Continuous vs Intermittent -Agonists in the Treatment of Acute Adult Asthma* A Systematic Review With Meta-analysis Gustavo J. Rodrigo, MD; and Carlos Rodrigo, MD Background: Since the late 1980s, there has been considerable clinical and academic interest in the use of continuous aerosolized bronchodilators for the treatment of patients with acute asthma. These studies have suggested that this therapy is safe, is at least as effective as intermittent nebulization, and may be superior to intermittent nebulization in patients with the most severely impaired pulmonary function. Objectives: To determine whether continuous nebulization offered an advantage over intermittent nebulization for the treatment of adults with acute asthma in the emergency department (ED). Design: Systematic review of randomized controlled trials of adults with acute asthma. Outcomes: Change in pulmonary function tests as primary outcome, and admissions to the hospital and side effects as secondary outcomes. Results: Six studies including 393 adults with acute asthma were selected. No significant differences were demonstrated between the two delivery methods in terms of pulmonary function measures obtained after 1hoftreatment (standardized mean difference [SMD], 0.15; 95% confidence interval [CI], 0.35 to 0.05) and after 2 to 3hoftreatment (SMD, 0.19; 95% CI, 0.39 to 0.01). No significant heterogeneity was demonstrated (p > 0.5). At the end of treatment, there was a significantly greater decrease in pulse rate when the continuous nebulizer was used (weighted mean difference [WMD], 6.82; 95% CI, 8.67 to 3.90 beats/min; 2, 2.55; degrees of freedom [df], 4; p 0.6). Additionally, the analysis showed a significant decrease of serum potassium concentration with the use of intermittent nebulization (WMD, 0.12; 95% CI, 0.24 to 0.01 mmol/l; 2, 0.5; df, 2; p 0.8). However, this finding was obtained on the analysis of only two trials. Finally, at the end of the study period, no significant differences were identified between patients treated with continuous or intermittent nebulization with respect to hospital admission (relative risk, 0.68; 95% CI, 0.33 to 1.38; 2, 2.06; df, 1; p 0.2). Conclusions: Overall, this review supports the equivalence of continuous and intermittent albuterol nebulization in the treatment of acute adult asthma. (CHEST 2002; 122:160 165) Key words: acute asthma treatment; albuterol; -agonists; intermittent or continuous nebulization Abbreviations: CI confidence interval; df degrees of freedom; ED emergency department; HEART highoutput extended aerosol respiratory therapy; PEF peak expiratory flow; SMD standardized mean difference; WMD weighted mean difference Inhaled 2 -agonists are the drugs of choice with which to treat patients with acute severe asthma. 1,2 In comparison to the systemic approach, inhalation is associated with a more rapid onset of *From the Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay. Manuscript received October 9, 2001; revision accepted January 23, 2002. Correspondence to: Gustavo J. Rodrigo MD, Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Av 8 de Octubre 3020, Montevideo 11600, Uruguay; e-mail: gurodrig@ adinet. com.uy. action and fewer systemic side effects. However, there are controversies regarding the use of 2 - agonists in the treatment of patients with acute asthma exacerbations. Thus, there is a consensus that frequent intermittent nebulizations (ie, every 20 min within the first hour) are appropriate, but continuous nebulization also has been proposed. 1,2 Thus, since the late 1980s, there has been considerable clinical and academic interest in the use of continuous aerosolized bronchodilators for the treatment of acute asthma. 3 This method of therapy has potential 160 Clinical Investigations
advantages in terms of time, costs, and medication delivery. This feature may allow deeper penetration into the airways and greater reduction of bronchoconstriction. Furthermore, this may result in fewer side effects. To date, a limited number of trials have examined this topic. Thus, therapy with continuous albuterol nebulization was considered to be better than intermittent therapy in children, 4 8 but in adults the data are contradictory and do not allow definitive conclusions. 9,10 We reviewed the literature to determine whether continuous nebulization offered an advantage over intermittent nebulization for the treatment of adults with acute asthma in the emergency department (ED). We also wanted to determine whether the intensity of the treatment and the severity of the exacerbation influenced the extent of the effect. Materials and Methods Literature Search and Selection of Studies A computerized search was conducted to identify literature on the topic of continuous vs intermittent nebulization with -agonists in adult patients with acute asthma. We searched for studies using the MEDLINE (1966 to 2001), EMBASE (1980 to 2001), and CINAHL (1982 to 2001) databases. The following MeSH terms were used in the search: Emerg* or acute or status and continuous or intermittent or multi-dose or dosage or nebuli* and -agonist or bronchodilat*. Also, a search of the Cochrane Controlled Trials Register was completed using the above terms. Finally, we checked bibliographies of all trials and review articles that had been identified from the databases and medical journals to determine potentially relevant citations. Criteria for considering trials included the following: (1) randomized controlled trials conducted in an ED setting; (2) studies with adult patients (ie, 18 years old) with acute asthma; (3) patients who had been randomized to receive either continuous or intermittent -agonists early in the ED treatment (continuous -agonist administration included frequent refilling of the nebulizer, use of a nebulizer and infusion pump, or use of a large-volume nebulizer with high-output extended aerosol respiratory therapy [HEART]); and (4) change in pulmonary function test results as the primary outcome (absolute or percent predicted of peak expiratory flow [PEF] and absolute or percent predicted FEV 1 ), and side effects/adverse effects and admissions to the hospital as secondary outcomes. Assessments included up to 3 h of treatment. Because the peak bronchodilator effect after the administration of multiple doses of salbutamol/albuterol occurs within 1 to 2 h, and because approximately two thirds of adults with acute asthma require 90 min of treatment with inhaled -agonists to have their conditions improve sufficiently to be discharged from the hospital, it is reasonable to expect significant improvement at this time. 11,12 The two authors independently examined (title and abstract) the output generated from the search. Any potentially relevant articles were obtained, irrespective of the original language of publication. From the full text of potentially relevant articles, the reviewers assessed each study independently, in terms of population, intervention, study design, and outcome, to determine whether the study met the inclusion criteria. Reviewers were masked to the authors names, the name of journal, and the date of publication. Agreement among reviewers was measured using statistics, and disagreement was settled by consensus. The methodological quality of each selected trial was assessed using the instrument of Jadad et al. 13 This instrument evaluates the quality of randomization and blinding, and the reasons for withdrawal on a score of 0 (worst) to 5 (best). Statistical Analysis For continuous variables, a random-effects standardized mean difference (SMD) or a weighted mean difference (WMD) and the 95% confidence interval (CI) were calculated for each study. All similar studies were pooled using random-effects SMD or WMD and 95% CIs. The SMD, reported in SD units, was used when the change in the same pulmonary function test was reported in different units (ie, the weighted sum of each trials times the group mean difference divided by its pooled SD). 14,15 The WMD was reported for pulmonary function tests using the same unit of measure (ie, the weighted sum of each trial s difference between the mean of the experimental and the control groups, reported on the same scale). 16 The contribution of each trial to the pooled estimate was proportional to the inverse of the variance. 17 The homogeneity of the effect size was tested with the method of DerSimonian and Laird, 18 with p 0.1 as the level of significance. Sensitivity analysis 19 was performed to examine the effect on the results of the following: (1) the severity of airway obstruction (PEF or FEV 1 50% of predicted vs 50% of predicted); (2) the methodological quality (Jadad et al 13 criteria, 3vs 3); and (3) -agonist dose (high vs low). The metaanalysis was done with a computer software package (Review Manager, version 4.1 2000; Cochrane Collaboration and Update Software). Results Sixty-two articles were identified in the initial search. Of these, reviewers found that 16 articles were potentially eligible. Most of the others were excluded because they were not clinical trials of patients with acute asthma. The reasons for subsequent exclusion were nonrandomized trials (n 6), 3,5,6,20 22 only a continuous nebulization group included in the study (n 1), 23 only pediatric patients included in the study (n 2), 7,8 and non-acute asthma patients included in the study (n 1). 4 Finally, six articles were selected for inclusion in the meta-analysis. 9,10,24 27 Four studies were from the United States, 9,24,26,27 one was from Canada, 25 and one was from Tunisia. 12 The statistic for inter-rater agreement on the inclusion or exclusion of potential trials was 1.0. All studies reported pulmonary function measures, five reported heart rates, two reported admission rates, and two reported serum potassium concentrations. Table 1 shows the characteristics of the trials included in this review. This review analyzed 393 adults who were included in six trials. One study 27 compared nebulized albuterol at high doses (ie, 7.5 mg) or standard doses (ie, 2.5 mg) given either continuously for 1 h, or www.chestjournal.org CHEST / 122 / 1/ JULY, 2002 161
Trial Patients, No. Table 1 Summary of Included Trials Jadad Score Baseline Severity Drug (Dose) Continuous Nebulizer Colacone et al 25 42 2 50% FEV 1 Albuterol (10 mg over 2 h) Large-volume nebulizer Lin et al 9 38 3 50% PEF Albuterol (30 mg over 110 HEART nebulizer min) Rudnitsky et al 24 99 2 Moderate to severe Albuterol (10 mg over 70 min) HEART nebulizer Reisner et al 26 20 2 60% PEF Albuterol (7.5 mg/h) Conventional nebulizer with infusion pump Shrestha et al 27 152 2 40% FEV 1 Albuterol (2.5 mg or 7.5 mg over 2 h) Frequent refilling of conventional nebulizer Besbes-Ouanes et al 10 42 3 50% PEF Albuterol (27.5 mg over 6 h) Frequent refilling of conventional nebulizer intermittently every hour for 2 h. The nebulized doses of albuterol in the first hour ranged between 2.5 and 16 mg. All studies reported the use of systemic corticosteroids, and four studies included acute severe asthma patients (pulmonary function, 50% of predicted). Effects on Pulmonary Function In the six selected studies, a variety of pulmonary function tests was recorded over the ED stay. Four studies recorded FEV 1 as percent predicted, three recorded absolute FEV 1, and two recorded both percent predicted and absolute PEF. The results were pooled at 1 h and at 2 to 3 h after the start of treatment. No significant differences were demonstrated between the two delivery methods in terms of pulmonary function measurements at 1 h and at 2 to 3 h. More specifically, there were no significant group differences in the SMD observed after 1 h of treatment (SMD, 0.15; 95% CI, 0.35 to 0.05) and after 2 to 3hoftreatment (SMD, 0.19; 95% CI, 0.39 to 0.01) [Fig 1]. No significant heterogeneity was demonstrated (p 0.5). In the same way, the four trials reporting responses to treatment as the change in the percentage predicted of FEV 1 9,25 27 did not show group differences after 1 h of treatment (WMD, 1.73; 95% CI, 8.51 to 5.05) and after 2 to 3 h of treatment (WMD, 2.18; 95% CI, 6.24 to 1.88). Side Effects and Hospital Admissions Five studies reported the final heart rate. 9,10,24 26 At the end of treatment, there was a significant, but small, decrease in pulse rate when continuous nebulization was administered (WMD, 6.82; 95% CI, 8.67 to 3.90 beats/min; 2, 2.55; degrees of freedom [df], 4; p 0.6) [Fig 2]. Additionally, only two studies 10,27 reported final serum potassium concentrations. The analysis showed a significant decrease with the use of intermittent nebulization (3.87 vs 3.76 meq/l, respectively; WMD, 0.12; 95% CI, 0.24 to 0.01 mmol/l; 2, 0.5; df, 2; p 0.8). Finally, two studies 9,10 reported hospital admissions, and no significant differences were identified between patients treated with continuous or intermittent nebulization at the end of the study period (relative risk, 0.68; 95% CI, 0.33 to 1.38; 2, 2.06; df, 1; p 0.2). Side effects such as tremor and palpitations were reported so infrequently that they could not be considered in this review. Sensitivity Analyses The robustness of the findings to different assumptions was analyzed in sensitivity analyses. Three subgroup analyses were specified as follows a priori: severity of airway obstruction (pulmonary function, 50% vs 50% of predicted); methodological quality (Jadad et al 13 criteria, 3 vs 3); and -agonist dose ( 5vs 5 mg/h of albuterol). Four studies included patients with severe asthma, and two included patients with moderate asthma. No benefit was observed after 1hoftreatment (severe asthma subgroup: SMD, 0.20; 95% CI, 0.43 to 0.04; 2, 3.5; df, 4; p 0.5; moderate asthma subgroup: SMD, 0.04; 95% CI, 0.40 to 0.33; 2, 0.4; df, 1; p 0.5) and after 2 to 3hoftreatment (severe asthma subgroup: SMD, 4.32; 95% CI, 8.78 to 0.14; 2, 1.7; df, 4; p 0.8; moderate asthma subgroup: SMD, 3.11; 95% CI, 10.2 to 16.4; 2, 1.38; df, 1; p 0.3). Similarly, the methodological quality of the studies did not alter the results. Thus, there were no differences in pulmonary function between high-quality and low-quality trials after 1hoftreat- ment (high-quality trials: SMD, 3.5; 95% CI, 11.6 to 4.6; 2, 1.24; df, 1; p 0.3; low-quality trials: SMD, 2.6; 95% CI, 7.3 to 1.9; 2, 3.59; df, 4; p 0.5) and after 2 to 3hoftreatment (highquality trials: SMD, 3.4; 95% CI, 12.0 to 5.3; 2, 0.89; df, 1; p 0.4; low-quality trials: SMD, 3.6; 95% CI, 8.4 to 1.2; 2, 3.26; df, 4; p 0.5). Finally, there was no apparent impact on pulmonary function 162 Clinical Investigations
Figure 1. Pooled SMD of the change in lung function 1 h and 2 to 3 h after the start of treatment. The width of the horizontal line represents the 95% CI around a point estimate (squares). The size of the point estimate represents the relative weight (% weight) of each trial in the pooled summary estimate (diamond). CN continuous nebulization; IN intermittent nebulization. when high doses or low doses of albuterol were used after 1 h of treatment (high doses: SMD, 0.0; 95% CI, 0.34 to 0.33; 2, 0.72; df, 2; p 0.7; low doses: SMD, 0.14; 95% CI, 0.42 to 0.13; 2, 3.38; df, 3; p 0.3) and after 2 to 3hoftreatment (high doses: SMD, 2.92; 95% CI, 8.94 to 3.11; 2, 0.86; df, 2; p 0.6; low doses: SMD, 4.16; 95% CI, 10.1 to 1.81; 2, 3.17; df, 3; p 0.5). Figure 2. Pooled WMD of heart rate at the end of treatment. The width of horizontal line represents 95% the CI around a point estimate (squares). The size of the point estimate represents the relative weight (% weight) of each trial in the pooled summary estimate (diamond). See the legend of Figure 1 for abbreviations not used in the text. www.chestjournal.org CHEST / 122 / 1/ JULY, 2002 163
Discussion The purpose of this systematic review is to determine whether continuous nebulization offered an advantage over intermittent nebulization for the treatment of adults with acute asthma in the ED. Our analysis failed to demonstrate statistically significant differences between groups in terms of pulmonary function or hospital admission rates. The intensity of treatment (ie, the albuterol dose) and the severity of the exacerbation did not influence the effect of either method of albuterol delivery. Thus, these findings argue against the routine use of continuous nebulization in the ED treatment of patients with acute asthma, and the decision to use one of these nebulization methods should be based on logistical and cost considerations. Overall, this review supports the equivalence of continuous and intermittent albuterol nebulization in the acute treatment of nonventilated adult asthma patients. Also, patients who received continuous nebulization showed lower pulse rates, and a decrease of serum potassium concentration compared to patients receiving the same -agonist via intermittent nebulization. However, these findings are based on only five trials and two trials, respectively. Consequently, this information should be interpreted with caution. Since all studies reviewed excluded patients with life-threatening asthma (for example those patients who have been considered for ventilation), these results should not be extrapolated to this group. This study met most of the methodological criteria that have been suggested for scientific reviews. 28,29 The patients had the typical features of patients with moderately to severely acute asthma when they presented for care to an ED. All of the included trials were randomized and placebo-controlled. Although sensitivity analysis and the tests of homogeneity suggest that the results of this meta-analysis were relatively robust, this review is limited by the number of selected trials and the quality of the data. Even if the number and size of the pooled studies were small, the exclusion of trials with lower reported methodological quality did not affect the conclusions. Clearly, the current conclusions may be seriously modified by the results of larger trials. 30 In summary, for adults seen and assessed for acute exacerbations of asthma, this review found no significant differences between the two methods for treatment delivery. Consequently, the choice of delivery method should reflect practice situations and economic considerations. However, the findings are based on a reduced number of trials, and these conclusions may not apply to patients with lifethreatening asthma. References 1 National Asthma Education and Prevention Program. 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