Inhaled Hypertonic Saline May Improve Lung Function in Cystic Fibrosis News Author: Laurie Barclay, MD CME Author: Désirée Lie, MD, MSEd Release Date: January 19, 2006; Jan. 19, 2006 Inhaled hypertonic saline improves lung function in those with cystic fibrosis, according to the results of 2 studies reported in the January 19 issue of The New England Journal of Medicine. "Inhaled hypertonic saline acutely increases mucociliary clearance and, in short-term trials, improves lung function in people with cystic fibrosis," write Mark R. Elkins, MHSc, from Royal Prince Alfred Hospital in Sydney, Australia, and colleagues from the National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. "Experimental data suggest that a long-term clinical trial evaluating the safety and efficacy of hypertonic saline as a treatment for cystic fibrosis is warranted." In this double-blind, parallel-group trial, 164 patients with stable cystic fibrosis who were at least 6 years of age were randomized to inhale 4 mL of either 7% hypertonic saline or 0.9% (control) saline twice daily for 48 weeks. Quinine sulfate (0.25 mg/mL) was added to each solution to mask the taste; a bronchodilator was given before each dose; and patients continued other standard therapies during the trial. The primary endpoint, which was the rate of change (slope) in lung function (reflected by the forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1], and forced expiratory flow at 25% to 75% of FVC [FEF25-75]) during the 48 weeks of treatment, was not significantly different between groups (P = .79). However, when averaged across all postrandomization visits in the 48-week treatment period, the absolute difference in lung function between groups was significant (P = .03). Compared with the control group, the hypertonic-saline group had significantly higher values for FVC (difference, 82 mL; 95% confidence interval [CI], 12 - 153) and FEV1 (68 mL; 95% CI, 3 - 132) values, but similar values for FEF25-75. The hypertonic-saline group also fared better than the control group in terms of fewer pulmonary exacerbations (relative reduction, 56%; P = .02) and a greater percentage of patients without exacerbations (76% vs 62%; P = .03). Furthermore, 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," the authors write. "A decrease in exacerbations is an important outcome for patients with cystic fibrosis with respect to the quality of life, days absent from normal activities, and cost." The US Cystic Fibrosis Foundation, the National Health & Medical Research Council of Australia, and the Australian Cystic Fibrosis Research Trust supported this study. The authors have disclosed no relevant financial relationships. Pfizer Australia, Pari Germany, Technipro Australia, and Glaxo Wellcome Australia provided supplies and equipment needed for this study. "Abnormal homeostasis of the volume of airway surface liquid in patients with cystic fibrosis is thought to produce defects in mucus clearance and airway defense," write Scott H. Donaldson, MD, from the University

of North Carolina at Chapel Hill, and coauthors of the second study. "Through osmotic forces, hypertonic saline may increase the volume of airway surface liquid, restore mucus clearance, and improve lung function." In this study, 24 patients with cystic fibrosis were randomized to receive treatment with inhaled hypertonic saline (5 mL of 7% sodium chloride) 4 times daily with or without amiloride pretreatment, and mucus clearance and lung function were measured during 14-day baseline and treatment periods. Compared with the amiloride-pretreatment group, patients who did not receive pretreatment with amiloride had a sustained (>/=8 hours) increase in 1-hour rates of mucus clearance (14.0% ± 2.0% vs 7.0% ± 1.5%; P = .02) and increased 24-hour rates of mucus clearance over baseline. Inhalation of hypertonic saline with placebo improved the FEV1 from baseline (mean difference, 6.62%; 95% CI, 1.6 - 11.7; P = .02). However, inhalation of hypertonic saline with amiloride did not improve FEV1 (mean difference, 2.9%; 95% CI, -2.2 to 8.0; P = .23). In patients treated with hypertonic saline and placebo, FVC, the FEF25-75, and respiratory symptoms also improved significantly. However, the residual volume as a proportion of total lung capacity did not change in either group. In vitro data suggested that the sustained improvement in mucus clearance was attributable to sustained hydration of airway surfaces, but that amiloride-induced inhibition of osmotically driven water transport explained the observed loss of clinical benefit. "In patients with cystic fibrosis, inhalation of hypertonic saline produced a sustained acceleration of mucus clearance and improved lung function," the authors write. "This treatment may protect the lung from insults that reduce mucus clearance and produce lung disease." The Cystic Fibrosis Foundation and the National Institutes of Health supported this study. Two authors have disclosed relevant financial relationships with Inspire Pharmaceuticals, Parion Sciences, and/or Respirics. One of these authors was named coinventor on a patent for dry-powder amiloride, which was subsequently licensed to Parion Sciences, and he also holds multiple other patents on compounds designed to treat lung diseases. Pari Respiratory Equipment supplied nebulizers and compressors used in this study. In an accompanying editorial, Felix Ratjen, MD, PhD, from the Hospital for Sick Children and the University of Toronto in Canada, notes some limitations of the first study. The improvement in lung function was small, with overlapping CIs in the 2 groups; and the maintenance antibiotic therapy for the study population differed from that used in many cystic fibrosis centers. "These studies do not determine whether the improvement in mucociliary transport arises from an increase in the volume of airway surface liquid, from an increase in airway clearance through the induction of cough, or from a combination of the two processes," Dr. Ratjen writes. "Pharmacologic intervention with a direct effect on chloride secretion, on sodium hyperabsorption, or both may ultimately be more effective in restoring the volume of airway surface liquid. In the meantime, hypertonic saline offers a new treatment strategy for patients and brings us closer to targeting the underlying abnormality, rather than the consequences of defective mucociliary clearance." Dr. Ratjen has disclosed no relevant financial relationships. N Engl J Med. 2006;354:229-250, 291-293 Clinical Context According to the authors, short-term administration of hypertonic saline may improve the rheologic properties and transportability of sputum, hydration of the airways and mucociliary clearance and lung function in patients with cystic fibrosis. Since frequency of exacerbations is a strong predictor of morbidity and mortality, the ability of hypertonic saline to enhance clinical outcomes is an important question, and according to the authors, long-term trials of the efficacy and safety of hypertonic saline as a treatment for cystic fibrosis are warranted. The current study is a parallel-group, randomized, controlled trial conducted at 16 adult and pediatric hospitals for more than 48 weeks comparing the use of hypertonic with normal saline in cystic fibrosis patients who were clinically stable.

Study Highlights Inclusion criteria were older than 6 years, clinically stable, FEV1 within 10% of the best value within 6 months, and at least 40% of predicted value. Exclusion criteria were pregnancy, lactation, smoking, colonization with Burkholderia cepacia, and use of hypertonic saline or antibiotics within 14 days. 81 patients were assigned to control treatment consisting of 0.9% saline and 83 to hypertonic saline consisting of 7% saline treatments twice daily for 48 weeks. Treatments were administered via a jet nebulizer and a compressor and preceded by a bronchodilator. Follow-up occurred at weeks 4, 12, 24, 36, and 48 at which clinical assessments, spirometry, and sputum microbiology were performed. Primary outcome was linear rate of change in lung function from baseline. Secondary outcomes were incidence of pulmonary exacerbations, body mass index (BMI), time free of exacerbations, quality of life, and time away from usual activities. Pulmonary exacerbations were defined either as need for intravenous antibiotics and 4 of 12 possible signs or symptoms; or 4 of 12 signs or symptoms regardless of whether antibiotics were used. Quality of life was measured using the Medical Outcomes Study 36-item Short Form General Health Survey (SF-36) and the Cystic Fibrosis Questionnaire for Adults and for Parents. Mean age was 18 years, 43% were female, BMI was 20 kg/m2, FEV1 was 76% of predicted value, and FVC was 88% of predicted value. Compliance rate was 63% for both groups. In the first 4 weeks, FEV1 increased with hypertonic saline but remained unchanged with normal saline. A difference in lung function favoring hypertonic saline persisted at all subsequent times. The linear slope of lung function incorporating FEV1, FVC, and FEF25-75 from week 0 to 48 showed no significant difference between the 2 groups. But the absolute level of lung function was higher in the hypertonic saline than in the control group (P = .03). The FEV1 was an average of 3.2% points higher in the hypertonic saline group, and the FVC was 2.8% points higher. This difference did not depend on baseline FEV1, use of recombinant human DNAase, or physiotherapy. The difference in FVC was significant in adults but not in children younger than age 18 years. The hypertonic group had fewer pulmonary exacerbations (0.39 vs 0.89 per patient; P = .02). The hypertonic group had fewer days of exacerbation (6 vs 17 days) vs the control group (P = .02). The 48-week exacerbation-free survival rate was higher in the hypertonic group (76% vs 62%). The mean number of exacerbations was 2.64 per participant in the control vs 1.32 per participant in the control group (P < .001). The mean number of days on which participants met criteria for symptom-defined exacerbations was 69 for the control and 22 for the hypertonic group (P < .001). The 48-week exacerbation-free survival rate was 41% in the hypertonic and 16% in the control group using the symptom-free definition. The 2 groups did not differ (167 vs 144 days) in the number of antibiotic days for any reason, but the number of antibiotic days for exacerbations was significantly fewer for the hypertonic group (11 vs 50 days). The hypertonic group had significantly fewer days of absenteeism from school or work (7 vs 24 days; P < .001). There were no differences in BMI, weight, and number of hospitalizations between the 2 groups. The mental health domain of the SF-36 was 5.2 points higher in the hypertonic group (P = .02). There were significantly fewer adverse events in the hypertonic group (2.89 vs 5.17 days per 336 days; P < .001).

Pearls for Practice The use of hypertonic vs normal saline for 48 weeks in patients with cystic fibrosis does not improve linear rate of lung function change but improves absolute lung function. Hypertonic vs normal saline is associated with improvement in pulmonary exacerbations and quality of life in patients with cystic fibrosis. Medscape Medical News 2006. © 2006 Medscape

AAP Grand Rounds 18:63-64 (2007) © 2007 American Academy of Pediatrics

Nebulized Hypertonic Saline as a Treatment for Bronchiolitis Source: Kuzik BA, Al Qadhi SA, Kent S, et al. Nebulized hypertonic saline in the treatment of viral bronchiolitis. J Pediatr. 2007;151(3):266 270; doi:10.1016/j.jpeds.2007.04.010[CrossRef][Medline] Researchers from Canada and the United Arab Emirates collaborated in a prospective, randomized, doubleblind, controlled, multicenter investigation to determine whether nebulized 3% hypertonic saline (HS) therapy of infants hospitalized with moderately severe bronchiolitis would result in shorter length of stay (LOS) compared with a control group receiving standard therapy without HS. Infants were eligible for enrollment if they were admitted to the hospital for treatment of moderately severe bronchiolitis, defined as a history of a preceding viral upper respiratory infection, the presence of wheezing or crackles, plus either SaO2