Download Oral dexamethasone in the treatment of croup: 0.15 mg/kg versus

Pediatric Pulmonology 20:362-368 (1995)
Oral Dexamethasone in the Treatment of Croup:
0.15 mglkg Versus 0.3 mglkg Versus 0.6 mglkg
G.C. Geelhoed, FRACP, and W.B.G. Macdonald, FRACP
Summary. The objective of this study was to compare the efficacy of a single dose of oral
dexamethasone of varying sizes in 120 children hospitalized with croup in two sequential double
'blind, randomized, controlled clinical trials (Trials A and B). The study was conducted in the
Emergency Department Observation Ward of a tertiary pediatric hospital. One hundred and
twenty children (age range 6 to 160 months) hospitalized with croup participated. Baseline
characteristics for the two groups in each trial were similar. In Trial A 60 children received either
0.6 or 0.3 mg/kg dexamethasone syrup; in Trial B 60 children received either 0.3 or 0.15 mg/
kg dexamethasone syrup. Duration of hospitalization, reduction in croup scores, and adrenaline
usage were evaluated. Median duration of hospitalization was similar for children in Trial A (7
and 8 hr), and in Trial B (9 and 9 hr). Croup scores following treatment did not differ and were
significantly lower than initial scores for all groups and in each trial. Other outcome measures
were similar for the two groups in each trial, including need for nebulized adrenaline, numbers
of patients admitted to intensive care, rate of return to medical care with reoccurrence of croup,
and readmission to hospital with croup following discharge from hospital. We conclude that oral
dexamethasone in a dose of 0.1 5 mg/kg is as effective as 0.3 or 0.6 mg/kg in relieving symptoms
and results in a similar duration of hospitalization in children with croup. Pediatr Pulmonol.
1995; 20:362-368.
0 1995 Wiley-Liss, Inc.
Key words: Croup, steroids, dexamethasone.
no statistical differences in the efficacy of oral dexamethasone or nebulized budesonide with regard to hospitalizaCroup (acute laryngotracheobronchitis) is one of the
tion time or croup scores, there was a consistent trend in
more common childhood respiratory illnesses. Children
favor of the oral preparation. Of the children who rewith moderate to severe airway obstruction are traditionmained hospitalized, children treated with oral dexamethally admitted to hospital for observation. Corticosteroids
asone had a significantly lower mean pulse rate than the
have been advocated as therapy in children hospitalised
aerosol budesonide-treated group at 8 and 12 hr, and a
with severe croup, however, studies in children with less
lower respiratory rate at 8 hr, implying less work of
severe illness have yielded conflicting result^.'^'^ In 1989,
breathing. We did not specifically set out to answer this
Kairys et al. published a meta-analysis of the nine methquestion, but it was our impression that oral medications
odologically satisfactory studies conducted up to that
(whether placebo or drug) were easier to administer to
time. The results suggested that steroid therapy was assodistressed young children than nebulized treatment. Many
ciated with faster clinical improvement in children hospisubjects found aerosol therapy distressing in its own right.
talized with croup than placebo treatment, and that a
Dexamethasone is also less expensive and requires no
dose of greater than 0.3 m g k g dexamethasone was more
facemask, tubing, or minimal time for delivery. Following
effective than lower doses.13Five further studies examinour 1993 study the practice in our emergency department
ing the use of inhaled and parenteral steroids in children
is to use oral dexamethasone rather than inhaled budesonhospitalized with croup have been published since and
ide for the above reasons. Although no side effects were
all showed benefits from treatment.'1,'2.14-'6
Three of three
studies have shown nebulized budesonide to be of benefit
in ~ r o u p , ' ~and
. ' ~the latter two studies found a reduction From the Emergency Department, Princess Margaret Hospital for Chilin duration of hospitalization. One of these studies" from dren, Perth, Western Australia.
our emergency department performed in 1993 also demonstrated that budesonide and oral dexamethasone (0.6 Received December 8, 1994; (revision) accepted for publication July
mglkg) were more effective than placebo, bringing about 8, 1995.
reduced hospitalization time, reduction in croup scores Address correspondence and reprint requests to G . C. Geelhoed, Prinafter 1 hr, and reduced need for nebulized adrenaline after cess Margaret Hospital for Children, Box D184 GPO, Perth, W. A.
1 hr of therapy compard to placebo. Although there were 6001, Australia.
INTRODUCTION
0 1995 Wiley-Liss, Inc.
Dexamethasone in Croup
TABLE 1-Croup
Score
Stridor
None
Only on crying, exertion
At rest
Severe (biphasic)
Retractions
None
Only on crying, exertion
At rest
Severe (biphasic)
0
1
2
3
0
1
2
3
noted in this or other studies using a single dose of dexamethasone of 0.6 mgkg, we felt it logical to evaluate
whether smaller doses would have similar beneficial effects in croup. This seemed especially important since
the alternative treatment (nebulized budesonide) results
in a much smaller dose of steroid being administered to
each child with croup.
This present study was conducted in two parts: Trial
A, to test the relative efficacy of a single dose of 0.3 mg/
kg oral dexamethasone compared to 0.6 mgkg in children
hospitalized with croup; and Trial B, to test the relative
efficacy of a single dose of 0.15 mgkg oral dexamethasone compared to 0.3 m g k g in children hospitalized with
croup. The second trial was undertaken as no difference
could be demonstrated between 0.3 and 0.6 m g k g of
dexamethasone. Our hypothesis was that smaller doses
of a single oral dose of dexamethasone would be as
effective as 0.6 mgkg in the treatment of croup.
PATIENTS AND METHODS
Children older than 3 months of age with no other acute
or chronic medical problems were eligible for inclusion in
the studies when they were admitted to Princess Margaret
Hospital for Children with a diagnosis of croup, defined
as the acute onset of inspiratory stridor, chest wall retractions, “barking” cough, and hoarse voice. Generally, only
those children with croup who have stridor and chest wall
retractions at rest are admitted to our hospital; milder
cases are discharged home from the emergency department. Inclusion criteria included a minimum croup score
of three (see Table 1). This was done to exclude children
with mild disease who were admitted for other reasons
such as living a long distance from medical care. Children
were also excluded when their families did not have a
telephone or had a limited command of the English language, whenever they had received steroid therapy of any
description in the preceding week, had a preexisting upper
airway condition, had a history of prolonged stridor, or
presented with a clinical picture suggesting a diagnosis
other than croup. In addition, children admitted directly
to the ICU with severe croup were excluded. Informed,
363
written consent was obtained from parents. The study
was approved by the hospital’s ethics committee.
Following enrollment, the parents completed a questionnaire in regard to current and past episodes of croup.
Croup score (see Table l), pulse rate, respiratory rate at
presentation, and arterial oxygen saturation (SaOJ from
a finger probe in room air using a Nellcor N-100 pulse
oximeter (Nellcor Incorporated, Hayward, California)
were recorded. Subjects were randomized to one of two
groups in each trial. In Trial A, one group received oral
dexamethasone BP (0.3 mgkg, maximum 6 mg), while
the other group received oral dexamethasone BP (0.6 mg/
kg, maximum 12 mg). In Trial B, one group received
oral dexamethasone BP (0.15 mgkg, maximum 3 mg)
while the other group received oral dexamethasone BP
(0.3 mgkg, maximum 6 mg). Treatments were administered in a double-blind fashion.
Subsequent management was administered according
to standard hospital practice. Due to lack of objective
evidence to support its use, mist therapy has not been
used in our institution for many years. Clinical observations were recorded hourly for the first 4 hr, and four
hourly thereafter until 24 hr after entry into the study or
until discharge. Nebulized adrenaline 1:100, 0.05 mLkg
(maximum 1.5 mL made up to 5 mL total with normal
saline) was administered if clinically indicated at any
time during the trials. Inhaled adrenaline treatments were
generally given for severe stridor and chest wall retractions equivalent to a croup score of five or six. If the
attending doctors considered that croup was severe and
that children failed to improve, patients could be withdrawn at any time to receive further steroids and be
transferred to intensive care. If the child was withdrawn
from the study, their study code was broken. Full observations continued for these children as results were analyzed
by intention to treat at trial entry. Children were discharged home based on the clinical judgment of the medical staff. Our main criteria for discharge were no stridor
or chest wall retractions at rest or a croup score of one
or zero. No child was sent home within 4 hr of receiving
nebulized adrenaline. Following discharge parents of the
children were contacted by telephone 7 to 10 days later
and asked whether their child had attended any medical
care for recurrent croup symptoms or for other reasons
related to their hospitalization, and whether they had been
readmitted to a hospital with croup.
The principal outcome measures were duration of hospitalization, reduction in croup scores, the proportion of
each group remaining hospitalized at 24 hr, and use of
nebulized adrenaline. Based on our 1993 study we compared use of adrenaline during the first hour following
treatment and subsequently. The former study“ showed
no difference in use of adrenaline in the first hour, but a
significant reduction after I hr in those children treated
with steroids compared to placebo. We also compared
364
Geelhoed and Macdonald
TABLE 2-Baseline
Characteristics of 120 Children Hospitalized With Croup’
B
A
Number
Male/female
Age (months)
Duration of symptoms (hr)
Temperature (“C)
Pulse rate
Respiratory rate
Sa02 in room air
Initial croup score
Previous croup
Viral/soasmodic2
0.3 m g k g
0.6 m g k g
0.15 m g k g
0.3 m g k g
29
18/11
35 (19)
18 (38)
38.0 (1.2)
146 (23)
31 (7)
97 (2)
3.8
12
15/6
31
25/6
42 (27)
25 (31)
37.8 (1.2)
144 (23)
33 (9)
96.9 (1.8)
3.7
29
2613
38 (34)
11 (17)
37.4 (0.9)
148 (29)
33 (9)
97 (1.7)
4.0
11
6/8
31
2 3 ~
32 (23)
16 (19)
37.5 (1.0)
147 (27)
33 (8)
97.3 (1.3)
3.7
14
10/6
11
12/3
‘No parameter was different for the two groups in each study with P
5
0.05. Numbers are mean (SD).
3 e e text for definition of “viral” and “spasmodic.”
TABLE 3-Outcome
Measures for 120 Children With Moderate Croup’
Trial
group
Median hospital stay (hr)
Hospitalized at 24 hr
Adrenaline in first hour ( y h )
Adrenaline after 1 hr (y/n)
ICU (y/n)
Represented with croup (y/n)’
Readmitted with croup (y/n)*
Children withdrawn from trial
A
B
0.3 nigkg
0.6 m g k g
0.15 mgkg
0.3 mgkg
7
6.9%
21%
0%
0%
7%
3%
0%
8
6.5%
16%
3%
0%
10%
6%
3%
9
3.4%
45 %
0%
0%
3%
0%
0%
9
0%
19%
0%
0%
3%
2%
0%
‘No outcome measure was different for the two groups in each study with P 5 0.05.
2Eight children were not followed up.
the number of children transferred to intensive care and
the number requiring further medical care with recurrent
croup following discharge. Kaplan-Meier survival analysis with log rank statistics was used to compare the two
groups in terms of duration of hospitalization. The influence of the two treatments on the likelihood of continuing
hospitalization and clinical improvement (croup score)
was assessed by COX’proportional hazards regression.
Mean croup scores at each observation time were compared, using Mann-Whitney U analysis for nonparametric, ordinal data, while the remaining normally distributed
observations were compared using unpaired Student’s t
tests. To demonstrate a difference of a doubling of the
duration of hospitalization time at the 5 % level of significance with 80% power, a sample size of 33 was required.
To demonstrate a significant difference of 20% in use of
adrenaline after the first hour at the 5% level of significance with 80% power, a sample size of 37 was required.
respectively, and 60 from each group were enrolled in
each trial. The majority of children not enrolled were
refusals by parents to take part in the study. A small
number of failures to enroll was due to staff not attempting
to enroll suitable subjects when the department was very
busy. The children whose parents refused were not different to the study population in any of the parameters
reported, including severity. The children’s age range was
6 to 160 months with 90% being younger than 6 years
of age. Baseline characteristics for the two groups in
each trial were similar (Table 2). Outcome measures were
similar for both groups in each trial (Table 3). The median
duration of hospitalization was similar for children in
both groups in each trial (Fig. 1). Twenty four hours
following entry into the study, there was no difference
between the number of children in each group who remained hospitalized with only two children in each group
remaining hospitalised in Trial A and only one child in
Trial B.
No difference was seen between the two groups in
RESULTS
either trial in regard to use of nebulized adrenaline either
During the study periods for Trial A (July 10 to August in the first hour posttreatment or subsequently (Table 3).
17, 1994) and Trial B (August 22 to December 7, 1994), Of the 120 children in both trials only one child who
92 and 72 children with croup were admitted to hospital received 0.6 mgkg dexamethasone required nebulized
Dexarnethasone in Croup
A
i
%
2
365
B
FN
W
l
40
i
vOsm,ik,l
II
0.3 mglkg
8
-n
Q
60
UJ
0
40
c
C
20
20
0
0
0
10
20
0
40
30
10
time (hrs)
20
40
30
time (hrs)
Fig. 1. Kaplan-Meier plot of percent children hospitalized vs time.
+
0.3 mg/kg
2
8fn
'1
o !
0
I
I
I
i
o !
I
I
I
1
2
4
6
8
0
2
4
6
8
time (hrs)
time (hrs)
Fig. 2. Croup score vs time for children hospitalized with croup. Croup scores for all four
groups were less than their initial score by 1 hr ( P < 0.05).
adrenaline after the first hour. She was discharged home
at 7 hr with no subsequent problems (Table 3).
There was no difference between the croup scores of
the two groups in either trial at any time. Mean croup
scores for the two groups in each trial were significantly
lower at 1 hr after treatment than their initial score and
continued to decline over the ensuing 3 hr ( P < 0.05)
(Fig. 2). This improvement was maintained for up to 8
hr posttreatment. After this time comparisons became
less meaningful as the numbers in each group had fallen
dramatically. One child who received 0.6 m g k g dexamethasone was withdrawn from the trial by their attending
physician in order to be given further steroids (Table 3).
During the study period, none of the 164 children admitted to hospital with croup was transferred to intensive
care. During the study period, children admitted with
croup and not included in the trials received 0.6 mg/
kg dexamethasone during Trial A and 0.3 m g k g during
Trial B.
Fifty-seven of the families in Trial A and 55 of the
families in Trial B were contacted following discharge
from hospital. Nine children attended a medical facility
subsequently for croup following discharge, and five children were readmitted to hospital; there was no significant
difference between the two groups in each trial (Table
3). There was no difference between the pulse rate, respiratory rate, temperature, or SaOz in air of the two groups
in either trial at presentation or for those who remained
hospitalized for 24 hr following administration of dexamethasone. No child had an SaOz lower than 90% at
any time.
Although no attempt was made to categorize children
as viral or episodic croup on entry into the trials, we
recorded whether children had symptoms of fever and
366
Geelhoed and Macdonald
rhinorrhea at home, had fever in hospital, the number of
previous episodes of croup, the number of admissions to
hospital with croup, and the duration of symptoms prior
to presentation. We arbitrarily defined viral croup as
having a temperature of greater than 38°C and/or fever
and rhinorrhea at home and symptoms of 6 hr or more,
and episodic spasmodic group as no history of fever and
rhinorrhea at home, a temperature of less than 38°C while
in hospital, duration of symptoms less than 4 hr, and at
least one episode of croup in the past. Based on these
definitions we were able to label 66 of the 120 children
as either viral or spasmodic. There was no difference in
the proportion of viral, spasmodic, or undefined children
in either of the two groups in both trials (Table 2). There
was no significant difference in the duration of hospitalization between the 43 “viral” children (1 1.5 hr) and the
23 “spasmodic” children (8.6 hr, P = 0.07).
DISCUSSION
These two trials have shown that treatment with small
doses of oral dexamethasone (0.15 mgkg) resulted in no
significant difference in the duration of hospitalization
and resolution of symptoms in children admitted with
croup than in a group reported by us when we used 0.6
mg/kg oral dexamethasone.I6 Because of the interplay
between clinical and social factors when deciding to discharge a patient with croup, we felt that it was possible
that a smaller dose of dexamethasone might have resulted
in a similar hospitalization time, but possibly a less dramatic effect on symptoms in the first few hours after
treatment. This would have resulted in higher croup scores
and a greater need for adrenaline after the first hour in
the 0.3 or 0.15 mgkg groups. This was not the case as
all outcome measures were similar for all four groups,
and we found little need for nebulized adrenaline after 1
hr of steroid treatment. In our previous study,I6 none of
the 50 children who received steroids required nebulized
adrenaline after 1 hr of steroid treatment compared with
20% of the 30 children in the placebo group. This decrease
in the use of adrenaline was also found by Super et al.”
In the two trials presented here, only one child out of
120 (0.8%) required adrenaline after the first hour. The
use of adrenaline during the first hour after treatment
with dexamethasone was not significantly different in
either trial, although the greater percentage who required
adrenaline in the 0.15 mg/kg group (45%) almost reached
statistical significance ( P = 0.06; Table 3). This group
also had the highest croup score at presentation (Fig. 1).
As the 0.15 mgkg group received the most adrenaline,
it might be argued that this contributed to their favorable
outcome. As the effects of adrenaline are thought to last
only a few h o ~ r s ” and
~ ’ ~ as the majority of adrenaline
treatments were administered on entry into the trial in
the first 5 to 10 min, it suggests that this group was more
distressed and the greater use of adrenaline should be
interpreted in that light and not as a failure of steroid
therapy. The subsequent favorable course of this group
supports this interpretation. Our 1993 studyL6demonstrated the ongoing need for adrenaline after 1 hr in those
children treated initially with adrenaline and placebo only.
As in our former study we have demonstrated the speed
with which children improve following administration of
oral steroids. This rapid lowering of the croup score along
with the dramatic decline in the need for adrenaline emphasizes the very early relief of symptoms achieved by
the use of steroids with consequent easing of patient,
parental, and clinician anxiety.
In the meta-analysis of Kairys et a1.,13 there appeared
to be a dose-response effect of steroids in croup. The
greatest clinical improvement was seen in studies in
which the highest doses of steroids (greater than 0.3 mg/
kg dexamethasone) were u ~ e d . ~ . ’To
- ’ ~the meta-analysis
should be added the studies of Kuusela and Vesikari”
and Super et a1.,I2both of which also used high doses of
steroids and both of which showed a beneficial effect
from drug treatment. The “low dose” studies in the metaanalysis, however, used an average dose of only 0.08 mg/
kg of de~amethasone.’.’~~~
These findings are compatible
with the existence of a “plateau” effect where an improvement in outcome occurs with increasing doses up to somewhere between 0.08 and 0.15 mgkg dexamethasone with
no further improvement achieved with greater doses.
No placebo group was included in our present trials
as we felt that the benefits of steroids in the treatment of
croup have now been
However, as no
placebo group was used in these trials and the 120 children
generally did so well, the question arises whether this
result could be explained independent of the effects of
steroids. A critic may be tempted to suggest that we only
treated mildly affected children with more severe cases
being missed or treated elsewhere. This does not appear to
be the case, as we did require subjects to have symptoms at
rest to be entered into the trials, and approximately 20% of
the subjects had severe stridor and chest wall retractions
requiring adrenaline when first seen. It is important to
note that Princess Margaret Hospital for Children is the
only tertiary childrens hospital for Western Australia with
a population of approximately 1.6 million. The city of
Perth is the most isolated city of its size in the world
ensuring that all serious cases of croup in the state are
referred to our emergency department, either directly or
transferred from other hospitals if requiring intensive
care. Historically our hospital admits between 300 to 500
cases of croup a year, with up to 10% of these children
being admitted to intensive care prior to the routine use
of steroids. During the study period none of the 164
children admitted to hospital with croup (either included
or excluded from the trials) was transferred to intensive
care and all had received dexamethasone.
Dexamethasone in Croup
We recognize that a clinical scoring system is not the
ideal means of assessing response to a therapeutic intervention, but alternative means of doing so are not practical
in this condition. Oxygen desaturation and the requirement for intubation are such rare events in children with
croup that they are not realistic parameters by which to
measure outcome, except perhaps in very large, multicenter studies. Clinical scoring systems are a well established means of evaluating therapeutic interventions in
c r o ~ p . * The
~ ~ ~croup
"
score used in this study differs from
that used in other studies in that we did not include
measures for degree of restlessness or cyanosis. Both of
these measures are difficult to standardize and are seen
primarily in children with very severe croup, a group that
was excluded from our study. A subjective assessment
of cyanosis was not necessary in our study as all children
were monitored at presentation and then at regular intervals with pulse oximetry. No patient in this study had a
recorded SaOz below 90%. To ensure an acceptable level
of interobserver agreement for our modified croup score,
a score was blindly assigned prospectively by two workers to 15 randomly selected children with croup not in
the trial. The weighted kappa statistic was 0.87, indicating
acceptable interobserver agreement.
The two trials, 0.3 vs 0.6 mgkg and 0.15 vs 0.3 mg/
kg, were conducted sequentially in the same department
with the protocol varying only in the doses administered.
To avoid randomization bias we have presented the results
as separate trials. However as the baseline characteristics
for the four groups in the two trials were similar (Table
2) and the same protocol was used for both trials, we
subsequently combined the two 0.3 mgkg groups and
compard the outcome of the resulting three groups, 0.15,
0.3, and 0.6 mgkg to achieve greater power to detect a
more subtle difference in outcome. No difference was
found. This was not surprising given the median duration
of hospitalization for the two groups in Trial A were 7
and 8 hr, and identical in Trial B being 9 hr, thus making
a type I1 error extremely unlikely.
As in our 1993 study, we did not attempt to distinguish
viral from spasmodic croup as it is often difficult in
practice to make this distinction and definitions of viral
and spasmodic croup vary. Studies have demonstrated
improvement following steroid administration in both virail2 and spasmodic'0," croup, although other investigators
have not distinguished between the two en ti tie^.^" Many
children presenting in our studies had features to suggest
both viral (e.g., fever and rhinorrhea) and spasmodic (e.g.,
recurrent episodes) features, and some workers argue that
the two conditions lie at either extreme of a continuous
s p e c t r ~ m .It' ~has been noted that the natural history of
spasmodic croup with early resolution of symptoms
would not allow time for steroids to help and could theoretically explain the early and similar outcome in our
different groups if the majority had spasmodic croup. We
367
arbitrarily categorized children as viral or spasmodic to
ensure that random selection of cases took place in the
two trials. Almost half of the subjects could not be categorized, using our stated definitions and having features of
both entities. However, more than half the children in
each study, 72% in Trial A and 54% in Trial B, had a
temperature of 38°C or more recorded in hospital or had
a reported fever at home often with rhinorrhea which
implies an infective process in the majority of children.
Also, many children had a prolonged duration of symptoms prior to presentation (Table 2). These findings would
be in keeping with the majority of studies in the metaanalysis and would argue against the notion that most
children in our studies had spasmodic croup and would
have recovererd quickly without steroid therapy. Finally,
the outcome of the 120 children in these current trials
including early decrease in croup scores, lack of need for
adrenaline after 1 hr, and short duration of hospital stay
is very similar to that of the 50 children who were treated
with steroids in our 1993 study16 and is in sharp contrast
to that of the 30 children in the placebo group. The
protocol for both the 1993 study and the current trials
differed only in the medications administered.
In summary, we have demonstrated that using oral
dexamethasone in a dose of 0.15 mgkg is as effective as
0.3 or 0.6 mgkg in children with croup with no significant
difference in the duration of symptoms and hospitalization time.
ACKNOWLEDGMENTS
We thank Mr. David McKnight and the staff of Pharmacy for their help and support in the setting up of this
study, and the staff of the Emergency Department for
participating so enthusiastically.
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