Efficacy of nebulized epinephrine versus salbutamol in ... - sepeap

Pediatric Pulmonology 31:284±288 (2001)
Ef®cacy of Nebulized Epinephrine Versus Salbutamol
in Hospitalized Infants With Bronchiolitis
Pablo Bertrand, MD, Hector AranõÂbar, MD, Edelmira Castro, NU, and Ignacio SaÂnchez, MD*
Summary. We enrolled 30 infants (median age 3 months, range 1±12 months), hospitalized for
bronchiolitis in a randomized double-blind trial, to examine the ef®cacy and safety of nebulized
epinephrine compared to salbutamol. Once admitted, patients were treated with either nebulized
0.5 mg of an 0.1% epinephrine solution (0.5 mL in 3.5 mL normal saline (NS)) or 2.5 mg nebulized
salbutamol (0.5 mL in 3.5 mL NS). They were evaluated daily before and after nebulization until
discharge. The outcome measures used were: baseline clinical score (based on respiratory rate,
subcostal retraction, presence of wheezing, and O 2 requirement), change in clinical O 2 score after
nebulization, duration of O 2 therapy, and duration of hospitalization.
A signi®cant improvement in the clinical score was noted on the ®rst day of hospitalization in
subjects receiving epinephrine (P ˆ 0:025); that change was not seen in those on salbutamol
(P ˆ 0:6). Nebulized epinephrine decreased the baseline clinical score faster than salbutamol
(P ˆ 0:02), though on the fourth study day there was no signi®cant difference between the two
scores. On the fourth and ®fth days of study there were more patients hospitalized in the
salbutamol group than in the epinephrine group (P ˆ 0:03 vs. P ˆ 0:025). No adverse effects
were associated with nebulized therapy.
We conclude that nebulized epinephrine is a more effective agent than salbutamol in the initial
treatment of bronchiolitis and is equally safe. Pediatr Pulmonol. 2001; 31:284±288.
ß 2001 Wiley-Liss, Inc.
Key words: bronchiolitis; wheezing; bronchodilators; infants; epinephrine; airway
hyperresponsiveness; healthcare costs; respiratory syncytial virus.
INTRODUCTION
Bronchiolitis is the main cause of acute respiratory
illness in infants under 12 months of age, 1,2 and is one of
the leading causes of hospital admissions in this age group
during the winter season in the United States. 3 Therapy
for bronchiolitis includes supportive measures such as
adequate hydration, management of secretions, and supplementary
oxygen. The use of bronchodilator therapy in
this disease remains controversial. Some studies have
demonstrated modest clinical improvement 4±7 or an
improvement in pulmonary function 8,9 with beta agonist
therapy. Other studies have concluded that salbutamol
does not bene®t infants. 10,11 Importantly, some studies
implicate salbutamol as causing arterial oxygen desaturation
in infants with acute bronchiolitis. 12,13 Despite this,
salbutamol is often the ®rst drug of choice for treatment
of bronchiolitis in clinical practice and in emergency
rooms.
Wohl and Chernick 14 postulated that mucosal edema in
the bronchioles may be an important cause of airway
obstruction in bronchiolitis, and therefore, an alpha/beta
agonist might be useful in the treatment of this disease.
There are published data indicating that nebulized racemic
epinephrine is bene®cial in patients with bronchiolitis
ß 2001 Wiley-Liss, Inc.
without causing adverse effects, and is more effective
than placebo 15 or albuterol. 16,17 In our previous study, 16
we compared only a single dose of drug.
The purpose of the present study was to compare the
clinical ef®cacy of multiple doses of epinephrine vs.
salbutamol in infants hospitalized with acute bronchiolitis.
METHODS
From May 1, 1994 to September 30, 1994 (winter in
the Southern Hemisphere), 30 patients admitted to our
hospital were enrolled in a prospective randomized
double-blind study. The inclusion criteria for the diagnosis
of bronchiolitis were infants under 1 year of age,
®rst wheezing episode, acute onset of respiratory distress,
and an x-ray study of the chest compatible with
Department of Pediatrics, School of Medicine, Catholic University of
Chile, Santiago, Chile.
*Correspondence to: Ignacio SaÂnchez, M.D., Section of Pediatric
Pulmonology, Department of Pediatrics, Catholic University of Chile, Lira
40, Casilla 114-D, Santiago, Chile. E-mail: igsan@med.puc.cl
Received 21 June 1999; Accepted 20 October 2000.

Epinephrine vs. Salbutamol in Bronchiolitis 285
TABLE 1ÐClinical Scoring System, Adapted From Bierman and Pierson 13 as Modi®ed by
Tal et al. 14 Respiratory rate (breaths/min)
Score 6 months Wheezing Retractions O 2 supply (%)
0 60 Audible inspiratory and ‡‡‡ >35
expiratory
bronchiolitis. Exclusion criteria were: prematurity, chronic
lung or cardiac disease, lower respiratory tract infection
within the previous 3 months, and bronchodilator or
steroid therapy within the previous month. The Catholic
University Hospital Research Ethics Committee approved
the study. Each parent gave informed consent
and signed authorization forms for the study.
The patients were randomized in a double-blind protocol
to receive either salbutamol (Aerolin 0.5%, Glaxo)
0.5 mL (2.5 mg) plus saline solution (0.9%) 3.5 mL to
make a total volume of 4 mL, or epinephrine (Adrenaline
1:1,000, Astra) 0.5 mL (0.5 mg) plus 3.5 mL of saline
solution. Both solutions were prepared by the same nurse
every day. Children received nebulization every 2±4 hr
by face mask, using a Hudson updraft nebulizer driven at
6±8 L/min by continuous oxygen ¯ow. They received the
study drug during the entire hospital admission under
the supervision of their own physician, who remained
blinded. Baseline assessment was performed on the ®rst
day of admission.
The patients had a complete physical examination performed
daily by one of the two investigators (P.B., H.A.),
who followed each patient during the entire study period.
Prior to the study, blinded pilot scoring done by the same
physicians showed excellent agreement in 10 infants
with acute bronchiolitis, with no difference greater than 1
point. We found differences mainly in scoring of
wheezing and chest retractions. The score of Bierman and
Pierson 18 as modi®ed by Tal et al. 19 was used (Table 1).
This clinical scoring system includes respiratory rate
(modi®ed for age), wheezing, use of accessory muscles,
and presence of cyanosis (modi®ed by measuring oxygen
concentration needed to keep SaO 2 at 94±97%). The
ABBREVIATIONS
NS Normal saline
O 2 Oxygen
PICU Pediatric intensive care unit
RE Racemic epinephrine
RSV Respiratory syncytial virus
SaO 2 Oxygen saturation
WBC White blood cell
score was done immediately before and within 20 min
after nebulizer treatment, with the subject being either
quietly awake or asleep. Daily scoring continued until
discharge from hospital. All infants were tested for
respiratory syncytial virus (RSV). The infants' pediatricians
followed their patients throughout the study period
and could withdraw them from the study if they noticed
any adverse reaction, poor response to treatment as de-
®ned by an increase in nebulization of greater than every
2 hr, or admission to the pediatric intensive care unit, or
by parental request. The study was considered over when
the infants were weaned off supplemental oxygen or had
a clinical score below 4, whichever came ®rst. At this
point, the patients were ready to be discharged, with
salbutamol on a p.r.n. basis.
The outcome measures used were: daily baseline clinical
score, oxygen saturation (SaO 2 ), change in score
after nebulization, respiratory rate change, and duration
of O 2 therapy and of hospitalization. Concomitant treatment
in both groups included oxygen supplementation,
¯uids, and general care. Adverse effects were looked for
in regards to tachycardia, tremor, and increase in systolic
or diastolic blood pressure after nebulization of each
medication.
Statistical analysis was performed using t-tests (twotailed)
for quantitative variables, chi-square test for
nominal data, and log-rank test for actuarial analysis.
Statistical signi®cance was de®ned as P < 0:05.
RESULTS
Patient Population
Thirty-three infants were eligible during the study
period. Three of them were excluded: two were on steroids,
and the other withdrew because of parental request.
Fourteen patients were randomized to the salbutamol
group, and 16 to the epinephrine group. There were 16
male patients (53%). The mean age was 3.7 0.6 months
in the salbutamol group and 3.9 0.4 months ( SEM)
in the epinephrine group (P ˆ 0:64). There was no difference
between groups in general baseline characteristics
(Table 2).

286 Bertrand et al.
TABLE 2ÐCharacteristics of Patients on Admission
Salbutamol Epinephrine
Variable (n ˆ 14) (n ˆ 16) P-value
Males 7 (50%) 9 (56%) 0.73
Age (months SEM) 3.7 0.6 3.9 0.4 0.64
Age

Epinephrine vs. Salbutamol in Bronchiolitis 287
Fig. 1. Evolution of clinical score in both groups. Note that
epinephrine produced a decrease in basal clinical score to less
than 5 more rapidly than did salbutamol (log-rank test, P < 0:02).
4.5 1.2; P ˆ 0.07). None of the patients had readmission
in a 2-week period after discharge. In the
salbutamol group, 3 patients had atelectasis, vs. none in
the epinephrine group.
Adverse Effects
Although use of salbutamol was associated with an
increase in heart rate on the second day which was
statistically signi®cant (146 4 bpm vs. 153 2.9 bpm;
P ˆ 0.02), this was not clinically relevant. Epinephrine
therapy was not associated with any adverse effects
during the study period.
DISCUSSION
Our data indicate that nebulized epinephrine (as opposed
to salbutamol) therapy improved clinical symptoms
in infants with bronchiolitis in several ways. First, epinephrine
decreased the clinical score after nebulization
during the ®rst day following admission. Secondly, epinephrine
was associated with a more rapid improvement in
baseline clinical score compared to salbutamol. This
improvement was re¯ected in reduced hospitalization
time in the epinephrine group.
Reijonen et al. 17 studied patients in an early phase of
bronchiolitis and showed a signi®cant improvement in
heart rate and oxygen saturation but not in clinical score
when racemic epinephrine was used. In the emergency
room, Menton et al. 23 using regular epinephrine showed
greater improvement in heart rate and oxygen saturation
compared to salbutamol, but they also did not ®nd any
difference in clinical score. However, they observed a
signi®cant decrease in the hospitalization rate in infants
treated with epinephrine. These two studies showed a
bene®cial effect of epinephrine in the early stages of
bronchiolitis.
Several studies have evaluated whether there is a
bene®cial effect of bronchodilators in bronchiolitis. Two
recent meta-analyses that addressed the ef®cacy of beta-2
agonist in bronchiolitis showed a modest impact in the
evolution of the disease. Flores and Horwitz 20 attributed
the absence of evidence to the lack of well-designed
inpatient trials and to the fact that beta-2 agonists had a
statistically signi®cant but clinically insigni®cant impact
on SaO 2 and heart rate in outpatient trials. Similarly,
Kellner et al. 21 showed a modest short-term improvement
in clinical features, but not in length of hospitalization.
There is recent evidence of a bene®cial effect of epinephrine
compared to albuterol in the acute phase of
bronchiolitis. Recent clinical trials have shown epinephrine
to be superior to placebo 15,22 and to salbutamol. 16,23
SaÂnchez et al. 16 showed a signi®cant clinical change 30
min after nebulization and also a decrease in pulmonary
resistance using racemic epinephrine, but not with salbutamol.
In the present study we obtained the same clinical
change as assessed by a modi®ed Bierman and Pierson
score in a similar age group of patients (< 12 months)
and a similar clinical score (5.6 1), but we used regular
epinephrine rather than racemic epinephrine.
We used epinephrine in our study because it is more
readily available than racemic epinephrine (RE) and less
costly. RE contains an equal amount of d- and l-isomers
of epinephrine, but the main pharmacologic activity is by
the l-isomer (15 times more potent than the d-isomer,
which has minimal activity). 24 There is good evidence
that epinephrine has similar ef®cacy to RE in the treatment
of infants with croup. 24 Our study would suggest
that epinephrine is also ef®cacious in the treatment of
infants with bronchiolitis. Mucosal edema in croup and
bronchiolitis may be diminished by alpha receptor stimulation
causing constriction of precapillary arterioles,
thereby reducing microvascular leakage. 25
After admission, 3 patients developed atelectasis in the
salbutamol group, and none in the epinephrine group. We
do not have a clear explanation for this phenomenon, but
it could be related to the presence of more edema in the
small airways in the salbutamol group.
The statement that epinephrine would produce more
undesirable cardiovascular effects than RE has not been
proven. In one study 26 in patients with laryngotracheitis
comparing RE and epinephrine, there was no difference
between groups in cardiovascular adverse reactions. This
result is consistent with our ®nding and the reports of
other authors who looked for adverse effects using
l-epinephrine. Based on previous studies with RE,
Menton et al. 23 used the maximum equivalent dose of
l-epinephrine (3 mg), and reported no adverse effects.
The presence of pallor in that study was not assessed. We
did not ®nd any adverse effect using one-sixth of their
dose of epinephrine. We still do not know the ideal dose,
but we believe that the dose of nebulized epinephrine has
to be similar for each patient regardless of weight. (Note
that the amount of drug that reaches the lungs is related to

288 Bertrand et al.
tidal volume, and is thus corrected for weight.) Our
prediction of the ideal dose is approximately 1 mg per
nebulization, taking into consideration previous reports in
patients with croup. 26,27
This is the ®rst study which has shown a signi®cant
decrease in clinical score severity during in-hospital
treatment in bronchiolitis patients treated with epinephrine
vs. salbutamol. In our study, recovery from the disease
(measured in comparison to baseline clinical score) was
more rapid in the epinephrine group compared to the
salbutamol group. The importance of this is the potential
bene®t of reducing healthcare costs by reducing hospitalization
time, based on a better clinical baseline score.
The difference in hospitalized days between both groups
was approximately one day (3.9 0.4 vs. 5.2 0.6).
Although we did not ®nd a signi®cant difference in the
average length of hospitalization comparing both groups,
we did ®nd a real difference on the fourth and ®fth days of
study in the number of patients still hospitalized. In the
USA, One day of hospitalization costs around $500 per
patient, and since bronchiolitis results in over 54,000
hospitalizations a year, this difference could mean a
saving of $27 million a year.
In summary, this study showed the greater ef®cacy of
l-epinephrine over salbutamol in treating bronchiolitis by
improving clinical status after nebulization and by more
rapidly decreasing the baseline clinical score on followup.
Since we only recruited 30 patients, we could not
demonstrate a difference in length of hospitalization and
oxygen dependence time. Nebulized epinephrine was not
associated with any adverse effects, and it should be
considered as the drug of choice in the treatment of acute
bronchiolitis because of its low cost and general
availability. Considerable savings in healthcare dollars
may be an additional bene®t related to the use of
nebulized epinephrine for the treatment of bronchiolitis.
ACKNOWLEDGMENTS
The authors thank Dr. Victor Chernick for his critical
review of the manuscript.
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