1 (206 mL, 95% CI 167–246), 3-h post-dose FRC (−346 mL, 95% CI −487 to −204) and CAT score (−1.07 units, 95% CI −2.09 to −0.05) versus placebo at week 12.
UMEC/VI did not result in improvements in EET at week 12 versus placebo, despite improvements in measures of lung function, hyperinflation and health status.
This gamma scintigraphy imaging study was the first to assess pulmonary and extrathoracic deposition and regional lung deposition patterns of a radiolabelled long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10μg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6μg), delivered by pressurized metered dose inhaler (pMDI) using novel co-suspension delivery technology. In this Phase I, randomized, single-centre, single-blind, single-dose, two-treatment, crossover, placebo-controlled study (PT003020), ten healthy male adults received two actuations of GFF pMDI (7.2/5.0μg per actuation) and placebo pMDI (containing phospholipid-based porous particles without active pharmaceutical ingredient), both radiolabelled with (99m)Tc, up to 5MBq per actuation. Gamma scintigraphy images of lungs, stomach, head and neck were recorded. In addition, images of the actuators after use, collected mouth washings and exhalation filters were acquired. On average, 38.4% of the emitted dose of radiolabelled GFF pMDI, and 32.8% of radiolabelled placebo pMDI, was deposited in the lungs. The percentage emitted dose detected in the oropharyngeal and stomach regions was 61.4% and 66.9% for radiolabelled GFF pMDI and placebo pMDI, respectively. For both treatments, ≤0.25% of the emitted dose was detected in the exhalation filter. The normalized outer/inner ratio was 0.57 and 0.59 for radiolabelled GFF pMDI and placebo pMDI, respectively, and the standardized central/peripheral ratio was 1.85 and 1.94 respectively, indicating delivery of both co-suspension delivery technology formulations throughout the airways. There were no new or unexpected safety findings. In conclusion, both formulations were efficiently and uniformly deposited in the lungs with similar regional deposition patterns, oropharyngeal and stomach deposition, exhalation fraction and actuator-recovered dose.
Background
Since forced expiratory volume in 1 second (FEV1) shows a weak correlation with patients’ symptoms in COPD, some volume parameters may better reflect the change in dyspnea symptoms after treatment. In this article, we investigated the role of inspiratory capacity (IC) on dyspnea evaluation among COPD patients with or without emphysematous lesions.
Methods
In this prospective study, 124 patients with stable COPD were recruited. During the baseline visit, patients performed pulmonary function tests and dyspnea evaluation using the modified Medical Research Council (mMRC) scale. Partial patients underwent quantitative computerized tomography scans under physicians’ recommendations, and emphysematous changes were assessed using the emphysema index (EI; low attenuation area [LAA]% −950). These subjects were then divided into the emphysema-predominant group (LAA% −950≥9.9%) and the non-emphysema-predominant group (LAA% −950<9.9%). After treatment for ~1 month, subjects returned for reevaluation of both pulmonary function parameters and dyspnea severity. Correlation analysis between the change in IC (ΔIC) and dyspnea (ΔmMRC) was performed.
Results
Correlation analysis revealed that ΔIC was negatively correlated with ΔmMRC (correlation coefficient [cc], −0.490, P<0.001) in the total study population, which was stronger than that between ΔFEV1 and ΔmMRC (cc, −0.305, P=0.001). Patients with absolute ΔmMRC >1 were more likely to exhibit a marked increase in IC (≥300 mL) than those with absolute ΔmMRC ≤1 (74.36% versus 35.29%; odds ratio [OR], 5.317; P<0.001). In the emphysema-predominant group, only ΔIC strongly correlated with ΔmMRC (cc, −0.459, P=0.005), while ΔFEV1 did not (P>0.05).
Conclusion
IC could serve as an effective complement to FEV1 in COPD patients undergoing dyspnea evaluation after treatment. For COPD patients with predominant emphysematous lesions, an increase in IC is particularly more suitable for explaining dyspnea relief than FEV1.
The Phase IV, 8-week, randomized, double-blind, placebo-controlled ACTIVATE study (NCT2424344) evaluated the effect of aclidinium/formoterol (AB/FF) 400/12 μg twice daily on lung hyperinflation, exercise capacity, and physical activity in patients with moderate-to-severe COPD. Patients received AB/FF (n=134) or placebo (n=133) (1:1) via the Genuair™/Pressair® dry powder inhaler for 8 weeks. From Weeks 5 to 8, all patients participated in behavioral intervention (BI; daily messages providing step goals). The primary end point was trough functional residual capacity (FRC) at Week 4. Exercise endurance time and physical activity were assessed at Week 4 (pharmacotherapy only) and at Week 8 (8 weeks of pharmacotherapy plus 4 weeks of BI). Other end points included post-dose FRC, residual volume, and inspiratory capacity (IC) at rest and during exercise. After 4 weeks, trough FRC improved with AB/FF versus placebo but did not reach significance (125 mL; P=0.0690). However, post-dose FRC, residual volume, and IC at rest improved significantly with AB/FF at Week 4 versus placebo (all P<0.0001). AB/FF significantly improved exercise endurance time and IC at isotime versus placebo at Week 4 (P<0.01 and P<0.0001, respectively) and Week 8 (P<0.05 and P<0.0001, respectively). AB/FF achieved higher step counts (P<0.01) with fewer inactive patients (P<0.0001) at Week 4 versus placebo. Following BI, AB/FF maintained improvements in physical activity at Week 8 and nonsignificant improvements were observed with placebo. AB/FF 400/12 μg demonstrated improvements in lung hyperinflation, exercise capacity, and physical activity versus placebo that were maintained following the addition of BI. A 4-week period of BI might be too short to augment the improvements of physical activity observed with AB/FF.
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. ResultsGFF 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. ConclusionsGFF 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 registrationPearl Therapeutics, Inc.; www.clinicaltrials.gov; NCT02347072 and NCT02347085. Registered 21 January 2015.
From a physiological standpoint, the lung volumes are either dynamic or static. Both subclasses are measured at different degrees of inspiration or expiration; however, dynamic lung volumes are characteristically dependent on the rate of air flow. The static lung volumes/capacities are further subdivided into four standard volumes (tidal, inspiratory reserve, expiratory reserve, and residual volumes) and four standard capacities (inspiratory, functional residual, vital and total lung capacities). The dynamic lung volumes are mostly derived from vital capacity. While dynamic lung volumes are essential for diagnosis and follow up of obstructive lung diseases, static lung volumes are equally important for evaluation of obstructive as well as restrictive ventilatory defects. This review intends to update the reader with the physiological basis, clinical significance and interpretative approaches of the standard static lung volumes and capacities.
Objective
To evaluate the influence of chronic heart failure (CHF) on resting lung volumes in patients with COPD, i.e., inspiratory fraction-inspiratory capacity (IC)/TLC-and relative inspiratory reserve-[1 − (end-inspiratory lung volume/TLC)].
Methods
This was a prospective study involving 56 patients with COPD-24 (23 males/1 female) with COPD+CHF and 32 (28 males/4 females) with COPD only-who, after careful clinical stabilization, underwent spirometry (with forced and slow maneuvers) and whole-body plethysmography.
Results
Although FEV1, as well as the FEV1/FVC and FEV1/slow vital capacity ratios, were higher in the COPD+CHF group than in the COPD group, all major "static" volumes-RV, functional residual capacity (FRC), and TLC-were lower in the former group (p < 0.05). There was a greater reduction in FRC than in RV, resulting in the expiratory reserve volume being lower in the COPD+CHF group than in the COPD group. There were relatively proportional reductions in FRC and TLC in the two groups; therefore, IC was also comparable. Consequently, the inspiratory fraction was higher in the COPD+CHF group than in the COPD group (0.42 ± 0.10 vs. 0.36 ± 0.10; p < 0.05). Although the tidal volume/IC ratio was higher in the COPD+CHF group, the relative inspiratory reserve was remarkably similar between the two groups (0.35 ± 0.09 vs. 0.44 ± 0.14; p < 0.05).
Conclusions
Despite the restrictive effects of CHF, patients with COPD+CHF have relatively higher inspiratory limits (a greater inspiratory fraction). However, those patients use only a part of those limits, probably in order to avoid critical reductions in inspiratory reserve and increases in elastic recoil.
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. ResultsA 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 registrationClinicalTrials.gov number: NCT01996319.
Three recent advances in assessment of routine lung function are reviewed. In both normal subjects and patients with obstructive lung disease, the flows during the forced vital capacity (FVC) manoeuvre depend significantly on the pattern of the preceding inspiratory manoeuvre. Accordingly, the latter should be standardized in clinical and epidemiological studies. Although the nature of this phenomenon is not fully understood, stress relaxation of lung tissues probably plays the primary role. The negative expiratory pressure technique provides a simple and reliable tool for detecting expiratory flow limitation both at rest and during exercise. The method does not require body plethysmography or the patient’s cooperation and coordination, and can be applied in any desired body posture. A simple method for monitoring FVC performance has been developed. It allows detection of flow limitation during the FVC manoeuvre.
Chronic obstructive pulmonary disease (COPD) patients often experience tidal expiratory flow-limitation (tEFL), a condition causing respiratory and cardiovascular detrimental effects. As the appearance of tEFL should increase expiratory (Rexp) relative to inspiratory (Rins) resistance, we hypothesized that Rexp/Rins can be used to detect tEFL.
Rexp/Rins was measured with a commercial plethysmograph in 109 healthy subjects and, before and after bronchodilation (BD), in 64 COPD patients, 36 with and 28 without tEFL according to the NEP technique.
Before BD, the median (interquartile range) of Rexp/Rins was significantly greater (P < 0.001) in COPD patients with tEFL (2.47(3.06;7.07)) than in COPD patients without tEFL (1.63(1.44;1.82)) and in healthy subjects (1.52(1.35;1.62)). In COPD patients Rexp/Rins above 1.98 predicted the presence of tEFL with 96% specificity and 92% sensitivity, Rexp²/Rins performing even better. After BD the predictive ability of Rexp/Rins slightly declined, but remained elevated.
The non-invasive measurement of Rexp/Rins is an easy, inexpensive, routinely usable method to detect tEFL in spontaneously breathing COPD subjects.
During spontaneous breathing at rest the alveolar pressure (P alv ) - flow (V̇) relation exhibits a prominent expiratory loop in many COPD patients. Among the possible determinants of the loop, tidal expiratory flow-limitation (tEFL) may be the main responsible. To compare the characteristics of the expiratory loop in COPD patients with flow-limitation (FL) and without flow-limitation (NFL), tEFL was assessed with the negative expiratory pressure technique in stable, mild to very severe COPD patients, undergoing body-plethysmography before and after bronchodilation (BD), an intervention which is able to reduce mechanical heterogeneity, recruitment/derecruitment and gas trapping, but rarely abolishes tEFL. The magnitude of the expiratory loop was indexed by the integral of P alv on V̇ during expiration (A exp ). Before BD, A exp was 360% greater in FL (n=35) than in NFL (n=25) patients (P<0.001). After BD, A exp was unchanged in NFL patients (ΔA exp 0%, P=0.882) and slightly decreased in FL patients who remained FL (n=32, ΔA exp -17%, P=0.064). Three FL patients became NFL after BD, and their A exp decreased markedly (ΔA exp -61%), reaching values similar to those observed in NFL patients at baseline. In conclusion, the greater A exp measured in FL relative to NFL COPD patients, its relative invariance after BD when flow-limitation persists, and its fall when flow-limitation is abolished indicate that tEFL is a major determinant of the magnitude of the expiratory loop. Furthermore, A exp can be used as a predictor of the presence of tEFL.
COPD and asthma have different risk factors and pathogenesis, but they share a pathophysiologic hallmark characterized by small airways disease. Although difficult to explore and measure, modifications of distal airways' pathophysiology and biology represent an early sign of obstructive disease and should be researched and assessed in everyday clinical practice. In the last 15 years, computed microtomography scans have shed light on the anatomy and physiology of the so-called silent zone, and research devoted to investigate the effect of inhaled treatments on small airway pathophysiology has been increasing. This narrative review offers a historical summary of researchers and landmark studies that reported, defined, and advanced the research on small airways. We then discuss the latest findings on the role and characteristics of the small airways' inflammatory and cellular structure, and we describe the assessment tools available to detect small airways dysfunction in COPD and asthma and the effect of bronchodilators and inhaled steroids on functional and biological biomarkers. Finally, we analyze the newest technological therapeutic advances aimed at small airways treatment in terms of inhalation devices and small particle size molecules.
Approximately 20% of COPD patients have been considered to have a 'nonhyperinflator phenotype'. However, this judgment depends on patients making a maximal inspiratory capacity (IC) maneuver at rest, since the IC during exercise is compared to this baseline measurement. We hypothesized that IC maneuvers at rest are sometimes submaximal and tested this hypothesis by measuring IC and associated neural respiratory drive at rest, during inhalation of CO 2 and exercise in patients with COPD. Twenty-six COPD patients (age 66±6 years, mean FEV 1 40±11% pred) and 39 healthy subjects (age 39±14 years, FEV 1 98±12% pred) were studied. IC and the diaphragm electromyogram (EMG di ) associated with it (EMG di -IC), forced inspiratory vital capacity (FIVC) and its corresponding EMG di (EMG di -FIVC) were measured during inhalation of 8% CO 2 (8% CO 2 -92% O 2 ) and room air. Incremental exhaustive cycle ergometer exercise was also performed in both patients with COPD and healthy subjects. IC, EMG di -IC, FIVC and EMG di -FIVC during breathing 8% CO 2 were significantly greater than those during breathing room air in both patients with COPD and healthy subjects (all p<0.001). EMG di -IC in patients with COPD constantly increased during exercise from 145 ± 40 µV at rest to 185 ± 52 µV at the end of exercise but change in IC was variable. Neural respiratory drive and IC increased during hypercapnia. Exercise related hypercapnia in patients with COPD raises neural respiratory drives which compensate for IC reduction, leading to underestimation of dynamic hyperinflation measured by IC at rest breathing room air.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease. The severity grading systems proposed by the Global initiative for Chronic Obstructive Lung Disease (GOLD) have changed over time. The aim of the study was to evaluate if the different GOLD classifications can capture the complexity of the disease by investigating the distribution of lung function and clinical parameters across the GOLD classification systems. This was an observational, retrospective, multicentre study. COPD patients were stratified according to the GOLD severity grading proposed in the 2007, and to the ABCD assessment tool present in the 2011, and 2017 versions of the initiative. Data from body plethysmography, DLCO, comorbidities, exacerbation history, pharmacological therapy and eosinophil counts were collected. A total of 1360 patients (73.4% males) were included in the analysis. Overall, 37% of the patients were severe-very severe according to GOLD 2007. Compared with GOLD 2011, applying the GOLD 2017 criteria, the proportion of the at risk categories (C and D) was reduced by ∼23%. Impairment in inspiratory capacity, DLCO and the prevalence of emphysema paralleled the GOLD 2007 classification only. The proportion of patients with ≥ 200 eosinophils/µL was higher in GOLD 2007 stages 3–4 compared with stages 1–2 (P = 0.008). Eosinophil levels were similar across risk classes in GOLD 2011 and 2017. Overall, 41.8% and 52.4% of the patients in the low risk groups according to GOLD 2011 and 2017 were exposed to inhaled corticosteroids. The GOLD 2011 and 2017 classifications, despite exploring symptoms and exacerbations, might miss other relevant patients’ clinical characteristics such as lung function and phenotypes, which have a significant impact on outcomes and disease severity.
Background:
Measurements of inspiratory capacity (IC) and vital capacity (VC) are used to recognize dynamic hyperinflation, but appropriate reference values are required to achieve accurate clinical interpretations. Altitude above sea level is a potential determining factor for lung volumes, including IC and VC.
Objective:
To describe IC and VC for healthy people who live in Mexico City at an altitude of 2,240 m above sea level.
Methods:
Healthy subjects ages 9-81 y completed slow spirometry by following 2005 American Thoracic Society/European Respiratory Society standards. Once associations were explored, linear regression models were constructed and values were compared with those from previously published equations.
Results:
A total of 441 healthy subjects (55.1% women) participated. The mean age was 32 y (minimum age, 9 y; maximum age, 81 y). IC and VC measurements were associated with sex, age, height, and weight. An accelerated increase in IC and VC was evident from 9 to 20 y of age, followed by a gradual decrease in both sexes. In general, IC was higher in our population than predicted by previously published reference equations.
Conclusions:
IC in healthy people at 2,240 m above sea level was higher than that of previous reports about European and Latin-American subjects of the same height, sex, and age who were at sea level. The present study provided robust reference values for persons who lived at a moderate altitude.
Background:
Dynamic hyperinflation is a major cause of dyspnea in patients with COPD. Dynamic hyperinflation is usually measured with cardiopulmonary exercise testing, but this test requires maximal effort from the patient, and inspiratory capacity (IC) measurements may influence test results. This study investigated another approach by measuring dynamic hyperinflation during the more natural and better-tolerated 6-min walk test (6MWT), using a mobile system for IC measurements.
Methods:
Twenty subjects were studied, including 10 healthy subjects and 10 subjects with COPD. Each subject performed a pair of 6MWTs.
Results:
The study showed that test-retest reliability in healthy subjects was excellent (intraclass correlation coefficient 0.995). In addition, mean resting IC in healthy subjects (3.27 ± 0.77 L) was not affected at the end of the 6MWT, whereas mean resting IC in subjects with COPD (2.45 ± 0.90 L) decreased to 1.93 L ± 0.68 L at the end of the 6MWT (P = .004). The tolerability of the device for subjects with COPD appeared to be only slightly hampered by an increased sense of dyspnea attributed to wearing a mask.
Conclusions:
This study provides a proof of principle for mobile IC measurements during the 6MWT, demonstrating good test performance, reasonable tolerability, and a power to differentiate normal from pathologic conditions.
Exacerbation of a disease implies worsening of the underlying pathophysiological process that characterizes the condition. Indeed the term exacerbate (derived from the Latin exacerberi, to irritate) has a dictionary definition (to make more violent, more severe) that suggests this. However, with respect to chronic obstructive pulmonary disease (COPD), it is not clear if we are justified in using the term “an exacerbation of COPD,” which implies worsening of the underlying disease or “an exacerbation in COPD,” which does not necessarily suggest worsening of the underlying disease process. However, since it has been shown that the cause of an acute exacerbation in COPD is not determined in around 30% of cases (1), this implies that in some cases exacerbations could be part of a cyclical worsening of the disease process itself, with or without known triggers. Indeed patients report that their condition is better or worse on some days than others, without obvious precipitating factors, although factors other than infection and air pollution, which are considered to be the major precipitants, seem to exacerbate symptoms and may lead to an exacerbation in a patient with COPD, (such as changes in weather and temperature and changes in physical activity). However, whether an exacerbation of COPD is an extension of the disease itself or is different from the disease process is still a matter of debate. Indeed, the term exacerbation-an endogenous or larly breathlessness, that exceeds day-to-day variations and does not respond to treatment with the patient’s regular medication.
Peripheral airway inflammation and dysfunction are key elements in the pathogenesis of COPD. The exhaled alveolar fraction of nitric oxide (CANO) is an indirect biomarker of lung peripheral inflammation. We tested whether inhaled long-acting bronchodilators (LABA) can affect CANO and we evaluated correlations with lung mechanics in patients with COPD.
Two-centre, randomised, double blind, crossover study including COPD patients with moderate-to-severe airflow obstruction. Following a pharmacological washout, multi-flow exhaled fraction of NO (FENO), plethysmography, lung diffusion (DLCO), single breath nitrogen washout test and dyspnoea were measured in a crossover manner at baseline and 30, 60 and 180 min following administration of salmeterol (Sal) or formoterol fumarate (FF). (ClinicalTrials.gov, number NCT01853787).
Fort-five patients were enrolled (median age: 71.8 years; 84.4% males). At baseline, CANO correlated with airway resistances (r = 0.422), residual volume/total lung capacity (RV/TLC; r = 0.375), transfer factor (r= -0.463) and forced expiratory volume in 1 s (FEV1; r= -0.375, all P < 0.01). After LABA administration, we found a significant reduction of FENO that reached statistical significance at 180’; no difference was found between FF and S. Consistently, a significant reduction of CANO was documented at 60’ and 180’ compared to baseline for both FF and S (P < 0.01 and P < 0.05, respectively). Changes in CANO were correlated with changes in vital capacity (r=-44; P < 0.001) and RV/TLC (r = 0.56; P < 0.001), but not FEV1.
In COPD, direct correlations were found between the levels of CANO and the magnitude of peripheral airway dysfunction. LABA reduced CANO levels. The reduction was associated with improvement in functional parameters reflecting air trapping.
Rationale:
Bronchodilation and exercise training (ExT) improve exercise tolerance in patients with chronic obstructive pulmonary disease (COPD); however, behavior modification is required to impact on daily physical activity (PA).
Objectives:
To assess whether tiotropium/olodaterol, ±ExT, would improve exercise endurance time (EET) and PA compared with placebo in patients participating in a self-management behavior-modification (SMBM) program.
Methods:
A 12-week, randomized, partially double-blind, placebo-controlled, parallel-group trial in patients with COPD (PHYSACTO®; NCT02085161). All patients were enrolled into SMBM and randomized 1:1:1:1 to once-daily placebo, tiotropium 5 µg, tiotropium/olodaterol 5/5 µg, or tiotropium/olodaterol 5/5 µg plus 8 weeks ExT. EET, measured by endurance shuttle walk test after 8 weeks, was the primary endpoint. Additional endpoints assessed downstream effects on PA (measured via accelerometry), and activity-related dyspnea and difficulty (using validated patient-reported questionnaires).
Measurements and main results:
SMBM + tiotropium/olodaterol, ±ExT, significantly improved EET at Week 8 versus SMBM + placebo (treatment ratio versus placebo: with ExT 1.46 [95% CI: 1.20, 1.78]; P=0.0002; without ExT 1.29 [1.06, 1.57]; P=0.0109). No significant increases in steps per day from baseline were observed over SMBM + placebo at Week 12 (increase of 1,098) when other therapies were added. Adding tiotropium/olodaterol, ±ExT, to SMBM reduced activity-related dyspnea versus placebo, while adding tiotropium/olodaterol + ExT reduced activity-related difficulty.
Conclusions:
Tiotropium/olodaterol, ±ExT, improved EET in patients with COPD taking part in an SMBM program. Combination bronchodilation, ±ExT, did not provide additional increases in objective PA compared with SMBM alone, but did reduce physical activity-related dyspnea and difficulty. Clinical trial registration available at www.clinicaltrials.gov, ID NCT02085161.
Introduction: The current GOLD (Global Initiative for Chronic Obstructive Lung Disease) recommendations suggest using long acting β2 agonists (LABA) and long acting muscarinic antagonists (LAMA) in combination for group B COPD patients with persistent symptoms, group C COPD patients with further exacerbations on LAMA therapy alone and for group D COPD patients with or without combination with inhaled corticosteroids (ICS). Thus, there is a lot of interest in developing LABA/LAMA combinations for maintenance therapy of chronic stable COPD.
Areas covered: Many LABA/LAMA combinations have successfully been approved through carefully designed pivotal clinical trials. The current clinical use of LABA/LAMA combinations in COPD will continue to evolve as new trials with and without inhaled corticosteroids are completed.
Expert opinion: Combining different classes of bronchodilators in a single inhaler is an attractive concept that can potentially improve patient adherence to therapy. Because LABA/LAMA combinations are the preferred treatment option for preventing COPD exacerbations in the updated GOLD guidelines for COPD, they will be clinically used. Future treatment of COPD should revolve around a personalized approach based on characterization of the COPD phenotype.
Small airways represent the key factor of chronic obstructive pulmonary disease (COPD) pathophysiology. The effect of different classes of bronchodilators on small airways is still poorly understood and difficult to assess. Hence, the acute effects of tiotropium (18 µg) and indacaterol (150 µg) on closing volume (CV) and ventilation inhomogeneity were investigated and compared in 51 stable patients (mean age (SD): 70±7 years; 82% males) with moderate to very severe COPD. Patients underwent body-plethysmography, arterial blood gas-analysis, tidal expiratory flow limitation (EFL), dyspnea assessment, and simultaneous recording of single breath nitrogen test (SBN) and transpulmonary pressure-volume curve (PL-V), before and one hour after drug administration. The effects produced by indacaterol on each variable did not differ from those caused by tiotropium, independent of the severity of disease, assessed according to the GOLD scale, and the presence of EFL. Bronchodilators significantly decreased the slope of phase III and CV (-5±4% and -2.5±2.1%, both P<0.001), with an increase in both slope and height of phase IV, and of the anatomical dead space. Arterial oxygen pressure and saturation significantly improved (3±3 mmHg and 2±2%, both P<0.001); their changes negatively correlated with those of phase III slope (r=-0.659 and r=-0.454, both P<0.01). The vital capacity (VC) increased substantially but the PL-V/VC curve above CV was unaffected. In conclusion, bronchodilators reduce the heterogeneity of peripheral airway mechanical properties and the extent of their closure, with minor effects on critical closing pressure. This should lessen the risk of small airways damage and positively affect gas exchange.
Dynamic hyperinflation is a common cause of dyspnea and functional limitation in patients with emphysema. Dynamic hyperinflation occurs in individuals with air-flow limitation when expiratory time is decreased during periods of relative tachypnea (such as during exercise or agitation, for example). In this setting, patients with emphysema develop lung hyperinflation, impairment of inspiratory respiratory muscles, and an increase in work of breathing. The associated decrease in inspiratory capacity results in the stimulation of several receptors, including chemoreceptors and pulmonary receptors, which signal the brain to increase tidal volume. The inability of the respiratory system to respond to signals of increased demand (eg, by enlarging tidal volume and increasing inspiratory flow) results in a dissociation between afferent and efferent signaling thereby intensifying breathing discomfort, or what clinicians term dyspnea. A thorough understanding of the physiology of dyspnea and pathophysiology of dynamic hyperinflation informs the interventions used to mitigate sensations of dyspnea and the physiologic effects of dynamic hyperinflation, respectively. Pharmacotherapy, pulmonary rehabilitation, breathing techniques, positive airway pressure, and lung volume reduction are well-studied interventions that target pathways to dyspnea in patients with dynamic hyperinflation.
Background:
Lung function has previously been related to increased mortality. Whether pulmonary impairment is associated with an increased mortality independent of cardiac dysfunction remains unclear.
Methods:
In 15010 individuals from the general population (age range 35-74years, 51% men) in the Gutenberg Health Study we performed spirometry and transthoracic echocardiography. N-terminal pro-B-type natriuretic peptide (Nt-proBNP) and high-sensitive troponin I (hsTnI) were measured in all individuals. 1819 individuals with pulmonary diseases were excluded from further analysis.
Results:
The median for forced expiratory volume in 1s (FEV1) was 94.2% and for forced vital capacity (FVC) 94.2% as a percentage of their predicted values. The median FEV1/FVC ratio was 79.1%. In 13191 subjects, 335 deaths were verified from death certificate over a median follow-up of 5.5years. Multivariable-adjusted Cox regression analyses for common cardiovascular risk factors and heart failure revealed that an increase of one standard deviation (SD) of percent predicted (%pred.) FEV1 was associated with a 22% risk reduction (hazard ratio [HR] per SD 0.78 [95% confidence interval (CI): 0.70, 0.86]). The association remained statistically significant after additional adjustment for diastolic dysfunction, Nt-proBNP or hsTnI. Comparable results were seen for %pred. FVC. After adjustment, no association of FEV1/FVC ratio with mortality could be shown. No significant interaction by heart failure was observed.
Conclusions:
The lung function parameters FEV1 and FVC, but not FEV1/FVC ratio, were related to all-cause mortality in individuals from the general population independent of cardiac function.
Purpose:
To determine whether the analysis of the slow expiratory transpulmonary pressure-volume (PL-V) curve provides an alternative to the single-breath nitrogen test (SBN) for the assessment of the closing volume (CV).
Methods:
SBN test and slow deflation PL-V curve were simultaneously recorded in 40 healthy subjects and 43 COPD patients. Onset of phase IV identified CV in SBN test (CVSBN), whereas in the PL-V curve CV was identified by: a) deviation from the exponential fit (CVexp), and b) inflection point of the interpolating sigmoid function (CVsig).
Results:
In the absence of phase IV, COPD patients exhibited a clearly discernible inflection in the PL-V curve. In the presence of phase IV, CVSBN and CVexp coincided (CVSBN/CVexp=1.04±0.04 SD), whereas CVsig was systematically larger (CVsig/CVexp=2.1±0.86).
Conclusion:
The coincidence between CVSBN and CVexp, and the presence of the inflection in the absence of phase IV indicate that the deviation of the PL-V curve from the exponential fit reliably assesses CV.
Background:
Lung diffusing capacity (DLCO) and lung volume distribution predict exercise performance and are altered in COPD patients. If pulmonary rehabilitation (PR) can modify DLCO parameters is unknown.
Objectives:
To investigate changes in DLCO and ventilation inhomogeneity following a PR program and their relation with functional outcomes in patients with COPD.
Methods:
This was a prospective, observational, multicentric study. Patients were evaluated before and after a standardized 3-week PR program. Functional assessment included body plethysmography, DLCO, transfer factor (KCO) and alveolar volume (VA), gas exchange, the 6-min walking test (6MWT) and exercise-related dyspnea. Patients were categorized according to the severity of airflow limitation and presence of ventilation inhomogeneity, identified by a VA/TLC <0.8.
Results:
Two hundred and fifty patients completed the study. Baseline forced expiratory volume in 1 s (FEV1) % predicted (mean ± SD) was 50.5 ± 20.1 (76% males); 137 patients had a severe disease. General study population showed improvements in 6MWT (38 ± 55 m; p < 0.01), DLCO (0.12 ± 0.63 mmol × min-1 kPa-1; p < 0.01), lung function and dyspnea. Comparable improvements in DLCO were observed regardless of the severity of disease and the presence of ventilation inhomogeneity. While patients with VA/TLC <0.8 improved the DLCO increasing their VA (177 ± 69 ml; p < 0.01), patients with VA/TLC >0.8 improved their KCO (8.1 ± 2.8%; p = 0.019). The latter had also better baseline lung function and higher improvements in 6MWT (14.6 ± 6.7 vs. 9.0 ± 1.8%; p = 0.015). Lower DLCO at baseline was associated with lower improvements in 6MWT, the greatest difference being between subjects with very severe and mild DLCO impairment (2.7 ± 7.4 vs. 14 ± 2%; p = 0.049).
Conclusions:
In COPD patients undergoing a PR program, different pathophysiological mechanisms may drive improvements in DLCO, while ventilation inhomogeneity may limit improvements in exercise tolerance.
Background:
An inspiratory capacity to total lung capacity (IC/TLC) ratio of ≤25% has emerged as a better marker of mortality in chronic obstructive pulmonary disease (COPD) patients. The relationship among the IC/TLC ratio to lower extremity skeletal muscle function remains unknown.
Methods:
Thirty-five men with moderate to severe COPD were divided into those with IC/TLC≤25% (n=16) and >25% (n=19). The subjects were tested for thigh muscle mass volume (MMT), maximal strength, power output of the lower extremities, and physical activity.
Results:
Total MMT in the IC/TLC<25% group was significantly lower (413.91±89.42cm(3)) (p<0.001) than in the IC/TLC>25% group (575.20±11.76cm(3)). In the IC/TLC≤25% group, maximal strength of the lower extremities and muscle peak power output of the lower extremities were 36-56% lower (p<0.01) than among the patients in the IC/TLC>25% group.
Conclusion:
IC/TLC≤25% is associated with reduced maximal strength and peak power output of the lower extremities. IC/TLC≤25% may have an important clinical relevance as an index to determine peripheral muscle dysfunction.
Introduction:
chronic obstructive pulmonary disease (COPD) is characterized by a high disability and increasing mortality. Bronchodilators are the cornerstone of pharmacological treatment in COPD, while therapeutic optimization with an improvement in symptoms and compliance represent the actual goals. This has led to the development of devices that combine different classes of inhalatory drugs. Recently, a novel combination of the long acting antimuscarinic agent glycopyrronium bromide and the beta2-agonist formoterol fumarate has been developed in a metered dose inhaler delivery system.
Areas covered:
the present article will discuss the current unmet needs in pharmacological therapy of COPD, will then briefly cover the pharmacokinetic and pharmacodynamic characteristics of the formoterol/glycopyrronium fixed dose combination and present the novel delivery system based on engineered microparticles and the co-suspension technology. Finally, efficacy and safety results of phase I, II and III trials will be reviewed. Expert Commentary: the novel combination therapy of formoterol/glycopyrronium is the first available as a metered dose inhaler and proved to have a good efficacy and safety profile compared to monocomponents and tiotropium. Although still limited, data from phase III trials provide good evidence to consider it a valid option in the pharmacological management of patients with COPD.
