Pediatric Pulmonology 40:292–299 (2005)

Randomized, Placebo-Controlled Trial of Albuterol

and Epinephrine at Equipotent Beta-2 Agonist
Doses in Acute Bronchiolitis
Shawn Ralston, MD,* Carol Hartenberger, RN, MPH, Theresa Anaya, MD,
Clifford Qualls, PhD, and H. William Kelly, PharmD
Summary. Our objective was to determine if nebulized racemic epinephrine is more efficacious
than nebulized albuterol or saline placebo in the treatment of bronchiolitis in the outpatient setting
when dosing is equivalent in terms of beta-2 agonist potency. Sixty-five patients between ages
6 weeks and 24 months with a diagnosis of bronchiolitis, defined as first-time wheezing, upper
respiratory symptoms and/or fever, and a Respiratory Distress Assessment Instrument score of at
least 4, were randomized to receive 5 mg nebulized albuterol, 5 mg nebulized racemic epinephrine,
or an equivalent volume of placebo at 0, 30, and 60 min. The primary outcome measure was need
for hospital admission or home oxygen. Secondary outcome measures were changes in clinical
scores and oxygen saturations. There were no significant statistical differences between groups in
terms of need for hospital admission or outpatient management with home oxygen therapy. There
were no differences between groups in terms of changes in clinical scores or oxygen saturations.
Racemic epinephrine and albuterol at equivalent doses had no effect on the need for
hospitalization or supplemental oxygen in bronchiolitis in the outpatient setting compared to
nebulized saline placebo, though this study may have missed less dramatic clinical effects due to
small sample size. Pediatr Pulmonol. 2005; 40:292–299. ß 2005 Wiley-Liss, Inc.

Key words: controlled trial; Respiratory Distress Assessment Instrument; bronchiolitis;

beta-2 agonist.

INTRODUCTION epinephrine to show an improvement in clinically relevant

Bronchiolitis, or viral-induced wheezing, is one of the
most common diagnoses at hospital admission in infants.
The hospitalization rate has increased almost 250% since
1986.1 Symptomatic medical management of bronchioli-
tis varies widely between centers, and no therapeutic
standard of care is agreed upon. Multiple comparisons of
symptomatic therapies in varying doses were done, and
outcomes varied widely.2–11
Two meta-analyses of the use of albuterol in bronch-
iolitis reported that it does not alter clinically relevant
outcomes such as need for oxygen, hospitalization, or
length of hospitalization compared with placebo.12,13 A
meta-analysis of the efficacy of epinephrine also con-
cluded that the evidence demonstrates only short-term
improvement in clinical scoring and physiologic mea-
sures, and no convincing effect on outcomes.14 Finally, a
recent systematic review of pharmacologic treatment in
bronchiolitis addressed the use of bronchodilators as well
as other therapies.15 This review concluded that the weight
of the evidence does not support the routine use of either
albuterol or epinephrine in bronchiolitis.
Almost none of the available studies compared similar
dosing of the two drugs or discussed their rationale for
dosing choice. For example, one of the few studies of
outcomes used a dose of 1.5 mg of albuterol, compared
with a 3 mg dose of L-epinephrine.2 Another complicating
factor is the use of differing preparations of epinephrine,
i.e., some studies used racemic epinephrine, and others
used just the active enantiomer, L-epinephrine. Epinephr-
ine was proposed as a ‘‘better’’ drug for bronchiolitis
because of its alpha-agonist activity, thereby reducing
airway edema in addition to its bronchodilator effect.16 It is
Department of Pediatrics, University of New Mexico Health Sciences
Center, Albuquerque, New Mexico.
Grant sponsor: Department of Health and Human Services/National
Institutes of Health/National Center for Research Resources/General
Clinical Research Center: Grant number: 5MO1 RR00997; Grant sponsor:
American Academy of Pediatrics.
*Correspondence to: Dr. Shawn Ralston, University of New Mexico Health
Sciences Center Pediatrics, Albuquerque, New Mexico.
E-mail: sralston@salud.unm.edu
Received 8 December 2004; Revised 8 March 2005; Accepted 8 March
2005.
DOI 10.1002/ppul.20260
Published online 4 August 2005 in Wiley InterScience
(www.interscience.wiley.com).

ß 2005 Wiley-Liss, Inc.

 Albuterol and Epinephrine in Acute Bronchiolitis
felt that viral lower respiratory tract infection causes
edema of the respiratory epithelium, contributing to small
airway obstruction.17 Recently, it was suggested that
deposition of nebulized epinephrine in the upper airway
reducing nasal obstruction may actually be responsible for
much of epinephrine’s clinical effect.18 However, epi-
nephrine also has significant beta-2 agonist activity which
has rarely been discussed, and pure alpha-agonism has not
been adequately studied in bronchiolitis.19,20
Epinephrine appears to have similar beta-2 agonist
potency to albuterol when both drugs are used in racemic
preparations.21–24 Prior comparisons of albuterol and
epinephrine in bronchiolitis all used doses of epinephrine
in excess of the doses of albuterol, sometimes by up to a
factor of 10. It is therefore possible that study results
favoring epinephrine were favorable not due to the alpha
effect of epinephrine, either at the upper or lower airway,
but due to the delivery of a higher dosage of beta-2 agonist.
A percentage of infants can be shown to respond to beta-2
agonist bronchodilators; however, delivery of medications
to infant small airways is quite poor with the currently
used technology.25–27 It is therefore possible that for beta-
2 agonist efficacy to become clinically apparent in infants
with bronchiolitis, a higher dose may be necessary. The
current study was undertaken to address the issue of
dosing of beta-2 agonists as a potential confounder in their
efficacy in bronchiolitis. A much higher dose of albuterol
(5 mg) than used in previous bronchiolitis studies was
selected, both to match commonly used doses of epine-
phrine and to maximize beta-agonist delivery to infant
small airways. Racemic epinephrine was chosen in order
to compare both drugs in racemic preparations using
equivalent dosing.
METHODS
This was a randomized, double-blind, placebo-con-
trolled study of racemic epinephrine and racemic albuterol
at equivalent doses in an academic urgent-care setting in
children who were mildly to moderately ill with bron-
chiolitis. Candidates for the study were patients between
ages 6 weeks and 24 months presenting to the urgent-care
clinic of the University of New Mexico Department of
TABLE 1— Respiratory Distress Assessment Instrument (Maximum Score ¼ 17)
Points 0 1
Wheezing on expiration None End
Wheezing on inspiration None Part
Location of wheezing None Segmental1
Supraclavicular retractions None Mild
Intercostal retractions None Mild
Subcostal retractions None Mild
Segmental indicates <2 of 4 lung fields, and diffuse indicates >3 of 4 lung fields.
1
293
Pediatrics (altitude, 5,000 feet) with a first episode of
bronchiolitis. Bronchiolitis was defined as wheezing
associated with symptoms of upper respiratory infection
and/or fever, which was defined as temperature of

38.08C. Inclusion criteria included a Respiratory Dis-
tress Assessment Instrument (RDAI) score of at least 4 in
order to enroll only infants who were conceivably at risk
for hospitalization, the primary outcome measure. The
RDAI (Table 1) is an assessment of wheezing and
retractions with scores ranging from 0–17, and was
chosen due to its frequent use in bronchiolitis studies.21
A score of 4 on the RDAI would be given to a child with
end-expiratory wheezing heard in half of all lung fields
and moderate subcostal retractions, for example. Exclu-
sion criteria were: history of premature birth at <36 weeks
of gestation, prior history of wheezing or asthma, history
of significant chronic disease, and history of systemic
steroid use for the current illness. Patients who were
considered physiologically unstable at presentation were
also not enrolled. Criteria for being considered physiolo-
gically unstable were any of the following: heart rate
consistently >200, respiratory rate consistently >90,
RDAI score >15, and oxygen saturations consistently
<70% breathing room air.
Patients were referred to the study by nurses, residents,
or attending physicians in the pediatric clinic through an
on-call pager system available 8 AM –5 PM. Patients were
then evaluated, and those meeting study criteria were
enrolled following attainment of an informed consent
from their parent or guardian. Each study participant’s
temperature, respiratory rate, heart rate, room air oxygen
saturation, and RDAI score were then recorded by a
research nurse. Duration of illness and demographic data
were recorded by interview of the parent or guardian and
chart review. Other therapies routinely performed during
the study included nasal suctioning and provision of
supplemental oxygen by nasal cannula or mask. Less than
10% of study participants received intravenous fluids.
At enrollment, patients were randomized to either 5 mg
racemic albuterol sulfate (n ¼ 23), 5 mg racemic epi-
nephrine (n ¼ 17), or 0.9% saline placebo (n ¼ 25), all in
3-ml nebulized doses. Medications were delivered with an
infant face mask and continuous flow of oxygen at 6 L/min.
2 3 4 Maximum
Half Three-quarters All 4
All 2
Diffuse1 2
Moderate Marked 3
Moderate Marked 3
Moderate Marked 3
294 Ralston et al.
A random number table generated by computer was used
by the research pharmacist to allocate patients to treatment
groups, and the research pharmacist was the only person
with access to the randomization. All study personnel
remained blind to medication identity throughout the
study period. Each solution was colorless and essentially
odorless. Study drug was prepared ahead of time by the
research pharmacist and placed in a locked refrigerator,
with sequential numbers corresponding to the next patient
enrolled. A drug was considered expired if not used within
72 hr of mixing. All drugs were stored in brown plastic
envelopes to prevent light inactivation, and prepared for
use in single-dose vials to limit the possibility of errors in
dosage due to measurement by differing personnel at time
of enrollment.
The study drug was administered by research personnel
at 0 and 30 min to all patients. Prior to each administration,
vital signs, an RDAI score, and room air oxygen
saturation, as well as an assessment of the child’s state
(i.e., awake and alert, agitated or crying, or asleep/drowsy)
were recorded by the same research nurse. At 60 min, if the
child’s RDAI score was >8 or room air oxygen saturation
was <90%, a third dose of study medication was
administered. If no third dose of study medication was
administered, a final assessment involving vital signs,
RDAI, room air oxygen saturation, and clinical state was
performed at 60 min. If a third dose of medication was
given, the final assessment was performed at 90 min. After
the final study assessment, the patient was returned to the
care of the referring clinic physician. The decision for
admission, the primary outcome measure, was made by
the responsible attending physician who was blind to all
study interventions. As an alternative to hospital admis-
sion, the University of New Mexico pediatric clinic also
used home oxygen therapy; however, given that this is not
standard practice in many institutions, patients who
received home oxygen were considered with the admis-
sion group for the primary outcome analysis. All enrolled
patients successfully completed the study. Adverse events
were defined as heart rate >200, withdrawal from the
study due to worsening clinical status, or discontinuation
of any study medications due to side effects. All patients
were followed to assess the need for admission within 24 hr
of study participation. Patient charts and emergency room
(ER) logs were examined for ER visits and follow-up
visits for the week following the study when that
information was available. The protocol was approved
by the Human Research Review Committee of the
University of New Mexico Health Sciences Center.
For power analysis, we considered the study by Menon
et al.,2 where in an ER setting, they found an 81%
admission rate in the albuterol-treated group and 33% in
the epinephrine-treated group. Preliminary data for our
clinic, obtained from billing records, suggested a com-
bined admission/home oxygen management rate of 75%
in the prestudy era, which was characterized by routine
albuterol use. Our clinic uses the strategy of sending some
patients home on oxygen instead of admitting them. This
practice is not the standard of care in most settings, where
any oxygen requirement would dictate hospital admission.
Therefore, we chose to include patients who were
admitted to the hospital and those who were managed
with home oxygen in one group. Our planned sample size
of 21 patients per arm (placebo, epinephrine, and
albuterol) is adequate to detect a difference in admission
rates of 75% for placebo or albuterol vs. 33% for
epinephrine, with 80% power and alpha ¼ 0.05. We
elected to continue enrollment in the study until the end
of the bronchiolitis season, in which we enrolled our sixty-
third patient, which resulted in 65 patients being enrolled
in the study. We ended the study with a mildly unbalanced
enrollment per group due to the inability to accurately
predict total enrollment for this seasonal illness in our
original randomization, due to the desire to enroll through
the end of the final season.
Statistical analysis was performed using SAS 8.0 (SAS,
Inc., Cary, NC). The main analysis of hospitalization and
use of home oxygen by medication group was performed
using Fisher’s exact test. Primary outcome proportions are
reported as percentages  standard error. The analysis of
repeated outcomes (heart rate, respiratory rate, RDAI, and
oxygen saturation) was performed using a repeated-
measures ANOVA. Since some patients completed the
study after two doses of medication rather than three, the
data for repeated measures consist of measurements at
baseline, after the first study medication, after the second
study medication, and at the end of the study. Potential
confounders such as fever, duration of illness prior to
study entry, age, and gender were considered as covariates
in the above analyses. The distribution of patient states
(e.g., crying, sleeping) by medication group was analyzed
by Fisher’s exact test.
RESULTS
Patient Enrollment
The 65 study patients were enrolled over five bronch-
iolitis seasons, from 2000–2004. Patients were only
enrolled in the bronchiolitis season, i.e., January, Febru-
ary, and March of each year, with enrollments of 17, 11,
14, 13, and 15 patients per season chronologically. During
the study months from 2000–2004, 199, 144, 191, 170,
and 172 patients under age 2 years were admitted to the
study hospital for bronchiolitis. The study enrollment as a
percentage of admissions for bronchiolitis was 8.5%,
7.6%, 7.3%, 7.6%, and 8.7%, respectively.
Of 155 patients screened, 82 met study criteria, and 17
parents refused participation, leaving 65 participants
(Fig. 1). Each of the 65 participants enrolled completed
 Albuterol and Epinephrine in Acute Bronchiolitis 295

Fig. 1. Study flow chart.

the study, and follow-up data were successfully obtained
on all 65 participants.
Patient Characteristics
Among the 65 study infants, 36 (55%) were male, 44
were Hispanic (68%), and 51 (78%) were insured by
Medicaid. There were no differences between groups with
respect to patient characteristics and degree or duration of
illness on presentation (Table 2).
Numbers Analyzed
All 65 participants were included in the final analysis on
an ‘‘intention to treat’’ basis. Based on retrospective chart
review of study participants’ medical records, there were
three protocol violations. Two patients had documentation
of prior wheezing which would have excluded them from
the study, but which neither their parents nor their
physicians reported at the time of study enrollment. One
was a 20-month-old girl who had documentation of a
wheezing illness at 7 months of age, and the other was a
3-month-old boy who had a documentation of prior
wheezing at 2 months of age. Poststudy chart review
revealed the prior wheezing illnesses in both instances.
The third protocol violation was an 8-month-old boy who
was on his fifth day of steroids at time of study enrollment,
a fact which was discovered only after hospital admission.
All three protocol violations were in the normal saline
group, and all three were admitted to the hospital. The
decision to analyze the study as intention-to-treat can be
supported by the fact that the decision to admit, the pri-
mary outcome measure, could not be influenced by the
prior history of wheezing in the 2 patients where this was
discovered by chart review, as neither the parents nor the
admitting physician registered the history in these 2
patients.
Outcomes
Six of 23 patients (26%  12%) were admitted to the
albuterol treatment group, 2 of 17 patients (12%  12%)

TABLE 2— Baseline Characteristics of Study Participants: Means (SD)

Placebo (n ¼ 25) Albuterol (n ¼ 23) Epinephrine (n ¼ 17)

Age (months) 7.3 (5.1) 7.7 (6.0) 7.9 (5.2)

Gender 60% male 65% male 35% male
Ethnicity 64% Hispanic 78% Hispanic 59% Hispanic
Medicaid 92% 74% 65%
Uninsured 4% 22% 24%
Duration of illness 5.7 days (6.5) 4 days (2.9) 5.2 days (3.9)
Respiratory rate 57 (10) 57 (11) 55 (9)
Oxygen saturation (on room air) 90% (5) 90% (4) 90% (4)
RDAI score 8 (2) 8 (2) 8 (2)
Heart rate 155 (19) 156 (17) 157 (17)
Percent febrile (>38.08C) 20% 35% 35%
Follow-up visits 1.6 (1.2) 1.9 (1.6) 1.8 (1.1)
296 Ralston et al.
were admitted to the epinephrine treatment group, and 5 of
25 patients (20%  11%) were admitted to the normal
saline group. Eight (35%  9%) albuterol-treated pati-
ents, 8 (47%  10%) epinephrine-treated patients, and 11
(44%  10%) normal saline-treated patients were mana-
ged with home oxygen. When the home oxygen and
hospital admission groups are considered together in one
group, 14 (61%  8%) albuterol-treated, 10 (59%  8%)
epinephrine-treated, and 16 (64%  8%) normal saline-
treated children required further oxygen therapy. There
were no differences in admission rates between groups,
including analysis with the protocol violations removed.
Thirty-seven (57%) patients met criteria for all three
doses of medication, whereas the remaining 28 patients
completed the study after two doses of medication.
Figure 2 summarizes primary outcome data. For second-
ary outcomes, no differences were found in oxygen
saturations or respiratory rates over time by treatment
group. RDAI scores decreased over time, but there were no
differences in this decrease between treatment groups.
Heart rate went up over time in children in the albuterol-
treated group. Univariate analysis showed that oxygen
saturation alone predicted hospital admission. Multi-
variate logistic regression did not reveal any significant
mitigating factors within treatment groups, including age,
duration of illness prior to presentation, gender, presence
of fever, RDAI score, respiratory rate, and insurance
status.
Adverse Events and Follow-Up Data
Predetermined adverse events were considered to be
sustained heart rate above 200 after medication adminis-
Fig. 2. Outcomes with standard error (all P > 0.05).
tration, removal of any patient by the clinical staff for
deterioration, and removal of any patient by parents for
perceived side effects. There were no patients removed
from study participation by the clinical staff or parents.
Two patients, an 11-month-old girl and a 5-month-old boy
both receiving albuterol, had a sustained heart rate above
200 beats per minute for more than 30 min. Both patients
with tachycardia self-resolved on discontinuation of
medication. One was admitted to the hospital for her
respiratory symptoms for 48 hr, and suffered no further
complications. The other was discharged home on oxygen
with two follow-up visits, without further complications.
Two patients were admitted to the hospital within 24 hr
of study participation: a 2-month-old male from the
epinephrine group who had a 32-hr hospitalization, and a
15-month-old male from the albuterol group who had a
92-hr hospital admission. Both hospitalizations were to the
general ward, and were without complications.
The number of follow-up visits required did not vary by
treatment group.
DISCUSSION
This study was designed with the primary endpoint of
hospitalization, in order to investigate the effect that
currently used therapies have on relevant clinical out-
comes. A ‘‘real-world’’ model for admission was used,
i.e., at the discretion of the treating physician, although
variables which might affect this decision were analyzed,
such as use of home oxygen and insurance status. The
patient population was chosen to reflect patients ‘‘at risk’’
for hospitalization but not certain to be hospitalized, i.e.,
minimum and maximum clinical severity scores were
used to define eligible patients. Exclusion criteria were
designed to include only typical bronchiolitis and to
carefully exclude children with prior wheezing episodes.
Since admission was the primary endpoint, very young
infants were excluded to decrease the possibility of
admission for reasons other than severity of illness, e.g.,
risk of apnea, perceived risk of serious bacterial infection,
or poor social situation.
A major difference in our study and prior studies is beta-
agonist drug dosing. We used 5-mg doses of both drugs
and the racemic preparation of epinephrine. We both
increased the typical dose of albuterol and used an
equivalent dose of epinephrine to control for its beta-
agonist potency, as previously explained. Table 3 provides
doses and preparations used in prior studies comparing
epinephrine and albuterol. The lack of significant findings
on any of our outcome measures adds depth to the
argument that the beta-agonist effect is not important in
treating bronchiolitis.
The mean patient age in our study was 7.6 months,
which is slightly older than in other studies, and our
mean RDAI score was 8, which is fairly similar to other
 Albuterol and Epinephrine in Acute Bronchiolitis 297
TABLE 3— Doses and Preparations of Albuterol and Epinephrine in Prior Comparison Studies

Study
4
Sanchez et al., 1993
Reijonen et al., 19955
Menon et al., 19952
Bertrand et al., 20018
Ray and Singh, 20023
Patel et al., 20027
Mull et al., 20046
Dose and preparation epinephrine Dose albuterol (all racemic preparations)
0.1 ml/kg racemic epinephrine 2.25% 0.15 mg/kg albuterol
0.9 mg/kg racemic epinephrine 0.15 mg/kg albuterol
3 mg l epinephrine 1.5 mg albuterol
0.5 mg l epinephrine 2.5 mg albuterol
0.1 ml/kg l epinephrine, 1:10,000 solution 0.1 mg/kg albuterol
0.0675 mg/kg racemic epinephrine 0.15 mg/kg albuterol
0.9 mg/kg racemic epinephrine 0.15 mg/kg albuterol

studies. In several studies considered supportive of the
use of epinephrine,2,4–6 the nonweighted mean age was
6.15 months, and the mean presenting RDAI score in
Reijonen et al.,5 Menon et al.,2 and Mull et al.6 was 8.8. Of
the recent negative studies,7,9–11 the nonweighted mean
age was approximately 4.5 months, and the mean RDAI
was 8.2. Wainwright et al.9 did not use the RDAI; however,
over 50% of their patient population had ‘‘mild’’ disease
by their own assessment.
Our study was patterned after Menon et al.,2 and is small
in size. Though the sample size would have detected a
dramatic effect on hospital admission rates, we were not
able to detect smaller effects which may still be clinically
significant. Indeed, there may be the suggestion of a
trend toward lower admission rates in the epinephrine-
treated group. We should have been able to detect smaller
differences in physiologic measures such as oxygen
saturation rate and RDAI across treatment groups, which
we did not find. The study by Menon et al.2 was powered to
detect a 3% difference in oxygen saturation rates, which
we also should have been able to detect. The hospital
admission rate in Menon et al.2 was quite high in the
albuterol-treated group, at 81%, vs. 33% in the epinephr-
ine-treated group. The attempt to calculate a baseline
hospital admission rate in our clinical setting prior to the
study was complicated by the use of home oxygen during
periods of hospital bed shortages in the winter months. We
elected to consider home oxygen-treated children with
admitted children, and found an ‘‘admission/home oxy-
gen’’ rate of 75% prior to the study period. Given that the
study occurred at an altitude of approximately 5,000 feet,
it is difficult to know if the home oxygen group represents
patients who would be admitted in other clinical settings,
or who would not have an oxygen requirement at sea level
and therefore not be admitted, or, most likely, some
combination of the two possibilities. Nevertheless, there is
an emerging literature to suggest that oxygen saturation is
the major factor in hospital admission and perhaps
responsible for our increasing hospitalization rates.28–30
No other clinical models have emerged to supersede
oxygen saturation as the primary deciding factor in hos-
pitalization for bronchiolitis.
Studies favoring epinephrine were often performed in
an ER setting, enrolling patients 24 hr a day, and may have
attracted sicker patients, therefore resulting in a higher
admission rate. Our study setting essentially doubled as
the pediatric emergency room during the study period,
because all nontrauma pediatric patients were generally
referred to the pediatric urgent-care clinic (study setting)
during the hours the study was in operation. However, the
fact that we did not enroll patients outside of the 8 AM –5 PM
time period may have caused us to miss sicker patients.
Prior studies of bronchodilators in bronchiolitis,
including epinephrine, reported benefits from these
therapies, based on improvements in physiologic mea-
sures only and a lack of effect on outcomes. One factor
which has rarely been discussed in detail or adequately
controlled for is the fact that many study participants are
receiving either continuous or intermittent supplemental
oxygen as well as other supportive therapies during and
prior to the study period. It seems likely that providing
supplemental oxygen is adequate to cause clinical severity
scores to decrease as well as other measures of respiratory
distress. In this study, the majority of patients received
oxygen continuously throughout the study, as well as
intermittent nasal suctioning and antipyretics if febrile.
RDAI scores went down equally across all groups. Of
interest, Abul-Ainine and Luyt11 noted significant
improvement in their patient population during a 30-min
stabilization period involving provision of oxygen and
antipyretics prior to initiation of study drug therapy, which
they concluded did not produce further benefit.
Another difficulty encountered in this study was the
need to enroll over five bronchiolitis seasons to complete
the study, with relatively few patients enrolled each
season. Although the research personnel doing the
majority of enrollment remained primarily the same,
changes in the clinical setting inevitably occur over a 5-
year period. We did not address the issue of interrater
reliability in scoring the RDAI in our study, as we were
only secondarily interested in this tool. However, we did
train study personnel on the instrument, and did repeated
scoring on practice patients prior to the study. The same
group of five research nurses enrolled and RDAI-scored
the majority of study patients, and the same nurse scored
each patient from study start to finish. Since our outcome
measure depended on the clinical sensibilities of a varied
group of attending physicians, any changes in clinical
298 Ralston et al.
practice related to bronchiolitis would have affected the
primary study outcomes, although likely equally across all
treatment groups due to randomization. To further assure
the similarity of our patient population over time to the
general clinic population, we obtained permission to
retrospectively analyze 130 ‘‘control’’ patients who met
study criteria and were matched to enrollment over the
five study seasons. These results revealed no significant
differences in terms of presenting vital signs, oxygen
saturations, duration of illness, and risk of hospital
admission or use of home oxygen.
In conclusion, providing higher doses of beta-agonist
activity in the treatment of bronchiolitis did not alter
patient outcomes in a statistically significant manner. We
also did not find a statistically significant effect on primary
or secondary outcomes in using racemic epinephrine when
compared to saline placebo. All patients generally
improved over time, as evidenced by decreasing RDAI
scores across all treatment groups, arguing for a positive
effect to supportive care such as suctioning, oxygen, and
antipyretics, or a significant effect from nebulized saline.
Because of the small study size, our results should be
interpreted with caution, as we may have missed less
dramatic effects on outcomes. However, we did have
statistical power to detect a 3% difference in oxygen
saturations between groups. Our results are not incon-
sistent with the majority of published reports, and if very
large numbers of patients are required for demonstrable
clinical effects, then the therapy is less likely to be useful.
Since there are minor adverse effects of drug therapy, it
may be argued that such treatment has an unfavorable risk/
benefit relationship and should not be part of routine
treatment of children with typical bronchiolitis.
REFERENCES
1. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson
LJ. Bronchiolitis-associated hospitalizations among US children,
1980–1996. JAMA 1999;282:1440–1446.
2. Menon K, Sutchliffe T, Klassen TP. A randomized trial
comparing the efficacy of epinephrine with salbutamol in the
treatment of acute bronchiolitis. J Pediatr 1995;126:1004–1007.
3. Ray MS, Singh V. Comparison of nebulized adrenaline versus
salbutamol in wheeze associated respiratory tract infection in
infants. Indian Pediatr 2002;39:12–22.
4. Sanchez I, De Koster J, Powell RE, Wolstein R, Chernick V.
Effect of racemic epinephrine and salbutamol on clinical score
and pulmonary mechanics in infants with bronchiolitis. J Pediatr
1993;122:145–151.
5. Reijonen T, Korppi M, Pitkakangas S, Tenhola S, Remes K. The
clinical efficacy of nebulized racemic epinephrine and albuterol in
acute bronchiolitis. Arch Pediatr Adolesc Med 1995;149:686–
692.
6. Mull CC, Scarfone RJ, Ferri LR, Carlin T, Salvaggio C, Bechtel
KA, Trephan MA, Rissman RL, Gracely EJ. A randomized trial
of nebulized epinephrine vs. albuterol in the emergency depart-
ment treatment of bronchiolitis. Arch Pediatr Adolesc Med 2004;
158:113–118.
7. Patel H, Platt RW, Pekeles GS, Ducharme FM. A randomized,
controlled trial of the effectiveness of nebulized therapy with
epinephrine compared with albuterol and saline in infants hos-
pitalized for acute viral bronchiolitis. J Pediatr 2002;141:818–
824.
8. Bertrand P, Aranibar H, Castro E, Sanchez I. Efficacy of
nebulized epinephrine versus salbutamol in hospitalized infants
with bronchiolitis. Pediatr Pulmonol 2001;31:284–288.
9. Wainwright C, Altamirano L, Cheney M, Cheney J, Barber
S, Price D, Moloney S, Kimberley A, Woolfield N, Cadzow S,
Fiumara F, Wilson P, Mego S, Vande Velde D, Sanders S,
O’Rourke P, Francis P. A multicenter, randomized, double-blind,
controlled trial of nebulized epinephrine in infants with acute
bronchiolitis. N Engl J Med 2003;349:27–35.
10. Hariprakash S, Alexander J, Carroll W, Ramesh P, Randell T,
Turnbull F, Lenney W. Randomized controlled trial of nebulized
adrenaline in acute bronchiolitis. Pediatr Allergy Immunol 2003;
14:134–139.
11. Abul-Ainine A, Luyt D. Short term effects of adrenaline in
bronchiolitis: a randomised controlled trial. Arch Dis Child 2002;
86:276–279.
12. Kellner JD, Ohlsson A, Gadomski AM, Wang EE. Efficacy of
bronchodilator therapy in bronchiolitis. A meta-analysis. Arch
Pediatr Adolesc Med 1996;150:1166–1172.
13. Flores G, Horwitz RI. Efficacy of beta2-agonists in bronchiolitis:
a reappraisal and meta-analysis. Pediatrics 1997;100:233–239.
14. Hartling L, Wiebe N, Russell K, Patel H, Klassen TP. A meta-
analysis of randomized controlled trials evaluating the efficacy of
epinephrine for the treatment of acute viral bronchiolitis. Arch
Pediatr Adolesc Med 2003;157:957–964.
15. King VJ, Viswanathan M, Bordley WC, Jackman AM, Sutton SF,
Lohr KN, Carey TS. Pharmacologic treatment of bronchiolitis in
infants and children: a systematic review. Arch Pediatr Adolesc
Med 2004;158:127–137.
16. Wohl ME, Chernick V. State of the art: bronchiolitis. Am Rev
Respir Dis 1978;118:759–781.
17. Aherne W, Bird T, Court SD, Gardner PS, McQuillin J.
Pathological changes in virus infections of the lower respiratory
tract in children. J Clin Pathol 1970;23:7–18.
18. Wohl ME, Chernick V. Treatment of acute bronchiolitis. N Engl
J Med 2003;349:82–83.
19. Barr FE, Patel NR, Newth CJ. The pharmacologic mechanism by
which inhaled epinephrine reduces airway obstruction in res-
piratory syncytial virus-associated bronchiolitis. J Pediatr 2000;
136:699–700.
20. Lenney W, Milner AD. Alpha and beta adrenergic stimulants in
bronchiolitis and wheezy bronchitis in children under 18 months
of age. Arch Dis Child 1978;53:707–709.
21. Lowell DI, Lister G, Von Koss H, McCarthy P. Wheezing in
infants: the response to epinephrine. Pediatrics 1987;79:939–
945.
22. Kjellman B, Tollig H, Wettrell G. Inhalation of racemic
epinephrine in children with asthma. Dose-response relation
and comparison with salbutamol. Allergy 1980;35:605–610.
23. Rohr AS, Spector SL, Rachelefsky GS, Katz RM, Siegel SC.
Efficacy of parenteral albuterol in the treatment of asthma.
Comparison of its metabolic side effects with subcutaneous
epinephrine. Chest 1986;89:348–351.
24. Coupe MO, Guly U, Brown E, Barnes PJ. Nebulised adrenaline in
acute severe asthma: comparison with salbutamol. Eur J Respir
Dis 1987;71:227–232.
25. Goldstein AB, Castile RG, Davis SD, Filbrun DA, Flucke RL,
McCoy KS, Tepper RS. Bronchodilator responsiveness in normal
infants and young children. Am J Respir Crit Care Med 2001;
164:447–454.
 Albuterol and Epinephrine in Acute Bronchiolitis
26. Chua HL, Collis GG, Newbury AM, Chan K, Bower GD, Sly PD,
Le Souef PN. The influence of age on aerosol deposition in
children with cystic fibrosis. Eur Respir J 1994;7:2185–2191.
27. Amirav I, Balanov I, Gorenberg M, Luder AS, Newhouse MT,
Groshar D. Beta-agonist aerosol distribution in respiratory
syncytial virus bronchiolitis in infants. J Nucl Med 2002;43:
487–491.
28. Mallory MD, Shay DK, Garrett J, Bordley WC. Bronchiolitis
management preferences and the influence of pulse oximetry
299
and respiratory rate on the decision to admit. Pediatrics 2003;111:
45–51.
29. Schroeder AR, Marmor AK, Pantell RH, Newman TB. Impact of
pulse oximetry and oxygen therapy on length of stay in
bronchiolitis hospitalizations. Arch Pediatr Adolesc Med 2004;
158:527–530.
30. Shaw KN, Bell LM, Sherman NH. Outpatient assessment of
infants with bronchiolitis. Am J Dis Child 1991;145:151 –
155.