649
Inhaled budesonide for treatment of recurrent wheezing in early childhood
77 children,
aged 11
moderately
severe
to 36 months (mean 24) with recurrent wheezing, were
treated with budesonide pressurised aerosol 400 µg twice daily or placebo for 12 weeks in a double-blind, parallel-group trial. Aerosols were inhaled from a spacer with a facemask. Budesonide significantly improved symptom scores of wheezing, sleep disturbance, and patient happiness. The frequency of severe exacerbations that required a course of oral prednisolone was also significantly reduced. The treatment effect appeared to be fully established after 6—8 weeks and no side-effects could be ascribed to the active treatment. The findings indicate that young children below 3 years of age can inhale a pressurised aerosol from a spacer with a facemask. Use of topically active glucocorticosteroids with this simple device may reduce symptoms and distress in young children with moderately severe recurrent wheeze and dyspnoea, and possibly reduce their requirement for oral steroids.
Introduction Recurrent wheezing and dyspnoea may be difficult to treat in children below the age of 3 years, yet is a major cause of illness and admission to hospital. In this age-group,
wheezing may have several causes, including intercurrent infection or asthma.12 Whatever the cause, it seems reasonable to suggest that the symptoms of wheeze and dyspnoea reflect similar inflammatory changes in the airways. If this hypothesis is correct, children with recurrent wheeze-whatever the cause-may benefit from inhaled glucocorticosteroids. However, adequate delivery of aerosolised topical glucocorticosteroids to young children may be difficult. We report the effect of budesonide, inhaled from a pressurised aerosol through a spacer with a facemask,3 in children below 3 years of age who had
recurrent
moderately severe recurrent wheezing. Patients and methods 77 children with recurrent wheezing, aged 11-36 months, were studied in 3 centres between October, 1988, and April, 1989. A diagnosis of recurrent wheeze was accepted when a physician had confirmed wheezing on at least three separate occasions during the previous year. No attempts were made to identify different underlying causes of wheezing within this group. Children who had received oral or inhaled glucocorticosteroids or nebulised sodium cromoglycate during the month before the study were excluded. Informed parental consent was obtained, and the trial was approved by local ethics committees. Patients were randomised to receive 12 weeks’ treatment with budesonide 400 Itg twice daily (four 100 Ilg puffs) from a pressurised aerosol or placebo (given in a similar manner). Aerosol was administered through a facemask, attached to a spacer (’Nebuhaler’, Astra) by a recently devised connectionwhich allowed a stepwise increase of the expiratory resistance until closure of the one-way valve was heard at every expiration. The amount of budesonide in spray particles below 5 urn diameter after 1 puff into
the spacer was measured by a cascade impactor: 86% of the initial amount of drug in such particles was still airborne after 30 s. Children were therefore allowed to breathe quietly through the spacer 15 times after each puff from the pressurised aerosol. The dead-space of the connection between facemask and spacer was 8 ml and in the children studied would have had little effect on the results as their expected tidal volume would be 6-7 ml/kg.4 The spacer volume was 750 ml so, in theory, children above 10 kg in weight should have received most of the drug delivered by the pressurised aerosol in respirable particles. Daily symptoms were assessed by the parents on an arbitrary scale from 0 to 3 (0 = none; 1 = mild; 2 moderate; and 3 severe). They were asked to assess wheeze, sleep disturbance caused by wheeze or cough, restriction of physical activity caused by wheeze or cough, cough alone, and happiness of the child. The use of concurrent medication was recorded as the number of doses used. The only other drug regularly used was 0-15 mg/kg nebulised salbutamol as required; and parents were urged to administer it if in any doubt. If severe exacerbations could not be successfully treated in this way, a short course of oral theophylline (10-20 mg/kg per day) was given; as a last resort a short course of oral prednisolone (1 mg/kg per day) was used. Children and parents attended the clinics every 2 weeks to check inhalation technique and diary cards, and for clinical assessment of the child, including examination for oral candida. Individual mean values for each variable were calculated for each 2-week period. Treatment effects were assessed by comparison of the relative changes from the start of the study. Student’s t test was used for comparison between the two groups, because the data seemed to fit a Gaussian distribution. A p value below 0,05 was considered to be significant. =
=
Results 77 children entered the study, 39 allocated to budesonide and 38 to placebo. 5 patients on placebo had to be withdrawn from the study,1 because of treatment failure and 4 because the parents were reluctant to follow the prescribed treatment; 1 patient on active treatment was withdrawn during the first week because of the second reason. No child was withdrawn because of difficulties in the use of the spacer and facemask. 71 completed the 12-week trial (45 boys, 26 girls; mean age 24 months, range 11-36). The treatment groups did not differ with respect to anthropometric data, atopy, family history of atopy, environmental exposure, or severity of recurrent wheeze before the study, with no significant differences in the number of days ever in hospital or the number of days ever on prednisolone because of wheezing (table I). During the first 2 weeks of the trial both groups had similar symptom scores and medication use (p > 0.1 for all comparisons). As the trial progressed, symptom scores were significantly improved on active treatment compared with placebo. Wheezing scores fell to about 25% of baseline on budesonide, but increased on placebo (fig 1; p < 0-05). Sleep ADDRESSES: Departments of Paediatrics, University Hospital of Copenhagen, Gentofte (H Bisgaard, MD, W. Petersen, MD); County Hospital of Hillerød, Hillerød (S L Munck, MD); and County Hospital of Aalborg, Aalborg, Denmark (J. P. Nielsen, MD); and Medical Department, AB DRACO, Lund, Sweden (S. V. Ohisson, PhD). Correspondence to Dr H Bisgaard, Department of Paediatrics, University Hospital of Copenhagen, DK-2900 Copenhagen, Denmark
650
TABLE !—COMPARISON OF STUDY GROUPS
TABLE II-ASSESSMENT OF EFFICACY FROM DIARY CARDS
weeks, after which little further reduction in symptom scores
and use of other medications was observed (figs 1 and
2). Oral candida was the only side-effect of inhaled treatment, found in 3 children who received budesonide and 3 who received placebo.
Discussion Mean values shown
disturbance from wheezing or cough was reduced to below 50% of baseline on active treatment, with no clear improvement during placebo treatment (p < 0-05). Parents’ assessment of the happiness of the child doubled during active treatment, but there was no change with placebo There were no significant differences in (p
Inhaled budesonide for treatment of recurrent wheezing in early childhood
77 children,
aged 11
moderately
severe
to 36 months (mean 24) with recurrent wheezing, were
treated with budesonide pressurised aerosol 400 µg twice daily or placebo for 12 weeks in a double-blind, parallel-group trial. Aerosols were inhaled from a spacer with a facemask. Budesonide significantly improved symptom scores of wheezing, sleep disturbance, and patient happiness. The frequency of severe exacerbations that required a course of oral prednisolone was also significantly reduced. The treatment effect appeared to be fully established after 6—8 weeks and no side-effects could be ascribed to the active treatment. The findings indicate that young children below 3 years of age can inhale a pressurised aerosol from a spacer with a facemask. Use of topically active glucocorticosteroids with this simple device may reduce symptoms and distress in young children with moderately severe recurrent wheeze and dyspnoea, and possibly reduce their requirement for oral steroids.
Introduction Recurrent wheezing and dyspnoea may be difficult to treat in children below the age of 3 years, yet is a major cause of illness and admission to hospital. In this age-group,
wheezing may have several causes, including intercurrent infection or asthma.12 Whatever the cause, it seems reasonable to suggest that the symptoms of wheeze and dyspnoea reflect similar inflammatory changes in the airways. If this hypothesis is correct, children with recurrent wheeze-whatever the cause-may benefit from inhaled glucocorticosteroids. However, adequate delivery of aerosolised topical glucocorticosteroids to young children may be difficult. We report the effect of budesonide, inhaled from a pressurised aerosol through a spacer with a facemask,3 in children below 3 years of age who had
recurrent
moderately severe recurrent wheezing. Patients and methods 77 children with recurrent wheezing, aged 11-36 months, were studied in 3 centres between October, 1988, and April, 1989. A diagnosis of recurrent wheeze was accepted when a physician had confirmed wheezing on at least three separate occasions during the previous year. No attempts were made to identify different underlying causes of wheezing within this group. Children who had received oral or inhaled glucocorticosteroids or nebulised sodium cromoglycate during the month before the study were excluded. Informed parental consent was obtained, and the trial was approved by local ethics committees. Patients were randomised to receive 12 weeks’ treatment with budesonide 400 Itg twice daily (four 100 Ilg puffs) from a pressurised aerosol or placebo (given in a similar manner). Aerosol was administered through a facemask, attached to a spacer (’Nebuhaler’, Astra) by a recently devised connectionwhich allowed a stepwise increase of the expiratory resistance until closure of the one-way valve was heard at every expiration. The amount of budesonide in spray particles below 5 urn diameter after 1 puff into
the spacer was measured by a cascade impactor: 86% of the initial amount of drug in such particles was still airborne after 30 s. Children were therefore allowed to breathe quietly through the spacer 15 times after each puff from the pressurised aerosol. The dead-space of the connection between facemask and spacer was 8 ml and in the children studied would have had little effect on the results as their expected tidal volume would be 6-7 ml/kg.4 The spacer volume was 750 ml so, in theory, children above 10 kg in weight should have received most of the drug delivered by the pressurised aerosol in respirable particles. Daily symptoms were assessed by the parents on an arbitrary scale from 0 to 3 (0 = none; 1 = mild; 2 moderate; and 3 severe). They were asked to assess wheeze, sleep disturbance caused by wheeze or cough, restriction of physical activity caused by wheeze or cough, cough alone, and happiness of the child. The use of concurrent medication was recorded as the number of doses used. The only other drug regularly used was 0-15 mg/kg nebulised salbutamol as required; and parents were urged to administer it if in any doubt. If severe exacerbations could not be successfully treated in this way, a short course of oral theophylline (10-20 mg/kg per day) was given; as a last resort a short course of oral prednisolone (1 mg/kg per day) was used. Children and parents attended the clinics every 2 weeks to check inhalation technique and diary cards, and for clinical assessment of the child, including examination for oral candida. Individual mean values for each variable were calculated for each 2-week period. Treatment effects were assessed by comparison of the relative changes from the start of the study. Student’s t test was used for comparison between the two groups, because the data seemed to fit a Gaussian distribution. A p value below 0,05 was considered to be significant. =
=
Results 77 children entered the study, 39 allocated to budesonide and 38 to placebo. 5 patients on placebo had to be withdrawn from the study,1 because of treatment failure and 4 because the parents were reluctant to follow the prescribed treatment; 1 patient on active treatment was withdrawn during the first week because of the second reason. No child was withdrawn because of difficulties in the use of the spacer and facemask. 71 completed the 12-week trial (45 boys, 26 girls; mean age 24 months, range 11-36). The treatment groups did not differ with respect to anthropometric data, atopy, family history of atopy, environmental exposure, or severity of recurrent wheeze before the study, with no significant differences in the number of days ever in hospital or the number of days ever on prednisolone because of wheezing (table I). During the first 2 weeks of the trial both groups had similar symptom scores and medication use (p > 0.1 for all comparisons). As the trial progressed, symptom scores were significantly improved on active treatment compared with placebo. Wheezing scores fell to about 25% of baseline on budesonide, but increased on placebo (fig 1; p < 0-05). Sleep ADDRESSES: Departments of Paediatrics, University Hospital of Copenhagen, Gentofte (H Bisgaard, MD, W. Petersen, MD); County Hospital of Hillerød, Hillerød (S L Munck, MD); and County Hospital of Aalborg, Aalborg, Denmark (J. P. Nielsen, MD); and Medical Department, AB DRACO, Lund, Sweden (S. V. Ohisson, PhD). Correspondence to Dr H Bisgaard, Department of Paediatrics, University Hospital of Copenhagen, DK-2900 Copenhagen, Denmark
650
TABLE !—COMPARISON OF STUDY GROUPS
TABLE II-ASSESSMENT OF EFFICACY FROM DIARY CARDS
weeks, after which little further reduction in symptom scores
and use of other medications was observed (figs 1 and
2). Oral candida was the only side-effect of inhaled treatment, found in 3 children who received budesonide and 3 who received placebo.
Discussion Mean values shown
disturbance from wheezing or cough was reduced to below 50% of baseline on active treatment, with no clear improvement during placebo treatment (p < 0-05). Parents’ assessment of the happiness of the child doubled during active treatment, but there was no change with placebo There were no significant differences in (p
