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Archimedes

SEARCH STRATEGY AND OUTCOME


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 and yielded 36 publications (Cochrane 0, PubMed 36), of which
3 studies were directly relevant to the
question. See table 2.

COMMENTARY

QUESTION 2
DOES COMBINED ORAL DEXAMETHASONE
AND EPINEPHRINE INHALATION HELP
INFANTS WITH BRONCHIOLITIS TO
RECOVER FASTER?

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
nd 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.

STRUCTURED CLINICAL QUESTION


In infants with bronchiolitis [patients],
does a combination of dexamethasone
and epinephrine [intervention] reduce
respiratory symptoms and speed up
recovery [outcome]?
606

Viral bronchiolitis is the most common


lower respiratory tract infection in infants.1
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.2
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 uids, administering oxygen and sometimes
mechanical ventilation. Most other medical therapies show con icting evidence or
are only supported by small studies. The
effectiveness of nebulised bronchodilators remains controversial.38 Lack of clear
data on optimal therapy has contributed
to the variability in the care of patients
with bronchiolitis.
The identied RCTs on the effectiveness of dexamethasone and nebulised
epinephrine combined are summarised
in table 2. 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 al9 showed
signicantly better results on Respiratory
Distress Assessment Instrument symptom
score on the 5th day in the intramuscular
dexamethasone plus nebulised epinephrine group (2.30.1) 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,10
there were no statistically signicant
differences in primary outcome (clinical
scores), but by using the KaplanMeyer
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 signicance
(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 signicantly 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 al11 was a methodological rigorous
trial carried out in Canada according to
the Cochrane guidelines for RCTs.12 The
power was sufcient 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 signicant (95% CI 0.41 to
1.03). However, the efcacy of the treatment is supported by a favourable effect
of the dexamethasoneepinephrine 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

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)
Arch Dis Child June 2011 Vol 96 No 6

Archimedes
Table 2

Does combined oral dexamethasone and epinephrine inhalation help infants with bronchiolitis to recover faster?

Citation

Study group

Study type

Outcome

Key results

Comments

Kuyucu et al9

69 infants aged 221 months


with bronchiolitis in the ED
4 groups:
intramuscularinh
1. DEXEPI (n=23)
2. DEXSAL (n=23)
3. PEPI (n=11)
4. PSAL (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))
Secondary
outcomes:
respiratory
complaints

Small sample size


Unclear if intention to treat
analysis was performed
Loss to follow-up
33%

Bentur et al10

61 infants aged 312 months


with bronchiolitis admitted to
hospital
2 groups:
inhinh
1. DEXEPI (n=29)
2. SEPI (n=32)
DEX inh 0.25 mg
Inhalations every 6 h

RCT

Plint et al11

800 infants aged 6 weeks12


months with bronchiolitis in
the ED
4 groups:
oralinh
1. DEXEPI (n=199)
2. DEXP (n=199)
3. PEPI (n=198)
4. PP (n=201)
Oral: 1 dd for 6 days (11 mg/
kg, 50.6 mg/kg)
Inh: 2 every 30 min

RCT

Primary outcomes:
clinical scores
(respiratory rate,
wheezing, retraction, general
condition, oxygen
saturation), duration of supplemental oxygen, duration
of intravenous
fluids
Secondary outcomes: discharge
rate expressed
by proportion of
children in hospital and length of
hospitalisation
Primary outcome:
reduction in hospital admission at
7 days
Secondary outcomes: shortening
of time to discharge
and duration of
symptoms (eg,
respiratory rate,
heart rate)

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 (meanSE) on 5th day:
group 1: 2.30.1
group 2: 2.50.1
group 3: 2.90.2
group 4: 3.40.2
Secondary: less respiratory complaints
in DEX groups, but not statistically
significant
Primary: no significant differences in
primary outcome
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 DEXEPI group
vs the SEPI group
(6 and 7 patients, respectively): 6.51.7
vs 9.11.9 days, respectively (p=0.018)

Primary: reduced hospital admission in


EPIDEX group (RR 0.65, 95% CI 0.45 to
0.95) with a NNT of 11
Secondary: earlier discharge from
medical care in DEXEPI 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 DEXEPI
group than in the placebo group

Sufficient power
Long stay in ER (4 h)
No significant differences after
adjustment for unexpected synergistic effect
Large doses of dexamethasone

Small sample size


Insufficient power
Unclear if intention to treat
analysis was performed
More severe cases than in Plint,
as admission was inclusion
criterion

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.

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-inammatory
effects of adrenergic agonists and steroids
are mediated by common pathways.1315
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
Arch Dis Child June 2011 Vol 96 No 6

albuterol with prednisolone had a temporary effect,16 while in another study there
was no additional effect of dexamethasone in salbutamol-treated patients.17
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.
QM van Dellen, F Kreier, CC de Kruiff,
N Boluyt, K Fijnvandraat
Academic Medical Center, Emma Childrens Hospital,
Amsterdam, The Netherlands
Correspondence to QM van Dellen, Academic
Medical Center, Emma Childrens Hospital,
Amsterdam, The Netherlands;
q.vandellen@amc.uva.nl
607

Archimedes
Competing interests None.
Provenance and peer review Not commissioned;
internally peer reviewed.
Accepted 27 March 2011
Arch Dis Child 2011;96:606608.
doi:10.1136/archdischild-2011-300067

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Arch Dis Child June 2011 Vol 96 No 6