Determinants of lung function and airway hyperresponsiveness in asthmatic children.

BACKGROUND: Asthma patients exhibit an increased rate of loss of lung function. Determinants to such decline are largely unknown and the modifying effect of steroid therapy is disputed. This cross-sectional study aimed to elucidate factors contributing to such decline and the possible modifying effect of steroid treatment. METHODS: We analyzed determinants of lung function and airway hyperresponsiveness (AHR) in a Scandinavian study of 2390 subjects from 550 families. Families were selected for the presence of two or more asthmatic children as part of a genetic study, Scandinavian Asthma Genetic Study (SAGA). RESULTS: The primary analysis studied the association between the lung function and delay of inhaled corticosteroids (ICS) after asthma diagnosis among asthmatic children and young adults with a history of regular ICS treatment (N=919). FEV(1) percent predicted (FEV(1)% pred) was 0.25% lower per year of delay from diagnosis until treatment (p=0.039). This association was significantly greater in allergy skin prick test negative children. There was no significant influence of gender, age at asthma onset, or smoking. In the secondary analysis of the whole population of 2390 asthmatics and non-asthmatics, FEV(1)% pred was inversely related to having asthmatic siblings (-7.9%; p<0.0001), asthma diagnosis (-2.7%; p=0.0007), smoking (-3.5%; p=0.0027), and positive allergy skin prick test (-0.47% per test; p=0.012), while positively related to being of female gender (1.8%; p=0.0029). Risk of AHR was higher by having asthmatic siblings (OR 2.7; p<0.0001), being of female gender (OR 2.0; p<0.0001), and having asthma (OR 2.0; p<0.0001). CONCLUSIONS: These data suggest that lung function is lower in asthmatics with delayed introduction of ICS therapy, smoking, and positive allergy skin prick test. Lung function is lower and AHR higher in female asthmatics and subjects with asthmatic siblings or established asthma.

Treatment of exercise-induced asthma with beclomethasone dipropionate in children with asthma.

A new hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP) aerosol markedly increases drug delivery to the airways. Therefore, even low doses of HFA-BDP should be effective, and the present study assesses this. A randomised, double-blind, crossover study was used to compare the effect of placebo, HFA-BDP 50 microg or 100 microg given q.d. (QVAR(TM) Autohaler(TM); 3M Pharmaceuticals, St. Paul, MN, USA) on exercise-induced bronchoconstriction and exhaled nitric oxide (eNO). After a 14-day run-in, 25 children (5-14 yrs old) entered three 4-week treatment periods, separated by a 1-week washout. After each period, the fall in forced expiratory volume in one second (FEV1), after an exercise test, and eNO were measured. Significant treatment effects with no carry-over or period effects were seen for both eNO and maximum fall in FEV1 after exercise. Differences were seen between placebo (fall in FEV1=27.9%; eNO=14.4 parts per billion (ppb)) and either dose of HFA-BDP, but not between the two active doses (50 microg: fall in FEV1=20.8%, eNO=9.3 ppb; 100 microg: fall in FEV1=20.9%, eNO=8.9 ppb). In conclusion, low q.d. doses of hydrofluoroalkane-beclomethasone dipropionate reduced exhaled nitric oxide and exercise-induced bronchoconstriction. Further studies are needed to assess whether q.d. administration of beclomethasone dipropionate is as effective as b.i.d. administration.

Perinatal risk factors of adverse outcome in very preterm children: a role of initial treatment of respiratory insufficiency?

AIM: To investigate risk factors of adverse outcome in a cohort of very preterm children treated mainly with nasal continuous positive airway pressure (CPAP) during the neonatal course. METHODS: In Denmark, preterm children are treated with nasal CPAP as a first approach to respiratory support. A national prospective study of all infants with a birthweight below 1000 g or a gestational age below 28 wk born in 1994-1995 was initiated to evaluate this approach. Of the 269 surviving children 164 (61%) were not treated with mechanical ventilation in the neonatal period. A follow-up of the children at 5 y of age was conducted. Data from the neonatal period and the 5-y follow-up were analysed. RESULTS: In multivariate analyses including 250 children, a severely abnormal neonatal brain ultrasound scan was predictive of cerebral palsy (OR = 19.9, CI 95%: 6.1-64.8) and intellectual disability (OR = 6.2, CI 95%: 2.3-16.5). A high Clinical Risk Index for Babies (CRIB) score (OR = 2.4, CI 95%: 1.1-5.5) and chronic lung disease (OR = 2.8, CI 95%: 1.2-6.9) were predictive of intellectual disability. In univariate analyses mechanical ventilation was associated with cerebral palsy (OR=4.3, CI 95%: 1.7-10.8) and intellectual disability (OR = 2.2, CI 95%: 1.2-4.2), but the associations became insignificant in multivariate analyses including chronic lung disease and a severely abnormal ultrasound scan. CONCLUSION: The associations between neonatal risk factors and adverse outcome in our cohort were very similar to those found in other cohorts with another initial treatment of respiratory insufficiency. We found no significant adverse effects of mechanical ventilation beyond what could be explained by associations with chronic lung disease and IVH 3-4/PVL.

Influence of particle size on lung deposition and pharmacokinetics of beclomethasone dipropionate in children.

We set out to evaluate lung deposition, systemic availability, and basic pharmacokinetic parameters of beclomethasone dipropionate (BDP) in children with chronic asthma. Plasma levels of BDP, 17 and 21 beclomethasone monopropionate (17-BMP and 21-BMP), and beclomethasone were measured after an intravenous infusion of 60 microg BDP and after inhalation of A) 100 microg HFA-BDP, B) 200 microg HFA-BDP, C) 200 microg HFA-BDP after ingestion of charcoal to block gastrointestinal (GI) absorption of drug, and D) 400 microg CFC-BDP. A breath-actuated pMDI (Autohaler) was used for HFA inhalations, and a pMDI with a large volume spacer (Volumatic) for CFC inhalations. Treatments A-D were given in a randomized, cross-over design. Fourteen patients aged 10-14 years completed all 5 study days. The mean systemic bioavailabilities in percent of dose leaving the canister valve (ex-valve) were 70% (100 HFA), 74% (200 HFA), 60% (200 HFA + charcoal), and 27% (400 microg CFC). After HFA treatment, 82% of the systemically available dose was absorbed through the lungs, and 18% from the gastrointestinal tract. The estimated bioavailability of BDP from the GI tract was 68%. BDP was metabolized to 17-BMP within minutes. Mean steady-state volume of distribution of 17-BMP was 84 L, and the mean terminal half-life (T((1/2))) after the four inhalations was 2.7 hr (range, 2.2-3.7 hr). Mean T((1/2)) and clearance after i.v. administration were 1.7 hr and 0.9 L/min, respectively. The HFA Autohaler delivers approximately three times as much BDP to the intrapulmonary airways as a CFC-pMDI with a large volume spacer.

[Effect of long-term treatment with inhaled budesonide on adult height of children with asthma]. / Langtidseffekt af inhaleret budesonid på voksenhøjde hos børn med asthma.

INTRODUCTION: Short-term studies have shown that inhaled corticosteroids may retard the growth of children with asthma. The effect of long-term treatment on adult height is, however, uncertain. MATERIAL AND METHODS: We conducted a prospective study of children with asthma to examine the effect of long-term treatment with inhaled budesonide on adult height. We report on 211 children who have attained adult height: 142 asthmatic children treated with budesonide, 18 asthmatic control patients who have never received inhaled corticosteroids, and 51 healthy siblings of patients in the budesonide group, who also served as controls. RESULTS: The children in the budesonide group attained adult height after a mean of 9.2 years of budesonide treatment (range 3-13 years) at a mean daily dose of 412 micrograms (range 110-877 micrograms). The mean cumulative dose of budesonide was 1.35 g (range 0.41-3.99 g). The mean differences between the measured and target adult heights were +0.3 cm (95% confidence intervals: -0.6; +1.2 cm) for the children treated with budesonide, -0.2 cm (95% confidence intervals: -2.4; +2.1 cm) for the control children with asthma, and +0.9 cm (95% confidence intervals: -0.4; +2.2 cm) for the healthy siblings. The adult height depended significantly (p < 0.001) on the child's height before budesonide treatment. Although growth rates were significantly reduced during the first years of budesonide treatment, these changes were not significantly associated with adult height. DISCUSSIONS: Children with asthma who have received long-term treatment with inhaled budesonide attain normal adult height.

Effect of long-term treatment with inhaled budesonide on adult height in children with asthma.

BACKGROUND: Short-term studies have shown that inhaled corticosteroids may reduce the growth of children with asthma. However, the effect of long-term treatment on adult height is uncertain. METHODS: We conducted a prospective study in children with asthma to examine the effect of long-term treatment with inhaled budesonide on adult height. We report on 211 children who have attained adult height: 142 budesonide-treated children with asthma, 18 control patients with asthma who have never received inhaled corticosteroids, and 51 healthy siblings of patients in the budesonide group, who also served as controls. RESULTS: The children in the budesonide group attained adult height after a mean of 9.2 years of budesonide treatment (range, 3 to 13) at a mean daily dose of 412 microg (range, 110 to 877). The mean cumulative dose of budesonide was 1.35 g (range, 0.41 to 3.99). The mean differences between the measured and target adult heights were +0.3 cm (95 percent confidence interval, -0.6 to + 1.2) for the budesonide-treated children, -0.2 cm (95 percent confidence interval, -2.4 to +2.1) for the control children with asthma, and +0.9 cm (95 percent confidence interval, -0.4 to +2.2) for the healthy siblings. The adult height depended significantly (P<0.001) on the child's height before budesonide treatment. Although growth rates were significantly reduced during the first years of budesonide treatment, these changes in growth rate were not significantly associated with adult height. CONCLUSIONS: Children with asthma who have received long-term treatment with budesonide attain normal adult height.

Breath-synchronized nebulization diminishes the impact of patient-device interfaces (face mask or mouthpiece) on the inhaled mass of nebulized budesonide.

The choice of patient-device interface (face mask or mouthpiece) influences the inhaled mass and the lung deposition of nebulized drugs. The use of a mouthpiece has been shown to double the lung deposition compared with use of a face mask. We have determined the inhaled mass of budesonide using a jet nebulizer with mouthpiece in either a constant output or breath-synchronized mode in children. We have also determined the inhaled mass when the jet nebulizer is used with a nonsealing face mask in a constant output mode. The study was a 1-day, randomized, crossover, single-center study involving 158 asthmatic children (age range 5.1-15.7 years). Nebulized budesonide was administered in three single nominal doses of 1.0 mg by means of a jet nebulizer. The inhaled mass of budesonide was defined as the amount of drug deposited on filters positioned between the nebulizer and the mouthpiece or face mask. The mean inhaled mass of budesonide from different age groups ranged from 1 7.1% to 21.6% of the nominal dose with breath-synchronized nebulization with a mouthpiece. With constant output nebulization with a mouthpiece, the mean inhaled mass ranged from 8.9% to 12.2%, and with a nonsealed face mask the mean inhaled mass ranged from 5.0% to 6.9%. For children using jet nebulizers with mouthpiece, breath-synchronized nebulization appears to be superior to conventional constant output nebulization. The use of jet nebulizers with nonsealing face masks should be avoided.

Short-term lower leg growth rate in children with rhinitis treated with intranasal mometasone furoate and budesonide.

BACKGROUND: Mometasone furoate (MF) aqueous nasal spray is a potent intranasal glucocorticoid with low systemic bioavailability. Knemometry has been shown to be a sensitive method of detecting systemic effects of exogenous steroids in children. OBJECTIVE: We sought to assess whether MF (100 or 200 microg) or budesonide intranasal aqueous spray (400 microg) influences the short-term lower leg growth rate in children with seasonal or perennial allergic rhinitis. METHODS: MF, budesonide, and placebo were administered once daily for 2 weeks to 22 children aged 7 to 12 years (mean, 10 years) in a randomized, double-blind, crossover study. Lower leg measurements were done before and after each 2-week treatment period. Two-week washout intervals separated each treatment period. RESULTS: There were no significant differences in lower leg growth rates among the MF 200 microg (0.95 +/- 0.79 mm; mean +/- SD), budesonide 400 microg (0.73 +/- 0.61 mm), or placebo (0.69 +/- 0.70 mm) groups. The growth rate of the group receiving a 100-microg dose of MF (1.16 +/- 0.67 mm) was greater than that for the group receiving placebo (P =.024) or budesonide (P =.033). No statistically significant sequence effect (P =.11), carry-over effect (P =.24), overall treatment effect (P =.086), or period effect (P =.065) was detected. CONCLUSION: No short-term adverse effects on linear lower leg growth rates were detected after once daily MF or budesonide at clinically relevant doses.

Systemic availability and pharmacokinetics of nebulised budesonide in preschool children.

AIM: To evaluate the systemic availability and basic pharmacokinetic parameters of budesonide after nebulisation and intravenous administration in preschool children with chronic asthma. METHODS: Plasma concentrations of budesonide were measured for three hours after an intravenous infusion of 125 micrograms budesonide. The children then inhaled a nominal dose of 1 mg budesonide through the mouthpiece of a Pari LC Jet Plus nebuliser connected to a Pari Master compressor, and the plasma concentrations of budesonide were measured for another six hours. The amount of budesonide inhaled by the patient ("dose to subject") was determined by subtracting from the amount of budesonide put into the nebuliser, the amount remaining in the nebuliser after nebulisation, the amount emitted to the ambient air (filter), and the amount found in the mouth rinsing water. RESULTS: Ten patients aged 3 to 6 years completed both the intravenous and the inhaled treatment. The mean dose to subject was 23% of the nominal dose. The systemic availability of budesonide was estimated to be 6.1% of the nominal dose (95% confidence intervals (CI), 4.6% to 8.1%) or 26.3% of the dose to subject (95% CI, 20.3% to 34.1%). Budesonide clearance was 0.54 l/min (95% CI, 0.46 to 0.62), steady state volume of distribution 55 litres (95% CI, 45 to 68), and the terminal half life was 2.3 hours (95% CI, 2.0 to 2.6). CONCLUSIONS: Approximately 6% of the nominal dose (26% of the dose to subject) reached the systemic circulation of young children after inhalation of nebulised budesonide. This is about half the systemic availability found in healthy adults using the same nebuliser.

Nasal continuous positive airway pressure and early surfactant therapy for respiratory distress syndrome in newborns of less than 30 weeks' gestation.

OBJECTIVE: To determine whether early versus late treatment with porcine surfactant (Curosurf) reduces the requirement of mechanical ventilation in very preterm infants primarily supported by nasal continuous positive airway pressure (nasal CPAP). DESIGN: Multicenter randomized, controlled trial. PATIENTS: The study population comprised 60 infants <30 weeks' gestation with respiratory distress syndrome (RDS) who had an arterial to alveolar oxygen tension ratio (a/APO2) of 0.35 to 0.22. The cohort from which the study population was generated comprised 397 infants. RESULTS: The need for mechanical ventilation or death within 7 days of age was reduced from 63% in the late-treated infants to 21% in early-treated infants. Increasing numbers of antenatal steroid doses also improved the outcome, especially in the early-treated infants. Six hours after randomization mean a/APO2 rose to 0.48 in the early-treated infants compared with 0.36 in the late-treated. The need of mechanical ventilation before discharge was reduced from 68% in the late-treated to 25% in the early-treated infants. CONCLUSIONS: Nasal CPAP in combination with early treatment with Curosurf significantly improves oxygenation and reduces the subsequent need for mechanical ventilation in infants <30 weeks' gestational age with RDS.

Drug delivery from the Turbuhaler and Nebuhaler pressurized metered dose inhaler to various age groups of children with asthma.

A total of 198 children aged 3 to 15 years inhaled a single dose of 200 micrograms budesonide from a Nebuhaler pressurized metered dose inhaler (pMDI) and a Turbuhaler dry powder inhaler in a randomized crossover study. The budesonide dose delivered to a patient was assessed by measuring the amount of drug deposited on a filter inserted between the inhaler outlet and the patient's mouth. The dose of budesonide deposited on the filter and the estimated dose of particles with a mass median aerodynamic diameter (MMAD) of 5 microns or less after inhalation from the Turbuhaler were both approximately twice the values inhaled from the pMDI Nebuhaler in children less than 5 years of age (P < 0.01). The variation in the dose delivered to the patient was similar for the two inhalers in children over 5 years old. In 3- to 4-year-old children, dose delivery to the patient was higher and/or more consistent from the pMDI Nebuhaler than from the Turbuhaler. Filter dose after Turbuhaler treatment varied significantly from peak inspiratory flow rate through the Turbuhaler (PIFTbh) (P < 0.01). The percentage of children producing a PIFTbh greater than 50 L/min decreased with age (89%, 45%, and 14% in 5-, 4-, and 3-year-old children, respectively). It is concluded that drug delivery to a child with asthma varies with age and inhalation device. Further studies are needed to assess the clinical importance of this finding.

Importance of training for correct Turbuhaler use in preschool children.

AIM: To study the impact of both audiovisual information and nurse-training on the use of budesonide Turbuhaler in preschool children who had never used a dry powder inhaler. DESIGN: A single-blind, randomized, parallel-group trial studied 72 children aged 3-5 y. All children and their parents were shown an instructional video and given written instruction. After this, peak inspiratory flow (PIF1) through Turbuhaler was measured. Children in group A (n = 36) then received individual training by a nurse while those in Group B (n = 36) did not and PIF2 was measured. Afterwards, Group B received similar individual training while Group A received no additional training, and PIF3 was measured. Group A was given a placebo Turbuhaler and encouraged to practice at home. Two weeks later, both groups returned to the clinic where PIF4 was measured. RESULTS: The number of children who were able to correctly perform PIF1, PIF2 and PIF4 in Group A was 27, 34 and 36, respectively. The corresponding numbers for Group B were 30, 29, and 29. No effect of training was seen in 3-y-old children. Individual training by a nurse was associated with a statistically significant increase in PIF2 (10 l/min; p = 0.014). Moreover, 2 weeks of home training was associated with an additional increase in PIF of 8 l/min compared with Group B (p < 0.015). After individual instruction and home training, mean PIF in children aged 4 and 5 was 56 (42-72) and 55 (41-66) l/min, respectively. CONCLUSION: After individual instruction and training at home, the vast majority of children aged 4 and 5 y can use Turbuhaler correctly. Audiovisual information and individual instruction is not sufficient in the majority of these children. Few 3-y-old children can learn the correct use of Turbuhaler.

Posterior subcapsular cataracts, bruises and hoarseness in children with asthma receiving long-term treatment with inhaled budesonide.

We assessed the effect of long-term treatment with inhaled budesonide (BUD) on the occurrence of posterior subcapsular cataracts (PSC), bruises and hoarseness in children with asthma. Slit lamp examinations were performed in 157 asthmatic children treated with inhaled BUD at a mean daily dose of 504 microg (range 189-1,322 microg) for 3-6 yrs (mean 4.4 yrs). Measurements were compared with 111 age-matched children with asthma, who had never received treatment of exogenous corticosteroids (control group). The children were examined for bruises, their tendency to bruise and occurrence of voice changes. No incidents of PSC ascribable to BUD treatment were seen. One patient in the BUD group had been diagnosed with PSC before the study and this was still present. There were no statistically significant differences in number of bruises between the two groups (BUD=33, controls=3.2; p=0.70), area covered by bruises (BUD=10 cm2, controls=10.1 cm2; p=0.97), tendency to bruise (BUD=5/10, controls=5/10) or occurrence of hoarseness (BUD=20%, controls=21%; p=0.92). Furthermore, there was no correlation between the occurrence of bruises or tendency to bruise and duration of treatment, accumulated or current dose of BUD. A 3-6 yr treatment of children with inhaled budesonide at an average daily dose of about 500 microg is not associated with an increased occurrence of posterior subcapsular cataract, bruises, tendency to bruise, hoarseness or other noticeable voice changes.

Effect of salmeterol treatment on nitric oxide level in exhaled air and dose-response to terbutaline in children with mild asthma.

The aim of this study was to investigate whether regular treatment with inhaled salmeterol modifies the dose-response curve to the inhaled short-acting beta2-agonist terbutaline or affects the concentration of nitric oxide (NO) in exhaled air of children with asthma. Twenty-two children aged 7 to 15 years (mean = 11.6 years) with mild asthma were treated with inhaled 50 microg salmeterol twice daily or placebo for 3 weeks in a randomized double-blind cross-over study. These treatments were followed by treatment with inhaled 200 microg budesonide twice daily for 3 weeks. On the last day of each period, NO level was measured in exhaled air and a cumulative dose-response experiment with terbutaline (cumulative dose: 1,475 microg) was performed. Baseline lung functions after salmeterol treatment were significantly higher than baseline after placebo (P + 0.05). Salmeterol treatment flattened out the dose-response curve to terbutaline such that higher doses of terbutaline were required to produce the same degree of bronchodilation (ED50 for FEV1 was increased by an estimated factor of 70 (95% CI: 0.8-6307) and ED50 for FEF25-75 by a factor of 41 (95% CI: 6.7-254); P < 0.05). NO levels were unaffected by salmeterol treatment (12.7 ppb; placebo = 10.7 ppb), but were significantly reduced during budesonide therapy (5.2 ppb; P < 0.001). The corresponding maximal NO levels were 19.5 (placebo), 22.9 (salmeterol), and 9.4 ppb (budesonide). We conclude that 3 weeks treatment with salmeterol does not affect NO levels in exhaled air, but it significantly changes the dose-response curve to terbutaline.

Bone mineral density in children with asthma receiving long-term treatment with inhaled budesonide.

The aim of our study was to assess the effects of long-term treatment with inhaled budesonide (BUD) on total body bone mineral density (BMD), total body bone mineral capacity (BMC), total bone calcium (TBC), and body composition in children with asthma. Dual energy X-ray absorptiometry (DEXA scan) was performed in 157 asthmatic children treated with inhaled BUD at a mean daily dose of 504 microg (range, 189 to 1,322 microg) for 3 to 6 yr (mean, 4.5 yr). Measurements were compared with those of 111 age-matched children also suffering from asthma but who had never been treated with exogenous corticosteroids for more than 14 d (control group). There were no statistically significant differences between the two groups in BMD (BUD = 0.915 g/cm2, controls = 0.917 g/cm2), BMC (BUD = 1,378 g, controls = 1,367 g), TBC (BUD = 524 g, controls = 519 g), or body composition (lean body weight = 27,600 g [BUD] and 26,923 g [control], % body fat = 20.1% [BUD] and 20.3% [control]). Furthermore, there was no correlation between any of these parameters and duration of treatment, accumulated or current dose of budesonide. Three to six years of treatment with inhaled budesonide at an average daily dose of 504 microg has no adverse effect on total BMD, total BMC, TBC, or body composition in children with chronic asthma.

Short-term knemometry and urine cortisol excretion in children treated with fluticasone propionate and budesonide: a dose response study.

Few thorough comparisons of the systemic effects of inhaled corticosteroids in children are available. The aim of this study was to compare the effect of budesonide and fluticasone propionate on short-term lower leg growth. Fluticasone propionate, budesonide and placebo were administered for 2 weeks in a randomized, double-blind, double-dummy, cross-over design. Twenty four children aged 6-12 yrs received 200 microg x day(-1) of each drug, or placebo. Another 24 children aged 6-12 years received 400 microg x day(-1) of each drug, or placebo. Dry powder inhalers were used. Lower leg length was measured by knemometry twice a week during all three treatment periods, and 24 h cortisol excretion in the urine was measured at the end of each period. In the low-dose group, lower leg growth rate was the same during treatment with placebo (0.35 mm x week(-1)), fluticasone propionate (0.38 mm x week(-1)) or budesonide (0.26 mm x week(-1)). No significant difference (p=0.39) in lower leg growth rate was found between treatment with 400 microg x day(-1) budesonide (0.30 mm x week(-1)) and 400 microg fluticasone propionate treatment (0.37 mm x week(-1)). Growth rate during treatment with budesonide, 400 microg x day(-1), was significantly lower than during placebo treatment (0.52 mm x week(-1)). Cortisol excretion in the urine during treatment with 200 microg x day(-1) fluticasone propionate was significantly reduced as compared with placebo (p=0.006), but not when compared with 200 microg x day(-1) budesonide (p=0.07). Budesonide 200 microg x day(-1) was not significantly different from placebo. Fluticasone propionate and budesonide, both at 400 microg x day(-1), resulted in a significant reduction in cortisol excretion in the urine as compared with placebo (p=0.001). It is concluded that, dose-for-dose, budesonide Turbuhaler and fluticasone propionate Diskhaler have similar systemic effects.

A randomized, double-blind dose reduction study to compare the minimal effective dose of budesonide Turbuhaler and fluticasone propionate Diskhaler.

BACKGROUND: New inhaled glucocorticosteroids and inhalers are being developed. Their clinical equipotency is difficult to assess and is often discussed. OBJECTIVE: This study was carried out to compare the effect of budesonide Turbuhaler and fluticasone propionate (FP) Diskhaler in a dose reduction study in children (ages 5 to 16 years) with asthma. METHODS: Children treated with budesonide administered through a pressurized metered-dose inhaler with a large volume spacer had their budesonide dose gradually reduced to define the minimal effective dose with this delivery system. After this period, 217 children were randomly allocated to treatment with half the dose of either budesonide Turbukaler or FP Diskhaler for 5 weeks in a double-blind trial. If no deterioration in asthma control was seen, the dose was further reduced by 50% at 5-week intervals until deterioration in asthma control was seen. Throughout the study, morning and evening peak expiratory flow, symptoms, and use of rescue beta 2-agonist were recorded in diaries. Lung function tests and a standardized exercise test were performed at the clinic at the end of each treatment period. Urine cortisol excretion (24 hours) was measured before and after the first 5-week treatment period. Standardized criteria for deterioration in asthma control, based on diary card variables and exercise testing, were used to determine the minimal effective dose for each patient; and from this, the number of dose reduction steps was calculated. RESULTS: No statistically significant difference was seen in number of dose reduction steps from baseline or in minimal effective dose between the two treatments; mean reduction was 1.59 dose steps for budesonide Turbuhaler and 1.65 dose steps for FP Diskhaler (p = 0.52), and minimal effective dose was 188 micrograms for budesonide Turbuhaler and 180 micrograms for FP Diskhaler. After these dose reductions, the same level of asthma control was observed in the budesonide Turbuhaler and FP Diskhaler groups. Furthermore, no statistically significant differences between the two inhaler-drug combinations were seen in daytime or nighttime symptoms, morning and evening peak expiratory flow, use of rescue beta 2-agonist, lung functions at the clinic, exercise-induced fall in lung function, or 24-hour urinary cortisol excretion during the first 5-week period. CONCLUSION: Microgram for microgram, budesonide Turbuhaler and FP Diskhaler are equally effective in treatment of children with moderate asthma.

Dose titration of nebulized budesonide in young children.

We compared the clinical effect of the glucocorticoid budesonide delivered from two nebulizers Aiolos and Pari LL in 38 children less than 4 years of age (mean age, 20.2 months) with chronic wheeze. The design was a controlled, single-blind, randomized, cross-over, dose titration study. After a 1-week run-in, patients were randomized to treatment with 1 mg budesonide b.i.d. for 2 weeks from either an Aiolos or a Pari LL nebulizer. This was followed by a gradual dose reduction period during which the budesonide dose was reduced at 2-week intervals until unacceptable asthma symptoms appeared or the placebo level was reached. The patient was then switched to budesonide 1 mg b.i.d. from the other nebulizer for 2 weeks, after which the dose was reduced at 2-week intervals as described for the first period. Patients who completed the study on placebo for 2 weeks without deterioration of their asthma were not included in the statistical analysis. During Period #1 the minimum effective dose of budesonide was 2 mg/day in 9 patients, 1 mg/day in 10 patients, and 0.5 mg/day in 13 patients. In Period #2 the corresponding figures were 14, 5, and 13 patients. Six patients were excluded after the first period because their asthma control did not deteriorate during dose reduction and when finishing on placebo for 2 weeks. For both nebulizers the reduction in budesonide dose was associated with a small increase in symptoms and use of rescue terbutaline. The mean dose of budesonide delivered to the patient by the Aiolos was twice as large as that delivered by the Pari LL: 26% vs. 13% of the nominal dose assessed by the filter method. Nevertheless, no statistically significant difference in clinical effect or mean minimal effective dose (1.1 mg for Aiolos and 1.2 mg for Pari LL) could be detected between the two nebulizers. No serious adverse events were observed. We conclude that the minimal effective dose of nebulized budesonide varies from 0.5 to 2.0 mg/day in young children with asthma. A higher drug delivery, as assessed by the filter method, does not necessarily result in better clinical control or lower minimal effective dose. Further studies are needed to assess whether this is due to insufficient sensitivity of the study design in detecting a difference in clinical effect, or whether measurements of drug delivery by the filter method do not reflect lung deposition or clinical effect in young children with wheezing.

Influence of budesonide on the response to inhaled terbutaline in children with mild asthma.

The aim of this study was to evaluate if continuous treatment with budesonide or salmeterol influences the bronchodilator response to terbutaline in children with asthma; 23 children, aged 7 to 16 years (mean = 11 years), with mild asthma were treated with inhaled budesonide 100 micrograms b.i.d. and placebo for three weeks in a randomized, double blind crossover study. These treatments were followed by treatment with inhaled salmeterol 50 micrograms b.i.d. for 3 weeks. On the last day of each period a cumulative dose-response experiment with terbutaline in the doses 50, 100, 250 and 500 micrograms (cumulative dose 900 micrograms) was performed. Lung function was measured before and 20 min after each terbutaline inhalation. Baseline pulmonary functions after budesonide treatment were significantly higher than the baseline measured after the two other treatments (p < 0.05). After budesonide treatment, the dose-response curve was shifted vertically upwards but otherwise parallel to the dose-response curve after placebo. The increase from baseline after the first cumulative dose of terbutaline was significantly lower after salmeterol treatment than after the two other treatments (p < 0.01). Maximal lung functions after 900 micrograms terbutaline also differed significantly between the three dose-response days; budesonide being significantly higher and salmeterol significantly lower than placebo (p = 0.02 and p < 0.001, respectively). It is concluded that budesonide treatment does not enhance the brochodilator response to terbutaline. Further studies are needed to assess if long-term continuous salmeterol treatment reduces the response to terbutaline.

[Pseudocroup treated with inhaled steroid (budesonide). A double-blind placebo-controlled trial]. / Pseudocroup behandlet med forstøvet steroid (budesonid). En dobbeltblind, placebokontrolleret undersøgelse.

The aim of this prospective, randomised, double blind study was to evaluate whether inhaled nebulized corticosteroid is effective in the treatment of croup. Thirty-seven children (aged 0.4-4.9 years) admitted to hospital with moderate to severe croup were allocated to treatment with either 2 mg nebulized budesonide (20) or saline (17). Disease severity was assessed by a clinical croup score based on stridor, cough, retractions, dyspnoea and cyanosis, and the overall clinical assessment was scored on a visual log scale (0-100). Two hours after treatment there was a significant improvement in croup score in the group treated with budesonide (8 to 4.5), but not in the group treated with saline (8 to 8). Furthermore, the overall clinical assessment score decreased significantly (50 to 25) in the group treated with budesonide, whereas it remained constant in the placebo group (60 to 62). The results indicate that nebulised budesonide can be used as a safe and effective alternative treatment in children with moderate to severe croup.