Asthma is a leading cause of health-related disability and hospitalization for children, and the prevalence of asthma has

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1 High-Dose Continuous Nebulized Levalbuterol for Pediatric Status Asthmaticus: A Randomized Trial Timothy Andrews, MD, Erin McGintee, MD, Manoj K. Mittal, MD, Lisa Tyler, RRT, Amber Chew, Xuemei Zhang, MS, Nicholas Pawlowski, MD, and Joseph J. Zorc, MD Objective To assess the use of high-dose continuous levalbuterol (LEV), the single active (R)-enantiomer of racemic albuterol (RAC), in the treatment of status asthmaticus. Study design Children age 6 to 18 years with severe asthma exacerbation were enrolled in this randomized, double-blind trial if they failed initial emergency department (ED) therapy with RAC and systemic steroids. Subjects received equipotent doses of RAC (20 mg/hour) or LEV (10 mg/hour) within a standardized inpatient protocol. Blood samples for measurements of albuterol enantiomer, potassium, and glucose levels were obtained from the first 40 subjects. The median time until discontinuation of continuous therapy was compared using the rank-sum test, and other outcomes were compared using general linear mixed models. Results A total of 81 subjects (40 in the RAC group and 41 in the LEV group) were enrolled; the 2 groups were similar at baseline. Both groups tolerated continuous therapy with similar changes in heart rate and serum potassium and glucose levels but higher serum (S)-albuterol concentrations in the subjects treated with RAC. The median time for continuous therapy was similar in the RAC and LEV groups (18.3 hours vs 16.0 hours), as were the other clinical measures. Conclusions Substituting high-dose continuous LEV for RAC did not reduce the time on continuous therapy and had similar adverse effects in children who had failed initial treatment with RAC. (J Pediatr 2009;155:205-10). See editorial, p 162 Asthma is a leading cause of health-related disability and hospitalization for children, and the prevalence of asthma has increased over recent decades. 1 Costs related to asthma, a substantial proportion of which are associated with emergency and inpatient care, also are increasing. 2 Concerns about the increasing burden of hospital care for asthma have led to the development of standardized treatment protocols using systemic corticosteroids and high-dose beta-agonists, such as albuterol. 3,4 Although standardization of care has led to reduced costs and lengths of stay, continued improvement in these protocols is needed. 5,6 In the past, albuterol was available as a racemic mixture of 2 enantiomers, (R)-albuterol and (S)-albuterol. Recently, a purified form of (R)-albuterol, also known as levalbuterol (LEV), has become available commercially (Xopenex Inhalation Solution; Sepracor, Marlborough, Massachusetts). (R)-albuterol binds the beta 2 -adrenergic receptors, producing the therapeutic bronchodilator effects of albuterol, along with such common adverse effects as tachycardia and tremor. The effects of (S)- albuterol remain controversial and were debated recently in 2 opposing editorials. 7,8 In vitro studies suggest that (S)-albuterol increases intracellular calcium, enhances airway hyperresponsiveness, and causes activation of eosinophils, all potentially detrimental effects in acute asthma that may oppose the therapeutic effects of (R)-albuterol Pharmacokinetic studies have found that (S)-albuterol has a longer half-life than (R)-albuterol, resulting in accumulation of the (S) enantiomer after repeated dosing with the racemic mixture. 12 Clinical studies assessing the effects of LEV and RAC on lung function in adults with stable asthma have yielded conflicting results. Some studies have demonstrated improved forced expiratory volume in 1 second (FEV 1 ) from LEV compared with equivalent doses of RAC, suggesting that the presence of the S isomer may impair bronchodilation; 13,14 however, other studies have found no difference in lung function between RAC and LEV. 15,16 Data for acutely ill children are limited. Carl et al 17 reported a reduced hospitalization rate after LEV was substituted for RAC in a clinical trial of ED treatment for asthma, but other investigators found no difference in lung function or clinical score between the 2 treatments in other ED FEV 1 LEV NAEPP RAC Emergency department Forced expiratory volume in 1 second Levalbuterol National Asthma Education and Prevention Program albuterol From The Children s Hospital of Philadelphia, Philadelphia, PA and the Divisions of Allergy and Immunology (T.A., E.M., N.P.) and Pediatric Emergency Medicine (M.M., A.C., J.Z.), Department of Pediatrics (L.T., X.Z.), University of Pennsylvania School of Medicine, Philadelphia, PA This investigator-initiated study was funded by an unrestricted research grant from Sepracor Inc. The authors declare no other affiliation, financial agreements, or involvement with this or any company that might be considered a conflict of interest. ClinicalTrials.gov registration number: NCT /$ - see front matter. Copyright Ó 2009 Mosby Inc. All rights reserved /j.jpeds

2 THE JOURNAL OF PEDIATRICS Vol. 155, No. 2 ED-based trials. 18,19 No studies have compared LEV and RAC in high-dose continuous therapy, as is recommended for children hospitalized with severe status asthmaticus. 4 The objective of the present study was to compare LEV and RAC in a group of children hospitalized for severe asthma who were receiving high-dose continuous beta-agonist therapy after failing to respond to standard ED therapy. Methods This was a randomized, double-blind, controlled trial conducted at an urban academic children s hospital. Our hospital s Institutional Review Board approved the study protocol before the start of enrollment. Research staff members were present in the ED from 8 a.m. to midnight each day to enroll potential study participants. To be eligible for the study, a patient had to be at least 6 (the age at which LEV is approved for use) and less than 19 years of age and have a diagnosis of asthma, defined as at least 2 previous visits at which a healthcare provider had prescribed a beta-agonist to treat acute symptoms. Eligible subjects were those who had been treated in the ED with a standardized protocol based on National Asthma Education and Prevention Program (NAEPP) guidelines, including, during the first hour, three 5-mg doses of nebulized racemic albuterol, two 500-mg doses of ipratropium, and a 2-mg/kg dose (to a maximum of 60 mg) of oral prednisolone or parenteral methylprednisolone. 4 After this initial therapy, each patient was assessed by an attending physician. Those who demonstrated continued symptoms of respiratory distress requiring continuous albuterol therapy were eligible for enrollment. Continuous albuterol is given in inpatient units according to an existing standard protocol that includes hourly assessments by a respiratory therapist; approximately 40% of patients admitted to inpatient units receive continuous therapy. To avoid confounding by additional therapies, patients were excluded if they had been started on intravenous beta-agonists or were being admitted to the intensive care unit, where treatment beyond the standard protocol is often given. Patients with other lung diseases (eg, cystic fibrosis), sickle cell disease, cardiac disease, pregnancy, or a history of allergy or other contraindication to albuterol also were excluded. Each subject was enrolled in the study only once. After informed consent was obtained, the patients were randomized to receive either RAC 20 mg/hour or LEV 10 mg/hour in a continuous nebulized formulation. Prenumbered sequential syringes containing the dose for the first 6 hours were prepared in advance by the research pharmacy using a randomization sequence of blocks of 6. Subsequent blinded doses were delivered to the inpatient unit by the pharmacy. The patients care was directed by the inpatient asthma protocol. Progression through the pathway was determined by standardized assessments by a trained respiratory therapist; severity was categorized as severe, moderate, or mild. Patients assessed as severe on continuous albuterol therapy received continuous cardiorespiratory monitoring Table. Baseline characteristics of the RAC and LEV groups RAC (n = 40) LEV (n = 41) Male, n (%) 26 (65%) 25 (61%) Age, mean, years (SD) 10.4 (3.5) 10.7 (3.3) Race, African American, n (%) 35 (88%) 40 (98%) Oxygen saturation, mean % (SD) 94.4% (3.6%) 94.5% (3.7%) Respiratory rate, mean per minute (SD) 33.3 (9.7) 34.0 (11.2) PASS, mean (SD) 1.8 (1.3) 2.3 (1.0) Previous hospitalization for asthma, n (%) 36 (90%) 36 (88%) Previous inhaled corticosteroid use, n (%) 28 (70%) 27 (66%) Albuterol treatments during 4 hours before 1.0 (1.2) 1.1 (1.2) ED, mean (SD) Use of levalbuterol at home, n (%) 5 (13%) 2 (5%) SD, standard deviation. and pulse oximetry and were assessed hourly for improvement with vital signs and a standardized respiratory assessment including a clinical asthma score, which has been demonstrated to have good interobserver agreement in previous research. 20 In patients with 2 consecutive hourly assessments of moderate severity, the beta-agonist dose was reduced by half and hourly assessments were continued. Those with 2 subsequent moderate assessments were advanced to intermittent albuterol, given every 2 hours. The study medication ended after discontinuation of continuous therapy, and further treatments with nebulized open-label RAC were given as needed. During the inpatient phase of the study, patients received oral prednisone/prednisolone or intravenous methylprednisolone 1 mg/kg up to a maximum of 30 mg every 6 hours. Ipratropium was not part of the standard order set for the protocol but could be ordered by the admitting physician. The inpatient protocol called for continuation of home medications, such as inhaled corticosteroids, during hospitalization. Study Measurements and Outcomes Research assistants interviewed the study subjects at the time of enrollment with a standard history form that assessed demographics, asthma history and severity, and medication use. Clinical measurements were obtained from standardized respiratory flowsheets. The study s primary endpoint was the duration of continuous albuterol therapy; secondary outcomes included spirometry and a clinical asthma score, the Pediatric Asthma Severity Score (PASS), which has been shown to have reliability, discrimination, and responsiveness at our institution. 21,22 The PASS was recorded hourly during continuous therapy as part of the respiratory assessment. Asthma severity is graded on a 6-point scale, summing individual assessment values (0, none/mild; 1, moderate; 2, severe) for each of 3 items: wheeze, prolonged expiration, and work of breathing. Spirometry was performed by respiratory therapists using a KoKoMate portable spirometer (nspire Health, Inc., Longmont, Colorado) at baseline and every 4 hours during continuous therapy. The best of 3 completed attempts was included in the subject s data. To assess the quality of the data, each flow-volume loop was reviewed in a blinded fashion by 2 investigators with subspecialty 206 Andrews et al

3 August 2009 ORIGINAL ARTICLES training in spirometry interpretation. Only measurements for which there was agreement about the adequacy of the tracing were used for the analysis. In the first 40 patients, an intravenous line was placed and blood samples were drawn at enrollment and every 6 hours during continuous therapy for measurement of serum (R)-albuterol, (S)-albuterol, and glucose concentrations and every 12 hours for measurement of serum potassium concentration. Any potassium values deemed to be hemolyzed or grossly hemolyzed by the laboratory were excluded from analysis Study Group O Levalbuterol Statistical Methods and Data Analysis The 2 study groups were compared at baseline for demographic and clinical factors using the c 2 test, t-test, or nonparametric rank-sum test, depending on the type and distribution of each variable. The primary outcome of duration of continuous therapy was compared using a nonparametric rank-sum test. Secondary outcome variables were compared using repeated analysis of variance. Linear mixed-effects models were used to examine changes over time and to account for different follow-up times, measurement times, and within-subject correlation. Initially, the study s sample size was calculated to detect a reduction in time on continuous therapy of 4 hours. But the Data and Safety Monitoring Board s review of the protocol determined that a 4-hour difference was not clinically significant; subsequently, the sample size was recalculated at 80 subjects to detect a 6-hour difference between the groups based on pilot data estimating a mean duration of 14 hours with a standard deviation of 8 hours (assuming 80% power and using a 2-tailed test with a = 0.05). At the request of the Institutional Review Board, an interim analysis of safety data only (vital signs and serum potassium and glucose) was conducted after 40 subjects were enrolled Hours of continuous therapy S-albuterol concentration (ng/ml) Study Group O Levalbuterol Hours of continuous therapy R-albuterol concentration (ng/ml) Figure 2. Mean levels of (R)- and (S)-albuterol in the 2 study groups. Levels and 95% CIs are expressed in ng/ml. Results Between April 2004 and February 2006, 143 eligible subjects were approached for enrollment in the study. Of these, 81 provided informed consent and were randomized, 40 to RAC and 41 to LEV (Figure 1; available at Several deviations from the planned protocol were recorded and accounted for in our data analysis. Of the 81 randomized subjects, 3 (all in the RAC group) never started on the study medication, due to clinical improvement before the initiation of continuous albuterol. One subject, also in the RAC group, worsened and was withdrawn from the protocol due to the decision to admit to the intensive care unit and treat with intravenous terbutaline and open-label continuous RAC. One subject in each group withdrew from the study treatment shortly after enrollment; the subject in the LEV group withdrew because of vomiting and was subsequently treated with intermittent albuterol, and the subject in the RAC group was continued on open-label RAC. Three subjects (1 in the LEV group and 2 in the RAC group) were switched to open-label albuterol during the study because of an inability to obtain the study medication. One subject in the RAC group received the study medication at a diluted concentration for 6 hours at the end of the first day of treatment before discontinuation of continuous therapy. One subject in the RAC group received LEV after the first 6 hours due to a pharmacy error. These subjects were included in their assigned group for intention-to-treat analysis. A subanalysis of subjects who successfully completed the protocol found similar results and is not presented here. Baseline characteristics were similar in the 2 study groups (Table). In both groups, most subjects had been hospitalized previously for asthma and had been treated with RAC at home before arrival to the ED; all subjects had been diagnosed with asthma. The mean serum concentrations of (R)- and (S)-albuterol measured in the first 40 subjects at baseline and throughout the duration of treatment are displayed in Figure 2. Mean (S)-albuterol concentration did not differ significantly between the 2 study groups at the time of enrollment (14.2 ng/ml for RAC and 11.7 ng/ml for LEV), representing treatment before arrival and over the initial hour of RAC treatment in the ED. The mean High-Dose Continuous Nebulized Levalbuterol for Pediatric Status Asthmaticus: A Randomized Trial 207

4 THE JOURNAL OF PEDIATRICS Vol. 155, No. 2 Proportion remaining on continuous Randomization group Levalbuterol Time in hours Figure 3. Survival analysis curve of time remaining on continuous albuterol therapy by study group. (S)-albuterol concentration rose to 28.6 ng/ml at 6 hours in the RAC group, compared with 5.5 ng/ml in the LEV group (P <.001); (S)-albuterol concentration continued to differ between the 2 groups at each subsequent time point. Additional therapies administered were similar in the 2 study groups. Ipratropium was administered to 44% of the study subjects overall during continuous therapy (38% of the RAC group and 49% of the LEV group). Some 90% of the subjects remained on intermittent therapy after discontinuation of continuous albuterol therapy, while 9 patients (6 in the RAC group and 3 in the LEV group) were restarted on continuous therapy during hospitalization in response to a worsening respiratory assessment. The primary outcome of duration of time on continuous albuterol therapy is displayed as a survival curve in Figure 3. The results were similar in the 2 groups when compared by intention-to-treat analysis, including all patients in the group to which they were randomized, and by per-protocol analysis, limited to patients who completed the protocol as planned; the figure presents the intention-to-treat results. The median duration of continuous therapy was 18.3 hours in the RAC group and 16.0 hours in the LEV group, with no significant differences when compared using the ranksum test (P =.75) or the log-rank test (P =.80). The mean duration of continuous therapy was 20.1 hours in the RAC group and 19.8 hours in the LEV group (difference, 0.3 hours; 95% confidence interval [CI] = -5.3 to 5.9 hours). The median time for subjects to be ready for discharge home, as assessed by the first 4-hour period between treatments, also was similar in the 2 study groups (45 hours for RAC; 46 hours for LEV). Baseline (S)-albuterol serum concentrations were not associated with duration of continuous therapy, and adjustment for (S)-albuterol did not affect the lack of association between study group and outcomes. Secondary outcomes were compared using linear mixed models. No differences in PASS score, respiratory rate, heart rate, or pulse oximetry in the 2 study groups were seen over the duration of study therapy. Over the first 24 hours of therapy, the mean heart rate ranged from 130 to 137 beats/minute, with a maximum of 174 beats/minute, and did not differ between the LEV and RAC groups at any time point. Serum glucose concentration peaked at 240 mg/dl at 6 hours, with no difference between the 2 groups. One patient in the LEV group had a serum glucose level exceeding the threshold of 500 mg/dl established for adverse event reporting, but this resolved without discontinuation of continuous albuterol therapy or other intervention. Mean serum potassium level was similar in the 2 study groups, at 3.6 mg/dl after 12 hours of therapy; 2 patients in the LEV group had a potassium concentration < 3 mg/dl (2.8 and 2.9 mg/dl) at this time point, but with no complications or discontinuation of therapy. Baseline spirometry measurements were attempted for all subjects, but only 37 (46%) were able to produce an acceptable tracing. The subjects who were able to complete spirometry tended to be older than other subjects (mean age, 11.6 vs 9.7 years), but measures of clinical status were similar in those who could and could not complete spirometry. The mean change in FEV 1 from baseline was greater in the LEV group at 4 hours after baseline (mean difference, 21%; 95% CI = 1% to 40%; P =.04) but did not differ between the 2 groups at any other time point. Discussion We sought to compare equivalent, blinded doses of RAC and LEV in a group of children receiving high-dose continuous albuterol therapy who had failed to respond to standardized ED therapy for status asthmaticus. Overall, we found no clinically significant differences between the 2 groups in time to discontinuation of continuous therapy or other measures of efficacy to suggest any benefit of LEV over RAC. Both highdose LEV and RAC appeared to be well tolerated, with similar measurements of heart rate and serum potassium and glucose concentrations and few complications. The literature addressing the efficacy and potential adverse effects of (S)-albuterol has been controversial and recently was summarized from contrasting points of view. 7,8 Studies in adults with stable asthma have found conflicting results when comparing lung function after equivalent doses of LEV and RAC. Some studies have suggested that the presence of the (S)-enantiomer may have detrimental effects on lung physiology and function, but others have not confirmed these results. 9-11,13,15 Studies of LEV in children with acute asthma exacerbations are limited and also conflicting. Carl et al 17 randomized 547 children presenting to an ED with acute asthma to standardized treatment with LEV or RAC and systemic 208 Andrews et al

5 August 2009 ORIGINAL ARTICLES corticosteroids. The children in the LEV group had a lower rate of hospitalization (36% vs 45%), suggesting a benefit of single enantiomer treatment. But Qureshi et al 18 studied a similar group of 129 pediatric ED patients and found no improvement in clinical asthma score or spirometry in the LEV group; the study was not powered to measure a difference in hospitalization rate. In addition to the difference in outcome measures, those 2 studies used different doses (RAC 5 mg in older children in the study of Qureshi et al vs 2.5 mg in the study of Carl et al), which may account for the differences observed. We are unaware of any previous systematic reviews or meta-analyses that have attempted to reconcile the available data or to conduct a cost-benefit assessment to assess the potential cost differences due to the higher cost of nebulized LEV compared with RAC. Likewise, no previous study has prospectively studied high-dose continuous LEV therapy in children. Expert panel guidelines for asthma published by the National Heart, Lung and Blood Institute recommend initiating continuous albuterol for patients with poor response to ED therapy and note the absence of data for high-dose continuous LEV. 4 Our results expand the data regarding the use of LEV in treating pediatric status asthmaticus. We found no clinically significant difference in the duration of continuous therapy or other clinical outcomes in the children treated with LEV and those treated with RAC. Several limitations of our study should be considered when applying our findings to the clinical setting, however. First, all of the patients in our study failed initial treatment with RAC and thus had an elevated baseline serum (S)-albuterol concentration measured at enrollment. We designed our protocol in this manner because most patients respond to standard albuterol therapy, and we would have needed to enroll many more patients on arrival to obtain a sample of this size that required continuous therapy. In addition, we sought to select a group of patients who had failed to respond to RAC therapy hypothetically due to an accumulation of (S)- albuterol. We reasoned that these patients might be most likely to benefit from substitution with LEV. Previous research in adults has suggested that (S)-albuterol concentrations may be related to response to LEV; 23 however, we found no difference after adjusting for (S)-albuterol measurements. But if (S)-albuterol has detrimental physiological effects on the airway, these effects possibly may have already begun during treatment before the ED visit, during initial ED therapy, and during the hours it took for the level to fall. We also chose to use doses of LEV and RAC containing the same amount of the (R) isomer, to ensure that these severely ill patients received adequate doses of the active enantiomer. It is possible that lower doses of LEV (or RAC) might be as effective, with fewer adverse effects. Further study of LEV initiated earlier in treatment of severe asthma and at other doses would help clarify these issues. Our study was a convenience sample conducted in a single center with a single approach to asthma therapy and thus may not be widely generalizable. We studied only patients with asthma of sufficient severity to merit continuous bronchodilator therapy (about 40% of the admitted patients at our institution). Evidence supporting continuous versus intermittent albuterol is limited, and further research could explore the intermittent use of RAC and LEV. 24 Although our protocol is standardized and based on national asthma guidelines, different results may be found using other measures of improved asthma severity. We supplemented our clinical assessment with spirometry to increase objectivity, but found that only some of these very ill children were able to perform spirometry, as reported previously. 25 We chose to exclude the most severely asthmatic patients, because many receive additional therapies in the intensive care unit that would be difficult to control. Concurrent conditions, such as pneumonia, were not systematically assessed, and may have differed between the 2 study groups. Finally, other agents, such as ipratropium, were prescribed for a subset of patients enrolled in our study; however, the rate of ipratropium use was similar in the 2 study groups, and the recent NAEPP guidelines state that ipratropium is not effective in hospitalized patients with asthma. Thus, this is unlikely to act as a confounder. 4 In conclusion, we found no benefit of substituting continuous high-dose LEV for RAC in a group of children who had failed initial therapy for severe asthma with RAC. Future studies should assess initial therapy with LEV in severe asthma and explore other therapies for pediatric status asthmaticus. n Submitted for publication June 25, 2008; last revision received Dec 16, 2008; accepted Jan 30, Reprint requests: Joseph J. Zorc, MD, Division of Emergency Medicine, Children s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA zorc@ .chop.edu. References 1. Mannino DM, Homa DM, Pertowski CA, Ashizawa A, Nixon LL, Johnson CA, et al. Surveillance for asthma United States, MMWR CDC Surveill Summ 1998;47: Weiss KB, Sullivan SD, Lyttle CS. Trends in the cost of illness for asthma in the United States, J Allergy Clin Immunol 2000;106: Schuh S, Reider MJ, Canny G, Pender E, Forbes T, Tan YK, et al. Nebulized albuterol in acute childhood asthma: comparison of two doses. Pediatrics 1990;86: National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institutes of Health; Johnson KB, Blaisdell CJ, Walker A, Eggleston P. Effectiveness of a clinical pathway for inpatient asthma management. Pediatrics 2000;106: McDowell KM, Chatburn RL, Myers TR, O Riordan MA, Kercsmar CM. A cost-saving algorithm for children hospitalized for status asthmaticus. Arch Pediatr Adolesc Med 1998;152: Ameredes BT, Calhoun WJ. (R)-albuterol for asthma: pro [a.k.a. (S)- albuterol for asthma: con]. Am J Respir Crit Care Med 2006;174: Barnes PJ. Treatment with (R)-albuterol has no advantage over racemic albuterol. Am J Respir Crit Care Med 2006;174: Handley D. The asthma-like pharmacology and toxicology of (S)-isomers of beta agonists. J Allergy Clin Immunol 1999;104:S Mitra S, Ugur M, Ugur O, Goodman HM, McCullough JR, Yamaguchi H. (S)-albuterol increases intracellular free calcium by muscarinic receptor activation and a phospholipase C-dependent mechanism in airway smooth muscle. Mol Pharmacol 1998;53: High-Dose Continuous Nebulized Levalbuterol for Pediatric Status Asthmaticus: A Randomized Trial 209

6 THE JOURNAL OF PEDIATRICS Vol. 155, No Volcheck GW, Kelkar P, Bartemes KR, Gleich GJ, Kita H. Effects of (R)- and (S)-isomers of beta-adrenergic agonists on eosinophil response to interleukin-5. Clin Exp Allergy 2005;35: Gumbhir-Shah K, Kellerman DJ, DeGraw S, Koch P, Jusko WJ. Pharmacokinetics and pharmacodynamics of cumulative single doses of inhaled salbutamol enantiomers in asthmatic subjects. Pulm Pharmacol Ther 1999;12: Nelson HS, Bensch G, Pleskow WW, DiSantostefano R, DeGraw S, Reasner DS, et al. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol 1998;102: Milgrom H, Skoner DP, Bensch G, Kim KT, Claus R, Baumgartner RA. Low-dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol. J Allergy Clin Immunol 2001;108: Lotvall J, Palmqvist M, Arvidsson P, Maloney A, Ventresca GP, Ward J. The therapeutic ratio of R-albuterol is comparable with that of R(S)-albuterol in asthmatic patients. J Allergy Clin Immunol 2001;108: Berger WE, Milgrom H, Skoner DP, Tripp K, Parsey MV, Baumgartner RA. Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a double-blind, randomized, placebo- and active-controlled trial. Curr Med Res Opin 2006;22: Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison of racemic albuterol and levalbuterol for treatment of acute asthma. J Pediatr 2003; 143: Qureshi F, Zaritsky A, Welch C, Meadows T, Burke BL. Clinical efficacy of racemic albuterol versus levalbuterol for the treatment of acute pediatric asthma. Ann Emerg Med 2005;46: Hardasmalani MD, DeBari V, Bithoney WG, Gold N. Levalbuterol versus racemic albuterol in the treatment of acute exacerbation of asthma in children. Pediatr Emerg Care 2005;21: Stevens MW, Gorelick MH, Schultz T. Interrater agreement in the clinical evaluation of acute pediatric asthma. J Asthma 2003;40: Gorelick MH, Stevens MW, Schultz TR, Scribano PV. Performance of a novel clinical score, the Pediatric Asthma Severity Score (PASS), in the evaluation of acute asthma. Acad Emerg Med 2004;11: Gorelick MH, Stevens MW, Schultz TR. Comparability of acute asthma severity assessments by parents and respiratory therapists. Arch Pediatr Adolesc Med 2002;156: Nowak R, Emerman C, Hanrahan JP, Parsey MV, Hanania NA, Claus R, et al. A comparison of levalbuterol with racemic albuterol in the treatment of acute severe asthma exacerbations in adults. Am J Emerg Med 2006;24: Camargo CA Jr., Spooner CH, Rowe BH. Continuous versus intermittent beta-agonists for acute asthma. Cochrane Database Syst Rev 2003; 4:CD Gorelick MH, Stevens MW, Schultz T, Scribano PV. Difficulty in obtaining peak expiratory flow measurements in children with acute asthma. Pediatr Emerg Care 2004;20: Andrews et al

7 August 2009 ORIGINAL ARTICLES Eligible subjects (n=144) Refused consent (n= 63) Enrolled (n=81) (n=40) Levalbuterol (n=41) 1 Admitted to ICU from ED 1 Withdrew 3 Never started on study med 4 Protocol deviation 1 Withdrew 1 Protocol deviation Completed protocol (n=31) Completed protocol (n=39) Figure. 1. Study enrollment diagram. High-Dose Continuous Nebulized Levalbuterol for Pediatric Status Asthmaticus: A Randomized Trial 210.e1