(Chest. 2003;124:844-849.)
© 2003
American College of Chest Physicians
An Evaluation of Nebulized Levalbuterol in Stable COPD*
Debapriya Datta, MD;
Anthony Vitale, BS, RPh;
Bimalin Lahiri, MD, FCCP and
Richard ZuWallack, MD, FCCP
* From the Section of Pulmonary and Critical Care Medicine (Drs. Lahiri and ZuWallack) and Department of Pharmacy (Mr. Vitale), St. Francis Hospital & Medical Center, Hartford; and Division of Pulmonary and Critical Care Medicine (Dr. Datta), University of Connecticut Health Center, Farmington, CT.
Correspondence to: Richard ZuWallack, MD, FCCP, Section of Pulmonary and Critical Care Medicine, St. Francis Hospital & Medical Center, 114 Woodland St, Hartford, CT 06105; e-mail: rzuwalla{at}stfranciscare.org
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Abstract
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Background: Levalbuterol, the R-isomer of albuterol, has advantages over racemic albuterol in asthma; however, the effectiveness of this ß-agonist in COPD has received little attention.
Objectives: To evaluate the effectiveness of a single dose of nebulized levalbuterol in COPD.
Design: A randomized, double-blind, placebo-controlled trial comparing nebulized levalbuterol to racemic albuterol, combined racemic albuterol and ipratropium, and placebo.
Patients: Thirty patients with stable COPD (FEV1 between 45% and 70% of predicted) were studied.
Methods: After withholding usual bronchodilator medications for appropriate washout periods, patients were randomized on separate visits to receive single doses of each the following nebulized bronchodilator medications: (1) levalbuterol, 1.25 mg; (2) racemic albuterol, 2.5 mg; (3) combined racemic albuterol, 2.5 mg, and ipratropium, 0.5 mg; or (4) placebo. FEV1, FVC, pulse rate, and oxygen saturation were measured at baseline, 0.5 h following nebulization, and hourly for 6 h. Hand tremor, using a 7-point scale, was measured at baseline, 0.5 h, 1 h, and 2 h. Treatment-placebo differences were analyzed using repeated-measures analysis of variance and least-squares means.
Results: The mean age (± SD) of patients was 69 ± 15 years. Mean FEV1 was 1.15 ± 0.49 L. By 0.5 h following study drug administration, all three nebulized bronchodilator treatments led to similar, significant improvements in FEV1 compared to placebo. These effects persisted at 1 h and 2 h for all three treatments; however, by 3 h, only the combined albuterol/ipratropium group had a mean change in FEV1 significantly greater than placebo. There were no significant differences between bronchodilator groups at any time period. A mild increase in pulse rate was observed in all treatment groups. There were no significant treatment-placebo differences in oxygen saturation or hand tremor.
Conclusion: For single-dose, as-needed use in COPD, there appears to be no advantage in using levalbuterol over conventional nebulized bronchodilators.
Key Words: bronchodilator • COPD • levalbuterol
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Introduction
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COPD is characterized by limitation to airflow, which is caused by chronic bronchitis and/or emphysema.1
Symptomatic disease is usually treated with maintenance bronchodilators, including inhaled anticholinergics, long-acting ß-agonists, and theophylline, and supplemented with as-needed, short-acting, inhaled ß-agonists.2
The anticholinergic bronchodilator ipratropium can be added to short-acting ß-agonists to augment peak bronchodilation and duration of effect.3
Racemic albuterol, the most commonly prescribed short-acting ß-agonist for relief of symptoms, is a 1:1 mixture of two mirror-image isomers, R-albuterol (levalbuterol) and S-albuterol.4
The R-isomer is predominately responsible for the bronchodilator effect of albuterol and, in vitro, has a higher affinity for ß receptors than racemic albuterol.5
The S-isomer, which is cleared at less than one tenth the rate of the R-isomer,6
has potentially negative effects, including elevation of intracellular calcium levels,7
small increases in bronchial hyperresponsiveness,8
a pro-inflammatory effect,9
and possible inverse agonist action.10
11
These effects may explain the finding that, in asthma patients with an FEV1 < 60% of predicted, 1.25 mg of nebulized levalbuterol provided more bronchodilation than an otherwise equivalent 2.5-mg dose of the racemic drug.10
The clinical significance of these potential negative influences of S-albuterol, however, has been questioned,12
13
and a study14
showed comparable potency and side effects of levalbuterol and racemic albuterol in patients with asthma.
Although levalbuterol has been studied in asthma, the potential usefulness of this short-acting bronchodilator in COPD has received little attention. Accordingly, this randomized, double-blinded, placebo-controlled, crossover trial was designed to compare the bronchodilator effect and side effects of single doses of nebulized levalbuterol with two commonly used as-needed bronchodilator regimens for COPD: racemic albuterol alone and combined racemic albuterol and ipratropium.
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Materials and Methods
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Patients
Thirty patients with a clinical diagnosis of COPD were recruited from office practices and a pulmonary clinic. Inclusion criteria were as follows: (1) signed informed consent approved by the institutional review board of the hospital; (2) a clinical diagnosis of COPD; (3) an FEV1 between 45% and 70% of predicted, and an FEV1/FVC ratio < 0.70; (4) stable disease, as indicated by the absence of a clinical exacerbation and no change in COPD medications in the preceding month; and (5) the ability of patients to withhold their bronchodilator medications for the appropriate washout time prior to each testing. Exclusion criteria were as follows: (1) a clinical diagnosis of asthma, and (2) any coexisting medical problem that might interfere with the conduct of the study or place the patient at risk by participating. Prior to the study, information on patient demographics and disease severity was obtained. This information included age, sex, race, height, weight, duration of COPD, history of hospitalizations for COPD, and current medications.
Study Design
This was a double-blind, crossover trial comparing single doses of the following four different nebulized treatments in randomized sequence, on separate days, at least 24 h apart: (1) racemic albuterol, 2.5 mg; (2) levalbuterol, 1.25 mg; (3) combined racemic albuterol, 2.5 mg, and ipratropium, 0.5 mg; and (4) placebo (normal saline solution). All test medications were diluted to 3 mL using normal saline solution, when necessary, and were dispensed as unit doses. An A Airlife Misty-Neb nebulizer (Allegiance HealthCare Corporation; McGaw Park, IL) was used to deliver the treatment; each patient used the same nebulizer apparatus for all four treatments. Maintenance bronchodilator medications were withheld prior to each test drug administration according to the following schedule: theophylline, 48 h; salmeterol, 24 h; ipratropium, 8 h, and albuterol, 6 h.
Measurements
The major outcome variable was the FEV1. Other variables included FVC, pulse rate, oxygen saturation (determined by pulse oximetry), and hand tremor. Since we could not find a validated scale for hand tremor, we used the following 7-point scale: 0 = no tremor, 1 = very slight tremor, 2 = mild tremor, 3 = mild-to-moderate tremor, 4 = moderate tremor, 5 = moderate-to-severe tremor, and 6 = severe tremor. The tremor of both pronated hands, with arms extended and slightly flexed, was rated. The same blinded investigator rated tremor in all patients. Testing commenced between 7 AM and 9 AM. FEV1, FVC, pulse rate, and oxygen saturation were measured immediately prior to drug nebulization, 0.5 h following drug administration, and hourly for 6 h. Hand tremor was measured at baseline, 0.5 h, 1 h, and 2 h.
Statistical Analysis
Patient characteristics are presented as mean ± SD. Comparisons of outcome variables among the study drugs at each time point were performed using repeated-measures analysis of variance, with least-squares means analyses for group comparisons. There was no significant drug order effect on outcome in this crossover study. Outcome variables are expressed as mean ± SE. Between-treatment changes were considered primary outcomes; p < 0.05 was considered significant.
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Results
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Of the 30 patients studied, 25 were men and 5 were women (mean age, 69 ± 15 years). The duration of COPD was 5.3 ± 4.5 years, and FEV1 was 1.15 ± 0.49 L. Twenty percent were receiving supplemental oxygen, and 13% were receiving oral corticosteroids. All patients were receiving as-needed, short-acting ß-agonists, and most were receiving long-acting ß-agonists. Sixty percent of the patients were receiving inhaled steroids.
The mean changes in FEV1 from baseline for the four groups are shown in Table 1
and Figure 1
. By 0.5 h following study drug administration, all three nebulized bronchodilator treatments led to similar, significant improvements in FEV1 compared to placebo (between-group changes). These effects persisted at 1 h for all three treatments. By 2 h, only the combined albuterol/ipratropium group had a mean change in FEV1 significantly greater than placebo (p = 0.04), although the bronchodilator effects of albuterol and levalbuterol tended to be significant at this time period (p = 0.09 and p = 0.12, respectively). The combined albuterol/ipratropium effect persisted to 3 h. There were no significant differences between bronchodilator groups at any time period.
The percentage of patients with a positive bronchodilator response (ie, both a > 12% increase and a > 0.20-L increase in FEV1) in the albuterol, combined albuterol/ipratropium, and levalbuterol groups was similar at 0.5 h (43%, 43%, and 40%, respectively) and significantly greater than placebo (13%) [p = 0.02, p = 0.02, and p = 0.03, respectively]. By 1 h, the proportion of bronchodilator responders in the three treatment groups remained similar (47%, 53%, and 40%, respectively), vs placebo (13%) [p = 0.007, p = 0.001, and p = 0.03, respectively]. By 2 h and 3 h, only the proportion of bronchodilator responders in the combined albuterol/ipratropium group (43% and 40%, respectively) remained significantly greater than placebo (17% and 7%, respectively) [p = 0.03 and p = 0.003, respectively]. None of the bronchodilators led to a bronchodilator response significantly greater than placebo from 4 to 6 h.
The change in FVC from baseline is shown in Table 2
. Similar to FEV1, all three treatments resulted in similar, significant increases in FVC compared to placebo at 0.5 h. This effect remained significant at 1 h only for the combined albuterol/ipratropium group. There were no significant treatment-placebo differences from 2 h onward, due in part to an increase in FVC in the placebo arm during the first 4 h of the study.
The effect of the bronchodilators on pulse rate, oxygen saturation, and tremor score are given in Tables 3
4
5
, respectively. Albuterol and levalbuterol resulted in similar, small increases in pulse at 0.5 h, but this effect disappeared by 1 h. There were no significant differences in oxygen saturation. Although the tremor score increased by less than one-half unit in all groups, there were no significant group differences in this outcome measure.
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Discussion
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The purpose of this study was to compare the effectiveness and side effects of a 1.25-mg dose of nebulized levalbuterol with two commonly used nebulized rescue bronchodilator regimens for COPD: 2.5 mg of racemic albuterol, and the combination of 2.5 mg racemic albuterol and 0.5 mg ipratropium. The R-isomer of the racemic drug has virtually all of the bronchodilator activity of albuterol. If, as a previous study15
in asthma might suggest, the S-isomer opposes the bronchodilator effect of the R-isomer, 1.25 mg of levalbuterol might be more effective than 2.50 mg of the racemic drug. In our study, levalbuterol resulted in significant bronchodilation compared to placebo at 0.5 h and 1 h following nebulization, but the magnitude of this effect was not significantly different from that of racemic albuterol or the combination of racemic albuterol and ipratropium. Although Figure 1
suggests that all bronchodilators appeared to have numerical benefit compared to placebo for 3 to 5 h after dosing, only the combination therapy led to significant bronchodilation past the 1-h observation period, and then only for 3 h. All three nebulized bronchodilator regimens were well tolerated. There was an increase in pulse in all three regimens, but this was only between 5 to 6 beats/min and was only observed at 0.5 h following drug administration. There were no significant treatment-placebo differences in oxygen saturation or hand tremor at any time period. Small but significant increases in hand tremor occurred with all treatments (including placebo), suggesting a strong placebo effect.
These results suggest that with single-dose, as-needed use, there is no special benefit from nebulized levalbuterol over racemic albuterol in patients with COPD. Furthermore, the bronchodilator duration of these short-acting ß-agonists appears to be significantly less than when the anticholinergic bronchodilator ipratropium is added in combination. This is in accord with previous studies3
16
testing this combination against its components. Of interest, the duration of action of both racemic albuterol and levalbuterol in our study is shorter than that described in other COPD trials. For instance, in a study of 652 patients with COPD, the mean duration of FEV1 response > 15% over baseline on day 1 of testing was 3 h for 3 mg of nebulized albuterol.3
The short duration of ß-agonist effect in our study was probably due in large part to the small number of study subjects, and consequent low power for the statistical analysis. Furthermore, inspection of Figure 1
shows an appreciable increase in FEV1 in the placebo arm, peaking at 2 h. This may reflect diurnal changes in airway tone in addition to a placebo effect. Many of our patients had severe respiratory disease and were receiving frequent doses of short-acting ß-agonists, and most were receiving regular, long-acting ß-agonists. This may have resulted in some tachyphylaxis, thereby reducing the effectiveness of this bronchodilator class. Small and questionably clinically meaningful decreases in peak FEV1 response and FEV1 area under the curve over time have been demonstrated with regular nebulized albuterol and albuterol-ipratropium therapy.3
16
A limitation of this study is the relatively small number of patients studied, thereby reducing its power for statistical inference. As mentioned above, this may have reduced the likelihood of demonstrating longer durations of action, and it may have reduced the ability of showing the superiority of the combination over the single ß-agonist therapies. However, since the levalbuterol effect on FEV1 was numerically slightly less than albuterol over most time points, it is highly unlikely there was a type I error. Since the S-isomer probably accumulates over time with regular bronchodilator use, the major benefit from using the R-isomer may only be observed when these drugs are administered regularly over time. We did not design our study to test this potential effect, since nebulized short-acting bronchodilators are usually administered on an as-needed rather than regular basis.
In conclusion, a single nebulized dose of levalbuterol 1.25 mg in 30 patients with COPD led to similar bronchodilator effects at 0.5 h and 1 h as racemic albuterol and the combination of racemic albuterol and ipratropium. The combination therapy had a longer duration of action. Side effects were absent to minimal in all groups. Compared to conventional nebulized bronchodilator therapy, there appears to be no advantage to using an occasional, single dose of nebulized levalbuterol in COPD. A study testing multiple doses of these ß-agonists administered on a regular basis would be needed to evaluate the potential negative effect of accumulation of the S-isomer.
Received for publication December 3, 2002.
Accepted for publication March 25, 2003.
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References
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- Lotvall, J, Palmqvist, M, Arvidsson, P, et al The therapeutic ratio of R-albuterol is comparable to that of RS-albuterol in asthmatic patients. J Allergy Clin Immunol 2001;108,726-731[CrossRef][Medline]
- Handley, D The asthma-like pharmacology and toxicology of (S)-isomers of ß-agonists. J Allergy Clin Immunol 1999;,S69-S76
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Abstract
Introduction
= albuterol/ipratropium; 
= levalbuterol; 
= placebo; *p < 0.05 vs placebo; **p < 0.01 vs placebo. All treatment groups resulted in significant increases in FEV1 at 0.5 h and 1 h. Only combined racemic albuterol/ipratropium led to a significant increase in FEV1 past 1 h.