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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.

Inhaled corticosteroids (ICSs) are the cornerstone and the first stage of asthma treatment. The objective of this study was to synthesize data on the potential effects of ICSs on growth in children. Studies on the short-term impact of ICSs on growth evaluated by knemometry cannot be extrapolated to the medium or long term and therefore have no utility in real life for a given person. In the medium term, the various ICSs given at the usual doses cause a small reduction in growth after 6 months of treatment. This slowdown occurs at the beginning of treatment, especially in younger children, and the growth velocity corrects itself later but without catching up. In the long term, the prolonged use of ICSs seems to induce a small reduction in the final size in adulthood (close to 1cm) occurring in the first 2 years of treatment without worsening over time. The impact of gender, age at onset of treatment, different ICSs, modes of inhalation, and severity of asthma should also be studied further. The benefit of ICSs in asthma treatment is greater than the risk of side effects, including on growth. The majority of the therapeutic effect is obtained for small to moderate doses of ICSs. Regular adjustment of ICS dose for optimal asthma control should also reduce ICS dose and the impact on growth.

Growth impairment in children with asthma, as a consequence of inhaled corticosteroids (ICS), is a major issue. Adverse systemic effects of ICS have been reviewed extensively, but no clinically relevant effects are reported if they are used in an appropriate dose as advocated in most guidelines. Growth studies can be divided into knemometry studies, intermediate term studies, and long term studies up to final adult height. These different studies provide different information. Knemometry demonstrates a dose dependent systemic effect, while all intermediate term studies demonstrate growth reduction of approximately one cm after one year of treatment. Most reassuring is that this delay seems to be temporary. The one study with a follow-up to final height shows no differences between the ICS and non-ICS treated children. The studies suggest that the use of ICS with respect to growth is safe if these drugs are used in a low to medium dose.

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.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.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.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; P0.01]; BDP-CFC estimate of difference, -0.13 [95% CI, -0.19 to -0.06 mm/wk; P0.001]). 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.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.

Growth of very low birthweight (VLBW) infants is used to monitor nutrition and intrauterine velocity is taken as the desired goal.We hypothesised that beside nutrition growth failure is caused by disease severity.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.Birthweight and gestational age were lower in 22 ventilated than in 23 unventilated infants (p0.01). 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 (p0.01) up to day 35, respectively. Chronic lung disease occurred in 12 infants, five of whom were treated with dexamethasone. Artificial ventilation (p0.01) and dexamethasone treatment (p0.05) 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 (p0.05) in ventilated than in non-ventilated infants, respectively. The correlation of LLL growth with body length (r=0.31, p0.05) and head growth (r=0.42, p0.01) was weak. Dexamethasone arrested growth; median LLL gain was 0.21 and 0.31 mm/d in ventilated infants with and without dexamethasone (p0.05).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.

Inhaled corticosteroids are an established treatment for asthma in childhood. The risk of adverse events associated with conventional doses of inhaled corticosteroids is low, but in children with asthma concern remains about the potential effects of these compounds on growth. Short-term growth in children can be measured with knemometry. This technique measures changes in lower leg length that can be detected over periods as short as days or even intradaily. However, nonlinearity of lower leg growth and the complexity of statural growth confound any attempts to derive a predicted height from short-term measurements of the lower leg. Knemometry is better at detecting growth suppression than growth promotion. With knemometry, inhaled fluticasone propionate 200 microg/day had no effect on lower leg growth, but beclomethasone propionate 400 microg/day significantly reduced lower leg growth. Inhaled budesonide also caused a dose-dependent reduction in lower leg growth, but this only reached significance at the 800 microg/day dose. Long-term growth in children is measured with stadiometry. Growth velocity can only be determined from measurements of height taken over a period of at least 1 year. There is no evidence that inhaled corticosteroids at conventional doses have an adverse effect on the final height of children, but it is important to be aware of the growth-impairing effect of poorly controlled asthma. All children with asthma receiving inhaled corticosteroids should have their growth monitored, and any deviation from the expected pattern should be investigated. The effect of early intervention with inhaled steroids in childhood warrants further investigation.

Short-term lower leg growth, the insulin-like growth factor axis, and collagen turnover were assessed in 16 adolescents with asthma during treatment with inhaled budesonide, 800 micrograms/d, from a pressurized metered dose inhaler with a volume spacer. The design was a randomized double blind, placebo-controlled two-period crossover trial with treatment periods of 4 weeks and a 1-week wash-out. Lower leg growth was assessed by knemometry. Serum levels of insulin-like growth factor-I, insulin-like growth factor-binding protein-3, and the following markers of collagen turnover were evaluated: Serum markers of type I collagen formation and degradation; the carboxy-terminal propeptide of type I procollagen and the carboxy terminal pyridinoline cross-linked telopeptide of type I procollagen (ICTP), the serum marker of type III collagen formation; the amino-terminal propeptide of type III procollagen (PIIINP) and the urinary concentrations of the type I collagen degradation products pyridinoline (PYD) and deoxypyridinoline (DPD) cross-links. Mean lower leg growth velocity was suppressed from 0.51 mm/week during placebo to 0.18 mm/week during budesonide treatment (p < 0.001). No statistically significant effects on insulin-like growth factor-1, insulin-like growth faster-binding protein-3, or carboxy-terminal propeptide of type I procollagen were observed. ICTP and PIIINP were reduced with 2.3 and 2.5 micrograms/liter (p < 0.001 and p < 0.001, respectively) during budesonide treatment, urinary concentrations of PYD and DPD with 32.9 nmol/mmol creatinine (p < 0.005) and 6.8 nmol/mmol creatinine (p < 0.005), respectively. Significant correlations between lower leg growth velocity and ICTP, PIIINP, PYD, and DPD during placebo (p < 0.01, p < 0.05, p < 0.01, and p < 0.01) and budesonide (p < 0.05, p < 0.05, p < 0.05, and p < 0.05) periods were found. Short term lower leg growth suppression in adolescents treated with inhaled budesonide, 800 micrograms/d, reflects suppression of type I and III collagen turnover.

Linear growth can be divided into three phases: during infancy it is influenced mainly by nutrition; thereafterthroughout childhood it comes under hormonal control; puberty constitutes the third phase. The pubertal growth spurt, which may account for up to 30 cm of linear growth, results from an increase in growth hormone pulse amplitude that is mediated by sex steroids. The rate of growth in childhood, onset of puberty and final height are determined by the impact of a range of environmental factors on genetic potential. These variables and the effect of asthma itself need to be taken into account when assessing the possible effect of inhaled corticosteroids on growth. Many asthmatic children have a slower growth rate than normal children, and a physiological delay in puberty which does not affect final adult height. Prolonged administration of oral corticosteroids retards growth. The mechanism is not fully understood, but may involve an indirect effect on growth hormone secretion following adrenal suppression. Short-term deceleration of growth has been demonstrated by knemometry in children taking inhaled corticosteroids, but there is no evidence of long-term growth suppression with conventional doses of inhaled corticosteroids. Growth should be monitored in children taking over 0·8 mg day −1 of inhaled corticosteroid, but the priority should be to treat the asthma adequately.

Rationale Low dose topical corticosteroids (CS) have either no effect on growth velocity (GV) or transient effects without impact on final adult height. Although many growth studies have been conducted; the relationship between CS exposure and GV, the no-effect exposure level and the relative sensitivity of GV versus cortisol suppression as markers of CS exposure, are poorly defined. Methods The data from 32 published stadiometry and knemometry studies were collated and CS exposure estimated in cortisol equivalents (CE, pg.h/mL). This was compared to the annualized ▵GV data (cm/y). Results ▵GV and CE were highly correlated and described by a non-linear sigmoid Emax model. The model predicted rank order potential to reduce GV, expressed as multiples of the pediatric dose (μg/d) were: oral prednisolone (5000μg/d) 0.14 > inhaled beclomethasone (400μg/d) 0.55 > inhaled budesonide (400μg/d) 0.68 > intranasal triamcinolone (220μg/d) 0.77 > inhaled triamcinolone (400μg/d) 0.78 > intranasal beclomethasone (336μg/d) 0.89 > inhaled mometasone (200μg/d) 2.0 > intranasal budesonide (128μg/d) 2.6 > inhaled fluticasone (200μg/d) 2.8 > intranasal mometasone (100μg/d) 120 > intranasal fluticasone (100μg/d) 150. Values >1 predict no significant impact on GV. The model also predicted that a detectable reduction in plasma cortisol should be apparent when ▵GV falls below −0.8cm/y, an equivalence endpoint used in growth studies. Conclusions Since ▵GV was non-linearly related to CS exposure, no-effect dose regimens are possible for CS with low systemic exposure. It also appears unlikely that growth inhibition should occur in the absence of detectable reductions in cortisol.