Background: Respimat Soft Mist Inhaler (SMI) is a new-generation inhaler offering improved lung deposition compared with other devices. Bronchodilators administered via Respimat SMI are preserved and stabilized with benzalkonium chloride (BAC) and ethylene diamine tetra-acetic acid (EDTA); both have been reported to cause paradoxical bronchoconstriction if a threshold dose is exceeded.
Objective: The aim of this randomized, double-blind, three-period, crossover study was to establish that the safety of inhaled ethanolic and aqueous placebo solutions (containing BAC and EDTA) is equivalent to that of inhaled normal saline solution when administered to asthma patients via Respimat SMI.
Methods: Thirty-seven asthma patients with airway hyper-reactivity were randomized to receive four actuations of each of the following three treatments via Respimat SMI, one on each of 3 study days: ethanolic placebo (12 microl 96% ethanol + 0.13 mug EDTA/actuation), aqueous placebo (12 microl water + 5.5 microg EDTA + 1.1 mug BAC/actuation), and normal saline (12 microl 0.9% sodium chloride/actuation). Pulmonary function tests were performed at baseline and at 5, 15, 30, 60, 120 and 180 min after inhalation; the primary endpoint was the lowest FEV(1) recorded between 0 and 30 min.
Results: The mean lowest FEV(1) recorded between 0 and 30 min after inhalation minus the study day baseline was -0.090 litres for ethanolic placebo, -0.121 litres for aqueous placebo and -0.094 litres for normal saline (SEM 0.034 litres for all). The mean treatment differences were: ethanolic placebo versus normal saline 0.004 litres (90% CI -0.075-0.083 litres, p = 0.002), and aqueous placebo versus normal saline -0.028 litres (90% CI -0.107-0.052 litres, p = 0.006). Since both 90% CIs fell within the pre-determined equivalence region of +/-0.15 litres, both treatments were considered equivalent to normal saline.
Conclusion: Ethanolic and aqueous solutions administered via Respimat SMI are safe with regard to paradoxical bronchoconstriction in asthma patients with airway hyper-reactivity.