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Three Part Question

In [infants with bronchiolitis]does a [combination of dexamethasone and epinephrine] reduce [respiratory symptoms and speed up recovery]?

Clinical Scenario

A 4-month-old girl with respiratory distress presents at the emergency room in January. On physical examination the child has a fever, nasal discharge and a dry wheezy cough with tachypnoea and dyspnoea. On auscultation you find inspiratory crackles and expiratory wheezing. You know that there is no evidence for the use of bronchodilators or corticosteroids in bronchiolitis, but you wonder whether the combination of dexamethasone and epinephrine could help your patient to recover more quickly.

Search Strategy

We searched the Cochrane Library for systematic reviews and PubMed for randomised controlled trials (RCTs).
MeSH terms were used in PubMed. Search strategies were: (“bronchiolitis”[MeSH Terms] OR “bronchiolitis”[All Fields]) AND ((“epinephrine”[MeSH Terms] OR “epinephrine”[All Fields]) OR (“dexamethasone”[MeSH Terms] OR “dexamethasone”[All Fields])). The search was limited to RCTs, English language and infants

Search Outcome

36 publications (Cochrane 0, PubMed 36), of which 3 studies were directly relevant to the question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kuyucu et al, 2004	69 infants aged 2–21 months with bronchiolitis in the ED 4 groups: intramuscular–inh 1. DEX–EPI (n=23) 2. DEX–SAL (n=23) 3. P–EPI (n=11) 4. P–SAL (n=12) DEX intramuscular 0.6 mg/kg Inhalations repeated as needed	RCT	Primary outcomes: clinical scores (heart rate, respiratory rate, Respiratory Distress Assessment Instrument (RDAI))	Primary: no significant differences between the primary outcome variables of the 4 groups within the first 120 min and at 24 h Significant differences on the 5th day on RDAI score: group 1 better than group 3 (p=0.02) group 1 better than group 4 (p=0.000) group 2 better than group 4 (p=0.01) RDAI score (mean±SE) on 5th day: group 1: 2.3±0.1 group 2: 2.5±0.1 group 3: 2.9±0.2 group 4: 3.4±0.2	Small sample size Unclear if intention to treat analysis was performed Loss to follow-up 33%
			Secondary outcomes: respiratory complaints	Secondary: less respiratory complaints in DEX groups, but not statistically significant
Bentur et al, 2005,	61 infants aged 3–12 months with bronchiolitis admitted to hospital 2 groups: inh–inh 1. DEX–EPI (n=29) 2. S–EPI (n=32) DEX inh 0.25 mg Inhalations every 6 h	RCT	Primary outcomes: clinical scores (respiratory rate, wheezing, retraction, general condition, oxygen saturation), duration of supplemental oxygen, duration of intravenous fluids	Primary: no significant differences in primary outcome	Small sample size Insufficient power Unclear if intention to treat analysis was performed More severe cases than in Plint, as admission was inclusion criterion
			Secondary outcomes: discharge rate expressed by proportion of children in hospital and length of hospitalisation	Secondary: the cumulative proportion of inhospital stay of patients was lower in the treatment group than in the placebo group, mainly on days 5 (40% vs 75%) and 6 after hospitalisation (30% vs 60%) (p<0.038) Post hoc subgroup analysis: length of hospitalisation in premature infants was 2.6 days shorter in the DEX–EPI group vs the S–EPI group (6 and 7 patients, respectively): 6.5±1.7 vs 9.1±1.9 days, respectively (p=0.018)
Plint et al, 2009	800 infants aged 6 weeks–12 months with bronchiolitis in the ED 4 groups: oral–inh 1. DEX–EPI (n=199) 2. DEX–P (n=199) 3. P–EPI (n=198) 4. P–P (n=201) Oral: 1 dd for 6 days (1×1 mg/kg, 5×0.6 mg/kg) Inh: 2× every 30 min	RCT	Primary outcome: reduction in hospital admission at 7 days	Primary: reduced hospital admission in EPI–DEX group (RR 0.65, 95% CI 0.45 to 0.95) with a NNT of 11	Sufficient power Long stay in ER (4 h) No significant differences after adjustment for unexpected synergistic effect Large doses of dexamethasone
			Secondary outcomes: shortening of time to discharge and duration of symptoms (eg, respiratory rate, heart rate)	Secondary: earlier discharge from medical care in DEX–EPI group than in placebo group (4.6 vs 5.3 days, p=0.02) and faster resumption of quiet breathing (mean ratio 0.83, 95% CI 0.50 to 0.80) and normal feeding (mean ratio 0.63, 95% CI 0.69 to 1.00) in the DEX–EPI group than in the placebo group

Comment(s)

Viral bronchiolitis is the most common lower respiratory tract infection in infants (Milner). In the United States, viral bronchiolitis causes more than 130 000 hospitalisations per year in children below 5 years of age, at a cost of almost US$900 million annually(HCUPnet). Despite the increase in hospitalisation rates and the large numbers of children affected by bronchiolitis, treatment remains supportive and consists of suctioning nasal secretions, tube feeding or intravenous fluids, administering oxygen and sometimes mechanical ventilation. Most other medical therapies show conflicting evidence or are only supported by small studies. The effectiveness of nebulised bronchodilators remains controversial (Wainwright, Kellner, Bertrand, Hartling, Patel, Hariprakash).Lack of clear data on optimal therapy has contributed to the variability in the care of patients with bronchiolitis.

The identified RCTs on the effectiveness of dexamethasone and nebulised epinephrine combined are summarised in the above table. The outcome measure used for effectiveness differed among the studies, being symptom scores at various time points (ranging from 120 min to 5 days), the proportion of hospitalised patients, length of hospitalisation and time to normalisation of breathing and feeding.

The study by Kuyucu et al showed significantly better results on Respiratory Distress Assessment Instrument symptom score on the 5th day in the intramuscular dexamethasone plus nebulised epinephrine group (2.3±0.1) compared to placebo groups. However, the results are unreliable as there is a large loss to follow-up in the placebo group. Admission or length of hospitalisation was not reported. In a small RCT reported by Bentur et al there were no statistically significant differences in primary outcome (clinical scores), but by using the Kaplan–Meyer method the authors demonstrated a lower cumulative proportion of hospitalised patients in the treatment group than in the placebo group, mainly on days 5 and 6 after hospitalisation. Although the difference reached statistical significance (p<0.038), the study was performed in a relatively small number of children (61 patients) with relatively severe respiratory syncytial virus bronchiolitis requiring hospitalisation. In post hoc subgroup analysis, a significantly shorter length of hospitalisation for ex-premature infants was found in the intervention group (6.5 vs 9.1 days, p=0.018). The study of Plint et al was a methodological rigorous trial carried out in Canada according to the Cochrane guidelines for RCTs. The power was sufficient to assess whether the combination of oral dexamethasone and nebulised epinephrine could avert hospital admission. Indeed, hospitalisation rate declined by 9.3% (respiratory rate 0.65 (95% CI 0.45 to 0.95); number needed to treat 11) compared to placebo, or dexamethasone or epinephrine alone. However, after adjustment for multiple comparisons, the effect was no longer statistically significant (95% CI 0.41 to 1.03). However, the efficacy of the treatment is supported by a favourable effect of the dexamethasone–epinephrine combination on secondary outcomes, such as earlier discharge from medical care (4.6 vs 5.3 days, p=0.02; mean ratio 0.83, 95% CI 0.50 to 0.80) and faster return to normal feeding (mean ratio 0.63, 95% CI 0.69 to 1.00). No relevant adverse reactions were found and both epinephrine and dexamethasone were well tolerated. The pathophysiological mechanism behind the synergistic effect of the combination of a bronchodilator and steroids is unclear, although the synergy has been documented in the treatment of asthma. It has been suggested that bronchodilators stimulate steroid receptor expression and that steroids stimulate (post)adrenergic receptors. Furthermore, the anti-inflammatory effects of adrenergic agonists and steroids are mediated by common pathways (Pace, Johnson, Sin).However, epinephrine is a powerful drug that may not be suitable for widespread use by inexperienced clinicians in emergency departments and primary care. Therefore, it would be interesting to determine if other bronchodilators in combination with steroids have effects similar to those of epinephrine. Studies on this subject in young children are sparse: in one RCT the combination of albuterol with prednisolone had a temporary effect (Goebel) while in another study there was no additional effect of dexamethasone in salbutamol-treated patients (klassen). Future studies should evaluate the combination of bronchodilators and steroids, which is more widely available and safer.

In summary, Plint et al demonstrate that treatment of viral bronchiolitis with oral dexamethasone and epinephrine inhalation is safe and effective in young children and helps infants with bronchiolitis to recover faster. In this study, the children spent at least 4 h in the emergency department, and the need for hospitalisation was assessed after this period. When implementing the results of this study, it is important to consider regional differences in the logistics of emergency departments. In Europe most emergency departments are not prepared for long stays, and therefore a higher proportion of children will have to be admitted. In that situation, treatment with the combination of oral dexamethasone and epinephrine inhalation would not reduce hospital admission but would be expected to reduce length of hospital stay and speed up recovery.

Editor Comment

DEX, dexamethasone; dd, daily dose; ED, emergency department; EPI, epinephrine; inh, inhaled; NNT, number needed to treat; P, placebo; RDAI, Respiratory Distress Assessment Instrument; RCT, randomised controlled trial; RR, respiratory rate; SAL, salbutamol; S, saline.

Clinical Bottom Line

The combination of oral dexamethasone and nebulised epinephrine in children with bronchiolitis probably reduces hospital admission within the first 7 days and is beneficial in reducing duration of symptoms and length of hospitalisation. (Grade A)

The optimum dose, frequency and duration of therapy are uncertain, but no relevant adverse reactions were found for epinephrine and dexamethasone and both were well tolerated. (Grade D)

It is unclear if the same results would be seen in a shorter admission emergency department setting (eg, in European hospitals). (Grade D)

References

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2. HCUPnet. Healthcare Cost and Utilization Project. Rockville, MD: Agency for Healthcare Research and Quality, 2003. http://www.ahrq.gov/data/hcup/hcupnet.htm (accessed 20 Apr 2011).
3. Wainwright C, Altamirano L, Cheney M, et al . A multicenter, randomized, double-blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis. N Engl J Med 2003;349:27–35.
4. Kellner JD, Ohlsson A, Gadomski AM, et al . Bronchodilators for bronchiolitis. Cochrane Database Syst Rev 2000;2:CD001266.
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10. Bentur L, Shoseyov D, Feigenbaum D, et al . Dexamethasone inhalations in RSV bronchiolitis: a double-blind, placebo-controlled study. Acta Paediatr 2005;94:866–71.
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