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.     

Bone density in asthmatic children treated with inhaled corticosteroids.

Volumetric trabecular bone mineral density of the lumbar spine (vTBMD) and distal radius (rTBMD) were measured in 20 prepubertal white asthmatic children treated with moderate to high doses of inhaled corticosteroids. The median standard deviation score for vTBMD (0.20, -0.56 to 2.09) and rTBMD (-0.04, -0.82 to 1.39) were within the normal range.     

Bone density in asthmatic children treated with inhaled corticosteroids

Volumetric trabecular bone mineral density of the lumbar spine (vTBMD) and distal radius (rTBMD) were measured in 20 prepubertal white asthmatic children treated with moderate to high doses of inhaled corticosteroids. The median standard deviation score for vTBMD (0.20, -0.56 to 2.09) and rTBMD (-0.04, -0.82 to 1.39) were within the normal range.     

Adrenal function in asthmatic children treated with inhaled budesonide

The effect of the inhaled topical steroid budesonide on adrenal function was evaluated in 33 children (aged 7-15 years) with moderate bronchial asthma. The trial was designed as a prospective single-blind study of the effect of budesonide in daily doses of 200 microgram through 400 microgram to 800 micrograms in three randomized consecutive periods of 8 weeks. The unstimulated diurnal production of cortisol was assessed by measurement of free cortisol in 24-hour urine samples at the end of each period. No significant dose-related suppression was found. The cortisol production did not differ significantly during treatment with 800 microgram budesonide as compared to treatment with 200 microgram budesonide (95% confidence interval: 74%-112%). It is concluded, that budesonide is a topical steroid with a favourable ratio between topical and systemic effects in asthmatic children.     

Growth of asthmatic children is slower during than before treatment with inhaled glucocorticoids

Reports on the influence of inhaled glucocorticoids on growth have been controversial. We studied the growth of prepubertal asthmatic children prior to and during glucocorticoid therapy. We collected retrospectively the notes of 201 asthmatic children aged 1–11 years receiving inhaled beclomethasone dipropionate or budesonide. We calculated their height and height velocity standard deviation scores (HSDS and HVSDS, respectively) before the treatment and up to 5 years during the treatment and compared those with the growth of healthy peers. The dose of the medication was calculated and the severity of asthma was assessed. The asthmatic children grew similarly to their healthy peers before treatment with inhaled glucocorticoids: the mean HSDS was +0.02 and the mean HVSDS +0.01 for boys and -0.16 and +0.13 for girls, respectively. Growth retardation took place soon after the start of the treatment, the most profound decrease in the growth velocity (the change in the mean HVSDS from +0.05 to -0.88) occurring during the first year of treatment. The growth-retarding effect of inhaled glucocorticoids was not dose dependent. In the covariance analysis the increasing severity of asthma had a significant interaction with repeated measurements, showing more growth retardation along with more severe asthma, especially during long-term treatment. Asthma per se does not impair growth, but inhaled glucocorticoids may do so. Careful monitoring of the growth of all asthmatic children receiving inhaled glucocorticoids is necessary because the growth-retarding effect of the medication is not dose dependent. Individual sensitivity might explain the differences seen in the growth patterns of children receiving inhaled glucocorticoids.     

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.     

The insulin–like growth factor axis and collagen turnover in asthmatic children treated with inhaled budesonide

Serum concentrations of growth hormone–dependent insulin–like growth factor I (IGF–I) and insulinlike growth factor binding protein–3 (IGFBP–3), the carboxy terminal propeptide of type I procollagen (PICP), the carboxy terminal pyridinoline cross–linked telopeptide of type I collagen (ICTP) and the amino terminal propeptide of type III procollagen (PIIINP) were studied in 14 prepubertal children with asthma (mean age 9.7 years) during treatment with inhaled budesonide. The study design was a randomized, crossover trial with two double–blind treatment periods (200 and 800 μg) and one open, non–randomized treatment period (400 μg ). All periods were 18 days'duration. Budesonide treatment was associated with a dose–related suppressive trend in serum concentrations of PIIINP when the 400 μg period was included (p < 0.01; z =–2.7) and when it was excluded from the calculations (p < 0.01; z =–2.6), indicating reduced synthesis of type III collagen. A similar trend was observed in ICTP levels when the 400 μg period was excluded from the calculations (p = 0.05; z =–1.9). No other statistically significant variations were seen.     

Short-term growth and adrenal function in children with asthma treated with inhaled beclomethasone dipropionate hydroflouroalkane-134a

Inhaled beclomethasone dipropionate (BDP) with the propellant hydrofluoroalkane-134a (HFA) has been designed to be equivalent in terms of safety to chlorofluorocarbon (CFC)-formulated metered dose inhalers (MDI). The aim was to assess whether BDP HFA MDI 100 microg twice daily was equivalent to BDP CFC MDI 100 microg twice daily in terms of effects on short-term lower leg growth rate (LLGR) and measures of hypothalamic-pituitary-adrenal (HPA) function. The study consisted of a randomized double-blind cross-over trial with three active, a run-in and two wash-out periods each consisting of 2 wk. The place of study was a secondary referral outpatient clinic. The subjects involved were 14 boys and 10 girls with asthma, aged 7-12 yr. They were all administered BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily. The outcome measures included LLGR and 24-h urine-free cortisol (UFC) and total cortisol metabolites (TCM). Mean (SD) LLGR during run-in and BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily periods were 0.43 (0.23), 0.09 (0.29), 0.10 (0.45) and 0.08 (0.27) mm/wk. The one-sided 97.5% confidence interval for the difference in LLGR between BDP HFA 100 microg and BDP CFC 100 microg was 0.24, thus, below the predefined criterion of 0.20 mm/week. Inter-period comparisons of active treatments showed no differences between means of LLGR, UFC or TCM. Though non-inferiority between BDP HFA and CFC 100 microg twice daily in terms of effects on LLGR was not found, equivalence was suggested by comparisons of LLGR during run-in and active treatments and by HPA function measures.     

Prevalence of hypothalamic-pituitary-adrenal axis suppression in children treated for asthma with inhaled corticosteroid

OBJECTIVE:

To determine the prevalence of hypothalamic-pituitary-adrenal (HPA) axis suppression in asthmatic children on inhaled corticosteroids (ICS).

METHODS:

Clinical and demographic variables were recorded on preconstructed, standardized forms. HPA axis suppression was measured by morning serum cortisol levels and confirmed by low-dose adrenocorticotropic hormone stimulation testing.

RESULTS:

In total, 214 children participated. Twenty children (9.3%, 95% CI 5.3% to 13.4%) had HPA axis suppression. Odds of HPA axis suppression increased with ICS dose (OR 1.005, 95% CI 1.003 to 1.009, P<0.001). All children with HPA axis suppression were on a medium or lower dose of ICS for their age (200 μg/day to 500 μg/day). HPA axis suppression was not predicted by drug type, dose duration, concomitant use of long-acting beta-agonist or nasal steroid, or clinical features.

CONCLUSION:

Laboratory evidence of HPA axis suppression exists in children taking ICS for asthma. Children should be regularly screened for the presence of HPA axis suppression when treated with high-dose ICS (>500 μg/day). Consideration should be given to screening children on medium-dose ICS.     

Long-term treatment with glucocorticoids/ACTH in asthmatic children. III. Effects on growth and adult height

The effect on growth of long-term treatment with prednisolone and/or ACTH (tetracosactrin) depot preparation was studied in 40 children with severe bronchial asthma. Height velocity was subnormal before treatment. During treatment the group of 17 children primarily treated with ACTH showed a moderate increase in mean velocity. Their height was not significantly altered, and neither was the age at peak height velocity nor adult height. In the group of 23 children treated with prednisolone the mean velocity decreased, resulting in a relative decrease in height. Peak height velocity was delayed by about 2 years in the boys but occurred at the expected time in the girls, as did menarche. Mean adult height was lower than expected after adjustment for mid-parenteral height. In 10 children ACTH was substituted for prednisolone, and their height velocity increased but not enough to affect adult height, which was just as low as in the patients treated with prednisolone only.     

Lower leg growth suppression caused by inhaled glucocorticoids is not accompanied by reduced thickness of the cutis or subcutis

Background: Exogenous glucocorticoids suppress short-term lower leg growth in children as assessed by knemometry. The knemometric measurements, however, may be confounded by reductions in the thickness of the cutis and subcutis over the knee. Aim: To assess whether inhaled glucocorticoid-induced suppression of short-term growth is accompanied by changes in the thickness of the cutis and subcutis. Methods: The study was a randomized, controlled, crossover trial with 1 wk treatment, run-in and washout periods. Active treatment was inhaled budesonide 200 μg twice daily. Short-term growth was assessed by knemometry, and the thickness of the cutis and subcutis over the knee, on the volar forearm and abdomen was measured by 20 MHz B-mode ultrasound. Material: Nineteen children with asthma aged 7 to 13 y. Results: Lower leg growth was significantly reduced during budesonide treatment (0.27 mm/wk) compared to the treatment-free period (0.54 mm/wk) (p = 0.02, 95%: -0.50 to -0.05). Variations in the thickness of the cutis were seen during budesonide treatment (mean ± SEM): -0.01 ± 0.03 mm over the knee, -0.02 ± 0.02 mm on the forearm and 0.01 ± 0.02 mm on the abdomen. The variations in the total thickness of the cutis and subcutis were -0.05 ± 0.12 mm, 0.06 ± 0.12 mm and -0.06 ± 0.10 mm during budesonide treatment. The variations in thickness of the cutis or subcutis were not statistically different during budesonide treatment and the treatment free period in any anatomical location.

Conclusions: Short-term lower leg growth suppression induced by inhaled glucocorticoids is not confounded by variations in thickness of cutis or subcutis. The present observations further establishes knemometry as a reliable tool for assessment of the risk of growth suppression of inhaled glucocorticoids in children with asthma.     

Hypothalamic‐pituitary‐adrenal axis suppression in asthmatic children on inhaled corticosteroids: Part 1. Which test should be used?

The effect of inhaled corticosteroids (ICS) on the hypothalamic-pituitary-adrenal axis (HPA) has been regarded as a 'benign physiological response'. A recent survey suggests that adrenal crisis might be more common in asthmatic children on ICS than previously thought. The clinical features of adrenal insufficiency are non-specific and can easily be missed. Accurate biochemical assessment of the axis is therefore mandatory. A review of the literature determined that all basal adrenal function tests, including plasma cortisol profiles, cannot identify which children can respond to stress. There is no evidence to suggests that the degree of the physiological adjustment of the HPA to ICS predicts clinically significant HPA suppression. Only gold standard adrenal function tests can assess the integrity of the whole axis. Of the two available tests, the correctly performed overnight metyrapone test (with ACTH levels) is safe and better by far. The use of cortisol profiles should only be used to demonstrate differences in systemic activity of various ICS and delivery devices. Regulatory bodies should insist on trials that evaluate the HPA with a gold standard adrenal function test before it is declared safe and allowed to be marketed. A re-analysis of studies that have utilized gold standard adrenal function tests only might identify the lowest safe dose and duration of ICS.     

Resting heart rate does not predict growth in preterm infants

Background

Previous reports indicate that preterm infants with higher baseline heart rate (HR) have greater weight gain than preterm infants with lower baseline HR. To verify this correlation and the potential utility of resting HR as a bench mark for risk of extrauterine growth restriction (EUGR), we studied preterm infants born between 32 and 36 weeks gestation. Earlier gestation infants (27 to 31 weeks) were included.

Methods

In retrospective chart review we collected heart rate (HR) and growth data on 156 infants between 27.0 and 34.0 weeks gestation from birth to hospital discharge.

Results

There was a significant increase in weight gain from day 10 of life in infants with higher resting HR compared to infants with lower resting HR. However, upon controlling for birth weight and gestational age, there was no significant relationship between HR and weight gain for any gestational age group of premature infants.

Conclusions

Contrary to previous reports, there was no significant relationship between HR and growth at any gestational age after controlling for birth weight and gestational age. It is important to continue to search for a clinical marker of risk for poor growth in preterm infants and to give an opportunity for nutritional interventions which may support better growth and developmental outcomes.     

Carbohydrate metabolism on high dose growth hormone therapy in children treated for leukaemia

Abstract The effect on carbohydrate metabolism of a high dose growth hormone (GH) regimen (1.2 U/kg per week) was assessed on 24 children who had previously been treated for leukaemia. Sixteen patients received high dose GH and eight patients received a conventional dose of GH (0.6 U/kg per week). Oral glucose tolerance tests (OGTT) were performed at baseline and after 3 months of treatment with GH. For the entire group between 0 and 3 months, there was a significant increase in mean (and standard deviation) fasting plasma glucose (0.3 ± 0.6 mmol/L), fasting insulin level (11 ± 26 mU/L), and 2 h insulin level (20 ± 40 mU/L). One patient, who received a conventional dose of GH, developed substantial carbohydrate intolerance. For the entire group, there was no change in response to a carbohydrate load at 3 months as measured by the area under the plasma glucose or insulin curve. There was no significant difference between conventional and high dose groups at 3 months as assessed by these parameters. This study demonstrates that a higher dose of GH may be used in these children in an attempt to improve their final height, without increased risk of carbohydrate intolerance in the short term.     

Carbohydrate metabolism on high dose growth hormone therapy in children treated for leukaemia

The effect on carbohydrate metabolism of a high dose growth hormone (GH) regimen (1.2 U/kg per week) was assessed on 24 children who had previously been treated for leukaemia. Sixteen patients received high dose GH and eight patients received a conventional dose of GH (0.6 U/kg per week). Oral glucose tolerance tests (OGTT) were performed at baseline and after 3 months of treatment with GH. For the entire group between 0 and 3 months, there was a significant increase in mean (and standard deviation) fasting plasma glucose (0.3 +/- 0.6 mmol/L), fasting insulin level (11 +/- 26 mU/L), and 2 h insulin level (20 +/- 40 mU/L). One patient, who received a conventional dose of GH, developed substantial carbohydrate intolerance. For the entire group, there was no change in response to a carbohydrate load at 3 months as measured by the area under the plasma glucose or insulin curve. There was no significant difference between conventional and high dose groups at 3 months as assessed by these parameters. This study demonstrates that a higher dose of GH may be used in these children in an attempt to improve their final height, without increased risk of carbohydrate intolerance in the short term.     

小剂量阿奇霉素对哮喘儿童气道反应性的影响

目的 探讨小剂量阿奇霉素对哮喘儿童气道反应性的影响.方法 中重度持续哮喘患儿104例分为A组(56例)和B组(48例).所有患儿均应用沙美特罗替卡松(50/100μg/剂)2剂/d,吸人4周,重度持续哮喘患儿加服孟鲁司特5 mg/d,合并过敏性鼻炎者加糠酸莫米松100～200μg/d喷鼻,然后进入观察期.A组继续吸入沙美特罗替卡松(剂量同前),并加口服阿奇霉素7.5 mg/( kg·d)(最大剂量250 mg/d),每周服药2d;B组仅继续吸入沙美特罗替卡松(剂量同前).观察期为12周.试验结束两组分别评定观察期内有症状天数;开始及结束时,两组分别检测一秒钟用力呼气量( FEV1)、最大呼气峰流量(PEF)占预计值的百分率,观察期第15天及结束时检测使FEV1下降20％的组胺激发剂量(PD20-FEV1);观察开始前24h及结束后24h分别检测24h尿17-羟皮质醇(17-OHCS)和17-酮皮质醇(17-KS);试验结束后2周检测血清丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST).结果 (1)A、B两组有症状天数分别为(2.13±1.18)d、(2.25±1.19)d,差异无统计学意义(t =0.54,P=0.59).(2)观察前、后PEF占预计值百分率:A组分别为(49.77±15.02)％、(82.73±7.81)％,差异有统计学意义(t=16.59,P=0.000),B组分别为(52.69±13.90)％、(81.15+7.28)％,差异有统计学意义(t=12.37,P=0.000);观察前、后FEV1占预计值百分率:A组分别为(50.48±15.08)％、(83.18±6.61)％,差异有统计学意义(t=16.25,P=0.000),B组分别为(53.29±13.89)％、(82.73±6.10)％,差异有统计学意义(t=12.83,P=0.000).(3)观察期第15天、结束时PD20-FEV1水平:A组分别为(65.13±26.08) μg、(460.79± 221.72) μg,差异有统计学意义(t=13.54,P=0.000),B组分别为(65.27±25.75) μg、(65.66±25.09) μg,差异无统计学意义(t=1.45,P=0.15);观察期结束时A、B两组间PD20 - FEV1水平比较,差异有统计学意义(t=13.29,P=0.000).(4)观察前、后24h尿17 -OHCS水平A组分别为(14.27±3.41) nmol/L、(14.43±3.69) nmol/L,B组分别为(14.31±3.66) nmol/L、(14.56±3.37)nmol/L,两组比较差异均无统计学意义;观察前、后24h尿17-KS水平A组分别为(22.43±5.69)nmol/L、(22.07±5.21) nmol/L,B组分别为(22.40±5.04)nmol/L、(22.54±4.74)nmol/L,两组比较差异均无统计学意义.(5)观察期结束后2周血清ALT水平A、B两组分别为(20.39±9.12)U/L、(20.83±7.83) U/L,差异无统计学意义(t=0.26,P=0.79);AST水平A、B两组分别为(20.68±8.67) U/L、(21.44±8.60) U/L,差异无统计学意义(t=0.45,P=0.66).结论 小剂量阿奇霉素口服12周,并联合沙美特罗替卡松吸入可降低哮喘患儿的支气管高反应性,但未减少患儿的有症状天数,也未使FEV1、PEF较单独应用沙美特罗替卡松改善明显,对患儿肾上腺功能及肝功能无影响.     

Acid suppression does not change respiratory symptoms in children with asthma and gastro-oesophageal reflux disease.

BACKGROUND: Epidemiological studies have shown an association between gastro-oesophageal reflux disease (GORD) and asthma, and oesophageal acid perfusion may cause bronchial constriction. However, no causative relation has been proven. AIM: To assess whether acid suppression would lead to reduced asthma symptoms in children with concomitant asthma and GORD. METHODS: Thirty eight children (mean age 10.8 years, range 7.2-16.8; 29 males) with asthma and a reflux index > or =5.0 assessed by 24 hour oesophageal pH monitoring were randomised to 12 weeks of treatment with omeprazole 20 mg daily or placebo. The groups were similar in age, gender, mean reflux index, and asthma severity. Primary endpoints were asthma symptoms (daytime wheeze, symptoms at night, in the morning, and during exercise) and quality of life (PAQLQ). Secondary endpoints were changes in lung function and the use of short acting bronchodilators. At the end of the study a repeated pH study was performed to confirm the efficacy of acid suppression. RESULTS: The change in total symptom score did not differ significantly between the omeprazole and the placebo group, and decreased by 1.28 (95% CI -0.1 to 2.65) and 1.28 (95% CI -0.72 to 3.27) respectively. The PAQLQ score increased by 0.62 (95% CI 0.29 to 0.95) in the omeprazole group compared to 0.50 (95% CI 0.29 to 0.70) in the placebo group. Change in lung function and use of short acting bronchodilators were similar in the groups. The acid suppression was adequate (reflux index <5.0) under omeprazole treatment. CONCLUSION: Omeprazole treatment did not improve asthma symptoms or lung function in children with asthma and GORD.     

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.