The Journal of Pediatrics
Volume 155, Issue 2 , Pages 162-164, August 2009

Love it or Lev it: Levalbuterol for Severe Acute Asthma—for Now, Leave It

Department of Pediatrics, Pulmonary Medicine Asthma Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Article Outline

ER, Emergency room, MDI, Metered-dose inhaler, SABA, Short-acting β-adrenergic agonists, SVN, Small-volume nebulizer

 

See related article, p 205

Despite increased awareness of asthma by both the lay and medical communities over the previous decade and the publication of national treatment guidelines,1, 2, 3, 4 acute asthma exacerbations continue to be a major reason for visits to pediatric emergency rooms (ER) in the United States. It is estimated that approximately 700 000 children with asthma make an ER visit for treatment and 200 000 are admitted to the hospital for further treatment each year.5 In addition, the annual direct expenditures for asthma in the United States are more than $37 billion. Asthma represents a considerable economic burden and utilizes a major portion of the healthcare resources each year,6 as well as being a significant cause of morbidity. Although prevention of acute exacerbations is the most important method of treating asthma, finding an effective and safe treatment schema to avoid or minimize the cost of hospitalization is clearly necessary.

The cornerstones of acute asthma management in the ER and hospital settings have long been systemic corticosteroids with frequent, repeated administration of inhaled short-acting β-adrenergic agonists (SABA), and little has changed in the past decade. Patients who fail to respond to such standard treatment regimens in the ER are typically admitted to the hospital for further treatment. Frequent doses of SABA and daily systemic corticosteroids remain the foundation of asthma management even in the inpatient setting, with little else added except for those sick enough to require intensive care.

In recent years, a number of studies have examined the dose, method of delivery, and frequency of administration of SABA to children in the ER and hospital settings. Frequent or continuous inhalation of relatively high-dose albuterol seems more effective than infrequent administration. Administration of albuterol, usually 10 to 15 mg/h by continuous nebulization, using racemic albuterol, has resulted in increased bronchodilation compared with intermittent treatment.7, 8 However, the use of small-volume nebulizer (SVN) administration systems has been replaced by multiple puffs from a metered-dose inhaler (MDI) in many EDs, with similar results and fewer adverse events.9, 10, 11, 12, 13 Nevertheless, for those with more severe acute exacerbations, initial treatment continues to be delivery of SABA via SVN until the patient can reliably and comfortably use an MDI.

Although there remains controversy over the preferred dose and delivery method of SABA, a more recent addition to the debate has been the choice of which SABA: levalbuterol or racemic albuterol. Racemic albuterol is a 50:50 mix of R (levalbuterol) and S-albuterol; levalbuterol has 100-fold greater affinity for the β-adrenergic receptor (ADRβ2) compared with S-albuterol and is responsible for the bronchodilator effect of the drug.14 The S-isomer also has a long serum half-life; it is cleared 10 times more slowly than levalbuterol and can be detected up to 12 hours after a single dose. The S isomer was initially believed to be inert and its presence in the racemic drug of no consequence. However, the literature is now rife with conflicting data regarding potential antitherapeutic effects of S-albuterol and purported advantages of levalbuterol, both in efficacy and in safety. Almost all of the data describing deleterious effects of S-albuterol (eg, promotion of inflammatory cell and smooth muscle proliferation, increased in airway responsiveness to spasmogens) derive from in vitro or animal studies and have not been documented in clinical trials in humans. In children with stable asthma, both better improvement in lung function with levalbuterol and no difference in bronchodilatation between levalbuterol and racemic albuterol15, 16, 17 have been described. Data on the use of levalbuterol compared with racemic in treatment of acute asthma are also controversial. A large, double-blinded, randomized trial reported a significantly lower rate of hospitalization in asthmatic children receiving levalbuterol in ER18; this result has not been replicated in subsequent studies.19, 20, 21 However, the subsequent studies enrolled fewer patients, were not powered to detect changes in hospitalization rates, used substantially higher doses of racemic albuterol compared with levalbuterol, added ipratropium to the only 1 comparator group, or enrolled patients with relatively mild exacerbations. Nevertheless, no studies conducted in the ER using intermittent dosing of levalbuterol compared with racemic albuterol have demonstrated any difference in improvement in lung function or in occurrence of adverse effects. What has not been examined as carefully is the use of continuously nebulized levalbuterol compared with racemic albuterol in patients hospitalized for acute asthma exacerbation.

The study by Andrews et al22 compared continuous nebulization of (molecularly) equipotent and relatively high doses of racemic albuterol (20 mg) with levalbuterol (10 mg) continuously administered to children admitted for treatment of severe acute asthma. All patients had failed to improve sufficiently for discharge after emergency department treatment with inhaled racemic albuterol, ipratropium, and systemic corticosteroids. Approximately 40% of admitted patients at the authors' institution are treated with continuously nebulized albuterol after hospital admission. Assessment and weaning of therapy was performed using a standardized and validated scoring system.23 No difference between the groups in time requiring continuous nebulization, time to reach discharge criteria, or β-adrenergic–mediated adverse effects (heart rate, hyperglycemia, hypokalemia) was demonstrated. Pulmonary function measurement was attempted, but less than 50% of the participants could perform acceptable tests. The levalbuterol group demonstrated better improvement in FEV1 at 4 hours after enrollment, but there was no difference in pulmonary function at other time points. The lack of any effect persisted even after adjusting for S-albuterol serum levels. The authors conclude that racemic albuterol and levalbuterol were equally effective and safe for continuous use.

The present study is the first to provide data on continuous use of levalbuterol in the hospital setting, adding important information about whether or not levalbuterol has any clinical advantage over the much less expensive racemic mixture. There are, however, some concerns regarding the study design that might have influenced the outcome. First, the number of protocol deviations was substantial and may have influenced outcome in this relatively small study cohort. In addition, 11% of the patients required reinstitution of continuous treatment after initially weaning to intermittent treatment. Twice as many patients in the racemic group required resumption of continuous treatment as did those in the levalbuterol group. Although the numbers are small, a trend may be present. A different study design would have obviated the potential antitherapeutic effect of S-albuterol. Treating all participants with lev albuterol on presentation to the ER and then randomly assigning the admitted patients who required continuous nebulizer treatments to either levalbuterol or racemic albuterol would have provided a better, albeit more costly design.

The greatest impediment to using levalbuterol for continuous nebulization regimens for acute asthma, without clear and highly clinically significant benefit, is its cost. The nebulized form of levalbuterol remains about 5 times as expensive as equivalent doses of the racemic mixture. Given that there appears to be no clinical or safety advantage to the use of levalbuterol in the hospital setting, the high price of the drug would argue against its use in this population.

The results reported in this study are perhaps disappointing in that they bring us no closer to a more effective drug for treatment of severe acute asthma; however, the outcome is not surprising. No amount of albuterol should be expected to result in rapid, complete resolution of acute severe asthma that fails to respond significantly to frequent doses of the very same drug in the ER. The airways of such patients are likely to be narrowed not only because of widespread bronchoconstriction caused by smooth muscle but also by mucosal edema, mucus hypersecretion, and inflammatory cell infiltrate into the airways, none of which will respond to administration of bronchodilators. Although albuterol may enhance ciliary beat frequency and block mast cell release of histamine, these effects on airway narrowing are trivial. We would expect no different action from levalbuterol . Moreover, at equivalent doses to racemic albuterol, levalbuterol produces the same degree of β-adrenergic–mediated adverse effects, and a clear antitherapeutic effect of S-albuterol has not been documented in this or other clinical trials. It is possible that there is a subset of acutely ill asthmatic patients for whom levalbuterol would be the preferred treatment, but to date there is no convincing means to identify such patients. Future studies might address this issue.

A more compelling issue is whether there are some asthmatic patients for whom any form of albuterol may not be useful.24 Recent trials have suggested that children with certain polymorphisms or haplotypes in the ADRβ2 receptor (eg, Arg16/Arg, Gln27/Glu) are slower to respond to treatment with frequent or continuous albuterol than those with other genotypes.25, 26 Future studies should focus on better characterization of patients, for instance by identifying at-risk genotypes, and then personalizing treatment regimens that will produce the greatest benefit and do no harm.

Back to Article Outline

References 

  1. National Asthma Education Program. Expert Panel Report: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute; 1991;
  2. National Asthma Education and Prevention Program. Expert Panel Report 2: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute; 1997;
  3. National Asthma Education and Prevention Program. Expert Panel Report 2: guidelines for the diagnosis and management of asthma: update on selected topics 2002. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute; 2002;
  4. National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute; 2007;
  5. Moorman JE, Rudd RA, Johnson CA, King M, Minor P, Bailey C, et al. National surveillance for asthma: United States, 1980-2004. MMWR Surveill Summ. 2007;56:1–54
  6. Kamble S, Bharmal M. Incremental direct expenditure of treating asthma in the United States. J Asthma. 2009;46:73–80
  7. Papo MC, Frank J, Thompson AE. A prospective, randomized study of continuous albuterol versus intermittent nebulized albuterol for severe status asthmaticus in children. Crit Care Med. 1993;21:1479–1486
  8. Camargo CA, Spooner CH, Rowe BH. Continuous versus intermittent beta-agonists in the treatment of acute asthma. Cochrane Database Syst Rev. 2003;(4):CD001115
  9. Dhuper S, Chandra A, Ahmed A, Bisat S, Meghekar A, Verma R, et al. Efficacy and cost comparisons of bronchodilator administration between metered dose inhalers with disposable spacers and nebulizers for acute asthma in an inner-city adult population. J Emerg Med. 2008;doi:10.1016/j.jemermed.2008.06.029
  10. Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2006;(2):CD000052
  11. Benito-Fernandez J, Gonzalez-Balenciaga M, Capape-Zache S, Vazquez-Ronco MA, Mintegi-Raso S, et al. Salbutamol via metered dose inhaler with spacer versus nebulization for acute treatment of pediatric asthma in the emergency department. Pediatr Emerg Care. 2004;20:656–659
  12. Ploin D, Chapius FR, Stamm D, Robert J, David L, Chatelain PG, et al. High dose albuterol by metered dose inhaler plus a spacer device versus nebulization in preschool children with recurrent wheezing: a double blind, randomized equivalence trial. Pediatrics. 2000;106(2 Pt 1):311–317Erratum in: Pediatrics 2000;106:623
  13. Rodrigo C, Rodrigo G. Salbutamol treatment of acute severe asthma in the ED: MDI versus hand-held nebulizer. Am J Emerg Med. 1998;16:637–642
  14. Slattery D, Wong SW, Colin AA. Lev albuterol hydrochloride. Pediatr Pulmonol. 2002;33:151–157
  15. Gawchik SM, Saccar CL, Noonan M, Reasner DS, DeGraw SS. The safety and efficacy of nebulized lev albuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allergy Clin Immunol. 1999;103:615–621
  16. Milgrom H, Skoner DP, Bensch G, Kim KT, Claus R, Baumgartner RA Lev albuterol Pediatric Study Group. Low-dose lev albuterol in children with asthma: safety and efficacy in comparison with racemic albuterol. J Allergy Clin Immunol. 2001;108:938–945
  17. Skoner DP, Greos LS, Kim KT, Roach JM, Parsey M, Baumgartner RA. Evaluation of the safety and efficacy of lev albuterol in 2-5 year-old patients with asthma. Pedatr Pulmonol. 2005;40:477–486
  18. Carl JC, Myers T, Kirchner HL, Kercsmar CM. Comparison of racemic albuterol and lev albuterol for treatment of acute asthma. J Pediatr. 2003;143:731–736
  19. Hardasmalani MD, DeBari V, Bithoney WG, Gold N. Lev albuterol versus racemic albuterol in the treatment of acute exacerbation of asthma in children. Pediatr Emerg Care. 2005;21:415–419
  20. Qureshi F, Zaritsky A, Welch C, Meadows T, Burke BL. Clinical efficacy of racemic albuterol versus lev albuterol for the treatment of acute pediatric asthma. Ann Emerg Med. 2005;46:29–36
  21. Ralston ME, Euwema MS, Knecht KR, Ziolowski TJ, Coakley TA, Cline SM. Comparison of lev albuterol and racemic albuterol combined with ipratropium bromide in acute pediatric asthma: a randomized controlled trial. J Emerg Med. 2005;29:29–35
  22. Andrews TA, McGintee E, Mittal MK, Tyler L, Chew A, Zhang X, et al. High-dose continuous nebulized lev albuterol versus racemic albuterol for pediatric status asthmaticus: a randomized trial. J Pediatr. 2009;155:205–210
  23. Gorelick MH, Stevens MW, Schultz T, Scribano PV. Performance of a novel clinical score, the Pediatric Asthma Assessment Score (PASS), in the evaluation of acute asthma. Acad Emerg Med. 2004;11:10–18
  24. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet. 2004;364:1505–1512
  25. Elbahlawan L, Binaei S, Christensen ML, Zhang Q, Quasney MW, Dahmer MK. Beta2-adrenergic receptor polymorphisms in African American children with status asthmaticus. Pediatr Crit Care Med. 2006;7:15–18
  26. Carroll CL, Stoltz P, Schramm CM, Zucker AR. β2-Adrenergic receptor polymorphisms affect response to treatment in children with severe asthma exacerbations. Chest. 2008 Nov 24;doi:10.1378/chest.08-2041

PII: S0022-3476(09)00349-7

doi:10.1016/j.jpeds.2009.03.062

Refers to article:

  • High-Dose Continuous Nebulized Levalbuterol for Pediatric Status Asthmaticus: A Randomized Trial , 22 May 2009

    Timothy Andrews, Erin McGintee, Manoj K. Mittal, Lisa Tyler, Amber Chew, Xuemei Zhang, Nicholas Pawlowski, Joseph J. Zorc
    The Journal of Pediatrics August 2009 (Vol. 155, Issue 2, Pages 205-210.e1)

The Journal of Pediatrics
Volume 155, Issue 2 , Pages 162-164, August 2009

Article Tools