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.     

Ritonavir-fluticasone interaction causing Cushing syndrome in HIV-infected children and adolescents

BACKGROUND: Ritonavir, a potent inhibitor of CYP3A4 enzyme, can lead to high systemic concentrations of fluticasone when these 2 drugs are coadministered. Exogenous Cushing syndrome (CS) in HIV-infected patients receiving ritonavir and fluticasone has been reported frequently in adults but not in children. Three patients, all receiving ritonavir-fluticasone, developed weight gain and altered fat distribution concerning for either lipodystrophy or CS. METHODS: Three patients were initially identified by their clinicians as having weight gain and altered fat distribution concerning for either lipodystrophy or CS. All 3 patients were receiving fluticasone and ritonavir, leading to concern about a potential medication interaction. After suspecting exogenous CS, all patient medication lists were reviewed to identify all children prescribed ritonavir-fluticasone. Blood adrenocorticotropic hormone (ACTH) and cortisol were obtained during routine clinic visits. Medication history, laboratory data and physical examination findings were abstracted from medical records. RESULTS: Seventeen (9%) of 189 patients in this pediatric HIV clinic had been prescribed ritonavir-fluticasone. Of 7 patients still taking ritonavir-fluticasone, CS features were present in 4 (57%) patients, including the 3 patients initially suspected of CS or lipodystrophy. Five (71%) patients, including all 4 with CS features, had low serum concentrations: median cortisol <0.2 microg/dL (normal, <0.2 microg/dL). Three of these 5 had ACTH measured, all of which were low: median ACTH 3.0 pmol/L (range, 2.2-<5.0 pmol/L). One patient taking ritonavir-fluticasone had suppressed cortisol but no CS features. The 2 patients with normal serum cortisol and ACTH values had persistent HIV viremia and were suspected of medication nonadherence. Clinical and laboratory abnormalities generally normalized in affected patients within 3 months after discontinuation of fluticasone alone (2) and ritonavir-fluticasone (3). CONCLUSIONS: Pediatric HIV physicians frequently prescribe fluticasone and ritonavir together. The combination can cause CS and adrenal suppression in children, potentially leading to misdiagnosis of lipodystrophy syndrome and to increased risk of adrenal crisis during acute illness. Alternatives to fluticasone should be used for treating children receiving ritonavir.     

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 microg/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 microg/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 microg daily for up to 16 weeks, half the children had evidence of adrenal suppression.     

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.     

What is the rationale for hydrocortisone treatment in children with infection-related adrenal insufficiency and septic shock?

Recent studies show that children who die from fulminant meningococcaemia have very low cortisol:adrenocorticotrophic hormone (ACTH) ratios within the first 8 h of presentation to emergency facilities compared with survivors. This observation supports the possibility that adrenal insufficiency may contribute to rapid cardiovascular collapse in these children. In recent years, the use of hydrocortisone treatment has become increasingly popular in the care of adult and paediatric patients with septic shock. In this review, the classical adrenal insufficiency literature is presented and the existing rationale for using titrated hydrocortisone treatment (2-50 mg/kg/day) to reverse catecholamine-resistant shock in children who have absolute adrenal insufficiency (defined by peak cortisol level <18 microg/dl after ACTH challenge) or pituitary, hypothalamic or adrenal axis insufficiency is provided. In addition, the concept of relative adrenal insufficiency (basal cortisol >18 microg/dl but a peak response to ACTH <9 microg/dl) is reviewed. Although there is a good rationale supporting the use of 7 days of low-dose hydrocortisone treatment (about 5 mg/kg/day) in adults with this condition and catecholamine resistant septic shock, the paediatric literature suggests that it is prudent to conduct more studies before recommending this approach in children.     

Low-dose adrenocorticotropic hormone stimulation testing in term infants

BACKGROUND: Low-dose adrenocorticotropic hormone (ACTH) stimulation testing is a commonly accepted way to evaluate adrenal function in children. However, there are no published data on the use of this test in term infants less than 12 months of age outside the newborn period. METHODS: We identified 14 infants at our center who were full term and had one or more ACTH tests at less than 12 months of age to evaluate for secondary adrenal insufficiency (AI). We retrospectively assessed peak cortisol response in these infants to determine whether a cut-off of 20 microg/dl is appropriate to distinguish normal from abnormal adrenal function in this age group. RESULTS: Five infants had peak cortisol > or =20 microg/dl on their first ACTH test and had a clinical picture consistent with normal adrenal function. Nine infants had peak cortisol <20 microg/dl on their first ACTH test. When retested later in infancy, four of these patients achieved peak cortisol > or =20 microg/dl. CONCLUSIONS: In term infants, the low-dose ACTH stimulation test is useful for demonstrating normal adrenal function but is of limited value in diagnosing secondary AI. For infants with peak cortisol <20 microg/dl, clinical observation and repeat ACTH testing later in infancy clarified diagnosis.     

Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia

Background A 4‐week course of high‐dose glucocorticoids may cause prolonged adrenal suppression even after a 9‐day tapering phase. In this study, adrenal function and signs and symptoms of adrenal insufficiency were prospectively assessed in children with acute lymphoblastic leukemia (ALL) after induction treatment including high‐dose prednisone (PDN) or dexamethasone (DXM). Procedures Sixty‐four children with ALL, treated according to the AIEOP ALL 2000 Study protocol, underwent low dose ACTH (LD‐ACTH) stimulation 24 hr after the last tapered steroid dose. In those with impaired cortisol response, additional LD ACTH tests were performed every 1–2 weeks until cortisol levels normalized. Signs and symptoms of adrenal insufficiency were recorded during the observation period. Results All patients had normal basal cortisol values at diagnosis. Twenty‐four hours after last glucocorticoid dose, morning cortisol was reduced in 40/64 (62.5%) patients. LD‐ACTH testing showed adrenal suppression in 52/64 (81.5%) patients. At the following ACTH test 7–14 days later, morning cortisol values were reduced in 8/52 (15.4%) patients and response to the test was impaired in 12/52 (23%). Adrenal function completely recovered in all patients within 10 weeks. No difference was found between patients treated with PDN or DXM. Almost 35% of children with impaired cortisol values at the first test developed signs or symptoms of adrenal insufficiency. One child developed a severe adrenal crisis during adrenal suppression. Conclusions High‐dose glucocorticoid therapy in ALL children may cause prolonged adrenal suppression and related clinical symptoms. Laboratory monitoring of cortisol levels and steroid coverage during stress episodes may be indicated. Pediatr Blood Cancer 2008;50:537–541. © 2007 Wiley‐Liss, Inc.     

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 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.     

Decreased cortisol secretion in nonclassical 21-hydroxylase deficiency before and during glucocorticoid therapy

OBJECTIVE: The cortisol response in patients with nonclassical 21-hydroxylase deficiency (NC21OHD) was assessed before and during hydrocortisone therapy and the findings were related to genotype. DESIGN: Comparative study. METHODS: The study sample comprised 41 patients (10 males) with NC21OHD, divided into two groups according to the genetic analysis of the CYP21 gene: Group A carried two mild mutations (n = 29), and Group B were compound heterozygotes for one mild and one severe mutation (n = 12). The 250 microg short ACTH test was performed at diagnosis. To evaluate the degree of treatment-induced suppression of adrenal function, 31 patients also underwent the 1 microg/1.73 m2 ACTH test during hydrocortisone therapy. Basal and stimulated cortisol levels and the increment in cortisol response were compared between Groups A and B and between the whole patient sample and healthy controls (32 subjects for the 250 microg test and 29 for the 1 microg/1.73 m2 test). RESULTS: The basal, stimulated, and incremental cortisol levels were similar in Groups A and B; therefore, all the patients were considered together. At diagnosis, the basal cortisol levels were similar in the patients and controls, but the stimulated and incremental cortisol levels were significantly lower in the patients (p <0.001 for both). During hydrocortisone therapy, the patients had slightly higher basal cortisol levels than the controls (p = 0.04), but significantly lower stimulated and incremental cortisol levels (p <0.001 for both). CONCLUSIONS: Cortisol levels in NC21OHD are similar in patients carrying two mild mutations and in compound heterozygotes for one mild and one severe mutation. Stimulated and incremental cortisol levels in response to the short ACTH test might be decreased not only during but also before hydrocortisone therapy. Therefore, coverage with a stress dose of hydrocortisone during serious intercurrent illness or surgery is recommended in patients with NC21OHD, especially those previously treated with corticosteroids.     

A low dose adrenocorticotropin test (1 microg ACTH) for the evaluation of adrenal function in children with beta-thalassemia receiving hypertransfusion with suboptimal iron-chelating therapy

A cross-sectional study of adrenal function was carried out in 48 patients with beta-thalassemia who were receiving hypertransfusion with suboptimal desferoxamine. A low dose adrenocorticotropic hormone (1 microg ACTH) stimulation test was performed using the cut-off criteria of peak cortisol for adrenal sufficiency >18 microg/dl. Adrenal impairment was diagnosed in 22 patients, giving a prevalence of 45.8%. The peak cortisol concentrations in normal and impaired adrenal function groups were 26.22 +/- 2.84 and 14.03 +/- 3.12 microg/dl, respectively, and the mean basal morning cortisol was 8.93 +/- 2.97 and 6.52 +/- 2.45 microg/dl, respectively. There was no significant difference in any clinical characteristic between the patients with impaired adrenal function and those with normal 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.     

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.     

The low dose synacthen test: experience in well preterm infants

A pilot study to establish what constitutes a normal response to the low dose synacthen test (using 500 ng/1.73 m2 of ACTH) in well preterm infants was carried out on seven well preterm infants. Previous studies on preterm neonates (using a dose of ACTH of 36 microg/kg) suggest that a normal adrenal response is a peak serum cortisol level of > or =360 nmol/l(24). The minimum peak serum cortisol achieved by our cohort was 358 nmol/l with 6/7 infants achieving more than 360 nmol/l. 71% attained a serum cortisol increment from basal level of > or =200 nmol/l. This pilot study suggests that the criterion used to denote a normal adrenal response in preterm neonates using a dose of 36 microg/kg of ACTH (which is a peak serum cortisol of > or =360 nmol/l) can also be a applied when a physiological dose of ACTH (as used in the low dose synacthen test) is used.     

Adrenal status in children with septic shock using low-dose stimulation test.

OBJECTIVES: There is paucity of data on the magnitude of absolute or relative adrenal insufficiency in septic shock, especially in children. We conducted a prospective study to determine the prevalence of adrenal insufficiency in children with septic shock using a low-dose Synacthen (1 microg) stimulation test. DESIGN: Cross-sectional study. SETTING: Pediatric intensive care unit in a tertiary care hospital in northern India. PATIENTS: Children with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We performed cortisol estimation at baseline and after low-dose Synacthen (1 microg) stimulation at 30 and 60 mins in children with fluid refractory septic shock admitted to our pediatric intensive care unit. Basal cortisol levels <7 microg/dL and peak cortisol level <18 microg/dL were used to define adrenal insufficiency. An increment of <9 microg/dL after stimulation was used to diagnose relative adrenal insufficiency. As there is lack of consensus on the cutoffs for defining relative adrenal insufficiency using the low-dose adrenocorticotropic hormone test, we evaluated different cutoff values (increment at 30 mins, increment at 60 mins, greater of the two increments) and evaluated their association with the incidence of catecholamine refractory shock and outcomes. Children with sepsis but without septic shock were sampled for baseline cortisol levels as a comparison. Thirty children (15 girls) with septic shock were included; median age (95% confidence interval) was 36.5 (9.39- 58.45) months. Median Pediatric Risk of Mortality score was 22.5 (14.13-24.87). Fifteen (50%) children survived. The median (95% confidence interval) cortisol values at baseline and 30 mins and 60 mins after stimulation were 71 (48.74-120.23) microg/dL, 78.1 (56.9-138.15) microg/dL, and 91 (56.17-166.44) microg/dL, respectively. The median baseline cortisol value in age- and gender-matched children with sepsis was 11.5 microg/dL. None of the children with septic shock fulfilled the criteria for absolute adrenal insufficiency. However, nine (30%) patients had relative adrenal insufficiency (increment in cortisol <9 microg/dL). Of these nine patients, five (56%) died; of the 21 patients with a greater increment in cortisol after stimulation, ten died (p = .69). Compared with patients in septic shock with normal adrenal reserve, those with relative adrenal insufficiency had a higher incidence of catecholamine refractory shock (p = .019) but no difference in mortality rate (p = .69). On the sensitivity and specificity analysis using various cutoffs of increment, the best discrimination for catecholamine refractory shock was obtained with a peak increment <6 microg/dL. CONCLUSIONS: Relative adrenal insufficiency is common in children with septic shock and is associated with catecholamine refractory shock.     

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.     

Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom

Background: Until recently, only two cases of acute adrenal crisis associated with inhaled corticosteroids (ICS) had been reported worldwide. We identified four additional cases and sought to survey the frequency of this side effect in the United Kingdom. Methods: Questionnaires were sent to all consultant paediatricians and adult endocrinologists registered in a UK medical directory, asking whether they had encountered asthmatic patients with acute adrenal crisis associated with ICS. Those responding positively completed a more detailed questionnaire. Diagnosis was confirmed by symptoms/signs and abnormal hypothalamic-pituitary-adrenal axis function test results. Results: From an initial 2912 questionnaires, 33 patients met the diagnostic criteria (28 children, five adults). Twenty-three children had acute hypoglycaemia (13 with decreased levels of consciousness or coma; nine with coma and convulsions; one with coma, convulsions and death); five had insidious onset of symptoms. Four adults had insidious onset of symptoms; one had hypoglycaemia and convulsions. Of the 33 patients treated with 500–2000 µg/day ICS, 30 (91%) had received fluticasone, one (3%) fluticasone and budesonide, and two (6%) beclomethasone. Conclusions: The frequency of acute adrenal crisis was greater than expected as the majority of these patients were treated with ICS doses supported by British Guidelines on Asthma Management. Despite being the least prescribed and most recently introduced ICS, fluticasone was associated with 94% of the cases. We therefore advise that the licensed dosage of fluticasone for children, 400 µg/day, should not be exceeded unless the patient is being supervised by a physician with experience in problematic asthma. We would also emphasise that until adrenal function has been assessed patients receiving high dose ICS should not have this therapy abruptly terminated as this could precipitate adrenal crisis.     

Topical fluticasone propionate lotion does not cause HPA axis suppression

OBJECTIVE: To establish the absence of adrenal suppression of fluticasone propionate (FP) 0.05% lotion when applied extensively to children (3 months to 6 years), with moderate to severe atopic dermatitis (AD). STUDY DESIGN: Open-label, conducted at 6 US centers; 44 subjects (3 to 71 months) with widespread AD (mean body surface area treated, 65%) received FP lotion twice daily for up to 4 weeks. RESULTS: No significant differences in mean cortisol levels were detected before or after treatment. At baseline, mean (+/-standard deviation) cortisols before and after cosyntropin (CST) stimulation were 13 +/- 6 microg/dL and 35 +/- 6 microg/dL, respectively. End-treatment, pre-CST, and post-CST cortisols were 12 +/- 6 microg/dL and 33 +/- 8 microg/dL, respectively. All 42 subjects with end-treatment post-CST cortisols demonstrated a normal adrenal response to CST (>18.0 microg/dL). FP lotion was well tolerated. Subjects who had blood drawn for bioavailability showed no correlation between FP levels and end-treatment post-CST cortisols. CONCLUSIONS: In patients as young as 3 months, FP lotion had no effect on HPA axis function and did not cause skin thinning even when used extensively over widespread, severe inflammatory disease. These results, together with others from studies using cream and ointment, provide further evidence of the safety of FP.     

Influence of Long Term Inhalation of Beclomethasone Dipropionate on Pituitary Adrenal Axis Function in Asthmatic Children

目的　通过检测相关激素水平 ,探讨哮喘患儿吸入二丙酸倍氯米松后对垂体 肾上腺轴功能的影响。方法　将研究对象分成 4组 :正常对照组、哮喘组、短期吸入二丙酸倍氯米松组和长期吸入二丙酸倍氯米松组。应用放射免疫法 ,测定上述 4组儿童的促肾上腺皮质激素 (ACTH)和皮质醇 (cortisol)水平 ,以评估垂体 肾上腺轴功能状态及吸入二丙酸倍氯米松后对其的影响。结果　 4组儿童的血清ACTH和cortisol水平之间无明显差别 ;ACTH兴奋实验短期吸入治疗组和长期吸入治疗组与正常对照组和哮喘组比较皮质醇基础值无明显降低 ,与哮喘组比较反应值 (刺激值 -基础值 )则明显降低 (P <0 .0 5 )。结论　吸入治疗一定时间后可使肾上腺皮质功能达到轻度抑制状态 ,但并不随吸入时间延长而产生累积抑制效应。     

Correlation between plasma and salivary cortisol levels in preterm infants

We sought to determine correlations between plasma and salivary cortisol levels in preterm infants in the basal state and after adrenocorticotropic hormone (ACTH) stimulation during the first week of life. Infants (n = 48) were given ACTH or saline solution; each injection was separated by 24 hours. Salivary and plasma cortisol levels correlated at baseline (r = 0.67, P <.0001) and 1 hour after ACTH stimulation (r = 0.40, P =.0047). ACTH increased cortisol levels in plasma from 12.3 +/- 6.4 to 30.3 +/- 13.2 microg/dL (P <.0001) and in saliva from 1.0 +/- 0.8 to 2.6 +/- 1.0 microg/dL (P <.0001). The adrenal response to ACTH can be detected in the saliva of premature newborns during the first week of life.