Efficacy of inhaled metaproterenol and orally-administered theophylline in patients with chronic airflow obstruction. Acute response to bronchodilator. An imperfect guide for bronchodilator therapy in chronic airflow limitation. Should study subjects see their previous responses: data from a randomized control trial. Domiciliary nebulized terbutaline in severe chronic airways obstruction. Breathlessness and exercise tolerance in chronic airflow obstruction: 2-hourly versus 4-hourly salbutamol by inhalation. Response of patients with chronic obstructive lung disease to the regular administration of nebulized isoproterenol. A double-blind crossover study. Domiciliary nebulised salbutamol solution in severe chronic airway obstruction. Evaluation of domiciliary treatment with terbutaline by wet nebulisation in patients with chronic bronchitis and emphysema. Bronchodilator treatment for partially reversible chronic obstructive airways disease. The efficacy of orally administered theophylline, inhaled salbutamol, and a combination of the two as chronic therapy in the management of chronic bronchitis with reversible air-flow obstruction. A comparative study of atropine sulfate and isoproterenol hydrochloride in chronic bronchitis. Mechanism of bronchodilator effect in chronic airflow limitation.
To evaluate comparative bronchodilator efficacy with chronic airflow obstruction (CAO), we randomly administered to ten patients week-long treatments consisting of: inhaled metaproterenol from a metered dose canister (1.30 mg six times a day) and doses of a sustained-release theophylline formulation sufficient to achieve plasma levels of 10-15 micrograms/ml; metaproterenol-placebo; theophylline-placebo; or placebo-placebo. At the end of each period, treatment responses were evaluated by spirometric tests, by exercise tolerance (12 minute walk and progressive cycle ergometry) and by subjective perception of dyspnea (oxygen cost diagram and breathlessness rating). Metaproterenol as a single treatment caused statistically significant improvements in spirometric variables and in the breathlessness rating. Theophylline as a single treatment caused significant changes in none of the test variables, though favorable trends were observed. Combined drug therapy was significantly better than metaproterenol only in the case of the breathlessness rating. We conclude that in the treatment of patients with CAO, inhaled metaproterenol is superior to oral theophylline. Our results permit no definite conclusion concerning added benefits of combined drug therapy. We conducted a four-period cross-over randomized trial in which we found that patients with chronic airflow limitation demonstrated symptomatic improvement with both inhaled albuterol and oral theophylline. The response, however, was not uniform. We therefore tested the ability of acute change in forced expired volume in one second (FEV1) following inhaled beta agonist to predict long-term symptomatic response to albuterol and theophylline. We found that the reproducibility of acute change in FEV1 over three repetitions was poor (intraclass correlation 0.17). Furthermore, the mean improvement FEV1 following inhaled albuterol across the three repetitions did not relate closely to symptomatic response to either albuterol or theophylline. We conclude that acute response to inhaled beta agonist is not useful for identifying patients with chronic airflow limitation who are likely to benefit from bronchodilator treatment. To test the relative merits of administering questionnaires with previous responses available (the informed condition) or unavailable (the blind condition), we administered blind and informed versions of a quality of life questionnaire (the Chronic Respiratory Disease Questionnaire, or CRQ) in a randomized, double-blind trial of bronchodilators in chronic airflow limitation. The responsiveness of the two methods, as reflected in the p-values associated with salbutamol and theophylline effects were comparable for three of the four dimensions of the CRQ. The data suggested possible increased responsiveness of the informed method for the emotional function dimension of the questionnaire. Changes in the informed CRQ dyspnea and fatigue dimensions showed stronger correlations with changes in spirometry, 6 minute walk distance, and rating of dyspnea after the walk test than did blind administration. Further, changes in all four CRQ dimensions showed stronger correlations with corresponding global ratings using the informed questionnaire. These results suggest that by letting study subjects see their previous responses the validity of subjective measures of health status in clinical trials can be improved. Forty-eight patients with severe chronic airways obstruction were given 5 mg terbutaline or placebo from a nebulizer twice daily for 2 + 2 weeks. Twenty three patients preferred terbutaline, 9 placebo and 16 had no preference. The baseline lung function and the 6 minute walking distance were not increased after the terbutaline period. The patients who preferred terbutaline indicated less dyspnoea after the terbutaline period as compared to the placebo period, but did not differ with regard to lung function or walking distance after the terbutaline treatment. The physiology behind the subjective relief from the terbutaline inhalations remains unexplained. Breathlessness, exercise tolerance, and spirometry were measured in 12 patients whose major symptom was breathlessness, secondary to severe chronic airflow limitation, during a double-blind crossover comparison of inhaled salbutamol in two dosages (200 micrograms 4-hourly and 200 micrograms 2-hourly) with placebo. Daily visual analogue scores of breathlessness, exercise tolerance and spirometry were all significantly improved with salbutamol in both dosages compared to placebo. The 2-hourly regimen was superior to the 4-hourly regimen only in terms of exercise tolerance. Walking distance had deteriorated significantly 2 hours after salbutamol on the 4-hourly regimen and was usefully increased by an extra dose of salbutamol on the 2-hourly regimen at the equivalent time, without side-effects. Salbutamol provided considerable symptomatic relief in addition to spirometric improvement in patients with chronic airflow limitation. The effect of the regular use of neublized isoproterenol in 14 patients with symptomatic chronic obstructive lung disease (COLD) was evaluated in a double-blind crossover 16-week study. FEV1, FVC and SGaw were measured before and 45 minutes after bronchodilator therapy every two weeks, while arterial blood gases were measured every eight weeks, before and 45 minutes after bronchodilator therapy. When the patients were considered as a group, there was no significant difference in mean symptom scores or objective pulmonary functions during the drug and placebo periods. Four patients had significantly higher (p less than .05) and two patients significantly lower mean values for at least one of the pulmonary function tests during the isoproterenol period. The patient who is most likely to benefit from isoproterenol on a regular basis appears to have the following characteristics; (1) consistent improvement in pulmonary function tests 45 minutes after use of nebulized bronchodilator; (2) moderate rather than severe COLD; and (3) a relatively normal DLCO. Nine patients with severe chronic airway obstruction secondary to chronic bronchitis and emphysema all preferred nebulised salbutamol solution to placebo in a double-blind controlled trial. Four of the patients who had previously received domiciliary nebulised salbutamol failed to complete the placebo period, though all completed the active period. Five others improved subjectively on active therapy, and showed a significant improvement in morning and evening peak flows. Symptom scores for breathlessness, wheezing, and sputum production were lower in the active treatment period and standard aerosol usage fell, although these changes might have been due to chance. Patients with severe chronic airway obstruction who do not respond to conventional bronchodilator therapy should be considered for this form of treatment. Domiciliary treatment with terbutaline by wet nebulisation (5 mg, four times daily) was compared with placebo in a double-blind study over four consecutive periods, each of seven days duration, in eight patients with severe airflow limitation due to chronic bronchitis and emphysema. Lung function tests performed at the conclusion of each treatment period showed small but significant improvements in FEV1 before and after 500 micrograms of terbutaline by metered dose inhaler (MDI), with reductions in functional residual capacity and residual volume for terbutaline compared with placebo. Morning and evening peak expiratory flow rate recordings were greater and there was a significant reduction in the use of terbutaline by MDI during the terbutaline treatment. Three patients were unable to complete the placebo treatment because of excessive symptoms. Analysing all individual results, only one patient appeared not to benefit from nebulised terbutaline, while the preference rating for the other seven patients was significantly in favour of terbutaline. The effect of six weeks' treatment with inhaled terbutaline (1 mg four times a day), optimised doses of theophylline (twice a day), the combination of theophylline and terbutaline, and placebo was studied in a randomised, double blind, crossover trial. Thirty patients with partially reversible chronic airflow obstruction and a mean forced expiratory volume in one second (FEV1) of 1.2 litres that improved by 25% were included in the study. Patients who developed non-infective exacerbations of airflow obstruction that required additional bronchodilator treatment were classed as "treatment failures." Such treatment failure occurred in 23 patients with placebo, in 22 patients with theophylline, in 12 patients with terbutaline, and in two patients taking the two drugs. Mean daily peak flow readings were highest with the combination of the two drugs, followed by terbutaline and then theophylline, and lowest with placebo. Thus a combination of terbutaline and theophylline was superior to either drug alone; inhaled terbutaline was superior to theophylline alone. Theophylline alone does not appear to have much place in the management of patients with partially reversible obstructive airways disease. The efficacy of bronchodilator therapy was assessed in the long-term management of patients with chronic bronchitis and varying degrees of reversible air-flow obstruction. Twenty-five patients with a mean forced expiratory volume in one second (FEV1) 38.7% predicted received: optimized doses of orally administered, sustained-release theophylline, inhaled salbutamol (200 micrograms 4 times a day), a combination of the 2 drugs, and identical placebo therapy for periods of 3 wk in a randomized, double-blind, crossover trial. Patients who deteriorated during treatment were assessed immediately and designated "treatment failures" if additional therapy proved necessary. Such "failures" occurred in 9 patients with placebo, in 8 with salbutamol, in 6 with theophylline, and in only 1 with combined therapy. Using a ranking system based on "treatment failures" and mean daily peak flow rates, first preference was given to combined therapy in 13 patients, theophylline in 6, salbutamol in 4, and placebo in 2. Thus, both combined therapy (p less than 0.001) and theophylline (p less than 0.05) were better than placebo, but this was not so for inhaled salbutamol. Objective improvements in FEV1 and forced vital capacity were a consistent finding with combined therapy compared with placebo, although not with single agents, and additive effects were clearly demonstrated. In the subgroup of patients able to tolerate placebo therapy, no subjective benefit could be discerned during any of the 3 periods of active treatment. Thus, the combination of orally administered, sustained-release theophylline and inhaled salbutamol offered significant advantages in the clinical control of patients with chronic bronchitis with air-flow obstruction. Fifteen subjects with chronic bronchitis were treated with inhaled atropine sulfate, isoproterenol hydrochloride, or placebo in a double blind crossover trial. Each drug was inhaled 4 times per day for 3 weeks. Baseline forced expiratory flows, specific airway conductance, airway resistnace, and functional residual capacity were measured weekly. These measurements were repeated 15 min and 60 min after laboratory inhalation of each agent, using a separate double blind protocol. No significant differences were observed among the mean baseline function studies during the 3 treatment periods. There were no significant differences in sputum production, sputum thickness, dyspnea, or mouth dryness among the 3 treatment periods. Side effects were mild; isoproterenol treatment was associated with an increased frequency of palpitations, and atropine treatment was associated with difficulty in voiding. Significant increases in lung function were apparent in the measurements made 15 min and 60 min after inhalation of atropine or isoproterenol. Mean values of flow and specific airway conductance increased, and mean values of airway resistance and functional residual capacity decreased after inhalation of either drug. There was no significant difference between the effects of atropine and isoproterenol on lung function, although both differed significantly from the effects of placebo (P less than 0.001). Inhaled atropine sulfate was as effective a bronchodilator as inhaled isoproterenol hydrochloride, and was well tolerated during the 3-week trial of daily therapy. To examine the mechanisms through which two bronchodilators (theophylline and salbutamol) influence dyspnea during daily activities.
                Twenty-four patients with chronic airflow limitation participated in a multiple crossover, randomized, placebo-controlled trial. The effect of theophylline and salbutamol, alone or combined, on pulmonary function and dyspnea during daily activities was examined. Correlations of changes in forced expiratory volume in 1 second (FEV1) and maximum expiratory pressures (MIPs) (independent variables) and changes in dyspnea score during daily activities (dependent variable) were also examined.
                The two drugs proved to be beneficial the effects in general were additive rather than synergistic. The drugs improved the FEV1; theophylline significantly improved the MIPs. The correlation between the changes in FEV1 and those in dyspnea score, after adjustment for the changes in MIPs, was 0.55 (p less than 0.001). The correlation between the changes in MIPs and those in dyspnea score, after adjustment for the changes in FEV1, was 0.39 (p less than 0.001).
                Changes in airway calibre and in respiratory muscle strength play an independent and important role in dyspnea during daily activities in patients with chronic airflow limitation. Changes in airway calibre may be of greater importance.
Use of short-acting beta-2 agonists on a regular basis for at least seven days in stable COPD is associated with improvements in post bronchodilator lung function and a decrease in breathlessness. Patients are far more likely to prefer treatment with beta-2 agonists than placebo, and less likely to drop out from such treatment. None of the studies included in this review reported sufficient data or were of sufficient length or size in order to provide reliable information on adverse effects. Therefore large scale, parallel, longer term studies would be needed to investigate the effect of treatment with regular inhaled beta-2 agonists on mortality, disease progression and side effects. Newer, long acting bronchodilators (including long-acting beta-2 agonists) are currently available and they may be more practical and/or effective in these patients. However, this review indicates that treatment with these older, inexpensive drugs is beneficial in patients with COPD.