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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]. REFERENCES 1. Lotvall J, Palmqvist M, Arvidsson P, et al. The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients. J Allergy Clin Immunol. 2001;108: 726-731. 2. Ramsay CM, Cowan J, Flannery E, et al. Bronchoprotective and bronchodilator effects of single doses of (S)-salbutamol, (R)salbutamol and racemic salbutamol in patients with bronchial asthma. Eur J Clin Pharmacol. 1999;55:353-359. 3. Cockcroft DW, Swystun VA. Effect of single doses of S-salbutamol, R-salbutamol, racemic salbutamol, and placebo on the airway response to methacholine. Thorax. 1997;52:845-848. 4. Penn RB, Frielle T, McCullough JR, et al. Comparison of R-, S-, and RS-albuterol interaction with human b1- and b2-adrenergic receptors. 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