Effects of standard and high doses of salmeterol on lung function of hospitalized patients with cystic fibrosis.

In a recent investigation we found that hospitalized patients with cystic fibrosis who received 0.5 cc of 0.5% albuterol nebulizer solution TID significantly increased their pulmonary function across the day, but fell back to baseline overnight. To determine whether this fall could be prevented by the long-acting beta-2 agonist salmeterol at both standard (2 puffs: 42 mcg BID) and high (4 puffs, 84 mcg BID) doses, we evaluated the effects of salmeterol vs. albuterol (2 puffs, 180 mcg QID, and 4 puffs, 360 mcg BID) in a placebo-controlled three-way random crossover, double-blind trial. Eighteen patients in the low-dose group and 10 of the same 18 patients in the high-dose group completed the 3 consecutive days of testing and received either salmeterol, albuterol, or placebo with each of four chest physiotherapy sessions given at 7 AM, 11 AM, 3 PM, and 7 PM. At standard doses (2 puffs), the mean percent changes in FEV1 pre- to post-7 AM therapy for salmeterol (5.5%) and albuterol (9.9%) were significantly greater than with placebo (-1.2%) (P < 0.05 and 0.01, respectively). The mean percent changes in FEV1 from morning baseline with salmeterol were also significantly greater than placebo before 3 PM (12.1% vs. 5.4%, P < 0.01), and neither albuterol nor salmeterol were significantly greater than placebo after 3 PM. At standard doses there was a significant carryover effect with salmeterol to the next morning for the FEV1 (7.3%) when compared to placebo (1.5%) and albuterol (-0.7%) (P < 0.05 and 0.05, respectively). At high doses (4 puffs), the mean percent change in FEV1 with pre- to post-7 AM therapy increased to 22.7% and remained significantly greater than with placebo until pretherapy at 7 PM. The carryover effect the next morning was 14.7%. Salmeterol at 4 puffs compared favorably to albuterol nebulizer therapy given TID in both the incidence of responders for the FEV1 (70% vs. 71%) and the mean changes after therapy at 7 AM (22.7% vs. 14.9%), and provided greater carryover effects to the next morning (14.7% vs. -0.7%), thus preventing the fall in pulmonary function back to baseline overnight. We recommend the use of high-dose salmeterol in hospitalized patients with FVC values of 40% of predicted or greater, starting with 2 and increasing to 4 puffs BID as tolerated.

The effects of albuterol on the lung function of hospitalized patients with cystic fibrosis.

Twenty-four hospitalized patients with cystic fibrosis were enrolled into a 2-d, double-blind, placebo-controlled, randomized crossover trial comparing albuterol inhalation aerosol with a saline placebo. Aerosols were administered with the first three of four chest physiotherapy sessions given 4 h apart. Spirometry was measured before and 45 min after 7:00 A.M. and 3:00 P.M. therapy and before therapy at 7:00 P.M. and 7:00 A.M. the next morning. The mean percent change in FVC, FEV1, and FEF25-75% at 7:00 A.M. was 10.7, 14.8, and 19.6% with albuterol versus 2.4, 1.0, and -0.8% with placebo (p = 0.0012, < 0.0001, and = 0.003, respectively). A greater than 8% change in FEV1 separated changes with albuterol versus placebo with 96% specificity and occurred in 75% of all patients with albuterol; 71% at 7:00 A.M. versus 24% at 3:00 P.M. The reduction in response at 3:00 P.M. (p < 0.01) was presumably due to prolonged effects of morning therapy ( > 4 h). Individual changes in spirometry were significantly more positive and homogeneous with albuterol versus placebo at both 7:00 A.M. and 3:00 P.M. The mean percent change for the FVC, FEV1, and FEF25-75 across the day (7:00 A.M. pretherapy to 7:00 P.M. pretherapy) was 8.1, 10.1, and 9.7% with albuterol versus 3.9, 3.5 and 2.6% with placebo (p = 0.029, 0.036, and 0.232, respectively). The more positive and homogeneous changes in spirometry with albuterol, along with greater changes in these measures across the day when compared with placebo, suggest that albuterol improves pulmonary function in a majority of hospitalized patients with cystic fibrosis.

Effects of acute viral respiratory tract infections in patients with cystic fibrosis.

To determine the effects of acute viral respiratory infections (ARI) in cystic fibrosis (CF) we studied all episodes of ARI in ten patients over a 2 year period. A daily diary card was kept on which they recorded all illnesses, including specific upper and lower respiratory symptoms, antibiotic use, and daily peak flow measurements. Recording of concurrent similar illnesses in other household members aided in confirming the onset of ARI, as did a home viral culturing technique and serial serum antibody levels against specific viral types. A total of 80% of the 35 recorded onsets of ARI (1.75/yr/subject) were confirmed by one or more of these methods. Five subjects with moderate to severe pulmonary function scores at the outset of the study had significantly greater decreases in PEFR during ARI episodes (42.4%) than those with milder disease (15.4%), and it took them significantly longer to recover to their baseline measurements (22 days vs. 15 days respectively). The majority of hospital admissions for pulmonary exacerbations were preceded by viral infections (7/8).

A trial of metaproterenol by metered-dose inhaler and two spacers in preschool asthmatics.

Because most young children have difficulty in coordination for correct use of metered-dose inhalers (MDI), a trial of two spacer devices attached to MDIs was performed. In 13 children with asthma, aged 2-5 years old, a collapsible bag (Inspir-Ease) and a tube spacer (Aerochamber) were tested in a double-blind crossover trial with metaproterenol (1,300 micrograms). Respiratory resistance was measured by the forced oscillation method. Thirty minutes after metaproterenol administration there was a significant decrease in resistance with both spacers, while no significant change occurred after placebo administration. There was no difference in degree of bronchodilation between the two spacers. It is concluded that metaproterenol can be safely and effectively administered to preschool asthmatics by an MDI with spacer devices.

The preventive effect and duration of action of nedocromil sodium and cromolyn sodium on exercise-induced asthma (EIA) in adults.

Nedocromil sodium, 4 mg, from a metered-dose inhaler, cromolyn sodium, (cr) 20 mg, from a Spinhaler, and placebo (pl) were compared in their efficacy and duration of action in preventing exercise-induced asthma. Twelve patients with asthma performed treadmill exercise tests 20 minutes, 2 hours, and 4 hours after a single dose of drug in a double-blind, crossover trial. Both active drugs were significantly better than pl at 20 minutes. Two hours after drug administration, only cr was significantly different from pl. The direct comparison between nedocromil and cr demonstrated no significant difference on FEV1, and the only significant difference was with forced expiratory flow between 25% and 75% of vital capacity at 2 hours. It is concluded that at these clinically recommended doses, both drugs are equally effective in preventing exercise-induced asthma with cr possibly having a somewhat longer duration of action.

A comparison of inhaled fenoterol and albuterol in asthma.

In 24 adult asthmatics the effects of clinically recommended doses of fenoterol (320 micrograms) and albuterol (180 micrograms) were compared to placebo in a double-blind, crossover trial. Bronchodilation in FEV1 was significantly greater than placebo for both active drugs: two hours on albuterol and five hours on fenoterol. Results of FEF25-75% were similar. There were no significant changes in pulse rate, blood pressure and electrocardiogram, but 11 patients had mild subjective side-effects on fenoterol.

A longitudinal study of bronchodilator responsiveness in cystic fibrosis.

The prevalence of bronchodilator responsiveness was evaluated in 20 outpatients with cystic fibrosis (CF) every 1 to 3 months for a 1-yr period and in 20 patients with CF during a hospital admission. All but 1 subject (95%) showed a significant bronchodilator response at least once on an outpatient basis; nonhospitalized subjects were responsive 49% of the time. Bronchodilator responsiveness was unrelated to long-term pulmonary severity or indexes of atopy but it was significantly influenced by season of the year; 70% of the population was responsive in winter compared with 25% in summer. Bronchodilator responsiveness increased during hospital admission together with improvement in baseline values; 23% of the population was responsive during the first 3 days compared with 80% by the end of the second week of admission. After discharge, a reverse pattern occurred, with decrease in bronchodilator responsiveness and a fall in baseline values. However, in some patients, bronchodilator responsiveness was lost when baseline values were still at their best. Bronchodilator responsiveness in CF tends to undulate with pulmonary exacerbations of the disease.

Normal values for forced oscillatory respiratory resistance in children.

Forced oscillatory respiratory resistance was measured in 138 healthy children aged 2- to 16-years-old using a commercial unit. Regression analysis was performed using the resistance measurements obtained at frequencies of 6 Hz and 26 Hz and averages of measurements obtained at frequencies of from 6-26 Hz, 6-10 Hz, and 22-26 Hz. The analysis suggested that regression curves and 95% confidence intervals obtained using a quadratic model with height as the independent variable provided the best prediction of normal values and their ranges. Three independent sets of resistance measurements, which were obtained for all 138 subjects, were used to calculate the average individual coefficients of variation (CV) for the five resistance parameters noted above; these ranged from 9 to 13%. This analysis suggested that the expected CV of repeated measurements would be about 10%. Finally, values from 13 children who had asthma with mild bronchial obstruction (FEV1 less than 80% of predicted) were compared with the normal values derived from the regression curves. Values from all but two of the children fell within the reference intervals, suggesting that FEV1 may be a more sensitive measure of obstruction than forced oscillatory resistance. The main applications of this new approach may be in the evaluation of young children, in following individual patients, and in bronchodilation and bronchial challenge tests.

Forced random noise resistance determination in childhood asthma.

The forced random noise method for measuring respiratory resistance was studied in terms of reproducibility and correlation with spirometry and flow volumes in 30 older children (four to 17 years) with asthma and in 16 infants and children below three years of age. In the 30 older children, the mean value of individual coefficient of variations for three repeated measurements was 7.4 percent. Resistance parameters correlated well with spirometric parameters with all but three correlation coefficients greater than 0.7. In 20 older asthmatic patients, 180 micrograms albuterol caused a significant reduction in resistance in 11 subjects. At the same time, FEV1 increased significantly in nine subjects but showed a paradoxic decrease in five. This paradoxic response is attributed to complex reflexes caused by the maximum inspiration and forced expiration and did not occur with resistance measurements. This method requires little subject cooperation, and therefore, is well suited for infants and children.

Fenoterol in exercise-induced asthma. Effect of dose on efficacy and duration of action.

The effectiveness of inhaled fenoterol doses of 0.4 mg and 0.8 mg in preventing exercise-induced asthma was investigated in 12 patients. Exercise-induced asthma was prevented by both doses for two hours after administration, but the effect of neither dose was significantly different from that of placebo four hours after. There was no statistically significant difference between the effects of the two fenoterol doses; and only a few patients were protected for more than two hours by the higher dose.