Bronchodilators delivered by nebuliser versus pMDI with spacer or DPI for exacerbations of COPD.

BACKGROUND: Bronchodilators are a central component for treating exacerbations of chronic obstructive pulmonary disease (COPD) all over the world. Clinicians often use nebulisers as a mode of delivery, especially in the acute setting, and many patients seem to benefit from them. However, evidence supporting this choice from systematic analysis is sparse, and available data are frequently biased by the inclusion of asthma patients. Therefore, there is little or no formal guidance regarding the mode of delivery, which has led to a wide variation in practice between and within countries and even among doctors in the same hospital. We assessed the available randomised controlled trials (RCTs) to help guide practice in a more uniform way. OBJECTIVES: To compare the effects of nebulisers versus pressurised metered dose inhalers (pMDI) plus spacer or dry powder inhalers (DPI) in bronchodilator therapy for exacerbations of COPD. SEARCH METHODS: We searched the Cochrane Airways Group Trial Register and reference lists of articles up to 1 July 2016. SELECTION CRITERIA: RCTs of both parallel and cross-over designs. We included RCTs during COPD exacerbations, whether measured during hospitalisation or in an outpatient setting. We excluded RCTs involving mechanically ventilated patients due to the different condition of both patients and airways in this setting. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data and assessed the risk of bias. We report results with 95% confidence intervals (CIs). MAIN RESULTS: This review includes eight studies with a total of 250 participants comparing nebuliser versus pMDI plus spacer treatment. We identified no studies comparing DPI with nebulisers. We found two studies assessing the primary outcome of 'change in forced expiratory volume in one second (FEV1) one hour after dosing'. We could not pool these studies, but both showed a non-significant difference in favour of the nebuliser group, with similar frequencies of serious adverse events. For the secondary outcome, 'change in FEV1 closest to one hour after dosing': we found a significant difference of 83 ml (95% CI 10 to 156, P = 0.03) in favour of nebuliser treatment. For the secondary outcome of adverse events, we found a non-significant odds ratio of 1.65 (95% CI 0.42 to 6.48) in favour of the pMDI plus spacer group. AUTHORS' CONCLUSIONS: There is a lack of evidence in favour of one mode of delivery over another for bronchodilators during exacerbations of COPD. We found no difference between nebulisers versus pMDI plus spacer regarding the primary outcomes of FEV1 at one hour and safety. For the secondary outcome 'change in FEV1 closest to one hour after dosing' during an exacerbation of COPD, we found a greater improvement in FEV1 when treating with nebulisers than with pMDI plus spacers.A limited amount of data are available (eight studies involving 250 participants). These studies were difficult to pool, of low quality and did not provide enough evidence to favour one mode of delivery over another. No data of sufficient quality have been published comparing nebulisers versus DPIs in this setting. More studies are required to assess the optimal mode of delivery during exacerbations of COPD.

Particle size matters: diagnostics and treatment of small airways involvement in asthma.

Small airways are an important site of inflammation and obstruction in asthma, which contributes to the severity of airway hyperresponsiveness (AHR) that is usually measured by nebulisation of large-particle stimuli. We investigated whether small and large particle sizes of aerosolised adenosine monophospate (AMP) provoke similar severity of AHR. Additionally, effects of the small-particle inhaled corticosteroid (ICS) ciclesonide and large-particle ICS fluticasone on AHR to large- and small-particle size AMP were assessed. After a 4-week run-in period using open-label fluticasone (100 µg b.i.d.), 37 mild-to-moderate asthmatics underwent provocations with standard-size (3.7 µm), large-particle (9.9 µm) and small-particle (1.06 µm) AMP. Subjects received 4-week ciclesonide (160 µg s.i.d.) or fluticasone (100 µg b.i.d.) treatment (double-blind and double-dummy) followed by large- and small-particle AMP provocation. Small-particle AMP induced a 20% decrease in forced expiratory volume in 1 s (FEV(1)) at a significantly higher dose than large-particle AMP. Ciclesonide and fluticasone had comparable effects on AMP provocations. Not all subjects reached the provocative concentration causing a 20% fall in FEV(1) (PC(20)) at the highest AMP dose. In those who did, ciclesonide improved small-particle AMP PC(20) by 1.74 doubling doses (DD) (p = 0.03), whereas fluticasone did not. Conversely, fluticasone improved large-particle AMP PC(20) significantly (1.32 DD; p = 0.03), whereas ciclesonide did not. Small-particle AMP provocation appears to be a promising tool to assess changes in small airway inflammation. Future adjustments are necessary taking into account the very small particle size used, with large exhaled fractions. In asthmatics reaching a PC(20) with small- and large-particle AMP provocations, ciclesonide improves hyperresponsiveness to small particle size AMP, and fluticasone to large particle size. This warrants further research to target provocations and treatment to specific airway sizes.

Physiology of the small airways: A gender difference?

Small airways are affected in asthma, but gender differences have not been investigated. This study aims to assess whether gender differences exist in the extent of small airway involvement in asthma. Sixteen patients with mild-to-moderate asthma (seven males, median (range) age 39 (19-56) years, FEV(1)%predicted 89% (62-120), PC(20) Methacholine (MCh) 0.4 mg/mL (0.1-4.2)) participated in the study. MCh-induced air trapping at end-expiratory CT scans, alveolar and bronchial exhaled Nitric Oxide (eNO), Single-Breath N(2) closing volume, FEF(25-75%), FEF(50%) and % change in FVC at PC(20) adenosine-5'-monophosphate (AMP) and at PC(20)MCh were evaluated. Multiple regression analyses evaluated whether gender, body mass index and age were explanatory variables for the severity of air trapping. Males had significantly larger MCh-induced increases in low attenuation areas on CT than females, 6% (1-9) versus 2% (-1-7), p=0.012. Males had significantly more signs of MCh-induced air trapping in the non-dependent lung lobes than females. Male gender was the sole factor explaining higher values of MCh-induced signs of air trapping. Females had higher bronchial eNO values than males, 4 nL/s (2-7) versus 2 nL/s (1-4), p=0.04. Small airway involvement in asthma as reflected by MCh-induced air trapping at CT was significantly larger in males than females even in this relatively small group. Bronchial eNO, reflecting partially small airway inflammation, was higher in females than males. These data suggest that the small airways are affected differently in males and females with asthma. Males exhibit small airway involvement by attenuated small airway patency and females by small airway inflammation.

Ciclesonide improves measures of small airway involvement in asthma.

Ciclesonide is delivered as a small-particle inhaled corticosteroid and improves lung function and airway hyperresponsiveness. The objective of the present study was to assess whether ciclesonide can specifically improve small airway function in asthma. A total of 16 mild-to-moderate asthma patients (seven males; median (range) age 39 (19-56) yrs and forced expiratory volume in one second (FEV(1)) 89 (62-120)% predicted) were randomised to 5 weeks' treatment with placebo or 320 mug ciclesonide once daily. The following small airway parameters were assessed: mean forced expiratory flow between 25 and 75% of forced vital capacity (FVC), percentage fall in FVC at provocative dose of adenosine-5'-monophosphate and of methacholine (MCh) causing a 20% fall in FEV(1), expiratory lung volume on computed tomography (CT) scan after MCh challenge, single-breath nitrogen closing volume and alveolar exhaled nitric oxide (eNO). Seven subjects received placebo and nine received ciclesonide. Both alveolar eNO and CT measurements of expiratory lung volume after MCh challenge decreased significantly with ciclesonide (median (range) decrease 4.4 (54.8-1.4) ppb and 59 (1,569- -117) mL, respectively), and compared with placebo (-0.4 (7.3- -3.4) ppb and -121 (20- -236) mL respectively). Ciclesonide did not significantly improve other small airways parameters. Inflammation and patency of small airways, reflected by alveolar exhaled nitric oxide and air trapping on computed tomography scan, both improve with ciclesonide even in this small number of patients. This indicates that ciclesonide exerts anti-inflammatory effects on small airways.

Changes in peak expiratory flow indices as a proxy for changes in bronchial hyperresponsiveness. Dutch Chronic Non-Specific Lung Disease study group.

Guidelines for asthma management advocate home peak expiratory flow (PEF) monitoring. It is commonly stated that PEF variability is a good proxy of bronchial hyperresponsiveness (BHR), a hallmark of asthma. However, this has hardly been tested longitudinally, as required to monitor asthma. This study assesses which PEF index correlates best with BHR longitudinally and whether the correlation improves when correcting PEF values for the known nonlinearity of mini-Wright PEF meters. Every 6 months, for a period of 2 yrs, PEF diary cards were filled in and BHR to histamine was tested in 104 patients with BHR and reversible airways obstruction, who started treatment with bronchodilators with (n=33) or without (n=71) inhaled corticosteroids. Within each subject, PEF indices and BHR were correlated longitudinally. The highest median correlation coefficients were obtained in the group of patients using inhaled corticosteroids. The PEF indices providing the best correlation with BHR were: mean PEF bronchodilator response (rho=-0.50) and within-day variation (% mean or % maximum) (with postbronchodilator values, rho=-0.50; without postbronchodilator values, rho=-0.40). Using PEF data corrected for the nonlinearity of the PEF meters did not result in higher correlation coefficients. Since current guidelines on asthma management recommend only bronchodilators on demand, the most useful peak expiratory flow index for reflecting bronchial hyperresponsiveness longitudinally is mean within-day peak expiratory flow variation (% mean or % maximum) (without postbronchodilator values). Since the correlation coefficients are not very strong, the authors suggest that peak expiratory flow measurements are not used as a proxy for bronchial hyperresponsiveness longitudinally but as a measurement in its own right. The use of corrections of peak expiratory flows for the nonlinearity of mini-Wright peak expiratory flow meters does not improve the correlation between peak expiratory flow and bronchial hyperresponsiveness.

Risk of overtreatment with current peak flow criteria in self-management plans. Dutch CNSLD Study Group. Chronic Non-Specific Lung Disease.

Home peak expiratory flow (PEF) measurements have become the cornerstone of asthma self-management plans. However, the cut-off values for changing treatment have not been formally tested. This study focusses on the possible overtreatment brought about by the different cut-off values and denominators currently employed. Data from 133 clinically stable asthmatic patients from a 2.5 yr follow-up study were analysed. The results showed that strict adherence to current criteria would lead to severe overtreatment, with up to 30% of clinically stable patients crossing into the lowest (red) zone at least once a year when personal best is the denominator and when it has not been limited to a defined time of day or to defined prior bronchodilator use. As expected, the passage of clinically stable patients into the lower zones became less frequent when cut-off values were sharpened and when time- and treatment-specific PEFs were used as the denominators. Strict adherence to commonly used peak expiratory flow cut-off values would lead to considerable overtreatment. In order to avoid overtreatment, the morning peak expiratory flow before any (bronchodilator) treatment should be related to the personal best peak expiratory flow measured under the same conditions. The choice of the right cut-off value will also depend on studies being performed to test the amount of undertreatment with a given value.

Mini-Wright peak flow meters are reliable after 5 years use. Dutch CNSLD Study Group.

In studies with a long-term follow-up, peak expiratory flow (PEF) meters are often used to assess bronchial obstruction. The question arises whether data obtained with these frequently used meters are still reliable after several years of use, and whether the old meters should be renewed after a certain period. In the present study, we tested the reliability of PEF values measured with mini-Wright PEF meters that had been used frequently for 5 yrs. The values obtained with these meters were compared with values measured with identical but new meters, in 50 patients with obstructive airways disease. Though statistically significant, there was no clinically significant difference in mean PEF measured with the old and new meters in most patients (mean difference 10.2 L.min-1). However, on an individual basis, the differences between old and new meters could be large (upper and lower limits of agreement (mean +/- 2 SD) being 63.6 and -43.2 L.min-1, respectively). We conclude that mean peak expiratory flow values measured with frequently used mini-Wright peak expiratory flow meters are still reliable after 5 yrs. In long-term studies, renewal of peak expiratory flow meters should be restricted to cases of obvious malfunction.

Lack of correlation between bronchoconstrictor response and bronchodilator response in a population-based study.

Bronchodilator and bronchoconstrictor responsiveness have been considered physiological opposites in patients with obstructive airways disease. Provocation challenges have been replaced by bronchodilator tests in the assessment of cases of severe airways obstruction. The aim of this study was to examine the relationship between bronchoconstrictor and bronchodilator responsiveness, and their supposed interchangeability, in a general population. From the Vlagtwedde-Vlaardingen follow-up study, 101 adults were recruited (mean (SD) age 55 (11) yrs, 67 males and 34 females, and 31 were smokers). All completed a questionnaire on airways symptoms. Bronchoconstrictor and bronchodilator responsiveness were assessed with cumulative dose-response curves, using histamine and terbutaline, respectively. Thus, it was possible to relate histamine sensitivity of the airways (the concentration of histamine, at which forced expiratory volume in one second (FEV1) falls by 10% (PC10)) to the maximal bronchodilator response (delta FEV1) and the sensitivity to the bronchodilator (cumulative dose of inhaled terbutaline at which FEV1 increases by 10% (RD10)). Subjects with a bronchoconstrictor response (PC10 < or = 16 mg x mL(-1); n=38) had more respiratory symptoms than those without (n=63) (40 versus 21%) and also lower baseline FEV1 values (90 versus 96% predicted), but had comparable bronchodilator responsiveness. Subjects with a bronchodilator response (delta FEV1 > or = 9% of the predicted value; n=13) did not differ from those without (n=88) for all parameters, including symptoms, allergy and pulmonary function. In those with a bronchoconstrictor response, there was a weak but significant correlation between the PC10 and RD10 (rho=-0.32), but not between PC10 and delta FEV1. This study suggests that bronchoconstrictor and bronchodilator responsiveness are not highly correlated, even in subjects with airways obstruction. Symptoms were associated with the presence of a bronchoconstrictor, but not a bronchodilator, response. We conclude that bronchoconstrictor and bronchodilator responsiveness are two different phenotypic markers that are not interchangeable in epidemiological studies.