Several authors have demonstrated that patients with cystic fibrosis (CF) present with an increased airways responsiveness. The use of bronchodilator therapy in patients with CF still remains controversial and there is no consensus as to the efficacy of inhaled adrenergic medication in the treatment of the disease. The reason for the controversy is that previous studies have shown that inhaled p-adrenergic agents may have variable effects on expiratory airflows in CF, ranging from an increase, no effect, or even a decrease in flows. Furthermore, studies of inhaled anticholinergic bronchodilators in patients with CF are limited and even more controversial. It is known that because of the permanent airways inflammation and structural damage to the bronchial tree that are inherent and present in CF patients, airflow obstruction is predominantly irreversible, and the maximal possible improvement is slight. Recently, we demonstrated that the combination of a 0-adrenergic and an anticholinergic agent, compared with each drug alone, provides a greater improvement in FEVi and a more significant decrease in lung volumes and airway resistance (Raw) in young CF patients who have been shown previously to respond to inhaled salbutamol (S). From this study, we concluded that muscarinic pathways appeared to be important in the pathogenesis of expiratory airflow obstruction in CF patients with previous bronchodilator response. However, because we used single usual doses of bronchodilators (S and ipratropium bromide [IB]) by nebulization, we were not able to ascertain whether this additive effect could have been obtained by giving an extra dose of the same bronchodilator and whether by using larger doses of drug the additive effect would still have been present.
To our knowledge, the use of high doses of bronchodilator agents has not been tested in CF patients. Therefore, in the present study, we tested the hypothesis that in CF patients with known positive response to bronchodilators, an additive effect could be obtained by using large doses of S or IB.
Nine CF patients (four male, five female), aged 6 to 22 years (mean ± SE, 12.8 ±1.6 years) with mild to severe lung disease (baseline FEVb 31 to 96 percent predicted; [mean, 58 ± 7.3 percent] and Shwachman Kulczycld score, 35 to 90 [73 ±6.3]) were studied. The protocol was approved by the Faculty of Medicine Ethics Committee for the Use of Human Subjects, University of Manitoba, and informed consent was obtained from the patients and parent(s) prior to the study. The patients were free from any acute pulmonary exacerbation for at least 4 weeks and refrained from using inhaled bronchodilators or caffeine-containing drinks for the 12 h immediately prior to the study days. No patient was receiving theophylline or steroid preparations for the previous 2 months. Four patients had a personal history of allergy (hay fever) and no patient had either a personal or a parental history of asthma. Only patients with a previous positive response to inhaled S, defined as an increase of >6 percent in FEVi, were included.
Patients were studied for 8 h each day on 2 separate days within a week period. Baseline pulmonary function tests (PFTs) included forced maximal expiratory flow volume curve, Raw, and static lung volume measurements by body plethysmography (Autobox 6200, Sensormedics, Yorba Linda, Calif). After baseline measurements, the patients received S and IB in a double-blind, randomized, crossover manner. On 1 day, the subjects received S 200 jig, S 400 |Lg, and IB 80 |ig by inhalation at 45-min intervals, using a metered dose inhaler and an aerochamber (Trudell Medical, Ontario, Canada) (sequence A). On the other day, the sequence was IB 80 jig, S 200 jig, and S 400 jig at 45-min intervals (sequence B). The randomization to sequence A or В was done by a nurse who was not involved in the tests and the code was not broken until the end of the study. Pulmonary function tests, heart rate (HR), and oxygen saturation (SaOj (Ohmeda Biox 3700), were obtained at baseline, 45 min after each of the 3 inhalations, and at 4 and 8 h after the last drug (Fig 1). At least three technically acceptable maneuvers were required for a mean to be reported for a given measurement in a subject. We compared baseline values with those done after each inhalation and throughout the day for forced vital capacity (FVC), forced expiratory volume in the first second (FEVJ, forced expiratory flow at 25 to 75 percent of vital capacity (FEF25-75), forced expiratory flow at 50 percent of vital capacity (FEF50), functional residual capacity (FRC), residual volume (RV), and Raw. Measurements for the entire group were expressed as the mean ± SE.
Figure 1. Protocol design during the 2 days of the study. Pulmonary function test (PFT), heart rate (HR), and oxygen saturation (SaOJ were measured at baseline, at 45-min intervals, after inhalation of salbutamol 200 |tg (SaJ, salbutamol 400 \ig (S^J, and ipratropium bromide 80 \Lg (IBgJ, and 4 and 8 h after baseline (sequence A) or using IBgo, San, and Sw (sequence B).