CLINICAL INVESTIGATIONS

Nebulized Budesonide Added to Standard

Pediatric Emergency Department Treatment
of Acute Asthma: A Randomized,
Double-blind Trial
Bryan D. Upham, MD, MSCE, Cynthia J. Mollen, MD, MSCE, Richard J. Scarfone, MD,
Jeffrey Seiden, MD, Amber Chew, and Joseph J. Zorc, MD, MSCE

Abstract
Objectives: The goal was to determine if adding inhaled budesonide to standard asthma therapy
improves outcomes of pediatric patients presenting to the emergency department (ED) with acute
asthma.
Methods: The authors conducted a randomized, double-blind, placebo-controlled trial in a tertiary care,
urban pediatric ED. Patients 2 to 18 years of age with moderate to severe acute asthma were randomized to receive either a single 2-mg dose of budesonide inhalation suspension (BUD) or normal sterile
saline (NSS) placebo, added to albuterol, ipratropium bromide (IB), and systemic corticosteroids (SCS).
The primary outcome was the difference in median asthma scores between treatment groups at 2 hours.
Secondary outcomes included differences in vital signs and hospitalization rates.
Results: A total of 180 patients were enrolled. Treatment groups had similar baseline demographics,
asthma scores, and vital signs. A total of 169 patients (88 BUD, 81 NSS) were assessed for the primary
outcome. No significant difference was found between groups in the change in median asthma score at
2 hours (BUD 3, NSS 3, p = 0.64). Vital signs at 2 hours were also similar between groups. Fifty-six
children (62%) were admitted to the hospital in the BUD group and 55 (62%) in the NSS group (difference 0%, 95% confidence interval [CI] = 14% to 14%). Neither multivariate adjustment nor planned subgroup analysis by inhaled corticosteroids (ICS) use prior to the ED significantly altered the results.
Conclusions: For children 2 to 18 years of age treated in the ED for acute asthma, a single 2-mg dose
of budesonide added to standard therapy did not improve asthma severity scores or other short-term
ED-based outcomes.
ACADEMIC EMERGENCY MEDICINE 2011; 18:665673 2011 by the Society for Academic Emergency
Medicine

From the Division of Pediatric Emergency Medicine, Department of Emergency Medicine, University of New Mexico
(BDU), Albuquerque, NM; the Division of Emergency Medicine, The Childrens Hospital of Philadelphia (BDU, CJM, RJS,
JS, AC, JJZ), and the Department of Pediatrics, University of
Pennsylvania (BDU, CJM, RJS, JS, JJZ), Philadelphia, PA; and
Virtua-West Hospital (JS), Voorhees, NJ.
Received October 22, 2010; revision received December 24,
2010; accepted December 29, 2010.
Presented at the American Academy of Pediatrics National
Conference and Exhibition, Section on Emergency Medicine,
Boston, MA, October 2008.
This trial was supported by the Crognale Foundation of the
Childrens Hospital of Philadelphia. The authors have no other
financial relationships relevant to this article to disclose.
Supervising Editor: Gregory P. Conners, MD, MPH, MBA.
Address for correspondence and reprints: Bryan D. Upham,
MD, MSCE; e-mail: bupham@salud.unm.edu.

2011 by the Society for Academic Emergency Medicine

doi: 10.1111/j.1553-2712.2011.01114.x

sthma is the most common chronic disease in

children, with recent estimates as high as 14%
for lifetime prevalence.1 In 2005, 3.8 million children with asthma had an exacerbation in the previous
year, and there were an associated 754,000 emergency
department (ED) visits with 198,000 hospitalizations.2
Recommendations for treatment of asthma exacerbations include the use of selective b2-agonists, ipratropium bromide (IB), and oral corticosteroids.3 Oral
corticosteroids improve pulmonary function and reduce
hospitalizations, but require 24 hours to reach peak
effect.4,5 Inhaled corticosteroids (ICS) are recommended
for long-term control of persistent symptoms, but are
not as effective for treatment of acute exacerbations as
systemic corticosteroids (SCS).3,6,7 However, recent
data indicate that ICS used in the acute setting may
have an additive effect to SCS,811 perhaps due to a
more rapid effect on topical plasma membrane-based

ISSN 1069-6563
PII ISSN 1069-6563583

665

666

Upham et al.

BUDESONIDE AS AN ADJUNCT TO ACUTE ASTHMA THERAPY IN CHILDREN

vasoconstriction.12 A recent Cochrane systematic

review of ICS use in acute asthma calls for further
study in this area.13
Budesonide inhalation suspension (BUD) is the only
nebulized corticosteroid approved for use in children in
the United States. Studies of BUD in children with acute
asthma report a more rapid improvement in oxygen
saturation, respiratory rate, heart rate,9 peak expiratory
flow rate,10 and asthma scores9,11 when compared to9
or combined with10,11 SCS. Children treated with BUD
are reported to be suitable for discharge from the hospital earlier.9,11 While these studies are promising, to
the best of our knowledge, no prior study has been
adequately powered to determine whether adding BUD
to standard therapy with bronchodilators and corticosteroids improves measures of acute asthma severity in
the ED setting. Our hypothesis was that adding a single, 2-mg dose of inhaled budesonide to standard acute
asthma therapy improves asthma scores at 2 hours
compared to standard therapy alone. If adding ICS to
standard acute asthma therapy improves symptoms
more rapidly or leads to fewer hospitalizations, it would
be an important adjunct to standard asthma therapy.
METHODS
Study Design
This was a double-blind, placebo-controlled, randomized trial of BUD added to standard acute asthma therapy. The Human Research Review Committee at our
institution approved the study prior to initiation, and
the trial was registered at http://www.clinicaltrials.gov
(NCT00393367). Parents gave informed consent, and
patients assented when appropriate.
Study Settings and Population
The study was conducted at an urban, tertiary care,
pediatric ED with an annual patient volume of over
75,000 patients. Patients were enrolled from November
2006 until October 2007. Patients presenting to the ED
with an acute asthma exacerbation were included if
they were 2 to 18 years of age, with a history of asthma

defined by at least two prior episodes of treatment with

bronchodilators. Screening was limited to patients triaged to the highest two acuity categories of a four-level
triage system.14 Each screened patient was evaluated
by a pediatric emergency medicine attending physician
or fellow, who determined the initial severity using the
asthma score reported by Qureshi et al.15 (Table 1). This
asthma score was chosen due to its similarity to the
pulmonary index score, age-specific respiratory rates,
and excellent interrater reliability.15 Patients who met
the above criteria, had an asthma score of 8 or greater,
and were prescribed SCS were eligible for enrollment.
Other criteria for enrollment included presence of an
English-speaking parent or guardian to provide
informed consent and a patient weight of at least 10 kg.
Patients were excluded if they used SCS in the prior
30 days; had chronic lung disease, sickle cell anemia,
immunodeficiency, cardiac disease requiring surgery or
medications, known renal or hepatic dysfunction,
impending respiratory failure, altered level of consciousness, exposure to varicella in the prior 21 days,
suspected foreign body or croup; had been enrolled in
the study previously; or had an adverse drug reaction
or allergy to the study drugs.
Study Protocol
All patients received standard acute asthma therapy
while the guardian was approached for consent to participate in the study. This therapy included albuterol
(3.75 mg for patients weighing 1020 kg, 5 mg for those >20 kg); IB (500 mcg); and prednisolone, prednisone,
or methylprednisolone (2 mg kg to a maximum of
60 mg). Participants were assigned using opaque envelopes that were prerandomized in variable-sized blocks.
Patients were stratified by age category (28 and 9
18 years) and history of ICS use (currently taking ICS at
study entry or not). Enrollment occurred in each strata
until that strata was filled. The study medication was
prepared by a respiratory therapist who was out of
sight of other staff, the patient, and the patients family.
To maintain blinding, the study medication was placed
into a shielded nebulization chamber. All nebulized

Table 1
Asthma Severity Score*
Asthma Scoring
Variable

1 Point

2 Points

Respiratory rate
23 yr
45 yr
612 yr
>12 yr
O2 saturation (%)

34
30
26
23
>95 on room air

3539
3135
2730
2427
9095 on room air

Wheeze

Normal or end-expiratory wheeze

Expiratory wheeze

Retractions

None or intercostals

Intercostal and substernal

Dyspnea

Speaks in sentences
or coos and babbles

Speaks in partial sentences

or utters short cries

*Asthma score from Qureshi et al.15

3 Points
40
36
31
28
<90 on room air or with
supplemental oxygen
Inspiratory and expiratory wheeze,
diminished breath sounds, or both
Intercostal, substernal, and
supraclavicular
Speaks in single words or short
phrases or grunts

ACADEMIC EMERGENCY MEDICINE July 2011, Vol. 18, No. 7

www.aemj.org

medications were administered by a respiratory therapist not involved in subject asthma scoring, treatment
decisions, or disposition decisions. To assess blinding,
we recorded which treatment the study physicians felt
the patient received at the time of the patients final disposition.
A total of three albuterol and two IB doses were
delivered back to back during the first treatment period: one albuterol IB dose while the guardian was
being approached for consent; two albuterol doses
mixed with BUD or saline placebo over the next 30
45 minutes (intervention); and one IB dose administered
separately immediately after the intervention (Figure 1).
The intervention consisted of either 8 mL of BUD
(0.5 mg 2 mL = 2 mg, AstraZeneca AB, Sdertlje,
Sweden) or 8 mL of normal sterile saline (NSS) placebo,
mixed with 1.5 mL (7.5 mg) or 2 mL (10 mg) of albuterol, for patients weighing 1020 kg and >20 kg,
respectively. The medications were delivered by the
respiratory therapist via an AirLife Mister Finity (Cardinal Health, Dublin, OH) medium-volume high-flow continuous nebulizer with tight-fitting face mask and an
oxygen flow rate of 8 L per minute.
Evaluations by the study physicians occurred at
hourly intervals after the intervention. At each evaluation, the study physicians could decide to observe the
patient for an hour, to treat the patient with continuous
albuterol for an hour (15 mg hour for patients weighing 1020 kg, 20 mg hour for those weighing >20 kg),
or to discharge the patient to home if the patient had
maintained sufficient improvement for 2 or more hours
after the intervention. Patients discharged to home
received a prescription for 4 days of prednisolone or

Identify Patient: Acute or Critical

Screening Physical, Asthma Score

Albuterol x 1
IB x 1
SCS

Screen
failures

BUD with Albuterol x 2

then
IB x 1

Consent

NS with Albuterol x 2
then
IB x 1

Randomization

Hourly ED Evaluation, Asthma Score

Observation or Continuous Albuterol each hour

Disposition
24 hours after intervention

Hospital

Home

Follow-up call,
Medical record review
Albuterol
BUD
Continuous Albuterol
IB
SCS

= 3.755 mg, nebulized

= Budesonide inhalation suspension 2 mg, nebulized
= 1520 mg/hour, nebulized
= 500 g, nebulized
= Systemic corticosteroids 2 mg/kg (60 mg max)

Figure 1. Study treatment flow diagram. BUD = budesonide

inhalation suspension; IB = ipratropium bromide; SCS = systemic corticosteroids.

667

prednisone (2 mg kg day to a maximum of 60 mg).

Patients who were not suitably improved four hours
after the intervention were admitted to the inpatient
floor or 23-hour observation unit for further management. All treatment and disposition decisions were
made solely at the discretion of the treating study physician. All patient guardians received a follow-up phone
call 3 to 5 days after the ED visit. If the guardian was
not contacted on the first call, a total of four more
attempts were made in the next 30 days, after which
the patient was considered lost to follow-up.
Measures
Asthma scores were obtained at study entry and at 1
and 2 hours after the intervention, and heart and respiratory rates and oxygen saturations were recorded
hourly up to 4 hours after the study intervention. Additional baseline data collected included patient demographics, clinical asthma history, and prior treatments.
The medical record was reviewed within 2 weeks of the
ED visit.
The primary outcome was the difference in median
asthma scores between study groups 2 hours after
intervention. A difference of two or more points was
considered clinically significant based on the study by
Sung et al.,11 using a similar asthma score. Secondary
outcomes included the differences in admission rates to
an inpatient floor or observation unit, heart rates, respiratory rates, and oxygen saturation.
Data Analysis
Two groups of subjects were recruited: those on ICS
controller therapy at the time of the study and those
not on ICS. Sample size estimates were calculated to
ensure each ICS group had sufficient numbers of subjects to allow separate subgroup analysis. Sample size
estimates were based on a minimal clinically important
difference in the asthma score of 2 and published rates
of pulmonary index score standard deviations with a
maximum of 2.5.10,11,16 Using this assumption, a twotailed sample size calculation based on the two-sample
t-test with a power of 0.9 and an alpha level of 0.05
gives a sample size of 68 subjects per ICS group.
Because the underlying distribution of the asthma score
could not be assumed to be normal, this number is
divided by the lowest possible asymptotic relative efficiency of 0.86 to give 80 subjects per ICS group. Dividing by 0.9 for an estimated dropout rate of 10% gives a
total of 90 subjects per ICS group, or 180 total subjects.
Because the asthma score contains subjective elements, we assessed the interrater reliability by having
two evaluators assign asthma scores to 20% of the
patients. These evaluations were completed within
20 minutes of each other. The results were compared
using the intraclass correlation coefficient.
The analysis was based on the principle of intention
to treat. The primary outcome, difference in asthma
scores at 2 hours, was evaluated using the Wilcoxon
rank sum test. Analysis was performed on each ICS
group separately and with both ICS groups combined.
Hospital admission was analyzed using the chi-square
test. T-tests were used to analyze changes in heart rate
and respiratory rate, and changes in oxygen saturation

668

Upham et al.

BUDESONIDE AS AN ADJUNCT TO ACUTE ASTHMA THERAPY IN CHILDREN

were evaluated using the Wilcoxon rank sum test.

Skewness and kurtosis testing was performed to ensure
the underlying distributions of the change in heart rate
and respiratory rates were normal.
Additional analyses of the primary outcome and secondary outcome of hospitalization included a per-protocol analysis, a post hoc analysis by presentation
severity (moderate or severe by initial asthma score), a
post-hoc sensitivity analysis for the primary outcome,
and logistic regressions for both outcomes to control
for variations in baseline characteristics. In the per-protocol and post hoc analyses, the Wilcoxon rank sum
test was used to compare the primary outcome, and a
chi-square test was used to compare hospitalization
admission.
In the sensitivity analysis for the primary outcome,
for the best case we assumed that patients who
received BUD but did not have a 2-hour score
improved to the minimum asthma score of 5, and
patients who received NSS but had no 2-hour score
worsened to the maximum score of 15. Likewise, for
the worst case we assumed that the BUD patients with
missing 2-hour scores worsened to 15 and those NSS
patients with missing 2-hour scores improved to 5.
To evaluate the effect of differences in covariates on
the primary outcome, a multivariate ordinal logistic
regression was performed to control for age, weight,
sex, race, baseline asthma severity, use of controller
medications, time since the exacerbation began, and
b2-agonist use. In this regression, a baseline model
including ICS and age strata was constructed and each
covariate tested against these two. Covariates were
included if their p-value was 0.2 or if they altered the
strata coefficients by 10% or more. A multivariate
logistic regression model was used to compare hospitalization rates by study group while controlling for the
same covariates above. This model was constructed in
a similar way to the one for the primary outcome. The
alpha level was set to 0.05 for all analyses, 95% confidence intervals (CIs) were calculated, and all comparisons were two-tailed. If statistically significant changes
were found, the alpha levels were adjusted for multiple
comparisons. Statistical analysis was performed using
Stata, version 9.2 (StataCorp, College Station, TX).
RESULTS
Of the 2,947 patients screened for eligibility, 2,650 did
not meet inclusion criteria (Figure 2). The most common reasons for not meeting inclusion criteria were:
1) the triage level was not acute or critical (57%),
2) the treatment was initiated prior to the asthma score
(12%), 3) the patient received SCS in the prior 30 days
(8%), and 4) the asthma score was less than 8 (7%). All
of the 180 patients included in the study received standard asthma therapy. Each of the 91 patients randomized to BUD received BUD, and 89 of those 91 patients
were evaluable for the primary outcome (one patient
was discharged to home before the 2-hour evaluation,
and one did not have a 2-hour score). Eighty-eight of
the 89 patients randomized to NSS placebo received
NSS placebo (one patient was inadvertently started on
standard therapy without placebo), and 81 of those 89

2,947 Patients screened

2,650 Did not meet
inclusion criteria
117 Refused

180 Enrolled and underwent randomization

91 Assigned to BUD
91 Received BUD

89 Have complete score data

91 Have hospitalization data
89 Have follow-up data

89 Assigned to placebo
88 Received placebo

81 Have complete score data

89 Have hospitalization data
86 Have follow-up data

Figure 2. Study flow diagram. BUD = budesonide inhalation

suspension.

patients were evaluable for the primary outcome. Two

patients in the NSS group withdrew from the study:
one for feeling jittery, and one for unspecified reasons at the guardians request. Five additional patients
in the NSS group could not be evaluated for the primary outcome because they were admitted to the inpatient ward before the 2-hour evaluation. Two patients
in the BUD group and four patients in the NSS group
were lost to follow-up.
Baseline Characteristics. Baseline demographic and
clinical characteristics were similar between treatment
groups (Table 2). BUD subjects had a slightly higher
rate of prior hospitalization and number of nebulized
albuterol treatments prior to ED arrival.
A total of 116 patients (64%) presented in the moderate severity range (asthma score 811), and 62 patients
(34%) presented in the severe (1215) range. One
patient was inadvertently scored at 8 when the actual
score was 7 due to an error in addition. Finally, one
patient was enrolled with a score of greater than 10.
Both patients were included in the analysis, but the latter could not be evaluated for the primary outcome.
Interrater Reliability. Forty study physicians participated in the study. Forty patients (22%) were assessed
for interrater reliability of the asthma score using the
intraclass correlation coefficient. The coefficient was
0.7, considered good reproducibility.17
Blinding. Study physicians correctly guessed that
patients received BUD in 35 of 91 (38%) of cases, and
they correctly guessed that patients received placebo in
41 of 87 (47%) of controls, suggesting effective blinding.
Primary and Secondary Outcomes. Both study groups
improved with treatment (Figures 3 and 4, Table 3), but
we found no significant difference between study groups
in the improvement in median asthma scores (BUD 3,
IQR = 4 to 2; NSS 3, IQR = 4 to 2; p = 0.64). Likewise, we found no significant difference in change in
heart rate, respiratory rate, or oxygen saturation 2 hours
after the intervention or overall initial hospitalization

ACADEMIC EMERGENCY MEDICINE July 2011, Vol. 18, No. 7

www.aemj.org

669

Table 2
Baseline Patient Characteristics by Study Group
Patients Not on ICS
Characteristic
Male, n (%)
Age, yr
Weight, kg
On ICS, n (%)
Ever hospitalized
n N,
% (95% CI)
Median albuterol
nebulizations
past 6 hours
(IQR)
Median asthma
score (IQR)
Respiratory rate,
breaths min
Heart rate,
beats min
Median oxygen
saturation, %
(IQR)

Patients on ICS

Combined

Budesonide
(n = 46)

Placebo
(n = 44)

Budesonide
(n = 45)

Placebo
(n = 44)

Budesonide
(n = 91)

Placebo
(n = 88)

36 (78)
6.0 (4.97.2)
27.2 (22.032.3)
0 (0)

22 (50)
6.1 (4.97.4)
29.4 (22.436.3)
0 (0)

28 (62)
6.4 (5.27.6)
28.6 (23.334.0)
45 (100)

32 (73)
6.5 (5.37.6)
30.5 (24.436.6)
44 (100)

64 (70)
6.2 (5.47.0)
27.9 (24.231.5)
45 (49)

54 (61)
6.3 (5.57.1)
29.9 (25.434.4)
44 (50)

36 46
78 (6489)
1.5 (02)

23 43
53 (3869)
0 (02)

41 45
91 (7998)
2 (03)

38 44
86 (7395)
1 (12)

77 91
85 (7691)
2 (03)

61 87
70 (5979)
1 (02)

11.5 (1013)

11 (912)

10 (912)

10 (912)

11 (912)

11 (912)

41 (3644)

40 (3543)

36 (3339)

38 (3542)

38 (3641)

39 (3642)

129 (123136)

127 (121132)

95 (9396)

125 (119131)

96 (9397)

125 (119131)

96 (9498)

127 (123132)

96 (9497)

95 (9397)

126 (120130)
96 (9497)

Values are reported with median (IQR) or mean (95% CI).

ICS = inhaled corticosteroids; IQR = interquartile range.

Baseline Asthma Score - NS Placebo

20
15
10

Number of Subjects

0
3

11

13

15

11

13

2-Hour Asthma Score - BUD

2-Hour Asthma Score - NS Placebo

15
10
0

20
15
10
5

15

20

Asthma Score

Number of Subjects

Asthma Score

11

13

15

11

13

Asthma Score

Change in 2-Hour Asthma Score - BUD

Change in 2-Hour Asthma Score - NS Placebo

15
10

20
15
10

5
0

15

20

Asthma Score

Number of Subjects

Number of Subjects

Number of Subjects

20
15
10
5
0

Number of Subjects

Baseline Asthma Score - BUD

-8

-6

-4

-2

Change in Asthma Score

-8

-6

-4

-2

Change in Asthma Score

Figure 3. Baseline, 2-hour, and change in asthma scores by treatment group. BUD = budesonide inhalation suspension;
NS = normal saline.

670

Upham et al.

BUDESONIDE AS AN ADJUNCT TO ACUTE ASTHMA THERAPY IN CHILDREN

Figure 4. Box-and-whiskers plot of change in 2-hour asthma

score by treatment group. BUD = budesonide inhalation suspension; NSS = normal sterile saline.

rates (Table 3). Also, there was no difference between

study groups in median asthma score improvement or
vital signs at 1 hour (data not shown). Of the 56 (62%)
patients initially admitted in the BUD group, 8 (14% of
those admitted or 9% overall) were admitted to the

23-hour observation unit. Similarly, of the 55 (62%)

patients initially admitted in the placebo group, 10 (18%
of those admitted or 11% overall) were admitted to the
23-hour observation unit. Two patients from each treatment group returned after discharge for readmission
within 72 hours. One of those patients (BUD group) had
been admitted to the 23-hour observation area. Including 72 hour readmissions, the overall hospital admission
rates were similar between treatment groups (BUD 63%,
95% CI = 52% to 75%; NSS 64%, 95% CI = 53% to 74%;
difference 1%, 95% CI = 15% to 13%).
Additional analysis of the primary outcome of change
in asthma score at 2 hours, and secondary outcome of
hospitalization, did not significantly alter the results.
This included a per-protocol analysis, a subgroup analysis of those patients by receipt of ICS prior to the study
(Table 4), a post-hoc analysis by presentation severity
(Table 5), a post-hoc sensitivity analysis of the primary
outcome, and multivariate logistic regressions of both
outcomes. In the per-protocol analysis, there was no
difference in the change in 2-hour asthma score (BUD
3, IQR = 4.5 to 2; NSS 3.5, IQR = 4.5 to 2; difference 0.5, p = 0.48) or hospitalization rate (BUD 62%,
95% CI = 51% to 73%; NSS 61%, 95% CI = 49% to
72%; difference 1%, 95% CI = 16% to 14%). The

Table 3
Change in Asthma Score and Vital Signs from Baseline to 2 Hours After Intervention, Initial Hospital Admissions

Mean Changes
Asthma score (IQR) n
Respiratory rate, breaths min (95% CI) n
Heart rate, beats min (95% CI) n
Median change in O2 saturation, % (IQR) n
Hospital admission, % (95% CI) n

Budesonide Group
(n = 91)
3
6
12
1
62

(4 to 2) 89
(8 to 4) 83
(7 to 17) 82
(1 to 3) 72
(51 to 72) 56

Placebo Group
(n = 88)
3
6
13
1
62

Difference Between Groups

(95% CI)

(4 to 2) 81
(8 to 3) 71
(9 to 17) 72
(1 to 3) 64
(52 to 73) 55

0
0 (3 to 3)
1 (7 to 6)
0
0 (14 to 14)

p-value
0.64
0.91

IQR = interquartile range.

Table 4
Change in Asthma Score and Vital Signs from Baseline to 2 Hours After Intervention and Initial Hospital Admissions by Prior ICS
status

Budesonide Group
Patients on ICS
Median change in asthma score (IQR) n
Mean change in respiratory rate,
breaths min (95% CI) n
Mean change in heart rate,
beats min (95% CI) n
Median change in O2 saturation, % (IQR) n
Hospital admission, % (95% CI) n
Patients not on ICS
Median change in asthma score (IQR) n
Mean change in respiratory rate,
breaths min (95% CI) n
Mean change in heart rate,
beats min (95% CI) n
Median change in O2 saturation % (IQR) n
Hospital admission, % (95% CI) n

Placebo Group

Difference Between
Groups (95% CI)

n = 45
3 (4 to 1.5) 44
5 (8 to 2) 41

n = 44
3 (4 to 1) 41
6 (8 to 2) 36

0
1 (4 to 5)

11 (4 to 18) 41

12 (7 to 17) 37

1 (9 to 8)

1 (1 to 3) 35
58 (42 to 72) 26
n = 46
3 (5 to 2) 45
6 (9 to 4) 42

1 (0 to 4) 31
61 (45 to 76) 27
n = 44
3.5 (4.5 to 2) 40
6 (10 to 2) 35

0
3 ( 24 to 17)

14 (7 to 21) 41

14 (8 to 20) 35

0 (9 to 9)

1.5 (0 to 3) 37
65 (50 to 79) 30

0 (2 to 2) 33
64 (48 to 78) 28

1.5
1 (18 to 21)

ICS = inhaled corticosteroids; IQR = interquartile range.

0.5
0 (4 to 5)

p-value
0.44

0.15
0.84

0.13

ACADEMIC EMERGENCY MEDICINE July 2011, Vol. 18, No. 7

www.aemj.org

671

Table 5
Change in Asthma Score from Baseline to 2 Hours After Intervention and Initial Hospital Admission by Exacerbation Severity

Budesonide Group
Moderate exacerbation (asthma score 811)
Median change in asthma score (IQR) n
Hospital admission, % (95% CI) n
Severe exacerbation (asthma score 915)
Median change in asthma score (IQR) n
Hospital admission, % (95% CI) n

3
55
4
74

n = 55
(4 to 1) 54
(41 to 68) 30
n = 35
(6 to 2) 34
(57 to 87) 26

Placebo Group
3
58
5
71

n = 60
(4 to 1) 56
(45 to 71) 35
n = 28
(6 to 5) 25
(51 to 87) 20

Difference Between
Groups (95% CI)

p-value

0
4 (22 to 14)

0.79

1
3 (19 to 25)

0.45

IQR = interquartile range.

sensitivity analysis indicated no difference in the worst

case where the missing patients in the NSS group
improved and those in the BUD group deteriorated (change in 2-hour asthma score, BUD 3, IQR = 4
to 2; NSS 3, IQR = 4 to 2; difference 0, p = 0.64) or in
the opposite best case (BUD 3, IQR = 4 to 2; NSS 3,
IQR = 4 to 2; difference 0, p = 0.64).
Adverse Events. A total of 106 adverse events (AEs)
were reported in 62 patients (33 BUD, 29 NSS). The
most commonly reported AEs were rhinorrhea, headache, diarrhea, sore throat, and cough. These were
equally distributed between treatment groups. Transient hyperglycemia was noted in two patients in the
BUD group. Five serious AEs were reported: four for
return with hospitalization (two from the BUD group,
two from NSS) and one for increased level of care. The
patient who required an increased level of care
received BUD, pediatric intensive care unit care for
30 hours and an additional day on the inpatient ward,
but recovered uneventfully.
DISCUSSION
This randomized, double-blind, placebo-controlled trial
of children with moderate-to-severe asthma exacerbation found no significant improvement in the clinical
asthma score, vital signs, or other outcomes when nebulized BUD was added to standard ED therapy including SCS. The results were similar when adjusted for
baseline differences in treatment groups and when limited to subgroups defined by prior ICS use.
Most of the research to date involving ICS and SCS
in acute asthma compares ICS to SCS or ICS to placebo; in these studies, the ICS group was not treated
with SCS.69,16,18,19 Some studies comparing ICS to SCS
in acute asthma reported improvements in asthma
scores9,16 or pulmonary function tests (PFTs)9,18,20 and
reduced length of stay19,20 in children. However, the trials by Schuh et al.6,7 concluded SCS to be superior to
ICS for children with mild, moderate, or severe acute
asthma. In a Cochrane systematic review, Edmonds
et al.13 concluded that the use of ICS for acute asthma
in the ED was associated with small improvements in
peak expiratory flows and forced expiratory volumes
and a decreased risk of hospitalization.
To date, the role of ICS as an adjunct to standard
acute asthma therapy has been unclear. The Cochrane
review included two studies in which ICS were given

in addition to SCS. Sung et al.11 conducted a trial in

children and found that the use of BUD was associated
with a decreased time to discharge from the hospital
(combining ED and inpatient stays). The present study
was considerably larger (180 patients vs. 44 patients)
than the trial by Sung et al. and assessed an asthma
score rather than duration of treatment. Other differences include a higher hospitalization rate in the current study (62% to 63% vs. 8% to 25%) and a twofold
higher dose of prednisone in the current study. Perhaps benefits of BUD are more easily discerned in
lower-severity patients or when lower doses of SCS
are used.
Nuhoglu et al.10 reported an increase in peak expiratory flow rate in pediatric ED patients with moderate
asthma exacerbations treated with methylprednisolone
plus BUD when compared to treatment with methylprednisolone plus placebo. However, as with the current study, these investigators found no difference in
asthma scores between the two study groups. Because
we did not attempt to perform pulmonary function testing, it is unknown if there was an improvement in peak
flow rates among patients in the BUD group.
LIMITATIONS
Due to the availability of study staff, the majority of
patients were enrolled between 8:00 am and midnight
and may not represent the full spectrum of asthma
exacerbations. This was a single-center study and
results may not be generalizable to other institutions
with different patient populations. The primary outcome was a clinical asthma score, and the study was
not powered to detect more salient outcomes, such as
hospitalization. It is possible that clinical improvement
occurred with BUD but was not detected by the score.
Objective measures such as oxygen saturation, heart
rate, and respiratory rate were not improved with the
addition of BUD, but other objective measures such as
PFTs were not performed. While PFTs are recommended to measure asthma severity when available,3
most children cannot complete these tests in the ED,21
and thus they are not routinely used to make disposition decisions.22
The admission rate in our study was higher than in
other studies,6,9,11,15 which may reflect the inclusion
criteria that limit the study population to subjects with
high triage acuity assessments. The children enrolled in
the study had a similar admission rate compared to all

672

Upham et al.

BUDESONIDE AS AN ADJUNCT TO ACUTE ASTHMA THERAPY IN CHILDREN

children with asthma at our institution with these triage

acuities during the study period (63%). Admissions to
the observation unit were counted as admissions, which
may also account for the higher rate of admission compared to older studies conducted before observation
units were widely available.
It is possible that patients in this study were too ill to
experience BUD benefits. However, since the vast
majority of children with mild asthma exacerbations
improve with standard therapy alone, we chose to
focus on a group of patients most likely to benefit. It is
also possible that by including patients with severe
exacerbations, results were biased toward the null
hypothesis. However, in a post hoc analysis of patients
by presentation severity, there were no differences in
the change in asthma score or hospitalization rate
between treatment groups (Table 5).
We chose the 2-hour point as the time for our primary outcome because the average time to disposition
at our institution is just over 2 hours. It is possible that
BUD had an effect beyond the 2-hour point, but this
seems unlikely because the peak plasma concentration
of BUD is at 20 minutes, and the terminal half-life is
2.3 hours.23,24
Budesonide inhalation suspension was delivered with
the second and third albuterol treatments. Due to moderate to severe bronchoconstriction, it is possible that
BUD would be more effective given after three albuterol treatments. BUD was combined with albuterol,
and this may render it less efficacious.
There were fewer patients evaluable for the primary
outcome in the NSS group. Perhaps the primary outcome of the study would differ if these patients were
included, but sensitivity analysis indicates that this difference did not affect the results.
CONCLUSIONS
In children 2 to 18 years of age with moderate-tosevere asthma exacerbations, addition of budesonide
inhalation suspension to standard therapy did not result
in improvements in asthma scores or other short-term,
ED-based outcomes. Based on these data, adding budesonide inhalation suspension as an adjunctive therapy to systemic corticosteroids does not appear to be
indicated. Future studies could assess other agents or
populations.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

The authors thank the patients and families for their participation,
and they thank the nurses, respiratory therapists, study physicians,
study coordinator, and research assistants from CHOP for their
invaluable assistance, patience, and hard work. Thanks also to
Loraine Upham for her support and for sewing 180 nebulizer
chamber blinding shields.

14.

References

16.

1. Bloom B, Dey AN. Summary health statistics for

U.S. children: national health interview survey,
2004. National Center for Health Statistics. Vital
Health Stat. 2006; 10:194.
2. Akinbami L. Asthma Prevalence, Health Care Use
and Mortality: United States, 2003-5. National Center
for Health Statistics. Available at: http://www.cdc.

15.

17.

18.

gov/nchs/data/hestat/asthma03-05/asthma03-05.htm.
Accessed Mar, 29, 2011.
National Asthma Education and Prevention
Program. Expert Panel Report 3: Guidelines for the
Diagnosis and Management of Asthma. Bethesda,
MD: National Institutes of Health, National Heart,
Lung, and Blood Institute. Available at: http://
www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
Accessed Mar 28, 2011.
Rodrigo G, Rodrigo C. Corticosteroids in the emergency department therapy of acute adult asthma: an
evidence-based evaluation. Chest. 1999; 116:28595.
Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA,
Bota GW. Early emergency department treatment
of acute asthma with systemic corticosteroids
(update). Cochrane Database Syst Rev. 2001;
1:CD002178.
Schuh S, Reisman J, Alsheri M, et al. A comparison
of fluticasone and oral prednisone for children with
severe acute asthma. N Engl J Med. 2000; 343:68994.
Schuh S, Dick PT, Stephens D, et al. High-dose
inhaled fluticasone does not replace oral prednisolone in children with mild to moderate acute
asthma. Pediatrics. 2006; 118:64450.
Rodrigo GJ. Comparison of inhaled fluticasone with
intravenous hydrocortisone in the treatment of
adult acute asthma. Am J Respir Crit Care Med.
2005; 171:12316.
Devidayal , Singhi S, Kumar L, Jayshree M. Efficacy
of nebulized budesonide compared to oral prednisolone in acute bronchial asthma. Acta Paediatr.
1999; 88:83540.
Nuhoglu Y, Atas E, Nuhoglu C, Iscan M, Ozcay S.
Acute effect of nebulized budesonide in asthmatic
children. J Invest Allerg Clin Immunol. 2005;
15:197200.
Sung L, Osmond MH, Klassen TP. Randomized,
controlled trial of inhaled budesonide as an adjunct
to oral prednisone in acute asthma. Acad Emerg
Med. 1998; 5:20913.
Wanner A, Hovarth G, Brieva JL, Kumar SD, Mendes ES. Nongenomic actions of glucocorticosteroids
on the airway vasculature in asthma. Proc Am Thorac Soc. 2004; 1:2358.
Edmonds ML, Camargo CA Jr, Pollack CV Jr, Rowe
BH. Early use of inhaled corticosteroids in the
emergency department treatment of acute asthma.
Cochrane Database Syst Rev. 2003; 3:CD002308.
Murphy KA. Pediatric Triage Guidelines. St. Louis,
MO. Mosby, 1997, pp 11, 3033, 3841, 4849.
Qureshi F, Pestian J, Davis P, Zaritsky A. Effect of
nebulized ipratropium on the hospitalization rates
of children with asthma. N Engl J Med. 1998;
339:10305.
Tsai YG, Lee MY, Yang KD, Chu DM, Yuh YS, Hung
CH. A single dose of nebulized budesonide
decreases exhaled nitric oxide in children with
acute asthma. J Pediatr. 2001; 139:4337.
Rosner B The intraclass correlation coefficient.
In: Fundamentals of Biostatistics. 6th ed. Belmont,
CA: Duxbury, Thomson Brooks Cole, 2006, pp 6135.
Matthews EE, Curtis PD, McLain BI, Morris LS,
Turbitt ML. Nebulized budesonide versus oral

ACADEMIC EMERGENCY MEDICINE July 2011, Vol. 18, No. 7

www.aemj.org

steroid in severe exacerbations of childhood

asthma. Acta Paediatr. 1999; 88:8413.
19. Scarfone RJ, Loiselle JM, Wiley JF II, Decker JM,
Henretig FM, Joffe MD. Nebulized dexamethasone
versus oral prednisone in the emergency treatment
of asthmatic children. Ann Emerg Med. 1995;
26:4806.
20. Singhi SC, Banerjee S, Nanjundaswamy H. Inhaled
budesonide in acute asthma. J Paediatr Child
Health. 1999; 35:4837.
21. Gorelick MH, Stevens MW, Schultz T, Scribano PV.
Difficulty in obtaining peak expiratory flow
measurements in children with acute asthma.
Pediatr Emerg Care. 2004; 20:226.

673

22. Pollack CV, Pollack ES, Camargo CA Jr, et al. A

prospective multicenter study of patient factors
associated with hospital admission from the emergency department among children with acute
asthma. Arch Pediatr Adolesc Med. 2002; 156:934
40.
23. Agertoft L, Andersen A, Weibull E, Pedersen S.
Systemic availability and pharmacokinetics of nebulised budesonide in preschool children. Arch Dis
Child. 1999; 80:2417.
24. AstraZeneca. Pulmicort Respules: Highlights of
Prescribing Information. Available at: http://
www1.astrazeneca-us.com/pi/pulmicortrespules.pdf.
Accessed Mar 29, 2011.