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.

Effect of lung deflation with indacaterol plus glycopyrronium on ventricular filling in patients with hyperinflation and COPD (CLAIM): a double-blind, randomised, crossover, placebo-controlled, single-centre trial.

BACKGROUND: Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with reduced biventricular end-diastolic volumes and increased morbidity and mortality. The combination of a long-acting ß agonist (LABA) and a muscarinic antagonist (LAMA) is more effective in reducing hyperinflation than LABA-inhaled corticosteroid combination therapy but whether dual bronchodilation improves cardiac function is unknown. METHODS: We did a double-blind, randomised, two-period crossover, placebo-controlled, single-centre study (CLAIM) at the Fraunhofer Institute of Toxicology and Experimental Medicine (Hannover, Germany), a specialty clinic. Eligible participants were patients aged at least 40 years with COPD, pulmonary hyperinflation (defined by a baseline residual volume >135% of predicted), a smoking history of at least ten pack-years, and airflow limitation (FEV1 <80% predicted and post-bronchodilator FEV1: forced vital capacity <0·7). Patients with stable cardiovascular disease were eligible, but those with arrhythmias, heart failure, unstable ischaemic heart disease, or uncontrolled hypertension were not. We randomly assigned participants (1:1) to either receive a combined inhaled dual bronchodilator containing the LABA indacaterol (110 µg as maleate salt) plus the LAMA glycopyrronium (50 µg as bromide salt) once per day for 14 days, followed by a 14-day washout, then a matched placebo for 14 days, or to receive the same treatments in reverse order. The randomisation was done using lists and was concealed from patients and investigators. The primary endpoint was the effect of indacaterol-glycopyrronium versus placebo on left-ventricular end-diastolic volume measured by MRI done on day 1 (visit 4) and day 15 (visit 5) in treatment period 1 and on day 29 (visit 6) and day 43 (visit 7) in treatment period 2 in the per-protocol population. Left-ventricular end-diastolic volume was indexed to body surface area. Safety was assessed in all participants who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02442206. FINDINGS: Between May 18, 2015, and April 20, 2017, we randomly assigned 62 eligible participants to treatment; 30 to indacaterol-glycopyrronium followed by placebo and 32 to placebo followed by indacaterol-glycopyrronium. The 62 randomly assigned patients were included in the intent-to-treat analysis. There were two protocol violations and therefore 60 were included in the per-protocol analysis. 57 patients completed both treatment periods. After indacaterol-glycopyrronium treatment, left-ventricular end-diastolic volume increased from a mean 55·46 mL/m2 (SD 15·89) at baseline to a least-squares (LS) mean of 61·76 mL/m2 (95% CI 57·68-65·84), compared with a change from 56·42 mL/m2 at baseline (13·54) to 56·53 mL/m2 (52·43-60·62) after placebo (LS means treatment difference 5·23 mL/m2 [95% CI 3·22 to 7·25; p<0·0001]). The most common adverse events reported with indacaterol-glycopyrronium were cough (in nine patients [15%] of 59) and throat irritation (in seven [12%]). With placebo, the most common adverse events reported were headache (in five patients [8%] of 61) and upper respiratory tract infection (in four [7%]). Two patients had serious adverse events: one (2%) after indacaterol-glycopyrronium (endometrial cancer) and one (2%) after placebo (myocardial infarction); these were not thought to be treatment related. No patients died during the study. INTERPRETATION: This is the first study to analyse the effect of LABA-LAMA combination therapy on cardiac function in patients with COPD and lung hyperinflation. Dual bronchodilation with indacaterol-glycopyrronium significantly improved cardiac function as measured by left-ventricular end-diastolic volume. The results are important because of the known association of cardiovascular impairment with COPD, and support the early use of dual bronchodilation in patients with COPD who show signs of pulmonary hyperinflation. FUNDING: Novartis Pharma GmbH.

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.

Impact of LABA/LAMA combination on exercise endurance and lung hyperinflation in COPD: A pair-wise and network meta-analysis.

BACKGROUND: The ability to exercise is an important clinical outcome in COPD, and the improvement in exercise capacity is recognized to be an important goal in the management of COPD. Therefore, since the current interest in the use of bronchodilators in COPD is gradually shifting towards the dual bronchodilation, we carried out a meta-analysis to evaluate the impact of LABA/LAMA combination on exercise capacity and lung hyperinflation in COPD. METHODS: RCTs were identified after a search in different databases of published and unpublished trials. The aim of this study was to assess the influence of LABA/LAMA combinations on endurance time (ET) and inspiratory capacity (IC), vs. monocomponents. RESULTS: Eight RCTs including 1632 COPD patients were meta-analysed. LABA/LAMA combinations were significantly (P < 0.05) more effective than the LABA or LAMA alone in terms of the improvement in ET (+43 s and +22 s, respectively) and IC (+107 ml and +87 ml, respectively). LABA/LAMA combinations showed the highest probability of being the best therapy with regard of both ET and IC (100% and 100%, respectively), followed by LAMA (66% and 64%, respectively) and LABA (32% and 36%, respectively), as indicated by the analysis of surface under the cumulative ranking curve (SUCRA). No publication bias was detected in this meta-analysis. CONCLUSIONS: This meta-analysis clearly demonstrates that if the goal of the therapy is to enhance exercise capacity in patients with COPD, LABA/LAMA combinations consistently meet the putative clinically meaningful differences for both ET and IC and, in this respect, are superior to their monocomponents.

The effect of N-acetylcysteine on exacerbations of chronic obstructive pulmonary disease: A meta-analysis and systematic review.

N-acetylcysteine (NAC) is an antioxidant and anti-inflammatory. Its effects on chronic obstructive pulmonary (COPD) outcomes, including exacerbation of and changes in lung function parameters, are controversial. To investigate the effects of NAC on COPD exacerbation and changes in lung function parameters in patients with COPD. A meta-analysis of randomized controlled trials retrieved from PubMed and Medline databases (12 trials; 2691 patients). High-dose [relative ratio (RR) = 0.90, 95% confidence interval (CI) = 0.82-0.996, P = 0.041] and low-dose (RR = 0.83, 95% CI = 0.69-0.99, P = 0.043) NAC reduced COPD exacerbation prevalence. Long-term (≥6 months), but not short-term, NAC reduced exacerbation prevalence (RR = 0.85, 95% CI = 0.74-0.98, P = 0.024). NAC did not affect exacerbation rate, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), or inspiratory capacity (IC). Long-term NAC therapy may reduce risk of COPD exacerbation.

Sex-Related Differences in Pulmonary Function following 6 Months of Cigarette Exposure: Implications for Sexual Dimorphism in Mild COPD.

Female smokers have increased risk of chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure. We have shown previously that chronic smoke exposure for 6 months leads to increased airway wall remodeling in female C57BL/6 mice compared with male C57BL/6 mice. These differences, however, were not evident in female ovariectomized mice exposed to cigarette smoke. Herein, we report on the pulmonary function test results from the flexiVent system, which was used to determine the potential functional consequences of the histologic changes observed in these mice. We found that tissue damping (G) was increased in female compared to male or ovariectomized female mice after smoke exposure. At low oscillating frequencies, complex input resistance (Zrs) and impedance (Xrs) of the respiratory system was increased and decreased, respectively, in female but not in male or ovariectomized female mice after smoke exposure. Quasistatic pressure-volume curves revealed a reduction in inspiratory capacity in female mice but not in male or ovariectomized female mice after smoke exposure. The remaining lung function measurements including quasistatic compliance were similar amongst all groups. This is the first study characterizing a sexual dimorphism in respiratory functional properties in a mouse model of COPD. These findings demonstrate that increased airway remodeling in female mice following chronic smoke exposure is associated with increased tissue resistance in the peripheral airways. These data may explain the importance of female sex hormones and the increased risk of airway disease in female smokers.

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 .

Preoperative Peak Oxygen Uptake in Lung Cancer Subjects With Neoadjuvant Chemotherapy: A Cross-Sectional Study.

BACKGROUND: In non-small-cell lung cancer patients, high peak oxygen uptake (peak V̇O2 ) predicts lower rates of postoperative complications and better long-term survival. Neoadjuvant chemotherapy (NAC) may negatively impact peak V̇O2 . METHODS: Cardiopulmonary exercise testing (CPET) was performed in 34 consecutive stage IIIA/IIIB non-small-cell lung cancer subjects scheduled for elective lung surgery. Using multivariate linear regression adjusted for potential confounders, we compared CPET results in subjects receiving or not receiving NAC (NAC+, n = 19; NAC-, n = 15). RESULTS: Adjusted peak V̇O2 was lower in NAC + compared with NAC- subjects (-5.3 mL/min/kg [95% CI -8.3 to -2.2], P = .01). Likewise, oxygen pulse, maximal work load, and ventilatory threshold were also lower in NAC+ subjects, whereas peak heart rate and breathing reserve were similar. NAC+ subjects presented lower values of diffusion capacity for carbon monoxide (DLCO) (P = .035) and hemoglobin concentrations (P < .001). DLCO was strongly correlated with peak V̇O2 (r(2) = 0.56). Adjustment for DLCO reduced the effect of NAC on peak V̇O2 without suppressing it. CONCLUSIONS: NAC was associated with lower preoperative peak V̇O2 in subjects with non-small-cell lung cancer. This lower aerobic fitness may result from NAC-induced reduction in pulmonary gas exchange or heart toxicity. Since lower fitness is linked to poorer outcome, the decision for NAC may have to be balanced with its possible toxicity.

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).

Can bronchodilators improve exercise tolerance in COPD patients without dynamic hyperinflation? / Os broncodilatadores podem melhorar a tolerância ao exercício na ausência de hiperinsuflação dinâmica em pacientes com DPOC?

OBJECTIVE: To investigate the modulatory effects that dynamic hyperinflation (DH), defined as a reduction in inspiratory capacity (IC), has on exercise tolerance after bronchodilator in patients with COPD. METHODS: An experimental, randomized study involving 30 COPD patients without severe hypoxemia. At baseline, the patients underwent clinical assessment, spirometry, and incremental cardiopulmonary exercise testing (CPET). On two subsequent visits, the patients were randomized to receive a combination of inhaled fenoterol/ipratropium or placebo. All patients then underwent spirometry and submaximal CPET at constant speed up to the limit of tolerance (Tlim). The patients who showed ΔIC(peak-rest) < 0 were considered to present with DH (DH+). RESULTS: In this sample, 21 patients (70%) had DH. The DH+ patients had higher airflow obstruction and lower Tlim than did the patients without DH (DH-). Despite equivalent improvement in FEV1 after bronchodilator, the DH- group showed higher ΔIC(bronchodilator-placebo) at rest in relation to the DH+ group (p < 0.05). However, this was not found in relation to ΔIC at peak exercise between DH+ and DH- groups (0.19 ± 0.17 L vs. 0.17 ± 0.15 L, p > 0.05). In addition, both groups showed similar improvements in Tlim after bronchodilator (median [interquartile range]: 22% [3-60%] vs. 10% [3-53%]; p > 0.05). CONCLUSIONS: Improvement in TLim was associated with an increase in IC at rest after bronchodilator in HD- patients with COPD. However, even without that improvement, COPD patients can present with greater exercise tolerance after bronchodilator provided that they develop DH during exercise. .

OBJETIVO: Investigar os efeitos moduladores da hiperinsuflação dinâmica (HD), definida pela redução da capacidade inspiratória (CI), na tolerância ao exercício após broncodilatador em pacientes com DPOC. MÉTODOS: Estudo experimental e randomizado com 30 pacientes com DPOC sem hipoxemia grave. Na visita inicial, os pacientes realizaram avaliação clínica, espirometria e teste de exercício cardiopulmonar (TECP) incremental. Em duas visitas subsequentes, os pacientes foram randomizados para receber uma combinação de fenoterol/ipratrópio ou placebo e, em seguida, realizaram espirometria e TECP com velocidade constante até o limite da tolerância (Tlim). Os pacientes com ΔCI(pico-repouso) < 0 foram considerados com HD (HD+). RESULTADOS: Nesta amostra, 21 pacientes (70%) apresentaram HD. Os pacientes HD+ apresentaram maior obstrução ao fluxo aéreo e menor Tlim do que os pacientes sem HD (HD-). Apesar de ganhos equivalentes de VEF1 após broncodilatador, o grupo HD- apresentou maior ΔCI(broncodilatador-placebo) em repouso em relação ao grupo HD+ (p < 0,05). Entretanto, isso não ocorreu com a ΔCI no pico do exercício entre os grupos HD+ e HD- (0,19 ± 0,17 L vs. 0,17 ± 0,15 L; p > 0,05). Similarmente, ambos os grupos apresentaram melhoras equivalentes do Tlim após broncodilatador (mediana [intervalo interquartílico]: 22% [3-60%] e 10% [3-53%]; p > 0,05). CONCLUSÕES: A melhora da CI em repouso após broncodilatador associou-se com ganho de tolerância ao esforço mesmo nos pacientes com DPOC que não apresentem HD. Por outro lado, pacientes sem melhora da CI em repouso ainda podem obter beneficio funcional com o broncodilatador desde que apresentem HD no exercício. .

Alterações espirométricas em doenças obstrutivas: afinal, o quanto é relevante? / Spirometric changes in obstructive disease: after all, how much is significant?

OBJETIVO: Estabelecer os limites superiores para mudanças em VEF1, capacidade vital lenta (CVL), CVF e capacidade inspiratória (CI) após o uso de placebo em pacientes com obstrução ao fluxo aéreo. MÉTODOS: Cento e dois adultos com obstrução ao fluxo aéreo (VEF1 = 62 ± 19% do previsto) foram incluídos neste estudo. Todos os participantes realizaram manobras de CVL e CVF antes e depois do uso de spray de placebo. As mudanças em VEF1, CVL, CVF e CI foram expressas em valores absolutos, porcentagem de variação em relação aos valores basais e porcentagem dos valores previstos, e foram calculados os IC95% e os percentis 95. A análise fatorial foi realizada a fim de determinar como essas alterações se agrupavam. RESULTADOS: Considerando os IC95% e percentis 95 e após o arredondamento dos valores, obtivemos os seguintes limites superiores para resposta significante: VEF1 = 0,20 L, CVF = 0,20 L, CVL = 0,25 L e CI = 0,30 L (em valores absolutos); VEF1 = 12%, CVF = 7%, CVL = 10% e CI = 15% (em porcentagem de variação em relação aos valores basais) e VEF1 = 7%, CVF = 6%, CVL = 7% e CI = 12% (em porcentagem dos valores previstos). CONCLUSÕES: Em pacientes com obstrução ao fluxo aéreo, a CI apresenta maior variabilidade do que a CVF e a CVL. Para a CI, valores maiores que 0,30 L e 15% de variação em relação ao valor basal devem ser considerados significantes. Para CVF, valores maiores que 0,20L e 7% de variação em relação ao valor basal são significantes. Alternativamente, alterações de mais de 0,20 L e 7% do previsto no VEF1 e na CVF devem ser consideradas significantes. Na análise fatorial, os parâmetros espirométricos se agruparam em três dimensões, expressando mudanças no fluxo, volume e hiperinsuflação dinâmica.

OBJECTIVE: To establish the upper limits for changes in FEV1, slow vital capacity (SVC), FVC, and inspiratory capacity (IC) after placebo administration in patients with airflow obstruction. METHODS: One hundred and two adults with airflow obstruction (FEV1 = 62 ± 19% of predicted) were included in the study. All of the participants performed SVC and FVC maneuvers before and after the administration of placebo spray. The changes in FEV1, SVC, FVC, and IC were expressed as absolute values, percentage of change from baseline values, and percentage of predicted values, 95% CIs and 95th percentiles being calculated. Factor analysis was performed in order to determine how those changes clustered. RESULTS: Considering the 95% CIs and 95th percentiles and after rounding the values, we found that the upper limits for a significant response were as follows: FEV1 = 0.20 L, FVC = 0.20 L, SVC = 0.25 L, and IC = 0.30 L (expressed as absolute values); FEV1 = 12%, FVC = 7%, SVC = 10%, and IC = 15% (expressed as percentage of change from baseline values); and FEV1 = 7%, FVC = 6%, SVC = 7%, and IC = 12% (expressed as percentage of predicted values). CONCLUSIONS: In patients with airflow obstruction, IC varies more widely than do FVC and SVC. For IC, values greater than 0.30 L and 15% of change from the baseline value can be considered significant. For FVC, values greater than 0.20 L and 7% of change from the baseline value are significant. Alternatively, changes exceeding 0.20 L and 7% of the predicted value can be considered significant for FEV1 and FVC. On factor analysis, spirometric parameters clustered into three dimensions, expressing changes in flows, volumes, and dynamic hyperinflation.

Acute effects of indacaterol on lung hyperinflation in moderate COPD: a comparison with tiotropium.

BACKGROUND: Evidence has been provided that high-dose indacaterol (300 µg) can reduce lung hyperinflation in moderate-to-severe chronic obstructive pulmonary disease (COPD). AIM: To study whether low-dose indacaterol (150 µg) also reduces lung hyperinflation in comparison with the recommended dose of tiotropium (18 µg) in moderate COPD. METHODS: This was a multicenter, randomized, blinded, 3-period cross-over, placebo-controlled study. Spirometry and lung volumes were measured before and 30, 60, 120, 180 and 240 min after the administration of single-doses of indacaterol, tiotropium, or placebo. The primary end-point was the change in peak inspiratory capacity (IC). The area under the 4-h curve (AUC(0-4)) for IC, 1-s forced expiratory volume (FEV(1)) and forced vital capacity (FVC) were secondary variables. RESULTS: 49 patients completed the study. On average, peak IC and AUC(0-4) for IC were significantly greater after indacaterol than placebo by 177 mL (p = 0.007) and 142 mL (p = 0.001), respectively. Differences in peak IC and AUC(0-4) for IC between tiotropium and placebo were 120 mL (p = 0.07) and 85 mL (p = 0.052), respectively. Differences between indacaterol and tiotropium were statistically insignificant. Peak IC increased by >20% in 12 patients with indacaterol and 9 with tiotropium (p = 0.001), and by >30% in 8 patients with indacaterol and 3 with tiotropium (p = 0.001). The effects of indacaterol and tiotropium on FEV(1) and FVC were statistically significant vs placebo. CONCLUSIONS: Low-dose indacaterol has a bronchodilator effect that is similar to the recommended dose of tiotropium, but it is slightly superior in reducing lung hyperinflation. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT00999908.

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.

[The topical application of mitomycin C in the treatment of scar formation and stenosis in hollow organs of the head and neck: a field report]. / Die topische Applikation von Mitomycin C in der Behandlung von Stenosen und Narben in Hohlorganen in der Hals-Nasen-Ohrenheilkunde--Ein Erfahrungsbericht aus 10 Jahren.

INTRODUCTION: The antibiotic und antitumoral effect of Mitomycin C (MMC), a derivative of Streptomyces caespitosus, has been known since 1956. Besides its use as an adjunction in the treatment of breast, lung and prostate cancer, or as a second-line cytostatic drug for head and neck squamous cell carcinoma (HNSCC), since 1963, MMC has also been successfully used in the suppression of post-operative scar formation, particularly in the field of ophthalmology. This is due to its modulation of fibroblast activity, which enables decreased scarring and fibrosis. In this résumé, we wish to recapitulate our long years of experience in the topical application of Mitomycin C in the treatment of scar formation and stenosis in head and neck organs. PATIENTS AND METHODS: A retrospective analysis on the basis of clinical disease courses and findings (image documentation, questionnaires, pulmonary function tests) covering an examination period of 10 years, was performed on 40 patients with stenosising lesions and a mean age of 54 years. The fields of application included laryngeal, tracheal, oesophageal stenosis and stenosis of the external ear canal and the choane. RESULTS: After combined application of MMC and surgical intervention in cases of recurrent stenosising processes in head and neck organs, especially the larynx and the trachea, a sustained improvement was achieved in the pre-operative stenosis level as well as in the pre-operative, severely limited, forced inspiratory volume in 1 second (F1V1). CONCLUSION: The topical application of MMC appears to be an effective adjunction as a concept of treatment for stenosising, scar-forming lesions. This topical application, however, is not a substitute for correct diagnosis and appropriate surgical treatment. It must be regarded as a purely adjunctive manoeuvre. During the 10 years in which it was used, the clinical findings confirmed an enhancement in the containment of complex cases without the occurrence of any complications.

Recombinant human thyrotropin-stimulated radioiodine therapy of large nodular goiters facilitates tracheal decompression and improves inspiration.

INTRODUCTION: The impact on tracheal anatomy and respiratory function of recombinant human (rh)TSH-stimulated (131)I therapy in patients with goiter is not clarified. METHODS: In a double-blinded design, patients (age 37-87 yr) with a large multinodular goiter (range, 99-440 ml) were randomized to placebo (n = 15) or 0.3 mg rhTSH (n = 14) 24 h before (131)I therapy. The smallest cross-sectional area of the trachea (SCAT; assessed by magnetic resonance imaging) and the pulmonary function were determined before, 1 wk, and 12 months after therapy. RESULTS: Data on goiter reduction have been reported previously. In the placebo group, no significant changes in the lung function or SCAT were found throughout the study. In the rhTSH group, a slight decrease was observed in the forced vital capacity 1 wk after therapy, whereas the mean individual change in SCAT was significantly increased by 10.5% (95% confidence interval = 0.9-20.0%). A further increase in SCAT to 117 +/- 36 mm(2) (P = 0.005 compared with 92 +/- 38 mm(2) at baseline) was seen at 12 months, corresponding to a mean of 31.4% (95% confidence interval = 16.0-46.8%). The expiratory parameters did not change significantly, whereas forced inspiratory flow at 50% of the vital capacity (FIF50%) increased from initially 3.34 +/- 1.33 liters/sec to ultimately 4.23 +/- 1.88 liters/sec (P = 0.015) in the rhTSH group, corresponding to a median increase of 24.6%. By 12 months, the relative improvements in FIF50% and in SCAT were inversely correlated to the respective baseline values (FIF50%: r = -0.47, P = 0.012; SCAT: r = -0.57, P = 0.001). CONCLUSION: On average, neither compression of the trachea nor deterioration of the pulmonary function was observed in the acute phase after rhTSH-augmented (131)I therapy. In the long term, tracheal compression is diminished, and the inspiratory capacity improved, compared with (131)I therapy alone.

Onset of symptomatic effect of mometasone furoate nasal spray in the treatment of nasal polyposis.

BACKGROUND: The efficacy of the intranasal corticosteroid mometasone furoate nasal spray (MFNS) for treatment of nasal polyposis was demonstrated in 2 large clinical trials. OBJECTIVE: To evaluate the onset of MFNS symptomatic effect, data from the 2 trials were pooled and analyzed to determine the first day subjects experienced significant symptom relief. METHODS: Subjects with nasal polyposis randomized to MFNS 200 microg twice daily or placebo scored symptoms on a 3-point scale (0 = none; 3 = severe) and measured peak nasal inspiratory flow immediately before the morning dose. Onset of symptomatic effect was defined as the first day a statistically significant (P < .05) lasting response was observed for MFNS compared with placebo. RESULTS: A total of 447 subjects with bilateral nasal polyps and clinically significant nasal congestion/obstruction were analyzed. Compared with placebo, MFNS 200 microg twice daily demonstrated statistically significant (P < .05) relief of anterior rhinorrhea by day 2 (-10.9% vs +5.7%), nasal congestion by day 3 (-15.1% vs -7.6%), postnasal drip by day 5 (+1.1% vs +4.6%), and sense of smell by day 13 (-9.6% vs -5.6%). Significant improvement in peak nasal inspiratory flow was seen by day 2 (increase of 6.22 L/min vs 1.48 L/min for placebo; P = .03). CONCLUSION: Mometasone furoate nasal spray 200 microg twice daily rapidly improves the symptoms of nasal polyposis, leading to lasting relief of most major symptoms within 2 (24 hours after the first dose) to 5 days of initiating therapy.

Capacidade inspiratória, limitação ao exercício, e preditores de gravidade e prognóstico, em doença pulmonar obstrutiva crônica / Inspiratory capacity, exercise limitation, markers of severity, and prognostic factors in chronic obstructive pulmonary disease

OBJETIVO: Correlacionar a capacidade inspiratória (CI), por cento do previsto, pós-broncodilatador (pós-BD), com outras variáveis indicativas de gravidade e prognóstico, na doença pulmonar obstrutiva crônica (DPOC). MÉTODOS: Oitenta pacientes estáveis com DPOC realizaram manobras de capacidade vital forçada, capacidade vital lenta, e teste de caminhada de 6 min, antes e após salbutamol spray (400 µg). Foram divididos em quatro grupos, segundo o volume expiratório forçado no primeiro segundo pós-BD. Diversas variáveis foram testadas, por análise univariada e multivariada, com a distância caminhada pós-BD, por cento do previsto. A CI pós-BD foi correlacionada com o estadiamento Global Initiative for Chronic Obstructive Lung Disease (GOLD) e o índice Body mass index, airway Obstruction, Dyspnea, and Exercise capacity (BODE). RESULTADOS: Por análise de regressão multivariada, a CI pós BD, por cento do previsto, (p = 0,001), o uso de oxigênio a longo prazo (p = 0,014), e o número de medicamentos usados (p = 0,044), mantiveram associação significativa com a distância caminhada, por cento do previsto. A CI < 70 por cento foi observada em 56 por cento dos pacientes em estágios GOLD 3 ou 4 comparado a 20 por cento em estágios GOLD 1 ou 2 ( p < 0,001). A CI < 70 por cento foi observada em 60 por cento dos pacientes com escore BODE 3 ou 4 vs. 33 por cento com BODE 1 ou 2 (p = 0,02). CONCLUSÃO: A CI, por cento do previsto, pós-BD é o melhor preditor funcional da distância caminhada, associando-se significativamente com o escore GOLD e o índice BODE. Por isso, propomos que a CI seja incluída na rotina de avaliação dos portadores de DPOC.

OBJECTIVE: To correlate the postbronchodilator (post-BD) inspiratory capacity (IC), percent of predicted, with other markers of severity and prognostic factors in chronic obstructive pulmonary disease (COPD). METHODS: Eighty stable patients with COPD performed forced vital capacity and slow vital capacity maneuvers, as well as the 6-min walk test, prior to and after receiving albuterol spray (400 µg). Patients were divided into four groups, based on post-BD forced expiratory volume in one second. Several variables were tested to establish correlations with the post-BD distance walked, using univariate and multivariate analysis. Post-BD IC was found to correlated with Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging and with the Body mass index, airway Obstruction, Dyspnea, and Exercise capacity (BODE) index. RESULTS: Multivariate regression analysis revealed that the distance walked, percent predicted, correlated significantly with the IC post-BD, percent predicted (p = 0.001), long-term oxygen use (p = 0.014), and number of medications used in the treatment (p = 0.044). IC < 70 percent was observed in 56 percent patients in GOLD stages 3 or 4 vs. 20 percent in GOLD 1 or 2 (p < 0.001). IC < 70 percent was observed in (60 percent) patients with BODE score 3 or 4 vs. (33 percent) BODE score 1 or 2 (p = 0.02). CONCLUSION: Post-BD IC percent predicted is the best functional predictor of distance walked and is significantly associated with GOLD staging and BODE index. Therefore, We propose that the inspiratory capacity should be added to the routine evaluation of the COPD patients.

Tiotropium and simplified detection of dynamic hyperinflation.

STUDY OBJECTIVE: To detect dynamic hyperinflation (DH) by evaluating reduction in inspiratory capacity (IC) during metronome-paced hyperventilation (MPH) in patients with moderate-to-severe COPD, studied before and after treatment with tiotropium. METHODS: IC and FEV(1) were measured before and immediately after MPH at two times resting the respiratory rate for 20 s in 60 COPD patients (28 men; mean age, 66 +/- 10 years [+/- SD]) before and after 30 days of treatment with tiotropium bromide, 18 mug. Patients were encouraged to maintain a constant tidal volume during MPH. RESULTS: At baseline, mean FEV(1) was 1.5 +/- 0.1 L (+/- SE) [57 +/- 1.6% of predicted], mean FVC was 2.6 +/- 0.1L (77 +/- 1.8% of predicted), and mean FEV(1)/FVC was 56 +/- 1%. After 180 mug of aerosolized albuterol sulfate, mean FEV(1) was 1.7 +/- 0.1 L (63 +/- 1.5% of predicted) [p < 0.001] and mean FEV(1)/FVC was 58 +/- 1%. Compared to baseline, after 30 days and 1.5 h after tiotropium there was an increase in IC of 0.18 +/- 0.04L (p < 0.0001); FEV(1) of 0.13 +/- 0.03 L (5.6 +/- 0.8% of predicted; p = 0.0002); FVC of 0.22 +/- 0.05 L (6.5 +/- 1.3% of predicted; p < 0.001); and decrease in end-expiratory lung volume (EELV)/total lung capacity (TLC) of - 3.1 +/- 0.6% (p = 0.0001); a decrease in end-inspiratory lung volume (EILV)/TLC of - 2.9 +/- 1.3% (p = 0.03); and no change in TLC (- 0.06 +/- 0.05 L). Results following MPH-induced DH at baseline and after 30 days of tiotropium were similar, with decreases in IC (- 0.35 +/- 0.03 L; p < 0.001); FEV(1) (- 0.05 +/- 0.04 L; p = 0.2); and FVC (- 0.22 +/- 0.03 L; p < 0.0001); no change in TLC; and increases in EELV/TLC (11.8 +/- 1.0% of predicted; p < 0.0001) and EILV/TLC (4.0 +/- 1.3% of predicted, p < 0.003). CONCLUSION: In patients with moderate-to-severe COPD, tiotropium did not reduce MPH-induced DH and reduction in IC, compared to baseline. However, because tiotropium induced bronchodilation and increased baseline IC, lower operational lung volumes may blunt the effect of MPH-induced DH. The noninvasive simplicity of MPH-induced DH provides a clinically useful screening surrogate to monitor changes in IC following treatment with tiotropium.

Optimal end-tidal concentration of sevoflurane to test an ankle clonus in children.

STUDY DESIGN: A prospective randomized study on the end-tidal concentrations of sevoflurane at which ankle clonus existed. SUMMARY OF BACKGROUND DATA: The ankle clonus reflex is a transient neurologic abnormality, which normally occurs in patients during emergence from general anesthesia. OBJECTIVE: To determine the optimal end-tidal concentration of sevoflurane to test an ankle clonus in children during emergence from general anesthesia. METHODS: We studied 30 children (aged 5-15 years). General anesthesia was induced with thiopental sodium. Anesthesia was maintained with sevoflurane, oxygen, and air. At completion of surgery, 3% volume of the end-tidal sevoflurane concentration was maintained for at least 10 minutes. Ankle clonus was checked at 1.0% to 0.1% volume of the end-tidal sevoflurane concentration with an interval of 0.05% volume. RESULTS: Of children, 80% had bilateral ankle clonus, which was found most frequently when patients responded poorly to verbal commands. The median of the end-tidal sevoflurane concentration for a reactive ankle clonus was 0.45% volume (interquartile range 0.5% to 0.4% volume). CONCLUSIONS: The ankle clonus should be tested at 0.45% volume of end-tidal sevoflurane concentration in children undergoing scoliosis surgery during emergence from the general anesthesia.

The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function.

Forced expiratory volume in 1 second (FEV1) has served as an important diagnostic measurement of chronic obstructive pulmonary disease (COPD) but has not been found to correlate with patient-centered outcomes such as exercise tolerance, dyspnea, or health-related quality of life. It has not helped us understand why some patients with severe FEV1 impairment have better exercise tolerance compared with others with similar FEV1 values. Hyperinflation, or air trapping caused by expiratory flow limitation, causes operational lung volumes to increase and even approach the total lung capacity (TLC) during exercise. Some study findings suggest that a dyspnea limit is reached when the end-inspiratory lung volume encroaches within approximately 500 mL of TLC. The resulting limitation in daily physical activity establishes a cycle of decline that includes physical deconditioning (elevated blood lactic acid levels at lower levels of exercise) and worsening dyspnea. Hyperinflation is reduced by long-acting bronchodilators that reduce airways resistance. The deflation of the lungs, in turn, results in an increased inspiratory capacity. For example, the once-daily anticholinergic bronchodilator tiotropium increases inspiratory capacity, 6-minute walk distance, and cycle exercise endurance time, and it decreases isotime fatigue or dyspnea. Pulmonary rehabilitation and oxygen therapy both reduce ventilatory requirements and improve breathing efficiency, thereby reducing hyperinflation and improving exertional dyspnea. Thus, hyperinflation is directly associated with patient-centered outcomes such as dyspnea and exercise limitation. Furthermore, therapeutic interventions--including pharmacotherapy and lung volume--reduction surgery--that reduce hyperinflation improve these outcomes.