Efficacy and safety of ciclesonide once daily and fluticasone propionate twice daily in children with asthma

BackgroundCiclesonide is a new inhaled corticosteroid (ICS). Information about its clinical efficacy and safety in relation to other ICS in children is needed for clinical positioning.ObjectiveThis 12-week, randomized, double-blind, double-dummy, three-arm, parallel-group study compared the efficacy and safety of ciclesonide with fluticasone propionate in children with mainly moderate and severe persistent asthma.MethodsSeven hundred and forty-four patients (aged 6–11 years) were randomized to ciclesonide (80 or 160 μg once daily) or fluticasone propionate (88 μg twice daily), following a 2–4-week run-in. Efficacy measurements included forced expiratory flow in 1 s (FEV₁), morning peak expiratory flow (PEF), asthma symptom scores, rescue medication use and quality of life. Systemic effect was assessed by 24-hour urine free cortisol adjusted for creatinine.ResultsFEV₁ and morning PEF increased from baseline in all groups (p < 0.0001). Ciclesonide 160 μg was not inferior to fluticasone propionate 176 μg for FEV₁ (p = 0.0030, one-sided). In all groups, asthma symptom score sums and rescue medication use significantly improved (p < 0.0001). The percentages of asthma symptom-, rescue medication- and nocturnal awakening-free days were high, with no significant differences between treatments. Quality of life scores improved with all treatments (p < 0.0001). A significant dose–response occurred between low and higher doses of ciclesonide for exacerbations and asthma control definitions. The incidences of adverse events were comparable across treatments. Urine free cortisol levels decreased significantly with fluticasone propionate (p = 0.0103), but not with ciclesonide.ConclusionOnce-daily ciclesonide has a clinical effect similar to that of fluticasone propionate, but does not suppress cortisol excretion, in children with moderate and severe asthma.     

Adrenal suppression, evaluated by a low dose adrenocorticotropin test, and growth in asthmatic children treated with inhaled steroids

The aim of the present study was to evaluate the prevalence of adrenal suppression and growth retardation in children using moderate doses of budesonide or fluticasone propionate. Seventy-five asthmatic children were randomly divided into three treatment groups: 30 to the fluticasone propionate (FP), 30 to the budesonide (BUD), and 15 to the cromone (CROM) group. FP doses were 500 microg/day during the first 2 months and 200 microg/day thereafter. The respective BUD doses were 800 and 400 microg/day. A low dose ACTH (0.5 microg/1.73 m2) test was performed before treatment and 2, 4, and 6 months later. The test was considered abnormal if the stimulated serum cortisol concentration was more than 2 SD lower than the pretreatment mean (<330 nmol/L). The low dose ACTH test was abnormal after both the high and low steroid doses in 23% of the children. At the 4 month measurement there were more abnormal tests in the BUD (n = 9) than in the FP (n = 5) group (P < 0.05). At that time also the stimulated concentration of serum cortisol was lower in the BUD than in the CROM group (P < 0.01), whereas the difference between the FP and CROM groups was not significant. During the study year the mean decrease in height SD score was 0.23 in the children treated with BUD, 0.03 in the children treated with FP, and 0.09 in the children treated with CROM; the difference between the BUD and FP groups was significant (P < 0.05). In conclusion, the low dose ACTH test revealed mild adrenal suppression in a quarter of the children using moderate doses of inhaled steroids. A FP dose of 200 microg/day caused less adrenal and growth suppression than did a BUD dose of 400 microg/day.     

The hypothalamic-pituitary-adrenal axis in asthmatic children.

Reduced responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in patients with various chronic allergic inflammatory disorders and a blunted HPA axis response of poorly controlled asthmatics before long-term treatment with inhaled corticosteroids (ICS) have been reported. It seems that pro- and anti-inflammatory cytokines might be involved in the attenuation of cortisol and adrenocorticotropic hormone (ACTH) responses to stress in these patients. Although long-term ICS treatment might produce mild adrenal suppression in some asthmatic children, improvement of adrenal function has been detected in the majority of cases. We postulate that the anti-inflammatory effects of ICS result both in asthma remission and HPA axis improvement. Adrenal suppression of some asthmatic patients on maintenance ICS seems to be a separate phenomenon, possibly constitutionally or genetically determined.     

Adrenal function as assessed by low-dose adrenocorticotropin hormone test before and after switching from inhaled beclomethasone dipropionate to inhaled fluticasone propionate.

Low-dose adrenocorticotropin hormone (ACTH) tests (0.5 microg/L 73 m2) were done before and after switching from inhaled beclomethasone dipropionate to inhaled fluticasone propionate in 12 patients 33-77 years old who had mild-to-severe asthma to compare the effects of these drugs on adrenal function. Low-dose ACTH tests were performed after the subjects had received inhaled beclomethasone dipropionate (200-900 microg/day) for at least 12 wk. Treatment was then switched to inhaled fluticasone propionate (200-600 microg/day) for at least 12 wk, and a second low-dose ACTH test was done. Pulmonary function was assessed on the basis of peak expiratory flow rate (PEFR, % of predicted value). After switching treatment, the daily dose of inhaled corticosteroid decreased by about 40%. Basal serum cortisol and ACTH levels were similar with both treatments. The adrenal response, as assessed by incremental rise in the serum cortisol level (peak minus basal) after ACTH challenge, improved significantly (5.6-7.9 microg/dL, p < 0.01) after switching to fluticasone. All three patients who had lower serum cortisol levels during beclomethasone treatment than during fluticasone treatment showed improvement in both the peak cortisol level and the incremental rise in cortisol. Mean morning and evening PEFRs significantly increased after switching from beclomethasone to fluticasone (morning: 71.2 to 76.0%, p < 0.01; evening: 67.3 to 72.1%, both p < 0.05). The diurnal variation of PEFR significantly decreased from 10.9% to 8.3% after switching treatment (p < 0.01). We conclude that switching from beclomethasone to fluticasone reduces the risk of adrenal dysfunction associated with inhaled steroids and improves pulmonary function.     

The effects of long term use of inhaled corticosteroids on linear growth, adrenal function and bone mineral density in children

In this study we aimed to investigate the long term effects of inhaled steroids on linear growth, adrenal function and bone mineral density. Thirty children with moderate asthma were randomly divided into two groups. Fifteen children (8 boys, 7 girls mean age; 10.6 +/- 2.1) were treated with budesonide (group 1), and 15 (9 boys, 6 girls, mean age; 9.6 +/- 2.4). with fluticasone propionate (group 2). Control group included 30 children. Anthropometric assessment, symptom and medication scores, pulmonary functions, bone mineral density, serum and urine cortisol levels and ACTH stimulation test were evaluated at the beginning of the study and after one year period. Symptom and medication scores, pulmonary functions improved significantly in both groups (p < 0.05). The mean annual growth was similar in group 1 and 2 and control group. Bone mineral density was comparable with control group at the beginning of the study and after one year. Mean serum cortisol level diminished at the end of the therapy but no significant differences were found between the initial and end values in respect to urine cortisol levels and cortisol/creatinine ratio. Of three groups ACTH stimulation test revealed that there were no significant difference between study and control groups. In conclusion, although we did not observed any side effects of inhaled corticosteroids we suggest that children treated with inhaled corticosteroids for a long time should be followed closely with respect to side effects.     

Comparable effects of inhaled fluticasone propionate and budesonide on the HPA-axis in adult asthmatic patients

This randomized, double-blind, double-dummy, multicentre cross-over study compared the effects on the hypothalamic-pituitary-adrenal (HPA) axis of fluticasone propionate (750 microg twice daily given via the Diskus) and budesonide (800 microg twice daily given via the Turbuhaler). Two treatment periods of 2 weeks each were preceded by a 2-week run-in period and separated by a 2-week washout period. During run-in and washout, patients received beclomethasone dipropionate (BDP) or budesonide at a constant dose of 1500-1600 microg day(-1). Sixty patients aged 18-75 years with moderate to severe asthma not fully controlled by treatment with 1500-1600 microg day(-1) budesonide or BDP entered run-in and 45 completed the study. HPA axis suppression was assessed by morning serum cortisol (area under the curve from 08.00 to 10.30 hours) and 12-h nocturnal urinary cortisol excretion, measured at the end of run-in (baseline 1), at the end of washout (baseline 2), and at the end of each treatment period. Neither budesonide nor fluticasone produced significant suppression of either parameter compared to baselines. Only a few patients had serum-cortisol and urinary cortisol values below the normal range, before and after treatment. This shows that the patients did not have adrenal suppression before entering the study. The ratio between the AUC serum cortisol measured after fluticasone treatment and after budesonide treatment was 0.99 (95% CI 0.92-1.06), indicating equivalent effects on the HPA axis. This result was achieved after having omitted two patients' results, due to their very sensitive reaction to budesonide, but not to fluticasone. Two exacerbations of acute asthma occurred during budesonide treatment and none during fluticasone treatment. Both treatments were well tolerated. In conclusion, budesonide 1600 microg day(-1) via Turbuhaler and fluticasone propionate 1500 microg day(-1) via Diskus had no clinical effects on the HPA axis in patients with moderate to severe asthma.     

Hypothalamic-pituitary-adrenal axis function after inhaled corticosteroids: unreliability of urinary free cortisol estimation

Free cortisol in the urine (UFC) is frequently measured in clinical research to assess whether inhaled corticosteroids (ICS) cause suppression of the hypothalamic-pituitary-adrenal axis. Thirteen healthy male subjects received single inhaled doses (of molar equivalence) of fluticasone propionate (FP), triamcinolone acetonide (TAA), budesonide (BUD), and placebo in this single blind, randomized, cross-over study. UFC output was measured using four commercial immunoassays in samples collected in 12-h aliquots over 24 h. The cortisol production rate was assessed from the outputs of cortisol metabolites. UFC showed a 100% increase over placebo levels in the Abbott TDX assay after the administration of BUD. The other assays detected variable suppression (ranging from 29-61% suppression for FP, 30-62% suppression for TAA, and 25% suppression to 100% stimulation for BUD). Suppression was more pronounced in the first 12 h after TAA and in the second 12 h after FP. Similar suppression was found in each 12-h period after BUD. UFC estimation based on immunoassays after ICS may be an unreliable surrogate marker of adrenal suppression. Many of the published studies describing or comparing the safety of different ICS should be reevaluated, and some should be interpreted with caution.     

Serum dehydroepiandrosterone sulfate concentration as an indicator of adrenocortical suppression in asthmatic children treated with inhaled steroids

ACTH regulates adrenal androgen production, which may thus be reduced during glucocorticosteroid therapy. Dehydroepiandrosterone sulfate is the most abundant androgen secreted by the adrenals. We wished to evaluate whether serum levels of dehydroepiandrosterone sulfate can be used as an indicator of adrenal suppression during inhaled steroid treatment in children. Sixty school-aged children with newly diagnosed asthma were randomly divided into budesonide (n = 30) and fluticasone propionate (n = 30) groups. Fifteen cromone-treated children served as a control group. The budesonide dose was 800 microg/d during the first 2 months and 400 microg/d thereafter. The respective fluticasone propionate doses were 500 and 200 microg/d. Serum dehydroepiandrosterone sulfate concentrations were measured before and after 2 and 4 months of treatment. In the budesonide group, serum dehydroepiandrosterone sulfate decreased from the baseline by a mean of 21% (95% confidence interval, 13-29%; P < 0.001) after 2 months of high dose treatment and by 16% (95% confidence interval, 8-25%; P < 0.001) after 4 months of treatment. In the fluticasone propionate group, the respective figures were 10% (95% confidence interval, 4-16%; P < 0.01) and 6% (95% confidence interval, 16% decrease-3% increase; P = NS). A low dose ACTH test indicated adrenocortical suppression at 4 months in 14 (23%) steroid-treated children. In these children, dehydroepiandrosterone sulfate decreased by a mean of 21% (95% confidence interval, 14-28%), whereas in those 46 steroid-treated children with normal ACTH test results, dehydroepiandrosterone sulfate decreased by 8% (95% confidence interval, 0-16%; P < 0.05 between these groups). In the control group, dehydroepiandrosterone sulfate levels tended to increase (by a mean of 26%), reflecting the normal physiological change at this age. In conclusion, inhaled steroid treatment suppresses dehydroepiandrosterone sulfate production in a dose-dependent manner. Monitoring of serum dehydroepiandrosterone sulfate concentrations can be used as a practical method to follow adrenocortical function and to detect its suppression during inhaled steroid treatment in children.     

Low serum dehydroepiandrosterone sulfate in women with primary Sj?gren's syndrome as an isolated sign of impaired HPA axis function.

OBJECTIVE: To assess the hypothalamic-pituitary-adrenal (HPA) and thyroid axes in women with primary Sj?gren's syndrome (pSS). METHODS: In 10 women with pSS and 10 age matched female controls, we evaluated serum dehydroepiandrosterone sulfate (DHEA-S), testosterone, androstenedione, follicle stimulating hormone, luteinizing hormone, thyroid stimulating hormone, prolactin, growth hormone, sex hormone binding globulin, cortisol, and adrenocorticotropin hormone (ACTH), in both basal condition and after stimulation with corticotropin releasing hormone, thyrotropin releasing hormone, and luteinizing hormone releasing hormone intravenously. Patients had not previously been treated with glucocorticoids. RESULTS: Patients with pSS had significantly lower basal mean DHEA-S values compared with healthy controls (2.4 +/- 0.4 vs 3.9 +/- 0.3 mumol/l; p < 0.05) and significantly lower DHEA-S values after stimulation. The cortisol/DHEA-S ratio in the patient group was higher than in controls (171 +/- 39 vs 76 +/- 5; p < 0.05). A correlation was found between basal ACTH and DHEA-S values in the patients (r = 0.650; p = 0.05). No correlation was seen between disease activity or age and the serum concentration of DHEA-S. The levels of other hormones both at baseline and after stimulation were similar in patients and controls. CONCLUSION: The results show that women with pSS have intact cortisol synthesis but decreased serum concentrations of DHEA-S and increased cortisol/DHEA-S ratio compared with healthy controls. The findings may reflect a constitutional or disease mediated influence on adrenal steroid synthesis. The thyroid axis and gonadotropin secretion were similar in patients and controls.     

Acute adrenal crisis in asthmatics treated with high-dose fluticasone propionate.

Four cases of asthma (one adult, three children) developing acute adrenal crisis after introduction of high-dose inhaled fluticasone proprionate are presented. The three children, aged 7-9 yrs, had been prescribed inhaled fluticasone, dosage 500-2,000 microg x day(-1) and duration 5 months-5 yrs. All presented with convulsions due to hypoglycaemia (blood glucose 1.3-1.8 mM). The fourth case was a male of 33 yrs with difficult-to-control asthma and had been taking fluticasone propionate 1,000-2,000 microg x day(-1) for 3 yrs. He presented with fatigue, lethargy, nausea and postural hypotension. Acute adrenal crisis in each case was confirmed by investigations which included measurement of acute phase cortisol levels, short and long Synacthen stimulation tests and glucagon stimulation tests. Other cases of hypthoalamic-pituitary-adrenal axis suppression were excluded.     

Side-effects of fluticasone in asthmatic children: no effects after dose reduction.

To assess long-term effects and side-effects of fluticasone propionate (FP), a 2-yr study was performed, comparing a step-down dose approach (1,000 microg.day(-1), with reductions every 2 months to 500, 200 and 100 microg.day(-1) for the remainder of the study) versus a constant dose (200 microg.day(-1)). In 55 children with chronic persistent asthma, aged 6-10 yrs, airways hyperresponsiveness (AHR) and systemic side-effects (height, bone parameters and adrenal cortical function) were assessed at predetermined intervals in a double-blind prospective 2-yr study. AHR improved after 4 months treatment with 1,000 microg.day(-1) FP followed by 500 microg.day(-1), without significant differences during long-term treatment between the two approaches. Dose-dependent reduction of growth velocity, adrenal cortical function and biochemical bone turnover was found during therapy with 1,000 and 500 microg.day(-1) FP when compared with 200 microg.day(-1). In conclusion, doses of 1,000 and 500 microg.day(-1) fluticasone propionate are associated with marked reductions of growth velocity, bone turnover and adrenal cortical function. However, conventional doses (< or =200 microg.day(-1) fluticasone propionate) appear to be safe in the long-term management of childhood asthma. From a safety point of view, high doses of fluticasone propionate should only be prescribed in exceptions, e.g. in persistent severe asthma.     

Inhaled corticosteroid therapy with nebulized beclometasone dipropionate

Inhaled corticosteroids (ICS) are the most effective anti-inflammatory agents for the management of chronic persistent asthma and are therefore recommended as first-line antiasthmatic therapy in children and adults. In various settings, the administration of ICS via nebulizer rather than hand-held inhaler (HHI) may have certain advantages, as many patients with HHI fail to use these devices properly or efficiently. In particular, young children, the elderly, the acutely ill, and those with restricted dexterity may be unable to coordinate inhalation with actuation of the device or to generate sufficient inspiratory flow to operate breath-actuated devices effectively. Compliance with nebulized therapy may also be better than that with a pressurized metered-dose inhaler (pMDI) plus spacer.Systematic reviews conclude that there is no significant difference in clinical effects between nebulizers and HHI. Performance and clinical effect of nebulization are influenced by several technical aspects such as the nebulizer–drug combination, nebulizer type, output and lung deposition. Among the currently available ICS, nebulized beclometasone dipropionate (BDP) has been in clinical use for more than 35 years, and has demonstrated marked clinical efficacy and a favorable tolerability profile in children and adults with chronic persistent asthma. The clinical efficacy of nebulized beclometasone is discussed in the present review using data from 13 published studies, which included a total of 1250 patients. Three multicenter, randomized, double-blind studies showed that nebulized BDP is as effective as BDP via pMDI plus spacer in a 2:1 dose ratio. Controlled trials involving 497 adults and children demonstrated similar clinical efficacy between nebulized BDP and either nebulized fluticasone propionate or nebulized budesonide. In all these trials, treatment-related adverse effects were generally uncommon, most were mild-to-moderate in severity, and most were associated with the respiratory system. Meta-analyses show that BDP, like other inhaled corticosteroids, has no major influence on patient height, urinary cortisol concentration, or bone metabolism, thus suggesting the absence of growth retardation or any marked effect on adrenal function or the hypothalamic-pituitary-adrenal axis when used in the approved dose range.Overall, nebulized BDP appears to have a particularly important place in asthma therapy: as a general alternative to HHIs (e.g. in patients with poor HHI compliance); when patients such as children or the elderly are unable to operate HHIs because of poor hand–lung coordination, lack of cooperation, or low inspiratory flow rate; and when high dosages of ICS are required, such as in adults with severe, corticosteroid-dependent asthma.     

Safety of inhaled corticosteroids in children

Inhaled corticosteroids (ICS) are now first-line therapy for persistent asthma in children. The major safety concerns of long-term ICS therapy for childhood asthma are potential effects on adrenal function, growth, and bone mass. Dosage, type of inhaler device, and individual drug characteristics influence systemic effects of ICS. Sensitive measures of basal adrenal function can show statistically significant changes during ICS therapy, but these do not accurately predict clinically meaningful adrenal axis suppression. Adrenal insufficiency is rare and confined to children receiving high doses of ICS. Dose-related inhibition of growth has been seen in some short- and intermediate-term studies, but long-term studies have found no detrimental effect on final height. ICS therapy has not been associated with significant changes in measurements of bone and bone biomarkers, but more studies of high doses and of therapy in adolescents are needed. Overall, although ICS are the most effective anti-inflammatory treatment available for asthma, high doses of ICS in children are still of concern. The risk of high doses is compounded in children with concomitant allergic conditions that require multiple forms of topical corticosteroids. Benefits of ICS clearly outweigh potential adverse effects and risks associated with poorly controlled asthma. Risk can be minimized by using the lowest effective ICS dose, limiting systemic availability of the drug through proper technique to minimize swallowed drug, and selection of agents with efficient first-path hepatic inactivation of swallowed drug. Adjuvant treatments can reduce the dose of ICS required for asthma control, allowing a reduction in overall systemic exposure for most children with mild-to-moderate persistent asthma. Therefore, these agents should be added to, but should not replace, ICS therapy.     

Oral hydrocortisone administration in children with classic 21-hydroxylase deficiency leads to more synchronous joint GH and cortisol secretion

In humans, GH and cortisol are secreted in a pulsatile fashion and a mutual bidirectional interaction between the GH/IGF-I axis and hypothalamic-pituitary-adrenal axis has been established. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in the synthesis of glucocorticoids and often mineralocorticoids, and adrenal hyperandrogenism. Substitution therapy is given to prevent adrenal crises and to suppress the abnormal secretion of androgens and steroid precursors from the adrenal cortex. However, treatment with twice or three times daily oral hydrocortisone does not mimic physiological adrenal rhythms and may influence the activity of the GH/IGF-I axis. We investigated the pattern of GH and cortisol secretion and the synchrony of joint GH-cortisol secretory dynamics in 15 children with classic 21-hydroxylase deficiency (5 males and 10 females; median age 9.5 yr, range 6.1-11.0 yr) and 28 short normal children (23 males and 5 females; median age 7.7 yr, range 4.9-9.3 yr). All subjects were prepubertal. Serum GH and cortisol concentrations were determined at 20-min intervals for 24 h. The irregularity of GH and cortisol secretion was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol secretion was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol secretory patterns was computed at various time lags covering the 24-h period. Children with CAH had significantly lower mean 24-h serum cortisol concentrations (6.4 +/- 2.2 vs. 10.4 +/- 2.6 microg/dl, P < 0.001), ApEn (GH) (0.64 +/- 0.13 vs. 0.74 +/- 0.17, P = 0.04), ApEn (cortisol) (0.54 +/- 0.13 vs. 1.08 +/- 0.18, P < 0.001) and cross-ApEn values of paired GH-cortisol secretion (0.78 +/- 0.19 vs. 1.05 +/- 0.12, P < 0.001) than normal children. There was no difference in mean 24-h GH concentrations between the two groups (4.5 +/- 2.9 vs. 4.5 +/- 1.9 mU/liter). In children with CAH, a significant positive correlation between GH and cortisol was noted at lag time 0 min (r = 0.299, P < 0.01), peaking at 20 min (r = 0.406, P < 0.0001), whereas in normal children, a significant negative correlation between the two hormones was noted at lag time 0 min (r = -0.312, P < 0.01). The above findings suggest that children with classic CAH have a more regular pattern of GH secretion and a more synchronous joint GH-cortisol secretory dynamics than their normal counterparts. These differences reflect bidirectional interactions between the GH/IGF-I axis and hypothalamic-pituitary-adrenal axis in humans, and are likely to evolve as a result of the exogenous administration of hydrocortisone at fixed doses and at specific time intervals, which leads to a more regular pattern in circulating cortisol concentrations, independent of variations in CRH and ACTH concentrations.     

Association among fraction of exhaled nitrous oxide,bronchodilator response and inhaled corticosteroid type

BACKGROUND:Fraction of exhaled nitrous oxide (FeNO) is a known marker of airway inflammation and a topic of recent investigation for asthma control in children.OBJECTIVE:To investigate the relationship among FeNO and bronchodilator response measured by spirometry and types of inhaled corticosteroids (ICS).METHODS:A one-year review of children tested with spirometry and FeNO in a regional pediatric asthma centre was conducted.RESULTS:A total of 183 children were included (mean [± SD] age 12.8±2.8 years). Fluticasone was used most commonly (n=66 [36.1%]), followed by ciclesonide (n=50 [27.3%]). Most children (n=73 [39.9%]) had moderate persistent asthma. Increased FeNO was associated with percent change in forced expiratory volume in 1 s (FEV₁) after bronchodilator adjusted for allergic rhinitis, parental smoking and ICS type (B=0.08 [95% CI 0.04 to 0.12]; P<0.001). Similarly, FeNO was associated with percent change in forced expiratory flow at 25% to 75% of the pulmonary volume (FEF_25–75) after bronchodilator adjusted for parental smoking and ICS type (B=0.13 [95% CI 0.01 to 0.24]; P=0.03). FeNO accounted for only 16% and 9% of the variability in FEV₁ and FEF_25–75, respectively. Mean-adjusted FeNO was lowest in fluticasone users compared with no ICS (mean difference 18.6 parts per billion [ppb] [95% CI 1.0 to 36.2]) and there was no difference in adjusted FeNO level between ciclesonide and no ICS (5.9 ppb [95% CI −9.0 to 20.8]).CONCLUSION:FeNO levels correlated with bronchodilator response in a regional pediatric asthma centre. However, FeNO accounted for only 16% and 9% of the variability in FEV₁ and FEF_25–75, respectively. Mean adjusted FeNO varied according to ICS type, suggesting a difference in relative efficacy between ICS beyond their dose equivalents.     

Adrenocortical responsiveness to graded ACTH infusions in normal young and elderly human subjects

The responses of plasma cortisol, aldosterone, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) to graded ACTH infusions (from 50 mU/h to 1,000 mU/h) in elderly subjects were compared with those in young subjects. There were no significant differences between young and elderly subjects in terms of the levels of plasma cortisol during ACTH infusion. The increment in median serum cortisol increase observed in elderly subjects was also equal to that found in young subjects. Plasma aldosterone concentration showed a gradual increase in response to ACTH infusion in both young and elderly individuals. There was no significant difference between the response of young and aged subjects. Significant increases in serum DHEA in response to ACTH infusion were observed in both young and aged individuals, however, the median increase of serum DHEA (delta DHEA) in the elderly subjects was markedly lower than that in the young ones. Serum DHEA-S concentrations prior to ACTH infusion were significantly lower in the elderly subjects. With graded infusions of ACTH, plasma DHEA-S concentrations in young subjects tended to increase gradually, whereas there was no significant increase in plasma DHEA-S concentrations in the elderly. These results are indicative that the responses of adrenal androgens in elderly subjects to small, graded doses of ACTH infusion are preferentially impaired; however, the responses of cortisol and aldosterone are well maintained.     

Adrenal Insufficiency in Hemodynamically Unstable Neonatesafter Open-Heart Surgery

Objective. To investigate if the low dose (1 µg) ACTH stimulation test appropriately assesses adrenal responsiveness in neonates undergoing open-heart surgery requiring cardio-pulmonary bypass. Design. In this retrospective study, adrenal axis response was assessed on the first post-operative day with the low-dose (1 µg) ACTH stimulation test. Age, gender, weight, RACHS category, inotrope score, and baseline and post-stimulation cortisol levels were collected. The association between basal serum cortisol levels and degree of response to the ACTH stimulation test was also investigated. Setting. Tertiary care referral center. Patients. Twenty-one neonates who underwent neonatal cardiac surgery on cardiopulmonary bypass and underwent an ACTH stimulation test. Interventions. Hydrocortisone 50 mg/m² bolus in four divided doses daily. Outcome Measures. Response to the low dose (1 µg) ACTH stimulation was assessed. Results. All neonates with hemodynamic instability in the immediate post-operative period had low basal serum cortisol levels. The basal mean serum cortisol level for the 21 patients who underwent the low dose ACTH stimulation test was 7.3 µg/dL (median 2.2, range 0.7–42). The mean serum cortisol level increased after the ACTH stimulation test in the 21 patients to 39.6 µg/dL (median 38, range 79–17). The mean inotrope score in the first 24 hours after surgery was 24 (median 17.5, range 7–76.5) and decreased to 17 (median 14, range 5–52.3) 24–48 hours after surgery. At 48 hours post-surgery the mean arterial pressure in the groups with a serum cortisol increase after ACTH stimulation (<30 µg/dL vs. >50 µg/dL) was significantly different (P value 0.026). Conclusions. The low dose (1 µg) ACTH stimulation test is a valid test to assess adrenal responsiveness among neonates after open heart surgery requiring CPB. Traditionally used basal serum cortisol level cutoff of <20 µg/dL used to define relative adrenal insufficiency may not be applicable in neonates undergoing open heart surgery on CPB thus indicating the need for re-defining adrenal insufficiency in this patient population.     

Adrenal Function as Assessed by Low-Dose Adrenocorticotropin Hormone Test Before and After Switching from Inhaled Beclomethasone Dipropionate to Inhaled Fluticasone Propionate

Low-dose adrenocorticotropin hormone (ACTH) tests (0.5 µg/L 73 m²) were done before and after switching from inhaled beclomethasone dipropionate to inhaled fluticasone propionate in 12 patients 33–77 years old who had mild-to-severe asthma to compare the effects of these drugs on adrenal function. Low-dose ACTH tests were performed after the subjects had received inhaled beclomethasone dipropionate (200–900 µg/day) for at least 12 wk. Treatment was then switched to inhaled fluticasone propionate (200–600 µg/day) for at least 12 wk, and a second low-dose ACTH test was done. Pulmonary function was assessed on the basis of peak expiratory flow rate (PEFR, % of predicted value). After switching treatment, the daily dose of inhaled corticosteroid decreased by about 40%. Basal serum cortisol and ACTH levels were similar with both treatments. The adrenal response, as assessed by incremental rise in the serum cortisol level (peak minus basal) after ACTH challenge, improved significantly (5.6–7.9 µg/dL, p<0.01) after switching to fluticasone. All three patients who had lower serum cortisol levels during beclomethasone treatment than during fluticasone treatment showed improvement in both the peak cortisol level and the incremental rise in cortisol. Mean morning and evening PEFRs significantly increased after switching from beclomethasone to fluticasone (morning: 71.2 to 76.0%, p<0.01; evening: 67.3 to 72.1%, both p<0.05). The diurnal variation of PEFR significantly decreased from 10.9% to 8.3% after switching treatment (p<0.01). We conclude that switching from beclomethasone to fluticasone reduces the risk of adrenal dysfunction associated with inhaled steroids and improves pulmonary function.     

A study of hypothalamic-pituitary-adrenal suppression following curative surgery for Cushing's syndrome due to adrenal adenoma

The hypothalamic-pituitary-adrenal axis was investigated in all six patients requiring glucocorticoid replacement 2.5-11 years after unilateral adrenalectomy for adrenal adenomas causing Cushing's syndrome. The hypothalamic-pituitary-adrenal axis was assessed by insulin induced hypoglycaemia and CRF testing in each patient. Two patients showed normal cortisol and ACTH responses to hypoglycaemia. Two patients showed subnormal cortisol responses to hypoglycaemia in the presence of high or normal basal ACTH concentrations. ACTH concentrations increased with both hypoglycaemia and CRF. Two patients showed subnormal cortisol responses to hypoglycaemia and CRF. One of these patients showed an ACTH rise following hypoglycaemia but not CRF. Defects at either hypothalamic-pituitary or adrenal levels were demonstrated and recovery of the axis appears to commence at the hypothalamic-pituitary level.     

HPA-axis effects of nebulised fluticasone propionate compared with oral prednisolone in childhood asthma

The aim of this study was to compare the effect of 7 days nebulised fluticasone propionate (FP) with oral prednisolone on 24-h urinary-free cortisol excretion, systemic exposure and safety. This was a randomised, double-blind, double-dummy, two-way crossover study. Thirty-one children (19 male, 12 female, mean age 8 years) with stable asthma were randomly assigned to 7 days treatment with either FP Nebules (2 x 0.5 mg/2 ml bd) or prednisolone tablets once daily (2 mg/kg/day for 4 days [maximum 40 mg] followed by 1 mg/kg/day or half the original dose for 3 days [maximum 20 mg]). After a 2-4 week washout period, patients received the second treatment for 7 days, followed by a 2-week follow-up visit. The primary outcome measure was 24-h urinary-free cortisol concentrations corrected for creatinine. Nebulised FP (1 mg bd) had significantly less effect on 24-h urinary-free cortisol excretion than oral prednisolone (8.9 ng/ml for FP and 5.0 ng/ml for prednisolone, P = 0.001). Systemic exposure to FP was also low. In conclusion, FP Nebules had significantly less effect on hypothalamic-pituitary-adrenal axis function than oral prednisolone in asthmatic children when used at doses recommended for the treatment of an acute exacerbation of asthma.