Expiratory flow limitation relates to symptoms during COPD exacerbations requiring hospital admission.

BACKGROUND: Expiratory flow limitation (EFL) is seen in some patients presenting with a COPD exacerbation; however, it is unclear how EFL relates to the clinical features of the exacerbation. We hypothesized that EFL when present contributes to symptoms and duration of recovery during a COPD exacerbation. Our aim was to compare changes in EFL with symptoms in subjects with and without flow-limited breathing admitted for a COPD exacerbation. SUBJECTS AND METHODS: A total of 29 subjects with COPD were recruited within 48 hours of admission to West China Hospital for an acute exacerbation. Daily measurements of post-bronchodilator spirometry, resistance, and reactance using the forced oscillation technique and symptom (Borg) scores until discharge were made. Flow-limited breathing was defined as the difference between inspiratory and expiratory respiratory system reactance (EFL index) greater than 2.8 cmH2O·s·L(-1). The physiological predictors of symptoms during recovery were determined by mixed-effect analysis. RESULTS: Nine subjects (31%) had flow-limited breathing on admission despite similar spirometry compared to subjects without flow-limited breathing. Spirometry and resistance measures did not change between enrolment and discharge. EFL index values improved in subjects with flow-limited breathing on admission, with resolution in four patients. In subjects with flow-limited breathing on admission, symptoms were related to inspiratory resistance and EFL index values. In subjects without flow-limited breathing, symptoms related to forced expiratory volume in 1 second/forced vital capacity. In the whole cohort, EFL index values at admission was related to duration of stay (Rs=0.4, P=0.03). CONCLUSION: The presence of flow-limited breathing as well as abnormal respiratory system mechanics contribute independently to symptoms during COPD exacerbations.

Changes in oscillatory impedance and nitrogen washout with combination fluticasone/salmeterol therapy in COPD.

INTRODUCTION: Combination inhaled corticosteroid/long-acting bronchodilator (ICS/LABA) therapy reduces the exacerbation rate and improves spirometry and quality of life in COPD. We hypothesized that ICS/LABA therapy also improves small airway function measured by FOT. METHODS: 14 subjects with COPD were commenced on combination fluticasone propionate/salmeterol therapy for 3 months. At baseline, subjects completed the St George Respiratory Questionnaire (SGRQ) and underwent standard pulmonary function tests as well as forced oscillation technique (FOT) and single and multiple breath nitrogen washouts. All tests were repeated at the completion of 3 months of therapy. RESULTS: Subjects were of mean (SD) age 65.9 years (8.4), BMI 30.0 (5.6), pack years 51.4 (21.1), post-bronchodilator FEV1% predicted 62.7 (20). At baseline, mean SGRQ total was 39.0 (17.7) and FRC% predicted 125.4 (31.3). From FOT, Rrs-total was 5.69 (1.29) cmH2O/L/s, Xrs-total -3.48 (2.16) cmH2O/L/s, EFL Index 3.51 (2.45) cmH2O/L/s. After 3 months of therapy, there were significant improvements in SGRQ score (-13.81, p < 0.0001) despite no change in FEV1 (+40 mL, p = 0.14). From FOT, total resistance (-0.63 cmH2O/L/s, p = 0.0004), reactance (+1.2 cmH2O/L/s, p = 0.013), and expiratory flow limitation (-1.21 cmH2O/L/s, p = 0.02) also improved. There were no significant changes in ventilation heterogeneity indices. CONCLUSION: Combination therapy is associated with improvements in small airways function in COPD, despite an absence of change in FEV1. FOT may be a clinically useful marker of small airway function in COPD that is responsive to treatment.

Day-to-day variability of oscillatory impedance and spirometry in asthma and COPD.

Variability in airway function may be a marker of disease activity in COPD and asthma. The aim was to determine the effects of repeatability and airway obstruction on day-to-day variability in respiratory system resistance (Rrs) and reactance (Xrs) measured by forced oscillation technique (FOT). Three groups of 10 subjects; normals, stable asthmatic and stable COPD subjects underwent daily FOT recordings for 7 days. Mean total and inspiratory Rrs and Xrs, and expiratory flow limitation (EFL) Index (inspiratory - expiratory Xrs), were calculated. The ICC's were high for all parameters in all groups. Repeatability, in terms of absolute units, correlated with airway obstruction and was therefore lowest in COPD. Day-to-day variability was due mostly to repeatability, with a small contribution from the mean value for some parameters. FOT measures are highly repeatable in health, stable asthma and COPD in relation to the wide range of measures between subjects. For home monitoring in asthma and COPD, either the coefficient of variation or individualized SDs could be used to define day-to-day variability.

The feasibility of home monitoring of impedance with the forced oscillation technique in chronic obstructive pulmonary disease subjects.

Respiratory system resistance (Rrs) and reactance (Xrs) measured by forced oscillation technique (FOT) can be potentially used for home monitoring in COPD. Our aims were to determine the technical acceptability, adherence and variability of unsupervised, home FOT measurements over ten consecutive days. Supervised spirometry and FOT measurements were made on ten clinically stable COPD subjects at their homes at the study initiation. Subjects then self-recorded FOT twice daily for ten consecutive days with data transmitted to the laboratory server via a 3G mobile network. Subjects had a mean (SD) age of 68(8) years, smoking history 38.4(8.7) pack/years, post-bronchodilator FEV1 42.4(12.0)% predicted, FEV1/FVC ratio 0.45(0.10), mean Rrs 121.7(26.1)% predicted and mean Xrs 746.8(330.3)% predicted. The supervised measurements of mean Rrs and mean Xrs were similar to the unsupervised measurements (p = 0.34 and p = 0.92, respectively). 197 of 200 possible measurements were transmitted, all of which were deemed to be technically acceptable. The within-subject standard deviation, Sw, of Rrs-total and Xrs-total were 0.47 and 1.0 cmH(2)O L s(-1), respectively. Subjects who have COPD make reliable, unsupervised FOT measurements at home with a high degree of adherence. The day-to-day variability of FOT measurements was similar to that of supervised laboratory recordings. These results support the conduct of larger, longer-term studies of FOT monitoring in COPD.

The relationship between airflow obstruction, emphysema extent, and small airways function in COPD.

BACKGROUND: The severities of COPD (FEV(1) % predicted) and airflow obstruction (FEV(1)/FVC) are considered to be due to both emphysema and small airways disease. To our knowledge, this has not been previously confirmed by combined measurements of emphysema and of small airway function. We hypothesized that small airways disease and emphysema extent contribute independently to the severity of both COPD and airflow obstruction. METHODS: Twenty-six subjects with COPD underwent measurements with forced oscillation technique (FOT) at 6 Hz and single-breath nitrogen washout. Respiratory system resistance, respiratory system reactance (Xrs), and expiratory flow limitation (EFL) index (measured as mean inspiratory Xrs − expiratory Xrs) were derived from FOT. Closing volume/vital capacity (CV/VC) was derived from the washout. Emphysema extent was measured as low attenuation areas < -910 Hounsfield units, expressed as a percentage of CT scan lung volume from multislice CT scans taken at total lung capacity. RESULTS: Subjects were aged (mean ± SD) 69.6 ± 8.0 years. Postbronchodilator FEV(1) was 64.8 ± 19.8% predicted, and diffusing capacity of lung for carbon monoxide was 50.7 ± 15.8% predicted. Emphysema extent was 22.6% ± 15.0% CT scan volume. CV/VC was 16.9% ± 7.9%; Xrs, -3.72 ± 3.03 cm H(2)O/L/s; and EFL index, 3.88 ± 3.93 cm H(2)O/L/s. In multiple regression analyses, FEV(1)/FVC was predicted by both emphysema and CV/VC (model r(2) = 0.54, P < .0001) whereas FEV(1) % predicted was predicted by emphysema and EFL index (model r(2) = 0.38, P = .0014). CONCLUSIONS: The severities of COPD and airflow obstruction are independently predicted by both small airways disease and emphysema extent.

Improved respiratory system conductance following bronchodilator predicts reduced exertional dyspnoea.

BACKGROUND: In COPD, improvements in lung mechanics following bronchodilator, measured using the forced oscillation technique (FOT), are more sensitive than spirometry at detecting improvement in lung function following bronchodilator. The relationship between these improvements in lung mechanics and improvements in functional outcomes, such as exertional dyspnoea, following bronchodilator, in COPD is unknown. METHODS: 17 COPD subjects were recruited into a double blind placebo controlled randomised cross over study. Dyspnoea was induced using a standardised six-minute walk test (6 MWT), and measured by borg score throughout the test. Measurement of respiratory system conductance (Grs), respiratory system reactance (Xrs), inspiratory capacity (IC) and spirometry were made at baseline and 1 h after a single dose of either 18 µg of tiotropium bromide plus 200 µg salbutamol, or placebo. RESULTS: Subjects had a mean baseline FEV(1) of 45.5 ± 11.0% predicted. The bronchodilator induced reduction in exertional dyspnoea correlated significantly with the increase in Grs (r(s) = 0.59, p = 0.01) and approached significance with FEV(1) (r(s) = 0.45, p = 0.07) but not with FVC (r(s) = 0.30, p = 0.24), Xrs (r(s) = 0.19, p = 0.47) or IC (r(s) = -0.08, p = 0.78). Increase in Grs was the best and sole predictor of reduction in exertional dyspnoea, explaining 41% of the variance. There was no additional contribution to the model from the increase in FEV(1) or IC. CONCLUSION: Bronchodilator induced improvements in exertional dyspnoea in moderate to severe COPD are predicted by improvements in Grs, measured by FOT, independent of improvements in spirometry or hyperinflation. The findings suggest that FOT may be useful for measuring response to bronchodilator in COPD.

Avoiding deep inspirations increases the maximal response to methacholine without altering sensitivity in non-asthmatics.

Airway hyperresponsiveness is characterised by a leftward shift of the dose-response curve (DRC) and an increase in the maximal response. Deep inspiration (DI) avoidance increases responsiveness in non-asthmatic, but not asthmatic, subjects. The aim was to determine the effect of DI avoidance on the sensitivity and maximal response of the FEV(1) DRC to methacholine. Thirteen non-asthmatic and ten asthmatic subjects underwent a standard cumulative high-dose methacholine challenge (0.1-200µmol). Subsequently, on separate days, increasing single doses of methacholine were administered after 10min of DI avoidance. A sigmoidal equation was fitted to the data to obtain values for α, the position constant, as a measure of sensitivity. The fall in FEV(1) at the highest common dose was used as a measure of the maximal response. The change in flow at 40% control vital capacity on the maximal (V˙40m) and partial (V˙40p) curves were calculated from the first manoeuvre after methacholine and the ratio of the values for V˙40m and V˙40p was calculated as a measure of the bronchodilator effect of DI (BD(DI)). In non-asthmatic subjects, avoiding DI increased the maximum fall in FEV(1) at the highest common dose (p=0.0001) but did not alter α (p=0.75). Avoiding DI before challenge did not alter BD(DI) (p=0.13). DI avoidance had no effect on airway responsiveness in asthmatic subjects. In non-asthmatic subjects, DI avoidance increases airway responsiveness by increasing the maximal response, but does not alter the sensitivity, suggesting that the loss of the effect of DI in asthma contributes to excessive bronchoconstriction.

Short-term variability of airway caliber-a marker of asthma?

Variability in airway caliber is a characteristic feature of asthma. Previous studies reported that the variability in respiratory system impedance (Zrs), measured by the forced oscillation technique during several minutes of tidal breathing, is increased in asthma and may be a marker of inherent instability of the airways. The aims of this study were to determine if short-term variability in impedance correlates with peak expiratory flow (PEF) variability or airway hyperresponsiveness (AHR). The SD of log-transformed impedance (lnZrsSD) was measured as a marker of short-term variability and compared with the diurnal variability of PEF over 2 wk in 28 asthmatic and 7 nonasthmatic subjects and with AHR to histamine in a cohort of 17 asthmatic and 82 nonasthmatic subjects. In addition, lnZrsSD was measured in eight nonasthmatic subjects before and after methacholine challenge in the upright and supine positions. There were no significant differences in lnZrsSD between asthmatic and nonasthmatic subjects (P = 0.68). Furthermore, in asthmatic subjects, lnZrsSD did not correlate with diurnal variability of PEF (rs = -0.12 P = 0.54) or with AHR to histamine (r = 0.10, P = 0.71). Neither methacholine challenge nor supine posture caused any significant change in lnZrsSD. We conclude that our findings do not support previous reports about the utility of short-term variability of impedance. Our findings suggest that, using standard methods for forced oscillometry, impedance variability does not provide clinically useful information about the severity of asthma.

A comparison of airway and serum matrix metalloproteinase-9 activity among normal subjects, asthmatic patients, and patients with asthmatic mucus hypersecretion.

BACKGROUND: The rate of decline in lung function is increased in asthmatic patients, particularly in those with coexisting asthmatic mucus hypersecretion (AMH), in whom inflammation and the activity of matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in serum and BAL fluid (BALF) may be increased. METHODS: Seven nonasthmatic subjects and 22 asthmatic subjects completed a questionnaire, and underwent lung function testing and bronchoscopy, during which AMH was diagnosed by the presence of mucus plugging. Subjects were classified as follows: mild/moderate asthma; severe asthma; and AMH. In BALF, we measured the differential WBC counts and MMP-9 activity by zymography. We measured total MMP-9 and TIMP-1 activity by enzyme-linked immunosorbent assay in BALF and serum. RESULTS: The mean (+/- confidence interval) FEV1 was lower in AMH patients (73 +/- 13% predicted) compared with nonasthmatic subjects (95 +/- 7%) and patients with mild/moderate asthma (73 +/- 9%; p < 0.05), and was similar to that of patients with severe asthma (80 +/- 20%). MMP-9 activity was greater in AMH patients and in patients with severe asthma compared with nonasthmatic subjects (p = 0.05 and p = 0.01, respectively), as were TIMP-1 activities (p = 0.001 and p = 0.04, respectively), but MMP-9/TIMP-1 ratios were not. MMP-9 activity increased across the four groups from nonasthmatic subjects to AMH patients (r = 0.58; p = 0.0009), but the differential and total WBC counts were similar. There were no relationships between FEV1 percent predicted and either MMP-9 activity or MMP-9/TIMP-1 ratio. There were no differences in serum MMP-9 activity, which did not correlate with MMP-9 activity in BALF. CONCLUSIONS: AMH and severe asthma were associated with greater proteolytic enzyme activities despite similar airway inflammation, which might play a role in remodeling and accelerated the decline in lung function in these patients.