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Background: Fluticasone propionate/formoterol (FP/FORM) is a pressurized metered-dose inhaler (pMDI; Flutiform®) approved for use in adolescents and adults and under development for pediatric use. Objective: To compare short-term growth in asthmatic children treated with FP/FORMtrial in an assessor-blinded, randomized, three-way crossover trial with run in, wash out, and active treatment periods, each of 2 weeks duration. Interventions were FP/FORM 100/10 μg b.i.d. with an AeroChamber Plus®)Flow-Vu®)Spacer, FP pMDI (Flixotide®)) 100 μg b.i.d. with a Volumatic®)spacer, and extra-fine BDP breath-actuated inhaler (Aerobec®)/QVAR®)Autohaler®)) 100 μg b.i.d. Lower leg growth rate (LLGR) was measured by knemometry. Results: The least square (LS) mean difference in LLGR between FP/FORM and FP (per protocol population) was-0.006 mm/week (95% CI:-0.095 to 0.084; p < 0.001 for noninferiority [noninferiority margin -0.200 mm/ week]). Both treatments elicited no change from baseline off-treatment growth rate. The LS mean treatment difference of FP/FORM versus BDP was 0.116 mm/week (95% CI:-0.004 to 0.235; p=0.057) and of FP versus BDP 0.163 mm/week (95% CI:0.078-0.249; p < 0.001). Results in the full analysis population were: FP/ FORM versus FP -0.012 mm/week (95% CI:-0.080-0.056; p < 0.001); FP/FORM versus BDP 0.143 mm/week (95% CI: 0.064-0.222; p < 0.001); FP versus BDP 0.163 mm/week (95% CI: 0.093-0.233; p < 0.001). Conclusions: FP/FORM pMDI with AeroChamber and FP pMDI with Volumatic spacer did not affect lower leg growth, measured by knemometry, in asthmatic children. Conversely, extra-fine BDP from a breath-actuated inhaler resulted in short-term growth suppression. [ABSTRACT FROM AUTHOR]

Background Pharmacodynamic assessment of the systemic effect of inhaled corticosteroids (ICSs) is often done by measuring 24-hour urine free cortisol (UFC) excretion. Knemometry assessing short-term lower-leg growth rate (LLGR) is a more rarely used alternative. Objective The primary aim of this study was to compare the sensitivity of LLGR and 24-hour UFC excretion for evaluating systemic exposure to ICSs in prepubertal children with asthma. The secondary aim was to evaluate factors influencing the precision of LLGR calculated by the traditional 1 leg nonparametric method versus a new 2 leg parametric method. Methods The study evaluated 60 children with mild asthma aged 5 to 12 years participating in a randomized controlled trial of ICSs with longitudinal concomitant assessments of LLGR and 24-hour UFC excretion. The sensitivity of the safety assessments was analyzed by comparing LLGR and 24-hour UFC in the placebo run-in period with values in the ICS treatment period by using paired t tests. Factors with a potential influence on LLGR were analyzed by means of ANOVA and the Levene test of homogeneity. Results The mean LLGR was significantly reduced during the ICS versus placebo run-in periods: 0.18 mm/wk (SD, 0.55 mm/wk) versus 0.45 mm/wk (SD, 0.39 mm/wk), with a mean difference of 0.27 mm/wk (95% CI, 0.05-0.48 mm/wk; P = .02). In contrast, there was no difference in 24-hour UFC excretion: 6.91 nmol/mmol (SD, 4.67 nmol/mmol) versus 7.58 nmol/mmol (SD, 6.17 nmol/mmol), with a mean difference of 0.67 nmol/mmol (95% CI, −1.13 to 2.48 nmol/mmol; P = .46). We observed no significant difference in parametric determined LLGR caused by the child's age or sex, investigator, or season of measurement, whereas some differences were observed for the nonparametric LLGR. Conclusion These findings suggest that knemometry is a more sensitive pharmacodynamic measure of systemic effects of ICSs than 24-hour UFC excretion and that a parametric determination of LLGR increases the sensitivity of the method. These findings should be considered by legislative authorities in the future. [ABSTRACT FROM AUTHOR]

Purpose A dry powder inhaler formulation of the inhaled corticosteroid fluticasone furoate (FF) is being evaluated for use in children. An important potential risk associated with the use of inhaled corticosteroids in children is growth suppression. Therefore, the aim of this study was to assess the short-term lower leg growth in children with asthma treated for 2 weeks with inhaled FF versus placebo from the ELLIPTA inhaler. Methods Prepubertal children with persistent asthma (n = 60; aged 5 to <12 years) were recruited into a randomized, double-blind, placebo-controlled, 2-way crossover, noninferiority study. The study consisted of four 2-week periods: run-in, 2 treatment periods, 1 washout period, and a 1-week follow-up period. Interventions were FF 50 µg and placebo once daily in the evening. Lower leg length was measured by using knemometry. Findings The randomized ITT population comprised 36 boys and 24 girls with a mean age of 8.7 (standard deviation, 1.5; range, 5–11) years; 58% had a duration of asthma ≥5 years. Fifty-eight subjects completed both treatment periods. The least squares mean growth rate was 0.31 mm/week during treatment with FF and 0.36 mm/week during the placebo period. The difference in adjusted least squares mean growth rates between FF and placebo was –0.052 mm/week with a 95% CI of –0.122 to 0.018. This finding was greater than the prespecified noninferiority margin of –0.20 mm/week. The overall incidence of adverse events was 35% with placebo and 22% with FF. Implications Inhaled FF 50 µg provided once daily for 2 weeks was noninferior to placebo in terms of effects on short-term lower leg growth in children with asthma. To further quantify the risk of growth suppression in children, intermediate-term growth studies should be conducted. Inhaled FF 50 µg was well tolerated in this study population. ClinicalTrials.gov identifier: NCT02502734. [ABSTRACT FROM AUTHOR]

During recent years, extra-fine particle inhaled corticosteroids with a median aerodynamic diameter ≤2 μm have been introduced in the treatment of asthma. The aim of this paper was to review pharmacokinetics and systemic activity of extra-fine particle hydroalkane pressurized metered dose inhaled (pMDI) ciclesonide and beclomethasone dipropionate in children. A literature review was performed. Systemic bioavailability of oral and pulmonary deposition of extra-fine ciclesonide and beclomethasone dipropionate was 52% and 82%, the half-life in serum 3.2 and 1.5 h and first-pass hepatic metabolism >99% and 60%, respectively. Secondary analyses of urine cortisol/creatinine excretion found no effects of ciclesonide pMDI between 40 and 320 μg/day or of beclomethasone dipropionate pMDI between 80 and 400 μg/day. Ciclesonide pMDI 40, 80 and 160 μg/day caused no effects on short-term lower leg growth rate as assessed by knemometry. Ciclesonide 320 μg/day was associated with a numerically short-term growth suppression equivalent to 30% which was similar to 25% and 36% suppression caused by beclomethasone dipropionate HFA and CFC 200 μg/day, respectively. Consistent with the differences in key pharmacokinetic features, beclomethasone dipropionate is associated with a systemic activity detected by knemometry at a lower dose than ciclesonide. Whether that correlates with a clinically important difference remains to be explored. Assessments of systemic activity of beclomethasone dipropionate <200 μg/day and of ciclesonide >180 μg/day as well as head-to-head comparisons are warranted. Preferably, such studies should apply the sensitive method of knemometry. [ABSTRACT FROM AUTHOR]

Background: A combination of the inhaled corticosteroid budesonide and the long-acting β2-agonist formoterol has been formulated in a novel dry powder inhaler, Spiromax®. The objective was to compare lower leg growth in children with asthma treated with inhaled budesonide+formoterol (BF) delivered from the Spiromax inhaler with BF from the Symbicort Turbohaler®. Methods: Prepubescent children with persistent asthma ( n=75, aged 6-11 years) were included in a randomized, double-blind, double-dummy, placebo-controlled, three-way crossover study with active treatment and placebo periods of 2 weeks duration. Lower leg length was measured every second week. As a secondary outcome parameter, 24-hr urine was collected for assessment of free cortisol. Interventions were dry powder BF 160+9 μg twice daily (b.i.d.; delivered dose) from the Spiromax inhaler and dry powder BF 200+12 μg b.i.d. (metered dose) from the Symbicort Turbohaler. Results: The least squares mean difference in lower leg growth rates (LLGR) between BF Spiromax and Symbicort Turbohaler was −0.086 mm/week [95% confidence interval (CI) −0.203, 0.032]. The pre-specified non-inferiority margin was −0.200 mm/week, so the lower limit of the 95% CI was just outside this margin. The difference between BF Spiromax and placebo was −0.20 mm/week (95% CI: −0.322, 0.086); p<0.001), between Symbicort Turbohaler and placebo −0.118 mm/week (95% CI: −0.236, −0.001; p=0.048). No statistically significant differences were seen in urine free cortisol assessments. Conclusions: As the lower limit of the CI of LLGR was marginally outside of the pre-specified non-inferiority margin between BF Spiromax 160+9 μg b.i.d. and Symbicort Turbohaler 200+12 μg b.i.d., non-inferiority could not be demonstrated. Further studies may be needed for comparison of systemic activity of BF Spiromax and Symbicort Turbohaler in children before firm conclusions about their comparability may be drawn. [ABSTRACT FROM AUTHOR]

Abstract: Background: Beclomethasone dipropionate–hydrofluoroalkane (BDP-HFA) is a non–chlorofluorocarbon (CFC)-propelled metered dose inhaler. Data is needed to support the registration of BDP-HFA in pediatric populations for countries in the European Union. Objective: The aim of the study was to assess short-term lower leg growth in children with asthma during treatment with BDP-HFA 100 μg BID compared with BDP-CFC 200 μg BID. Methods: Children with asthma were included in this open-label, randomized, crossover study with 2-week run-in, active treatment, and washout periods. Lower leg length was measured every second week. As a secondary outcome parameter, 24-hour urine was collected for assessment of free cortisol. Interventions were inhaled BDP-HFA 100 μg BID with AeroChamber Plus spacer and BDP-CFC 200 μg BID with Volumatic spacer. Results: In 63 patients with asthma aged 5 to 11 years, BDP-HFA 100 μg BID was noninferior to BDP-CFC 200 μg BID, as the lower margin of CI (–0.03 to 0.10 mm/wk) of the estimated difference (0.03 mm/wk) was greater than the prespecified lower limit for noninferiority of –0.12 mm/wk. Mean (SD) lower leg growth rate during run-in, BDP-HFA 100 μg BID, and BDP-CFC 200 μg BID was 0.36 (0.17), 0.27 (0.21), and 0.23 (0.18) mm/wk, respectively (BDP-HFA estimate of difference, –0.09 [95% CI, –0.16 to –0.03 mm/wk; P < 0.01]; BDP-CFC estimate of difference, –0.13 [95% CI, –0.19 to –0.06 mm/wk; P < 0.001]). No statistically significant differences were seen in urinary free cortisol assessments. Eight and 6 mild to moderate adverse events in 10 children were reported during treatment with BDP-HFA and BDP-CFC, respectively. One event in each group was judged to be probably related to the study medication; no others were judged to be related. Conclusions: No statistically significant differences were found in lower leg growth between BDP-HFA 100 μg BID with AeroChamber Plus spacer and BDP-CFC 200 μg BID with Volumatic spacer during 2-week treatment. Evidence of differences in systemic activity between the treatments was not found. EudraCT registration: 2007-007455-14. [Copyright &y& Elsevier]

When validated recommendations for standardization and measurement procedures are used short-term assessment of lower leg growth by knemometry is a highly accurate and reproducible method for assessment of systemic activity of inhaled glucocorticoids. Crossover and parallel designs applying consistent measurement intervals can be used. Crossover designs with a single-blind run in and washout and doubleblind active periods are as sensitive as designs using randomized placebo periods. In populations of children, short-term knemometry appears to be capable of defining specific glucocorticoids, application devices and doses that do not suppress long-term height growth. Although no specific cut-off level can be identified in individuals from the available randomized, double-blind short-term knemometry and intermediateterm height growth rate studies, good evidence have been provided that if the short-term lower leg growth suppression in populations of children is higher than approximately 25%, the risk of intermediate-term growth suppression becomes significant with a mean height growth rate retardation in the range of approximately 0.5-1.5 cm during the first year of treatment. Short-term knemometry should be performed as an integral part of the safety assessments of new inhaled glucocorticoids and inhalation devices in children with asthma, before intermediateterm height growth evaluations are initiated. [ABSTRACT FROM AUTHOR]

Measurement of short-term lower-leg growth rate in children by knemometry has become established as an integral part of the available measures of systemic activity of inhaled corticosteroids (ICS) in children. The aim of this study was to compare the effects of the novel ICS ciclesonide (CIC) and the ICS fluticasone propionate (FP) on lower-leg growth rate and hypothalamic-pituitary-adrenal-axis function in children with mild asthma. In a double-blind, placebo-controlled, threeperiod crossover study, 28 children, aged 6-12 yr, sequentially received daily doses of CIC 320 lg, FP 375 lg (330 lg ex-actuator) and placebo via a spacer in a randomized order. Each 2-wk treatment period was followed by a 2-wk washout period. Knemometry was performed at the beginning and end of each treatment period. Cortisol levels in 12-h overnight urine were measured at the end of each treatment period. No statistically significant differences were seen in lower-leg growth rates between CIC (0.30 mm/wk) and placebo (0.43 mm/wk) treatments. Lower-leg growth rate during FP treatment (0.08 mm/wk) was significantly reduced compared with both placebo [least squares (LS) mean: -0.35 (95% CI: -0.53, -0.18; p = 0.0002)] and CIC [LS mean: -0.23 (95% CI: -0.05, -0.40; p = 0.0137)]. Cortisol levels in 12-h overnight urine were significantly lower in the FP group when compared with CIC (p < 0.05); however, there were no statistically significant differences between each of the active treatments and placebo. CIC had no significant effect on lower-leg growth rate in children aged 6-12 yr with mild asthma. In contrast, a similar dose of FP significantly reduced lower-leg growth rate compared with placebo and CIC. [ABSTRACT FROM AUTHOR]

Short-term knemometry is a highly sensitive and accurate method for non-invasive assessment of systemic activity of inhaled corticosteroids in children with asthma. However, there are no randomized data available to elucidate the relation between inhaled corticosteroid suppressed short-term lower leg and height growth. The aim of the present study was to assess the relation between short-term lower leg and 1-yr height growth in children with asthma treated with inhaled budesonide from the new Pulairmax® inhaler 200 lg once daily in the morning or montelukast 5 mg once daily. A total of 52 pre-pubertal children with asthma were included in a randomized open-label parallel group study. Length of the lower leg and height were measured by knemometry and stadiometry, respectively, at study entry and after 2, 4, 12, 20, 28, 36, 44 and 52 wks. Lower leg and height growth rates were significantly lower in the budesonide than in the montelukast group (p < 0.0001). Mean 2-wks lower leg growth rate was 0.17 mm/wk in the budesonide and 0.39 mm/wk in the montelukast treated children (p = 0.02). Mean 1-yr height growth rate was 5.51 cm/yr in the budesonide and 6.51 cm/yr in the montelukast group [95% CI: (0.20; 1.79)]. There was a strong linear correlation between lower leg and height growth in both groups, rho = 0.96 (budesonide) and 0.98 (montelukast). In conclusion, 1-yr height growth suppression of budesonide 200 μg administered via the Pulairmax® inhaler once daily in the morning was indicated from suppressed short-term lower leg growth providing evidence that shortterm knemometry is able to predict 1-yr height growth suppression of inhaled corticosteroids. Short-term knemometry should be performed as part of the safety assessments of new inhaled corticosteroids and inhalation devices in children with asthma before long-term height growth evaluations are initiated. [ABSTRACT FROM AUTHOR]

Abstract : Background: Growth of very low birthweight (VLBW) infants is used to monitor nutrition and intrauterine velocity is taken as the desired goal. Aim: We hypothesised that beside nutrition growth failure is caused by disease severity. Methods: Prospective longitudinal study of 45 VLBW infants undergoing intensive care, mechanical ventilation was used as proxy to disease severity. Nutritional intake, body weight, length, head circumference, and lower leg length (LLL) were measured during the first 5 weeks of life. Results: Birthweight and gestational age were lower in 22 ventilated than in 23 unventilated infants (p <0.01). Median daily intake was 3.2 and 2.8 g/kg for protein (n.s.), 108 and 112 kcal/kg for energy (n.s.), 175 and 160 ml/kg for volume (p <0.01) up to day 35, respectively. Chronic lung disease occurred in 12 infants, five of whom were treated with dexamethasone. Artificial ventilation (p <0.01) and dexamethasone treatment (p <0.05) were independent predictors of weight gain. Median weight gain (8.2 and 9.7 g/kg/d), head growth (0.45 and 0.60 cm/week), and LLL growth (0.28 and 0.35 mm/d) were lower (p <0.05) in ventilated than in non-ventilated infants, respectively. The correlation of LLL growth with body length (r =0.31, p <0.05) and head growth (r =0.42, p <0.01) was weak. Dexamethasone arrested growth; median LLL gain was 0.21 and 0.31 mm/d in ventilated infants with and without dexamethasone (p <0.05). Conclusion: In VLBW infants, fetal growth rates are not reached with current feeding practice. In addition to inadequate nutrition, factors directly related to disease and treatment contribute to postnatal growth failure. [Copyright &y& Elsevier]

Background: Knemometry has been used to accurately measure linear growth in both neonates and children over the last 20 years. It has been used principally as a research tool. Aim: To investigate whether serial measurement of lower leg length (LLL) by knemometry is a useful addition to other measures of growth in the neonatal unit. Methods: A 1-year prospective hospital-based cohort study from 2004 to 2005. Knemometry was performed every 3–4 days from the time of consent to time of discharge. Infants were grouped by gestation at birth for analysis (<28 weeks, 28–31 weeks, 32–36 weeks and >36 weeks gestation). The main outcome assessed was longitudinal growth. Subgroup analyses were performed on infants <10th percentile for weight, surgical infants and infants who had received antenatal steroids. Results: LLL measured by knemometry correlated well with postmenstrual age ( r = 0.93) and weight ( r = 0.93). The mean (SD) increase in LLL was 0.45 (0.7) mm/day. Conclusion: Change in LLL correlates well with change in weight and postmenstrual age in the neonatal period but adds little extra information to routine practice in the neonatal unit. [ABSTRACT FROM AUTHOR]

Abstract: Background: It is essential to assess potential growth effects of any newly developed corticosteroid. Fluticasone furoate is a recently approved, enhanced- affinity intranasal corticosteroid with low systemic bioavailability and proven efficacy in treating allergic rhinitis. Objective: The aim of the current study was to assess whether treatment with fluticasone furoate nasal spray affected the short-term lower-leg growth rate in children with allergic rhinitis. Methods: Prepubertal children with seasonal or perennial allergic rhinitis of at least 1 year''s duration were included in this single-center, randomized, double-blind, placebo-controlled, crossover study. The study consisted of 4 periods, each of 2 weeks'' duration screening, then 2 treatment periods separated by a washout). Study medications were fluticasone furoate nasal spray 110 µg and placebo nasal spray, both administered QD in the morning. The primary end point, lower-leg growth rate (measured in millimeters per week), was assessed by knemometry. Adverse events were also assessed. Results: Fifty-eight patients were randomized to the study and comprised the intent-to-treat (ITT) population (mean [SD] age, 9.1 [1.4] years; 39 males, 19 females). Five patients were excluded from the ITT group due to protocol violations; thus, 53 patients (mean [SD] age, 9.0 [1.4] years; 35 males, 18 females) comprised the growth population (a de facto per-protocol group). In the growth population, the adjusted mean lower-leg growth rate was 0.40 and 0.42 mm/wk with fluticasone furoate and placebo, respectively. The difference in adjusted mean lower-leg growth rate between fluticasone furoate and placebo was -0.016 mm/wk (95% CI, −0.13 to 0.10). Fluticasone furoate was noninferior to placebo, as the lower boundary of the 95% CI was above the prespecified noninferiority margin of −0.20 mm/wk. These results were supported by the ITT analysis. Fluticasone furoate nasal spray was well tolerated and had an adverse-event profile similar to that of placebo nasal spray. Nasopharyngitis (placebo, 4; fluticasone furoate, 1) and headache (placebo, 3; fluticasone furoate, 1) were the most frequent adverse events during the treatment periods. Conclusion: In this study, fluticasone furoate nasal spray 110 µg QD for 2 weeks had no effect on lower-leg growth rate in these prepubertal children with allergic rhinitis. [Copyright &y& Elsevier]

Background: Treatment with topical glucocorticoids in children with atopic eczema may be associated with systemic adverse effects, such as suppression of growth. Aim: To asses if treatment with topical mometasone furoate 0.1% or topical tacrolimus 0.1% affects short-term growth in children with atopic eczema. Primary outcome measures were lower leg growth rates measured by knemometry. Methods: Twenty 5- to 12-year-old prepubertal children with atopic eczema were included in a randomised, investigator-blind crossover study with five periods: two treatment periods, a run in, a wash out and a run out. All periods were of 2-week duration. The subjects applied mometasone furoate ointment 0.1% once daily during one treatment period and tacrolimus ointment 0.1% twice daily during the other treatment period. Results: As compared to run in mean lower leg growth rate during mometasone furoate and tacrolimus treatment was reduced by 0.09 and 0.06 mm/week, respectively, (F = 1.12, p = 0.35). Consistently, no statistically significant effects on urine levels of eosinophil protein X and crossed-linked N-telopeptides were detected. Conclusion: Treatment with mometasone furoate or tacrolimus does not affect short-term growth in children with mild to moderate atopic eczema. [ABSTRACT FROM AUTHOR]

Inhaled beclomethasone dipropionate (BDP) with the propellant hydrofluroroalkane-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 μg twice daily was equivalent to BDP CFC MDI 100 μg 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 μg, BDP CFC 100 μg and 200 μg 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 μg, BDP CFC 100 μg and 200 μg 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 μg and BDP CFC 100 μg 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 μg 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. [ABSTRACT FROM AUTHOR]

Background : Knemometry studies of growth suppressive effects of inhaled glucocorticoids in children with asthma usually allow participating children to use concomitant inhaled β 2 -agonists. Systemic β 2 -agonists, however, have been found to suppress growth hormone secretion and this has caused concern about a possible confounding effect of inhaled β 2 -agonists on results of growth studies of exogenous glucocorticoids. Aim : The study evaluated whether inhaled salbutamol adversely affects short-term growth. Subjects and methods : Fifteen children aged 6–12 years with mild asthma were enrolled in a single-blind, randomized crossover study with two 2-week treatment periods and a 1-week run-in. During the active period treatment dry powder salbutamol (Ventoline Diskhaler®) 200&ThickSpace;µg was inhaled three times a day. During the comparative period no treatment was given. Knemometry of the right lower leg was performed on the first and the last day of each period. Results : Mean lower leg growth rates (SEM) during no-treatment and salbutamol periods were 0.35 (0.06) and 0.42 (0.07)&ThickSpace;mm per week, respectively ( P &ThickSpace;=&ThickSpace;0.35, t &ThickSpace;=&ThickSpace;-0.98, 95% CI: 0.25–0.93&ThickSpace;mm per week). Conclusions : Inhaled salbutamol 200&ThickSpace;µg three times daily does not suppress short-term growth in asthmatic children. Inhaled β 2 -agonists in equipotent doses and regimens can be safely used in short-term knemometric growth studies of exogenous glucocorticoids without any risk of confounding the results. [ABSTRACT FROM AUTHOR]

Background: Measurement of short-term lower-leg growth rate in children by means of knemometry has become established as an integral part of the available measures of systemic activity of topical steroids in children. Objective: We sought to determine the effects of clinically effective doses of the novel inhaled corticosteroid ciclesonide on lower-leg growth rate and hypothalamic-pituitary-adrenal axis function in children with asthma. Methods: In a double-blind, placebo-controlled, 4-period crossover study, 24 children aged 6 to 12 years sequentially received ciclesonide (40, 80, and 160 μg) in randomized order once daily in the evening. Each 2-week treatment period was followed by a 2-week washout period. Knemometry was performed at the beginning and end of each treatment period. Cortisol levels in 12-hour overnight urine were measured at the end of each treatment period. Results: No statistically significant differences were seen in lower-leg growth rates between any of the ciclesonide treatments and placebo. Lower-leg growth rates were 0.412 mm/wk for placebo, 0.425 mm/wk for 40 μg of ciclesonide, 0.397 mm/wk for 80 μg of ciclesonide, and 0.370 mm/wk for 160 μg of ciclesonide. There was no statistically significant dose-response effect. Likewise, no statistically significant differences or dose-response effects were found for urinary cortisol adjusted for creatinine. Conclusion: Short-term lower-leg growth rate and hypothalamic-pituitary-adrenal axis function are not affected by treatment with ciclesonide in doses intended for clinical use in children. [Copyright &y& Elsevier]

To assess the relation between short-term growth and intermediate term growth in children with asthma treated with inhaled glucocorticoids.An open 12 months parallel group trial with visits to the clinic on day 1, after 2, 4, 8, 12, 20, 28, 36, 44 and 52 weeks.Setting: Outpatient clinic in a secondary referral centre.Subjects: Sixteen children with asthma aged 9 (6–13) years; 16 matched healthy subjects.Knemometry and stadiometry.Interventions: Dry-powder inhaled budesonide 200 μg twice daily.Primary outcome measures: Intra-group comparisons of mean lower leg growth rates.Secondary outcome measures: Inter-group comparisons of mean lower leg growth rates and intra-group comparisons of mean height-standard deviation scores.One year mean lower leg growth rate (0.36 mm/week) did not differ from the rates during the 2 (0.27 mm/week;P = 0.23), 4 (0.33 mm/week;P = 0.54), 8 (0.36 mm/week;P = 0.79) or 12 (0.33 mm/week;P = 0.49) weeks intervals in the asthma group. Similarly, in the healthy children 2 (0.56 mm/week;P = 0.63), 4 (0.46 mm/week;P = 0.36), 8 (0.43 mm/week;P = 0.49) and 12 (0.43 mm/week;P = 0.66) weeks mean growth rates did not vary statistically significantly from the 1 year growth rate (0.42 mm/week). Mean lower leg growth rates, however, were consistently lower during all periods in the children with asthma (P = 0.02–0.03). At completion of the study mean height-standard deviation score in the asthma group (−0.19) was significantly suppressed as compared with the score at study entry (−0.03) (P = 0.02), whereas no statistically significant variation was detected in the control group.Short-term lower leg growth rates are consistent with intermediate term growth rates in group studies in children with asthma treated with inhaled dry powder budesonide 400 μg/day. Short-term group knemometry should be an integral part of growth evaluations of new inhaled glucocorticoids, doses and inhalation devices in children with asthma. [ABSTRACT FROM AUTHOR]

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 microg 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. [ABSTRACT FROM AUTHOR]

To assess the effects of steroid wet-wrap therapy on short-term growth and bone turnover, eight prepubertal (M:F,5:3) children with a median age of 5.1years (range 3.3-8.8) were studied over a 2-week period prior to therapy and at 2-week intervals during therapy. Short-term growth was assessed by measuring lower leg length velocity (LLLV) by knemometry and bone and collagen turnover was assessed by urinary deoxypyridinoline crosslink excretion corrected for creatinine excretion (DPD). Median duration of study during occlusive dressings was 12 weeks (range 2-18). Topical beclomethasone dipropionate diluted 1:10 or 1:4 in white soft paraffin was applied under tubular (Tubifast ® ) bandages in 7/8 children. Median LLLV before and during therapy were 0.43 mm/week (10 th ,90 th centile; 0.0,0.7) and 0.42 mm/week (10 th ,90 th centile; -0.35,1.01), respectively (not significant). Median DPD before and during therapy were 25.9 nmol/l/creatinine (10 th ,90 th centile; 20.8, 33.0) and 26.3 nmol/l/creatinine (10 th ,90 th centile; 21.7, 34.1) respectively (not significant). Non-invasive assessment of the effects of steroid wet-wrap therapy can be performed in children with eczema. These preliminary results show no substantial growth promoting or adverse effects of therapy. [ABSTRACT FROM AUTHOR]

Small preterm infants experience a unique postnatal period characterized by slow growth, inadequate nutrition and growth inhibiting treatments. Many have already been growth-restricted in utero. Studying this period is important when developing growth optimizing strategies for these infants and, in a broader context, as a model of extreme conditions that restrict growth. By following short-term growth of 48 very-low-birth-weight (VLBW; birth weight <1,500 g) infants for 9 postnatal weeks, we found that circulating insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 levels are low and reflect rigorously measured (knemometry and weight) concurrent growth velocity. Moreover, weight growth velocity is correlated with the ratio of lesser to highly phosphorylated IGFBP-1 but not with absolute IGFBP-1 concentrations. Thus, IGF-I, IGFBP-3 and the phosphorylation status of IGFBP-1 in circulation are likely to be involved in growth regulation during the postnatal period in VLBW infants. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: To investigate the impact of short-term growth measurements on predicting the individual growth response to GH treatment, and to elucidate the possible reasons for the limited accuracy of current growth prediction models for GH-treated children. Methods: Short-term growth measurements by knemometry and stadiometer in 99 short, GH-treated children (27 girls, 72 boys), aged 10.3 ± 2.3 years, from the Children’s University Hospital, Leipzig, Germany. Results: GH treatment significantly accelerated the mean height velocity (HV) from 4.3 ± 1.0 to 8.1 ± 1.8 cm/year during the first year of treatment, the average height standard deviation score (SDS) shifted by +0.52 SD. The variation in HV also increased, from S[sup 2] = 1.0 before to S[sup 2] = 3.4 cm[sup 2] /year[sup 2] during treatment. Lower leg length (LLL) velocity accelerated from 1.6 ± 0.7 before treatment to 3.4 ± 1.0 cm/year during the first 8 weeks of treatment. Four coefficients of correlation appeared clinically meaningful: (1) LLL velocity vs. body HV during the first year of GH treatment (r = 0.87), indicating that GH acts simultaneously on leg and rump growth; (2) early (first 8 weeks) LLL velocity vs. 1-year body HV during treatment, with r = 0.61 (R[sup 2] = 0.38), indicating that 38% of the variation in HV during the first year of treatment is already predictable by an initial 8-week period of knemometry; (3) early (first 8 weeks) LLL velocity vs. 1-year LLL velocity during treatment, with r = 0.63 (R[sup 2] = 0.39), and (4) early (first 8 weeks) LLL velocity vs. later LLL velocity, up to the end of the first year, with r = 0.53 (R[sup 2] = 0.28) indicating that the early response on lower leg growth persists for at least 1 year of GH treatment. Conclusions: (1) Thirty-eight percent of the variation in HV during the first year of GH treatment is predictable by an initial 8-week period of knemometry. This parallels early changes in biochemical markers of bone turnover after GH treatment. (2) There is evidence for a baseline variability in HV both in healthy children and in children with growth disorders that make growth prediction difficult.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Growth problems are often seen in children with asthma. Rarely, these problems may be caused by poor asthma control. Negatively-deviating growth curves in asthmatic boys aged 8–15 years are often associated with a chronic delay in growth and puberty. Daily treatment with any dose of systemic corticosteroids suppresses the growth rate for as long as the treatment is maintained. The risk of growth rate suppression due to inhaled corticosteroids depends on the dose, administration regimen and delivery device. The risk becomes significant with ≥800 μg budesonide from a metered-dose inhaler with a spacer, and with ≥400 μg budesonide or fluticasone propionate from a dry-powder inhaler. Regardless of the treatment modality applied, all children with asthma should have their height growth measured at least every 6 months, and indications for endocrine work-up should follow general criteria for a growth-insufficient child.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The relationship between ponderal, linear and lower leg growth in children recovering from severe malnutrition remains unclear. We report on the early growth of 141 severely malnourished Bangladeshi children aged 6 to 36 months of age who were followed for 90 d. Mean (SD) weight for height (WHZ) and height for age (HAZ) catch-up growth Z scores over the 90 d were 1.6 (0.85) and 0.47 (0.325) respectively. mean (SD) lower leg length growth was 10.35 (4.5) mm. Change in HAZ was significantly associated with initial WHZ, but linear growth occurred in the presence of severe wasting and no threshold WHZ score was identified. Lower leg length gain correlated throughout with ponderal indices but with change in HAZ score only after day 45. Only initial WHZ score and maternal height predicted for linear growth and only accounted for 20 % of total variance. We conclude that linear growth occurs early in severely malnourished children but that knemometry behaves as a ponderal index acutely. [ABSTRACT FROM PUBLISHER]

The analysis of short-term growth needs repetitive measurements of body stature or of segments of the body. When body stature is measured at monthly intervals, an irregular incremental pattern becomes obvious with a number of large-scale components such as series of prepubertal and pubertal growth spurts, seasonal influences on height gain, and influences of the psychosocial and economic background. When measurement intervals decrease, incremental patterns appear even more irregular, and a number of short-scale components become apparent that are distinct from measurement error. The review summarizes the analysis of short-term growth, and presents the current findings supporting different views on how growth progresses at short term. In particular, observations are presented that suggest growth being a pulsatile, a periodic, a saltatory, and a chaotic event. Some recent animal studies and studies in human newborns are added in detail as they illustrate short-term growth on the basis of accurate 24-hour measurements of the lower leg. The latter investigations support the idea of short-term growth being characterized by chaotic series of ‘mini growth spurts’ that occur at intervals of approximately 4–5 days, not only in human neonates, but also in rats. The amplitude of mini growth spurts ranges between 2 and some 10 mm, and growth velocity of each spurt also varies considerably so that one spurt needs between less than 1 and up to several days for completion. [ABSTRACT FROM AUTHOR]

Systemic activity of the intranasal glucocorticosteroid budesonide administrated once daily from a dry-powder inhaler (Turbuhaler®) was assessed by knemometry. Lower leg length was measured weekly in 38 children aged 7-15 (mean 11.3) years with allergic or perennial rhinitis. The design was a randomized, double-blind, parallel-group study. After 4 weeks' run-in, the children were allocated to 4 weeks' treatment with either budesonide 200 or 400 μg or placebo. Fourteen children in the budesonide 200-μg group, 13 in the 400-μg group, and 10 in the placebo group completed the study. In the placebo and budesonide 200-μg groups, growth velocities during run-in (0.36 and 0.28 mm/week, respectively) and treatment periods (0.34 and 0.27 mm/week, respectively) were almost identical. In the budesonide 400-μg group (run-in: 0.040 mm/week), a nonsignificant reduction in mean growth velocity of 0.18 mm/week was seen(P = 0.11). There were no statistically significant differences among the run-in mean lower leg growth velocities (F = 1.12; P = 0.34), among growth velocities during treatment (F = 1.10; P = 0.34), or among the run-in and treatment growth velocities in the three groups (F = 1.19; P = 0.32). These results provide good evidence that systemic activity is low in children with allergic or perennial rhinitis treated with once daily budesonide in doses of 200- and 400-μg administered intranasally from a dry-powder inhaler. [ABSTRACT FROM AUTHOR]

Glucocorticoid use in children is not only associated with the side effects which are seen in adults, but also with severe adverse effects on statural growth. As little as 2.5–5.0 mg prednisolone/day can cause a retardation in statural growth. A direct relationship exists between the dose of glucocorticoid used and statural growth. The use of knemometry, a sensitive technique for measuring the growth of long bones in children has increased the accuracy of growth rate measurements. Many factors, such as disease process, sex, dailyvs alternate day therapy, ethnic variations or whether the patient has been immobilized must be considered when evaluating the effects on stature of a particular glucocorticoid. Although alternate day therapy may benefit some patients (particularly those with juvenile chronic arthritis), not all patients respond beneficially to this type of regimen. New generations of glucocorticoids which may not be as detrimental to the growing child should now be considered. [ABSTRACT FROM PUBLISHER]

We studied the differential inhibitory effects of conjugated oestrogens on lower leg length and standing height increments in 17 excessively tall girls compared to a control group of 17 tall healthy untreated girls. Standing height, lower leg length and body weight were recorded at weekly or monthly intervals. Standing height velocity dropped from 150 microns/day to 122 microns/day, whereas daily weight gain increased from 17 to 48 g/day during oestrogen treatment. The oestrogen induced decrease of standing height velocity could be explained by a marked inhibition of lower leg growth velocity from 42 microns/day to 30 microns/day (native data) or 35 microns/day to 8 microns/day (data corrected for weight gain) (P less than 0.001), whereas no differences of trunk growth velocity could be detected. Thus, the findings strongly suggest that pharmacological doses of oestrogens only affect epiphyseal growth. [ABSTRACT FROM AUTHOR]

Cross-sectional and longitudinal studies of human growth have revealed almost every detail of the typical human growth pattern. Yet, the description of this pattern is still limited to the traditional vocabulary of 'growth rates', i.e. height or length differences divided by certain time intervals such as months or years. Almost no information is yet available on finer details of this pattern. This review concerns the existing experimental and clinical data collected by a novel and non-invasive technique of accurate lower leg length measurment named 'knemometry' that has been used for the study of short-term growth. This technique estimates the distance between heel and knee of the sitting child with an accuracy (technical error) of 0.09-0.16 mm. Several authors have presented evidence that lower leg growth is non-linear. There is not only a marked day-to-day variation of the lower leg length which far exceeds the error of the measurement itself, but there is also a characteristic up-and-down pattern of lower leg growth consisting of sharp growth spurts ('mini-growth-spurts') alternating with periods of decreased growth velocity every 30-55 days in 45 out of 73 healthy children. This patter can be visualized by the calculation of 'mean daily lower leg growth velocities', an approach that gives information on the kinetic properties of the growth process. In spite of much initial criticism, knemometry has opened a fascinating new dimension of the physiology of human growth and provided finer details of growth than hitherto obtainable by conventional techniques of growth measurement. [ABSTRACT FROM AUTHOR]

Recently a novel and non-invasive technique of lower leg length measurement (knemometry) was introduced. The method estimates the distance between heel and knee in the sitting child with an accuracy of 0.09 mm(SD). Two female patients with anorexia nervosa, aged 14:4 and 13:7 years, weighing minus 27 and minus 38% of normal weight for age, were measured repeatedly with this method within periods of 72 and 129 days during hospitalization und up to 133 days thereafter. During the first 40 days of hospitalization, patient 1 was measured 30 times and showed significant shrinkage of the lower leg length of -0.040 mm/day (P less than 0.001). Over the remainder of her hospital stay her mean lower leg length increment still was much less (+0.036 mm/day) than that expected just by increase of soft tissue due to rapid weight gain (+0.126 kg/day). The second patient also showed significant shrinkage of lower leg length during a 4 month period after discharge from the hospital (-0.009 mm/day, P less than 0.01). This is the first demonstration of long term lower leg shrinkage in children. Its origin remains unclear, but this shrinkage is clearly distinct from either arbitrary changes of lower leg length due to errors of measurement or changes of body diameters due to temporary alterations of soft tissue (i.e. during periods of weight loss). We speculate that progressive atrophic changes of the epiphyseal plates still open in both patients may account for the observed long term shrinkage of lower leg length. [ABSTRACT FROM AUTHOR]

Background: The growth-suppressive effect of systemic glucocorticoids in children is well established, however, recovery of growth after withdrawal of short-term treatment in school-age children has not been evaluated. Objective: To assess short-term growth after withdrawal of systemic glucocorticoids. Methods: A post-hoc analysis of data from a double-blind lower leg growth trial which compared 5 mg prednisolone once daily in the evening with placebo was performed. The study consisted of run-in, treatment, wash-out and run-out periods of 1 week duration. In 10 children with asthma (mean age 11 years) lower leg growth measured with the knemometer could be studied up to 3 weeks after withdrawal of prednisolone. Results: Mean (SEM) lower leg growth rates during run-in, prednisolone treatment and the first, second and third weeks after withdrawal of prednisolone were 0.48 (0.15), –0.27 (0.20), 0.53 (0.19), 0.72 (0.16) and 0.66 (0.14) mm/week, p < 0.001. Mean growth rates during run-in and the first, second and third weeks after withdrawal of prednisolone did not vary, p = 0.68. Conclusion: Recovery of suppressed lower leg growth rates occurs within a week after withdrawal of exogenous glucocorticoids. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]