Inhaled budesonide in acute asthma?

Abstract

See related article, p 433 . Inhaled corticosteroids (CS) are the cornerstone of outpatient asthma control, but use of systemic CS dominates the immediate anti-inflammatory treatment of asthma attacks. A preference for needles, syrups, and tablets over nebulizers and inhalers for delivering a “burst” of CS is intuitive to many clinicians, especially when optimal effects of inhaled CS have been described in weeks rather than hours. This view is supported by a recent report demonstrating superior outcomes with oral prednisone compared with inhaled fluticasone for a subset of children with severe asthma.1Schuh S Reisman J Alshehri M Dupuis A Corey M Arseneault R et al.A comparison of inhaled fluticasone and oral prednisone for children with severe acute asthma.N Engl J Med. 2000; 343: 689-694Crossref PubMed Scopus (166) Google Scholar In contrast, other investigations have shown inhaled CS to be clearly better than placebo in adults2Rodrigo G Rodrigo C. Inhaled flunisolide for acute severe asthma.Am J Respir Crit Care Med. 1998; 157: 698-703Crossref PubMed Scopus (155) Google Scholar and children,3Singhi S Banerjee S Nanjundaswamy H. Inhaled budesonide in acute asthma.J Paediatr Child Health. 1999; 35: 483-487Crossref PubMed Scopus (43) Google Scholar as well as equal or superior to systemic CS in children.4Devidayal Singhi S Kumar L Jayshree M. Efficacy of nebulized budesonide compared to oral prednisolone in acute bronchial asthma.Acta Paediatr. 1999; 88: 835-840Crossref PubMed Google Scholar, 5Matthews EE Curtis PD McLain BI Morris LS Turbitt ML. Nebulized budesonide versus oral steroid in severe exacerbations of childhood asthma.Acta Paediatr. 1999; 88: 841-843Crossref PubMed Google Scholar, 6Volovitz B Bentur L Finkelstein Y Mansour Y Shalitin S Nussinovitch M et al.Effectiveness and safety of inhaled corticosteroids in controlling acute asthma attacks in children who were treated in the emergency department: a controlled comparative study with oral prednisolone.J Allergy Clin Immunol. 1998; 102: 605-609Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 7Scarfone RJ Loiselle JM Wiley JF Decker JM Henretig FM Joffe MD. Nebulized dexamethasone versus oral prednisone in the emergency treatment of asthmatic children.Ann Emerg Med. 1995; 26: 480-486Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar The status quo persists in favor of systemic CS for acute asthma despite the relative lack of knowledge about the short-term8Wolthers OD Pedersen S. Short term linear growth in asthmatic children during treatment with prednisolone.BMJ. 1990; 301: 145-148Crossref PubMed Scopus (114) Google Scholar and long-term consequences of single or repeated systemic exposures and despite efficacy data that are less robust than commonly perceived.9Rodrigo G Rodrigo C. Corticosteroids in the emergency department therapy of acute adult asthma: an evidence-based evaluation.Chest. 1999; 116: 285-295Crossref PubMed Scopus (92) Google Scholar Greater confidence in the effectiveness of inhaled CS could at least promote the option of topically treating asthma exacerbations with a goal of reduced systemic CS exposure. In this issue of The Journal, Tsai et al10Tsai Y-G Lee M-Y Yang KD Chu D-M Yuh SY Hung C-H. A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthma.J Pediatr. 2001; 139: 433-437Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar support the use of inhaled CS in the emergency setting by showing that a single dose of nebulized budesonide (up to 2 mg) decreases expired nitric oxide (NO), increases expiratory flow rates, and reduces asthma symptoms within 6 to 12 hours. Measurements of expired nitric oxide (FENO) have proven useful in the assessment of pediatric lung inflammation11Hunt J Gaston B. Airway nitrogen oxide measurements in asthma and other pediatric respiratory diseases.J Pediatr. 2000; 137: 14-20Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar; this investigation is novel in its use of FENO in an attempt to detect inflammatory changes after inhalation of CS for acute asthma. A similar effect has been shown with systemic CS,12Massaro AF Gaston B Kita D Fanta C Stamler JS Drazen JM. Expired nitric oxide levels during treatment of acute asthma.Am J Respir Crit Care Med. 1995; 152: 800-803Crossref PubMed Scopus (325) Google Scholar, 13Baraldi E Azzolin NM Zanconato S Dario C Zacchello F. Corticosteroids decrease exhaled nitric oxide in children with acute asthma.J Pediatr. 1997; 131: 381-385Abstract Full Text PDF PubMed Scopus (214) Google Scholar but this is the first demonstration of a substantial and sustained drop with a single dose of inhaled CS. A measurable anti-inflammatory response to a single high dose of inhaled CS has been suggested by another recent investigation showing reduction in sputum eosinophilia and airway reactivity in adults with stable asthma 6 hours after a single dose of 2.4 mg of budesonide administered through a dry-powder inhaler.14Gibson PG Saltos N Fakes K. Acute anti-inflammatory effects of inhaled budesonide in asthma: a randomized controlled trial.Am J Respir Crit Care Med. 2001; 163: 32-36Crossref PubMed Scopus (149) Google Scholar Classically, the effect of systemic CS on NO has been ascribed to inhibition of inducible NO synthase, but it is also likely to involve effects on pH regulatory and S-nitrosothiol metabolic enzymes.11Hunt J Gaston B. Airway nitrogen oxide measurements in asthma and other pediatric respiratory diseases.J Pediatr. 2000; 137: 14-20Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar The correlation between FENO values in both symptom scores and peak flow scores after, but not before, treatment underscores that the NO measurements may be more valuable in the longitudinal assessment of asthma therapy than in the initial evaluation of severity; this study suggests that the principal may be applicable for acute, as well as chronic, asthma. In comparing systemic and inhaled steroids in the emergency treatment of asthma, it is interesting to note that intergroup differences described by Tsai et al10Tsai Y-G Lee M-Y Yang KD Chu D-M Yuh SY Hung C-H. A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthma.J Pediatr. 2001; 139: 433-437Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar between budesonide and placebo were significant first at 6 hours for NO and then later at 12 hours for peak flows and symptoms. This effect of a single dose of nebulized budesonide on symptom and lung function measurements is similar to that described with systemic CS.9Rodrigo G Rodrigo C. Corticosteroids in the emergency department therapy of acute adult asthma: an evidence-based evaluation.Chest. 1999; 116: 285-295Crossref PubMed Scopus (92) Google Scholar The time lag has been explained by the need for CS-induced transcriptional effects to take place before reductions in inflammation can be anticipated.15McFadden Jr., ER Inhaled glucocorticoids and acute asthma: therapeutic breakthrough or nonspecific effect? [letter, comment].Am J Respir Crit Care Med. 1998; 157: 677-678Crossref PubMed Scopus (42) Google Scholar This is in contrast to investigations of repeated administration of high-dose inhaled flunisolide through a metered-dose inhaler in adults2Rodrigo G Rodrigo C. Inhaled flunisolide for acute severe asthma.Am J Respir Crit Care Med. 1998; 157: 698-703Crossref PubMed Scopus (155) Google Scholar and nebulized dexamethasone7Scarfone RJ Loiselle JM Wiley JF Decker JM Henretig FM Joffe MD. Nebulized dexamethasone versus oral prednisone in the emergency treatment of asthmatic children.Ann Emerg Med. 1995; 26: 480-486Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar or budesonide3Singhi S Banerjee S Nanjundaswamy H. Inhaled budesonide in acute asthma.J Paediatr Child Health. 1999; 35: 483-487Crossref PubMed Scopus (43) Google Scholar, 4Devidayal Singhi S Kumar L Jayshree M. Efficacy of nebulized budesonide compared to oral prednisolone in acute bronchial asthma.Acta Paediatr. 1999; 88: 835-840Crossref PubMed Google Scholar, 6Volovitz B Bentur L Finkelstein Y Mansour Y Shalitin S Nussinovitch M et al.Effectiveness and safety of inhaled corticosteroids in controlling acute asthma attacks in children who were treated in the emergency department: a controlled comparative study with oral prednisolone.J Allergy Clin Immunol. 1998; 102: 605-609Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar in children with acute asthma showing an early (<3 hours) improvement in outcomes. It has been suggested that these early responses might demonstrate a topical effect on airway and/or vascular smooth muscle tone not achievable by oral or injected CS.2Rodrigo G Rodrigo C. Inhaled flunisolide for acute severe asthma.Am J Respir Crit Care Med. 1998; 157: 698-703Crossref PubMed Scopus (155) Google Scholar, 4Devidayal Singhi S Kumar L Jayshree M. Efficacy of nebulized budesonide compared to oral prednisolone in acute bronchial asthma.Acta Paediatr. 1999; 88: 835-840Crossref PubMed Google Scholar, 6Volovitz B Bentur L Finkelstein Y Mansour Y Shalitin S Nussinovitch M et al.Effectiveness and safety of inhaled corticosteroids in controlling acute asthma attacks in children who were treated in the emergency department: a controlled comparative study with oral prednisolone.J Allergy Clin Immunol. 1998; 102: 605-609Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 15McFadden Jr., ER Inhaled glucocorticoids and acute asthma: therapeutic breakthrough or nonspecific effect? [letter, comment].Am J Respir Crit Care Med. 1998; 157: 677-678Crossref PubMed Scopus (42) Google Scholar Tsai et al10Tsai Y-G Lee M-Y Yang KD Chu D-M Yuh SY Hung C-H. A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthma.J Pediatr. 2001; 139: 433-437Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar suggest that there is a trend for an early inhaled CS effect in their investigation in that only the budesonide-treated patients maintained improvement in symptom scores and peak flows throughout the 6-hour interval between terbutaline nebulizations. Many questions remain to be answered before a new era of acute asthma therapy with nebulized budesonide or another inhaled CS emerges. The choice of a single, high dose of nebulized budesonide in this study does little to answer questions about what the optimal inhaled CS, delivery technique, dose, and dose frequency are for acute asthma therapy, especially because budesonide was not compared with the standard “add-on” care of oral or injected CS. There is a confusing array of inhaled CS and delivery devices available, with only slow-to-accumulate information about the comparative potency and adverse effects16O'Byrne PM Pedersen S Measuring efficacy and safety of different inhaled corticosteroid preparations.J Allergy Clin Immunol. 1998; 102: 879-886Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar; and it is likely that drug, dose, and delivery differences have contributed to conflicting answers to the root question of efficacy. Another concern is the extent to which patient population (age, severity of illness, atopy, infection, length of illness, use of other medications) determines the efficacy of inhaled CS for acute asthma. It is important to note that Tsai et al10Tsai Y-G Lee M-Y Yang KD Chu D-M Yuh SY Hung C-H. A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthma.J Pediatr. 2001; 139: 433-437Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar selected children for dust mite allergy and for the absence of obvious viral respiratory tract infection in an effort to show maximal NO responses. This is in stark contrast to the usual setting in which the majority of children with asthma exacerbations have a viral respiratory tract infection. The subjects' responses to treatment are also atypical in that the authors successfully treated 24 of 26 subjects in the emergency department with initial peak expiratory flow rates on the order of 100 L/min using oral β-agonists and 2 doses of inhaled terbutaline (0.1 mg/kg/dose) separated by 6 hours; only half of their patients received any CS therapy at all. It may be that the severity and/or duration of symptoms in these subjects was less than that in the subjects of most emergency department reports, in which aggressive use of inhaled β2-agonists, as often as every 20 minutes, is required. The availability of a 12-hour observation period may also have enabled this conservative β2-agonist use. These restrictions may have unveiled inhaled CS effects that would be otherwise insignificant in the usual mix of wheezing children with colds and frequent bronchodilator use. The severity and duration of asthma attacks have also been shown to be important in studies of both inhaled and oral CS, with evidence that exacerbations lasting longer than 24 hours are most responsive to an inhaled CS.2Rodrigo G Rodrigo C. Inhaled flunisolide for acute severe asthma.Am J Respir Crit Care Med. 1998; 157: 698-703Crossref PubMed Scopus (155) Google Scholar Again, caution should be exercised before generalizing the results of Tsai et al10Tsai Y-G Lee M-Y Yang KD Chu D-M Yuh SY Hung C-H. A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthma.J Pediatr. 2001; 139: 433-437Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar into practice, but there are 3 important messages advanced by their report. First, a single high dose of nebulized budesonide can have measurable clinical and anti-inflammatory effects within hours in children with acute asthma. Second, FENO may be a relevant index of the success of anti-inflammatory asthma therapy in both short- and long-term care settings. Such a noninvasive index could be of immense value in monitoring the early and late effects of CS and other medications in investigations of acute asthma. And lastly, many of the questions raised by the limitations of their study design could best be addressed by large, multicenter investigations of children presenting with asthma attacks of differing severity in which different forms of inhaled and systemic CS are compared in those receiving standard care with inhaled β2-agonists. The study by Tsai et al10Tsai Y-G Lee M-Y Yang KD Chu D-M Yuh SY Hung C-H. A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthma.J Pediatr. 2001; 139: 433-437Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar is closely preceded by the approval of budesonide as the first nebulized controller medication for asthma in the United States, a confluence that will hopefully spark additional interest and support for further research at a time when many clinicians already incorporate an increase in inhaled CS in their outpatient asthma action plans. A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthmaThe Journal of PediatricsVol. 139Issue 3PreviewThis study was conducted to investigate whether a single dose of nebulized budesonide effectively decreased airway inflammation as demonstrated by exhaled nitric oxide (eNO) levels. A single dose of nebulized budesonide, but not nebulized terbutaline, rapidly decreased eNO levels in 6 hours. The decrease in eNO levels induced by nebulized budesonide was correlated to an increase in peak expiratory flow rate. (J Pediatr 2001;139:433-7) Full-Text PDF