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Three Part Question

In [children presenting with an acute exacerbation of asthma] is the [early use of inhaled corticosteroids alone or in combination with systemic corticosteroids] effective at [reducing hospital admission rates and improving symptoms]?

Clinical Scenario

An 8 year-old known asthmatic patient presents to the Emergency Department with a typical exacerbation of asthma. He is partially improved after one bronchodilator treatment and oral steroids. You wonder if inhaled corticosteroids (ICS) would benefit the systemic steroids you are already prescribing.

Search Strategy

Medline 1966-11/15 using OVID interface, Cochrane Library (2015), and Embase

Search Outcome

109 studies were identified; three papers addressed the clinical question in a pediatric population

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Alangari AA, et al. April 2014 Saudi Arabia	A total of 906 ED visits in children 2 to 12 years old with moderate or severe acute asthma were studied. The study group received nebulized budesonide (1500mcg) and the control group received placebo. Both groups received 2mg/kg of prednisolone, salbutamol and ipratropium bromide.	Double-Blind Randomized Controlled Trial	1. Admission rate determined at 4 hours: 16.4% of study and 18.3% of control groups were admitted (P=0.38) A subgroup analysis shows that of those with severe asthma (score of >/= 13/15) 35.5% of study group and 53.4% of control group were admitted (p=0.03)	2. Change in asthma score: There was no significant difference in the decrease in asthma severity score between the two groups. Subgroup analysis of patients with severe asthma (score of >/= 13/15) showed improvement with the study group (P=0.02)	This study was a single center study which limits the generalizability of results. It also evaluated 906 ED visits that were comprised of 723 individual patients that were allowed to participate in this study as many as 5 different times. This could result in selection bias depending on unequal randomization of an individual. The benefit seen in severe asthmatics was also based on a subgroup analysis.
			3. Total ED length of stay (LOS): Mean LOS in study group vs control group was 2.79 +/- 0.85 hr vs 2.76 +/- 0.84 hr (P>0.05)	4. Comparison of admission rates and re-evaluations at 72 hours post discharge from ED: Nineteen patients in study group and sixteen in control group returned for unscheduled visit to a health care facility. (P>0.05) Three patients in the study group and five in the control group were admitted to the hospital. (P>0.05)
Arulparithi CS, et al. June 2014 India	Sixty-one Children aged 5-12 were enrolled and given either three doses of nebulized salbutamol (0.15mg/kg) with budesonide (800mcg) and a single dose of placebo tablets [study group] or three doses of salbutamol (0.15mg/kg) with placebo solution and a single dose of oral prednisolone (2mg/kg) [control group]	Double Blind Randomized Control Trial	1. Heart Rate, Respiratory Rate, and O2 Saturation q20 minutes for an hour: Study group patients had a significantly decreased heart rate (p=0.0002). Decrease in respiratory rate and Improvement in O2 saturation were not significantly different (P = 0.334 and 0.814, respectively)	2. Peak Expiratory Flow Rate (PEFR) at one and four hours: Improvement in PEFR at 4 hours was significantly improved in the study group (P=0.024)	This was a single center study and sample size was limited. Only 17 study, and 18 control children were able to perform FVC. Peak flows at one hour were not reported. It is unclear if those deemed fit for discharge were in fact discharged Subsequent returns (bounce backs) to the ED were not monitored. Fitness for discharge was based on a study with low sensitivity
			3. Fitness for discharge @ 2 hours based on a clinical severity score: 53% of study group versus 26% of control group were deemed fit for discharge (p=0.0278)
Su XM, et al October 2013 China	Children presenting to the ED with an acute asthma exacerbation were studied. In 10 trials, these children were randomized into Inhaled corticosteroids (ICS) vs placebo, ICS vs systemic steroids (SC), or ICS and SC vs SC. Across studies, different drugs and doses were used as the study medication: budesonide (0.4-2mg) and fluticasone/flunisolide (0.5-2mg).	Meta-Analysis utilizing 10 RCTs that included 829 children	1. Odds ratio for hospital admission rate for inhaled corticosteroids versus placebo based on 4 randomized controlled trials: 0.15 (95% CI 0.03 to 0.93, p=0.042)	2. Odds ratio for hospital admission rate for inhaled corticosteroids and systemic steroids versus inhaled corticosteroids based on 2 randomized controlled trials: 0.69 (95% CI 0.22 to 2.14, p=0.517)	Publication Bias. Each study has its own selection criteria and many factors differ across studies such as: lung function markers, atopic status, age, dosage of medication, severity of disease, medications used prior to enrollment which can confound analysis. Wide variation amongst hospital admission rates exist (0-61%). This could result in differences in selection criteria (as mentioned above) or admission criteria such as which severity score is used.
			3. Odds ratio for hospital admission rate for inhaled corticosteroids vs systemic steroids based on 4 randomized controlled trials: 1.54 (95% CI 0.30 to 7.83, p=0.604)

Comment(s)

Inhaled corticosteroids are currently being used as part of a maintenance regimen in children with moderate to severe asthma. The use of ICS has been shown to reduce the frequency of acute asthma exacerbations and the need for hospitalization. It is believed that ICS can exert its effects on eosinophil production and reduce the airways responsiveness to adenosine 5’-monophosphate in as little as 2 hours. In addition, the side effect profile, given its direct action on the lungs, is believed to be more forgiving with respect to hyperglycemia and adrenal effects. The application of inhaled corticosteroids in the treatment of acute asthma exacerbation seems promising in theory, however, at this time there is not enough evidence to support the use of inhaled corticosteroids as an alternative to systemic corticosteroids or in conjunction with them.

Clinical Bottom Line

There is no evidence to suggest that conventional therapy plus inhaled corticosteroids is more effective than conventional therapy alone in the treatment of children with moderate asthma exacerbations. In children with severe asthma exacerbations, a benefit to conventional therapy plus inhaled corticosteroids exists when compared to conventional therapy. However, this evidence is based on a subgroup analysis from a single study and additional focused studies are needed to provide further support.

References

1. Alangari AA, Malhis N, Mubasher M, et al. Budesonide Nebulization Added to Systemic Prednisone in the Treatment of Acute Asthma in Children: A Double-Blind, Randomized, Controlled Trial Chest 2014; 772-778
2. Arulparithi CS, Babu TA, Ravichandran C, et al. Efficacy of Nebulised Budeonide versus Oral Prednisolone in Acute Severe Asthma Indian Journal of Pediatrics 2015; 328-332
3. Su XM, Yu N, Kong LF, et al. Effectiveness of inhaled corticosteroids in the treatment of acute asthma in children in the emergency department: A meta-analysis Annals of Medicine 2014; 24-30