Combivent

Study objective: This study tests the hypothesis that the administration of multiple doses of inhaled albuterol (A), ipratropium bromide (IB), and flunisolide (F) provides an additional benefit to adults with acute severe asthma compared with the administration of A plus IB (A/IB) or A plus F (A/F).

Design: Randomized, double-blind, prospective trial.

Patients and interventions: One hundred seventy-two patients who presented to an emergency department were assigned to receive A, IB, and F (ie, triple drug treatment [TDG]; 56 patients), A/IB (60 patients), or A/F (56 patients). All drugs were administered through a metered-dose inhaler and spacer at 10-min intervals for 3 h.

Results: Patients who received TDG had an overall 64% greater improvement (95% confidence interval [CI], 24 to 103%; p = 0.002) in FE[V.sub.1] (mean [[+ or -] SD], 2.1 [+ or -] 0.6 L) than those who received A/F (mean, 1.7 [+ or -] 0.6 L), and a 41% greater improvement (95% CI, 1 to 80%; p = 0.04) than those who received A/B (mean, 1.8 [+ or -] 0.6 L). Differences between groups increased with time (p = 0.001). At 3 h, there was a trend toward a reduction in hospital admission rates (A/B group, 25%; A/F group, 20%; and TDG group, 11%). The patients who were the most likely to benefit (ie, those with a greater improvement in pulmonary function and a significant reduction in the hospitalization rate) from TDG were those with more severe obstruction (ie, FE[V.sub.1], < 30% of predicted). The benefit of TDG was equally evident independent of the patient's previous use of corticosteroids.

Conclusions: The data suggest that there was a therapeutic benefit from the addition of IB and F to A administered in high doses, particularly in those patients in whom the FE[V.sub.1] was < 30% of the predicted value.

Key words: acute severe asthma; albuterol; emergency department treatment; flunisolide; ipratropium bromide

Abbreviations: A = albuterol; ANOVA = analysis of variance; CI = confidence interval; ED = emergency department; F = flunisolide; IB = ipratropium bromide; MDI = metered-dose inhaler; PEF = peak expiratory flow; Sa[O.sub.2] = arterial oxygen saturation; TDG = triple drug treatment

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The management of acute asthma exacerbations in adults includes inhaled [beta]-agonists, systemic corticosteroids, and supplemental oxygen. (1,2) Nevertheless, clinical experience and research have shown that not all patients respond to that treatment. (3,4) Consequently, in the last decade it has been demonstrated that the administration of anticholinergic agents and inhaled corticosteroids to acute asthma patients who have been treated with [beta]-agonist agents improves pulmonary function and reduces the hospitalization rate. Thus, the use of multiple doses of ipratropium bromide (IB) seems to be indicated in the treatment of children and adults with acute severe asthma in the emergency department (ED). Studies (5-10) have reported a substantial reduction in hospital admissions and significant differences in lung function favoring the combined treatment. In the same way, inhaled corticosteroids have shown early therapeutic benefits in acute asthma patients: a significant improvement in pulmonary function at 2 h posttreatment in addition to a significant reduction in hospital admissions. (11-13) In both treatments, the patients who were the most likely to benefit were those with more severe obstructions and those with a long duration of symptoms before ED presentation. However, to our knowledge, there have been no studies that have evaluated the potential additional benefits of a triple drug treatment (TDG) protocol (ie, inhaled [beta]-agonists, IB, and corticosteroids) on acute severe adult asthma treatment.

We conducted a double-blind, randomized, prospective trial to test the hypothesis that patients with acute severe asthma who are given high-dose inhaled therapy with [beta]-agonists, IB, and flunisolide (F) will have a greater improvement in pulmonary function and fewer hospital admissions than those given [beta]-agonists plus IB or [beta]-agonists plus F. Subgroup analysis was performed using the following: (1) severity of obstruction at presentation (ie, patients with FE[V.sub.1] values < 30% of predicted vs patients with FE[V.sub.1] values > 30% of predicted), and (2) use of corticosteroids before presenting at the ED (ie, patients who used corticosteroids vs patients who did not use corticosteroids).

MATERIALS AND METHODS

Subjects

We studied all adult patients with acute asthma who were seen in the ED of the Hospital Central de las Fuerzas Armadas in Montevideo, Uruguay, over a 12-month period (August 1999 to August 2000). This ED sees approximately 80,000 patients annually, with about 1,200 visits per year for adult patients with acute asthma. The criteria for inclusion of patients in the study were as follows: (1) diagnosis of asthma using the criteria of the American Thoracic Society (14); (2) age between 18 and 50 years; (3) FE[V.sub.1] and peak expiratory flow (PEF) of < 50% of predicted values; and (4) an expressed willingness to participate in the study, with written informed consent obtained. Patients were excluded it' they had a fever (ie, a temperature of > 38[degrees]C), or a history of chronic cough, cardiac disease, hepatic disease, renal disease, or other disease, or pregnancy. The Hospital Ethics Committee approved the study.

Design

Subjects were entered in a double-blind, randomized manner into one of three groups. The TDG group received albuterol (A) and IB (or A/IB) (Combivent; Boehringer Ingelheim KG; Ingelheim am Rhein, Germany [100 [micro]g albuterol sulfate and 21 [micro]g IB per actuation]) and F (Flunitec; Boehringer Ingelheim KG [250 [micro]g per actuation]) by means of 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 (400 [micro]g A, 84 [micro]g IB, and 1,000 [micro]g F). The A/IB group received four puffs from identical MDIs that contained A (Ventolin; GlaxoSmithKline, London, UK [100 [micro]g per actuation]) and IB (Atrovent; Boehringer Ingelheim KG [21 [micro]g per actuation]) at 10-min intervals (400 [micro]g A and 84 [micro]g IB). Finally, the A plus F (or A/F) group received four puffs from identical MDIs that contained A (Ventolin; GlaxoSmithKline [100 [micro]g per actuation]) and F (Flunitec; Boehringer Ingelheim KG [250 [micro]g per actuation]) at 10-min intervals (400 [micro]g A and 1,000 [micro]g F). Each puff was followed by two deep inhalations from the spacer. Patients did not receive another treatment in the ED prior to study therapy. The spacer device is a pear-shaped extension tube that is 22 cm in length and has a 750-mL volume with a one-way inhalation valve. The protocol involved 3 h of treatment (ie, 24 puffs or 2,400 [micro]g A, 504 [micro]g IB, and 6,000 [micro]g F each hour). The hospital pharmacy prepared three treatments in random sequence using a random number table, in identical canisters, which then were numbered consecutively. For each study patient, the treatment nurse selected the next numbered canister from an opaque envelope, and investigators made all measurers unaware of the patient's group assignment. Therapy with aminophylline and systemic steroids were excluded in all patients. The protocol included the administration of oxygen if arterial oxygen saturation (Sa[O.sub.2]) decreased to < 92%. However, during the study, all patients presented Sa[O.sub.2] values of > 92%.

Measures

The following variables were measured in each patient immediately before starting treatment and at 30-min intervals for 3 h after presentation: FE[V.sub.1]; PEF; respiratory rate; heart rate; and Sa[O.sub.2]. PEF was measured with a peak flowmeter (mini-Wright; Clement Clarke; Harlow, UK). The highest of three values was recorded. FE[V.sub.1] was measured using a spirometer (Compact; Vitalograph Ltd; Maids Moreton House, 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. (15) Heart rate was measured from a continuous ECG. Sa[O.sub.2] was measured with a finger oximeter (model N-180 pulse oximeter; Nellcor; Hayward, CA). At the end of the therapy, the patient was asked to indicate the presence or absence of each of six symptoms (ie, 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 wheezier and shorter of breath than usual. A decline in the PEF, if available, was considered. When it was possible, the patient's relatives were asked to confirm the patient's information. The decision to discharge or admit a patient to the hospital was made at the end of the protocol by senior ED staff without knowledge of the previous patient group allocation. Patients were discharged from the ED according the following criteria: if accessory-muscle use was abated; if wheezing was judged to be minimal or completely resolved; if patients were free of dyspnea; and if FE[V.sub.1] or PEF was > 60% of predicted. The physicians prescribed oral prednisone (60 mg for 7 days) for all patients discharged from the hospital, or IV steroids for those who were admitted to the hospital.

The primary outcome measures were improvement in pulmonary function (ie, FE[V.sub.1] or PEF) and hospital admission rate. Secondary outcomes were heart rate, Sa[O.sub.2], and side effects.

Statistical Analysis

Mean values ([+ or -] SD) were calculated for continuous variables. The 95% confidence intervals (CIs) were calculated with standard Formulas. (16) In a previous study, (9) we estimated that the mean ([+ or -] SD) final FE[V.sub.1] value to be expected at 3 h was 1.8 [+ or -] 0.5 L. Estimations from statistical power calculations showed that the use of 54 subjects per group was needed to detect a 0.2-L difference in FE[V.sub.1] and a 19% difference in hospital admissions, with [alpha] = 0.05 and [beta] = 0.20 (ie, with 80% power). Changes in FE[V.sub.1] and PEF for the three treatments were evaluated using repeated-measures analysis of variance (ANOVA). The data for the three groups at any time were compared by one-way, repeated-measures ANOVA test for normally distributed independent samples or by the Kruskall-Wallis test for non-normally distributed continuous variables. When the F value indicated significant differences among group means, post hoc pairwise multiple comparisons were performed using the Tukey honestly significant difference test. The Pearson [chi square] test with Yates correction or the Fisher exact test was used for categoric variables. A p value of (0.05 using a two-tailed test was taken as being of significance for all statistical tests. All data were analyzed with a statistical software package (SPSS, version 10.0 for Windows; SPSS Inc; Chicago, IL).

RESULTS

Of about 1,200 adult patients who had visited the ED with acute asthma, 179 patients were enrolled into the study. The main reason for exclusion from the study was for FEV, >150% of predicted. Of the 179 patients included in the study, 7 (TDG, 2 patients; A/IB group, 2 patients; and A/F group, 3 patients) requested early withdrawal and were excluded (age requirement, 3 patients; FE[V.sub.1] requirement, 2 patients; and cardiac disease, 2 patients). The remaining 172 patients (mean age, 33.0 [+ or -] 10.5 years) were analyzed, with 56 assigned to the TDG group, 60 to the A/IB group, and 56 to the A/F group. All included patients underwent spirometry. There were no intubated or ventilated patients included in the study. The baseline characteristics of the 172 patients are presented in Table 1. There were no significant differences among groups for the characteristics examined. We classified the exacerbations according to the pulmonary function (ie, FE[V.sub.1]) of the patient at presentation, with the FE[V.sub.1] expressed as a percentage of the predicted value, as defined by the guidelines. (1,2) A main finding of our study was the pronounced severity of most exacerbations. Almost 75% of the patients had life-threatening attacks (ie, FE[V.sub.1], < 30% of predicted), (2) and about 26% of patients had severity features at presentation (ie, FE[V.sub.1], > 30 to 50% of predicted). In 9% of patients, the symptoms appeared in patients < 6 h before their arrival to the ED, and just over a quarter of the patients had used corticosteroids within the previous 7 days.

The relationship between the cumulative doses of A, IB, and F, and the changes in PEF and FE[V.sub.1] were analyzed (Fig 1, 2). The mean PEF (as percentage of the predicted value) improved significantly over baseline values for the three 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 (treatment by time), repeated-measures ANOVA showed significant differences among the groups (p = 0.03). At 3 h of treatment, patients receiving the TDG showed a greater mean PEF (70.4% predicted) compared with those receiving A/IB (63.5% predicted; p = 0.05) and A/F (62.2% predicted; p = 0.03). The final improvements from baseline were 114% [+ or -] 57% for the TDG group, 95% [+ or -] 55% for the A/IB group, and 95% [+ or -] 44% for the A/F group (Table 2). Patients who received the TDG had an overall 20% greater increase (95% CI, 1 to 39%; p < 0.05) in PEF than the A/F group and a 19% greater increase (95% CI, 1 to 38%; p < 0.05) than the A/IB group. The ANOVA suggested that differences between groups increased with time (p = 0.001). At 180 min, the mean differences were as follows: TDG group vs A/F group, 44.4 L/min (95% CI, 10.4 to 77.1; p = 0.01); TDG group vs A/IB group, 44.5 L/min (95% CI, 16.0 to 72.9; p = 0.002); and A/F group vs A/IB group, 0.7 L/min (95% CI, -30.7 to 32.1; p = 0.7). The same pattern held for changes in FE[V.sub.1]. The improvements over baseline were significant in the three groups (p < 0.01). There was a significant difference between groups (p = 0.04). Patients receiving TDG had a mean 189% [+ or -] 121% improvement from baseline, patients receiving A/IB had a 149% [+ or -] 98% improvement from baseline, and patients receiving A/F had a 126% [+ or -] 91% improvement from baseline (Table 2). Patients who received TDG had an overall 64% greater improvement (95% CI, 24 to 103%; p = 0.002) in FE[V.sub.1] than those who received A/F, and a 41% greater improvement (95% CI, 1 to 80%; p = 0.04) than those who received A/IB. At 180 min, the mean differences were as follows: TDG group vs A/F group, 0.2 L (95% CI, 0.0 to 0.4; p = 0.02); TDG group vs A/IB group, 0.2 L (95% CI, 0.0 to 0.4; p = 0.05); and A/F group vs A/IB group, 0.0 L (95% CI, -0.2 to 0.2; p = 0.8). Also, the differences among groups increased with time (p = 0.001).

[FIGURES 1-2 OMITTED]

At the end of the protocol (3 h), there was a trend toward a reduction in hospitalizations (A/IB group, 25% [15 patients]; A/F group, 20% [11 patients]; and TDG group, 11% [6 patients]). However, this difference did not reach statistical significance (p = 0.1).

In the subgroup analysis, patients were divided according to the following criteria: (1) the severity of obstruction at presentation (ie, FE[V.sub.1], < 30% of predicted [119 patients] vs FE[V.sub.1], > 30% of predicted [53 patients]); and (2) the use of corticosteroids before presenting to the ED (ie, patients who had used corticosteroids vs patients who had not used corticosteroids). The TDG subgroup of patients with more severe obstruction (ie, FE[V.sub.1], < 30% of predicted) showed a significant increase (p = 0.03) in pulmonary function (Fig 3) and a decrease in the hospitalization rate (p = 0.04) [Fig 4] compared with the A/IB and A/F subgroups of patients. On the contrary, there were no differences among the subgroups in terms of patients who had FE[V.sub.1] > 30% of predicted (p = 0.7) and had been admitted to the hospital (p = 0.3).

[FIGURES 3-4 OMITTED]

Finally, the use of corticosteroids before presenting to the ED did not modify pulmonary function response (Fig 5) and admission rates. TDG group patients had significant FE[V.sub.1] increases, regardless of their previous use of corticosteroids (previous use, p = 0.04; no previous use, p = 0.04), and nonsignificant decreases in hospitalization rates (previous use, p = 0.1: no previous use, p = 0.6).

[FIGURE 5 OMITTED]

There were no differences among groups in heart rate (p = 03). The 3-h mean heart rates were 110 [+ or -] 16 beats/min for the TDG group, 103 [+ or -] 18 beats/min for the A/IB group, and 104 [+ or -] 18 beats/min for the A/F group. However, the differences among groups increased with time (p = 0.001), and there was a trend toward an increase in heart rate in the TDG group. Despite continuous ECG recording, there were no signs of arrhythmia. The three groups produced nonsignificant increases in Sac)2 (p = 0.6). The final mean Sa[O.sub.2] levels were 96.8% [+ or -] 2.1% for the TDG group, 96.8% [+ or -] 1.8% for the A/IB group, and 96.6% [+ or -] 1.6% for the MB group. Finally, there was a higher incidence of two of the six symptoms that were monitored. TDG group patients showed a higher incidence of palpitations, and the A/IB group patients presented a high rate of dry mouth. No patient experienced clinical deterioration in the ED.

DISCUSSION

The objective of this study was to determine whether the administration of multiple doses of a TDG protocol (ie, A, IB, and F) delivered by an MDI with a spacer device would provide an additional benefit to adults with acute severe asthma compared with the administration of A/IB or A/F. Our data showed that TDG improved lung function and produced an overall nonsignificant decrease in hospital admissions. At the end of the protocol, patients who received TDG had an absolute 44 L/min greater improvement in PEF and 0.2-L greater improvement in FE[V.sub.1] than did patients who had received A/F, and a 45 L/min greater improvement in PEF and a 0.2-L improvement in FE[V.sub.1] than did patients who had received A/IB. On the contrary, there were no differences between the A/IB and A/F groups. Also, there was a trend toward a reduction of hospitalizations between groups (A/IB group, 25%; A/F group, 20%; and TDG group, 11%), although they did not reach statistical significance. However, this outcome is difficult to evaluate because it requires large sample sizes to obtain statistical significance.

Additional analyses were conducted to determine whether we could identify subgroups of patients who reacted differently to the three treatments. Thus, previous studies (5-13) indicated greater benefits of dual therapy (ie, A/IB or A/F) in patients with more severe airflow obstruction at ED presentation. In accordance with these data, in our study the patients who were the most likely to benefit (ie, greater improvement in pulmonary function and a significant reduction in the hospitalization rate) from the TDG were those with more severe obstruction (ie, FE[V.sub.1], < 30% of predicted). The benefit of TDG was equally evident independent of the previous use of corticosteroids. The reason that pretreatment steroid administration had no detectable impact on ED response to therapy could be explained by the fact that this early response would be produced by a topical effect on airway and/or vascular smooth muscle tone that was not achievable by parenteral steroid administration. (17)

The improvement pattern in the TDG group was concordant with previous data. Thus, multiple doses of A/IB produced an early improvement in lung function (at 20 to 30 min of treatment) (5-10) followed by a later increase associated with the use of high doses of F (at 90 to 120 min of treatment). (11-13) These findings agree with the biphasic time course of response to therapy in asthma patients, with fast and slow components. (18) The immediate phase of recovery following bronchodilator therapy appears to be due to the resolution of smooth muscle contraction, and the more slowly resolving stage probably represents the effects of airway inflammation. The IB speed of onset of the effect is 3 to 30 min, with up to 50% of the response occurring in 3 min and 80% in 30 min, and with a peak bronchodilator effect observed within 1 to 2 h. (19,20) On the other hand, a nonspecific vascular effect at the level of the airway with vasoconstriction, a decrease in capillary membrane permeability, and a decrease of mucus production could explain the late pulmonary function improvement (2 h). (21,22)

Our trial sample presented the typical features of severe adult asthma patients when they presented for care to an ED. On average, they had a mean level of lung function (ie, PEF or FE[V.sub.1]) of 30% of predicted, a mean age between 30 and 40 years, and a female/male ratio of 60%. Also, 9% of patients reported an exacerbation duration of < 6 h prior to ED presentation. (3,4,23)

In the present study, minimal adverse effects were seen after the administration of high doses of A, IB, and F. The only difference was a higher incidence in palpitations in the TDG group. The three groups showed slight increases in heart rate and oxygen saturation. These findings are in accordance with those of previous studies (5-13) that used similar doses of these drugs, and suggest that the use of repeated doses of A, IB, and F administered by means of an MDI with a spacer device is safe and well-tolerated.

Finally, the large pulmonary function increase obtained in this study is probably related to the following factors: (1) we delivered the drugs through an MDI and a spacer rather than by nebulization, which is a more inefficient method; (2) we used a multiple-dose protocol consisting of cumulative high doses of A, IB, and F (ie, 24 puffs or 2,400 [micro]g A, 504 [micro]g IB, and 6,000 [micro]g F each hour for 3 h); (3) the severity of patients (almost 75% had an FE[V.sub.1] of < 30% of predicted); and (4) the relative lack of steroid treatment received by patients in the 24 h prior to the ED admission.

To our knowledge, this is the first randomized controlled trial evaluating TDG in adults with exacerbations of severe acute asthma. The use of TDG modified the outcomes of adult patients with acute asthma in terms of an increase in pulmonary function and a reduction in the number of hospital admissions. Our data support a therapeutic benefit from the addition of IB and F to A administered in high doses through an MDI plus a spacer, particularly in those patients in whom the FE[V.sub.1] was < 30% of the predicted value.

The current standard treatment of acute severe asthma in the ED includes inhaled bronchodilators (ie, [beta]-agonist and anticholinergic agents), systemic corticosteroids, and supplemental oxygen. This study showed an additional effect when we added high doses of inhaled steroids to the [beta]-agonist and anticholinergic agents. However, systemic corticosteroids were not administered because they require 6 to 24 h to improve pulmonary function. (24,25) So, this study does not answer the question of whether therapy with inhaled steroids is superior to that with systemic corticosteroids when given early, and/or whether they have any effect in addition to that of the systemic steroids. Studies addressing this issue are needed before the modification of the standard treatment.

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* From the Departamento de Emergencia (Dr. G. J. Rodrigo), Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay; and Unidad de Cuidado Intensivo (Dr. C. Rodrigo), Asociacion Espanola la de Socorros Mutuos, Montevideo, Uruguay.

Manuscript received June 6, 2002; revision accepted November 26, 2002.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

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

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