ABSTRACT

In hypersecretory diseases such as bronchiectasis and cystic fibrosis there is ab­normal and increased secretion of mucus which the mucociliary system fails to clear. This results in mucus accumulation, cough, bacterial colonization, and in­fections (1). Treatment of mucociliary dysfunction aims to reduce mucus secre­tion and to increase its clearance. This treatment includes glucocorticoids, p2-adrenergic agonists, antibiotics, and mucoactive agents (2).Osmotic agents have been shown to increase clearance of mucus and are regarded as promising mucoactive agents (3). Knowledge of the effect of the osmotic agents on the mucociliary system originates from the use of hypertonic saline, an ionic substance, which has been shown to increase clearance of mucus in healthy subjects (4) and in patients with bronchitis (5), asthma (4), and cystic fibrosis (6). However, hypertonic saline has the disadvantage that it is rapidly absorbed, and thus its effect may be very short acting. Although salt itself is inexpensive and easily available, delivery of hypertonic saline requires an expen361

sive nebulizer. An additional recent concern is that high salt concentration at the airway surface could inactivate the airway defensins and increase infections (7).Mannitol, a naturally occurring sugar alcohol (C6H140 6; MW 182), is a nonionic osmotic agent with low permeability (8) that has been recently shown to increase mucociliary clearance (9). It is not absorbed by the gastrointestinal tract, and it is not metabolized to any appreciable extent when given parenterally. Mannitol, as a dry powder, is a stable substance and can resist moisture resorption even at high relative humidities. Because of these characteristics it is an ideal substance to encapsulate and be delivered conveniently to the patient using porta­ble nonexpensive inhalation devices. Mannitol also has a low permeability, and therefore it is likely to be retained in the airway lumen longer than the hypertonic saline.Initial investigations of the effect of mannitol on the clearance of mucus were performed in healthy and mild asthmatic subjects (9). These subjects had normal resting lung function and mucociliary clearance, and they had also demon­strated an increase in clearance in response to hypertonic saline (4). These initial studies (9) established that mannitol (1) can stimulate the normal mucociliary system to increase clearance of mucus above the normal baseline level; (2) can as a dry powder have an effect in the small airways; (3) is well tolerated; and (4) induces cough which is not excessive and is acceptable to the subjects.We have now further investigated the effect of mannitol in patients with abnormal mucociliary clearance-namely, patients with bronchiectasis and cys­tic fibrosis. METHODS

The mannitol powder (Mannitol BP, Rhone Poulenc Chemicals Pty., Ltd., Brookvale, NSW, Australia) was specially prepared for inhalation (9-11). Mannitol was delivered from capsules containing 5, 10, 20, and 40 (± 0.2) mg using a dry powder inhaler. The dry powder inhaler devices used in these studies were the Dinkihaler (Rhone Poulenc Rorer, Collegeville, PA) and the Inhala-tor™ (Boehringer Ingelheim, Pty., Ltd., Ingelheim, Germany). Patients inhaled the mannitol with a vital capacity maneuver and a fast inspiratory flow followed by a breath hold of 5 seconds. At a flow rate equal or greater than 60 L/min, the majority of particles are in the respirable range (<7 pm). Measurement of Mucociliary Clearance

In brief, our technique for measuring clearance of mucus involves inhaling a radioaerosol of sulfur colloid tagged with technetium of relatively large droplets (MMAD 6 pm, GSD 1.7). The radioaerosol is delivered with a controlled breath­

ing pattern to ensure deposition in the conducting airways. The initial radioactiv­ity deposited in the lung and the amount subsequently retained was monitored using a gamma camera linked to a computer. Details of our technique have been published elsewhere (4,9-11). Only the right lung was analyzed, which was di­vided in three regions: central, intermediate, and peripheral.