Bacharier LB, Raissy HH, Wilson L, McWilliams B, Strunk RC, Kelly HW. Pediatrics. 2004;113:1693–1699
Purpose of the Study.
To determine the safety of 36 months of inhaled budesonide administration on hypothalamic-pituitary-adrenal (HPA) axis function in children with mild to moderate asthma.
Sixty-three children enrolled in the previously published Childhood Asthma Management Program (CAMP) study with mild to moderate asthma (mean age: 9.5 ± 1.9 years). CAMP participants were between 5 and 12 years of age.
Children received placebo, nedocromil (16 mg/day by metered-dose inhaler), or budesonide (400 μg/day by Turbuhaler). HPA axis function was assessed at baseline and after 12 and 36 months of continuous treatment using serum cortisol levels at 0, 30, and 60 minutes after administration of 0.25 mg of adrenocorticotrophic hormone (ACTH) and 24-hour urinary free-cortisol (UFC) excretion. Data for children treated with placebo and nedocromil were combined and compared with those treated with budesonide.
Serum cortisol measurements were obtained for 54 children at 12 months (5 missed the study visit, and 4 had declines in cortisol after ACTH) and 56 children at 36 months (5 missed the visit, and 2 declined participation). After adjusting for age at randomization, race, gender, clinic, body surface area, and baseline serum cortisol level, there were no differences in serum cortisol levels during ACTH simulation testing between treatment groups. During the study, the serum cortisol levels at successive time points tended to decrease in both treatment groups. Additionally, cortisol levels of children who did and did not receive supplemental ICSs during the study were similar. Oral corticosteroids were prescribed to 6 participants before randomization (3 budesonide and 3 placebo/nedocromil), and additional courses were used during the study for exacerbations. When all groups were combined, oral corticosteroid use 4 months preceding the 12- and 36-month visits did not affect cortisol levels after ACTH stimulation. Subgroup analyses confirmed these findings, adjusting for any supplemental corticosteroid use. Technical problems allowed UFC measurement at only the 36-month visit for 56 patients. Although UFC levels were similar in both treatment groups, ICS use within the 4 months before the 36-month visit was borderline significantly lower (22 vs 34 μg/m2 per 24 hours; P = .05); however, oral prednisone did not show any effect. Finally, there was no difference in serum cortisol or UFC between treatment groups based on cumulative ICS dose.
No effect on HPA axis function was observed after chronic budesonide treatment at 400 μg/day in children with mild to moderate asthma. There was no cumulative effect on HPA axis function over a 3-year period.
Despite the proven efficacy of ICSs, there remains concern regarding the long-term effects of their use with resultant underutilization. Several short-term studies of systemic effects related to low-dose ICSs have demonstrated little effect on HPA axis activity, but studies on long-term use are lacking. This study is the first of long-term studies to help detect or refute potential long-term effects of ICSs in children and thus far dispels fears regarding the use of ICSs for asthma control.