Combivent

The current management of acute asthma consists of regular inhaled bronchodilator therapy, supplemental oxygen, and in most instances, systemic corticosteroids.[1] [Beta][sub.2]-agonists usually are recommended as initial bronchodilating agents[2] whether delivered by nebulizer[3] or by metered-dose inhaler with the addition of a spacer device.[4] It has also been suggested that inhaled ipratropium bromide should be combined with [Beta][sub.2]-agonists in the early stages of treatment, particularly when asthma is severe.[5] The rationale for the use of anticholinergic therapy is the fact that exaggerated cholinergic reflex mechanisms have been found to be present in asthma. This combination of inhaled bronchodilator therapy has been shown in several studies to produce greater bronchodilatation than monotherapy with [Beta][sub.2]-agonists alone.[6-8] Although additional bronchodilator benefit for the combination approach has been shown in both adult and pediatric populations, the clinical importance of this result remains to be defined. Moreover, the published studies have used various combinations of [Beta][sub.2]-agonists and anti-cholinergics and have not always controlled concomitant interventions. We therefore undertook the present study to confirm the bronchodilator efficacy of a fixed-dose combination of nebulized ipratropium bromide (0.5 ma) plus salbutamol sulfate (3.0 ma) compared with nebulized salbutamol sulfate alone (3.0 mg). We attempted to extend earlier studies by collecting prospective data on immediate and long-term treatment outcomes, including the need for supplemental medications at hospital discharge and the need for hospitalization.

Materials and Methods

The study was a multicenter, double-blind randomized, active controlled trial conducted at 13 academic and nonacademic centers in Canada. Written and informed consent was obtained from all patients before enrollment and the study received ethical approval from appropriate institutional review boards at the participating centers. The study took place between May 1992 and May 1993. All sites had the same spirometers, oximetry monitors, and nebulizer masks. Research staff received standardized training in their use.

Patients

Patients were eligible for recruitment if they presented to the emergency department with a complaint of acute asthma and if they met the following criteria: (1) had a diagnosis of asthma consistent with American Thoracic Society (ATS) criteria; (2) were between 18 to 55 years of age inclusive; (3) were able to perform reproducible spirometry; and (4) had an initial [FEV.sub.1] less than or equal to 70% of their predicted normal value. Patients were excluded if they were in extremis, had smoked more than 10 pack-years, had a history consistent with COPD, or suffered from other significant medical illnesses. Patients who, in the opinion of the emergency department physician, required drugs other than the nebulized study drugs, methylprednisolone, or oxygen were excluded as were pregnant or lactating women. Occupational status or potential work exposures were not obtained.

Intervention

Following enrollment and measurement of baseline [FEV.sub.1], patients were randomized to receive in double-blind fashion either a fixed-dose combination of ipratropium bromide and salbutamol sulfate (0.5 mg and 3.0 ma, respectively) or salbutamol sulfate alone (3.0 mg). Study drugs were supplied in unit dose vials that were preservative free. The study vials were indistinguishable from one another. Bronchodilator therapy was administered via nebulizer, driven with oxygen at a flow rate of 8 L/min. Arterial oxygen saturation was monitored continuously by fingertip pulse oximeter to ensure that oxygen saturation remained above 90% (Critical Systems Oximeter; Milwaukee). In addition, all patients received an IV bolus of 125 mg of methylprednisolone (within 15 min of nebulization). Supplemental oxygen was given continuously as required during the monitoring period. Spirometry was repeated at 45 and 90 min following the start of nebulization. Once eligibility criteria were met, demographic data, relevant medical history, clinical assessment, including seated BP, pulse, respiratory rate, oxygen saturation, the presence of cough, wheezing, and the use of accessory muscles were assessed. [FEV.sub.1] was measured three times at each assessment time and the highest of two reproducible (within 5%) measurements was recorded (Spirovit SP-200; Schiller, Switzerland). [FEV.sub.1] measurements were taken at baseline and repeated at 45 and 90 min. Standard predicted values for spirometry were used.[9] BP, pulse, respiratory rate, and oxygen saturation were also repeated at 30, 45, and 90 min.

Following the 90-min study period, emergency department physicians were free to treat patients at their discretion while remaining blind to the treatment allocation. (Randomization codes were broken only at the study's conclusion following recruitment of all patients.) Research staff recorded each patient's subsequent emergency department treatment, final disposition (whether admitted or discharged), and, if discharged, the discharge medications prescribed by the emergency department physician. For the duration of this study and for 2 weeks after its completion, research staff checked the records of participating emergency departments daily to determine if previously studied patients had required additional emergency department care or hospitalization.

Statistical Analysis

A sample size of 326 evaluable patients was deemed adequate for a 90% statistical power, a priori, to detect a 150-mL difference between [FEV.sub.1] increases from baseline and 45 min. Analysis was based on an intent-to-treat basis. The magnitude of the change in [FEV.sub.1] over the 90-min period was compared using analysis of variance. Data were also compared using Student's t test where appropriate. The data were analyzed (SAS, version 6.08). A p value less than 0.05 was considered significant.

Excluded Patients

Of 952 patients screened against inclusion or exclusion criteria for this study, 606 were found to be ineligible.

Patients were excluded for the following reasons: smoking history greater than 10 pack-years, 155; in extremis or with severe obstruction, 43; ATS definition of chronic obstructive lung disease, 10; previously recruited into the study, 19; receiving treatment for or suspected of having glaucoma, three; uncontrolled hypertension, three; known allergy or contraindications to study drugs or their excipients, 12; known or suspected to be pregnant or nursing, 17; suspected to have pneumonia, pneumothorax, or pneumomediastinum, 26; history of chest surgery, 13; other respiratory conditions, 13; required treatment of asthma attack other than study treatment regimen, 18; had been in other clinical trials within 3 months previously, 18; had an acute myocardial infarction, pulmonary edema, or other life-threatening disease, six; or had obvious or previously diagnosed serious hepatic or renal impairment or bladder neck obstruction, six. Patients failing to meet the inclusion criteria were as follows: no diagnosis of asthma according to ATS criteria, outside the age range, nine; unable to perform spirometry, 60; [FEV.sub.1] [is greater than] 70% of predicted normal, 259; and unwilling or unable to sign witnessed informed consent form, 156. The remaining 342 patients were randomized into the study with 171 patients in each treatment group. Of 342 patients randomized, two patients received no study drugs. Of the 342 patients randomized, 17 patients in the combination therapy group and 16 patients in the salbutamol alone group were either withdrawn by the study physician or requested to be withdrawn early.

Results

Demographic characteristics and baseline parameters did not differ significantly between both groups

(Tables 1 and 2).

(*) All values not significant.

The mean baseline [FEV.sub.1] in both groups was not statistically different with a value of 1.62 L (0.05 L) in the combination therapy group vs 1.53 L (0.05 L) in the salbutamol alone group. There was no difference in time from baseline measurements of [FEV.sub.1] to the initiation of treatment between the groups. The median time from presentation to the emergency department until initiation of treatment was likewise not significantly different.

Both groups improved significantly with the mean change in [FEV.sub.1] from baseline in the salbutamol group being 0.52 L (0.04 L) at 45 min and 0.52 L (0.04 L) at 90 min. In the combination therapy group, the change was 0.58 L (0.04 L) at 45 min and 0.61 L (0.04 L) at 90 min. The results were not statistically different. The absolute change in [FEV.sub.1]1 from baseline is shown in Figure 1. There was a trend toward a greater bronchodilator effect in the combination therapy group.

There was no significant difference in the number of adverse reactions between the groups. Fewer hospitalizations and asthma exacerbations were seen in the combination group, but this difference did not reach statistical difference.

Discussion

This study showed a slightly greater bronchodilator effect (90 mL greater [FEV.sub.1] at 90 min) when combination therapy with both salbutamol and ipratropium bromide compared with salbutamol alone was used in the therapy of acute asthma. The results differ from previously published studies in which statistically significant benefit was shown with the combination therapy.[6,7] The reasons for this are unclear.

Patients in our study had a higher mean [FEV.sub.1] of 1.57 L at baseline compared with previous studies, eg, 1.18[+ or -] 0.64 L in the study of Rebuck et al.[6] In the latter study, the authors showed an additional bronchodilator effect when subjects presenting with an [FEV.sub.1] less than 1 L were analyzed separately. Paradoxically, when a similar analysis was completed in this study (data not shown), there was even less difference between the study groups.

This study result is surprising given that in previous studies where a benefit of combination treatment has been shown used a similar dose of ipratropium (0.5 mg), but generally higher doses of [Beta]-agonists[7,8,10-12] were used. The less severe airflow obstruction in the study group overall may have indicated patients were coming to the emergency department earlier or pretreating themselves with higher does of bronchodilator prior to arrival. Although Rossing et al[13] previously showed that there was no difference in baseline lung function or in response to bronchodilator when those who had been pretreated in the community with [Beta]-agonists were compared to those who were not, their study may not have had the power to detect such a difference. In our much larger study, close to 90% of patients had pretreated themselves with [Beta]-agonists. In the remaining patients who had not taken [Beta]-agonists in the 6 h prior to presentation, there was a significant 211-mL treatment difference favoring the combination therapy. Patients in this study were approximately 10 years younger than in previously published studies making similar comparisons[6,9-11] and this again may have effected the results. Although to our knowledge this is the largest population of patients studied to address the benefit of combination therapy, it brought with it the disadvantage of being multicentered, and therefore, patients may not have been as homogeneous as in previous single-center studies.[10-12] These differences are best exemplified by baseline [FEV.sub.1] values that ranged from 1.35 to 1.90 L across centers. As might be expected, this variation in baseline led to variations in response with eight of 13 centers demonstrating a greater bronchodilator response following combination therapy. A similar designed study recently completed in New Zealand and carried out in two centers did show a statistically significant difference favoring the combination arm of the study.[14] Interestingly, although the level of airflow obstruction was worse in the New Zealand study, with baseline [FEV.sub.1] being 1.39 L compared with 1.58 L in the Canadian study, the same caveat applied to the New Zealand study in that those with more severe obstruction (baseline [FEV.sub.1] [is less than] 1 L) were less likely to respond favorably to the combination, especially if the patient had taken bronchodilator in the previous 6 h (personal communication; Dr. J. Garrett; May 1996). These data suggest that once maximal bronchodilatation has occurred, further therapeutic benefit can be achieved only by the addition of corticosteroids and its adjunct anti-inflammatory effect. An additional reason this study may not have shown a benefit is the fact that only a single dose of bronchodilator was used whereas current recommendations suggest that multiple doses are more appropriate.[1]

In contrast, a pediatric study has been published recently showing benefit both in terms of better bronchodilatation and fewer hospitalizations favoring combination therapy.[15] In this study, three groups received nebulized salbutamol, 0.15 mg/kg per dose, for three doses in 60 min along with three doses of ipratropium bromide, 250 [micro]g per dose, or one dose of 250 [micro]g of ipratropium bromide or finally with no ipratropium bromide. At 100 min, the mean percentage of predicted improved from 33.4 to 56.7% in group 1, from 34.2 to 52.3% in group 2, and from 35.4 to 48.4% in group 3 (p=0.0001). The differences between groups were larger in those children with a baseline [FEV.sub.1] [is less than] 29% of the predicted value. In addition, there was a significant reduction in hospitalizations for the subjects with the lower [FEV.sub.1] at presentation (p=0.027). The p value for hospitalization did not reach significance when data for all subjects were analyzed.

Although no statistical benefit was shown overall in terms of bronchodilation, like the pediatric study, the current study had a higher proportion of hospitalizations occurring in the salbutamol group (11.2%) compared with the combination therapy group (5.9%)

In this study, all patients received IV methylprednisolone 125 ma, compared with earlier studies in which systemic corticosteroids were given at the investigators' discretion. Thus, in the Rebuck et al study,[6] approximately 13% received systemic corticosteroids and repeated measures of analysis of variance using steroid and aminophylline therapy as two baseline covariates showed that the detected differences among regimens were not attributable to concomitant therapy. The result of this analysis is what one would expect given the time course of response to systemic corticosteroids,[16] but there remains a possibility that corticosteroids may have (in fact) had some impact.

In summary, we have shown no benefit to the routine use of a combination solution containing ipratropium bromide and salbutamol when compared with salbutamol alone. Despite our results, one should not conclude that combination therapy has no role in acute asthma. As a first step to better defining the appropriate therapy, a meta-analysis of the published literature, including the most recent large studies, would be a useful addition to the literature. Such a study might allow subgroup analysis to define patients who would benefit from combination therapy. Future studies should try to better define patients who may have greater benefit from the use of ipratropium bromide in the initial emergency department management of acute asthma. In addition, studies are needed to define the ongoing requirement for ipratropium bromide particularly in hospitalized patients. The economic benefits in terms of differences in hospitalization rates should also be further explored.

ACKNOWLEDGMENT: We would like to acknowledge secretarial support from Dawn Sedmak.

Appendix

Writing committee: Drs. J.M. FitzGerald, R. Hodder, R. Levy, M. Newhouse.

Participating centers and investigators. Vancouver Hospital and Health Sciences Center, Vancouver, BC: Dr. J. Mark FitzGerald (Principal Investigator); Dr. Anton Grunfeld; Dr. Raja Abboud; Dr. Bill Lange. St. Paul's Hospital, Vancouver, BC: Dr. Peter Pare (Principal Investigator); Dr. Tony Bai; Dr. David Kassen; Dr. Jeremy Etherington. Royal Columbian Hospital, Vancouver, BC: Dr. Anthony Nolan (Principal Investigator); Dr. Joseph Haegert; Dr. Grant Innes. Royal Alexandra Hospital, Eclmonton, AB: Dr. Allan Shustack (Principal Investigator); Dr. Allan Walker; Dr. Garnet Cummings. Victoria General Hospital, Halifax, NS: Dr. Dennis Bowie (Pnncipal Investigator); Dr. Robert McLeod; Dr. Douglas Sinclair. Hopital du Saint - Sacrement, Montreal, PQ: Dr. Jean Bourheau (Principal Investigator); Dr. Michael Rouleau; Dr. Andre Lachance. Royal Victoria Hospital, Montreal, PQ: Dr. Robert Levy (Principal Investigator); Dr. James Ducharme. Montreal Chest Hospital, Montreal, PQ: Dr. Ronald Olivenstein (Principal Investigator); Dr. James Martin. Victoria Hospital, London, ON: Dr. David McCormack (Principal Investigator); Dr. Mary Eisenhauer; Dr. Charles George. Credit Valley Hospital, Mississauga, ON: Dr. Emad Amer (Principal Investigator); Dr. Stephen Fowler. Ottawa Civic Hospital, Ottawa, ON: Dr. Richard Hodder (Principal Investigator); Dr. Jan Ahuja; Dr. Ian Stiell. Toronto Hospital, Western Division, Toronto, ON: Dr. Kenneth Chapman (Principal Investigator); Dr. Desmond Colohan; Dr. Mohamud Daya. St. Joseph's Hospital, Hamilton, ON: Dr. Michael Newhouse (Principal Investigator); Dr. Andrew McCallum.

References

[1] FitzGerald JM, Hargreave FE. The assessment and management of acute life-threatening asthma. Chest 1989; 95:888-94

[2] Hargreave FE, Dolovich J, Newhouse MT. The assessment and treatment of asthma: a conference report. J Allergy Clin Immunol 1990; 85:1098-1111

[3] Morley TF, Marozsane E, Zappasodi ST, et al. Comparison be beta-adrenergic agents delivered by nebulizer versus metered-dose inhaler with inspirease in hospitalized asthmatic patients. Chest 1988; 94:1205-10

[4] Turner MT, FitzGerald JM. An overview of the optimal delivery of bronchodilators in asthma and COPD [abstract]. Am Rev Respir Dis 145(suppl)

[5] Chapman K. The role of anticholinergics in the management of severe, acute asthma. Res Clin Forums 1993; 15:35-41

[6] Rebuck AS, Chapman KR, Abboud R, et al. Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Am J Med 1987; 82:59-64

[7] Louw SJ, Goldin JG, Varis S. Relative efficacy of nebulized ipratropium bromide and fenoterol in acute severe asthma S Afr Med J 1990; 77:24-6

[8] Leary B, Gomm SA, Allen SC. Comparison of nebulized salbutamol with nebulized ipratropium bromide in acute asthma. Br J Dis Chest 1983; 77:159-63

[9] Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma: American Thoracic Society. Am Rev Respir Dis 1987; 136:225-44

[10] O'Driscoll BR, Taylor RJ, Hursley MG, et al. Nebulized salbutamol with and without ipratropium bromide in acute airflow obstruction. Lancet 1989; 11:1418-20

[11] Higgins RM, Stradling JR, Lane DJ. Should ipratropium bromide be added to beta agonists in the treatment of acute severe asthma? Chest 1988; 94:718-22

[12] Ward MJ, MacFarlane JT, Davies D. A place for ipratropium bromide in the treatment of severe acute asthma. Br J Dis Chest 1985; 79:394-98

[13] Rossing TH, Fanta CH, McFadden ER Jr. Effect of outpatient treatment of asthma with beta agonists on the response to sympathomimetics in an emergency room. Am J Med 1983; 75:781-84

[14] Garrett JE, Town I, for the New Zealand Combivent Study Group. Comparison of nebulization therapy combining ipratropium bromide (0.05 ma) plus salbutamol sulphate (3.0 ma) alone in acute asthma [abstract 450P]. Thorax 1995; 50:4

[15] Schuh S, Johnson DW, Callahan S, et al. Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose salbutamol therapy in severe childhood asthma. Pediatrics 1995; 126:639-45

[16] Barnes NC. Effects of corticosteroids in acute severe asthma. Thorax 1992; 47:582-83

(*) From the Respiratory Clinic, Vancouver Hospital and Health Sciences Centre, Vancouver, BC, Canada; and additional institutions (see appendix).

Presented in part at the American Thoracic Society Annual Meeting, Boston, May 1994.

Supported in part by a research grant from Boehringer Ingelheim (Canada) Ltd.

Canadian Combivent Study Group, See Appendix for a full list of investigators and their institutional affiliations.

Manuscript received March 28,1996; revision accepted August 8. Reprint requests: Dr. FitzGerald, Respir Clinic, Vancouver Hospital, 2775 Heather St, Vancouver, BC, Canada V5Z 3J5

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