Effect of Hypertonic Saline on Mucus Clearance in Children Ages 5-12 With Cystic Fibrosis

Our current understanding of the pathogenesis of CF lung disease stems from data that demonstrate the presence of airway surface liquid (ASL) dehydration in CF. ASL dehydration in CF is caused by defective chloride secretion through the cystic fibrosis transmembrane regulator (CFTR) and increased sodium reabsorption through the epithelial sodium channel (ENaC). ASL dehydration, in turn, interferes with the mucociliary clearance apparatus, causing a breach in a critical line of lung host defense. A number of novel therapeutics are now being developed to address this basic defect of disease, including the use of inhaled hypertonic saline.

Previous work demonstrated that inhaled hypertonic saline (HS) reduces exacerbation frequency and improves lung function in patients with clinically apparent lung disease. A number of issues revolving around the use of HS in CF remain unresolved. First, the typical patients enrolled in previous studies were adults (mean age = 26 yrs) with established lung disease (mean FEV1=78%). Despite our hypothesis that HS should positively affect MCC in preserved/normal airways, a common view of HS is that it benefits CF patients by inducing cough and transiently promoting the clearance of thick CF secretions. It has been questioned, therefore, whether HS will benefit patients who are younger and have mild (or undetectable) lung disease and potentially normal (though unmeasured) rates of MCC. Second, it is unclear whether the substantial beneficial effects of HS in CF were achieved because of a long (>4 hours) duration of action or in spite of an extremely short (~45 minutes) duration of action (the traditional view based upon experiments in normal epithelia). This issue is important, as it relates to the development and dosing of hydrator therapies that may have different pharmacodynamic profiles. Certainly, if twice daily dosing of a short acting compound is sufficient to provide significant clinical benefit, it would reduce the challenge of drug discovery for CF and ease the treatment burden imposed upon patients. The study of HS in CF provides us an opportunity to address this issue.

The hypothesis being tested is that HS will rehydrate CF airway secretions, producing a sustained acceleration in MCC in young children with CF, regardless of whether a measurable mucus clearance defect exists at this relatively early stage of disease. We predict a substantial acceleration of MCC will reduce the exacerbation rate in young children with CF. In addition, with the growing number of treatment modalities that are prescribed to patients with CF, adherence to complex and time consuming medical regimens becomes increasingly problematic and important. We therefore, wish to test an improved drug delivery platform for HS- the eFlow (Pari Pharma) vibrating mesh nebulizer, which has the potential to reduce treatment times, improve compliance, and increase treatment efficacy.