Circadian Variation of Bronchial Caliber and Antigen-induced Late Asthmatic Response: Design of Study

Although some patients received oral bronchodilators as needed (a combination of short-acting salbutamol [2 mg] and aminophylline [100 mg]), and 2 patients received inhaled cromolyn sodium 3 times per day and 4 received oral ketotifen twice per day regularly, all of these medications were withdrawn for at least 38 h before and throughout the study. Each patient had the morning and the evening challenge studies on separate days, and the order of the studies was determined in a single blind manner. The studies were separated by at least 4 weeks and at most 6 weeks. Each challenge study consisted of two consecutive days, the diluent-inhaled control day followed by the antigen challenge day.
Morning Challenge Study
Measurement of FEV, was started at 10 am on day 1. Just after the measurement, the same dose of diluent (0.9 percent sodium chloride with 0.5 percent phenol) as that of the antigen solution used for bronchial challenge (see subsequent text) was inhaled. Measurements of FEV, were made 10, 30, and 60 min afterward to examine IAR. Then FEV, measurements were made every 4 h from 2 pm to 10 am on day 2. These six FEV, values were used as controls. The house-dust solution was inhaled just after the measurement at 10 am on day 2. House-dust extract was diluted in the diluent to 1:100 (weight/volume) immediately before use. Measurements of FEV, were made 10, 30, and 60 min afterward to examine IAR. Then, FEV, measurements were made every 4 h from 2 pm to 10 am on day 3. Measurements of FEV, were made by using a hot-wire auto-spirometer (AS-1500, Minato Ikagaku, Osaka, Japan). Values were expressed as percent predicted normal FEV, based on the equations of Sumida for Japanese schoolchildren, which are as follows: FEV, (ml) in boys = 34.82 x height (cm)-2,746; FEV, (ml) in girls = 34.42 x height (cm) – 2,829. The FEV, just before the inhalation was used as a baseline value in each patient to assess the magnitudes of IAR and LAR. An IAR was regarded as positive when there was 15 percent or more decrease in FEV, from the baseline value among 3 values at 10, 30, and 60 min after the inhalation. The LAR was regarded as positive when there was at least 1 FEV, value among 6 values from 4 to 24 h after the antigen inhalation which decreased by 15 percent or more from the value at the same hour on the control day. The magnitude of the LAR was expressed as the maximum decrease in FEV, from the baseline value.
The diluent and the house-dust solution were nebulized with a glass jet nebulizer (Nishoshiki, Nihon Shoji, Osaka, Japan) with an airflow of 8 L/min. The aerosol particle size from the nebulizer was 1 to 10 jim, and output of distilled water by the nebulizer was 0.20 ml/min. The inhaled dose of the house-dust solution was determined through a preliminary study in each patient so as not to cause an IAR, since bronchial constriction at different clock hours during the morning and the evening challenges might affect the magnitude of the LAR (Table 1). The same nebulizer was used in both challenge studies in each patient. The aerosol was inhaled by tidal breathing.
Evening Challenge Study
Measurement of FEV, was started at 6 pm on day 1. The diluent and the house-dust solution were inhaled just after the FEV, measurement at 6 pm on days 1 and 2, respectively. Following these inhalations, FEV, measurements were made at the same interval as in the morning challenge study. Six FEV, values from 10 pm to 6 pm on the next day were regarded as the values of each day.
Analysis
Standard methods were used to calculate the mean, SD, and CV Student s paired t test was used to compare variables. A p value of less than 0.05 was considered statistically significant.

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