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A 6 year old girl comes to your outpatient paediatric clinic with a two month history of cough and shortness of breath, requiring, nearly three times a week, administration of β2 agonists by jet nebuliser. She has often been noticed to wheeze at school during the gymnastic class, and also when she’s laughing or crying; almost once a week she awakes during the night complaining of cough and respiratory difficulties.
Your diagnosis is persistent asthma,1 and after a short course of nebulised salbutamol (albuterol) and oral steroids you decide to start, twice a day, prophylaxis with inhaled steroids, via a spacer device. As her mother is working away from home until late afternoon, she asks you if a once daily administration would have the same efficacy.
Structured clinical question
In children with mild to moderate persistent asthma [patient] does once daily and twice daily administration of inhaled steroids [intervention] have the same efficacy [outcome]?
Search strategy and outcome
The search was conducted independently by two reviewers (the authors).
Medline 1966 to December 2001 using OVID interface, Cochrane Library (2001), PubMed clinical queries using “inhaled steroids” OR “glucocorticoids” OR “glucocorticosteroids” OR “budesonide” OR “mometasone” OR “flunisolide” OR “fluticasone propionate” OR “beclomethasone dipropionate” AND (“once versus twice” OR “once with twice daily” OR “OD” OR “BID administration”) AND “asthma”. Limits: all children:0–18 years, randomised controlled trial.
Clinical evidence—no systematic reviews; 29 studies found, seven were relevant. (Papers available as abstracts only and studies including both adults and children aged >12 were excluded.) See table 3.
As the study of Baker et al evaluated the efficacy of different doses of budesonide (four groups) compared to placebo, six studies were found that specifically compare the once daily versus twice daily administration of inhaled steroids.
Overall the methodological quality of the included studies was not always satisfactory: although most of the references mentioned the number of patients excluded from the study, withdrawals and drop outs were described and commented on only in the papers by Heuck et al and Moller et al; intention to treat analysis was reported to be used by Jonasson et al and by LaForce et al; allocation concealment was unclear in most of cases and often details of methods used to generate the random allocation sequence were lacking.
▸CLINICAL BOTTOM LINE
In mild to moderate persistent asthma, in children, inhaled steroids should continue to be given twice daily.
Once daily administration might have a similar efficacy in some subgroups of patients with more stable asthma, but further well conducted randomised controlled studies are needed.
This overview found a heterogeneous group of trials with different results; although the majority of studies reported no significant difference between the two regimens, the overall findings of the seven studies are not sufficient to support the evidence that administering inhaled steroids once daily and twice daily has the same efficacy.
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Table 3 Dosage regimen of inhaled steroids in asthma
Citation Study group Study type (level of evidence from the Oxford CEBM) Outcome Key results Comments
Campbell et al (1998) 167 children, aged 5–12 y with symptomatic asthma, multicentre study OD v BID budesonide by dry powder for 8 wk Double blind RCT (level 1b) Jadad score: 2 PEF, FEV1, FVC, wellbeing and symptom score, albuterol use, adverse events OD > BID for evening PEF: +19.7 l/min v + 8.3 l/min (p=0.013), no other significant differences (morning PEF: +24.6 l/min v +15.2 l/min, p=0.059) Ten patients excluded from the all-patients treated population A greater number of patients randomised to the BID arm: 90 v 77 Patient compliance not assessed Jonasson et al (1998) 163 children, age 7–16 y, with mild asthma, outpatient clinic OD v BID budesonide by dry powder for 12 wk Double blind RCT (level 1b) Jadad score: 3 PEF, FEV1, FVC, symptom score, ß agonist use, metacoline challenge, exercise test, adverse events OD v BID budesonide: Absolute reduction in FEV1% -0.05 (95% CI -3.3 to +3.0) Absolute reduction in PEF 2.9 l/min (95% CI -10.8 to +16.6) Patients with near normal lung function: FEV1 at baseline >100%, reversibility of 3% Heuck et al (1998) 24 children, age 5.6–12.5 y, with mild asthma, outpatient clinic OD v BID budesonide by MDI + spacer; crossover trial, 2 treatment periods of 4 wk Double blind RCT (level 1b) Jadad score: 3 Lower leg growth, PEF, symptom score, albuterol use, markers of collagen turnover Significant reduction of lower leg growth rate (p=0.04) and markers of collagen turnover with BID OD v BID budesonide: Absolute reduction in morning PEF (95% CI -4 to +15 l/min ), in evening PEF (95% CI -3 to +16 l/min) Small study; the trial did not include a placebo period Moller et al (1999) 206 children, age 5–15 y, with stable asthma, multicentre study OD v BID budesonide by dry powder for 12 wk Double blind RCT (level 1b) Jadad score: 3 FEV1, FVC, FEF25–75, PEF, symptom score, albuterol use, adverse events OD v BID budesonide: Absolute reduction for morning PEF -2.8 l/min (90% CI -10.4 to + 4.5) Absolute reduction for FEV1% -0.08 (95% CI -3.4 to +0.9) Difference in patients demographic characteristics (duration of asthma in months) between OD and BID Baker et al (1999) 480 children, aged 6 mth to 8 y, with moderate persistent asthma, multicentre study Budesonide inhalation suspension by jet nebuliser: 0.25 mg OD v 0.25 mg BID v 0.50 mg BID v1 mg OD v placebo for 12 wk Double blind RCT (level 1b) Jadad score: 2 FEV1, PEF, symptom score, adverse events and in a subgroup cortisol testing 0.50 mg BID budesonide v placebo: absolute reduction for FEV1 in l/min 0.13 (p<0.050) 1 mg OD budesonide v placebo: absolute reduction for FEV1 in l/min 0.07 (NS) Lost to follow up: 27% Differences in % patients using inhaled steroids before entering into the study between OD and BID groups Jonasson et al (2000) 122 children, aged 7–16 y, with mild asthma, outpatient clinic OD v BID budesonide by dry powder for 27 wk Double blind RCT (level 1b) Jadad score: 3 FEV1, FEF25–75, PEF, exercise test, metacoline challenge, symptom score, growth rate, eosinophil count, compliance No significant differences between BID and OD Compliance declined rapidly LaForce et al (2000) 242 children, aged 4–11 y, with persistent stable asthma, multicentre study OD v BID fluticasone propionate by dry powder for 12 wk Double blind RCT (level 1b) Jadad score: 3 FEV1, PEF symptom score, night-time awakening, albuterol use, adverse events BID v OD fluticasone: Absolute reduction for FEV1 change in % (95% CI -11.28 to -0.124); for morning PEF (95% CI -27.26 to + 9.26) Asthma had to remain stable for all the study period; high rate of discontinuation in the placebo group