Andrew H. Travers, Brian H. Rowe, Samantha Barker, Arthur Jones and Carlos A. Camargo, Jr. DOI /chest

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1 The Effectiveness of IV β-agonists in Treating Patients With Acute Emergency Department * Asthma in the Andrew H. Travers, Brian H. Rowe, Samantha Barker, Arthur Jones and Carlos A. Camargo, Jr Chest 2002;122; DOI /chest The online version of this article, along with updated information and services can be found online on the World Wide Web at: CHEST is the official journal of the American College of Chest Physicians. It has been published monthly since Copyright 2002 by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. ( ISSN:

2 The Effectiveness of IV -Agonists in Treating Patients With Acute Asthma in the Emergency Department* A Meta-analysis Andrew H. Travers, MD, MSc; Brian H. Rowe, MD, MSc; Samantha Barker, MD; Arthur Jones, RT; and Carlos A. Camargo, Jr., MD, DrPH Objectives: To determine the benefit of IV 2 -agonists for severe acute asthma treated in the emergency department (ED). Methods: Randomized controlled trials were identified using EMBASE, MEDLINE, and CINAHL; the Cochrane Airways Review Group database; hand searching; bibliographies; pharmaceutical companies; and author contact. Studies where IV 2 -agonists were compared to placebo and/or existing standards of care were considered. Where appropriate, trials were combined using odds ratios (ORs) or weighted mean differences with 95% confidence intervals (CIs). Results: From 746 identified references, 55 potentially relevant articles were identified and 15 articles were included. All trials were performed outside North America and were published prior to Three main treatment strategies were reviewed: strategy 1 (three articles), IV 2 -agonists with inhaled 2 -agonists vs inhaled 2 -agonists; strategy 2 (six articles), IV 2 -agonists alone vs inhaled 2 -agonists; and strategy 3 (six articles), IV 2 -agonists vs IV methylxanthines. Compared to all treatments, IV 2 -agonist use did not lead to clinical or statistical significant differences in vital signs, pulmonary functions, laboratory measures, adverse effects, or clinical success. Although statistically nonsignificant, seven methodologically strong studies demonstrated that peak expiratory flows and heart rates were unchanged following 2 -agonist use compared to all other treatments at 60 min (8.3 L/min [95% CI, 17.6 to 34.2] and 3.65 beats/min [95% CI, 2.9 to 10.2], respectively), with an increased risk of adverse effects (OR, 1.98; 95% CI, 0.5 to 8.2). Conclusions: Evidence is lacking to support the use of IV 2 -agonists in ED patients with severe acute asthma. Moreover, the clinical benefit appears questionable, while the potential clinical risks are obvious. The only recommendations for IV - 2 agonist use should be in those patients in whom inhaled therapy is not feasible, or in the context of a controlled clinical trial comparing IV 2 -agonists with standard care vs standard care alone. (CHEST 2002; 122: ) Key words: asthma; -agonists; emergency department; IV; pulmonary function; side effects Abbreviations: ABG arterial blood gas; CI confidence interval; CPG clinical practice guideline; df degrees of freedom; ED emergency department; OR odds ratio; PEFR peak expiratory flow rate; PFT pulmonary function test; RCT randomized controlled trial; WMD weighted mean difference The general approach to treating patients with acute asthma is to use inhaled -agonist bronchodilators and corticosteroids. For severe acute asthma, penetration of inhaled -agonists to the affected small conducting airways may be impeded, and consequently responses may be a result of drug reaching the receptors via the systemic circulation. In these circumstances, if bronchodilatation occurs *From the Division of Emergency Medicine (Drs. Travers and Rowe) and Department of Radiology (Dr. Barker), University of Alberta and Capital Health Authority, Edmonton, AB, Canada; Respiratory Care Department (Mr. Jones), University of Texas, San Antonio, TX; and the Department of Emergency Medicine (Dr. Camargo), Massachusetts General Hospital Boston, MA. Presented at the American College of Emergency Physicians Annual Meeting, Las Vegas, NV, October 1999, and the Canadian Association of Emergency Physicians Annual Meeting, Quebec City, PQ, Canada, October, These results have been electronically published by the Airways Review Group in the Cochrane Collaboration (Cochrane Database of Systematic Reviews. The Cochrane Library, Issue 4, Oxford, UK: Update Software). Dr. Travers received a grant from the Canadian Association of Emergency Physicians to complete this work. Dr. Rowe is supported by a salary award from the Canadian Institute of Health Research as the Chair in Emergency Airway Diseases (Ottawa, ON). Dr. Camargo is supported by grant HL from the National Institutes of Health (Bethesda, MD). Correspondence to: Andrew Travers, MD, MSc, Division of Emergency Medicine, University of Alberta, 1G1.50 WMC, th St, Edmonton, AB, T6G 2B7 Canada; ahtravers@ shaw.ca 1200 Clinical Investigations

3 predominantly in response to the systemic distribution of the drug, IV rather than inhaled administration of bronchodilators may provide an earlier clinical response. 1 For editorial comment see page 1116 The research investigating the role of IV agonists in the emergent treatment of asthma has spanned 25 years. At present, each of the clinical practice guidelines (CPGs) in Europe (British Thoracic Society), Canada (Canadian Association of Emergency Physicians), and the United States (National Asthma Education and Prevention Program) recommend inhaled -agonist therapy for all cases of asthma that present to the emergency department (ED). 2 5 Each CPG suggests IV and subcutaneous -agonists as second-line therapy for use in patients unresponsive to inhaled bronchodilator and systemic corticosteroid therapy, or if the inhaled route is not practical for the patient (ie, excessive coughing, too weak to inspire adequately, or moribund patient). 2 5 IV use is not approved in the National Asthma Education and Prevention Program guidelines. 5 Each CPG variously describe near-death asthma or life-threatening asthma as qualifying terms for adult candidates for IV or subcutaneous administration. These are listed as alternative therapies paralleling inhalational anesthetics and IV methylxanthines. However, most of the CPG recommendations for IV or subcutaneous agents originate from low-grade and/or low levels of evidence; as a result, debate regarding the IV route of treatment continues. This lack of consensus reflects the fact that no systematic review of the IV or subcutaneous -agonist literature for the treatment of asthmatic exacerbations has been published to date. Consequently the objective of this review was to determine if the evidence from randomized trials supports the use of IV -agonists in the treatment of patients with severe acute asthma who present to the ED. Inclusion Criteria Materials and Methods To be eligible for inclusion in this review, a study had to meet all of the following criteria: (1) design, randomized controlled trials (RCTs) or quasi RCTs (allocation on days of the week, or some other method); (2) population, studies recruiting adult or pediatric patients with severe acute asthma from the ED (or its equivalent); (3) interventions, administration of IV (selective or nonselective) -agonists vs the administration of placebo, other IV bronchodilators (ie, methylxanthines), or other inhaled selective or nonselective -agonists; included studies could also use other recognized standard treatment (ie, corticosteroids); and (4) outcomes, pulmonary functions, vital signs, adverse effects, and clinical scores. Agreement for relevance for review was measured using statistics. Study Identification Electronic databases were searched from 1966 to 2000, exploding -agonist treatment (all routes, formulations, and brand names) and asthma; the search was restricted to RCTs using standardized and validated strategies. 6 This search was performed on MEDLINE, EMBASE, CINAHL, the Controlled Trials Register of the Cochrane Library, and the Cochrane Airway Review Group Asthma and Wheeze Registry. These Cochrane registries include studies identified by the Cochrane Collaboration through standardized searching and hand searching of journals for controlled clinical trials. Reference lists of all available primary studies and review articles were reviewed to identify potential relevant citations. Trials were not excluded on the basis of language. Included authors, major pharmaceutical producers of asthma medications (AstraZeneca, Boehringer Ingelheim, Glaxo, 3M Pharmaceuticals), and other asthma researchers were contacted regarding the existence of other published, unpublished, or interim results on -agonist research. The reference lists from the search strategy was independently reviewed, and clearly irrelevant articles were discarded. If the title, abstract, or descriptors suggested any potential relevance, the full text article was retrieved. Agreement for relevance for review was measured using statistics. Each relevant article was then assessed by two independent, nonblinded reviewers for inclusion in this review. Agreement for relevance for inclusion was measured using statistics. Disagreement was resolved by consensus or third-party adjudication. Quality Assessment of Trials The previously validated Jadad 5-point scale (score 0 to 5) was used to assess randomization (0 to 2 points), double blinding (0 to 2 points), and withdrawals and dropouts (0 to 1 point). 7 For allocation assessment, concealment was described as either adequate, inadequate, or unclear using Cochrane methodology. 8 Two reviewers independently assessed quality, and interrater reliability was measured by using simple agreement,, and weighted statistics, with disagreement resolved by third-party adjudication. Data Extraction Data for the trials were independently extracted with a structured form by two blinded reviewers and entered into the software program (Review Manager Version 4.0.4; Cochrane Collaboration; Oxford, UK). Primary study authors were requested to confirm data extraction and provide additional clarification or information for the review. In cases where tables were unavailable, graphs were enlarged and values were approximated. Data Analysis All similar studies were pooled using random effects weighted mean differences (WMDs) for continuous variables, and random effects odds ratios (ORs) for dichotomous variables, with 95% confidence interval (CIs) where appropriate. With pooled effects, heterogeneity was tested using the Breslow-Day test; p 0.05 was considered statistically significant. For those summary effect outcome measures with statistical heterogeneity, a priori subgroup analyses were classified on the following basis: (1) population, adult vs pediatric and severity of illness based on pulmowww.chestjournal.org CHEST / 122 / 4/ OCTOBER,

4 nary function test (PFT) results; and (2) intervention, selective vs nonselective -agonists, IV vs inhaled -agonists, IV with inhaled vs inhaled -agonists, IV -agonists vs IV methylxanthines, and infusion vs bolus -agonists. Sensitivity analyses were completed on the strength of methodologic quality (high vs low) and statistical method of analysis (random vs fixed effects). Systematic Review Results The Airways Review Group database search revealed 976 references that represented 740 original publications (76%): 258 articles (35%) in EMBASE, 250 articles (34%) in MEDLINE, 2 articles (0.3%) from CINAHL, 224 articles (30%) from both MEDLINE and EMBASE, and 6 articles (0.7%) cited in all three. An independent review of the abstracts and titles of these publications identified 31 potentially relevant studies. The agreement for relevance was high ( 0.83). Twenty-four additional references were added from bibliographic searching of relevant articles and overviews; a total of 55 full-text articles were reviewed for inclusion. Unpublished literature was requested from pharmaceutical companies and the authors of all included studies, but none were identified. Of these 55 articles, a total of 15 studies (27%) were included in the overview ( 0.87). Of the 40 studies that were excluded, 30 studies (55%) were nonrandomized, 7 studies (13%) included treatment of patients with nonacute asthma or nonasthmatics, and 3 studies (5%) examined non-iv routes of administration. Table 1 illustrates that the evidence for intervention with IV agonists spans a period of 25 years: 7 articles (47%) published in the 1970s, 5 articles (33%) from the 1980s, and 3 articles (20%) from the 1990s. Twelve of the studies (80%) were conducted in Europe, 1 study (7%) was conducted Asia, and 2 studies (13%) were conducted in Australia. No trials meeting our inclusion criteria were conducted in North America. Methodologic Quality Many of the included articles were double-blind, controlled trials; however, the methodologic quality varied across studies. Using the method of Jadad et al, 7 seven studies (47%) were rated as strong (Jadad score 3 to 5) and eight studies (53%) were rated as weak (Jadad score 0 to 2). Agreement between the two independent assessments of study quality was high ( ranged from 0.59 to 1.0 for each domain). There was no significant correlation between quality scores and the year of publication of the trial (Pearson r 0.38, p 0.17). Regarding concealment of allocation methodology, 5 studies (33%) were rated as having clearly blinded allocation and 10 studies (67%) were rated as having unclear allocation blinding ( 1.0). There was no statistically significant association between those studies that were rated as strong methodologically and those that had blinded allocation ( , degrees of freedom [df] 1, p 0.05). Study Design Thirteen of the studies (87%) followed a parallel protocol, whereas 2 of the studies (13%) followed a crossover model. 9,10 Eleven studies (73%) introduced IV -agonists immediately on entry. The remaining four studies introduced IV -agonists within 30 to 75 min of study entry, during which Table 1 Descriptions of Included Studies Source Country Quality Sample Size Patients Intervention Treatment Comparison Treatment Bloomfield et al 9 /1979 Scotland High 20 Adult Salbutamol, 500 g IV bolus Salbutamol, 5 mg inhaled Browne et al 1 /1997 Australia High 29 Pediatric Salbutamol, 15 g/kg IV bolus Salbutamol, mg inhaled Cheong et al 11 /1988 England High 61 Adult Salbutamol, 12.5 g/min IV Salbutamol, 5 mg inhaled Femi-Pearse et al 20 /1977 Nigeria Low 50 Adult Salbutamol, 200 g IV bolus Aminophylline, 250 mg IV Hambleton and Stone 21 /1979 England Low 18 Pediatric Salbutamol, 4 g/kg IV bolus Aminophylline, 4 mg/kg IV Hussein et al 17 /1986 Germany Low 20 Pediatric Reproterol, 0.2 g/kg/min IV Salbutamol, 75 g/kg inhaled Johnson et al 18 /1978 England Low 39 Adult Salbutamol, 10 g/min IV Aminophylline, 1 mg/min Lawford et al 13 /1978 England High 13 Adult Salbutamol, 20 g/min IV Salbutamol, 10 mg inhaled Salmeron et al 14 /1994 France High 47 Adult Salbutamol, 8.3 g/min IV Salbutamol, 10 mg inhaled Sharma et al 22 /1984 India Low 30 Adult Salbutamol, 250 g IV bolus; terbutaline, 250 g IV bolus Aminophylline, 250 mg IV Aminophylline, 250 mg IV Swedish Society of Medicine 15 /1990 Sweden Low 176 Adult Salbutamol, 5 g/kg IV bolus Salbutamol, 0.15 mg/kg inhaled Tribe et al 10 /1976 Australia High 23 Adult Salbutamol, 100 g IV bolus Aminophylline, 250 mg IV Van Renterghem et al 12 /1987 Belgium Low 23 Adult Terbutaline, 6 g/kg IV bolus Terbutaline, 0.1 mg/kg inhaled Williams et al 19 /1975 England High 20 Adult Salbutamol, 8.3 g/min IV Aminophylline, 500 mg IV Williams et al 16 /1981 England Low 15 Adult Terbutaline, 250 g IV bolus Terbutaline, 2.5 mg inhaled 1202 Clinical Investigations

5 time the patients received either inhaled agonists 1,11,12 or IV aminophylline. 12 There were three main treatment strategies utilized in the studies under review. Three studies 1,11,12 utilized strategy 1 where IV -agonists were compared to inhaled -agonist, where both groups of patients received a run-in phase of inhaled -agonist therapy. Six studies 9,13 17 utilized strategy 2, where IV -agonists were compared with inhaled agents, with no inhalational therapy in the IV -agonist arm. The remaining six studies 10,18 22 utilized strategy 3, where IV -agonists were compared with IV methylxanthines, where neither group received inhaled -agonist therapy. Populations Participants were selected from a sample of patients who presented to the ED or its equivalent with severe acute asthma. All patients were admitted to the hospital. The majority of studies focused on adult patients only (age range, 15 to 65 years), with only three studies 1,17,21 evaluating children (age range, 0.8 to 14.7 years). The median sample size across the studies was 23, with a range of 13 to 176 patients. All studies enrolled patients with severe asthma, though there was variability in the parameters and definitions used for inclusion criteria. Nine studies 9,11 16,19,20 used vital signs (heart rate 100 beats/min) and PFT results ( 20% expected) as primary inclusion criteria. Five studies 12,14,16,19,21 required abnormalities in arterial blood gas (ABG) measurements. Four articles 10,18,21,22 listed simple clinical symptoms and signs of severe shortness of breath or wheezing as inclusion criteria. The inclusion criteria in two articles 1,14 described standardized clinical assessment scales for severe asthma. These definitions of severity are described elsewhere. 23,24 Interventions All patients received supplemental oxygen by face mask and systemic corticosteroids. No patients received inhaled steroids or inhaled anticholinergic agents in any of the studies. All studies used selective IV 2 -agonists. Table 1 demonstrates that nine studies 1,9,10,12,15,16,20 22 administered IV 2 -agonists as a bolus (range, 100 to 500 g, or 4 to 15 g/kg), whereas six studies 11,13,14,18,19,21 administered the IV 2 -agonist as an infusion (range, 8.3 to 20 g/min to total doses of 500 to 3,000 g). Most studies (73%) used salbutamol; three studies evaluated terbutaline, and one study evaluated reproterol. One study 22 ran a triple-parallel protocol comparing IV salbutamol vs IV terbutaline vs IV aminophylline. Consequently, this study was treated as two studies: IV salbutamol vs aminophylline, and IV terbutaline vs aminophylline. Outcomes Each article evaluated primary outcomes within a 2-h period. Nevertheless, six studies extended the observation interval longer: 3 h, 22 5 h, 11 6 h, h, 1,21 and 36 h. 17,18 Multiple statistical tests were performed in each study, with a mean of 24 (varying from 0 to 80). No mention of adjustments for multiple testing were identified in these articles, and 11 articles (73%) made no mention of possible type I errors. More than 240 individual outcome measurements were abstracted from the studies. Scores from a variety of symptom scales were occasionally used to describe outcomes; however, due to the different scores used, no pooled analyses were conducted. In addition, a number of PFT results were employed (including peak expiratory flow rate [PEFR], FEV 1, FVC, percentage of predicted PEFR, and percentage of predicted FEV 1 ); nonetheless, variability in the type of PFT employed limited comparisons between studies. There were no descriptions of any patients who were intubated or died during any of the study observation periods. Five trials 9,11,16,18,19 used improvements in PFTs (namely PEFR) as the primary outcome. Five articles described a primary outcome variable of clinical improvement, but the definition varied widely between studies. Three of these studies 10,13,15 relied on the impression by the patient or physician of improvement in symptoms. The remaining two studies used predefined clinical determinants of success. The first article defined three unique primary clinical measures of success: earlier ED discharge time (defined as the start of hourly inhaled salbutamol therapy), faster recovery time (to cessation of nebulae 2 -agonists every 30 min, and 60 min), and less oxygen dependence (defined at the 2-h window as the requirement for medical oxygen to maintain oxygen saturations 93%). 1 The second article 14 defined clinical success as the presence of at least two of the following points at 60 min: (1) a decrease in a clinical index rating of at least three points, (2) a decrease in Paco 2 of at least 3 mm Hg, and (3) an increase in PEFR of at least 50 L/min. Consequent to the variety of outcomes, only seven domains were analyzed in which sufficient data were available and similarly derived: serial PEFR, serial percentage of predicted PEFR, serial FEV 1, serial heart rate, serial ABG values, autonomic side effects, and clinical improvement. CHEST / 122 / 4/ OCTOBER,

6 Pulmonary Function Results Table 2 demonstrates that across the 6-h observation in the seven articles reporting PEFR, no statistical differences in PEFR were identified between those patients who received IV 2 -agonists vs inhaled 2 -agonists or IV methylxanthines. Moreover, differences between the summary outcome measures in each stratum were of questionable clinical significance with pooled estimates of treatment effect ranging from a 0.4 to 19.4 L/min. Over the course of 6 h, there were no statistically or clinically significant differences with respect to FEV 1 or percentage of predicted PEFRs (not shown). There was intermittent heterogeneity present in these analyses, and this is addressed further in the discussion. HRs Nine articles described heart rate results over a 6-h period recorded in Table 2. Over this time, there were higher heart rates in those patients who received IV 2 -agonists (range, 4.0 to 12.3 beats/min). These differences were statistically significant in the 15-min and 45-min periods, and the 2-h to 6-h strata, each of which provided homogeneous pooled estimates. However, the differences in heart rates are of questionable clinical significance. ABG Measurements Six articles described ABG measurements, and five articles described carbon dioxide tensions. There was no statistical difference in either the Pao 2 or Paco 2 between IV 2 -agonists and comparison treatments. In addition, there was no heterogeneity across any stratum. Autonomic Side Effects Despite concern regarding the potential side effects of IV 2 -agonists, only 10 studies (67%) reported this information. Autonomic effects included cardiovascular (palpitations, tachycardia, hypertension), neurologic (tremor, headache), and/or GI effects (nausea, vomiting). The pooled OR suggests that adverse effects were experienced approximately twice as frequently when receiving IV treatment as with the comparison treatment. Nevertheless, this result was not statistically significant and significant heterogeneity was present in the pooled estimate. Clinical Improvement Five articles reported a primary outcome variable of clinical improvement, but there was variability in the measurement. The pooled OR suggests that the proportion of patients who did not improve with IV therapy was the same as the proportion of patients Table 2 Summary Effect Measures of Included Studies* Variables WMD 95% CI REM 2 Continuous variables Absolute PEFR, L/min 15 min , (df 4), NS 30 min , (df 3), NS 45 min , (df 2), NS 60 min , (df 6), p min , (df 3), p to6h , (df 4), NS Heart rate, beats/min 15 min , (df 4), NS 30 min , (df 4), p min , (df 2), NS 60 min , (df 8), p min , (df 5), p to 6 h , (df 5), NS ABG, mm Hg Pao , (df 5), NS Paco , (df 4), NS Dichotomous variables Adverse side effects (OR, 1.98) 0.48, (df 8), p 0.05 Fail to improve with treatment (OR, 2.08) 0.32, (df 4), p 0.05 *REM random effects model; NS not significant. Negative numbers favor IV treatment; positive numbers favor control. Breslow Day test for heterogeneity. OR 1 favors IV treatment; OR 1 favors control Clinical Investigations

7 who received the comparison treatment. Significant heterogeneity was present in this pooled estimate. Subgroup Analysis An insufficient number of pediatric articles with similar outcome measures were identified, and this precluded any subgroup comparison on the basis of age. An insufficient number of similar outcomes prevented any formal comparison of results based on type or dose of 2 -agonists. There was no statistical difference in any of the outcome domains when comparing 2 -agonists administered as an IV bolus vs infusion. There was no change in the trends of the summary statistics for any of the outcome domains when strategy 2 was compared to strategy 3. Too few studies with sufficient similar outcomes limited any meaningful comparison of strategy 1 vs strategy 2 or strategy 3. Sensitivity Analysis: Methodologic Quality Using the methods of Jadad et al 7, a strong methodologic study was defined as having a Jadad score of 3 to 5, and a weak study as having a Jadad score of 0 to 2. From Table 3 it is evident that the stronger methodologic studies fail to demonstrate a clinical or statistical difference between IV 2 - agonists or the comparison treatment in terms of PEFR and clinical success. Moreover, although not statistically significant, IV 2 -agonists appear to have an increased risk of adverse effects and increased heart rate compared to the control treatment. By comparing the two groups, it is clear that the weak methodologic studies had larger effect sizes, favoring the control treatment. Although these were statistically nonsignificant, the treatment effects from the weak methodologic were orders of magnitude larger or even discordant from the results of the methodologically strong studies. Subgroup analysis by fixedeffects modeling demonstrated no differences in results except for more strata with statistically significant lower serial heart rates for the non-iv groups (range, 0.1 to 14.1 beats/min). Discussion The literature has been conflicting regarding the use of IV 2 -agonists in patients with acute asthma, and this systematic review is the first to examine the available evidence of the effect of treating severe acute asthmatics with IV 2 -agonists. The subsequent meta-analysis included 15 randomized trials over 25 years that included 584 adults and children across nine countries. IV 2 -agonists administered either by bolus or infusion compared to inhaled Table 3 Sensitivity Analysis by Strong vs Weak Methodologic Quality* Strong Methodologic Quality (Jadad Score 3 to 5) Weak Methodologic Quality (Jadad Score 0 to 2) No. of No. of Studies WMD or OR 95% CI 2 Studies WMD or OR 95% CI 2 Variables PEFR at 60 min 4 WMD 8.30 L/min (df 3) NS 3 WMD L/min (df 2) NS PEFR at 120 min 2 WMD 1.27 L/min (df 1) NS 4 WMD L/min (df 3) NS PEFR final 3 WMD L/min (df 2) NS 3 WMD L/min (df 2) NS Heart rate at 60 min 5 WMD 4.89 beats/min (df 4) NS 3 WMD 0.69 beats/min (df 2) Heart rate at 120 min 4 WMD 8.92 beats/min (df 3) NS 2 WMD 4.44 beats/min (df 1) Side effects 5 OR (df 4) NS 5 OR (df 4) NS Fail to improve 4 OR (df 3) 1 OR NS (one study) *From Jadad et al. 7 See Table 2 for expansion of abbreviation. Negative numbers favor IV treatment; positive numbers favor control. OR 1 favors IV treatment; OR 1 favors control. p CHEST / 122 / 4/ OCTOBER,

8 2 -agonists or IV methylxanthines did not lead to any statistically significant differences in pulmonary functions, laboratory measures of ventilation and oxygenation, or clinical descriptions of improvement. Subgroup and sensitivity analysis consistently demonstrated that the use of IV 2 -agonists was associated with an increased risk of autonomic side effects and higher heart rates; however, they were never shown to be statistically significant in this regard. When examining the quality of articles involving IV agents in acute asthmatic presentations, it is obvious that greater care must be incorporated into further work if clarity is to emerge. There were broad discrepancies among outcomes from studies 7,8 where methodologic quality was scored using two accepted methods. Moreover, statistical planning and sample size calculations were not carefully considered in most studies. No studies were large enough to protect against type II error, and sample size calculations were rarely reported. Furthermore, multiple statistical testing was performed in many studies, increasing the risk of type I error. The literature has examined three treatment strategies involving IV 2 -agonists. Originally, IV 2 - agonists were compared to IV aminophylline in most clinical trials in the 1970s and early 1980s (40% of the included articles). As the standard of care for asthma has been refined, the routine use of aminophylline has diminished, and inhaled 2 -agonists have been increasingly used. 2 5 Consequently, there was a shift in focus to compare IV vs nebulae 2 -agonists (40% of the included articles). Whether IV 2 -agonists improve bronchodilator response when administered in addition to nebulae bronchodilators was only addressed in three studies (20%) under review. Although the evidence suggests that IV 2 -agonists alone are no better than inhaled 2 -agonists, the role of IV 2 -agonists in addition to inhaled 2 -agonists remains unclear. There are several potential limitations of this study. First, this review analyzed only the IV route of administration, and did not evaluate the literature on subcutaneous routes of administration. Based on the consistent lack of benefit shown with the IV 2 - agonists, it is unlikely that subcutaneous agents would differ in effect when compared to nebulized agents. Second, there was significant heterogeneity in pooled estimates for many of the summary outcome measures despite the demonstration of similarities in design, populations, interventions, and outcome measurements between the 15 studies. Nevertheless, on further sensitivity analysis it appeared that studies of weak methodologic quality account for the majority of this heterogeneity. In particular, one article (Swedish Society, 1990) 15 was responsible for the majority of the heterogeneity based on the following points: (1) differential methodologic quality, the Swedish Society article was rated as having low methodologic quality; (2) different populations, all articles studied patients with extremely severe asthma; however, the majority of studies enrolled patients with mean PEFRs in the range of 50 to 100 L/min, whereas the Swedish study evaluated patients with mean PEFRs in the range of 160 to 170 L/min (still defined as severe 200 L/min by international guidelines); and (3) different cointerventions, the Swedish study did not administer any corticosteroid therapy until 2 h into the study protocol, whereas all other studies introduced corticosteroid therapy at the time of enrollment into the study. The effects of each of these factors on the homogeneity of the outcome domains were confounding in isolation and in whole by the very large sample size of the Swedish study (n 176) in relation to the relatively smaller studies (sample range, 14 to 71). When analyzed by strong vs weak methodologic quality, the treatment effects favoring control were less pronounced in the methodologically stronger studies. This would suggest that the methodologically stronger studies fail to demonstrate a clear difference between the two comparison treatments. Third, despite the intensive search strategy employed, there still exists a possibility of study selection bias or publication bias in this meta-analysis. For example, we may be erroneously estimating the nonsignificant effects of IV 2 -agonists due to missing unpublished negative or positive trial results. Although a comprehensive search of the published English and non-english literature for potentially relevant studies was conducted, using a systematic strategy to avoid bias, some studies may have still been missed. In addition, attempts were made to contact first and corresponding authors. Despite these endeavors, no unpublished or non-english articles were uncovered; still, we recognize that they may exist. Fourth, the best outcome measure for success in treating acute asthma was measured variably between studies. Better standardization of this outcome would improve study comparability. Most studies included pulmonary functions as their primary outcome measures. The inherent variability of these PFTs in acute asthma, emphasizes the need for further research into alternative and valid measures. In addition, the evaluation of adverse side effects was complicated by a lack of standardized reporting. Conclusion Despite the methodologic limitations, the results of this work clarify the use of IV 2 -agonists in the 1206 Clinical Investigations

9 treatment of severe acute asthma. The use of IV 2 -agonists compared to inhaled 2 -agonists or IV methylxanthines did not lead to any significant differences in pulmonary functions, laboratory measures of ventilation and oxygenation, or clinical failure/success. Although statistically nonsignificant, IV 2 -agonists produced slightly more autonomic side effects and tachycardia than do comparison treatments. Consequently, the clinical benefit appears questionable, while the potential clinical risks are obvious. The only recommendations for IV 2 - agonist use should be in those patients in whom inhaled therapy is not feasible, or in the context of a controlled clinical trial comparing IV 2 -agonists with standard care vs standard care alone. ACKNOWLEDGMENT: The authors thank Stephen Milan, Anna Bara, and Jane Dennis of the Cochrane Airways Review Group. The editorial assistance of Professor Paul Jones (Cochrane Airways Review Group Coordinating Editor) and the abstraction of data by Carol Spooner were greatly appreciated. References 1 Browne GJ, Penna AS, Phung X, et al. Randomized trial of intravenous salbutamol in early management of acute severe asthma in children. Lancet 1997; 349: Lipworth BJ. Treatment of acute asthma. Lancet 1997; 350:sii18 sii23 3 Beveridge RC, Grunfeld AF, Hodder RV, et al. Guidelines for the emergency management of asthma in adults. Can Med Assoc J 1996; 155: Ernst P, Fitzgerald J, Spier S. Canadian Asthma Consensus Conference: summary of recommendations. Can Respir J 1996; 3: National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health, 1997; 1 6 Mulrow C, Oxman A. Cochrane collaboration handbook. The Cochrane Library. Issue 4, Oxford, UK: Oxford Update Software, updated quarterly, Jadad AR, Moore RA, Carroll D, et al. Assessing the quality or reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: Schultz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995; 273: Bloomfield P, Carmichael J, Petrie GR, et al. Comparison of salbutamol given intravenously and by intermittent positivepressure breathing in life-threatening asthma. BMJ 1979; 1: Tribe AE, Wong RM, Robinson JS. A controlled trial on intravenous salbutamol and aminophylline in acute asthma. Med J Aust 1976; 2: Cheong B, Reynolds SR, Rajan G, et al. Intravenous -agonist in severe acute asthma. BMJ 1988; 297: Van Renterghem D, Lamont H, Elinck W, et al. Intravenous vs nebulized terbutaline in patients with acute severe asthma: a double-blind randomized study. Ann Allergy 1987; 59: Lawford P, Jones BJM, Milledge JS. Comparison of intravenous and nebulised salbutamol in initial treatment of severe asthma [abstract]. BMJ 1978; 1:84 14 Salmeron S, Brochard L, Mal H, et al. Nebulized vs intravenous albuterol in hypercapnic acute asthma: a multicenter, double-blind randomized study. Am J Respir Crit Care Med 1994; 149: Swedish Society of Medicine. High-dose inhaled vs intravenous salbutamol combined with theophylline in severe acute asthma. Eur Respir J 1990; 3: Williams SJ, Winner SJ, Clark TJH. Comparison of inhaled and intravenous terbutaline in acute severe asthma. Thorax 1981; 36: Hussein A, von der Hardt H, Muller W, et al. Intravenous infusion of reproterol in the treatment of acute severe asthma in children. Monatsschr Kinderheilkd (German) 1986; 134: Johnson AJ, Spiro SG, Pidgeon J, et al. Intravenous infusion of salbutamol in severe acute asthma. BMJ 1978; 1: Williams SJ, Parrish RW, Seaton A. Comparison of intravenous aminophylline and salbutamol in severe asthma [abstract]. BMJ 1975; 4: Femi-Pearse D, George WO, Ilechukwu ST, et al. Comparison if intravenous aminophylline and salbutamol in severe asthma [abstract]. BMJ 1977; 1: Hambleton G, Stone MJ. Comparison of IV salbutamol with IV aminophylline in the treatment of severe, acute asthma in childhood. Arch Dis Child 1979; 54: Sharma TN, Gupta RB, Gupta PR, et al. Comparison of intravenous aminophylline, salbutamol, and terbutaline in acute asthma. Indian J Chest Dis Allied Sci 1984; 26: Chronic bronchitis, asthma, and pulmonary emphysema: a statement by the Committee on Diagnostic Standards for Non-tuberculosis Respiratory Disease; American Thoracic Society. Am Rev Respir Dis 1962; 85: National Asthma Campaign. Initial assessment of severity of asthma in children. In: Asthma management handbook Melbourne, Australia: National Asthma Campaign, CHEST / 122 / 4/ OCTOBER,

10 The Effectiveness Asthma of IV in β-agonists the Emergency in Treating Department Patients * With Acute Andrew H. Travers, Brian H. Rowe, Samantha Barker, Arthur Jones and Carlos A. Camargo, Jr Chest 2002;122; DOI /chest This information is current as of December 1, 2009 Updated Information & Services References Citations Open Access Permissions & Licensing Reprints alerting service Images in PowerPoint format Updated Information and services, including high-resolution figures, can be found at: l.html This article cites 19 articles, 12 of which can be accessed free at: 0.full.html#ref-list-1 This article has been cited by 2 HighWire-hosted articles: 0.full.html#related-urls Freely available online through CHEST open access option Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: Information about ordering reprints can be found online: Receive free alerts when new articles cite this article. Sign up in the box at the top right corner of the online article. Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online article figure for directions