Steroids and bronchodilators for acute bronchiolitis in the first two years of life: systematic review and meta-analysis

Lisa Hartling, Ricardo M Fernandes, Liza Bialy, Andrea Milne, David Johnson, Amy Plint, Terry P Klassen, Ben Vandermeer, Lisa Hartling, Ricardo M Fernandes, Liza Bialy, Andrea Milne, David Johnson, Amy Plint, Terry P Klassen, Ben Vandermeer

Abstract

Objective: To evaluate and compare the efficacy and safety of bronchodilators and steroids, alone or combined, for the acute management of bronchiolitis in children aged less than 2 years.

Design: Systematic review and meta-analysis.

Data sources: Medline, Embase, Central, Scopus, PubMed, LILACS, IranMedEx, conference proceedings, and trial registers. Inclusion criteria Randomised controlled trials of children aged 24 months or less with a first episode of bronchiolitis with wheezing comparing any bronchodilator or steroid, alone or combined, with placebo or another intervention (other bronchodilator, other steroid, standard care).

Review methods: Two reviewers assessed studies for inclusion and risk of bias and extracted data. Primary outcomes were selected by clinicians a priori based on clinical relevance: rate of admission for outpatients (day 1 and up to day 7) and length of stay for inpatients. Direct meta-analyses were carried out using random effects models. A mixed treatment comparison using a Bayesian network model was used to compare all interventions simultaneously.

Results: 48 trials (4897 patients, 13 comparisons) were included. Risk of bias was low in 17% (n = 8), unclear in 52% (n = 25), and high in 31% (n = 15). Only adrenaline (epinephrine) reduced admissions on day 1 (compared with placebo: pooled risk ratio 0.67, 95% confidence interval 0.50 to 0.89; number needed to treat 15, 95% confidence interval 10 to 45 for a baseline risk of 20%; 920 patients). Unadjusted results from a single large trial with low risk of bias showed that combined dexamethasone and adrenaline reduced admissions on day 7 (risk ratio 0.65, 0.44 to 0.95; number needed to treat 11, 7 to 76 for a baseline risk of 26%; 400 patients). A mixed treatment comparison supported adrenaline alone or combined with steroids as the preferred treatments for outpatients (probability of being the best treatment based on admissions at day 1 were 45% and 39%, respectively). The incidence of reported harms did not differ. None of the interventions examined showed clear efficacy for length of stay among inpatients.

Conclusions: Evidence shows the effectiveness and superiority of adrenaline for outcomes of most clinical relevance among outpatients with acute bronchiolitis, and evidence from a single precise trial for combined adrenaline and dexamethasone.

Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that (1) LH, DJ, AP, TPK, and BV have support from the Canadian Institutes for Health Research for the submitted work; (2) none of the authors has relationships with Canadian Institutes for Health Research that might have an interest in the submitted work in the previous 3 years; (3) none of their spouses, partners, or children has financial relationships that may be relevant to the submitted work; and (4) the authors have no non-financial interests that may be relevant to the submitted work.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4788007/bin/harl821041.f1_default.jpg
Fig 1 Flow diagram for study selection
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4788007/bin/harl821041.f2_default.jpg
Fig 2 Results from meta-analysis of direct comparisons for admission rates from emergency department (day 1 and day 7) in outpatients. Only comparisons with quantitative results are shown
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4788007/bin/harl821041.f3_default.jpg
Fig 3 Comparisons (14 studies) contributing to mixed treatment analysis for admissions at day 1. Numerals within figure are studies at low risk of bias (four in total)
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4788007/bin/harl821041.f4_default.jpg
Fig 4 Results of mixed treatment analysis for admissions at day 1, showing probability ranking and probability of being best statistic
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4788007/bin/harl821041.f5_default.jpg
Fig 5 Results from meta-analysis of direct comparisons for length of stay in inpatients. Only comparisons with quantitative results are shown
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4788007/bin/harl821041.f6_default.jpg
Fig 6 Comparisons (19 studies) contributing to mixed treatment analysis for length of stay. Numerals within figure are studies at low risk of bias (two in total)
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4788007/bin/harl821041.f7_default.jpg
Fig 7 Results of mixed treatment analysis for length of stay, showing probability ranking and probability of being best statistic

References

    1. Wright AL, Taussig LM, Ray CG, Harrison HR, Holberg CJ. The Tucson Children’s Respiratory Study: II. Lower respiratory tract illness in the first year of life. Am J Epidemiol 1989;129:1232-46.
    1. Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med 2009;360:588-98.
    1. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010;375:1545-55.
    1. Viswanathan M, King VJ, Bordley C, Honeycutt AA, Wittenborn J, Jackman AM, et al. Management of bronchiolitis in infants and children. Evid Rep Technol Assess (Summ) 2003;69:1-5.
    1. Smyth R, Openshaw P. Bronchiolitis. Lancet 2006;368:312-22.
    1. Babl FE, Sheriff N, Neutze J, Borland M, Oakley E. Bronchiolitis management in pediatric emergency departments in Australia and New Zealand: a PREDICT study. Pediatr Emerg Care 2008;24:656-8.
    1. Plint AC, Johnson DW, Wiebe N, Bulloch B, Pusic M, Joubert G, et al. Practice variation among pediatric emergency departments in the treatment of bronchiolitis. Acad Emerg Med 2004;11:353-60.
    1. Christakis DA, Cowan CA, Garrison MM, Molteni R, Marcuse E, Zerr DM. Variation in inpatients diagnostic testing and management of bronchiolitis. Pediatrics 2005;115:878-84.
    1. Barben J, Kuehni CE, Trachsel D, Hammer J: Swill Paediatric Respiratory Research Group. Management of acute bronchiolitis: can evidence based guidelines alter clinical practice? Thorax 2008;63:1103-9.
    1. Bialy L, Smith M, Bourke T, Becker L. The Cochrane Library and bronchiolitis: an umbrella review. Evid Based Child Health 2006;1:939-47.
    1. American Academy of Pediatrics. Diagnosis and management of bronchiolitis. Pediatrics 2006;118:1774-93.
    1. Scottish Intercollegiate Guidelines Network (SIGN). Bronchiolitis in children. A national clinical guideline. Report No 91. SIGN, 2006.
    1. Turner T, Wilkinson F, Harris C, Mazza D: Health for Kids Guideline Development Group. Evidence based guideline for the management of bronchiolitis. Aust Fam Physician 2008;37:6-13.
    1. Muething S, Schoettker PJ, Gerhardt WE, Atherton HD, Britto MT, Kotagal UR. Decreasing overuse of therapies in the treatment of bronchiolitis by incorporating evidence at the point of care. J Pediatr 2004;144:703-10.
    1. Touzet S, Refabert L, Letrilliart L, Ortolan B, Colin C. Impact of consensus development conference guidelines on a primary care of bronchiolitis: are national guidelines being followed? J Eval Clin Pract 2007;13:651-6.
    1. Plint AC, Johnson DW, Patel H, Wiebe N, Correll R, Brant R, et al. Epinephrine and dexamethasone in children with bronchiolitis. N Engl J Med 2009;360:2079-89.
    1. Corneli HM, Zorc JJ, Mahajan P, Shaw KN, Holubkov R, Reeves SD, et al. A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis. N Engl J Med 2007;357:331-9.
    1. Shojania KG, Sampson M, Ansari MT, Doucette S, Moher D. How quickly do systematic reviews go out of date? A survival analysis. Ann Intern Med 2007;147:224-33.
    1. Schuh S, Coates AL, Binnie R, Allin T, Goia C, Corey M, et al. Efficacy of oral dexamethasone in outpatients with acute bronchiolitis. J Pediatr 2002;140:27-32.
    1. Ioannidis JPA. Integration of evidence from multiple meta-analyses: a primer on umbrella reviews, treatment networks and multiple treatments meta-analyses. Can Med Assoc J 2009;181:488-93.
    1. Caldwell DM, Ades AE, Higgins JPT. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 2005;331:897-900.
    1. Higgins JPT, Green S, eds. The Cochrane handbook for systematic reviews of interventions. The Cochrane Collaboration, 2008.
    1. Owens DK, Lohr KN, Atkins D, Treadwell JR, Reston JT, Bass EB, et al. Grading the strength of a body of evidence when comparing medical interventions: Agency for Healthcare Research and Quality and the Effective Health Care Program. J Clin Epidemiol 2010;63:513-23.
    1. Schünemann H, Brozek J, Oxman A, eds. GRADE handbook for grading quality of evidence and strength of recommendation. Version 3.2. The GRADE Working Group, 2009.
    1. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.
    1. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-58.
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.
    1. Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 2004;23:3105-24.
    1. Higgins JP, Whitehead A. Borrowing strength from external trials in a meta-analysis. Stat Med 1996;15:2733-49.
    1. Smith TC, Spiegelhalter DJ, Thomas A. Bayesian approaches to random-effects meta-analysis: a comparative study. Stat Med 1995;14:2685-99.
    1. Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison. Stat Med 2010;29:932-44.
    1. Glasziou PP, Shepperd S, Brassey J. Can we rely on the best trial? A comparison of individual trials and systematic reviews. BMC Med Res Methodol 2010;10:23.
    1. Hartling L, Wiebe N, Russell K, Patel H, Klassen TP. Epinephrine for bronchiolitis. Cochrane Database Syst Rev 2004;1:CD003123.
    1. Scarfone RJ. Controversies in the treatment of bronchiolitis. Curr Opin Pediatr 2005;17:62-6.
    1. Wohl MEB, Chernick V. State of the art: bronchiolitis. Am Rev Respir Dis 1978;118:759-81.
    1. Openshaw PJ. Antiviral immune responses and lung inflammation after respiratory syncytial virus infection. Proc Am Thorac Soc 2005;2:121-5.
    1. Thomas LH, Sharland M, Friedland JS. Steroids fail to down-regulate respiratory syncytial virus-induced IL-8 secretion in infants. Pediatr Res 2002;52:368-72.
    1. Giembycz MA, Kaur M, Leigh R, Newton R. A Holy Grail of asthma management: toward understanding how long-acting beta(2)-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids. Br J Pharmacol 2008;153:1090-104.
    1. Black JL, Oliver BG, Roth M. Molecular mechanisms of combination therapy with inhaled corticosteroids and long-acting beta-agonists. Chest 2009;136:1095-100.
    1. Frey U, von Mutius E. The challenge of managing wheezing in infants. N Engl J Med 2009;360:2130-3.
    1. Bush A. Practice imperfect—treatment for wheezing in preschoolers. N Engl J Med 2009;360:409-10.
    1. Zhang L, Sanguebsche LS. The safety of nebulization with 3 to 5 ml of adrenaline (1:1000) in children: an evidence based review. J Pediatr (Rio J) 2005;81:193-7.
    1. Halliday HL, Ehrenkranz RA, Doyle LW. Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2010;1:CD001146.
    1. Onland W, De Jaegere AP, Offringa M, van Kaam AH. Effects of higher versus lower dexamethasone doses on pulmonary and neurodevelopmental sequelae in preterm infants at risk for chronic lung disease: a meta-analysis. Pediatrics 2008;122:92-101.
    1. Karemaker R, Kavelaars A, Wolbeek M, Tersteeg-Kamperman M, Baerts W, Veen S, et al. Neonatal dexamethasone treatment for chronic lung disease of prematurity alters the hypothalamus-pituitary-adrenal axis and immune system activity at school age. Pediatrics 2008;121:e870-8.
    1. Wilson-Costello D, Walsh MC, Langer JC, Guillet R, Laptook AR, Stoll BJ, et al. Impact of postnatal corticosteroid use on neurodevelopment at 18 to 22 months’ adjusted age: effects of dose, timing, and risk of bronchopulmonary dysplasia in extremely low birth weight infants. Pediatrics 2009;123:e430-7.
    1. Karemaker R, Karemaker JM, Kavelaars A, Tersteeg-Kamperman M, Baerts W, Veen S, et al. Effects of neonatal dexamethasone treatment on the cardiovascular stress response of children at school age. Pediatrics 2008;122:978-87.
    1. Flores G, Horwitz RI. Efficacy of beta2-agonists in bronchiolitis: a reappraisal and meta-analysis. Pediatrics 1997;100:233-9.
    1. King VJ, Viswanathan M, Bordley WC, Jackma AM, Sutton SF, Lohr KN, et al. Pharmacologic treatment of bronchiolitis in infants and children: a systematic review. Arch Pediatr Adolesc Med 2004;158:127-37.
    1. Barbi E, Neri E, Ventura A. Nomina sunt consequentia rerum: time for a change in the definition of bronchiolitis? Arch Pediatr Adolesc Med 2004;158:403.

Source: PubMed

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