There have been many investigations examining the physiologic responses of subjects to single bron-chodilator drugs, the physiologic responses to one drug in comparison to another, and the method of inhalation. The majority of these studies have looked at the safety and relative efficacies of the medications in relation to the speed of onset of bronchodilation in the treatment of asthmatic subjects, the time of peak response, the duration of the response, and the degree of side effects. There is still debate as to whether there is a best drug or method of delivery for circumstances such as laboratory testing.
In our USAF Reference Cardiopulmonary Laboratory, nearly one third of our studies of pulmonary function involved bronchodilator agents in patients with reversible bronchospastic disease. It is obviously important to use the best medication and method of delivery to derive optimal changes on the tests of pulmonary function—within the twin restraints of cost and time available. In our laboratory, we had access to two different methods of delivery (compressed air-driven nebulizer and metered-dose inhalers) and medications from three major classes of autonomic active bronchodilator medications: (1) catecholamines (isoproterenol and isoetharine); (2) resorcinols (meta-proterenol and terbutaline); arid (3) saligenin (albuterol [salbutamol]).
We therefore designed this double-blind crossover study to determine whether any one medication, method of delivery, or combination of medication and method of delivery would be statistically superior in a busy laboratory for the demonstration of short-term reversibility in a group of subjects with stable asthma.
Materials and Methods
Ten patients 25 to 59 years of age were selected for this study (Table 1). All met the criteria for asthma as previously described; the duration of illness ranged from three to 20 years. None of the subjects had a history of either heart disease or other recent or chronic respiratory disease. All subjects did have a history of treatment with bronchodilator drugs but were all currently in stable condition by clinical history. The subjects were advised not to take any bronchodilator medication at least 12 hours prior to testing of pulmonary function. Each subject volunteered to participate and completed a standard consent form.
Using a double-blind crossover design, each subject received a standard inhaled dose of either a medication or a placebo in a randomized fashion for a total of ten working days (Table 2). The medications included the following: metaproterenol (Alupent) liquid and metered-dose inhalant, terbutaline (Brethine) liquid; iso-etharine metered-dose inhaler (Bronkometer); isoetharine liquid (Bronkosol); isoproterenol liquid (Isuprel); isoproterenol oral inhaler (Norisodrine); albuterol oral inhaler (Ventolin); plus a placebo metered-dose inhaler (Boehringer-Ingelheim) and physiologic saline solution for mixing medication in the compressed air-driven device. The doses were delivered either by metered-dose inhaler or by an intermittent, patient-actuated, compressed air-driven nebulizer (Maximyst).
The patients were carefully instructed and coached in the proper use of both the compressed air-driven nebulizer and the metered-dose inhalers. Standard doses were mixed for the nebulizer, and the medication was delivered intermittently by the patients repeated actuation of the compressed air-driven device. The 10-minute to 15-minute period of delivery was monitored by a trained cardiopulmonary technician not involved in any phase of the testing evaluation. Each patient was studied at the same time of the day during the course of the study to rule out any circadian variation.
Measurements of pulmonary (unction were made using a commercial system (Hewlett-Packard Pulmonary Function Analyzer). This system was calibrated daily according to the manufacturers instructions and was checked for quality control before each patient s study using a battery-operated 3-L super syringe with flow and volume capabilities. One cardiopulmonary technician, trained in the USAF method of standard pulmonary function testing, instructed each patient as to the proper method for performing each test. Each subject performed a minimum of three studies which met the standards of the American Thoracic Society and the Occupational Safety and Health Administration before and at 15 minutes after medication. The pulse rate and any adverse reactions were noted and recorded at the same intervals. Pulmonary function tests consisted of the forced vital capacity (FVC), forced expiratory volume in one second (FEV), mean forced expiratory flow over the middle half of the FVC (FEF25-75%), peak expiratory flow rate (PEF), functional residual capacity (FRC), total lung capacity (TLC), ratio of closing volume to vital capacity (CV/VC), and ratio of closing capacity to total lung capacity (CC/TLC).
The mean and standard deviations were determined by standard equations. Tkking the pulmonary function before medication as baseline, the postbronchodilator values were divided by the baselines. A ratio greater than one indicated higher postbronchodilator values, while a ratio less than one indicated the values after medication were lower. We considered a 12.3 percent or 0.18-L increase in FEV1 to be a significant improvement after medication. Relationships between baseline pulmonary function and responses to the bronchodilator and delivery device were examined by analysis of variance for repeated measures (BMDP Data Description and Data Management Package, University of California Statistical Package). A p value of 0.05 or less was considered statistically significant.
Table 1—Demographic Data on Subjects
|Subject, Race, Sex, Age (yr)||Height,cm||Weight,kg||SmokingHistory,
|1, B, M, 25||180||91||6||3 yr/stable|
|2, B, F, 26||165||57||Nonsmoker||6 yr/stable|
|3, W, F, 26||183||73||Nonsmoker||5 yr/stable|
|4, W, F, 59||163||67||18||15 yr/stable|
|5, W, M, 41||168||65||20||20 yr/stable|
|6, W, F, 46||163||71||Nonsmoker||14 yr/stable|
|7, W, M, 36||180||86||5||10 yr/stable|
|8, W, M, 27||185||71||Nonsmokef||5 yr/stable|
|9, W, F, 27||160||57||Nonsmoker||15 yr/stable|
|10, W, F, 28||165||65||Nonsmoker||8 yr/stable|
Table 2—Schedule for Delivery of Medication
|Sample||Medication||System of Delivery||Dose|
|1||Isoetharine||Nebulizer||0.5 ml in 2.5 ml of physiologic saline|
|2||Isoetharine||Metered-doseinhaler||2 inhalations (340|ig/dose)|
|3||Isoproterenol||Metered-doseinhaler||2 inhalations (250jjLg/dose)|
|4||Metaproterenol||Metered-doseinhaler||2 inhalations (650p.g/dose)|
|5||Metaproterenol||Nebulizer||0.3 ml in 2.5 ml of physiologic saline|
|6||Albuterol||Metered-doseinhaler||2 inhalations (100iLg/dose)|
|7||Terbutaline||Nebulizer||0.5 ml in 2.5 ml of physiologic saline|
|9||Isoproterenol||Nebulizer||0.5 ml in 2.5 ml of physiologic saline|
|10||Placebo||Nebulizer||3.0 ml of physiologic saline|