INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The use of anticholinergic drugs as the initial bronchodilators have been consistently reported to be inferior to the use of a beta-adrenergic agent on improving airflow in status asthmaticus (1). On the other hand, the use of both classes of bronchodilators, either simultaneously or in sequence, has produced contradictory results. Recently, a series of systematic reviews have begun to clarify this point. First, a review of 10 randomized controlled trials of children and adolescents (2) receiving ₂-agonists for acute asthma, with and without the addition of inhaled anticholinergics, showed significant group differences in lung function supporting the combination treatment; additionally, multiple-dose anticholinergic protocols, mainly in children and adolescents with severe exacerbations, reduced the risk of hospital admission by 30%. In a second meta-analysis (adult patients) of 10 randomized, double-blind, placebo-controlled trials (3), ipratropium bromide (IB) was associated with a significant increase in pulmonary function (effect size = 0.38, 95% CI: 0.27 to 0.48) and a 27% reduction in hospital admissions. Finally, a third systematic review (4), which included 10 randomized, double-blind, controlled trials (5), with 1,483 adults with acute asthma, showed a 10% increase in pulmonary function (the greatest improvement in patients with more severe obstruction) and a 38% admission rate reduction. Surprisingly, almost all these beneficial effects were obtained with the utilization of single-dose protocols consisting of small doses of IB. Because there is substantial evidence that patients with acute asthma respond to increasing doses of bronchodilators (15), that thought can be applied to IB therapy. In fact, in a double-blind, randomized preliminary trial (16), we studied the effects of high and cumulative doses of albuterol and IB in the treatment of acute adult asthma and obtained an additional 30% increase in pulmonary function in the IB group. However, there have been no larger clinical trials that study the effects of multiple-dose protocols in adult patients.

Consequently, we designed a larger double-blind, randomized, prospective trial to test our hypothesis that patients with acute asthma given combination high dose therapy with IB and ₂-agonists will have greater improvement in pulmonary function and fewer hospital admissions than those given ₂- agonists alone. Subgroup analysis was performed using: (1) duration of attacks prior to emergency department (ED) presentation (patients with  24 h versus patients with < 24 h), (2) severity of obstruction at presentation (patients with  30% of predicted FEV₁ versus patients with > 30% of predicted FEV₁) and (3) use of inhaled ₂-agonists before presenting at the ED (patients who received ₂-agonists versus patients who did not).

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Patients

We studied all adult patients with acute asthma who were seen in the ED of the Hospital Central de las FF.AA. in Montevideo, Uruguay, during a 1-yr period. This department sees approximately 60,000 patients annually, with about 1,200 visits/yr for adult patients with acute asthma. All patients met the diagnosis criteria of asthma of the American Thoracic Society (17). The inclusion criteria for patients were: (1) age between 18 and 50 yr, (2) a FEV₁ and a peak expiratory flow (PEF) less than 50% of predicted value, (3) patients were excluded if they had fever ( 38° C) or history of chronic cough, cardiac, hepatic, or renal disease, glaucoma, bladder dysfunction, prostatism, or other medical diseases, or pregnancy, and (4) an expressed willingness to participate in the study, with written informed consent obtained. The Hospital Ethics Committee approved the study.

Protocol

Subjects were entered in a double-blind, randomized manner into one of two groups. The IB group received albuterol and IB (Combivent; Boehringer, Ingelheim, KG, Ingelheim am Rhein, Germany) (120 µg albuterol sulfate and 21 µg IB per actuation) delivered by a metered-dose inhaler (MDI) into a spacer device (Volumatic; Allen & Hanburys Ltd, Greenford, UK) in a dose of four puffs at 10-min intervals (480 µg albuterol and 84 µg IB). The second group (control) received four puffs from an identical MDI that contained albuterol at 10-min intervals (480 µg). Each puff was followed by two deep inhalations from the spacer. Patients did not receive another treatment in the ED prior to study therapy. Volumatic is a 750-ml pear-shaped extension tube 22 cm long with a one-way inhalation valve. The protocol involved 3 h of this treatment (24 puffs or 2,880 µg albuterol and 504 µg IB each h). The hospital pharmacy prepared the IB and control treatments in random sequence, using a random number table, in identical canisters, which were then numbered consecutively. For each study patient, the treatment nurse selected the next numbered canister from an opaque envelope, and all measures were made by investigators unaware of the patients' group assignment. Aminophylline, systemic steroids, and oxygen treatments were excluded in all patients. The protocol included the administration of oxygen if Sa_O2 decreased to < 92%; however, during the study, all patients presented Sa_O2values > 92%.

Measures

The following variables were measured in each patient immediately before starting treatment and at 30-min intervals for 3 h after presentation: FEV₁, PEF, respiratory rate, heart rate, accessory-muscle use, dyspnea, and wheezing. Additionally, serum theophylline concentration was determined from all subjects' pretreatment. PEF was measured with a mini-Wright peak flow-meter (Clement Clarke, Harlow, UK). The highest of three values was recorded. FEV₁ was measured using a Vitalograph Compact spirometer (Vitalograph Ltd, Buckingham, UK). Three successive maximal expiratory curves were recorded at each assessment, and the highest value was selected according to the criteria of the American Thoracic Society (18). Heart rate was measured from continuous electrocardiogram. Sa_O2 was measured with a finger oximeter (N-180 Pulse oximeter; Nellcor, Hayward, CA). Accessory-muscle use was defined as visible retraction of the sternocleidomastoid muscles (19). Dyspnea was defined as the patient's own assessment of breathlessness. Wheezing was defined as musical or whistling breath sounds heard with a stethoscope during expiration. these clinical factors were graded in a scale from 0 to 3 in which 0 denoted absent, 1 mild, 2 moderate, and 3 severe. At the end of the therapy, the patient was asked to indicate the presence or absence of each of six symptoms (nausea, palpitations, tremor, anxiety, headache, and dry mouth). Also, an interviewer determined the duration of symptoms before presentation, which specifically included how long the patient had been more wheezy and short of breath than usual; a decline in the PEF, if available, was considered. When it was possible, patient's relatives were asked to confirm patient's information. The decision to discharge or admit a patient was made at the end of the protocol by senior ED staff without knowledge of previous patient group allocation. Patients were discharged from the ED according to the following criteria: if accessory-muscle use was abated, if wheezing was judged minimal to completely resolved, if they were free of dyspnea, and if FEV₁ or PEF was > 60% of predicted. The physicians prescribed oral prednisone (60 mg for 7 d) for all discharged patients, or intravenous steroids for those who were admitted.

Primary outcome measures were improvement in pulmonary function (FEV₁ or PEF), and admission rate. Secondary outcomes were clinical measures, respiratory and heart rates, Sa_O2, side effects, and proportion of patients who reached the discharge threshold during the 3-h treatment for each group.

Statistical Methods

All data were analyzed with a "SPSS PC plus" software package (SPSS Inc., Chicago, IL). Estimations from power calculations showed that the use of 180 subjects was sufficiently sensitive to detect a 38 L/min difference in PEF, a 0.25 L difference in FEV₁, and 17% difference in hospital admissions, with  = 0.05 and  = 0.20 (i.e., with 80% power). In a previous study (20), we could estimate the mean (± SD) final FEV₁ value (expressed in liters) to be expected at 3 h was 1.52 ± 0.50. Changes in FEV₁ and PEF were evaluated using repeated-measures analysis of variance (ANOVA), with one between-subject factor (IB control) and one within-subject factor (time). One-way repeated-measures ANOVA was used to compare baseline values for each variable, after assessing both normality of distributions and homoscedasticity. When the F value indicated significant differences between group means, post hoc pairwise multiple comparisons were performed using the Scheffé test. To provide a graphic summary, Kaplan-Meier curves of the proportion of patients who reached the discharge threshold during the 3 h of treatment were used. Baseline data of the two treatments were compared by t test for normally distributed independent samples, or the Mann-Whitney U test for non-normally distributed continuous variables. Chi-square with Yate's correction or Fisher's exact test were used for categorical variables. A p value less than 0.05 using a two-tailed test was taken as being of significance for all statistical tests. Means values ± SD were calculated for continuous variables. Clinical factors graded on a scale of 0 to 3 were reported as medians and interquartile ranges. The 95% confidence intervals (CI), relative risk (RR), relative risk reduction (RRR), and number needed to treat (NNT) were calculated with standard formulas (21).

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

One hundred ninety-five patients were assessed in the ED. Of these, 15 (eight in the control group and seven in the IB group) did not fit the inclusion criteria for the study because they did not meet the age requirement (seven patients), or the FEV₁ requirement (five patients), or had cardiac disease (three patients). Of the remaining 180 patients, (mean age ± SD, 34.4 ± 10.5 yr), 88 were randomly assigned to the IB group and 92 to the control group. Analyses were by intention-to-treat, although no withdrawals occurred. Baseline characteristics of the 180 patients are presented in Table 1. There were no significant differences between groups for the characteristics examined.

The relationship between the cumulative doses of albuterol and IB and the change in PEF and FEV₁ were analyzed (Figures 1 and 2). Mean PEF improved significantly over baseline values for both groups (p < 0.001). The magnitude of PEF improvements over baseline values was significant at all times of treatment (p < 0.01). The two-way repeated-measures ANOVA showed a significant difference between groups (p = 0.001). The final improvements from baseline were 102.0 ± 62.5% for the IB group and 81.5 ± 60.1% for the control group. Subjects who received IB had an overall 20.5% (95% CI: 2.6 to 38.4%, p = 0.02) greater improvement in PEF from the control group. Compared with the control group, the IB group had better PEF at 30, 60, 90, 120, 150, and 180 min (all p < 0.01). The ANOVA suggested that differences between groups increased with time (p = 0.001). The mean PEF values at 30, 60, 90, 120, 150, and 180 min were 271.8 ± 84.1, 296.5 ± 87.9, 314.3 ± 91.1, 324.4 ± 96.0, 332.2 ± 98.4, and 335.9 ± 100.2 L/min, respectively, in the IB group, and 227.1 ± 71.7, 250.7 ± 78.5, 262.0 ± 80.3, 271.8 ± 80.5, 280.3 ± 83.4, and 286.1 ± 89.2 L/min in the control group (mean final difference = 49.8, 95% CI: 21.8 to 77.8 L/min). The same pattern held for changes in FEV₁. The improvement over baseline was significant in both groups (p < 0.01). There was a significant difference between both groups (p = 0.001). Subjects receiving IB had a 153.7 ± 96.0% improvement from baseline, and control subjects had a 105.6 ± 98.2% improvement from baseline. Patients who received IB had an overall 48.1% (95% CI: 19.8 to 76.4%, p = 0.001) greater improvement in FEV₁ from that of the control group. Compared with the control group, the IB group had better FEV₁ at 30, 60, 90, 120, 150, and 180 min (all p < 0.01). The mean FEV₁ values at 30, 60, 90, 120, 150, and 180 min were 1.56 ± 0.64, 1.78 ± 0.73, 1.87 ± 0.77, 1.95 ± 0.80, 2.04 ± 0.84, and 2.05 ± 0.85 L, respectively, in the IB group, and 1.25 ± 0.52, 1.43 ± 0.54, 1.48 ± 0.58, 1.50 ± 0.60, 1.54 ± 0.59, and 1.56 ± 0.63 L in the control group (mean final difference = 0.50, 95% CI: 0.28 to 0.72 L). Also, differences between groups increased with time (p = 0.001).

View larger version (16K): [in this window] [in a new window]   Figure 1.   PEF values (percent of predicted) after the administration of albuterol (control) or albuterol plus ipratropium bromide (IB). Data points are mean values, and the brackets represent 1 SD; **p < 0.01 versus IB.

View larger version (17K): [in this window] [in a new window]   Figure 2.   FEV1 values (percent of predicted) after the administration of albuterol (control) or albuterol plus ipratropium bromide (IB). Data points are mean values, and the brackets represent 1 SD; **p < 0.01 versus IB.

In the subgroup analysis, patients were divided according to; (1) the duration of their asthma attacks prior to ED presentation ( 24 h versus < 24 h), (2) the severity of obstruction at presentation ( 30% of predicted FEV₁ versus > 30%), and (3) the use of inhaled ₂-agonists before presenting at the ED (patients who used ₂-agonists versus patients who did not use ₂-agonists). Patient with symptoms  24 h had significantly greater improvement of mean FEV₁% predicted for the IB group than did the control group (p = 0.003) (Figure 3), and lower admission rates (RR = 0.32, 95% CI: 0.16 to 0.64). On the contrary, there was no significant differences in pulmonary function (p = 0.09) and hospital admissions (RR = 0.93, 95% CI: 0.45 to 1.91) between patients with < 24 h. In the same way, IB subgroup patients with more severe obstruction ( 30% of predicted FEV₁) showed a significant increase (p = 0.001) in pulmonary function (Figure 4) and a decrease in hospitalization rate (RR = 0.61, 95% CI: 0.38 to 0.99) compared with the control group; there were no differences between the subgroups with > 30% of predicted FEV₁ (p = 0.6) (RR = 0.39, 95% CI: 0.10 to 1.46). Finally, the use of inhaled ₂-agonists before presenting at the ED did not modify the pulmonary function response (Figure 5) and the admission rates. Patients treated with IB had significant FEV₁ increases regardless of previous use of ₂-agonists (p = 0.01 previous use; p = 0.03 no previous use) and nonsignificant decreases in hospitalization rates (RR = 0.56, 95% CI: 0.31 to 1.01, and RR = 0.48, 95% CI: 0.20 to 1.15).

View larger version (21K): [in this window] [in a new window]   Figure 3.   FEV1 values (percent of predicted) after the administration of albuterol (control) or albuterol plus ipratropium bromide (IB) in patients with previous durations of the attack  24 h (left panel ) or < 24 h (right panel ). Data points are mean values, and the brackets represent 1 SD; *p < 0.5, **p < 0.01 versus IB.

View larger version (20K): [in this window] [in a new window]   Figure 4.   FEV1 values (percent of predicted) after the administration of albuterol (control) or albuterol plus ipratropium bromide (IB) in patients with FEV1 at presentation  30% (left panel ) or > 30% (right panel ). Data points are mean values, and the brackets represent 1 SD; **p < 0.01 versus IB.

View larger version (22K): [in this window] [in a new window]   Figure 5.   FEV1 values (percent of predicted) after the administration of albuterol (control) or albuterol plus ipratropium bromide (IB) in patients with previous (left panel ) or no previous (right panel ) use of beta-agonists. Data points are mean values, and the brackets represent 1 SD; *p < 0.5, **p < 0.01 versus IB.

At the end of protocol (3 h), 39% (n = 36) of patients in the control group and 20% (n = 18) in the IB group were admitted (p = 0.01). The use of high doses of IB reduced the risk of hospital admission 49% (RR = 0.51, 95% CI: 0.31 to 0.83). Five (95% CI: 3 to 17) patients would need to be treated with high doses of IB to prevent a single admission. Kaplan-Meier estimated curves of the proportion of patients who reached the discharge threshold during the 3 h of treatment showed a significant difference in favor of the IB group (log-rank test = 0.005) (Figure 6). The IB group showed higher rates of patients who obtained the discharge threshold than the control group at 90, 120, 150, and 180 min. The proportions (95% CI) at these treatment times were 57% (47 to 67%), 61% (51 to 71%), 63% (53 to 73%), and 79% (71 to 87%), respectively, in the IB group, and 34% (25 to 43%), 36% (27 to 45%), 38% (28 to 48%), and 61% (52 to 70%), respectively, in the control group.

View larger version (12K): [in this window] [in a new window]   Figure 6.   Kaplan-Meier estimated curves showing the percent of patients in the albuterol (control) and ipratropium (IB) groups who obtained the discharge threshold during the treatment time. Log-rank test = 8.16, p < 0.005.

There was no difference between control and IB groups in heart rate (p = 0.4). The 3-h mean heart rates were 102.8 ± 17.6 in the control group and 100.0 ± 17.3 in the IB group (difference = 2.8, 95% CI: 4.4 to 10.0). Patients in the control group had a mean increase in heart rate of 0.5 ± 15.5 beats/ min and those in the IB group had a mean increase of 1.9 ± 12.6 beats/min from baseline values. Despite continuous ECG recording, there were no signs of arrhythmia. Both groups produced nonsignificant increases in Sa_O2 (p = 0.5). The mean final Sa_O2 levels were 97.3 ± 1.7% in the control group and 97.1 ± 1.6% in the IB group (difference = 0.2, 95% CI: 1.0 to 1.4). Finally, there was a higher incidence in only one of six symptoms monitored (Table 2). Patients treated with IB showed a higher incidence in dry mouth. No patient had clinical deterioration in the ED.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

In this randomized, double-blind, controlled trial, we demonstrated a significant advantage when high doses of IB and albuterol are combined (multiple-dose protocol) in the emergency treatment of adult acute severe asthma. The improvements associated with IB were reflected in higher bronchodilator responses (mean FEV₁ increase = 0.5, 95% CI: 0.28 to 0.72 L), lower rates of hospital admissions (RR = 0.51, 95% CI: 0.31 to 0.83), shorter time to obtain the discharge threshold, and minimal side effects. On the basis of our data, approximately five adults with acute asthma would need to be treated with IB to prevent one hospitalization. This represents a substantial reduction in cost, given the higher cost of admission compared with that of the drug. In our hospital, the cost of hospitalization is $700/d. On the contrary, because IB is administered with albuterol, the incremental cost is related only to the cost of the drug ($4 per 200 puffs).

Previous recent studies have suggested the use of high doses of anticholinergics and -agonists in the treatment of patients with acute asthma. Thus, a systematic review (2) of randomized controlled trials of children and adolescents with acute asthma showed a 30% reduction (RR = 0.72, 95% CI: 0.53 to 0.99, NNT = 11) in hospital admission rate and a significant improvement in spirometry, exceeding half SD in change, after the addition of multiple doses of IB to ₂-agonists (22- 25). All of studies reviewed in this meta-analysis used wet nebulization. A second meta-analysis (3) with data from 10 studies (adult patients) found a significant increase in pulmonary function (effect size = 0.38, 95% CI: 0.27 to 0.48), and a RR of hospitalization of 0.73 (95% CI: 0.53 to 0.99). Again, all studies used nebulization. Finally, the most recent systematic review of 10 randomized, double-blind, controlled trials that enrolled almost 1,500 adults with acute asthma (4) demonstrated a 10% (effect size = 0.14, 95% CI: 0.04 to 0.24) increase in pulmonary function and a 38% admission rate reduction (OR = 0.62, 95% CI: 0.44 to 0.88). The greatest improvement in pulmonary function was observed in patients with more severe obstruction (FEV₁ or PEF less than 35% of predicted at presentation; effect size = 0.38, 95% CI: 0.09 to 0.67). However, these beneficial effects were obtained with the utilization of single-dose protocols (the typical therapeutic protocol used have consisted in a dose of 0.5 mg of nebulized IB mixed with albuterol on admission), with the exception of one study. In this trial, Weber and colleagues (14) conducted a small (n = 67) randomized and blinded study in ED patients with acute bronchospasm treated via continuous nebulization with either a combination of IB (1 mg/h) plus albuterol or albuterol alone. They found that although the direction of all three outcome measures (PEF [standardized mean difference = 0.45], hospital admissions [OR = 0.47], and length of stay [mean difference of 20 min]) favored a reduction of IB therapy, there was no statistically significant difference between groups. Reasons for this apparent lack of significant differences in outcome measures may include one or more of the following factors: (1) the small number of patients enrolled, (2) the study included patients with acute asthma with a relative higher PEF at presentation (mean percent of predicted PEFR = 44.8%), and (3) the study included both asthma and COPD exacerbations in the ED. In the same way, Qureshi and colleagues (25) conducted a randomized, double-blind study of 434 children who had acute exacerbations of asthma. These investigators concluded that among children with severe obstruction, the addition of only 1 mg of nebulized IB to albuterol significantly decreases the hospitalization rate (RR = 0.71, 95% CI: 0.54 to 0.92). They reported a virtually identical benefit of IB with respect to hospital admissions (NNT = 6). Finally, in a double-blind, randomized preliminary study (16), a multiple-dose protocol of albuterol alone was compared with albuterol combined with IB (2,400 µm of albuterol and 480 µg of IB each hour). For the first time, drugs were administered through a MDI and spacer, and after 3 h of protocol, a significant additional bronchodilatation was found in the IB group (mean PEF difference = 116.8, 95% CI: 7.4 to 226.2 L/min).

The patients most likely to benefit from the addition of high doses of IB are those with more severe obstruction (FEV₁  30% of predicted) and with long duration of symptoms before the ED presentation ( 24 h). This finding is similar to results of the two adult systematic reviews (3, 4). In the same way, in two previous pediatric studies (26, 27), a statistically significant difference in admission rates was found only among patients with more severe obstruction. In our study, subjects were required to remain in the ED for the entire treatment period (3 h); therefore, the length of stay was not an outcome. However, we measured a substitute end point: the proportion of patients who reached the discharge threshold during the 3 h of treatment, in accord with previous criteria. Thus, the IB group showed a higher rate of patients who obtained the discharge threshold than the control group as early as at 90 min.

The higher degree of bronchodilatation obtained in this study is probably related to the following factors: (1) we delivered the drugs through a MDI and spacer rather than nebulization, and (2) we use a multiple-dose protocol consisting of cumulative high doses of albuterol and IB (24 puffs or 2,880 µg of albuterol and 504 µg of IB each h for 3 h); thus, the data of our study suggest that -agonists and IB should be administered repeatedly and frequently during the management of acute severe asthma rather than once, as in previous studies.

In the present study, minimal adverse effects were seen after the administration of high doses of albuterol alone or albuterol plus IB. The only difference was a higher incidence in dry mouth in the IB. Both groups showed slight increases in heart rate and oxygen saturation. These findings are in accord with the minimal serum albuterol levels obtained after the asthma treatment with high doses of albuterol delivered by MDI and spacer (28). Further, when IB is given by inhalation, its therapeutic margin is wide, and it has no important side effects (29).

Conclusions

The use of IB modified the outcome of acute adult patients in terms of an increase of pulmonary function, a reduction of hospital admissions, and a substantial reduction in costs. Our data support a considerable therapeutic benefit from addition IB to albuterol administered in high doses through MDI plus spacer, particularly in those patients in whom the FEV₁ was less than 30% of the predicted, and had a long duration of symptoms before the ED presentation ( 24 h). As a result, the addition of multiple doses of IB to -agonists (multiple-dose protocols) seems indicated as first-line therapy in adult patients with severe exacerbations of asthma. The unique features of this study are: (1) it is the larger randomized trial that uses an IB multiple-dose protocol in acute adult asthma, and (2) it is the first large trial that employed MDI and spacer rather than nebulization. All the studies reviewed in previously referred meta-analysis used nebulization. However, costs for nebulized therapy are higher than for MDI therapy because trained personnel must supervise the administration of the therapy, and the materials used for nebulization must be discarded after use. Thus, MDI and spacer is a convenient, versatile, and cost-effective way to deliver high doses of IB to the lower respiratory tract (30).