Sunday, May 27, 2012

Hypertonic Not Better Than Isotonic Saline in Young Cystic Fibrosis Patients

SAN FRANCISCO – Inhaled hypertonic saline did not reduce the number of pulmonary exacerbations in infants and children with cystic fibrosis in a randomized trial.
The trial pitted 7% hypertonic saline in 158 pediatric patients against 0.9% isotonic saline as a control in 163 patients. The solutions were nebulized twice daily for 48 weeks, with both groups getting albuterol or levalbuterol beforehand. The patients ranged in age from 4 to 60 months. Adherence was at least 75% in each group, judging from returned study drug ampoules, reported lead investigator Dr. Margaret Rosenfeld at an international conference of the American Thoracic Society.
In the hypertonic saline group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% confidence interval [CI], 2.0-2.5), and the mean number of total antibiotic treatment days for pulmonary exacerbations was 60 (95% CI, 49-70). In the control group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% CI, 2.1-2.6), and the mean total number of antibiotic treatment days was 52 (95% CI, 43-61).
No significant differences were seen in secondary end points, including height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores. Adverse event profiles were similar, with cough the most common adverse event in about 40% of each group (JAMA 2012 May 20 [doi:10.1001/jama.2012.5214]).
"There is great interest in the CF [cystic fibrosis] community about developing early intervention strategies to delay or prevent CF lung disease before the bronchiectasis becomes irreversible. From our current evidence, hypertonic saline does not fulfill that role. Based on its inability to reduce the rate of pulmonary exacerbations, we would not recommend that it be used in this age range," said Dr. Rosenfeld, a pediatric pulmonologist and associate professor of pediatrics at the University of Washington in Seattle.
The finding was a surprise because hypertonic saline is known to prevent exacerbations in older children and adults, perhaps by helping the lungs cough out bacteria. There has been hope it would also help very young children, and its use in that population has increased substantially in recent years, Dr. Rosenfeld noted (N. Engl. J. Med. 2006;354:229-40).
"We’ve been scratching our heads about" why that hope didn’t pan out in the trial. "We have a number of hypotheses. The first one is that pulmonary exacerbations may be really different beasts in infants and young children. [Perhaps] they are mostly triggered by viral respiratory infections. Hypertonic saline can’t prevent people from getting respiratory viruses," she said at the conference.
Exacerbations might have been too blunt a primary outcome measure, according to an editorial that accompanied the published study in JAMA.
Very young children with CF have not yet developed the outright lung damage that makes older patients particularly susceptible to exacerbations. Perhaps more subtle markers of early disease onset and progression were needed in the trial, wrote Dr. Elliott Dasenbrook, associate director of the Adult Cystic Fibrosis Program at Case Western Reserve University, Cleveland, and Dr. Michael Konstan, director of the school’s Cystic Fibrosis Center and chairman of its pediatrics department.
"Although the results of the study suggest that inhaled hypertonic saline should not be used routinely in young children, the final verdict on its use for infants and young children has not been rendered. It would be disheartening if a viable therapeutic option was discarded because of negative study results when more sensitive end points might have detected benefit from the intervention. Testing therapeutic agents in infants and young children may require different end points capable of assessing onset and progression of disease," they wrote (JAMA 2012 May 20 [doi: 10.1001/jama.2012.5853]).
There was one "tantalizing" hint in the trial that hypertonic saline may delay structural damage, Dr. Rosenfeld said. Among the 22 children aged 4-16 months in the hypertonic saline group who had pulmonary function tests, forced expiratory volume in 0.5 seconds (FEV0.5) was a mean of 38 mL greater (95% CI, 1-76) than among the 23 children tested in the control group, the only significant pulmonary function difference.
Perhaps that could be a marker in future trials, but "statistically significant difference does not necessarily imply clinical significance," Dr. Dasenbrook and Dr. Konstan noted. "Even though the results of infant pulmonary function testing appear encouraging, ... these exploratory end points should be viewed as hypothesis generating, and research exploring the clinical effects of these differences is needed."
That research is likely to happen. "We would like to study [hypertonic saline] further and see if we get a signal if we choose more physiologic end points," Dr. Rosenfeld said.
Dr. Rosenfeld disclosed that she is an adviser to Genentech and Vertex Pharmaceuticals, and receives research grants from Vertex. Dr. Dasenbrook is a consultant for Savara and Gilead. Dr. Konstan is an adviser to Aradigm and a consultant for Boehringer Ingelheim, Genentech, Novartis, PARI Respiratory Equipment, Vertex, and several other companies. He receives grants or has grants pending from several companies, and receives speaker’s fees from Genentech and Novartis.