ArticlesComparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial
Introduction
Cystic fibrosis is the most common lethal recessive disorder of white populations. Most of the morbidity and mortality is from pulmonary disease, which is characterised by bronchial and bronchiolar obstruction by thick tenacious secretions that are difficult to clear.1 Retention of abnormal airway secretions promotes recurrent respiratory infections, cycles of inflammation, and progressive lung damage.
DNA derived from the degeneration of neutrophils is a major contributor to the viscosity of airway secretions and is present in high concentration in the sputum of patients with cystic fibrosis.2 The human enzyme deoxyribonuclease I was cloned and sequenced in 1990. Clinical trials of recombinant human deoxyribonuclease (rhDNase) have shown improvements in lung function and a reduction in protocol-defined infective exacerbations.3, 5 The enzyme is believed to work by cleaving extracellular DNA in airway secretions, thus aiding expectoration of sputum.6
Daily rhDNase is widely used in the treatment of cystic fibrosis, but there are unresolved issues. Although many patients improve on treatment, there is wide variation in individual response.7 The long-term benefit of rhDNase remains uncertain, and its effect on airway inflammation is still not clear.8 Moreover, this therapy is expensive, and the long-term cost-effectiveness has not been established. The current dose recommended in children, 2·5 mg once daily, is as effective as two daily doses of 2·5 mg.5 There have been no studies on the use of alternate-day rhDNase, which if equally effective would halve the drug cost and treatment time.
Nebulised hypertonic saline is a potential alternative mucolytic therapy for cystic fibrosis. Hypertonic saline has been used for decades as an agent to aid airway clearance and sputum induction in various respiratory disorders. In short-term studies in cystic fibrosis, hypertonic saline seemed to have beneficial effects on lung function, mucociliary clearance, and sputum expectoration,9, 12 similar to those of rhDNase. It is much cheaper than rhDNase, but there have been no medium-term or long-term comparisons between hypertonic saline and rhDNase.
We aimed to test the hypothesis that hypertonic saline and alternate-day rhDNase are as effective as daily rhDNase in improving respiratory function in children with cystic fibrosis.
Section snippets
Study population
Children with cystic fibrosis, previously diagnosed on standard criteria, were enrolled from two institutions (Great Ormond Street Hospital for Children NHS Trust and the Royal Brompton and Harefield NHS Trust, London, UK). Inclusion criteria were age between 5 and 18 years; ability to carry out spirometry; and either current treatment with rhDNase or a forced expiratory volume in 1 s (FEV1) of less than 70% of predicted.13 Exclusion criteria were inability to take the trial medication; known
Results
48 children were randomised, eight to each of the six possible treatment orders. One 14-year-old girl withdrew from the study almost immediately after randomisation without starting the first treatment, owing to what became a prolonged illness. Table 1 gives the characteristics of the remaining 47 children as observed at the baseline assessment. Eight children were unable to complete all three treatment periods (figure 1). Four patients had severe declines in their pulmonary status and required
Discussion
This randomised trial compared the effects of hypertonic saline and rhDNase in cystic fibrosis patients over 12 weeks. This duration was used because the response to rhDNase at 12 weeks is strongly predictive of response at 1 year.7 We found that treatment with daily rhDNase results in a significantly greater increase in FEV1 than hypertonic saline over 12 weeks and that daily and alternate-day rhDNase result in similar increases in FEV1. The mean difference in cost for 12 weeks' treatment was
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