Pediatrics International

(2004)

46

, 539544

Original Article

Additive effects of dexamethasone in nebulized salbutamol or

L

-epinephrine treated infants with acute bronchiolitis

SEMANUR KUYUCU, SELMA UNAL, NECDET KUYUCU AND ESAT YG

LGOR

Department of Pediatrics, Faculty of Medicine, Mersin University, Mersin, Turkey

Abstract

Background

: Although it is the most common lower respiratory infection of infancy, the optimal treatment
for acute bronchiolitis is still controversial. The aim of this study was to compare the early and late effects of
nebulized

L

-epinephrine (EPI) and intramuscular dexamethasone (DEX) combination therapy with nebulized
salbutamol (SAL) and dexamethasone combination and bronchodilators alone in outpatients with acute
bronchiolitis.

Methods

: A total of 69 infants aged 221 months who were admitted to the Pediatrics Department of the
Faculty of Medicine, Mersin University, with acute bronchiolitis were included in a randomized, placebo-
controlled, prospective trial study. Patients were assigned to receive either nebulized

L

-epinephrine (3 mg) or
salbutamol (0.15 mg/kg) and 15 min later, either dexamethasone 0.6 mg/kg or placebo (PLA), intramuscu-
larly, in a double-blind randomized fashion. The study groups were: epinephrine + dexamethasone group
(group 1,

n

= 23), salbutamol + dexamethasone group (group 2,

n

= 23), epinephrine + placebo group (group
3,

n

= 11), and salbutamol + placebo group (group 4,

n

= 12). The outcome measures were heart rate,
respiratory rate and Respiratory Distress Assessment Instrument (RDAI) score determined at 30, 60, 90 and
120 min, 24 h, and 5 days after the first therapy. Patients were then followed-up during the subsequent
2 months for the prevalance of respiratory complaints regarding bronchial hyperreactivity.

Results

: There were no significant differences between the outcome variables of the four groups within the
first 120 min and at 24 hours, or between the rates of requirement of a second dose of the same bronchodilator.
However, fifth day RDAI score values of both DEX groups were significantly lower than that of SAL + PLA
group (

P =

0.000 and

P

= 0.01, respectively). The fifth day score value of group 1 was also significantly better
than that value of EPI + PLA group but not different from group 2.

Conclusions

: A single dose of intramuscular dexamethasone added to nebulized

L

-epinephrine, or salbutamol
therapies resulted in better outcome measures than bronchodilators alone in the late phase (fifth day) of mild
to moderate degree bronchiolitis attack. However, effects of EPI + DEX combination was not different from
SAL + DEX combination.

Key words

bronchiolitis, dexamethasone,

L

-epinephrine, salbutamol.
Acute bronchiolitis is the most common lower respiratory
tract infection of infancy. Although signs and symptoms may
be serious, most infections are self-limited and improvement
occurs within several days. Approximately 12% of affected
infants less than one year of age require hospitalization.

1

Treatment of hospitalized patients with bronchiolitis includes
supportive measures, such as supplementary oxygen and
adequate hydration in addition to antiviral chemotherapy in
selected cases.

13

The optimal therapy for bronchiolitis is
controversial. Although some studies suggest a positive
response to

2

-agonists,

2,4,5

many reports discourage their use
because of the lack of a proven therapeutic effect.

68

The pathophysiological changes that occur during acute
bronchiolitis are inflammatory obstruction in the small
airways with submucosal edema, cellular infiltration, epithelial
necrosis, and mucous plugging. It is not yet understood to
what degree the bronchoconstriction (or smooth muscle con-
traction) contributes to the obstruction of airways during
acute viral infection.

9

Treatment with a combined

and

agonist and/or steroids should theoretically be beneficial.

10

Some clinical trials have shown epinephrine to be superior
to placebo and/or salbutamol in acute bronchiolitis.

1113

Correspondence: Semanur Kuyucu MD, Mersin University Faculty
of Medicine, Department of Pediatrics, Zeytinlibahe, 33079,
Mersin, Turkey. Email: semanurkuyucu@yahoo.com
Received 14 July 2003; revised 19 January 2004; accepted
26 February 2004.
540 S Kuyucu

et al

.
Tal

et al

. showed that combined salbutamol and dexametha-
sone treatment significantly improved the clinical condition
of infants hospitalized with acute wheezing.

14

However,
Klassen

et al

. did not find an adjunctive effect of oral
dexamethasone therapy on the clinical course of salbutamol-
treated inpatients with acute bronchiolitis.

15

To our knowledge, corticosteroid and epinephrine
combination has not been evaluated before in the therapy of
acute bronchiolitis. The aim of our study was to compare the
short and long-term effects of nebulized

L

-epinephrine and
intramuscular dexamethasone combination therapy with
nebulized salbutamol and dexamethasone combination
and bronchodilators alone in outpatients with acute
bronchiolitis.

Patients and Methods

The study was conducted in pediatric outpatient clinics and
the emergency department of the Faculty of Medicine,
Mersin University, during the winter months. Patients were
eligible for the study if they met the following criteria: aged
between 2 and 21 months; they were admitted with their
first episode of wheezing; clinical findings compatible
with acute bronchiolitis (acute onset wheezing with or
without cough, tachypnea, and increased respiratory effort,
accompanied by clinical evidence of a viral illness such as
coryza and fever); and Respiratory Distress Assessment
Instrument (RDAI)

16

score

4. Patients were excluded from
the study if they had: a history of prior wheezing; previous
treatment with bronchodilators; a previous diagnosis of
asthma or allergic bronchitis by a physician; a personal
history of atopic dermatitis or allergic rhinitis; any chronic
cardiac or pulmonary disease; any steroid treatment within
the previous 2 weeks; signs of severe respiratory disease as
evidenced by a pulse rate

200 beats/min, a respiratory rate
of

100 breaths/min, a RDAI score of

15, or profound
lethargy; clinical and/or radiological evidence of a bacterial
infection; or a parental history of asthma or atopic disease.
Informed consent was obtained in all cases and the study
was approved by the research ethics committee of the
hospital.
Enrollment occurred between approximately 08.00 hours
and 17.00 hours when, after the initial assessment, the attending
pediatrician called one of the investigators. History regarding
the recent symptoms, duration of illness, infectious contact,
recent similar symptoms of the siblings, smoking habits of
the parents and socioeconomic status were obtained from
parents. A complete physical examination, complete blood
counting and chest X-rays were performed.
Primary outcome measures included respiratory rate, heart
rate and RDAI score, which were assessed by investigators
when the infants were relatively calm and had been breathing
room air for at least 15 min. The RDAI score is based on two
respiratory variables, wheezing and retraction, and is scored
using the following scales: expiratory wheezing (04 points);
inspiratory wheezing (02 points); location of wheeze (02
points); supraclavicular retraction (03 points); intercostal
retraction (03 points); and subcostal retraction (03
points).

16

The same patient was assessed by two independent
observers and the mean of the two scores was used for data
analysis.
Eligible patients were randomly assigned to receive either
0.15 mg/kg of a 1-mg/mL solution of salbutamol (Ventolin)
added to 0.9% saline solution to make a total of 3 mL, or
3 mL (3 mg) of 1 : 1000 L-epinephrine (Epinephrine) solution.
Solutions were given through a compressed type nebulizer
(Medic-Aid Ltd, West Sussex, UK) with continuous flow of
oxygen 56 L/min for 10 min. Fifteen minutes following the
administration of both nebulized medications, dexametha-
sone 0.6 mg/kg, or a placebo was given intramuscularly in a
randomised fashion independent of the first randomization.
Medication doses were based on previous clinical trials in
patients with either bronchiolitis or croup.

2,5,11,15

Preparation
and administration of nebulized solutions were performed
by a trained emergency department nurse. Parents and
investigators remained blinded to administered medications
throughout the study period.
The clinical assessment was performed on admission and
repeated 30, 60, 90 and 120 min after the first treatment. If
the patients had not experienced an improvement in the
RDAI score of at least 4 points by 120 min, they were given
the same medications (epinephrine or salbutamol) in the
same doses again and reassessment was then performed 30
and 60 min after the second dose. After the completion of the
first part of the study the patients were discharged and
reassessed at 24 hours, and 5 days later by the same observer
(N.K.). In addition, they were followed-up by regular
hospital visits during the subsequent two months in regards
to respiratory complaints such as exercise-induced cough and
wheezing.
For continuous variables, an independent two-tailed

t

-test
was performed by using pooled or separate variance estimates
as appropriate. Dichotomous events were analyzed by using
the chi-squared test. All statistical analyzes were conducted
with SPSS for Windows, Release 10.0 (

SPSS

19891992).

Results

A total of 69 children, aged 221 months, completed the total
study duration of 5 days. The distribution of participants
according to study groups were as follows; epinephrine +
dexamethasone group (group 1,

n

= 23), salbutamol + dex-
amethasone group (group 2,

n

= 23), epinephrine + placebo
group (group 3,

n

= 11), and salbutamol + placebo group
Dexamethasone in bronchiolitis 541
(group 4,

n

= 12). Three patients from group 1, one patient
from group 2, eight patients from group 3 and nine patients
from group 4 did not come to control visits on either the 24th
hour, or fifth day and hence, were not included in the
analysis. The reasons for drop-outs were not known.
The four groups were similar with respect to age, temper-
ature, baseline clinical measurements and RDAI scores
(Tables 1 and 2). The disease duration before admission in
group 2 was longer than group 1, but it was similar for the
other groups
When the response to therapy was evaluated longitudi-
nally within each of the groups, the 120th minute hearth rate,
respiratory rate and RDAI score values were found to be
significantly better than the baseline values of these
parameters for every group (

P

< 0.05).
The 90-minute heart rate value (137.6

2.6) of group 2
was significantly lower than that (144.1

1.5) of group 3
(

P =

0.04). Other heart rate, respiratory rate, and RDAI score
values of all groups at 30, 60, 90 and 120 min were similar
(

P

> 0.05) (Table 2). Fifth day RDAI score value of group 1
[2.3

0.1(mean

SE)] was significantly lower than group 3
(2.9

0.2) and group 4 (3.4

0.2) (

P =

0.02 and

P

= 0.000,
respectively). The fifth day score value of group 2 (2.5

0.1)
was also significantly better than group 4 (

P =

0.01) and,
though not statistically significant, group 3 (

P =

0.09). The
fifth day RDAI score values of group 1 and group 2 were not
significantly different.
A second dose of same medication (epinephrine or salb-
utamol) was given to five (21.7%) patients from group 1,
eight (34.8%) patients from group 2, five (45.4%) patients
from group 3 and four (33.3%) patients from group four,
since they did not show a substantial (

4 points) improve-
ment in RDAI score at 120 min. There were no significant
differences between the retreatment rates of each group
(

P

> 0.05). All of these patients showed a decrease

4 points
in their scores 60 min after the second dose of medication
when compared to the score at baseline. None of the patients
in any group required hospitalization.
During the subsequent two months, 17 patients from
group 1, 16 patients from group 2, and a total of 13 patients

Table 1

Admission characteristics of the study groups
EPI + DEX
(

n

= 23)
SAL + DEX
(

n

= 23)
EPI + PLA
(

n

= 11)
SAL + PLA
(

n

= 12)
Age (mo)

7.2



0.8 7.9



1.0 9.6



1.3 9.9



1.7
Temperature (

C)

37.7



0.1 37.4



0.1 37.3



0.2 37.4



0.1
Duration of illness (d)

2.5



0.1 3.5



0.3* 2.6



0.2 2.6



0.2
Sibling history

6 (26%) 3 (13%) 5(50%) 2 (16.7%)
Passive smoking 18(78.2%) 19(82.6%) 8(72.5%) 8 (66.7%)

EPI, nebulized epinephrine; DEX, dexamethasone im; SAL, nebulized salbutamol; PLA, placebo im.

Values are expressed as mean

SEM and n (%);

recent similar symptoms among siblings. *Signicantly different from group 1,

P

< 0.01.

Table 2

Comparison of outcome variables at different time points
Variable EPI + DEX
(

n

= 23)
SAL + DEX
(

n

= 23)
EPI + PLA
(

n

= 11)
SAL + PLA
(

n

= 12)
Heart rate (beats/min)
Baseline 148.5



2.7 141.8



3.2 144.5



3.3 149.0



3.7
120 min 134.5



3.3 135.0



2.5 138.6



2.3 138.2



3.1
24th hour 130.9



2.2 134.2



2.7 131.6



3.1 132.8



2.0
5th day 121.7



1.3 123.7



1.7 125.4



2.4 128.5



2.6
Respiratory rate (breaths/min)
Baseline 72.2



1.94 69.6



1.95 68.0



2.6 66.5



3.2
120 min 48.2



1.3 50.6



2.2 49.6



2.9 45.6



1.9
24th hour 44.9



2.4 49.0



2.7 44.2

3.2 42.0 2.5
5th day 33.1 1.2 37.7 1.8 36.5 2.3 41.1 2.9
RDAI score
Baseline 7.3 0.2 7.2 0.2 7.4 0.1 7.7 0.1
120 min 3.8 0.2 4.0 0.3 4.2 0.3 4.4 0.4
24th hour 3.4 0.2 3.9 0.3 3.7 0.3 3.8 0.3
5th day 2.3 0.1** 2.5 0.1* 2.9 0.2 3.4 0.2
All values are expressed as mean SE. *Signicantly different from group 4 (P = 0.01); **signicantly different from group 3 (P = 0.02)
and group 4 (P = 0.000).
542 S Kuyucu et al.
from group 3 and group 4 were followed-up. Four patients
(23.5%) from the epinephrine + dexamethasone group, three
patients (18.8%) from salbutamol + dexamethasone group
and six patients (46.2%) from the placebo group showed
respiratory complaints such as exercise-induced cough and
mild wheezing. Although these symptoms were more
prevalent in patients who were given placebo + broncho-
dilator than in those treated with dexamethasone plus
epinephrine or salbutamol, the differences were not statisti-
cally significant.
No side-effects such as pallor, vomiting or tremor were
encountered in the patients.
Discussion
This prospective double-blind placebo-controlled trial showed
that a single dose of dexamethasone added to nebulized
L-epinephrine or salbutamol treatments on admission resulted
in better outcome measures than bronchodilators alone, on
the fifth day after intervention in mild to moderate cases of
acute bronchiolitis. However, bronchodilator plus dexameth-
asone regimens were not superior to bronchodilators for
the first two hours or at the 24th hour. Neither nebulized
L-epinephrine nor salbutamol was more beneficial than the
other.
One of the limitations of this study was the relatively
small number of patients in the placebo groups. Either
treatment failure or treatment success may have led to the
reluctance of patients in the placebo group to return for
follow-up. However, the highly significant statistical
differences between dexamethasone and placebo groups may
overcome this issue.
Studies examining the effectiveness of bronchodilators in
bronchiolitis have shown variable and conflicting results.
2,5,8,1113
Some reports have demonstrated that short-term effects of
either nebulized salbutamol or epinephrine were better than
placebo in the treatment of acute bronchiolitis.
2,4,5,12,14
Other
studies did not show a significant improvement in clinical
scores, SaO
2
or pulmonary mechanics with regular nebulized
salbutamol in bronchiolitis.
68,13,17
However, these studies
exclusively included hospitalized patients, and one study
used only oxygen saturation as the primary outcome measure.
6
Recently, a meta-analysis evaluating eight randomized
controlled trials of inhaled
2
-agonists in bronchiolitis could
not determine any evidence that conclusively supported the
efficacy of
2
-agonist therapy for bronchiolitis.
18
Studies
evaluating the effects of nebulized epinephrine on bronchio-
litis have shown more encouraging results. Nebulized racemic
epinephrine or L-epinephrine resulted in significant clinical
improvement, lower hospitalization rates, and/or significant
improvement in pulmonary resistance.
1113
Two of these
studies have found that nebulized racemic epinephrine
13
and
L-epinephrine
11
had more beneficial effects than salbutamol
on clinical index and pulmonary mechanics in acute bronchio-
litis. Two recent reports comparing nebulized epinephrine
and/or nebulized salbutamol to placebo in moderate to severe
bronchiolitis revealed that these bronchodilators were no
more effective than placebo.
19,20
We could not find any
significant differences between the short-term RDAI scores
and single physiologic variable values of salbutamol and
epinephrine-treated groups. However, both treatment modalities
were equally effective in improving these parameters from
baseline values.
A virushost immune system interaction through the
respiratory airways during viral infection results in inflam-
mation of the small airways with cellular infiltration and
secretion of inflammatory substances such as virus-specific
IgE, free O
2
radicals, arachidonic acid metabolites, histamine
and eosinophil cationic protein (ECP).
9,2123
Leucotriene C
4
was demonstrated in nasopharyngeal secretions of infants
with acute bronchiolitis reaching peak levels 38 days after
the onset of the illness.
24
This inflammatory process have an
important role in the pathogenesis of acute bronchiolitis, and
is not only responsible for the acute stage, but also for the
late effects such as postbronchiolitis wheezing and airway
hyperreactivity.
9,23,25,26
A recent in vitro study has demon-
strated the inhibitory effects of fluticasone propionate on
RSV-induced increases of IL-8 and RANTES (regulated on
activation, normal T expressed and secreted).
27
These
findings relevant to inflammation form the rationale in favor
of anti-inflammatory treatment, namely glucocorticoids, in
acute bronchiolitis.
The results of studies about the efficacy of corticosteroids
in acute bronchiolitis remains controversial. Some studies
showed that parenteral or oral steroids, alone or together with
salbutamol, had no significant effect on the outcome
measures in infants hospitalized with bronchiolitis.
15,28,29
However, long-term follow-up of these patients after the
acute attack were not performed. Cade et al. found no signif-
icant differences in the late and long-term outcome measures
of acute RSV bronchiolitis treated with inhaled steroids.
30
Age of the patient is one of the important determinants of the
response to steroids. Martinez et al. demonstrated the correla-
tion between intrinsically smaller airways or preexisting
impaired lung function with an increased frequency of
wheezing in infancy.
31
Infants and children <2 years of age
who wheeze because of intrinsically smaller airways can be
expected to be less responsive to steroid effects than others.
However, those with a combination of congenitally smaller
airways and further obstruction caused by the release of
inflammatory mediators might show, at least partly, relief or
prevention of inflammation as a response to corticosteroids.
Tal et al. reported that a combination of salbutamol and
dexamethasone was significantly superior to salbutamol alone,
dexamethasone alone, or placebo suggesting a synergistic
Dexamethasone in bronchiolitis 543
effect of this combination on clinical improvement in infants
with acute wheezing.
14
They reported that no differences in
the course of the disease or response to treatment had been
found between infants who were diagnosed with asthma and
those diagnosied with bronchiolitis. Sheth et al. showed that
dexamethasone reversed the chronic virus-induced airway
obstruction characterized by airway hyperreactivity, increased
production of airway eicosanoids and increased number of
bronchiolar mast cells in experimental rats.
25
Reijonen et al.
demonstrated that early anti-inflammatory therapy with
nebulized budesonide or with cromolyn sodium significantly
decreased wheezing episodes after bronchiolitis.
26
Those
children with high nasopharyngeal ECP concentrations
(>870 ng/g) benefited especially from anti-inflammatory
therapy.
21
A recent meta-analysis investigating the role of systemic
corticosteroids in infants hospitalized with an attack of bron-
chiolitis, most of whom were experiencing their first attack,
revealed a statistically significant improvement in clinical
symptoms, length of stay and duration of symptoms.
32
They
found that the response rate was better in those with higher
symptom scores at admission. There is further evidence
supporting the hypothesis that the likelihood of response to
corticosteroids increases with severity of the disease.
33
These
data may explain the lack of a significant additive response
by intramuscular dexamethasone in the early phase of our
study which included mild to moderate cases not requiring
hospitalization. However, the dexamethasone-treated groups
of the present study showed significantly lower score values
on the fifth day examination, when compared to placebo-
treated groups. Hence, beneficial effects of parenteral dexa-
methasone treatment may be more pronounced in the late
phase of the disease among milder bronchiolitis cases.
The rationale for using intramuscular dexamethasone is
that it's quickly absorbed when given intramuscularly,
achieving high plasma levels within 15 min and has a higher
potency than other corticosteroids. However, clinical effects
may peak after 34 h and dexamethasone has a long half-life
of 3672 h.
27,34
Therefore, a single dose of dexamethasone
should be sufficient for a bronchiolitis attack.
For research purposes, bronchiolitis is often defined as
first time wheezing associated with clinical evidence of a
viral infection in infants.
4,11
However, some of these children
are infantile asthmatics who will continue to wheeze
therafter, and this is difficult to predict when they are first
seen. Castro-Rodriquez et al. have developed a clinical index
to define the risk of asthma in early wheezer infants.
35
A
loose index required any wheezing in the first 3 years of life
plus two major criteria (parental asthma and physician-
diagnosed atopic dermatitis), or one major and one minor
criteria. This index gave a specifity of 84.7% and a negative
predictive value of 73.2%. Since our trial excluded infants
with recurrent wheezing, family history of atopic disease,
personal history of atopic disease and wheezing without
colds, we can predict that at least 75% of our study group
will not develop asthma. Hence, the significant clinical
improvement obtained by bronchodilator therapies during the
first few hours and the late beneficial effects of dexametha-
sone adjunctive therapy cannot be explained by an response
of the asthmatic effect in the present study.
In conclusion, a single high dose of intramuscular dexa-
methasone given as adjunctive to nebulized bronchodilators
early in the course of mild to moderate bronchiolitis cases
may diminish the ongoing inflammatory processes which are
responsible for the late effects of the infection and hence,
result in a more favorable and shortened disease process.
However, larger studies including acute bronchiolitis cases
with varying degres of severity are needed in order to
determine the differential effects of corticosteroids according
to severity and phase of the disease.
References
1 Lugo RA, Nahata MC. Pathogenesis and treatment of
bronchiolitis. Clin. Pharm. 1993; 12: 95116.
2 Schuh S, Canny G, Reisman JJ, Kerem E, Bentur L, Petric M
et al. Nebulized albuterol in acute bronchiolitis. J. Pediatr.
1990; 117: 6337.
3 Nahata MC, Schad PA. Pattern of drug usage in bronchiolitis.
J. Clin. Pharm. Ther. 1994; 19: 1178.
4 Klassen TP, Rowe PC, Sutcliffe T, Ropp LJ, McDowell IW,
Li MM. Randomized trial of salbutamol in acute bronchiolitis.
J. Pediatr. 1991; 118: 80711.
5 Chevallier B, Aegerter P, Parat S, Bidat E, Renaud C,
Logardere B. Comparative study of nebulized salbutamol
against placebo in the acute bronchiolitis in 33 infants aged
16 months. Arch. Pediatr. 1995; 2: 11217.
6 Ho L, Collis G, Landan LI, Le Souef PN. Effect of salbutamol
an oxygen saturation in bronchiolitis. Arch. Dis. Child. 1991;
66: 10614.
7 Seidenberg J, Mir Y, von der Hardt H. Hypoxaemia after
nebulized salbutamol in wheezy infants: the importance of
aerosol acidity. Arch. Dis. Child. 1991; 66: 6725.
8 Wang EEL, Milner R, Allen V, Maj H. Bronchodilators for
treatment of mild bronchiolitis: a factorial randomized trial.
Arch. Dis. Child. 1992; 67: 28993.
9 Price JF. Acute and long-term effects of viral bronchiolitis in
infancy. Lung 1990; 168 Suppl: 41421.
10 Wahl MEB, Chernick V. State of the art; bronchiolitis. Am.
Rev. Respir. Dis. 1978; 118: 75981.
11 Menon K, Sutcliffe T, Klassen TP. A randomized trial
comparing the efficacy of epinephrine with salbutamol in the
treatment of acute bronchiolitis. J. Pediatr. 1995; 126: 10047.
12 Kristjnsson S, Lodrup Carlsen KC, Wennergren G,
Strannegard I-L, Carlsen K-H. Nebulized racemic adrenaline in
the treatment of acute bronchiolitis in infants and toddlers.
Arch. Dis. Child. 1993; 69: 6504.
13 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: 14551.
544 S Kuyucu et al.
14 Tal A, Bavilski C, Yohai D, Bearman JE, Gorodischer R,
Moses SW. Dexamethasone and salbutamol in the treatment of
acute wheezing infants. Pediatrics 1983; 71: 138.
15 Klassen TP, Sutcliffe T, Watters LK, Wells GA, Allen UD,
Li MM. Dexamethasone in salbutamol-treated inpatients with
acute bronchiolitis: a randomized, controlled trial. J. Pediatr.
1997; 130: 1916.
16 Lowell DI, Lister G, Von Koss H, McCarthy P. Wheezing in
infants: the response to epinephrine. Pediatrics 1987; 79:
93945.
17 Hughes DM, Le Souef PN, Landau LI. Effect of salbutamol on
respiratory mechanics in bronchiolitis. Pediatr. Res. 1987; 22:
836.
18 Flores G, Horwitz RI. Efficacy of
2
-agonists in bronchiolitis.
a reappraisal and meta-analysis. Pediatrics 1997; 100: 2339.
19 Abul-Ainine A, Luyt D. Short term effects of adrenaline in
bronchiolitis: a randomised controlled trial. Arch. Dis. Child.
2002; 86: 2769.
20 Patel H, Platt RW, Pekeles GS, Ducharme FM. A randomized
controlled trial of the effectiveness of nebulised therapy with
epinephrine compared with albuterol and saline in infants hos-
pitalized for acute viral bronchiolitis. J. Pediatr. 2002; 141:
81824.
21 Reijonen TM, Korppi M, Kleemola M, Savolainen K,
Kuikka L, Mononen I, Remes K. nasopharyngeal eosinophil
cationic protein in bronchiolitis: relation to viral findings and
subsequent wheezing. Pediatr. Pulmonol. 1997; 24: 3541.
22 Noah TL, Becker S. Respiratory syncytial virus-induced
cytokine production by a human bronchial epithelial cell line.
Am. J. Physiol. 1993; 294: 4728.
23 Black-Payne C. Bronchiolitis. In: Hilman BC (eds). Pediatric
Respiratory Disease: Diagnosis and Treatment. W.B.
Saunders, Philadelphia 1993; 20518.
24 Volovitz B, Welliver RC, DeGastro G, Krystofik DA,
Ogra PL. The release of leukotrienes in the respiratory tract
during infection with respiratory syncytial virus: role in
obstructive airway disease. Pediatr. Res. 1988; 24: 5047.
25 Sheth KK, Sarkness RL, Clough JJ, McAllister PK,
Castleman WL, Lemanske RF. Reversal of persistent post-
bronchiolitis airway abnormalities with dexamethasone in rats.
J. Appl. Physiol. 1994; 76: 3338.
26 Reijonen T, Korppi M, Kuikka L, Remes K. Anti-inflammatory
therapy reduces wheezing after bronchiolitis. Arch. Pediatr.
Adolesc. Med. 1996; 150: 5127.
27 Noah TL, Wortman IA, Becker S. The effect of fluticasone
propionate on respiratory syncytial virus-induced chemokine
release by a human bronchial epithelial cell line. Immunophar-
macology 1998; 39: 1939.
28 Roosevelt G, Sheehan K, Grupp-Phelan J, Tanz RR,
Listernick R. Dexamethasone in bronchiolitis: a randomised
controlled trial. Lancet 1996; 348: 2925.
29 Springer C, Bar-Yishay E, Uwayyed A, Avital A, Vilozni D,
Godfrey S. Corticosteroids do not affect the clinical or physio-
logical status of infants with bronchiolitis. Pediatr. Pulmonol.
1990; 9: 1815.
30 Cade A, Brownlee KG, Conway SP, Haigh D, Short A, Brown J
et al. Randomized placebo-controlled trial of nebulised cortico-
steroids in acute respiratory syncytial viral bronchiolitis. Arch.
Dis. Child. 2000; 82: 12630.
31 Martinez FD, Morgan WJ, Wright AL, Holberg CJ,
Taussig LM. Diminished lung function as a predisposing factor
for wheezing respiratory illness in infants. N. Engl. J. Med.
1988; 319: 11127.
32 Garrison MM, Christakis DA, Harvey E, Cummings P,
Davis RL. Systemic cortocosteroids in infant bronchiolitis: a
meta-analysis. Pediatrics 2000; 105: E44.
33 Schuh S, Coates AL, Binnie R et al. Efficacy of oral dexame-
thasone in outpastients with acute bronchiolitis. J. Pediatr.
2002; 140: 2732.
34 Klassen TP. Recent advances in the treatment of bronchiolitis
and laryngitis. Pediatr. Clin. North. Am. 1997; 44: 24961.
35 Castro-Rodriquez JA, Holberg CJ, Wright AL, Martinez FD. A
clinical index to define risk of asthma in young children with
recurrent wheezing. Am. J. Respir. Crit. Care Med. 2000; 162:
14036.