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Three Part Question

In [an infant with bronchiolitis] does [nebulised adrenaline compared to other treatments] reduce [the need for admission]?

Clinical Scenario

A 4 month old infant attends the emergency department in the late morning with bronchiolitis. It is the first episode of wheeze. Clinically, there is moderate indrawing and recession, tachypnoea (RR=50), reasonable air movement on auscultation, and the oxygen saturation is 94% in air. You want to admit the infant, but the mother is breast-feeding and keen to get home by 3pm, when her other children get home from school. You have heard that in North America, nebulised adrenaline has been used in some cases and admission has been avoided.

Search Strategy

Medline 1966-12/00 using the OVID interface; Cochrane Library (2002); Clinical Evidence (Issue 7); DARE; PubMed clinical queries.
Medline: (exp bronchiolitis OR exp bronchitis) AND (exp epinephrine OR exp catecholamines) LIMIT to clinical trial. - 23 references (14 irrelevant to question). Cochrane: "bronchiolitis" - 4 systematic reviews (3 irrelevant - anticholinergics and wheeze, ribavirin, immunoglobulin); 1 protocol.
Clinical Evidence: "child health - bronchiolitis"- 2 systematic reviews (one irrelevant - adrenaline not included) and 1 protocol for SR. DARE: "bronchiolitis" - 8 systematic reviews - (5 irrelevant, 2 SRs were by the same authors - one referenced in Cochrane and one referenced in journal; 1 protocol). PubMed: "bronchiolitis" AND "epinephrine" [therapy, sensitive] - 33 references (23 irrelevant to question). Of the 10 relevant, 2 not RCTs.

Search Outcome

Nine papers adressed the question of nebulised adrenaline and bronchiolitis (two of them specifically answering the question).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kristjansson S et al, 1993, Sweden	29 infants (<18 months) with acute bronchiolitis Adrenaline cf placebo	Double blind RCT (Grade A)	Symptom score	Significant improvement with adrenaline	Both groups included recurrent wheezers
			Oxygen saturation	Significant improvement with adrenaline
Sanchez I et al, 1993, Canada	24 infants (<1yr) with first episode of bronchiolitis Adrenaline vs salbutamol	Double blind crossover RCT (Grade A)	Clinical score	Significant improvement with adrenaline cf Salbutamol; NNT = 4 (95% CI 3-7)	Mean age 4.6 months (+/- 0.5) Patients sedated with chloral hydrate
			Pulmonary mechanics	Significant improvement with adrenaline cf salbutamol
Menon K et al, 1995, Canada	42 first time wheezers less than 12 months old Nebulised adrenaline (2 doses) vs nebulised salbutamol	Double Blind RCT (Grade A)	Hospital admission	Significant difference 33% cf 81% admitted; NNT=2 (95% CI 1-5)	Small study
			Oxygen saturation	Significantly higher in adrenaline groupat 1 h (96% vs 94%)
Reijonen T et al, 1995, Finland	100 consecutive wheezers less than 24 months admitted Compared adrenaline, salbutamol and placebo (normal saline)	Double blind RCT (Grade A)	Mean symptom score change using the Respiratory Distress Assessment Instrument (RDAI)	Significant between adrenaline and placebo (but not significant between salbutamol and placebo)	Included some recurrent wheezers
Kellner JD et al, 1996, Canada	Wheeze <24 months Looking at a range of bronchodilators (including adrenaline) compared to placebo	Systematic Review - most studies double blind RCTs (Grade A)	Clinical score	Slight improvement in bronchodilator group; RR=0.76 (95% CI 0.6-0.95)	May have seen a slight improvement because of inclusion of recurrent wheezers
			Hospital admission	No difference; RR = 0.85 (95% CI 0.47-1.53)
Bertrand P et al, 2001	30 infants (<12 mth) with acute bronchiolitis Adrenaline vs salbutamol	Double blind RCT (Grade A)	Clinical score	Significant improvement with adrenaline cf salbutamol at day 1, although by day 4, no difference
			Length of stay	At day 4, significantly less adrenaline still admitted
Ray MS & Singh V 2002	91 infants (<24 mth with 1st or 2nd episode of wheeze) L-adrenaline 3 doses vs salbutamol	Double blind RCT (Grade A)	Hospital admission	6/45 v 14/46 = ARR of 17% (0.5%, 33.7%), NNT = 6 (3, 200)	Some infants with 2nd episode of wheeze included 90% subjects were less than 12 mth of age (mean age 5-6 mth)
			Clinical score, SaO2, RR	Significant improvement in adrenaline group cf salbutamol. SaO2 only showed improvement after 2nd and subsequent doses, not 1st
Abul-Ainie A & Luyt D. 2002	38 infants (<12 mth) with bronchiolitis L-adrenaline (1 dose) vs placebo (normal saline)	Double blind RCT (Grade A)	Clinical score	NSD	Only 1 dose adrenaline given All patients admitted regardless of clinical state to assess safety No adverse events with adrenaline
			SaO2	NSD
Lodrup Carlsen KC et al, 2000	16 infants with acute bronchiolitis, given adrenaline Compared with 7 healthy controls	Controlled trial (Grade C)	Before and after lung function	Lung function in bronchiolitis reduced and improved significantly after adrenaline. Also improved clinical score	Only 1 dose adrenaline given All patients admitted regardless of clinical state to assess safety No adverse events with adrenaline

Comment(s)

There are only two studies (Menon et al and Ray and Singh) that specifically answer the question and both of these studies show a reduction in hospital admission with adrenaline; the study groups are similar to the patient in the clinical scenario. A systematic review that includes adrenaline as one of a number of bronchodilators fails to show significant differences in outcomes compared to placebo. However, adrenaline has an alpha-adrenergic action which is thought to be important in bronchiolitis (as well as the beta-adrenergic bronchodilatation effects). The positive effect of adrenaline may therefore have been diluted in the systematic review by the inclusion of agents that have little or no effect. A systematic review on the effect of adrenaline in bronchiolitis is underway (protocol in Cochrane Library (1)). The Menon and Ray studies compared adrenaline with salbutamol, which is not routinely used in the UK in this condition. For this reason, data on studies comparing adrenaline to placebo in bronchiolitis are also presented. Most studies comparing the two show a benefit of adrenaline over placebo as well as benefit over pure beta-adrenergic agonists. There are studies showing similar benefits with L-adrenaline as well as racemic adrenaline. It is thought that the alpha-adrenergic properties of adrenaline are important in bronchiolitis, as the vasoconstriction of the pulmonary vessels reduces mucosal oedema and exudate, thereby reducing airway obstruction. Only one study (Abul-Ainine et al) failed to show a difference between adrenaline and placebo. Only one dose of adrenaline was used, however, which may be a reason for the lack of difference. Admission rates were not examined as all patients were admitted. This study does confirm the safety of adrenaline in this condition. The regimes used were 3ml of 1:1000 adrenaline nebulised at arrival and 30 minutes later, followed by observation for at least two hours (Menon et al); and 0.1mg/kg/dose given at 20 minute intervals three times and then observation for three hours (Ray and Singh). Currently, a multi-centre trial in the UK comparing nebulised adrenaline with placebo is under discussion.

Clinical Bottom Line

Nebulised adrenaline reduces hospital admission in bronchiolitis. Nebulised adrenaline is superior to salbutamol and placebo in relieving symptoms in bronchiolitis. Nebulised adrenaline is safe in bronchiolitis.

References

1. Kristjansson S, Lodrup Carlsen KC, Wennergren G, et al. Nebulised racemic adrenaline in the treatment of acute bronchiolitis in infants and toddlers. Arch Dis Child 1993;69(6):650-4.
2. Sanchez I, De Koster J, Powell RE, et al. Effect of racemic epinephrine and salbutamol on clinical score and pulmonary mechanics in infants with bronchiolitis. J Pediatr 1993;122(1):145-51.
3. Menon K, Sutcliffe T, Klassen TP. A randomized trial comparing the efficacy of epinephrine with salbutamol in the treatment of acute bronchiolitis. J Pediatr 1995;126(6):1004-7.
4. Reijonen T, Korppi M, Pitkakangas S, et al. The clinical efficacy of nebulized racemic epinephrine and albuterol in acute bronchiolitis. Arch Pediatr Adolesc Med 1995;149(6):686-692
5. Kellner JD, Ohlsson A, Gadomski AM, et al. Efficacy of bronchodilator therapy in bronchiolitis: A meta-analysis. Arch Pediatr Adolesc Med 1996;150(11):1166-1172.
6. Bertrand P, Aranibar H, Castro E et al. Efficacy of nebulised epinephrine versus salbutamol in hospitalised infants with bronchiolitis Pediatr Pulmonol 2001;31:284-8.
7. Ray MS, Singh V. Comparison of nebulized adrenaline versus salbutamol in wheeze associated respiratory tract infections in infants. Indian Pediatr 2002;39:12-22.
8. Abul-Ainine A, Luyt D. Short term benefits of adrenaline in bronchiolitis: a randomised controlled trial. Arch Dis Child 2002;86:276-9.
9. Lodrup Carlsen KC, Carlsen KH. Inhaled nebulized adrenaline improves lung function in infants with acute bronchiolitis. Respir Med 2000;94:709-14.
10. Hartling L, Klassen T. Epinephrine for bronchiolitis (Protocol for a Cochrane Review). The Cochrane Library Issue 2, 2002.