Webb Ka

Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD

The aim of this study was to test the hypothesis that use of tiotropium, a new long-acting anticholinergic bronchodilator, would be associated with sustained reduction in lung hyperinflation and, thereby, would improve exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease. A randomised, double-blind, placebo-controlled, parallel-group study was conducted in 187 patients (forced expiratory volume in one second 44±13% pred): 96 patients received 18 µg tiotropium and 91 patients received placebo once daily for 42 days. Spirometry, plethysmographic lung volumes, cycle exercise endurance and exertional dyspnoea intensity at 75% of each patients maximal work capacity were compared. On day 42, the use of tiotropium was associated with the following effects at pre-dose and post-dose measurements as compared to placebo: vital capacity and inspiratory capacity (IC) increased, with inverse decreases in residual volume and functional residual capacity. Tiotropium increased post-dose exercise endurance time by 105±40 s (21%) as compared to placebo on day 42. At a standardised time near end-exercise (isotime), IC, tidal volume and minute ventilation all increased, whilst dyspnoea decreased by 0.9±0.3 Borg scale units. In conclusion, the use of tiotropium was associated with sustained reductions of lung hyperinflation at rest and during exercise. Resultant increases in inspiratory capacity permitted greater expansion of tidal volume and contributed to improvements in both exertional dyspnoea and exercise endurance.

Physiological changes during symptom recovery from moderate exacerbations of COPD.

Acute exacerbations of chronic obstructive disease (AECOPD) are characterised by worsening dyspnoea that is variably prolonged. In this study, physiological changes during moderate AECOPD were examined and the factors associated with dyspnoea resolution over time were determined. In total, 20 patients experiencing an AECOPD were evaluated within 72 h of initial worsening of symptoms (day 0) with pulmonary function testing, metabolic testing and symptom assessment using the dyspnoea domain of the Chronic Respiratory Disease Questionnaire (CRQ). Treatment was optimised and testing was repeated after 7, 14, 30 and 60 days. At day 0, patients were very short of breath (CRQ-dyspnoea mean±sem 2.4±0.3) and showed significant airflow obstruction (forced expiratory volume in one second (FEV1) 41±3% predicted) and lung hyperinflation (forced residual capacity (FRC) 164±7% pred). By day 60 CRQ-dyspnoea improved to 4.6±0.5 (some shortness of breath); FRC and residual volume decreased by 5 and 11%, respectively; inspiratory capacity (IC) and slow vital capacity increased by 18 and 17%, respectively; and FEV1 increased by 18% with no change in FEV1/FVC. Total lung capacity did not change during AECOPD, and thus, changes in IC reliably reflected changes in end-expiratory lung volume. In conclusion, moderate acute exacerbation of chronic obstructive pulmonary disease is characterised by worsening airflow obstruction and lung hyperinflation. Improvement of dyspnoea following acute exacerbations of chronic obstructive pulmonary disease was associated with reduction in lung hyperinflation and consequent increase in expiratory flow rates.

Evaluation of bronchodilator responses in patients with “irreversible” emphysema

Given the emerging physiological and clinical rationale for pharmacological lung-volume reduction, assessment of volume responses to bronchodilators is likely to be highly relevant in chronic obstructive pulmonary disease (COPD). The authors examined the magnitude of lung-volume reduction after acute bronchodilator treatment in patients with advanced emphysema. Eighty-four stable patients with emphysema (mean±sem forced expiratory volume in one second (FEV1): 32±1% predicted) performed spirometry and body plethysmography before and 15–30 min after 200 µg salbutamol. Only irreversible patients with a postbronchodilator change in FEV1 <10% pred were considered in this study. Postsalbutamol, the majority of subjects (83%) had significant improvements in one or more lung volumes: on average, residual volume (RV), functional residual capacity (FRC), inspiratory capacity (IC), forced vital capacity and slow vital capacity changed by −18±2, −10±1, 8±1, 9±1 and 7±1% pred (p<0.0005 each). Total lung capacity (TLC) decreased 0.12±0.04 L (p<0.01). Change in IC reflected change in FRC (r=−0.60, p<0.0005), but more strongly in the 57% of patients with no significant change in TLC (r=−0.93, p<0.0005). The magnitude and frequency of volume responses were greatest in patients with the most severe COPD; for example, RV decreased by 0.51±0.09 L (23±4% pred) and 0.27±0.04 L (14±2% pred) in severe and moderate subgroups, respectively. Significant reductions in lung hyperinflation occurred in the absence of a change in forced expiratory volume in one second after low-dose salbutamol in a majority of patients with advanced emphysema; the greatest changes occurred in those with the most severe disease.

Reliability of ventilatory parameters during cycle ergometry in multicentre trials in COPD

We studied the distribution profiles and repeatability of key exercise performance parameters in the first large multicentre trials to include these measurements in chronic obstructive pulmonary disease (COPD). After a screening visit, 463 subjects with COPD (mean±sd forced expiratory volume in 1 s 43±13% predicted) completed two run-in visits before treatment randomisation. At the run-in visits, measurements were conducted at rest, at a standardised time near end-exercise (isotime) and at peak exercise during constant work rate (CWR) cycle tests at 75% of each individual’s maximum work capacity. The intraclass correlation coefficient was used to evaluate the test-retest repeatability of measurements of endurance time (ET), inspiratory capacity (IC), ventilation and dyspnoea intensity (Borg scale) during exercise. IC, ventilation and dyspnoea ratings were normally distributed; ET showed rightward skew (median<mean, skewness of 10.9 (much greater than zero)) with 16% of the sample exceeding 1 sd of the mean. ET was highly repeatable across run-in visits: 7.9±4.8 and 8.4±5.1 min (R = 0.84). IC values at rest, isotime and peak exercise were all highly repeatable (R≥0.87). Ventilation was repeatable over the same time-points (R≥0.92), as was dyspnoea intensity at isotime (R = 0.79) and at peak exercise (R = 0.81). In conclusion, key perceptual and ventilatory parameters can be reliably measured during CWR cycle exercise in multicentre clinical trials in moderate to very severe COPD.

Abnormal sarcoplasmic reticulum Ca2+-sequestering properties in skeletal muscle in chronic obstructive pulmonary disease

The objective of this study was to investigate the hypothesis that alterations in sarcoplasmic reticulum (SR) Ca(2+)-cycling properties would occur in skeletal muscle in patients with moderate to severe chronic obstructive pulmonary disease (COPD). To investigate this hypothesis, tissue samples were obtained from the vastus lateralis of 8 patients with COPD [age 65.6 +/- 3.2 yr; forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) = 44 +/- 2%; mean +/- SE] and 10 healthy age-matched controls (CON, age 67.5 +/- 2.5 yr; FEV(1)/FVC = 77 +/- 2%), and homogenates were analyzed for a wide range of SR properties. Compared with CON, COPD displayed (in mumol.g protein(-1).min(-1)) a 16% lower maximal Ca(2+)-ATPase activity [maximal velocity (V(max)), 158 +/- 10 vs. 133 +/- 7, P < 0.05] and a 17% lower Ca(2+) uptake (4.65 +/- 0.039 vs. 3.85 +/- 0.26, P < 0.05) that occurred in the absence of differences in Ca(2+) release. The lower V(max) in COPD was also accompanied by an 11% lower (P < 0.05) Ca(2+) sensitivity, as measured by the Hill coefficient (defined as the relationship between Ca(2+)-ATPase activity and free cytosolic Ca(2+) concentration for 10-90% V(max)). For the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) isoforms, SERCA1a was 16% higher (P < 0.05) and SERCA2a was 14% lower (P < 0.05) in COPD. It is concluded that moderate to severe COPD results in abnormalities in SR Ca(2+)-ATPase properties that cannot be explained by changes in the SERCA isoform phenotypes. The reduced catalytic properties of SERCA in COPD suggest a disturbance in Ca(2+) cycling, possibly resulting in impairment in Ca(2+)-mediated mechanical function and/or second messenger regulated processes.

Vocal cord paralysis and respiratory muscle weakness: An unusual presentation of chronic polyneuropathy

A case of chronic polyneuropathy that manifested with an unusual combination of vocal cord paralysis and respiratory muscle weakness is reported. In addition, results of an exercise test carried out to assess the severity and mechanisms of exertional breathlessness in this unique condition with combined obstructive and restrictive disorders are described.