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PEDIATRICS/ORIGINAL RESEARCH
Clinical Efficacy of Racemic Albuterol Versus Levalbuterol
for the Treatment of Acute Pediatric Asthma
Faiqa Qureshi, MD
Arno Zaritsky, MD
Camille Welch, MPH
Teresa Meadows, RN
Bonnie L. Burke, MS
From the Department of Pediatric Emergency Medicine, Children’s Hospital of The King’s
Daughters, Eastern Virginia Medical School, Norfolk, VA (Qureshi); the Pediatric ICU,
University of Florida College of Medicine, Gainesville, FL (Zaritsky); and the Center for
Pediatric Research, Eastern Virginia Medical School, Norfolk, VA (Welch, Meadows, Burke).
Study objective: An efficacy treatment study is conducted comparing levalbuterol to racemic albuterol
for acute pediatric asthma in the emergency department (ED).
Methods: This was a prospective, double-blind, randomized, controlled study involving 129 children
(2 to 14 years), presenting to a pediatric ED with an acute moderate or severe asthma exacerbation.
Children were treated using a standard ED asthma pathway. Primary outcomes were changes from
baseline in clinical asthma score and the percentage of predicted forced expiratory volume in 1 second
after the first, third, and fifth treatment. Secondary outcomes included number of treatments, length of
ED care, rate of hospitalization, and changes in pulse rate, respiratory rate, and oxygen saturation.
Occurrence of adverse events was recorded.
Results: Sixty-four children in the racemic albuterol and 65 children in the levalbuterol group completed
the study. There were no differences between groups in primary outcomes, secondary outcomes, or
adverse events.
Conclusion: There was no difference in clinical improvement in children with acute moderate to severe
asthma exacerbations treated with either racemic albuterol or levalbuterol. [Ann Emerg Med. 2005;
46:29-36.]
0196-0644/$-see front matter
Copyright ª 2005 by the American College of Emergency Physicians.
doi:10.1016/j.annemergmed.2005.02.001
INTRODUCTION
Background
Inhaled b-adrenergic agonists are the mainstay of therapy for
treating acute asthma exacerbations. Albuterol is the most
frequently administered b-adrenergic agonist. Until recently,
albuterol preparations were formulated as a racemic mixture of
equal parts of 2 mirror-image enantiomers, the R- and Senantiomers. The R- enantiomer was thought to be responsible
for the drug’s bronchodilating activity and adverse effects,
whereas the S- enantiomer was believed to be pharmacologically
inert.1-5 Some studies, however, postulated that the S- enantiomer may increase airway reactivity by several mechanisms
such as increasing intracellular calcium,6,7 enhancing airway
responsiveness to spasmogens,8,9 and facilitating the release of
acetylcholine from dysfunctional prejunctional muscarine
autoreceptors.10 Because S- enantiomer clearance is slower than
that of the R- enantiomer,11 repeated dosing with racemic
albuterol may result in an accumulation of the S- enantiomer,
thus increasing the undesirable adverse effects of the racemate.
The potential for the S- enantiomer to cause adverse effects led
Volume 46, no. 1 : July 2005
to the development of a single R- enantiomer of albuterol,
marketed as levalbuterol.
Importance
Levalbuterol, (R-), albuterol, is promoted as being more
efficacious, with fewer adverse effects than racemic, (RS-),
albuterol, but it costs substantially more. Studies in patients
with chronic asthma have suggested improved bronchodilation
with R- albuterol compared with the RS-albuterol.12-14 There
are few data about the efficacy of levalbuterol for treating acute
asthma.
Goals of This Investigation
This study was designed as a superiority trial to determine
whether levalbuterol improved clinical asthma score and
pulmonary function tests compared with racemic albuterol in
children presenting to the emergency department (ED) with an
acute, moderate to severe asthma exacerbation. We also
compared the adverse effects of the 2 drugs.
Annals of Emergency Medicine 29
Racemic Albuterol Versus Levalbuterol for Pediatric Asthma
Editor’s Capsule Summary
What is already known on this topic
The single previous study of levalbuterol in the treatment
of acute pediatric asthma in the emergency department
(ED) reported that it was more effective than racemic
albuterol (which costs less). These results need to be
replicated to be adopted for general practice.
What question this study addressed
This prospective, double-blinded, randomized trial was
designed to determine whether levalbuterol was superior
to racemic albuterol for the treatment of acute pediatric
asthma in the ED as determined by asthma severity
scoring at disposition or a maximum of 5 nebulized
treatments.
What this study adds to our knowledge
This study of patients with moderate illness did not find
a clinical difference in asthma scores at disposition but
was not powered to detect differences in admission rates.
Conflicting results in the previous trial of levalbuterol
may be due to differences in severity of illness or in how
and when admission decisions were made.
How this might change clinical practice
There is not consistent evidence that levalbuterol is
superior to racemic albuterol in the treatment of
moderate pediatric asthma exacerbations, and the cost is
greater.
MATERIALS AND METHODS
Study Design and Setting
This was a prospective, double-blind, randomized
controlled trial of children with acute asthma who presented to
the pediatric ED of a tertiary-care children’s hospital (average
annual census 40,000). The institutional review board of the
Eastern Virginia Medical School approved the study.
Selection of Participants
Children who were between the ages of 2 and 14 years, had a
known history of asthma, and presented to the pediatric ED
with an acute asthma exacerbation associated with an initial
clinical asthma score greater than 8 or a forced expiratory
volume in 1 second (FEV1) that was less than 70% of predicted
were considered for enrollment. Asthma was defined as 2 or
more previous episodes of wheezing treated with b-adrenergic
agonists, with or without the addition of steroids. An acute
exacerbation was defined as worsening of the child’s asthma
symptoms or increased difficulty breathing. The enrollment
values for the FEV1 and asthma score were chosen to select
children whose asthma exacerbation was considered moderate to
severe to capture children who would more likely show
significant changes in response to treatment.
30 Annals of Emergency Medicine
Qureshi et al
Children younger than 2 years were not enrolled to avoid
including children with bronchiolitis. Children older than 14
years were not enrolled to focus on the patient population in
whom data were most needed. Children were excluded from the
study for any of the following reasons: use of ipratropium or
levalbuterol within 24 hours of presentation to the ED, use of
oral or parenteral steroids within the past week, use of inhaled
steroids greater than 400 mg per day of beclomethasone or its
equivalent in the last week, history of chronic underlying lung
disease, history of heart disease, pregnant or breastfeeding
women, participation in another clinical trial involving an
investigational product in the past 30 days, or the need for
immediate airway intervention. Before enrollment, signed
informed consent was obtained from a parent or legal guardian
and signed assent from the child, if appropriate.
Methods of Measurement and Data Collection
and Processing
The initial severity of each asthma episode was based on a
previously published clinical asthma scoring system,15 validated
and used extensively in our ED to evaluate the degree of
respiratory distress in all children, especially those too young or
too uncooperative to perform reliable pulmonary function tests
(more than 1,200 patients annually). The score is a modification of the scoring system proposed by the National Institutes of
Health16 and rates the severity of an episode based on signs,
symptoms (respiratory rate, auscultatory findings, retractions,
dyspnea), and oxygen requirement. In children older than 5
years who demonstrated good respiratory effort and reproducible technique (3 attempts within 6% of each other), baseline
pulmonary function tests were also recorded using a KoKo
spirometer (PDS Instrumentation, Louisville, CO). For this
study, the FEV1 was used as the pulmonary function test
measure.
The asthma exacerbation was classified as ‘‘mild’’ if the
asthma score was 5 to 7 or the FEV1 was greater than 70% of
the predicted value, ‘‘moderate’’ if the asthma score was 8 to 11
or the FEV1 was 50% to 70% of predicted, and ‘‘severe’’ if the
asthma score was 12 to 15 or the FEV1 was less than 50% of
predicted. To limit potential investigator bias, classification of
asthma severity throughout the study was done by a core
of 8 experienced ED nurses after specific training (interrater
reliability, r=0.92).
At the start of our study, levalbuterol did not have US Food
and Drug Administration approval for use in children younger
than 12 years; thus, the US Food and Drug Administration
approved an Investigational New Drug Application (# 58,853)
in October 1999. To comply with US Food and Drug
Administration regulations, the study was performed only when
a specially trained research coordinator from our clinical trials
unit was present in the ED to enroll patients. Because of the
unavailability of this person for almost a year and limited
availability thereafter, the study period ran from June 2000 to
February 2003.
Volume 46, no. 1 : July 2005
Qureshi et al
Children were randomized to treatment with either
levalbuterol or racemic albuterol by using a computerized
random-number generator, and allocation concealment was
maintained by the pharmacy staff. To ensure balanced patient
enrollment, a block randomization scheme using blocks of 10 (5
levalbuterol and 5 racemic albuterol) was implemented. Unit
doses of levalbuterol (1.25 mg) or racemic albuterol (2.5 mg) to
provide up to 5 treatments per patient were sealed and placed in
the Pyxis medication cabinet in the ED. Both drugs were
provided by Sepracor Inc (Marlborough, MA). The contents of
the medication syringes were identical in appearance and
volume (2 mL).The drug packages were labeled sequentially,
and enrolled patients were assigned the next numbered package.
ED staff, patients, and the research team were blinded to the
medication assignment. Children weighing less than 25 kg
received 2.5 mg of racemic albuterol or 1.25 mg of levalbuterol
for each treatment, and children weighing 25 kg or greater
received 5 mg of racemic albuterol or 2.5 mg of levalbuterol (ie,
2 unit doses of either drug) per treatment. These doses represent
an equivalent amount of the R- enantiomer of albuterol. The
medication was given by a small-volume, handheld nebulizer
(Salter Laboratories, Arvin, CA) driven by 100% oxygen at 6 to
8 L per minute. Facemasks were used for children younger than
5 years; children older than 5 years received the medication
through a mouthpiece.
All children were treated using a standard ED asthma clinical
pathway, during which children were given the first 3 nebulized
albuterol treatments at 20-minute intervals, with subsequent
treatments given at 30- to 60-minute intervals at the discretion
of the attending physician, based on clinical asthma score and
pulmonary function tests. Ipratropium bromide therapy was
delayed until after the third nebulized study treatment. All
children received 2 mg/kg of prednisone or equivalent corticosteroid by mouth with the second albuterol treatment. Study
participation was complete at disposition or after 5 nebulized
treatments. A disposition decision (ie, discharge to home or
admission to the hospital) was made by the attending physician
based on relief of symptoms, improvement in the clinical
asthma score or pulmonary function tests, and the ability to
maintain oxygen saturations greater than 94% on room air.
The asthma score and pulmonary function tests (when
possible) were recorded at baseline and again at 5 to 10 minutes
after the first, third, and fifth nebulizer treatment. Concurrently,
pulse rate, respiratory rate, pulse oximetry, and oxygen
supplementation, if required, were recorded. The total number
of study treatments and time of disposition decision were also
recorded. Children were observed for and also queried on
the occurrence of the following adverse events: headache,
tremulousness, nausea, vomiting, and lightheadedness.
To evaluate the pharmacokinetics of the plasma R- and
S- enantiomers after nebulization of levalbuterol or racemic
albuterol and to evaluate the pharmacodynamic effects of
albuterol on the serum potassium concentration, blood samples
(3.5 mL) were obtained from patients who consented to this
optional blood drawing. Blood samples were drawn before or
Volume 46, no. 1 : July 2005
Racemic Albuterol Versus Levalbuterol for Pediatric Asthma
within 5 minutes of beginning the first nebulizer treatment and
5 to 10 minutes after the third and last (fourth or fifth)
treatments. Samples were collected in a tube containing
ethylenediaminetetraacetic acid and placed in an ice slurry. The
plasma was then separated in a refrigerated centrifuge at 3,000
to 4,000 revolutions per minute for 15 minutes, and the plasma
aliquot was placed in a high-density polypropylene tube and
stored at 20 C until assayed by Sepracor. Serum potassium
was measured in the central chemistry laboratory of the hospital.
To look for possible cardiac electrophysiologic effects as a
result of either a direct effect of the medication or a decreased
serum potassium concentration, continuous cardiac monitoring
was performed, and a rhythm strip was obtained if any
significant abnormalities were noted.
Outcome Measures
The main study outcomes were changes from baseline in
clinical asthma score and FEV1 after the first, third, and fifth
nebulizer treatments. Secondary outcomes included number of
nebulized treatments until disposition; length of ED care; rate of
hospitalization; occurrence of adverse events; and changes in pulse
rate, respiratory rate, and oxygen saturation over time. Length of
ED care was defined as the interval between the baseline
assessment of the patient and time of disposition decision.
Additionally, we planned to study differences in response to
treatment comparing children with high versus low concentrations of the S- enantiomer at baseline and at disposition.
Primary Data Analysis
Descriptive analysis was conducted to summarize baseline
patient characteristics by treatment group. Categorical data were
described using frequencies and relative frequencies and then
compared between groups using a c2 test or Fisher’s exact test
when cell-count assumptions were violated. Distributions of
continuous variables were evaluated for normality using the
Shapiro-Wilk test and graphically using histograms and box
plots. Because data were nonparametric, they were described
using the median and 25th and 75th percentiles (interquartile
range) and then compared using Wilcoxon rank sum test.
Because the difference in the proportion of male and female
patients randomized to each study drug was significant, possible
confounding was explored. Because no confounding was
discovered, adjustment was not necessary and crude results are
reported. Comparisons between groups were made after the
first, third, and fifth treatments. The c2 test or Fisher’s exact test
when cell count assumptions were violated was used to test for
differences in initial asthma severity classification and disposition between treatment groups. Treatment effects of percentage
change from baseline in FEV1, clinical asthma score, pulse rate,
respiratory rate, and pulse oximetry, as well as number of
nebulizations and length of care, were tested using the Wilcoxon
rank sum test. Initially, an intent-to-treat analysis (excluding the
2 children dropped because they did not meet inclusion criteria)
was performed, which found no differences between groups.
A per-protocol analysis, which would be more likely to detect
Annals of Emergency Medicine 31
Qureshi et al
Racemic Albuterol Versus Levalbuterol for Pediatric Asthma
Figure 1. Enrollment data. *Other: Language/comprehension barrier, no guardian present, research coordinator unavailable.
a difference if one were present, was then done to examine the
effect of the 2 drugs, and these results are reported. Statistical
analyses were performed with the SAS System for Windows,
Release 8.01 (SAS Institute, Inc., Cary, NC), and statistical
significance was declared at an a level of 0.05 using 2-sided
significance tests.
Before the onset of the study, an absolute difference in
asthma score or FEV1 improvement between treatment groups
of 10% was assumed, with a common standard deviation of
10% for asthma score or 17% for FEV1 based on data obtained
from our previous asthma studies.15,17 Based on this assumption, a minimum of 23 children per group was required to test
differences in asthma score improvement or 61 children per
Table 1. Baseline patient characteristics.
Levalbuterol
N=65
Patient Characteristics
Median age, y (IQR)
Male, No. (%)*
Black, No. (%)
Median height, cm (IQR)
Median weight, kg (IQR)
Previous medication use, %
b-Agonist
Inhaled steroids
Singulair
Severity of asthma (%)
Moderate
Severe
Median asthma score (IQR)
Median FEV1 % predicted (IQR)y
6
52
54
132
22
(3, 8)
(80)
(83)
(113, 148)
(16, 36)
5.5
33
54
122
22
(3, 9)
(52)
(84)
(114, 140)
(16, 29)
78
28
14
77
16
6
63
37
10 (9, 12)
25 (21, 34)
69
31
10 (9, 12)
27 (25, 32)
IQR, Interquartile range (25th percentile, 75th percentile).
*Significant difference between groups at a=0.05 using c2.
y
Levalbuterol (N=24) and racemic albuterol (N=22).
32 Annals of Emergency Medicine
RS-Albuterol
N=64
group to test differences in FEV1 improvement to achieve 90%
power with a 2-sided t test, a level of 0.05. Therefore, the goal
was to enroll at least 61 children per group to test both primary
outcomes.
RESULTS
Characteristics of Study Subjects
Figure 1 shows patient enrollment data. After consenting, 10
patients were withdrawn from the study, 2 of whom should not
have been included. One other patient who received racemic
albuterol was withdrawn from the study because of an episode
of hyperventilation with decreased oxygen saturations, diaphoresis, and complaints of her legs twitching after the third study
nebulizer treatment. The patient recovered without further
complications. One patient in the levalbuterol group was
withdrawn by the ED attending physician after 3 treatments
with the study drug because of parental concerns that the child
was not improving. This child received 2 additional nebulizer
treatments with racemic albuterol and ipratropium and was
discharged. Six children were not included in the final
per-protocol analysis because their medications were not given
according to study protocol. One hundred twenty-nine
patients completed the study, 64 in the racemic albuterol group
and 65 in the levalbuterol group.
Baseline demographics (Table 1) were comparable among
treatment groups, except that more male than female patients
were randomized to the levalbuterol group. Only 24 children in
the levalbuterol group and 22 in the racemic albuterol group
were able to perform reliable pulmonary function tests.
Main Results
No differences were detected between groups after the first,
third, and fifth nebulizer treatments in the primary outcome of
Volume 46, no. 1 : July 2005
Qureshi et al
Racemic Albuterol Versus Levalbuterol for Pediatric Asthma
Table 2. Secondary outcomes by treatment group.
Levalbuterol
N=65
Median number of nebulizations (IQR) 3
Median length of care, minutes (IQR) 121
Patients hospitalized, No. (%)
7
Median change in pulse rate (IQR)*
After first nebulization
C9
After third nebulizationy
C22
After fifth nebulizationz
C18
Median change in respiratory
rate (IQR)
After first nebulization
2
After third nebulizationy
4
After fifth nebulizationz
5
Median change in pulse
oximetry, % (IQR)
After first nebulization
C1
After third nebulizationy
C1
After fifth nebulizationz
C1
RS-Albuterol
N=64
(3, 4)
3 (3, 5)
(90, 160) 125 (95, 167)
(11)
8 (13)
(0, C14)
C8 (0, C16)
(C15,C28)C21 (C12, C29)
(C9, C31) C18 (C9, C26)
(4, C2) 2 (4, 0)
(8, 0)
4 (8, 0)
(12, 1) 4 (6, 2)
(0, C3)
(1, C3)
(1, C4)
C1 (0, C3)
C1 (1, C2)
1 (2, 0)
IQR, Interquartile range (25th percentile, 75th percentile).
*Changes in pulse rate, respiratory rate and pulse oximetry are from baseline.
y
Levalbuterol (N=59) and racemic albuterol (N=58).
z
Levalbuterol (N=16) and racemic albuterol (N=17).
Figure 2. Primary outcomes by treatment group. Data are
presented as box plots in which the diamond represents the
mean and the 5 horizontal lines represent the 90th, 75th, 50th,
25th, and 10th percentiles. *Analyses not conducted because
of low number of subjects.
improvement in asthma score or percentage of predicted FEV1
(Figure 2), and no differences were found in the secondary
outcomes of the number of nebulizer treatments given; length of
care; rate of hospitalization; and changes in pulse rate,
respiratory rate, and pulse oximetry readings (Table 2). There
was no difference between the groups in the number of children
who received ipratropium after the third nebulizer treatment
(46% in the levalbuterol and 38% in the racemic albuterol
group). Table 3 shows the prevalence of adverse events. There
were no differences between groups.
Twenty-two patients (11 levalbuterol and 11 racemic
albuterol) allowed blood samples to be drawn, but samples from
4 children (2 in each group) sent for albuterol assay were lost.
Serum potassium decreased below 3.0 mEq/L in 6 patients (3 in
each study group), none of whom showed any concurrent
clinical or cardiac rhythm abnormality. Only 2 of these patients
returned the next day for a repeated check of serum potassium,
which was greater than 4 meq/L for both patients.
Median enantiomer concentrations for each group of
children are shown in Figure 3. Although samples were missing
Volume 46, no. 1 : July 2005
for some patients, marked increases in the S- enantiomer
concentrations are seen in the racemic albuterol group, whereas
the increase in R- enantiomer concentrations appears similar in
children receiving either form of albuterol. Because there were
few patients with complete data in each treatment group,
statistical analysis of plasma concentrations and treatment
effects was impractical.
LIMITATIONS
Because the majority of patients had moderate asthma
exacerbations, it is difficult for us to separately analyze the
treatment effect for patients with severe asthma. Similar to our
previous observations with ipratropium bromide in acute
asthma,15 an increased therapeutic response to the levalbuterol
may be observed in children with severe disease and thus justify
the higher cost of the drug for their treatment. Second, many
patients were unable to perform reliable pulmonary function
tests, limiting the ability to show significant differences between
groups for this characteristic. Third, hospitalization rate was a
secondary outcome for this study. Because our baseline
hospitalization rate was already low (13%), we would have had
to enroll many more children to show a possible difference in
hospitalization rate between groups. Fourth, the study was
designed as a superiority trial to determine whether levalbuterol
is more effective than racemic albuterol. The lack of a significant
difference does not mean that levalbuterol is equivalent to
racemic albuterol because the study was not adequately powered
to evaluate equivalency. Finally, patients were enrolled only
when a research coordinator was available, which made the
study period longer than anticipated. To ensure that there was
no fundamental change in the study population, we compared
demographic and clinical characteristics between the first 30
Annals of Emergency Medicine 33
Racemic Albuterol Versus Levalbuterol for Pediatric Asthma
Qureshi et al
Table 3. Prevalence of adverse events.
Levalbuterol,
No. (%) (N=65)
RS-Albuterol,
No. (%) (N=64)
24 (37)
5 (8)
8 (12)
9 (14)
3 (5)
1 (2)
21 (33)
11 (17)
4 (6)
3 (5)
3 (5)
1 (2)
Tremulousness
Nausea/vomiting
Headache
Lightheadedness
Drop in potassium \3.0 meq/L
Other*
*One child receiving racemic albuterol had tachycardia O200 beats/min. One
child receiving levalbuterol had an elevated temperature (38 ) before discharge.
patients enrolled into the study and the last 30 and found no
significant differences between the 2 groups.
DISCUSSION
We found no difference in clinical improvement or outcome
in children with acute moderate to severe asthma exacerbations
treated with either racemic albuterol or levalbuterol.
The study was originally designed and sample size calculated
with the expectation that the majority of enrolled children
would provide reliable pulmonary function tests. Unfortunately,
few enrolled children could perform this maneuver successfully,
so we used the asthma score as a uniform parameter for
stratifying patients by their severity of illness. Although the
study is underpowered for the FEV1, it is sufficiently powered to
detect a clinical difference between groups for the coprimary
measure, percentage of change in asthma score.
In our ED, the physicians and nurses rely mainly on the
asthma score as a composite index of signs and symptoms by
which to judge asthma severity and response to therapy rather
than the peak expiratory flow rate, which we find to be very
effort dependent and thus often not reliable in assessing the
severity of the episode. A recent study of 219 stable asthmatic
children also showed little relationship between percentage of
predicted FEV1 and asthma severity.18 Our asthma score has
demonstrated excellent face validity for stratifying asthma
severity based on the likelihood of hospitalization. In 2 previous
studies15,19 involving almost 1,000 children, we found that the
hospitalization rate for children with asthma scores in the
moderate range consistently averaged 10% to 12%, and in
patients with scores in the severe range, the hospitalization rate
ranged from 38% to 53%, depending on whether or not
ipratropium bromide was used. In the present study, the
baseline asthma score and baseline percentage of predicted
FEV1 had a moderate correlation (r=0.64; P\.001) and were
used as coprimary outcomes.
Several studies in patients with chronic asthma concluded
levalbuterol was more effective than the racemic, with fewer
adverse effects.12-14 This conclusion was disputed by Lotvall
et al,1 who used progressively increasing doses of R-, S- and
RS-albuterol in a group of chronic mild to moderate asthmatic
adults and reported that the R-albuterol and RS-albuterol were
comparable on a 2:1 potency ratio, both for improving FEV1
34 Annals of Emergency Medicine
Figure 3. Enantiomer concentrations over time by treatment
group. Median changes in baseline in R- and S- enantiomer
concentrations after the third and last nebulized treatment.
and causing adverse effects. Other authors have also questioned
the results of the earlier studies, claiming study designs were
inadequate to evaluate differences between the 2 formulations
and failed to demonstrate a significant dose-related response
for either drug.20,21 Additionally, they found no significant
differences in adverse effects for equipotent doses of the 2
medications.
There are few studies evaluating the use of R-albuterol in
acute asthma; 2 are published only as abstracts.22,23 Two other
studies on the efficacy of levalbuterol in acute asthma
exacerbations were recently published.24,25 In the adult study,24
91 patients with acute asthma were divided into groups of 12 to
14 patients and sequentially entered into 1 of 7 dose cohort
treatments of levalbuterol or racemic albuterol. Levalbuterol
appeared to be a more effective bronchodilator than racemic
albuterol, especially in a subset of patients with more severe
disease. The open-label, nonrandomized study design and the
small number of patients in each drug cohort are major
limitations of this study.
The pediatric study by Carl et al25 was a double-blind
controlled trial involving 482 children with acute asthma who
presented to the ED. Children were treated according to an
asthma care algorithm and randomized to receive either
2.5 mg of racemic albuterol or 1.25 mg of levalbuterol every
20 minutes (maximum 6 doses). Hospitalization rate was
significantly lower in the group receiving levalbuterol (36% vs
45%). However, similar to our study, there was no difference
between groups in any of the secondary outcome measures, such
as the number of nebulizer treatments given, mean length of ED
stay, respiratory rate, or oxygen saturation at the time of ED
discharge and the need for intensification of therapy or
admission to the pediatric ICU. The b-adrenergic-mediated
adverse effects were similar in both groups.
There is a marked difference in baseline hospital admission
rates between Carl’s study and ours (45% versus 13%), which
could be explained by several factors. The average admission
rate for asthmatic patients from our ED during the last 4 years
Volume 46, no. 1 : July 2005
Qureshi et al
has been 24%. In a previous study (overall admission rate 27%),
we showed that for children with moderate asthma the
admission rate was 10%, and for the severe asthmatic patients
receiving ipratropium bromide, it was 37.5%.15 Because the
majority of the children in this study had moderate asthma
exacerbations, the hospitalization rate of 11% and 13% in the 2
treatment groups is consistent with our usual admission rate. In
contrast, Carl et al25 report a 42% average admission rate for all
asthmatic patients at their hospital, and the higher rates of
admission reported in their study are probably in keeping with
their baseline high rate of hospitalization. The high rate of
admission may also have been influenced by their decision to
determine patient disposition at 120 minutes. In our ED, we
typically wait for 4 hours before making the decision to
hospitalize. Waiting the additional time may allow the
corticosteroids to exert a greater therapeutic effect and possibly
avoid hospitalization. In the data presented in the study by Carl
et al,25 we are not given a breakdown of the number of children
who had moderate or severe asthma exacerbations. Thus, it is
difficult to determine whether their high admission rate was a
result of enrolling sicker patients, a reflection of different
clinical practices and different thresholds for admitting patients,
disposition determination at 120 minutes, or a chance enrollment of patients who were more responsive to the levalbuterol.
Given the difference in results observed in these 2 studies,
more research on the efficacy of levalbuterol for reducing
hospitalization is indicated.
A major strength of our study is that we used weight-based
doses of albuterol in accordance with National Institutes of
Health recommendations,16 giving a higher dose of albuterol to
children weighing more than 25 kg. All children were treated in
a consistent manner using an established ED asthma-treatment
pathway. The only deviation from this pathway was delaying
the administration of ipratropium bromide until after the third
nebulized study treatment. The reason for this protocol
deviation was to maximize our ability to observe an effect from
the levalbuterol because it is possible that the pharmacologic
effect of ipratropium in acute asthma is, at least partially,
related to antagonizing the adverse cholinergic effect of the
S- enantiomer.
The main drawback to the use of levalbuterol is its cost. The
average wholesale price of 1.25 mg of levalbuterol is more
than twice that of 2.5 mg of generic albuterol, ($2.70 versus
$1.27, based on the Red Book Pharmacy’s Fundamental
Reference, 2004 Edition).26 However, the acquisition cost (actual
price paid) by hospitals and pharmacies reflects a greater price
differential. At our hospital, the acquisition cost for the drugs to
the pharmacy is $0.12 for a unit dose of 2.5 mg generic
albuterol and $1.98 for a unit dose of 0.63 mg levalbuterol (16
times greater cost for the levalbuterol). During acute asthma
exacerbations, larger doses of albuterol are often required to
achieve adequate drug delivery to the distal airways to maximize
therapeutic response. The cost of levalbuterol in these higher,
more frequent doses will greatly exceed the cost of racemic
albuterol.
Volume 46, no. 1 : July 2005
Racemic Albuterol Versus Levalbuterol for Pediatric Asthma
In summary, although levalbuterol may have theoretic
advantages over racemic albuterol, we were unable to demonstrate differences in clinical improvement or adverse effects in
children with acute moderate to severe asthma treated with
either levalbuterol or racemic albuterol.
Supervising editor: Kathy N. Shaw, MD, MSCE
Author contributions: FQ and AZ conceived the study, designed
the trial, and obtained research funding. TM maintained data
collections and data entry. CW analyzed the data under the
supervision of BB. FQ drafted the manuscript, and all
authors contributed substantially to its revisions. FQ takes
responsibility for the paper as a whole.
Funding and support: The study was supported by an
unrestricted research grant from Sepracor, Inc., Marlborough,
MA, who provided medication and partial financial support for
the research team.
Publication dates: Received for publication July 1, 2004.
Revisions received November 10, 2004; and January 17, 2005.
Accepted for publication February 2, 2005. Available online May
31, 2005.
Presented as a poster at the 2004 Pediatric Academic
Societies’ annual meeting, May 2004, San Francisco, CA.
Address for reprints: Faiqa Qureshi, MD, Division of Pediatric
Emergency Medicine, Children’s Hospital of The King’s
Daughters, 601 Children’s Lane, Norfolk, VA 23507;
757-668-9222, fax 757-668-7568; E-mail [email protected].
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