Decreased cortisol response to insulin induced hypoglycaemia in asthmatics treated with inhaled fluticasone propionate

Aims: To assess adrenal function in asthmatic children treated with inhaled fluticasone propionate for up to 16 weeks. Methods: Children with asthma and bronchial hyperresponsiveness to inhaled methacholine were treated with inhaled fluticasone 250–750 µg/day via Volumatic spacer. The insulin tolerance test (ITT) was performed to assess adrenal function. Results: Eighteen asthmatic patients (10 boys, 8 girls), aged 7–17 years received inhaled fluticasone therapy at a median dose of 477 µg/m² per day for 5–16 weeks. Adrenal suppression, defined as 60 minute serum cortisol less than 500 nmol/l, was found in 9 of 18 children. Following the ITT, the median basal and 60 minute serum cortisol concentrations of the suppressed group were 135.0 and 350.0 nmol/l, respectively; the corresponding values for the unsuppressed group were 242.2 and 564.7 nmol/l. Repeat ITT in the suppressed group 2–3 months after discontinuation of fluticasone revealed that all patients had a 60 minute serum cortisol greater than 500 nmol/l. Conclusion: After therapy for asthma with inhaled fluticasone at approximately 500 µg daily for up to 16 weeks, half the children had evidence of adrenal suppression.     

Adrenal function in children with severe asthma treated with high-dose inhaled glucocorticoids: recommended screening tests in outpatient conditions

BACKGROUND: A number of previous studies have suggested that adrenal suppression occurs in asthmatic children treated with high-doses of inhaled glucocorticoids (IGC). This study was designed to determine the frequency of adrenal suppression in children with severe asthma treated with recommended doses of IGC: namely 500-1,000 microg/day of fluticasone propionate or the equivalent of budesonide (1,000-2,000 microg/day) for a period of at least 12 months. METHODS: Early morning cortisol (F) and ACTH serum levels were measured in 27 severe asthmatics aged 6-16 years old. The children underwent a low dose ACTH test (1 microg/1.73 m2) with a parallel glucose measurement. Twenty-four hour urine collection was performed before examination for free F (UfF) and creatinine levels. There were no clinical manifestations of adrenal hypofunction in the analyzed children. RESULTS: Of the 27 patients, 22 had normal basal and post-stimulatory levels of F and normal UfF, and the other five (18.5%) had basal serum F levels of <400 nmol/l. Four of the five also had normal post-stimulatory levels of F and normal UfF. One child had a subnormal peak F value of 484 nmol/l during the ACTH test. None of the patients had a suppressed serum ACTH level, but an elevated ACTH level was found in four children. This study provided biochemical evidence of suboptimal adrenal function in one child in the examined group (3.7%) and a good response to stimulation in all the others, even in those with slightly reduced basal cortisol levels. CONCLUSION: This study showed that the use of fluticasone in doses of up to 1,000 microg/day (or the equivalent of budesonide) as long-term treatment of children with severe asthma did not substantially affect their adrenal function.     

Growth and adrenal suppression in asthmatic children on moderate to high doses of fluticasone propionate

OBJECTIVE: Growth and adrenal suppression have been reported in asthmatic children using high-dose inhaled fluticasone propionate (FP). Inhaled FP, given at moderate doses (250-750 microg/day), has not been documented to be associated with growth or adrenal suppression in asthmatic children until recently. We report three cases illustrating these side effects. METHODS: Growth and adrenal suppression, after the introduction of inhaled FP, were observed in three prepubertal young asthmatic children referred to our asthma clinic and growth clinic. Growth centile and velocity were assessed by longitudinal stadiometry height measurements. Early morning plasma cortisol levels, and glucagon stimulation tests were used to assess the pituitary adrenal axis. RESULTS: Severe growth and adrenal suppression were noted in three children while they were on moderate doses of inhaled FP. Improvements in growth and adrenal function were observed following cessation or dose reduction of inhaled FP. CONCLUSIONS: Unexpected growth and adrenal suppression may occur in young asthmatic children using moderate doses of inhaled FP.     

Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled fluticasone.

BACKGROUND AND AIMS: Clinical adrenal insufficiency has been reported with doses of inhaled fluticasone proprionate (FP) > 400 microg/day, the maximum dose licensed for use in children with asthma. Following two cases of serious adrenal insufficiency (one fatal) attributed to FP, adrenal function was evaluated in children receiving FP outwith the licensed dose. METHODS: Children recorded as prescribed FP > or = 500 microg/day were invited to attend for assessment. Adrenal function was measured using the low dose Synacthen test (500 ng/1.73 m2 intravenously) and was categorised as: biochemically normal (peak cortisol response > 500 nmol/l); impaired (peak cortisol < or = 500 nmol/l); or flat (peak cortisol < or = 500 nmol/l with increment of < 200 nmol/l and basal morning cortisol < 200 nmol/l). RESULTS: A total of 422 children had been receiving FP alone or in combination with salmeterol; 202 were not investigated (137 FP within license; 24 FP discontinued); 220 attended and 217 (age 2.6-19.3 years) were successfully tested. Of 194 receiving FP > or = 500 microg/day, six had flat responses, 82 impaired responses, 104 were normal, and in 2 the LDST was unsuccessful. Apart from the index child, the other five with flat responses were asymptomatic; a further child with impairment (peak cortisol 296 nmol/l) had encephalopathic symptoms with borderline hypoglycaemia during an intercurrent illness. The six with flat responses and the symptomatic child were all receiving FP doses of > or = 1000 microg/day. CONCLUSION: Overall, flat adrenal responses in association with FP occurred in 2.8% of children tested, all receiving > or = 1000 microg/day, while impaired responses were seen in 39.6%. Children on above licence FP doses should have adrenal function monitoring as well as a written plan for emergency steroid replacement.     

Systematic review of the dose-response relation of inhaled fluticasone propionate.

AIMS: To examine the dose-response relation of inhaled fluticasone for both efficacy and adrenal function in children with asthma. METHODS: Systematic review of double blind randomised dose-response studies of fluticasone in children of at least 4 weeks duration. MAIN OUTCOME MEASURES: FEV1, morning peak expiratory flow, night awakenings, beta agonist use, major exacerbations, 12 or 24 hour urinary cortisol, peak plasma cortisol post-stimulation. RESULTS: Seven studies of 1733 children with asthma met the inclusion criteria for efficacy. The dose-response curve for each efficacy outcome measure suggested that the response began to plateau between 100 and 200 microg per day with additional efficacy at the 400 microg per day dose shown in one study of severe asthmatics. Five studies of 1096 children with asthma met the inclusion criteria for assessment of adrenal function. The largest placebo controlled study of 437 children reported no difference in 24 hour urinary cortisol between placebo and fluticasone at doses of 100 and 200 microg per day. The non-placebo controlled study of 528 children reported significant suppression of overnight urinary cortisol levels with fluticasone at 400 compared with 200 microg per day. CONCLUSIONS: There is insufficient data to determine the dose-response of fluticasone in children at doses >400 microg per day. The dose-response curve for fluticasone appears to plateau between 100 and 200 microg per day for efficacy. There was additional efficacy at the 400 microg per day dose in children with severe asthma; however there was evidence of adrenal suppression at this dose.     

Fluticasone propionate in asthma: a long term dose comparison study.

BACKGROUND: Few dose ranging studies have investigated optimal dosing with inhaled corticosteroids in children with asthma. AIMS: To compare the efficacy and tolerability of fluticasone propionate 100 or 200 microg twice daily in children with moderate to severe asthma for one year. METHODS: One year, randomised, double blind, parallel group, multicentre study. Children aged 4-11 years (n = 528) with moderate to severe asthma who had previously received high dose inhaled corticosteroids were given fluticasone propionate 100 or 200 microg twice daily for the 52 week treatment period. Efficacy (exacerbations, lung function, and symptoms) and tolerability (adverse events and cortisol levels) were measured. RESULTS: There was a non-significant decreased risk of experiencing an exacerbation at any time with fluticasone propionate 200 microg twice daily compared with fluticasone propionate 100 microg twice daily. This difference reached significance among patients with more severe asthma (defined by previous inhaled corticosteroid dose >800 microg/day). Daily record card morning peak expiratory flow (PEF) in the total population improved significantly more with the higher dose of fluticasone propionate (between group difference, weeks 1-52: 11.4 l/min). Clinic visit mean PEF improved from baseline with both doses, but the response was significantly greater with the higher dose (between group difference, week 52: 17.8 l/min). Both doses were equally well tolerated and overnight urinary cortisol concentrations were unchanged or slightly increased during treatment with either dose. CONCLUSION: This long term dose comparison study shows that treatment with fluticasone propionate 200 micro g twice daily may offer benefits over a lower dose, particularly in children with more severe asthma.     

Monitoring growth in asthmatic children treated with high dose inhaled glucocorticoids does not predict adrenal suppression.

AIMS: To determine whether routine outpatient monitoring of growth predicts adrenal suppression in prepubertal children treated with high dose inhaled glucocorticoid. METHODS: Observational study of 35 prepubertal children (aged 4-10 years) treated with at least 1000 microg/day of inhaled budesonide or equivalent potency glucocorticoid for at least six months. Main outcome measures were: changes in HtSDS over 6 and 12 month periods preceding adrenal function testing, and increment and peak cortisol after stimulation by low dose tetracosactrin test. Adrenal suppression was defined as a peak cortisol < or =500 nmol/l. RESULTS: The areas under the receiver operator characteristic curves for a decrease in HtSDS as a predictor of adrenal insufficiency 6 and 12 months prior to adrenal testing were 0.50 (SE 0.10) and 0.59 (SE 0.10). Prediction values of an HtSDS change of -0.5 for adrenal insufficiency at 12 months prior to testing were: sensitivity 13%, specificity 95%, and positive likelihood ratio of 2.4. Peak cortisol reached correlated poorly with change in HtSDS (rho = 0.23, p = 0.19 at 6 months; rho = 0.33, p = 0.06 at 12 months). CONCLUSIONS: Monitoring growth does not enable prediction of which children treated with high dose inhaled glucocorticoids are at risk of potentially serious adrenal suppression. Both growth and adrenal function should be monitored in patients on high dose inhaled glucocorticoids. Further research is required to determine the optimal frequency of monitoring adrenal function.     

Systematic review of the dose-response relation of inhaled fluticasone propionate

Aims: To examine the dose-response relation of inhaled fluticasone for both efficacy and adrenal function in children with asthma. Methods: Systematic review of double blind randomised dose-response studies of fluticasone in children of at least 4 weeks duration. Main outcome measures: FEV₁, morning peak expiratory flow, night awakenings, ß agonist use, major exacerbations, 12 or 24 hour urinary cortisol, peak plasma cortisol post-stimulation. Results: Seven studies of 1733 children with asthma met the inclusion criteria for efficacy. The dose-response curve for each efficacy outcome measure suggested that the response began to plateau between 100 and 200 µg per day with additional efficacy at the 400 µg per day dose shown in one study of severe asthmatics. Five studies of 1096 children with asthma met the inclusion criteria for assessment of adrenal function. The largest placebo controlled study of 437 children reported no difference in 24 hour urinary cortisol between placebo and fluticasone at doses of 100 and 200 µg per day. The non-placebo controlled study of 528 children reported significant suppression of overnight urinary cortisol levels with fluticasone at 400 compared with 200 µg per day. Conclusions: There is insufficient data to determine the dose-response of fluticasone in children at doses >400 µg per day. The dose-response curve for fluticasone appears to plateau between 100 and 200 µg per day for efficacy. There was additional efficacy at the 400 µg per day dose in children with severe asthma; however there was evidence of adrenal suppression at this dose.     

Systemic effects of a short course of betamethasone compared with high-dose inhaled budesonide in early childhood asthma

Forty children aged 1-3 y completed a placebo-controlled study on the effects of 10 d of inhaled budesonide for asthma caused by respiratory tract infection. The effects on symptoms were significantly better in the active than in the placebo group. In 20 of these children the systemic effects of high-dose inhaled budesonide for 10 d and the effect of a 3-d course of oral betamethasone on asthma exacerbation were evaluated. Systemic effects were evaluated by measuring morning cortisol in serum and urine, and the bone markers osteocalcin, ICTP (the C-terminal telopeptide region of type I collagen) and PIIINP (an N-terminal propeptide of type III procollagen) in serum before and at the end (d 7-10) of treatment (1600 microg budesonide d(-1) for 3 d and 800 microg for 7 d). In 9 children, measurements were taken on d 3 of a 3-d course of betamethasone (6, 4 and 2 mg) for asthma exacerbation and 14 d later. There were no signs of systemic effects after 7-10 d of budesonide. After 3 d of betamethasone, serum cortisol decreased from a median of 263 to 26 nmol l(-1), urine cortisol/creatinine from 19.9 to 7.2 nmol l(-1), osteocalcin from 31.4 to 5.5 microg l(-1), ICTP from 19.4 to 8.5 microg l(-1) and PIIINP from 12.3 to 5.9 microg l(-1). Two weeks later, the levels were back to normal. In conclusion, short courses of oral betamethasone have pronounced systemic effects, whereas 10 d of high doses of budesonide do not produce significant systemic effects.     

Adrenal function and high dose inhaled corticosteroids for asthma

OBJECTIVE: To investigate effects on adrenal function of fluticasone, a recently released inhaled steroid preparation with lower systemic bioavailability than beclomethasone dipropionate. METHODS: 34 children on high doses (400-909 micrograms/m2/d) of inhaled beclomethasone dipropionate or budesonide were recruited into a double blind, crossover study investigating the effects on adrenal function of beclomethasone and fluticasone propionate, given using a standard spacer (Volumatic). The 24 hour excretion rates of total cortisol and cortisol metabolites were determined at baseline (after a two week run in), after six weeks treatment with an equal dose of beclomethasone, and after six weeks of treatment with half the dose of fluticasone, both given through a spacer device. RESULTS: The comparison of effects between fluticasone and beclomethasone during treatment periods, although favouring fluticasone in all measured variables, reached significance only after correction for urinary creatinine excretion (tetrahydrocortisol and 5 alpha-tetrahydrocortisol geometric means: 424 v 341 micrograms/m2/d). The baseline data showed adrenal suppression in the children taking beclomethasone (total cortisol geometric means: 975 v 1542 micrograms/d) and a dose related suppression in the children taking budesonide. Suppressed adrenal function in the children who were taking beclomethasone at baseline subsequently improved with fluticasone and beclomethasone during treatment periods. CONCLUSIONS: Fluticasone is less likely to suppress adrenal function than beclomethasone at therapeutically equivalent doses. The baseline data also support the claim that spacer devices should be used for the administration of high doses of inhaled topical steroids.     

Effects of 2 inhaled corticosteroids on growth: results of a randomized controlled trial.

OBJECTIVE: To compare the long-term effect of treatment with fluticasone propionate or beclomethasone dipropionate on growth in asthmatic children. DESIGN: Prospective, multicenter, randomized, double-blind, parallel-group study. SETTING: Children requiring regular treatment with inhaled corticosteroids and with a sexual maturity rating of Tanner stage 1 (prepubertal). PATIENTS: Three hundred forty-three children aged 4 to 11 years with asthma. The growth population (excluding patients with protocol violations likely to affect growth measurements) included 277 patients. INTERVENTIONS: Fluticasone propionate or beclomethasone dipropionate, both at a dosage of 200 microg administered twice daily via a dry powder inhaler (Diskhaler) for 12 months. MAIN OUTCOME MEASURES: Growth velocity, lung function, and serum and urinary cortisol levels. RESULTS: The adjusted mean growth velocity in the fluticasone group was significantly greater than that in the beclomethasone group (5.01 [SE, 0.14] vs 4.10 [SE, 0.15] cm/y; difference, 0.91 cm; 95% confidence interval, 0.63-1.20 cm; P<.001). Both treatments improved lung function, with significant differences in favor of fluticasone. Adverse events were similar in both groups, and there were no significant differences in effect on serum and urinary cortisol levels. CONCLUSIONS: The more favorable risk-benefit ratio of fluticasone indicates that this agent is preferable to beclomethasone for the long-term treatment of children with asthma, especially if moderate doses are required.     

The relation between adrenal function and the severity of bronchial hyperresponsiveness in children as measured by the methacholine provocation test

BACKGROUND: There is no satisfactory explanation why some individuals experience severe attacks of asthma, yet others, exposed to similar stimuli, have a milder form of the disease. OBJECTIVE: We tested the hypothesis that children with more severe disease may have relative adrenal insufficiency compared to the children with milder disease. PATIENTS AND METHODS: Sixteen children with chronic asthma aged 8-16 years old were studied. Adrenal function was evaluated by the 24-h excretion of urinary free cortisol (UFC) before and after ACTH stimulation, and by plasma cortisol levels before and 60 min after ACTH administration. The severity of bronchial hyperresponsiveness was evaluated by the methacholine provocation test. RESULTS: Nine children had 20% fall in forced expiratory volume in 1 sec (FEV1) after a provocative concentration (PC20FEV1) of methacholine > or =2.5 mg/ml and were considered as having mild-moderate bronchial hyperresponsiveness (Group A). Seven children had a PC20FEV1 of < or =1.25 mg/ml and were considered as having severe bronchial hyperresponsiveness (Group B). No significant difference was found between the peak plasma cortisol response to ACTH between the two groups (634+/-182 and 586+/-137 nmol/l, respectively). However, there was a significant statistical difference (p <0.01) in the 24-h UFC response to ACTH between the children from Group A (345+/-107 nmol/m2 ) and the children from Group B (161+/-125 nmol/m2). CONCLUSIONS: Based on the low levels of 24-h UFC secretion in severely asthmatic children in our study, we propose the encouragement of provision of a short course of inhaled steroids to be kept at home for the emergency therapy of those children identified as having high-risk asthma.     

Evaluation of hypothalamic-pituitary-adrenal axis suppression by low-dose (0.5 microg) and standard-dose (250 microg) adrenocorticotropic hormone (ACTH) tests in asthmatic children treated with inhaled corticosteroid

The aim of this study was to compare the results of low-dose (LDT) and standard-dose (SDT) ACTH tests in the assessment of adrenal function in 30 asthmatic children (mean age 9.35 +/- 1.9 years, 19 boys) who were treated with budesonide Turbohaler at conventional 400 microg or 600 microg daily doses for 8 weeks by a prospective, randomized, and open parallel study. Budesonide did not lead to any significant suppression of the hypothalamic-pituitary-adrenal (HPA) axis in either treatment group. However, when individual patient values were examined at the end point, peak cortisol concentrations after LDT were below 2 SDs of the pretreatment values in four patients (13.3%). Also, the increment in cortisol values was <200 nmol/l in all four patients. Decreased 24-hour urinary free cortisol excretion provided further evidence for HPA axis suppression in these patients. Two of these four poor responders to LDT showed normal stimulation with SDT. In conclusion, even with moderate doses and short-term use, adrenal suppression may occur in certain susceptible patients. The low-dose ACTH test is more reliable than SDT for the evaluation of such patients.     

Comparison of the efficacy and safety of inhaled fluticasone propionate 200 micrograms/day with inhaled beclomethasone dipropionate 400 micrograms/day in mild and moderate asthma.

This study was designed to compare the efficacy and safety of a new inhaled corticosteroid, fluticasone propionate at a total daily dose of 200 micrograms, with beclomethasone dipropionate 400 micrograms/day in childhood asthma. A total of 398 asthmatic children (aged 4-19 years) were randomised to receive either fluticasone propionate 200 micrograms daily or beclomethasone dipropionate 400 micrograms daily for six weeks inhaled via a spacer device from a metered dose inhaler. During the study the patients recorded morning and evening peak expiratory flow rate (PEFR), symptom scores, and use of beta 2 agonist rescue medication. In addition, clinic visit PEFR and forced expiratory volume in one second were measured. Safety was assessed by recording all adverse events and by performing routine biochemistry and haematology screens including plasma cortisol concentration before and after treatment. For the purposes of analysis the diary card data were grouped into three periods: week 3 (days 15-21), week 6 (days 36-42), and weeks 1-6 (days 1-42). The results showed no significant difference between treatments on most efficacy parameters. However, there were significant differences in changes from baseline in favour of fluticasone propionate for % predicted morning PEFR both at week 3 (fluticasone propionate 6.1%, beclomethasone dipropionate 3.9%) and at week 6 (fluticasone propionate 8.3%, beclomethasone dipropionate 5. 9%) and % predicted evening PEFR at week 6 (fluticasone propionate 7.3%, beclomethasone dipropionate 4.9% and over weeks 1-6 (fluticasone propionate 5.5%, beclomethasone dipropionate 3.6%. Comparison between groups showed that the group receiving fluticasone propionate had a lower % of days with symptom-free exercise at week 6 (fluticasone propionate 87%, beclomethasone dipropionate 81%) and % days without rescue medication at week 6 (fluticasone propionate 87%, beclomethasone dipropionate 80%) and over weeks 1-6 (fluticasone propionate 80%, beclomethasone dipropionate 73%). Except for a higher incidence of sore throat in the fluticasone propionate group, the two treatments did not differ with regard to safety. There was no evidence of adrenal suppression with either treatment. In conclusion, fluticasone propionate 200 microgram daily ws at least as effective and as well tolerated as beclomethasone dipropionate 400 microgram daily in childhood asthma.     

Comparison of the efficacy and safety of inhaled fluticasone propionate 200 micrograms/day with inhaled beclomethasone dipropionate 400 micrograms/day in mild and moderate asthma

This study was designed to compare the efficacy and safety of a new inhaled corticosteroid, fluticasone propionate at a total daily dose of 200 micrograms, with beclomethasone dipropionate 400 micrograms/day in childhood asthma. A total of 398 asthmatic children (aged 4-19 years) were randomised to receive either fluticasone propionate 200 micrograms daily or beclomethasone dipropionate 400 micrograms daily for six weeks inhaled via a spacer device from a metered dose inhaler. During the study the patients recorded morning and evening peak expiratory flow rate (PEFR), symptom scores, and use of beta 2 agonist rescue medication. In addition, clinic visit PEFR and forced expiratory volume in one second were measured. Safety was assessed by recording all adverse events and by performing routine biochemistry and haematology screens including plasma cortisol concentration before and after treatment. For the purposes of analysis the diary card data were grouped into three periods: week 3 (days 15-21), week 6 (days 36-42), and weeks 1-6 (days 1-42). The results showed no significant difference between treatments on most efficacy parameters. However, there were significant differences in changes from baseline in favour of fluticasone propionate for % predicted morning PEFR both at week 3 (fluticasone propionate 6.1%, beclomethasone dipropionate 3.9%) and at week 6 (fluticasone propionate 8.3%, beclomethasone dipropionate 5. 9%) and % predicted evening PEFR at week 6 (fluticasone propionate 7.3%, beclomethasone dipropionate 4.9% and over weeks 1-6 (fluticasone propionate 5.5%, beclomethasone dipropionate 3.6%. Comparison between groups showed that the group receiving fluticasone propionate had a lower % of days with symptom-free exercise at week 6 (fluticasone propionate 87%, beclomethasone dipropionate 81%) and % days without rescue medication at week 6 (fluticasone propionate 87%, beclomethasone dipropionate 80%) and over weeks 1-6 (fluticasone propionate 80%, beclomethasone dipropionate 73%). Except for a higher incidence of sore throat in the fluticasone propionate group, the two treatments did not differ with regard to safety. There was no evidence of adrenal suppression with either treatment. In conclusion, fluticasone propionate 200 microgram daily ws at least as effective and as well tolerated as beclomethasone dipropionate 400 microgram daily in childhood asthma.     

Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled fluticasone

Background and Aims

Clinical adrenal insufficiency has been reported with doses of inhaled fluticasone proprionate (FP) >400 μg/day, the maximum dose licensed for use in children with asthma. Following two cases of serious adrenal insufficiency (one fatal) attributed to FP, adrenal function was evaluated in children receiving FP outwith the licensed dose.

Methods

Children recorded as prescribed FP ⩾500 μg/day were invited to attend for assessment. Adrenal function was measured using the low dose Synacthen test (500 ng/1.73 m² intravenously) and was categorised as: biochemically normal (peak cortisol response >500 nmol/l); impaired (peak cortisol ⩽500 nmol/l); or flat (peak cortisol ⩽500 nmol/l with increment of <200 nmol/l and basal morning cortisol <200 nmol/l).

Results

A total of 422 children had been receiving FP alone or in combination with salmeterol; 202 were not investigated (137 FP within license; 24 FP discontinued); 220 attended and 217 (age 2.6–19.3 years) were successfully tested. Of 194 receiving FP ⩾500 μg/day, six had flat responses, 82 impaired responses, 104 were normal, and in 2 the LDST was unsuccessful. Apart from the index child, the other five with flat responses were asymptomatic; a further child with impairment (peak cortisol 296 nmol/l) had encephalopathic symptoms with borderline hypoglycaemia during an intercurrent illness. The six with flat responses and the symptomatic child were all receiving FP doses of ⩾ 1000 μg/day.

Conclusion

Overall, flat adrenal responses in association with FP occurred in 2.8% of children tested, all receiving ⩾1000 μg/day, while impaired responses were seen in 39.6%. Children on above licence FP doses should have adrenal function monitoring as well as a written plan for emergency steroid replacement.     

Fluticasone propionate in asthma: a long term dose comparison study

Background: Few dose ranging studies have investigated optimal dosing with inhaled corticosteroids in children with asthma. Aims: To compare the efficacy and tolerability of fluticasone propionate 100 or 200 µg twice daily in children with moderate to severe asthma for one year. Methods: One year, randomised, double blind, parallel group, multicentre study. Children aged 4–11 years (n = 528) with moderate to severe asthma who had previously received high dose inhaled corticosteroids were given fluticasone propionate 100 or 200 µg twice daily for the 52 week treatment period. Efficacy (exacerbations, lung function, and symptoms) and tolerability (adverse events and cortisol levels) were measured. Results: There was a non-significant decreased risk of experiencing an exacerbation at any time with fluticasone propionate 200 µg twice daily compared with fluticasone propionate 100 µg twice daily. This difference reached significance among patients with more severe asthma (defined by previous inhaled corticosteroid dose >800 µg/day). Daily record card morning peak expiratory flow (PEF) in the total population improved significantly more with the higher dose of fluticasone propionate (between group difference, weeks 1–52: 11.4 l/min). Clinic visit mean PEF improved from baseline with both doses, but the response was significantly greater with the higher dose (between group difference, week 52: 17.8 l/min). Both doses were equally well tolerated and overnight urinary cortisol concentrations were unchanged or slightly increased during treatment with either dose. Conclusion: This long term dose comparison study shows that treatment with fluticasone propionate 200 µg twice daily may offer benefits over a lower dose, particularly in children with more severe asthma.     

Monitoring growth in asthmatic children treated with high dose inhaled glucocorticoids does not predict adrenal suppression

Aims: To determine whether routine outpatient monitoring of growth predicts adrenal suppression in prepubertal children treated with high dose inhaled glucocorticoid. Methods: Observational study of 35 prepubertal children (aged 4–10 years) treated with at least 1000 µg/day of inhaled budesonide or equivalent potency glucocorticoid for at least six months. Main outcome measures were: changes in HtSDS over 6 and 12 month periods preceding adrenal function testing, and increment and peak cortisol after stimulation by low dose tetracosactrin test. Adrenal suppression was defined as a peak cortisol ⩽500 nmol/l. Results: The areas under the receiver operator characteristic curves for a decrease in HtSDS as a predictor of adrenal insufficiency 6 and 12 months prior to adrenal testing were 0.50 (SE 0.10) and 0.59 (SE 0.10). Prediction values of an HtSDS change of –0.5 for adrenal insufficiency at 12 months prior to testing were: sensitivity 13%, specificity 95%, and positive likelihood ratio of 2.4. Peak cortisol reached correlated poorly with change in HtSDS (ρ = 0.23, p = 0.19 at 6 months; ρ = 0.33, p = 0.06 at 12 months). Conclusions: Monitoring growth does not enable prediction of which children treated with high dose inhaled glucocorticoids are at risk of potentially serious adrenal suppression. Both growth and adrenal function should be monitored in patients on high dose inhaled glucocorticoids. Further research is required to determine the optimal frequency of monitoring adrenal function.     

Effects of nebulized corticosteroids therapy on hypothalamic–pituitary–adrenal axis in young children with recurrent or persistent wheeze

Inhaled corticosteroids (ICS) are preferred drugs for the long-term treatment of all severities of asthma in children. However, data about the safety of ICS in infants is lacking. So, it is essential to do further clinical studies to examine the safety and efficacy of ICS in this population. In this study, the effects of nebulized budesonide and nebulized fluticasone propionate suspensions on hypothalamic–pituitary–adrenal axis is examined in infants with recurrent or persistent wheeze. Thirty-one children aged 6–24 months admitted to our hospital between January and December 2005 with symptoms of recurrent or persistent wheeze were included in the study. The patients were randomly allocated to receive 0.25 mg BUD or 0.25 mg fluticasone propionate twice daily for 6 wk and half dose for another 6 wk with a jet nebulizer at home. Blood samples for basal cortisol concentration, adrenocarticotropic hormone, glucose, HbA1c and electrolytes were obtained at the beginning and at the end of the study. Adrenal function assessment was based on changes in cosyntropin-stimulated plasma cortisol levels. The study was completed with 31 patients, 16 of whom received BUD and 15 FP. All patients except one had plasma cortisol concentrations above 500 nmol/l (18 μg/dl) or had an incremental rise in cortisol of >200 nmol/l after stimulation. Although nebulized steroids seem to be safe in infancy, we recommend that adrenal functions should be tested periodically during long-term treatment with nebulized steroids.     

A placebo controlled trial of fluticasone propionate in asthmatic children

Fluticasone propionate is a synthetic steroid for use by the inhaled route. It's high topical potency and low systemic bioavailability make it suitable for use in asthmatic children. A total of 258 children were randomised in a double-blind study to receive fluticasone propionate (50 g bd) as the dry powder formulation inhaled via a Diskhaler inhaler, or matched placebo (with current therapy) for 4 weeks throughout which time diary cards were completed. During clinic visits lung function and adrenal function were measured. Fluticasone propionate produced a significantly greater increase in morning peak expiratory flow rate (PEFR) (adjusted mean difference over days 1–28, 17 l/min (95% CI; 10, 24);P<0.001) and evening PEFR (adjusted mean difference over days 1–28, 16 l/min (95% CI; 9, 23);P<0.001). In addition, diary card symptom scores, beta₂-agonist rescue and clinic lung function improved significantly on fluticasone propionate. There were few adverse events and basal plasma cortisol remained within the normal range. In conclusion fluticasone propionate at 50 g bd is superior to placebo (current therapy) in the treatment of childhood asthma with no evidence of adverse effects.