In this pilot study, inhaled 7% HS was well tolerated for up to two weeks in infants and toddlers with CF, with high treatment adherence. This study expands on the results of two prior single-dose safety studies of 7% HS in infants and preschool children with CF 17,18
, as it is the first to assess acute tolerability in unsedated infants and to evaluate the safety of and adherence to repeated doses of HS in young children with CF. HS tolerability rates from our study as well as those of Subbarao, et al and Dellon, et al compare favorably with those reported in CF patients over 6 years of age. Of 19 participants evaluated for test dose intolerance, one was intolerant. Of 18 participants evaluated for intolerance at the final study visit one was intolerant. Based on home diaries, increased cough in the hour after study drug was observed in 39% of participants on Day 1, falling to 8% on Day 13. Runny nose or sneezing was reported in a median of 15% of participants across all study days, perhaps reflecting study recruitment from October through April. All other symptoms reported by parents were rare. Adherence, as reported by diaries and returned study drug ampoules, was also high, though this may not represent “real world” adherence rates due to the short duration of the study, close observation of the participants, and the selection bias of highly motivated families participating in research.
The safety of inhaled HS has also been evaluated in single and multiple-dose studies in young children without CF. Zar and colleagues administered a single dose of 5% HS to more than 600 children 1 month to 5 years of age with possible tuberculosis, HIV or suspected HIV, or intensive care unit admission due to pneumonia 22-24
. The most commonly reported side effects were wheezing that responded to bronchodilator therapy (< 2%) and cough (2% to 41%). Five studies have evaluated repeated daily doses of 3% HS as acute treatment for viral bronchiolitis in hospitalized or ambulatory non-CF infants 25-29
. In all five studies, a significant improvement in clinical symptoms was observed in patients treated with HS compared to patients receiving isotonic saline. No significant adverse events were ascribed to HS. Recently, high volume isotonic saline was found to be as effective as 3% saline in the treatment of mild bronchiolitis in infants evaluated in the emergency department. 28
. No adverse effects were ascribed to nebulized therapy among the 186 participants. Therefore, HS appears to be safe even in acutely ill infants with airway obstruction.
We chose to evaluate a concentration of 7% HS based on the results of a single-dose study of mucociliary clearance and tolerability of inhaled saline in concentrations ranging from 0.9% to 12% among 10 adults with CF 11
. Adverse event rates were not concentration-dependent in patients receiving 3% to 7% HS. However, 12% HS caused throat irritation in a higher percentage of patients compared to 3% or 7%, but did not further improve mucociliary clearance. Based on these findings, all subsequent studies of chronic administration of HS in CF patients have used a saline concentration of either 6% or 7% 12-16
The dose of sodium chloride absorbed by inhalation of 7% HS should not place infants at risk of hypernatremia. Seven percent HS provides 1.2 mEq NaCl per mL of solution. After 15 minutes of nebulization of a 4 mL ampoule of HS in infants, about 2 mL of the original 4 mL has been nebulized 18
. If we assume that the entire nebulized dose is systemically absorbed by the infant, then, with twice daily dosing, an infant would absorb 4.8 mEq of NaCl daily. CF infants are prescribed one-eighth teaspoon of table salt daily (as a supplement to avoid hyponatremic dehydration), which provides 12.5 mEq NaCl daily. In addition, the recommended daily allowance for sodium for healthy infants (not accounting for losses from the skin through sweating, which are increased in CF), range from 5.2 mEq per day for a 5 kg 6 month old to 13 mEq per day for a 16 kg toddler 30
. Thus, the additional sodium intake associated with inhalation of HS twice daily is small compared to both the recommended daily allowance of sodium and routinely prescribed table salt supplements, and should not pose a risk of hypernatremia.
The limitations of the current study must be highlighted. First, the sample size was small, limiting the precision with which we could estimate the rate of HS intolerance. Furthermore, 7 of the 20 participants received the test dose under sedation, which may alter the delivery and tolerability of inhaled drugs. On the other hand, sedation, required for infant lung function testing, did allow evaluation of physiologic response to acute inhalation of HS as measured by forced expiratory flows. In addition, the duration of exposure was relatively short (14 days), so that the safety of longer term exposure in this population remains unknown. Lastly, this study does not address the efficacy of inhaled HS in this population. Thus, it would be premature to introduce inhaled HS into clinical practice in children with CF <6 years of age based on the results of this pilot study.
In conclusion, results from this pilot study indicate that 7% HS is well tolerated and safe in infants and preschoolers with CF. Adherence is also high when 7% HS is administered twice a day for 14 days. We are currently conducting a randomized, double blind, controlled trial of the safety and efficacy of 7% vs. 0.9% HS inhaled twice daily for a year in children with CF <6 years of age. The results of this study will provide information regarding the efficacy and longer-term adherence and safety of HS in the youngest CF patients.