Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis. Effect of hypertonic saline, amiloride, and cough on mucociliary clearance in patients with cystic fibrosis. The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial. Controlled trial of intermittent aerosol therapy with sodium 2-mercaptoethane sulphonate in cystic fibrosis.
Patients with cystic fibrosis are known to have decreased mucociliary clearance. It has previously been shown that inhalation of a 7.0% solution of hypertonic saline significantly improved mucociliary clearance in a group of adult patients with cystic fibrosis. The aim of this study was to measure the response to increasing concentrations of inhaled hypertonic saline.
                Ten patients (seven men) of mean (SE) age 22 (4) years and mean forced expiratory volume in one second (FEV1) 52.0 (6.7)% predicted completed the study. Mucociliary clearance was measured using a radioaerosol technique for 90 minutes after the interventions which comprised 0.9% NaCl + voluntary cough (control), 3.0% NaCl, 7.0% NaCl, and 12% NaCl.
                There was a significant increase in the amount of activity cleared from the right lung with all concentrations of hypertonic saline (HS) compared with control. The amount cleared at 90 minutes on the control day was 12.7% (95% confidence interval (CI) 9.8 to 17.2) compared with 19.7% (95% CI 13.6 to 29.5) for 3% HS, 23.8% (95% CI 15.9 to 36.7) for 7% HS and 26.0% (95% CI 19.8 to 35.9) for 12% HS. The improvement in mucociliary clearance was not solely due to coughing as the number of coughs recorded on the control day exceeded that recorded on any other day. The hypertonic saline did not induce a clinically significant change in FEV1.
                Within the range of concentrations examined in this study, the effect of hypertonic saline appears to be dose dependent. Inhalation of hypertonic saline remains a potentially useful treatment for patients with cystic fibrosis. In patients with cystic fibrosis (CF), dehydration of airway secretions leads to a decrease in mucociliary clearance (MCC). We examined the acute effect of MCC of a single administration by aerosolization of hypertonic saline (7%) (HS), amiloride (0.3% in 0.12% NaCl) (AML) and a combination of AML and HS (AML + HS) in 12 patients with CF using a radioaerosol technique. Isotonic saline [0.9%] (IS) was used as a control solution. As both the AML and HS solutions induced cough in some patients, the last nine patients studied also underwent a cough clearance day. This was to eliminate the possible confounding effect of cough on MCC measurement. Patients ranged from 18 to 28 yr (mean +/- SD, 22 +/- 3) with an FEV1 of 27 to 112% predicted (61 +/- 30%). Following deposition of the radioaerosol, baseline clearance was assessed for 30 min. This was followed by a 30-min intervention period. Assessment of post-intervention clearance for a further 30 min was then performed. Comparison of the amount of radioaerosol cleared from the right lung was made at 60 min (%C60) and 90 min (%C90) using repeated measures ANOVA. The percent cleared at 60 and 90 min was significantly increased with HS (%C60 = 26.5%, %C90 = 29.4%) and the combination of AML + HS (%C60 = 23.1%, %C90 = 27.4%) compared with both IS (%C60 = 14.7%, %C90 = 17.5%) and COUGH (%C60 = 18.0%, %C90 = 19.5%), p < 0.01. Inhalation of hypertonic saline is a potentially useful treatment in patients with cystic fibrosis. It has been postulated that hypertonic saline (HS) might impair the antimicrobial effects of defensins within the airways. Alternative non-ionic osmotic agents such as mannitol may thus be preferable to HS in promoting bronchial mucus clearance (BMC) in patients with cystic fibrosis (CF). This study reports the effect of inhalation of another osmotic agent, dry powder Mannitol (300 mg), compared with its control (empty capsules plus matched voluntary cough) and a 6% solution of HS on BMC in 12 patients with cystic fibrosis (CF). Mucus clearance was measured using a radioaerosol/gamma camera technique. Post-intervention clearance was measured for 60 min, followed by cough clearance for 30 min. Neither mannitol nor HS improved BMC during the actual intervention period compared with their respective controls. However during the post-intervention measurement there was a significant improvement in BMC for both the mannitol (8.7+/-3.3% versus 2.8+/-0.7%) and HS (10.0+/-2.3% versus 3.5+/-0.8%). There was also a significant improvement in cough clearance with the Mannitol (9.7+/-2.4%) compared with its control (2.5+/-0.8%). Despite premedication with a bronchodilator, a small fall in forced expiratory volume in one second (FEV1) was seen immediately after administration of both the mannitol (7.3+/-2.5%) and HS (5.8+/-1.2%). Values of FEV1 returned to baseline by the end of the study. Inhaled mannitol is a potential mucoactive agent in cystic fibrosis patients. Further studies are required to establish the optimal dose and the long-term effectiveness of mannitol. Inhaled hypertonic saline acutely increases mucociliary clearance and, in short-term trials, improves lung function in people with cystic fibrosis. We tested the safety and efficacy of inhaled hypertonic saline in a long-term trial.
                In this double-blind, parallel-group trial, 164 patients with stable cystic fibrosis who were at least six years old were randomly assigned to inhale 4 ml of either 7 percent hypertonic saline or 0.9 percent (control) saline twice daily for 48 weeks, with quinine sulfate (0.25 mg per milliliter) added to each solution to mask the taste. A bronchodilator was given before each dose, and other standard therapies were continued during the trial.
                The primary outcome measure, the rate of change (slope) in lung function (reflected by the forced vital capacity [FVC], forced expiratory volume in one second [FEV1], and forced expiratory flow at 25 to 75 percent of FVC [FEF25-75]) during the 48 weeks of treatment, did not differ significantly between groups (P=0.79). However, the absolute difference in lung function between groups was significant (P=0.03) when averaged across all post-randomization visits in the 48-week treatment period. As compared with the control group, the hypertonic-saline group had significantly higher FVC (by 82 ml; 95 percent confidence interval, 12 to 153) and FEV1 (by 68 ml; 95 percent confidence interval, 3 to 132) values, but similar FEF25-75 values. The hypertonic-saline group also had significantly fewer pulmonary exacerbations (relative reduction, 56 percent; P=0.02) and a significantly higher percentage of patients without exacerbations (76 percent, as compared with 62 percent in the control group; P=0.03). Hypertonic saline was not associated with worsening bacterial infection or inflammation.
                Hypertonic saline preceded by a bronchodilator is an inexpensive, safe, and effective additional therapy for patients with cystic fibrosis. (ClinicalTrials.gov number, NCT00271310.)
                Copyright 2006 Massachusetts Medical Society. Daily recombinant human deoxyribonuclease (rhDNase) is an established but expensive treatment in cystic fibrosis. Alternate-day treatment, if equally effective, would reduce the drug cost. Hypertonic saline improved lung function to the same degree as rhDNase in short-term studies. We compared the effectiveness of daily rhDNase, hypertonic saline, and alternate-day rhDNase in children with cystic fibrosis.
                In an open cross-over trial, 48 children were allocated in random order to 12 weeks of once-daily rhDNase (2.5 mg), alternate-day rhDNase (2.5 mg), and twice-daily 5 mL 7% hypertonic saline. The primary outcome was forced expiratory volume in 1 s (FEV(1)). Secondary outcomes were forced vital capacity, number of pulmonary exacerbations, weight gain, quality of life, exercise tolerance, and the total costs of hospital and community care.
                Mean FEV(1) increased by 16% (SD 25%), 14% (22%), and 3% (21%) with daily rhDNase, alternate-day rhDNase, and hypertonic saline, respectively. There was no difference between daily and alternate-day rhDNase (2% [95% CI -4 to 9], p=0.55). However, daily rhDNase showed a significantly greater increase in FEV(1) than hypertonic saline (8% [2 to 14], p=0.01). The average difference in 12-week cost between daily and alternate-day rhDNase was pound513 (95% CI -546 to 1510) and that between daily rhDNase and hypertonic saline was pound1409 (440 to 2318). None of the secondary clinical outcomes showed significant differences between treatments.
                Hypertonic saline, delivered by jet nebuliser, is not as effective as daily rhDNase, although there is variation in individual response. There is no evidence of a difference between daily and alternate-day rhDNase. Twenty-seven patients with cystic fibrosis completed a controlled trial comparing the effects of an inhaled mucolytic drug, sodium-2-mercaptoethane sulphonate (Mistabron, UCB Pharmaceutical Division, Brussels, Belgium), with inhaled iso-osmolar hypertonic saline. As a group the 22 patients with chronic sputum production showed small but statistically significant improvement in pulmonary function tests after Mistabron therapy, both when compared with a control period, and with iso-osmolar saline results. Subjective measurements by diary card failed to show any changes. No significant changes were found in five patients with no measurable sputum production. The inhalations were given after physiotherapy and were well tolerated. There were no significant side effects. The results suggest that Mistabron has a beneficial therapeutic effect unrelated to its high osmolality, and the intermittent inhalation of Mistabron may have a role in the treatment of selected patients with cystic fibrosis.
Treatment with 7% HS for 48 weeks showed a small improvement in FEV1 at four weeks; however, this was not sustained at 48 weeks (primary outcome measure of the only long-term trial). Unlike RhDNAse, HS can't, in the long term, be said to improve lung function. However, it did improve quality of life and reduce pulmonary exacerbations. Delivered following a bronchodilator, HS appears inexpensive and safe with no increased infection risk.
We believe there is sufficient evidence to recommend using HS in CF; qualifying this we highlight that the only long-term trial failed to demonstrate a significant difference in its primary outcome (lung function) with improvements only in secondary outcomes.