Higher dose inhaled corticosteroids in childhood asthma

What we do doesn't work and what we don't do does

Inhaled corticosteroids are the most effective regular prophylactic drugs for chronic persistent asthma in children. But uncertainty remains over the role of higher dosages (>400 μg/day beclomethasone equivalent) in treating persistent poorly controlled asthma; minor exacerbations in the community; or acute attacks.

For the symptoms of chronic persistent asthma the effectiveness of inhaled corticosteroids compared with placebo has been shown repeatedly in randomised controlled trials,1 and comparative trials have shown them to be more effective than sodium cromoglycate, nedocromil, theophylline, and long acting β agonists. This effectiveness has to be balanced against the possibility of adverse effects, but in routine use at lower dosages (≤400 μg/day) important adverse effects are rare. This much is widely accepted, although there are concerns about overdiagnosing asthma and overuse of inhaled steroids, particularly in children aged under 5.2 The diagnosis of asthma must be made carefully and regular prophylaxis started only if warranted by persistent symptoms. The dose of inhaled steroids should be periodically stepped down—and perhaps discontinued if a child remains asymptomatic for more than a month or two. Most parents do this anyway.

But what are the effects of increasing the dose? Increasing the dosage of inhaled steroids to obtain better control of persistent asthma is widely practised with little or no formal evidence of effectiveness. Dose response studies suggest that most of the symptomatic benefit obtainable from inhaled steroids occurs at lower doses, with little effect from dose increments.3 A well designed trial over one year of doubling the dose of beclomethasone versus adding salmeterol in 177 children aged 6–16 who remained symptomatic when already taking 400 μg of beclomethasone daily found no significant beneficial effect from either treatment.4 Nevertheless, in normal practice outside randomised trials doubling the dose of inhaled steroid might achieve some benefit by compensating for poor adherence and inhaler technique. Another randomised trial of the common practice of doubling the dose of inhaled steroid for mild exacerbations (36 exacerbations studied in 28 children aged 6–14 over 6 months) also found no evidence of effectiveness.5

But in acute attacks of asthma, and using much higher doses, mounting evidence suggests that inhaled steroids may be as effective as oral corticosteroids in all but the most severe episodes. One trial compared nebulised budesonide (2 mg 8 hourly) with two doses of prednisolone 2 mg/kg on admission and at 24 hours in 46 children admitted to hospital with severe asthma. Life threatening episodes were excluded. Outcomes were comparable at 24 hours and at 3 and 24 days' follow up.6

Three studies in emergency rooms (including 213 patients)7-9 were included in a recent systematic review.10 The treatments compared with prednisone were nebulised dexamethasone 1.5 mg/kg,7 budesonide 1600 μg by turbohaler,8 and nebulised budesonide 800 μg three doses at 30 minute intervals.9 The review found no significant difference in admission rates, with a non-significant trend favouring inhaled steroids (odds ratio 0.49, 95% confidence interval 0.22 to 1.07), and concluded that inhaled steroids appear to be at least as effective as oral steroids in children with exacerbations of asthma. One further emergency room trial published since the review did find prednisone better than 2 mg fluticasone by metered dose inhaler and spacer at 4 hours (100 children aged over 5, mean forced expiratory flow in 1 second 45% predicted at trial entry, admission rate 31% on fluticasone v 10% on prednisone).11 This study, however, specifically included children with the most severe asthma on presentation (FEV₁ <60% predicted). Of these studies in acute asthma6-11 only two 7 9 included children aged under 5.

A further trial comparing high dose inhaled steroid with placebo was performed in an emergency room in India.12 It included 60 children aged 3–12 presenting with asthma attacks of moderate severity (mean peak expiratory flow rate 54% predicted); they were judged on arrival to need nebulised salbutamol but not immediate systemic steroids. They were also treated with budesonide 400 μg half hourly for three doses by metered dose inhaler and spacer or with placebo. Those receiving inhaled steroids were less likely to require oxygen for more than two hours (23% v 50%), to need systemic steroids and aminophylline when reassessed at two hours (7% v 27%), and to require admission when reassessed at four hours (0% v 23%).

Taken together, these studies suggest that the common practice of doubling the dose of inhaled steroid is ineffective both for persistent poor control and for exacerbations. Instead, they suggest that a substantially increased dose of inhaled steroid may be as effective as systemic steroids for all but the most severe exacerbations, obtaining equivalent benefit using a much lower total dose of corticosteroid.

It is hardly surprising that it takes more than a doubling of the dose of inhaled steroid to achieve effectiveness in exacerbations of asthma, when bronchospasm and increased mucus production reduce the proportion of the inhaled dose reaching the small airways. To overcome the problem of getting enough salbutamol to the receptors by inhalation during exacerbations we often increase the dosage by a factor of about 19 (2.5 mg 4 hourly instead of 200 μg 6 hourly). It is illogical to restrict ourselves to a doubling of inhaled doses in this situation and resort to oral corticosteroids as the next upward step in steroid dosage.

What may be more appropriate in doctors' and patients' management of asthma is a graded response over a wide potential range of doses of both bronchodilators and inhaled steroids. In exacerbations, self management plans should probably allow for up to at least a fivefold increase in the dose of both treatments, according to severity of symptoms. Such an approach, if carefully taught, might control exacerbations better and reduce cumulative exposure to corticosteroids. This could, and should, be tested in randomised trials.

For severe exacerbations, oral prednisolone, with its advantages of reliability, simplicity, convenience, and low cost, will remain the treatment of choice, though the alternative of high dose inhaled steroids should be considered for children with frequent exacerbations and when the oral steroids are vomited.