Research Concerning Expiratory Flow and Bronchodilator Response in Asthma

Thirty subjects complaining of episodic increase in shortness of breath with wheezing and at least 15 percent variability in forced expiratory volume in one second (FEV1) documented by spirometry were considered appropriate subjects for the study. All had persistent respiratory symptoms without an appreciable change in their frequency or severity during the week preceding the study. Five subjects did not complete the study, four of them for reasons not related to the study. The fifth subject quit the study because of severe side effects. A sixth subject could not be used for analysis because he inadvertently received the same medication for both the treatment weeks. The remaining 24 subjects, 22 men and 2 women, aged 23-63 years, form the material for this report.

Informed consent was obtained from all patients after explaining to them the nature of the study and possible side effects of atropine and isoproterenol. All medications except sympathomimetic aerosols were continued unchanged for the duration of the study. Find out more information about wheezing and asthma in young children following the link.


On the first day, forced vital capacity (FVC), FEV15 maximum midexpiratory flow rate (FEF25_75), inspiratory vital capacity, and forced inspiratory volume in one second were measured with a low resistance wedge-spirometer (model 370, Med-Science Electronics). Airway resistance (Raw), functional residual capacity (FRC), and specific airway conductance (Gaw/VL), were measured with a variable pressure body plethysmograph (Warren Collins, Inc). A maximum expiratory flow volume curve breathing air (MEFVair) was obtained and was followed by a second one after breathing a gas mixture containing 20 percent oxygen and 80 percent Helium for one minute and then inspiring to total lung capacity (MEFVHeIOX). Peak expiratory flow (Vmax), peak flow at 50 percent of the vital capacity (Vmax50) and after expiration of 75 percent of the vital capacity (Vmax75) was calculated from both MEFVair and MEFVHelox. The flow volume curves were obtained three times with adequate rest periods between tests. The results were calculated from the best of the three tests. For analysis, MEFVair and MEFVHeIox curves were superimposed at the residual volume. The volume at which MEFVHel0X joined MEFVair and remained so for the rest of the vital capacity was taken as the isoflow volume and was expressed as a percentage of the vital capacity (VisoV). For the calculation of VisoV, only those curves were used in which the vital capacity breathing air agreed within 200 ml with that breathing Helox.

The patients then inhaled two puffs of isoproterenol dispensed by a metered-dose, freon-propelled aerosol device (Isuprel-Mistometer) at one-minute intervals, each puff delivering 125 fig of the drug. Fifteen minutes after the last inhalation, all the above tests were repeated. The percentage of change from the prebronchodilator values of all the measurements were calculated.

The subjects were randomized and received isoproterenol or atropine in a double-blind fashion, and neither the investigators nor the patients were aware of the identity of the drugs used. Isoproterenol hydrochloride in 1:200 solution in saline, or atropine sulphate in dosage 0.08 mg per kg body weight dissolved in saline solution were administered in 0.5 ml aliquots. Both drugs were given by a DeVilbiss hand nebulizer which delivered about 0.02 ml of the solution on each inhalation with uniform particle size. Patients were instructed to take the drug by inhalation four times daily at approximately four- to five-hour intervals, by first exhaling close to the residual volume, then sealing the lips tightly around the delivery end of the nebulizer and squeezing the nebulizer bulb during inspiration. Care was taken to avoid the medicine coming in contact with the eyes. They were cautioned about the possible side effects and were advised to reduce the amount of medicine to only 0.25 ml if these were unacceptable. If the side effects still remained severe, they were instructed to decrease the frequency of administration to 12-hour intervals. If the side effects still remained severe, they were to discontinue the study after informing the investigators.

Respiratory system

The patients reported to the laboratory on the day after six days of the therapeutic program, three to four hours after taking the drug under study. Patients were questioned as to the overall relief in their respiratory symptoms compared to the week prior to starting the study, the number of acute attacks of dyspnea, change in exercise tolerance, cough, expectorations and wheezing. Lastly, they were asked about side effects and whether they reduced the dosage of the drug under study. These were recorded separately so that at the time of assessing response to drugs the answers to the last two questions were not available to the investigators making this assessment A physical examination of the respiratory system was performed following the interview.

All the measurements made on the first visit were then repeated except that administration of isoproterenol and postisoproterenol testing was not done. The person making the tests was not aware of the patients response to questions.

After the testing was done, the drugs were switched, ie, subjects receiving isoproterenol received atropine, and vice versa. The patients were given the same instructions as on day 1. The patients reported after taking the second drug for six days, on 14th day of the study, again three to four hours after taking the study-drug. The same sequence of questions, examinations and tests was followed as on the second visit except that one additional question was asked at the beginning of the third visit. “Which of the two medications would you prefer to use, the first one, or the second one?”

The data from the last two visits were compared to determine whether a given patient responded better to the first or to the second drug. In every instance, the determination of the response was recorded without the knowledge of side effects.

The double-blind code was broken after all the subjects had completed the study. The side effects and any adjustments in the dosage made by the patients were also reviewed at this point.

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