- Email: [email protected]
Mirror images: is levalbuterol the fairest of them all?
Miles Weinberger, MD Professor of Pediatrics Director, Pediatric Allergy and Pulmonary Division University of Iowa College of Medicine Iowa City, IA 52242
REFERENCES 1. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA 1999;282:1440-6. 2. Centers for Disease Control Prevention. Bronchiolitis-associated outpatient visits and hospitalizations among American Indian and Alaska native children—United States, 1990-2000. MMWR 2003;52:707-10. 3. Van Woensel JB, van Aalderen WM. Treatment for bronchiolitis: the story continues. Lancet 2002;360:101-2. 4. Nelson R. Bronchiolitis drugs lack convincing evidence of efficacy. Lancet 2003;361:939. 5. Dabbous IA, Tkachyk JS, Stamm SJ. A double-blind study on the effects of corticosteroid in the treatment of bronchiolitis. Pediatrics 1966;37:477-84. 6. Springer C, Bar-Yishay E, Uwayyed K, Avital A, Vilozni D, Godfrey S. Corticosteroids do not affect the clinical or physiological status of infants with bronchiolitis. Pediatr Pulmonol 1990;9:181-5. 7. Roosevelt G, Sheehan K, Frupp-Phelan J, Tanz RR, Listernick R. Dexamethasone in bronchiolitis: a randomized controlled trial. Lancet 1996;348:292-5. 8. Klassen TP, Sutcliffe T, Watters LK, Wells GA, Allen UD, Li MM. Dexamethasone in salbutamol-treated inpatients with acute bronchiolitis: a randomized, controlled trial. J Pediatr 1997;130:191-6. 9. De Boeck K, Van der Aa N, Van Lierde S, Corbeel L, Eeckesl R. Respiratory syncytial virus bronchiolitis: a double-blind dexamethasone efficacy study. J Pediatr 1997;131:919-21. 10. Csonka P, Kaila M, Laippala P, Iso-Justaja¨rvi M, Veskikari T, Ashorn P. Oral prednisolone in the acute management of children age 6-35 months with viral respiratory infection-induced lower airway disease: a randomized, placebo-controlled trial. J Pediatr 2003;143:725-30. 11. Schuh S, Coates AL, Binnie R, Allin T, Goia C, Corey M, et al. Efficacy of oral dexamethasone in outpatients with acute bronchiolitis. J Pediatr 2002;140:27-32.
12. Garrison MM, Christakis DA, Harvey E, Cummings P, Davis RL. Systemic corticosteroids in infant bronchiolitis: a meta-analysis. Pediatrics 2000;105:e44. Available at:http://www.pediatrics.org/cgi/content/full/105/4/ e44. 13. Van Woensel JBM, Wolfs TFW, van Aalderen WMC, Brand PLP, Kimpen JLL. Randomized double-blind placebo-controlled trial of prednisolone in children admitted to hospital with respiratory syncytial virus bronchiolitis. Thorax 1997;52:634-7. 14. Goebel J, Estrada B, Quinonez J, Nagji N, Sanford D, Boerth RC. Prednisolone plus albuterol versus albuterol alone in mild to moderate bronchiolitis. Clin Pediatr 2000;39:213-20. 15. Schuh S, Canny G, Reisman JJ, Kerem E, Bentur L, Petric M, et al. Nebulized albuterol in acute bronchiolitis. J Pediatr 1990;117:633-7. 16. Schuh S, Johnson D, Canny G, Reisman J, Shields M, Kovesi T, et al. Efficacy of adding nebulized ipratropium bromide to nebulized albuterol therapy in acute bronchiolitis. Pediatrics 1992;90:920-3. 17. Kellner JD, Ohlsson A, Gadomski AM, Wang EEL. Efficacy of bronchodilator therapy in bronchiolitis: a meta-analysis. Arch Pediatr Adolesc Med 1996;150:1166-72. 18. Bertrand P, Aranibar H, Castro E, Sanchez I. Efficacy of nebulized epinephrine versus salbutamol in hospitalized infants with bronchiolitis. Pediatr Pulmonol 2001;31:284-8. 19. Patel H, Platt RW, Pekeles GS, Ducharme FM. A randomized controlled trial of the effectiveness of nebulized therapy with epinephrine compared with albuterol and saline in infants hospitalized for acute viral bronchiolitis. J Pediatr 2002;141:818-24. 20. Wainwright C, Altamirano L, Cheny M, Cheney J, Barber S, Price D, et al. A multicenter, randomized, double-blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis. N Engl J Med 2003;349:27-35. 21. Weinberger M. Clinical patterns and natural history of asthma. J Pediatr 2003;142:S15-S20. 22. Lemanske RF. Viruses and asthma: inception, exacerbation, and possible prevention. J Pediatr 2003;142:S3-S8. 23. Weinberger M. Treatment strategies for viral respiratory infectioninduced asthma. J Pediatr 2003;142:S34-S39. 24. Wohl MEB, Chernick V. State of the art: bronchiolitis. Am Rev Respir Dis 1978;118:759-81.
MIRROR IMAGES: IS LEVALBUTEROL THE FAIREST OF THEM ALL? ympathomimetics have been a mainstay of asthma therapy since the ancient Chinese discovered the benefits of the herbal remedy Ma Huang. At the turn of the 20th century, epinephrine became the b-agonist of choice for the treatment of acute asthma. Epinephrine affected both b1- and b2-receptors. Most of the undesirable side effects, such as tachycardia and muscle tremor, resulted from stimulation of the b1-receptor, which prompted the pharmaceutical industry to develop selective b2-agonists. These reduced, but did not eliminate, side effects particularly in higher doses. Albuterol, the most widely used inhaled b2-agonist, exists in two isomeric forms—the R- and S- enantiomers. Until recently, albuterol preparations have been racemic mixtures (equal combinations of the R- and S- enantiomers). Regulatory drug agencies now require information on in-
S
ED
702
Emergency department
Editorials
dividual isomers of new racemic drugs, which spurred an interest in the development of single isomeric forms. Levalbuterol (the R- enantiomer of albuterol) has been introduced and marketed for the treatment of asthma. Clinical studies in stable asthmatics and normal volunteers demonstrated that the bronchodilator effect of albuterol rests solely with the R- enanSee related article, p 731. tiomer.1,2 These studies have shown that R- albuterol and RS- albuterol (racemic) were Reprint requests: Meyer Kattan, MD, comparable on a 2:1 potency CM, Mount Sinai School of Medicine, Pediatric Pulmonary and Critical Care ratio and that the effects of S- Division, Box 1202-B, One Gustave L. albuterol were the same as Levy Place, New York, NY 10029. placebo. Animal and in vitro E-mail: [email protected]. J Pediatr 2003;143:702-4. studies raised concern that the Copyright ª 2003 Mosby, Inc. All rights S- albuterol was detrimental. reserved. These reports indicated 0022-3476/2003/$30.00 + 0 that S- albuterol had pro- 10.1016/j.jpeds.2003.10.018 The Journal of Pediatrics December 2003
inflammatory effects, increased smooth muscle responsiveness to cell mediators, and antagonized the effects of Ralbuterol.3,4 Several clinical studies supported these observations by demonstrating that a lower dose of R- albuterol produced the same degree of efficacy when administered alone than as a racemic mixture.5,6 There were similar systemic effects with R- and RS- albuterol, indicating a better therapeutic ratio. Clinical data are conflicting, but the weight of evidence does not indicate that S- albuterol increases bronchial responsiveness.7,8 Critical evaluations of studies regarding therapeutic differences have been published and will not be discussed here.9,10 Studies carried out in the clinical setting in which albuterol is recommended for use, namely, acute exacerbations of asthma, are lacking. National guidelines do not recommend chronic use of b-agonists but in some reports the R- and Senantiomers were administered daily for more than three weeks.6,11 The importance of comparing drugs in the actual clinical setting is illustrated in emergency department studies with the nonselective b-agonist, epinephrine. Heart rate increases when epinephrine is used in stable asthma, but typically falls when it is administered for acute asthma exacerbations.12 The undesired sympathomimetic effect on the heart is outweighed by the decreased heart rate resulting from a reduction in the work of breathing. The large randomized controlled clinical trial by Carl et al in this issue of The Journal is an important study comparing Rand RS- albuterol in the emergency management of asthma.13 The primary outcome was the hospital admission rate. The hospitalization rate was significantly lower in the group receiving R- albuterol compared with the group receiving RS- albuterol (36% vs 45%). No advantage of R- albuterol was apparent once the child was admitted to the hospital. The decision to admit was left to the discretion of the emergency department (ED) attending physicians who were not directly involved with the study. Admission of asthma patients to the hospital is based on social and environmental criteria, availability of beds and past asthma history, not solely on the current medical issues. These factors are particularly important in urban centers where poverty and inadequate access to follow-up care may adversely affect outcome.14 Therefore it is important to examine the objective secondary outcomes in this study. These outcomes were some of the usual medical criteria on which decisions to admit patients to the hospital are based, in the absence of objective measures of lung function. In fact, the asthma care algorithm used in the study, and which determined the need for admission, relied on these same criteria. The mean length of ED stay, the number of aerosols administered, the respiratory rate at time of discharge from the ED, oxygen saturation, and need for intensification of therapy were similar in the two groups. No data on pulmonary function were provided. There is no obvious explanation for the difference in admission rate based on the objective secondary outcomes. This raises the possibility that factors unrelated to drug efficacy were important factors in determining the need for admission. Editorials
Other ED studies assessing drug efficacy have been published with hospital admission as the primary outcome without strictly defining the need for admission. Because hospital admission is difficult to control for confounding factors, we need to improve this outcome measure to more accurately reflect the information we wish to capture. This could be achieved by using a predetermined endpoint for assessment of the need for admission, such as two or four hours, regardless of whether the patient is admitted. Admission could then be defined as not meeting a minimum number of objective outcome criteria. The majority of relapses after discharge from the ED occurs in the first 48 hours and should be included as an outcome measure in evaluating ED drug regimens.15 Larger and more frequent doses of albuterol are used in the ED compared with doses given in studies of stable asthmatics, making it more likely that differences between the two enantiomers would be apparent. However, Carl et al found no differences in heart rate, respiratory rate, or the occurrence of tremor, which is consistent with the results of the majority of clinical studies. In the absence of pulmonary function measurements, the results of the objective outcomes in the ED and during the hospitalizations do not support the hypotheses that RS- albuterol either antagonizes the bronchodilator effect or increases airway responsiveness. Any benefits of R- albuterol need to be weighed against the substantially higher cost of the drug.16 The average wholesale price of the unit dose of R- albuterol is twice that of the unit dose of RS- albuterol and five times the price of the dose from the multiple dose bottle of RS- albuterol with saline. This study compared only unit dose costs, which underestimates the potential difference in price of the two enantiomers. Nevertheless, the observed decrease in admission rate reduced costs sufficiently to pay for the substantially higher cost of R- albuterol. Given these results, should R-albuterol be substituted for RS- albuterol in the treatment of acute asthma in children? This study was conducted in an urban ED with an unusually high admission rate. In the home or office setting, and for some patients in the ED, albuterol by metered-dose inhaler and spacer device with a mask or mouthpiece is effective, less time-consuming to administer, and should remain the treatment of choice.17-19 In patients unable to use the metered-dose inhaler, RS- albuterol should remain the first choice until there is additional confirmation of a benefit of Ralbuterol. In all settings, it is important to keep in mind that individual patient responses may vary. In the minority of patients in whom there are obvious adverse effects with RSalbuterol, R- albuterol may be better tolerated. R- albuterol may also benefit children with an acute exacerbation requiring higher and more frequent doses than are usually administered in the ED. Alternatives to larger inhaled doses should be considered for this group of patients who do not seem responsive to the initial inhaled treatments. There is accumulating evidence in acute severe asthma that earlier use of intravenous b-agonists in the ED results in more rapid recovery and earlier discharge than inhaled therapy.20 It remains to be seen whether in those patients, a b2-agonist 703
administered intravenously provides greater therapeutic benefit than higher or continuous doses of inhaled albuterol. Because the study by Carl et al leaves unanswered questions regarding benefits that are directly attributable to the drug, confirmation of the findings is needed. It is noteworthy that this study is completed at a time when congressional lawmakers in the United States debate authorization of funds for research for the comparison of drugs to treat the same condition.21 This study demonstrates that neither aggressive marketing nor administrative decisions based solely on drug costs can serve as a substitute for welldesigned clinical trials. Meyer Kattan, MD, CM Pediatric Pulmonary and Critical Care Division Mount Sinai School of Medicine New York, NY 10029
REFERENCES 1. Lipworth BJ, Clark DJ, Koch P, Arbeeny C. Pharmacokinetics and extrapulmonary b2 adrenoceptor activity of nebulised racemic salbutamol and its R and S isomers in healthy volunteers. Thorax 1997;52:849-52. 2. Lotvall J, Palmqvist M, Arvidsson P, Maloney A, Ventresca GP, Ward J. The therapeutic ratio of R- albuterol is comparable with that of RS- albuterol in asthmatic patients. J Allergy Clin Immunol 2001;108: 726-31. 3. Baramki D, Koester J, Anderson AJ, Borish L. Modulation of T-cell function by (R)- and (S)-isomers of albuterol: anti-inflammatory influences of (R)-isomers are negated in the presence of the (S)-isomer. J Allergy Clin Immunol 2002;109:449-54. 4. Mazzoni L, Naef R, Chapman ID, Morley J. Hyperresponsiveness of the airways following exposure of guinea-pigs to racemic mixtures and distomers of b2-selective sympathomimetics. Pulmonol Pharmacol 1994;7:367-76. 5. Gawchik SM, Saccar CL, Noonan M, Reasner DS, DeGraw SS. The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allergy Clin Immunol 1999;103:615-21. 6. 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;108:938-45. 7. Cockcroft DW, Davis BE, Swystun VA, Marciniuk DD. Tolerance to the bronchoprotective effect of b2-agonists: comparison of the enantiomers of salbutamol with racemic salbutamol and placebo. J Allergy Clin Immunol 1999;103:1049-53. 8. 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;52:845-8. 9. Ind PW. Salbutamol enantiomers: early clinical evidence in humans. Thorax 1997;52:839-40. 10. Ahrens R, Weinberger M. Levalbuterol and racemic albuterol: are there therapeutic differences? J Allergy Clin Immunol 2001;108:681-4. 11. National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis and management of asthma. Bethesda (MD): National Heart, Lung, and Blood Institute; 1997. Report No.: NIH publication no. 97-4051. 12. Ben-Zvi Z, Lam C, Spohn WA, Gribetz I, Mulvihill MN, Kattan M. An evaluation of repeated injections of epinephrine for the initial treatment of acute asthma. Am Rev Respir Dis 1983;127:101-5. 13. Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison of racemic albuterol and levalbutreol for treatment of acute asthma. J Pediatr 2003;143:731-6. 14. Kattan M, Mitchell H, Eggleston P, Gergen P, Crain E, Redline S, et al. Characteristics of inner-city children with asthma: the National Cooperative Inner-City Asthma Study. Pediatr Pulmonol 1997;24:253-62. 15. Fischl MA, Pitchenik A, Gardner LB. An index predicting relapse and need for hospitalization in patients with acute bronchial asthma. N Engl J Med 1981;305:783-9. 16. Asmus MJ, Hendeles L. Levalbuterol nebulizer solution: is it worth five times the cost of albuterol? Pharmacotherapy 2000;20:123-9. 17. Newhouse MT. Asthma therapy with aerosols: are nebulizers obsolete? A continuing controversy. J Pediatr 1999;135:5-8. 18. Schuh S, Johnson DW, Stephens D, Callahan S, Winders P, Canny GJ. Comparison of albuterol delivered by a metered dose inhaler with spacer versus a nebulizer in children with mild acute asthma. J Pediatr 1999;135:22-7. 19. Chou KJ, Cunningham SJ, Crain EF. Metered-dose inhalers with spacers vs nebulizers for pediatric asthma. Arch Pediatr Adolesc Med 1995;149:201-5. 20. Browne GJ, Wilkins BH. Use of intravenous salbutamol in acute severe asthma. Anaesthesia 2003;58:729-32. 21. Pear R. Congress weighs drug comparisons. New York Times, August 24, 2003.
THE JOURNEY TO METABOLIC CONTROL IN DIABETES: MANY MORE MILES TO GO he findings of the Diabetes Control and Complications Trial (DCCT) in patients older than 13 years with type 1 diabetes, together with the availability of improved methods of monitoring glycemia (self blood glucose monitoring and glycated hemoglobin [HbA1c] measurement), resulted in greatly increased efforts to improve glycemic control to reduce the risk of long-term complications.1 The insulins available at the time of the DCCT included neutral protamine Hagedorn (NPH), Regular, Lente, and Ultralente. None of these insulins replicates the normal endogenous basal insulin
T DCCT HbA1c NPH
704
Diabetes Control and Complications Trial Glycated hemoglobin Neutral protamine Hagedorn
Editorials
secretion that is needed to control hepatic glucose production and catabolism during fasting, nor the rapid onset and shortaction peak insulin secretion to cover food intake. Thus, improved metabolic control seen in the intensively treated group in the DCCT was associated with more hypoglycemia than in the conventionally treated patients. This was particularly true in the adolescent cohort. As health care teams gained more
See related article, p 737. Reprint requests: Janet H. Silverstein, MD, Division of Endocrinology, Department of Pediatrics, University of Florida, Box 100296, Gainesville, FL 326100296. E-mail: [email protected]. edu J Pediatr 2003;143:704-6. Copyright ª 2003 Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0 10.1067/S0022-3476(03)00616-4
The Journal of Pediatrics December 2003
REFERENCES 1. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA 1999;282:1440-6. 2. Centers for Disease Control Prevention. Bronchiolitis-associated outpatient visits and hospitalizations among American Indian and Alaska native children—United States, 1990-2000. MMWR 2003;52:707-10. 3. Van Woensel JB, van Aalderen WM. Treatment for bronchiolitis: the story continues. Lancet 2002;360:101-2. 4. Nelson R. Bronchiolitis drugs lack convincing evidence of efficacy. Lancet 2003;361:939. 5. Dabbous IA, Tkachyk JS, Stamm SJ. A double-blind study on the effects of corticosteroid in the treatment of bronchiolitis. Pediatrics 1966;37:477-84. 6. Springer C, Bar-Yishay E, Uwayyed K, Avital A, Vilozni D, Godfrey S. Corticosteroids do not affect the clinical or physiological status of infants with bronchiolitis. Pediatr Pulmonol 1990;9:181-5. 7. Roosevelt G, Sheehan K, Frupp-Phelan J, Tanz RR, Listernick R. Dexamethasone in bronchiolitis: a randomized controlled trial. Lancet 1996;348:292-5. 8. Klassen TP, Sutcliffe T, Watters LK, Wells GA, Allen UD, Li MM. Dexamethasone in salbutamol-treated inpatients with acute bronchiolitis: a randomized, controlled trial. J Pediatr 1997;130:191-6. 9. De Boeck K, Van der Aa N, Van Lierde S, Corbeel L, Eeckesl R. Respiratory syncytial virus bronchiolitis: a double-blind dexamethasone efficacy study. J Pediatr 1997;131:919-21. 10. Csonka P, Kaila M, Laippala P, Iso-Justaja¨rvi M, Veskikari T, Ashorn P. Oral prednisolone in the acute management of children age 6-35 months with viral respiratory infection-induced lower airway disease: a randomized, placebo-controlled trial. J Pediatr 2003;143:725-30. 11. Schuh S, Coates AL, Binnie R, Allin T, Goia C, Corey M, et al. Efficacy of oral dexamethasone in outpatients with acute bronchiolitis. J Pediatr 2002;140:27-32.
12. Garrison MM, Christakis DA, Harvey E, Cummings P, Davis RL. Systemic corticosteroids in infant bronchiolitis: a meta-analysis. Pediatrics 2000;105:e44. Available at:http://www.pediatrics.org/cgi/content/full/105/4/ e44. 13. Van Woensel JBM, Wolfs TFW, van Aalderen WMC, Brand PLP, Kimpen JLL. Randomized double-blind placebo-controlled trial of prednisolone in children admitted to hospital with respiratory syncytial virus bronchiolitis. Thorax 1997;52:634-7. 14. Goebel J, Estrada B, Quinonez J, Nagji N, Sanford D, Boerth RC. Prednisolone plus albuterol versus albuterol alone in mild to moderate bronchiolitis. Clin Pediatr 2000;39:213-20. 15. Schuh S, Canny G, Reisman JJ, Kerem E, Bentur L, Petric M, et al. Nebulized albuterol in acute bronchiolitis. J Pediatr 1990;117:633-7. 16. Schuh S, Johnson D, Canny G, Reisman J, Shields M, Kovesi T, et al. Efficacy of adding nebulized ipratropium bromide to nebulized albuterol therapy in acute bronchiolitis. Pediatrics 1992;90:920-3. 17. Kellner JD, Ohlsson A, Gadomski AM, Wang EEL. Efficacy of bronchodilator therapy in bronchiolitis: a meta-analysis. Arch Pediatr Adolesc Med 1996;150:1166-72. 18. Bertrand P, Aranibar H, Castro E, Sanchez I. Efficacy of nebulized epinephrine versus salbutamol in hospitalized infants with bronchiolitis. Pediatr Pulmonol 2001;31:284-8. 19. Patel H, Platt RW, Pekeles GS, Ducharme FM. A randomized controlled trial of the effectiveness of nebulized therapy with epinephrine compared with albuterol and saline in infants hospitalized for acute viral bronchiolitis. J Pediatr 2002;141:818-24. 20. Wainwright C, Altamirano L, Cheny M, Cheney J, Barber S, Price D, et al. A multicenter, randomized, double-blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis. N Engl J Med 2003;349:27-35. 21. Weinberger M. Clinical patterns and natural history of asthma. J Pediatr 2003;142:S15-S20. 22. Lemanske RF. Viruses and asthma: inception, exacerbation, and possible prevention. J Pediatr 2003;142:S3-S8. 23. Weinberger M. Treatment strategies for viral respiratory infectioninduced asthma. J Pediatr 2003;142:S34-S39. 24. Wohl MEB, Chernick V. State of the art: bronchiolitis. Am Rev Respir Dis 1978;118:759-81.
MIRROR IMAGES: IS LEVALBUTEROL THE FAIREST OF THEM ALL? ympathomimetics have been a mainstay of asthma therapy since the ancient Chinese discovered the benefits of the herbal remedy Ma Huang. At the turn of the 20th century, epinephrine became the b-agonist of choice for the treatment of acute asthma. Epinephrine affected both b1- and b2-receptors. Most of the undesirable side effects, such as tachycardia and muscle tremor, resulted from stimulation of the b1-receptor, which prompted the pharmaceutical industry to develop selective b2-agonists. These reduced, but did not eliminate, side effects particularly in higher doses. Albuterol, the most widely used inhaled b2-agonist, exists in two isomeric forms—the R- and S- enantiomers. Until recently, albuterol preparations have been racemic mixtures (equal combinations of the R- and S- enantiomers). Regulatory drug agencies now require information on in-
S
ED
702
Emergency department
Editorials
dividual isomers of new racemic drugs, which spurred an interest in the development of single isomeric forms. Levalbuterol (the R- enantiomer of albuterol) has been introduced and marketed for the treatment of asthma. Clinical studies in stable asthmatics and normal volunteers demonstrated that the bronchodilator effect of albuterol rests solely with the R- enanSee related article, p 731. tiomer.1,2 These studies have shown that R- albuterol and RS- albuterol (racemic) were Reprint requests: Meyer Kattan, MD, comparable on a 2:1 potency CM, Mount Sinai School of Medicine, Pediatric Pulmonary and Critical Care ratio and that the effects of S- Division, Box 1202-B, One Gustave L. albuterol were the same as Levy Place, New York, NY 10029. placebo. Animal and in vitro E-mail: [email protected]. J Pediatr 2003;143:702-4. studies raised concern that the Copyright ª 2003 Mosby, Inc. All rights S- albuterol was detrimental. reserved. These reports indicated 0022-3476/2003/$30.00 + 0 that S- albuterol had pro- 10.1016/j.jpeds.2003.10.018 The Journal of Pediatrics December 2003
inflammatory effects, increased smooth muscle responsiveness to cell mediators, and antagonized the effects of Ralbuterol.3,4 Several clinical studies supported these observations by demonstrating that a lower dose of R- albuterol produced the same degree of efficacy when administered alone than as a racemic mixture.5,6 There were similar systemic effects with R- and RS- albuterol, indicating a better therapeutic ratio. Clinical data are conflicting, but the weight of evidence does not indicate that S- albuterol increases bronchial responsiveness.7,8 Critical evaluations of studies regarding therapeutic differences have been published and will not be discussed here.9,10 Studies carried out in the clinical setting in which albuterol is recommended for use, namely, acute exacerbations of asthma, are lacking. National guidelines do not recommend chronic use of b-agonists but in some reports the R- and Senantiomers were administered daily for more than three weeks.6,11 The importance of comparing drugs in the actual clinical setting is illustrated in emergency department studies with the nonselective b-agonist, epinephrine. Heart rate increases when epinephrine is used in stable asthma, but typically falls when it is administered for acute asthma exacerbations.12 The undesired sympathomimetic effect on the heart is outweighed by the decreased heart rate resulting from a reduction in the work of breathing. The large randomized controlled clinical trial by Carl et al in this issue of The Journal is an important study comparing Rand RS- albuterol in the emergency management of asthma.13 The primary outcome was the hospital admission rate. The hospitalization rate was significantly lower in the group receiving R- albuterol compared with the group receiving RS- albuterol (36% vs 45%). No advantage of R- albuterol was apparent once the child was admitted to the hospital. The decision to admit was left to the discretion of the emergency department (ED) attending physicians who were not directly involved with the study. Admission of asthma patients to the hospital is based on social and environmental criteria, availability of beds and past asthma history, not solely on the current medical issues. These factors are particularly important in urban centers where poverty and inadequate access to follow-up care may adversely affect outcome.14 Therefore it is important to examine the objective secondary outcomes in this study. These outcomes were some of the usual medical criteria on which decisions to admit patients to the hospital are based, in the absence of objective measures of lung function. In fact, the asthma care algorithm used in the study, and which determined the need for admission, relied on these same criteria. The mean length of ED stay, the number of aerosols administered, the respiratory rate at time of discharge from the ED, oxygen saturation, and need for intensification of therapy were similar in the two groups. No data on pulmonary function were provided. There is no obvious explanation for the difference in admission rate based on the objective secondary outcomes. This raises the possibility that factors unrelated to drug efficacy were important factors in determining the need for admission. Editorials
Other ED studies assessing drug efficacy have been published with hospital admission as the primary outcome without strictly defining the need for admission. Because hospital admission is difficult to control for confounding factors, we need to improve this outcome measure to more accurately reflect the information we wish to capture. This could be achieved by using a predetermined endpoint for assessment of the need for admission, such as two or four hours, regardless of whether the patient is admitted. Admission could then be defined as not meeting a minimum number of objective outcome criteria. The majority of relapses after discharge from the ED occurs in the first 48 hours and should be included as an outcome measure in evaluating ED drug regimens.15 Larger and more frequent doses of albuterol are used in the ED compared with doses given in studies of stable asthmatics, making it more likely that differences between the two enantiomers would be apparent. However, Carl et al found no differences in heart rate, respiratory rate, or the occurrence of tremor, which is consistent with the results of the majority of clinical studies. In the absence of pulmonary function measurements, the results of the objective outcomes in the ED and during the hospitalizations do not support the hypotheses that RS- albuterol either antagonizes the bronchodilator effect or increases airway responsiveness. Any benefits of R- albuterol need to be weighed against the substantially higher cost of the drug.16 The average wholesale price of the unit dose of R- albuterol is twice that of the unit dose of RS- albuterol and five times the price of the dose from the multiple dose bottle of RS- albuterol with saline. This study compared only unit dose costs, which underestimates the potential difference in price of the two enantiomers. Nevertheless, the observed decrease in admission rate reduced costs sufficiently to pay for the substantially higher cost of R- albuterol. Given these results, should R-albuterol be substituted for RS- albuterol in the treatment of acute asthma in children? This study was conducted in an urban ED with an unusually high admission rate. In the home or office setting, and for some patients in the ED, albuterol by metered-dose inhaler and spacer device with a mask or mouthpiece is effective, less time-consuming to administer, and should remain the treatment of choice.17-19 In patients unable to use the metered-dose inhaler, RS- albuterol should remain the first choice until there is additional confirmation of a benefit of Ralbuterol. In all settings, it is important to keep in mind that individual patient responses may vary. In the minority of patients in whom there are obvious adverse effects with RSalbuterol, R- albuterol may be better tolerated. R- albuterol may also benefit children with an acute exacerbation requiring higher and more frequent doses than are usually administered in the ED. Alternatives to larger inhaled doses should be considered for this group of patients who do not seem responsive to the initial inhaled treatments. There is accumulating evidence in acute severe asthma that earlier use of intravenous b-agonists in the ED results in more rapid recovery and earlier discharge than inhaled therapy.20 It remains to be seen whether in those patients, a b2-agonist 703
administered intravenously provides greater therapeutic benefit than higher or continuous doses of inhaled albuterol. Because the study by Carl et al leaves unanswered questions regarding benefits that are directly attributable to the drug, confirmation of the findings is needed. It is noteworthy that this study is completed at a time when congressional lawmakers in the United States debate authorization of funds for research for the comparison of drugs to treat the same condition.21 This study demonstrates that neither aggressive marketing nor administrative decisions based solely on drug costs can serve as a substitute for welldesigned clinical trials. Meyer Kattan, MD, CM Pediatric Pulmonary and Critical Care Division Mount Sinai School of Medicine New York, NY 10029
REFERENCES 1. Lipworth BJ, Clark DJ, Koch P, Arbeeny C. Pharmacokinetics and extrapulmonary b2 adrenoceptor activity of nebulised racemic salbutamol and its R and S isomers in healthy volunteers. Thorax 1997;52:849-52. 2. Lotvall J, Palmqvist M, Arvidsson P, Maloney A, Ventresca GP, Ward J. The therapeutic ratio of R- albuterol is comparable with that of RS- albuterol in asthmatic patients. J Allergy Clin Immunol 2001;108: 726-31. 3. Baramki D, Koester J, Anderson AJ, Borish L. Modulation of T-cell function by (R)- and (S)-isomers of albuterol: anti-inflammatory influences of (R)-isomers are negated in the presence of the (S)-isomer. J Allergy Clin Immunol 2002;109:449-54. 4. Mazzoni L, Naef R, Chapman ID, Morley J. Hyperresponsiveness of the airways following exposure of guinea-pigs to racemic mixtures and distomers of b2-selective sympathomimetics. Pulmonol Pharmacol 1994;7:367-76. 5. Gawchik SM, Saccar CL, Noonan M, Reasner DS, DeGraw SS. The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allergy Clin Immunol 1999;103:615-21. 6. 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;108:938-45. 7. Cockcroft DW, Davis BE, Swystun VA, Marciniuk DD. Tolerance to the bronchoprotective effect of b2-agonists: comparison of the enantiomers of salbutamol with racemic salbutamol and placebo. J Allergy Clin Immunol 1999;103:1049-53. 8. 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;52:845-8. 9. Ind PW. Salbutamol enantiomers: early clinical evidence in humans. Thorax 1997;52:839-40. 10. Ahrens R, Weinberger M. Levalbuterol and racemic albuterol: are there therapeutic differences? J Allergy Clin Immunol 2001;108:681-4. 11. National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis and management of asthma. Bethesda (MD): National Heart, Lung, and Blood Institute; 1997. Report No.: NIH publication no. 97-4051. 12. Ben-Zvi Z, Lam C, Spohn WA, Gribetz I, Mulvihill MN, Kattan M. An evaluation of repeated injections of epinephrine for the initial treatment of acute asthma. Am Rev Respir Dis 1983;127:101-5. 13. Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison of racemic albuterol and levalbutreol for treatment of acute asthma. J Pediatr 2003;143:731-6. 14. Kattan M, Mitchell H, Eggleston P, Gergen P, Crain E, Redline S, et al. Characteristics of inner-city children with asthma: the National Cooperative Inner-City Asthma Study. Pediatr Pulmonol 1997;24:253-62. 15. Fischl MA, Pitchenik A, Gardner LB. An index predicting relapse and need for hospitalization in patients with acute bronchial asthma. N Engl J Med 1981;305:783-9. 16. Asmus MJ, Hendeles L. Levalbuterol nebulizer solution: is it worth five times the cost of albuterol? Pharmacotherapy 2000;20:123-9. 17. Newhouse MT. Asthma therapy with aerosols: are nebulizers obsolete? A continuing controversy. J Pediatr 1999;135:5-8. 18. Schuh S, Johnson DW, Stephens D, Callahan S, Winders P, Canny GJ. Comparison of albuterol delivered by a metered dose inhaler with spacer versus a nebulizer in children with mild acute asthma. J Pediatr 1999;135:22-7. 19. Chou KJ, Cunningham SJ, Crain EF. Metered-dose inhalers with spacers vs nebulizers for pediatric asthma. Arch Pediatr Adolesc Med 1995;149:201-5. 20. Browne GJ, Wilkins BH. Use of intravenous salbutamol in acute severe asthma. Anaesthesia 2003;58:729-32. 21. Pear R. Congress weighs drug comparisons. New York Times, August 24, 2003.
THE JOURNEY TO METABOLIC CONTROL IN DIABETES: MANY MORE MILES TO GO he findings of the Diabetes Control and Complications Trial (DCCT) in patients older than 13 years with type 1 diabetes, together with the availability of improved methods of monitoring glycemia (self blood glucose monitoring and glycated hemoglobin [HbA1c] measurement), resulted in greatly increased efforts to improve glycemic control to reduce the risk of long-term complications.1 The insulins available at the time of the DCCT included neutral protamine Hagedorn (NPH), Regular, Lente, and Ultralente. None of these insulins replicates the normal endogenous basal insulin
T DCCT HbA1c NPH
704
Diabetes Control and Complications Trial Glycated hemoglobin Neutral protamine Hagedorn
Editorials
secretion that is needed to control hepatic glucose production and catabolism during fasting, nor the rapid onset and shortaction peak insulin secretion to cover food intake. Thus, improved metabolic control seen in the intensively treated group in the DCCT was associated with more hypoglycemia than in the conventionally treated patients. This was particularly true in the adolescent cohort. As health care teams gained more
See related article, p 737. Reprint requests: Janet H. Silverstein, MD, Division of Endocrinology, Department of Pediatrics, University of Florida, Box 100296, Gainesville, FL 326100296. E-mail: [email protected]. edu J Pediatr 2003;143:704-6. Copyright ª 2003 Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0 10.1067/S0022-3476(03)00616-4
The Journal of Pediatrics December 2003