Tiotropium, a novel once-daily inhaled anticholinergic, has been shown to improve lung function over a 24-h period. In order to extend these findings, health-outcomes were evaluated over 1 yr in chronic obstructive pulmonary disease (COPD) patients.Spirometric results, peak expiratory flow rate (PEFR), salbutamol use and effects on dyspnoea, health-related quality of life and COPD exacerbations were assessed in two identical 1-yr randomized double-blind double-dummy studies of tiotropium 18mg once daily (n=356) compared with ipratropium 40mg q.i.d. (n=179).Screening forced expiratory volume in one second (FEV1) were 1.25¡0.43 L (41.9¡12.7% of the predicted value) (tiotropium) and 1.18¡0.37 L (39.4¡10.7% pred) (ipratropium). Trough FEV1 at 1 yr improved by 0.12¡0.01 L with tiotropium and declined by 0.03¡0.02 L with ipratropium (pv0.001). Significant improvement in PEFR, salbutamol use, Transition Dyspnea Index focal score, and the St George9s Respiratory Questionnaire total and impact scores were seen with tiotropium (pv0.01). Tiotropium reduced the number of exacerbations (by 24%, pv0.01), and increased time to first exacerbation (pv0.01) and time to first hospitalization for a COPD exacerbation (pv0.05) compared with ipratropium. Apart from an increased incidence of dry mouth in the tiotropium group, adverse events were similar between treatments.Tiotropium was effective in improving dyspnoea, exacerbations, health-related quality of life and lung function in patients with chronic obstructive pulmonary disease, and exceeds the benefits seen with ipratropium. The data support the use of tiotropium once-daily as first-line maintenance treatment in patients with chronic obstructive pulmonary disease.

We investigated ventilation inhomogeneity during provocation with inhaled histamine in 20 asymptomatic nonsmoking subjects. We used N2 multiple-breath washout (MBW) to derive parameters Scond and Sacin as a measurement of ventilation inhomogeneity in conductive and acinar zones of the lungs, respectively. A 20% decrease of forced expiratory volume in 1 s (FEV1) was used to distinguish responders from nonresponders. In the responder group, average FEV1 decreased by 26%, whereas Scond increased by 390% with no significant change in Sacin. In the nonresponder group, FEV1 decreased by 11%, whereas Scond increased by 198% with no significant Sacin change. Despite the absence of change in Sacin during provocation, baseline Sacin was significantly larger in the responder vs. the nonresponder group. The main findings of our study are that during provocation large ventilation inhomogeneities occur, that the small airways affected by the provocation process are situated proximal to the acinar zone where the diffusion front stands, and that, in addition to overall decrease in airway caliber, there is inhomogeneous narrowing of parallel airways.

Rationale Small airways function studies in lung disease have used three promising multiple breath washout (MBW) derived indices: indices of ventilation heterogeneity in the acinar (S acin ) and conductive (S cond ) lung zones, and the lung clearance index (LCI). Since peripheral lung structure is known to change with age, ventilation heterogeneity is expected to be affected too. However, the age dependence of the MBW indices of ventilation heterogeneity in the normal lung is unknown. Objectives The authors systematically investigated S acin , S cond or LCI as a function of age, testing also the robustness of these relationships across two laboratories. Methods MBW tests were performed by never-smokers (50% men) in the age range 25e65 years, with data gathered across two laboratories (n¼120 and n¼60). For comparison with the literature, the phase III slopes from classical single breath washout tests were also acquired in one group (n¼120). Measurements and main results All three MBW indices consistently increased with age, representing a steady worsening of ventilation heterogeneity in the age range 25e65. Age explained 7e16% of the variability in S acin and S cond and 36% of the variability in LCI. There was a small but significant gender difference only for S acin . Classical single breath washout phase III slopes also showed age dependencies, with gender effects depending on the normalisation method used. Conclusions With respect to the clinical response, age is a small but consistent effect that needs to be factored in when using the MBW indices for the detection of small airways abnormality in disease.

It has been shown that structural changes in small airways of smokers with average smoking histories greater than 35 pack-years could be reflected in the single-breath washout test. The more sophisticated multiple breath washout test (MBW) has the potential to anatomically locate the affected small airways in acinar and conductive lung zones through increased phase III slope indices S(acin) and S(cond), respectively. Pulmonary function, S(acin), and S(cond) were obtained in 63 normal never-smokers and in 169 smokers classified according to smoking history (< 10 pack-years; 10-20 pack-years; 20-30 pack-years; > 30 pack-years). Compared with never-smokers, significant changes in S(acin) (p = 0.02), S(cond) (p < 0.001), and diffusing capacity (DL(CO); p < 0.001) were detected from greater than 10 pack-years onwards. Spirometric abnormality was significant only from greater than 20 pack-years onwards. In smokers with greater than 30 pack-years and DL(CO) less than 60% predicted, the presence of emphysema resulted in disproportionally larger S(acin) than S(cond) increases. We conclude that S(cond) and S(acin) can noninvasively detect airway changes from as early as 10 pack-years onwards, locating the earliest manifestations of smoking-induced small airways alterations around the acinar entrance. In these early stages, the associated DL(CO) decrease may be a reflection of ventilation heterogeneity rather than true parenchymal destruction. In more advanced stages of smoking-induced lung disease, differential patterns of S(acin) and S(cond) are characteristic of the presence of parenchymal destruction in addition to peripheral airways alterations.

To identify the site and cause of airflow limitation in patients with parkinsonism, we tested pulmonary function in 27 patients with extrapyramidal disorders. In 24 patients, an abnormal flow-volume loop contour, showing either regular (18 patients) or irregular (6 patients) flow oscillations, was found. On direct fiberoptic visualization of the upper airway, these oscillations corresponded to either rhythmic (4 to 8 Hz) or irregular involuntary movements of glottic and supraglottic structures. Ten patients had physiologic evidence of upper-airway obstruction, which was symptomatic in four. We conclude that the upper-airway musculature is frequently involved in extrapyramidal disorders. This causes upper-airway dysfunction that can be severe enough to limit airflow.

We investigated acinar airway involvement in 20 patients with stable asthma, using the phase III slope analysis of the multiple breath N2 washout previously applied in a group of patients with COPD (Am. J. Respir. Crit. Care Med. 1998;157:1573-1577). This technique quantifies severity of conductive and acinar components of ventilation maldistribution separately, through indices S(cond) and S(acin), which increase when respective ventilation inhomogeneities increase. We also investigated the effect of salbutamol inhalation on S(cond) and S(acin) in patients with asthma and compared it with that obtained in patients with COPD. Baseline measurements in the patients with asthma show that (1) acinar ventilation inhomogeneity was indeed abnormal in patients with asthma (S(acin) = 0.195 +/- 0.026 L-1) despite the normal diffusing capacity in this group; S(acin) values were intermediate between those obtained in unaffected individuals and patients with COPD, and that (2) conductive ventilation inhomogeneity was abnormal in the patients with asthma (S(cond) = 0.076 +/- 0.006 L-1) but similar to that obtained in the patients with COPD. Measurements after salbutamol inhalations showed significant changes in S(cond) and S(acin) only in the patients with asthma (p < 0.001). This study primarily demonstrated significant, but partially reversible, acinar airway impairment in patients with asthma, as compared with the more severe baseline acinar airway impairment in patients with COPD, which was not reversible after salbutamol inhalation.

In conclusion, indacaterol treatment improved the ability of patients with COPD to exercise. In addition, the improvements observed in resting and end-exercise IC indicate reductions in lung hyperinflation after 3 weeks treatment (ClinicalTrials.gov registration number: NCT00620022).

We investigated ventilation inhomogeneity in patients with chronic obstructive pulmonary disease (COPD) through use of the multiple breath N2 washout test (MBW). From an alveolar slope analysis throughout the MBW, we derived two indices, S(cond) and S(acin), as a measure of ventilation inhomogeneity in conductive and acinar zones of the lungs, respectively (J. Appl. Physiol. 1997;83:1807-1816). We evaluated the relationship of S(cond) and S(acin) to standard lung-function indices by means of a principal-components factor analysis, which linked correlated indices to independent factors accounting for 81% of the total variance within the COPD group. S(acin) was linked to the so-called acinar lung-zone factor, which also comprises diffusion capacity measurements. S(cond) was linked to the so-called conductive lung-zone factor, which also comprises specific airway conductance (S(Gaw)) and forced expiratory flows. FEV1 divided by FVC (FEV1/FVC) was the only variable linked to both the conductive and the acinar lung-zone factors. The fact that S(cond) and S(acin) were linked to independent factors provides statistical confirmation of the hypothesis that S(cond) and S(acin) reflect independent lung alterations, whereas FEV1/FVC behavior indicates a combined conductive and acinar contribution to airways obstruction.