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Oral Dexamethasone for Bronchiolitis: A Randomized Trial

Khalid Alansari, Mahmoud Sakran, Bruce L. Davidson, Khalid Ibrahim, Mahmoud

Alrefai and Ibrahim Zakaria
Pediatrics 2013;132;e810; originally published online September 16, 2013;
DOI: 10.1542/peds.2012-3746

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Oral Dexamethasone for Bronchiolitis: A Randomized Trial
Khalid Alansari, Mahmoud Sakran, Bruce L. Davidson, Khalid Ibrahim, Mahmoud
Alrefai and Ibrahim Zakaria
Pediatrics 2013;132;e810; originally published online September 16, 2013;
DOI: 10.1542/peds.2012-3746
Updated Information & including high resolution figures, can be found at:
References This article cites 29 articles, 7 of which can be accessed free
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2013 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from at Indonesia:AAP Sponsored on October 2, 2013

Oral Dexamethasone for Bronchiolitis: A Randomized
WHAT IS KNOWN ON THIS SUBJECT: Some infants presenting with AUTHORS: Khalid Alansari, MD, FRCPC, FAAP(PEM),a,b
bronchiolitis are later diagnosed with asthma. Corticosteroid Mahmoud Sakran, MD,a Bruce L. Davidson, MD, MPH,c
treatment of all infants with bronchiolitis is not clearly Khalid Ibrahim, MD,a Mahmoud Alrefai, MD,a and Ibrahim
efcacious. Zakaria, MDa
aDivision of Pediatric Emergency Medicine, Department of

WHAT THIS STUDY ADDS: We used infant eczema or asthma Pediatrics, Hamad Medical Corporation, Doha, Qatar; bWeill
Cornell Medical College, Doha, Qatar; and cPulmonaryCritical
history in a rst-degree relative to select patients with Care Medicine Division, University of Washington School of
bronchiolitis for dexamethasone or placebo blinded treatment. Medicine, Seattle, Washington
Dexamethasone treatment of 5 days led to signicantly earlier KEY WORDS
readiness for discharge from inrmary treatment. bronchiolitis, dexamethasone therapy, respiratory syncytial virus,
length of stay, respiratory infections
CIcondence interval
PECpediatric emergency center
abstract Drs Alansari, Alsakran, and Davidson did the literature search,
study design, data analysis and interpretation, and primary
OBJECTIVE: Determine whether dexamethasone treatment added to drafting of the manuscript; Drs Alansari, Alsakran, Ibrahim,
salbutamol reduces time to readiness for discharge in patients with Alrefai, and Zakaria recruited patients for the study; and all
authors contributed manuscript content and revisions and
bronchiolitis and possible asthma.
approved the nal manuscript as submitted.
METHODS: We compared efcacy and safety of dexamethasone, 1 mg/kg, This trial has been registered at
then 0.6 mg/kg for 4 more days, with placebo for acute bronchiolitis in (identier NCT01065272).
patients with asthma risk, as determined by eczema or a family history
of asthma in a rst-degree relative. All patients received inhaled doi:10.1542/peds.2012-3746
salbutamol. Time to readiness for discharge was the primary Accepted for publication Jul 19, 2013
efcacy outcome. Address correspondence to Khalid Alansari, MD, Department of
RESULTS: Two hundred previously healthy infants diagnosed with bron- Pediatrics, Hamad Medical Corporation, Doha, Qatar. E-mail:
chiolitis, median age 3.5 months, were enrolled. Five placebo recipients
needed admission to intensive care unit during inrmary treatment PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

(P = .02). Among 100 dexamethasone recipients, geometric mean time Copyright 2013 by the American Academy of Pediatrics
to readiness for discharge was 18.6 hours (95% condence interval FINANCIAL DISCLOSURE: The authors have indicated they have
no nancial relationships relevant to this article to disclose.
[CI], 14.9 to 23.1 hours); among 90 control patients, 27.1 hours (95%
CI, 21.8 to 33.8 hours). The ratio, 0.69 (95% CI, 0.51 to 0.93), revealed FUNDING: This study was hospital sponsored by Hamad Medical
Corporation with a grant of US $51 000.
a mean 31% shortening of duration to readiness for discharge favor-
POTENTIAL CONFLICT OF INTEREST: The authors have indicated
ing dexamethasone (P = .015). Twenty-two dexamethasone and 19 they have no potential conicts of interest to disclose.
control patients were readmitted to the short stay inrmary in the
week after discharge (P = .9). No hospitalizations or side effects were
reported during 7 days of surveillance.
CONCLUSIONS: Dexamethasone with salbutamol shortened time to
readiness for inrmary discharge during bronchiolitis episodes in
patients with eczema or a family history of asthma in a rst-degree
relative. Inrmary and clinic visits in the subsequent week occurred
similarly for the 2 groups. Pediatrics 2013;132:e810e816

e810 ALANSARI et al

Bronchiolitis is the most common se- previously.20 Because steroid use is Infants aged #18 months presenting to
rious lower respiratory tract illness in known to decrease admission rate and the unit for treatment of moderate to
young infants, affecting mainly children length of emergency stay in children severe viral bronchiolitis who had
between 2 and 5 months of age.1,2 The with asthma21 but failed to do so in a positive history for eczema or were
highest incidence in temperate climates bronchiolitis,22 identifying asthmatic or known to have a parent or a full sibling
is reported in winter.3,4 It is a common preasthmatic patients and targeting with a prior physician diagnosis of
cause for inpatient admissions, espe- them with steroid treatment early might asthma were eligible for the study.
cially in infants less than 6 months of improve symptoms and hasten recovery. Consecutive patients were recruited
age,5 but is usually self-limited and lasts A shorter stay and possibly a lower except when a study nurse was un-
about a week in previously healthy chance of needing return visits or sub- available or the unit was too busy to
children. The proportion of presenting sequent hospitalization are desirable recruit. Eczema was considered present
patients needing admission varies de- goals of better bronchiolitis therapy. We if there was a prior physician diagnosis
pending on many factors. A recent reasoned that we might focus steroid or the patient had rash consistent with
multicenter prospective cohort study treatment on an atopic population, eczema on presentation. Moderate to
from the United States found 43% were enriched for possible asthma and pre- severe bronchiolitis was dened as
admitted,6 whereas a single-center senting with bronchiolitis, if we targeted a prodromal history consistent with vi-
study from the United Kingdom repor- infants and young children with eczema ral upper respiratory tract infection
ted a 36% admission rate.7 In a recent or rst-degree relatives (a parent or followed by wheezing or crackles on
US study of term, otherwise healthy sibling) with asthma23 and that for them, auscultation and a Wang bronchiolitis
infants, the rates of emergency de- dexamethasone could be safe and ef- severity score24 of $4 on presentation.
partment visits and admissions were fective, alleviating severe symptoms and The Wang bronchiolitis severity score
77 and 71 per 1000 patient-years, re- decreasing the length of hospitalization ranges from 0 to 12 and has 4 variables,
spectively.8 or inrmary connement. Therefore, we each receiving a score from 0 to 3, with
compared blinded oral dexamethasone higher scores denoting worse status.
Recent meta-analyses do not support
to placebo in acute infant bronchiolitis in Patients were excluded from the study if
the routine use of bronchodilators,9
patients with eczema or a rst-degree they had 1 or more of the following
steam or nebulized normal saline,10
relative with asthma, all of whom also characteristics: preterm birth #34
anticholinergics,11 or steroids12 to
received salbutamol. weeks gestation, previous history of
treat bronchiolitis. After years of re-
wheezing, steroid use within 48 hours of
search, the mainstay of treatment
METHODS presentation, obtundation and pro-
remains supportive care, with supple-
gressive respiratory failure necessitat-
mental oxygen and hydration therapy.1315 Setting and Participants ing intensive care unit admission,
Five percent nebulized saline appears
The study was conducted between history of apnea within 24 hours before
superior to placebo for improving the
February 2010 and March 2012 in the presentation, oxygen saturation #85%
Wang bronchiolitis severity score,16 as on room air at the time of recruitment,
short stay unit of the Pediatric Emer-
does 3% nebulized saline,17 and the gency Center (PEC) of Hamad General history of a diagnosis of chronic lung
combination of nebulized hypertonic Hospital, the only pediatric emergency disease, congenital heart disease, and
saline with other therapies may also facility in the State of Qatar. The PEC immunodeciency or exposure to vari-
have promise.18 serves an average of 280 000 patients cella within 21 days before enrollment.
The evidence linking atopic asthma to annually and manages 42 beds in Written, informed consent, sought from
bronchiolitis is complex, and the re- a short stay inrmary unit, to which a parent or legal guardian for consec-
lationship remains as perplexing now patients are admitted if they are too ill utive eligible patients as soon as the
as when summarized more than a de- to be sent home but do not need the patient was admitted to the unit, was
cade ago.19 The challenge in dis- intensive care unit. Patients admitted obtained for all participants. The study
tinguishing the rst attack of asthma in to the unit are assessed at least every 6 was approved by the hospital institu-
infants, usually rst associated with hours by a pediatrician to determine tional review board and registered.
viral lower respiratory tract infection readiness for discharge. The length of
and later presenting as unremitting stay in the unit for bronchiolitis ranges Study Procedures
wheezing, from the episodic wheezing from 6 to 168 hours. In 2011, we saw Patients were examined on presen-
of infant bronchiolitis due to repeated 8718 infants and young children in 10 666 tation in the examination area of the
viral infections, has been highlighted visits for bronchiolitis. center, and those needing additional

PEDIATRICS Volume 132, Number 4, October 2013 e811

treatment or observation were admit- mL was allowed to be administered with Statistical Analysis
ted to the short stay inrmary unit. 2 mL of normal saline at a maximum Time to readiness for discharge was
Consecutive patients with bronchiolitis frequency of every hour, and additional plotted by univariate KaplanMeier
were assessed for study eligibility treatment (eg, supplementary oxygen, survival analysis to depict the pro-
within 2 hours of the initial physician hydration) weregivenatthediscretionof portion of patients remaining in the
assessment. Patients for whom written the treating physician. Patients were to PEC inrmary in each group. The ac-
informed consent was obtained un- be withdrawn from study drug dosing if celerated failure time model with log
derwent plain chest radiography, and clinical deterioration was determined logistic function analysis was used to
nasopharyngeal swabs were taken for to warrant intensive care admission. calculate and compare the geometric
respiratory syncytial virus detection Patients were judged ready for dis- mean times to readiness for discharge
(Quick Vue RSV-Strip; Quidel, San Diego, charge when the treating physician de- for each treatment group by their ra-
CA). Then, the enrolling physicians termined the patient did not need tio.26,27 This model uses all patient val-
accessed a sealed envelope in con- supplementary oxygen, was feeding
ues to provide geometric means, their
secutive order containing a random adequately without intravenous uids,
ratio and its 95% condence interval (CI),
number corresponding to a recently and had minimal or absent wheezing,
and a P value for the log-transformed
prepared package of blinded study crackles, and chest retractions, pro-
data. We compared follow-up data col-
medication identied with the same vided the patient had an oxygen satu-
lected for each group and proportion
number. The study pharmacist and ration $94% and severity score ,4. At
of patients medically ready for dis-
study statistician had the randomiza- discharge, patients were sent home
charge at 12, 18, 24, 36, and 48 hours. To
tion list, containing generated random with salbutamol metered-dose inhalers
estimate sample size, we started with
numbers with 1 of 2 codes identifying with an appropriately sized Aero-
a prestudy survey of duration of stay
sterilely prepared dexamethasone or chamber with mask attachment (Forest
in the PEC for 28 patients meeting our
placebo (vehicle) for oral administra- Laboratories, Dublin, Ireland). Daily
study inclusion criteria, which showed
tion, which had the same color, smell, follow-up by study nurse by telephone
that approximately 39% were dis-
and taste. At least 3 packages of blinded was mandatory for 1 week after dis-
charged by 12 hours. We believed a
charge. The patient could return to the
study medication were prepared to be difference of 20% between treatment
pediatric emergency center earlier if
available for each day during the groups for percentage discharged at 12
bronchiolitis seasons. Dexamethasone hours would be clinically signicant.
was prepared at a concentration of Study Measurements and With a sample size of 93 patients per
1 mg/mL. Study medications were ad- Outcomes group, there would be 80% power to
ministered orally after enrollment at nd a signicant difference (P , .05,
The primary outcome, elapsed time
a dosage of 1 mL/kg for the rst day and 2-sided) if 30% were the result in the
from randomization until the treating
then 0.6 mL/kg once daily for 4 days control therapy group. To compensate
physician decided the patient was
starting from the second day after en- for dropouts, we planned to recruit 200
clinically ready for discharge, was
rollment, a regimen previously tested in patients altogether.
documented for all patients. We also
a less selective patient population.25 Categorical and continuous variables
recorded the number of patients using
Patients who vomited the medicine were expressed as frequency (per-
as-needed epinephrine nebulization. For
within half an hour after administra- the week after inrmary discharge, we centage) and mean 6 SD. Descriptive
tion had a similar dose repeated. noted patients needing hospital admis- statistics were used to summarize all
All patients received 2.5 mg salbutamol sion, patients needing readmission to baseline demographic and clinical
nebulization mixed with 2 mL normal the short stay inrmary unit (site of characteristics of the patients. Quanti-
saline at 0, 30, 60, and 120 min and then initial treatment) but not hospital ad- tative variable means between the 2
every 2 hours until ready for discharge, mission, and patients visiting a clinic or independent groups were analyzed by
which is standard treatment in our unit revisiting the emergency center briey using unpaired t and Wilcoxon rank
for bronchiolitis. Inhaled therapies for the same illness. Daily calls from the sum tests. Associations between 2 or
were delivered through a tight-tted study nurse recorded information on more qualitative and categorical vari-
face mask by pressurized oxygen with general well-being, work of breathing, ables were assessed by using the x 2
the owmeter set at 10 L/min. Nebulized feeding intolerance, vomiting, diarrhea, test. For small cell frequencies, x 2 test
epinephrine (0.5 mL/kg) at a minimum and need for physician visits and hos- with a continuity correction factor was
dose of 2.5 mL and maximum dose of 5 pitalization. used. Signicant values were reported

e812 ALANSARI et al

with their corresponding 95% CI. P ,

.05 was considered the threshold for
statistical signicance. Statistical an-
alyses were performed by using a
statistical software package (SPSS,
version 19.0; IBM SPSS Statistics, IBM
Corporation). Data were transferred
from the SPSS package to Stata SE 11.0
(StataCorp, College Station, TX) for ac-
celerated failure time model analysis.

Role of the Funding Source

Hamad Medical Corporation approved
US$ 51 000 for the project. No other
support was provided by any source.
Hamad provided care to the patients,
and its institutional review board ap-
proved the study and consent form but
played no other role in the study.
Hamad employed all the physicians
except Dr Davidson.

Two hundred previously healthy infants
diagnosed with viral bronchiolitis, me-
dian age 3.5 months (range, 29 days
12.1 months) were enrolled in the study
during bronchiolitis seasons, between
February 2010 and March 2012 (Fig 1).
Consecutive eligible patients were
recruited, and informed consent was
obtained from at least 1 parent. Ten
infants were excluded from the analysis: FIGURE 1
Study owchart of enrolled patients.
3 should have been excluded from en-
rollment (1 had a history of apnea just
before admission, and 2 did not meet Efcacy admission or making outpatient visits in
the inclusion criteria of the study). Five The dexamethasone group was ready the week after discharge were similar
infants in the control group and none in for discharge earlier, with a mean du- in the 2 groups (Table 2). Daily telephone
the dexamethasone group (P = .02, ration 69% (95% CI, 51% to 83%) of the surveillance revealed no particular side
Fishers exact test) needed intensive mean duration for the placebo group, effect concerns in either treatment
care admission at 26, 36, 86, 140, and P = .015. Geometric mean durations group. A signicant difference in pro-
141 hours, respectively, and 2 more until readiness for discharge were 18.6 portion of patients ready for discharge
infants were electively removed by hours (95% CI, 14.9 to 23.1 hours) and became evident in this sample size by 18
their parents. Of the 190 infants re- 27.1 hours (95% CI, 21.8 to 33.8 hours) hours and disappeared by 48 hours
maining, 100 were randomly assigned for dexamethasone and placebo, re- (Table 2, Fig 2).
to receive dexamethasone and 90 to spectively (Table 2). Among the second- In the 7 days after discharge, inrmary
receive placebo. Subjects baseline ary outcomes, 19 dexamethasone and care was needed for 22 (22%) of the
characteristics were similar in the 2 31 placebo recipients received nebu- dexamethasone group, with an average
treatment arms before enrollment lized epinephrine (P = .03). The pro- stay of 17 hours, and 19 (21%) of the
(Table 1). portions of patients needing hospital placebo group, with an average stay of 18

PEDIATRICS Volume 132, Number 4, October 2013 e813

TABLE 1 Baseline Characteristics of Enrolled Infants generalizable treatment could alleviate
Characteristics Dexamethasone, Placebo, P Value the overall burden of this disease in
n = 102 n = 98 many clinical settings.
We built our study question and methods
Age, months, mean 6 SD 3.4 6 2.2 3.9 6 2.0 .8
Duration of symptoms before enrollment, days, mean 6 SD 4.5 6 3.3 4.4 6 2.7 .8 on the work of many others. When atopic
Male/female, n 70/32 57/41 manifestations were prevalent in pa-
Baseline Wang severity score, mean 6 SD 6.45 6 3.34 6.84 6 1.62 .09 tients with bronchiolitis, a single dose of
Baseline O2 saturation, %, mean 6 SD 97 6 1.4 97 6 1.5 .9
Respiratory syncytial virus positivity, n (%) 39 (38%) 38 (39%) .9 dexamethasone showed improvement
Chest x-ray, n (%) in respiratory assessment scores in 1
Normal 39 (38%) 35 (36%) .7 small study.28 A subgroup analysis for
Collapse or lobar consolidation 15 (15%) 16 (16%) .8
Lesser inltrates 48 (47%) 47 (48%) .9
patients with atopic family histories
Atopic history, n (%) suggested the possibility of dexameth-
Eczema in patient 31 (30%) 31 (32%) .9 asone effect (P = .07) in an otherwise
First-degree patient relative with asthma, n (%)
negative study in which dexamethasone
Mother with asthma 19 (19%) 22 (22%) .5
Father with asthma 22 (22%) 22 (22%) .9 1 mg/kg intramuscularly or placebo
Both parents with asthma 5 (4.9%) 5 (5%) 1.0 was given for 3 days.29 In other studies,
Full sibling with asthma 77 (76%) 70 (71%) .5 a lower dose daily of dexamethasone
Patient with eczema and a rst-degree relative with 19 (19%) 20 (20%) .5
asthma (0.15 mg/kg) in unselected patients with
bronchiolitis30 and somewhat higher
daily doses administered multiple times
(0.5 mg/kg, then 0.3 mg/kg) to hospi-
hours, P = .9. Nineteen dexamethasone asthma in a parentor fullsibling appears talized patients31 were not superior to
and 11 placebo recipients made a clinic to identify a population of infants and placebo, so we chose higher dosages. A
or brief PEC visit (P = .2). No inrmary- young children with bronchiolitis who previously reported multicenter ran-
discharged patients needed hospitali- will have a clinically signicant benet of domized controlled trial comparing just
zation in the week after discharge. earlier (by 31%) readiness for discharge a single dose of dexamethasone with
without undue risk from early steroid placebo showed no difference between
administration. Because the criteria we the 2 groups in the decision about
DISCUSSION tested were present in 66% of a similar hospital admission at 4 hours and the
A literature review showed that a pre- population of patients with a rst epi- length of hospital stay.22 Although we
vious history of eczema in the patient or sode of bronchiolitis,22 applying this also found no difference in readiness

TABLE 2 Primary and Secondary Outcomes

Primary Outcomes

Outcome Dexamethasone (95% CI), N = 100 Placebo (95% CI), N = 90

Geometric mean time to readiness for discharge 18.6 h (14.9 to 23.1 h) 27.1 h (21.8 to 33.8 h)
Ratio of geometric means 0.69 (0.51 to 0.93), P = .015

Secondary Outcomes

Percentage of Patients Ready for Discharge in Each Treatment Group at Time After Enrollment

Time (h) Dexamethasone % (95% CI), N = 100 Placebo % (95% CI), N = 90 Difference (95% CI) P Value

12 48.0 (38.5 to 57.7) 36.6 (27.4 to 46.7) 11.3 (22.6 to 25.3) .11
18 54.0 (44.3 to 63.4) 36.6 (27.4 to 46.9) 17.3 (3.4 to 31.3) .01
24 65.0 (55.2 to 73.7) 50.0 (39.9 to 60.1) 15.0 (1.1 to 28.9) .03
36 77.0 (67.8 to 84.2) 57.7 (47.5 to 67.5) 19.2 (6.1 to 32.3) .005
48 82.0 (73.2 to 88.4) 68.8 (58.7 to 77.5) 13.1 (0.9 to 25.3) .03

Outcome Dexamethasone %, N = 100 Placebo %, N = 90 P Value

Patients using as-needed epinephrine nebulization 19 31 .03

Patients needing hospital admission in the week after discharge 0 0
Patients needing inrmary care but not hospital admission in the week after discharge 22 19 .9
Patients with clinic visits but not hospital admission in the week after discharge 19 11 .2

e814 ALANSARI et al

hospitalization and still be safe. Our

positive ndings take advantage of
prior trials of dexamethasone dosage
and dose frequency, and we selected
for randomization an especially po-
tentially responsive and proportionally
plentiful patient subset.
Our study is limited in its detail of safety
reporting. Study nurses asked ques-
tions from a checklist, but we collected
general rather than specic responses.
We did not measure the prevalences of
patient eczema or atopy in the rst-
degree family in our bronchiolitis
population during the study, but sub-
sequent surveying suggests it is more
FIGURE 2 than half, perhaps nearly as many as
Bronchiolitis discharges from the PEC. two-thirds of acute bronchiolitis pre-
for discharge at 4 hours, we found signicant difference in subsequent
an overall geometric mean shorter need for postdischarge readmission to CONCLUSIONS
length of stay for patients treated with inrmary care or outpatient clinic vis- Oral dexamethasone administered with
dexamethasone (and salbutamol), its, and no inrmary-discharged pa- salbutamol signicantly reduced the
probably because the treatment was tient needed hospital admission. It duration until clinical readiness for dis-
targeted to patients with eczema or might be that postdischarge revisits charge in the treatment of bronchiolitis
a rst-degree relative with asthma, are unavoidable. All our study patients in patients with eczema or a family
rather than the entire population with in both groups received salbutamol history of asthma in a rst-degree
bronchiolitis. inhalations, probably providing com- relative. We speculate that a some-
Another recent bronchiolitis treatment parable effect to the epinephrine re- what more prolonged dosing regimen
study25 found with marginal statistical ceived in the aforementioned study. may also reduce the need for post-
signicance that with repeated daily However, in light of the data of Plint and discharge visits.
dosing of dexamethasone for 6 days colleagues,25 perhaps a more pro-
altogether, with 2 doses of epinephrine longed or less abruptly tapered dexa- ACKNOWLEDGMENT
in the emergency department, hospital methasone regimen could not only The authors thank Dr Rajvir Singh for
admission within the subsequent 7 allow earlier discharge but also reduce his thoughtful guidance in biostatistical
days could be reduced. We found no the need for postdischarge visits and analysis.

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