#1.  Plint AC et al.  Epinephrine and Dexamethasone in Children with Bronchiolitis.  NEJM 2009;360:2079-89.  

In this RCT, 800 infants 6 weeks to 12 months were randomly assigned to one of four study groups:  2 treatments of nebulized epinephrine + 6 doses oral dexamethasone, nebulized epi + oral placebo, nebulized placebo + oral dex, or nebulized placebo and oral placebo.  Primary outcome measure was hospital admission within 7 days of ED visit.   In the unadjusted analysis, only the kiddos in the nebulized epi + oral dex group had a lower risk of admission (NNT = 11).  When the results were adjusted for multiple comparisons, there was no statistically significant difference between groups.  No serious adverse effects in any group.

The statistical debate this brought out was between the traditional frequentist interpretation which relies on p values to define significance, and the increasingly popular Bayesian approach to analyzing study results which gives more importance to the effect size of the therapy and the risks of the therapy, rather than to a p value.  So, for some in the room, even thought the adjusted p value was not statistically significant, a NNT of 11 with relatively benign therapies would be worth it.  A cautionary note-this study required giving dex in the ED and then for 5 additional days.   There were also a fair number of exclusion criteria:  excluded prior wheezer/asthmatics, cardiopulm dz, severe distress, preemies, varicella exposure, immunodeficient.  Inclusion criteria required RDAI scores (bronchiolitis score) 4-15, indicating mild-fairly severe bronchiolitis.

        

#2.  Corneli HM et al.  A Multicenter, Randomized, Controlled Trial of Dexamethasone for Bronchiolitis.  NEJM 2007;357:331-9.  

In this large RCT, 600 infants (2 to 12 months) with moderate to severe bronchiolitis were randomized to receiving either one dose of dexamethasone (1 mg/kg) or placebo.  Primary outcome was hospital admission after 4 hours of ED observation.   Although both groups had improvement during their ED course, there was no significant difference in 4 hour admission rate (NNT = 300), and no significant difference in bronchiolitis scores or other later outcomes including hospital LOS, or later medical visits/admissions.  Again, no significant adverse events.    Although the authors chose an ED relevant outcome (admission rate), there was some discussion that steroids might not make much of a difference in the first few hours.  Then again, there were no differences in their secondary outcomes either.  As in the first study, similar inclusion/exclusion criteria; as in first study, they excluded prior wheezers or asthma history.  And, although infants with known asthma were excluded, they did look at subgroups of pts with eczema or FH of asthma as markers for higher risk of asthma/potential benefit for steroids, also looked at different age groups, but in all subgroups steroids still no benefit.  In both of these studies, the average RDAI score of 8-9 puts these patients in the moderate severity category, and upper limit of age in both studies was 12 months;  would older (maybe asthmatic), or less sick/more sick kids behave differently?

Is there any harm from steroids?  Unknown for single use, but I wonder if giving steroids sets the pt up to receive steroids more easily if they come in again with wheezing associated with a URI.  In a NEJM article by Ducharme in 1/22/2009,  preschool children receiving recurrent inhaled steroids at the beginning of URIs had less rescue oral steroid use, but also had smaller gains in height and weight.  Another study  (700 kids) in that same issue of NEJM (Panickar) found no benefit from oral steroid use in preschool children with viral-induced wheezing .

#3.  Walsh P et al.  Comparison of Nebulized Epinephrine to Albuterol in Bronchiolitis.  AEM 2008;15:305–313.

This study deserves 2 initial strong shout-outs; Kate McQuillan, formerly research director in our department is an author, and ACMC was the second study site.  Other studies have shown short-term clinical improvement with albuterol, but no sig. decrease in admission rates.  This RCT compared 703 patients up to 18 months old receiving either 3 doses of nebulized racemic albuterol or one dose of nebulized racemic epinephrine + 2 saline nebs.   Primary outcome was successful ED discharge (no admission for subsequent 72 hours).  Admission decision was made after 2 hours in the ED.   Unlike the other 2 studies, the inclusion criteria were broad, and they included former preemies and prior wheezers (and had a higher upper age limit than the other 2 studies).    The crude analysis showed no difference in the 2 groups, but when they adjusted for severity of illness, infants receiving albuterol were slightly more likely to be successfully discharged (NNT = 6 for mild, NNT = 11 for moderate, NNT = 40 for severe).   These results held up for subgroups of first wheezers and patients less than 12 months of age.  A hx of recurrent wheezing or FH of asthma also did not change the treatment effects.  A few issues; their illness severity score was created by the authors, and was meant to be a research tool, not a clinical instrument-impossible to decipher.  Admission decisions were made after only 2 hours after receiving study drugs, and pts with a prolonged ED stay were called admissions.  The epi group had more moderately ill (and fewer mildly ill) patients than the albuterol group→potential bias in favor of epi.  The study design gave 3 active treatments of albuterol then admission decision which may favor the albuterol group (epi group received saline during last 2 treatments).  Few adverse effects, but one death in the epi group was reported within 30 days (what if the trial had been larger?).  Number of eligible but not enrolled patients unknown.

So, where does that leave us?    Easy first choice-suctioning, and then more suctioning.  Some kind of nebulization treatment, even if it’s just a saline neb, is very reasonable.  Trying an albuterol or epinephrine neb should be generally safe, and a small-moderate percentage of infants will respond to albuterol or epi.    From a show of hands at the end of the JC, the majority in the room were willing to try nebulized epinephrine and dexamethasone.   Need to remember, if you’re going to give epi and dex based on the Plint article, it’s 6 days of steroids.  Others in the room were not convinced of the synergy of inhaled epinephrine and dexamethasone, and based on the negative Corneli steroid article, would not give steroids.  Harwood said it best-during the past 30 years, treatment for bronchiolitis has been cyclical-new studies come out, therapies change, we change our practice, then newer studies refute the prior findings.  

While it would be satisfying to have a clear consensus, a variety of treatment options can be supported by the current literature, and there is no single clear correct answer.  The quest will continue-we briefly touched on nebulized hypertonic saline, but there had only been 4 published studies with a total of 254 infants as of a Cochrane review in 2009, and although HS may significantly reduce hospital LOS and clinical severity scores, it has been primarily studied in inpatient populations, in small studies, and in many cases the patients also received bronchodilators (not ready for ED prime-time).