Comparison of oral and inhaled metaproterenol for prevention of exercise-induced asthma

The effectiveness of inhaled versus oral metaproterenol in preventing exercise-induced asthma (EIA) was studied. Inhaled metaproterenol given 10 min before the exercise significantly reduced the degree of EIA in a group of twenty-four patients, and in 75% of them completely prevented it. The mean percentage decrease in FEV₁ was 6-5% with the inhaler and 30.1%, with placebo. When inhaled 1 hr before the exercise, metaproterenol was still better than placebo but its effectiveness was considerably lower. Metaproterenol tablets had a slight protective effect given I hr before, and none when administered 2 hr before exercise. There was no correlation between the protective effect against EIA and the bronchodilating effect obtained before exercise. Metaproterenol administered by metered-dose inhaler is a very effective prophylactic medication against clinically troublesome EIA, while metaproterenol tablets should not be recommended for this purpose.     

Comparison of ultrasonically nebulized distilled water and hyperventilation with cold air in asthma

To assess the potential value of brief non-pharmacologic challenge tests in the measurement of bronchial responsiveness and to investigate whether the responses are induced by similar mechanisms, we carried out comparative five-minute inhalation challenges with ultrasonically nebulized distilled water and cold air hyperventilation in nine asthmatic subjects. Decrements in FEV1 following both challenges were closely correlated (r = 0.885) and ranged from 8% to 59% of baseline following challenge with the former and from 6% to 59% following the latter. Each method was therefore equally effective in demonstrating bronchial hyperresponsiveness. Moreover, the strong correlation between the responses to both challenges coupled with previous observations suggests that the two stimuli may act by similar mechanisms.     

Differences between swimming and running as stimuli for exercise-induced asthma

Summary Thirteen children each exercised for 6 min by running on a treadmill and by tethered swimming, breathing air at room temperature and either 8% or 99% relative humidity continuously. Ventilation, gas exchange and heart rate were closely matched in all four tests in each child, with a mean oxygen consumption of 32.3±1.7ml·min^–1·kg^–1. The post-exercise fall in FEV₁ expressed as a percentage of the baseline FEV₁ (FEV₁) was significantly greater after running compared with swimming breathing either humid or dry air. The FEV₁ was also related to respiratory heat loss (RHL) calculated from measurements of inspired and expired gas temperature and humidity. At a standardised RHL, the difference between running and swimming was highly significant [FEV₁ (%) ± SE=39±5 and 28±4 respectively, p<0.01]. These experiments suggest that the type of exercise influences the severity of exercise-induced asthma even under conditions of the same metabolic stress and respiratory heat loss.     

Comparison between Bricanyl Turbuhaler and Ventolin metered dose inhaler in the treatment of exercise-induced asthma in adults

The aim of the present study was to compare the effect of Bricanyl Turbuhaler (0.5 mg x 1 terbutaline) with the effect of albuterol metered dose inhaler (0.1 mg x 2 albuterol) in patients with reproducible bronchoconstriction. The study was performed as a double-blind placebo-controlled trial in sixteen asthmatic adults. Bronchoconstriction was induced by steady state running on a treadmill. Both 0.5 mg terbutaline and 0.2 mg albuterol have good bronchodilating effects in patients with exercise-induced asthma. There was, however, a faster onset of action after albuterol. The clinical value of this observed difference is uncertain.     

Issues in exercise-induced asthma

It is concluded that challenge by exercise and ISH induces asthma by the same mechanism, the protective effect of water vapor is evidence that the events that lead to bronchial smooth muscle contraction begin in the airway lumen, it is the loss of water rather than the loss of heat from the airways that is the primary stimulus to EIA and HIA, the mechanism by which water loss induces asthma is by increasing the osmolarity of the epithelial fluid, in some subjects with asthma, cooling of the airways enhances the response to water loss, the increase in osmolarity stimulates the production and release of bronchoactive substances from mast cells and epithelial cells, vagal afferent pathways are activated by changes in osmolarity and by the released mediators, and vagal efferent activity may be modified by alpha-adrenoceptor antagonists and SCG.     

Eosinophils in exercise-induced asthma

The variations in serum levels of eosinophil cationic protein (ECP) have been measured after exercise challenge of 13 patients with asthma with exercise-induced asthma (EIA) and nine patients with asthma without EIA. The patients were treated before exercise in a randomized and blinded fashion with inhalation of one dose of either disodium chromoglycate, terbutaline, or budesonide and in an open study with 4 weeks of inhaled budesonide. In the group with EIA, there was, in some patients, an initial increase in serum levels of ECP after exercise, but 60 minutes after exercise, the levels were significantly reduced (p less than 0.001). Disodium chromoglycate and 4 weeks of budesonide treatment inhibited this reduction. Histamine challenge of the group with EIA produced a similar fall in serum ECP levels (p less than 0.001). The group without EIA had initially lower levels of ECP than the group with EIA (p less than 0.05 to p less than 0.01), and ECP stayed unaltered after exercise. The preexercise serum ECP levels correlated significantly to the maximal fall in peak expiratory flow in the untreated group (r = 0.91; p less than 0.001) and in the group receiving one dose of budesonide (r = 0.62; p less than 0.05). The blood eosinophil counts were unchanged after challenge and not related to lung function. The results suggest that the ECP content in serum reflects the degree of allergic inflammation in the lungs and thereby the degree of bronchial hyperreactivity.     

Deconditioning of exercise-induced asthma

The majority of asthmatic children develop a significant degree of bronchospasm after a moderate amount of exercise. Etiology of this phenomenon has remained unknown. Pulmonary function tests, measurements of blood gases, and immunological assessments have been essentially normal. This study was designed to investigate the role of conditioning process in the development of exercise-induced bronchospasm (EIB). Fifty asthmatic children, between the ages of 8 and 15, were subjected to a standardized test of exercise. Thirty-six of the children who developed EIB were divided into an experimental and a control group. The experimental procedure was designed as a classical extinction procedure in which the conditioned stimulus (exercise) was presented without the occurrence of conditioned response of EIB. Only the experimental group received isoproterenol inhalation before the exercise to prevent the occurrence of EIB, while the control groups received plain air in a similar manner. The experimental group showed a significant improvement after the extinction procedure. A 6 month follow-up indicated that the majority of the children in the experimental group maintained the gains that were acquired during the experimental procedure.     

Complement changes during exercise-induced asthma

Two groups of asthmatic children, one with and one without a history of post-exercise wheezing, and one non-asthmatic adult, were exercised on a treadmill, and their complement levels were measured before and after exercise. The first group of patients had the most obvious fall in FEV₁ and all showed a slight rise in haemolytic complement following exercise. Two of the patients of the second group also had a rise in haemolytic complement. The C4 litre did not change in any of the asthmatic children who did not wheeze after exercise, but there were changes, albeit inconsistent, in the litres of C4 in four of the six patients who exhibiled post exercise wheezing. C3 breakdown products were not detected in any of the sera, following exercise. The role of complement in exercise-induced bronchospasm is not clear, but there does appear lo be a greater liability of the complement system in patients who are susceptible lo this form of provocation.     

Late response in exercise-induced asthma

Eight subjects induced bronchospasm by free-range running. Four of these demonstrated a hue response at 5-6 hr after exercise. When compared lo the other group of four subjects, who also developed an early response but no late response, the difference in FEV₁ at 5-6 hr was highly statistically significant. Although the phenomenon is not universally manifest it should no longer be held that there is no late response in exercise-induced asthma.     

Problems of interpreting exercise-induced asthma

Factors affecting exercise-induced asthma are reviewed based on studies in large numbers of children and young adults. Evidence is presented to show that running is a more potent and reproducible stimulus than cycling and that walking and swimming have a small and variable effect. The greatest amount of exercise-induced asthma is found after 6 to 8 minutes of steady-state running at a work rate equivalent to about two thirds of the working capacity of the subject. Exercise may be repeated every 2 hours throughout the day without any diminution of its effect in causing postexercise bronchoconstriction. The use of exercise in assessing drugs used to treat asthma is discussed, and the importance of the type of exercise test and the use of placebo preparations is emphasized. Serial exercise tests may be used to study the duration of protection from exercise-induced asthma afforded by drugs such as cromolyn sodium.     

Metabolic changes in exercise-induced asthma

Five patients with a history of post-exercise bronchoconstriction and eleven control subjects were exposed to gradually increasing work loads on a bicyle ergometer. The asthmatic patients showed higher blood lactic acid levels at all work loads than the control subjects. In contrast to findings in the controls, the plasma free fatty acid in the asthmatics failed to ‘rebound’ following the cessation of exercise; and in two out of three patients plasma FFA did not rise after epinephrine injection. In addition, the asthmatic patients consumed less oxygen during the exercise than the controls. The results of this study suggest that patients with post-exercise asthma may have to rely more on carbohydrates as the main source of energy because of the reduced availability of FFA. Since the consumption of oxygen is also reduced, this may lead to a higher lactate production.     

The effect of zafirlukast on repetitive exercise-induced bronchoconstriction: the possible role of leukotrienes in exercise-induced refractoriness

BACKGROUND: Single doses of zafirlukast attenuate exercise-induced bronchoconstriction (EIB), but previous studies have not measured zafirlukast's effects after regular dosing or its duration of effect beyond 4 hours. OBJECTIVE: The purpose of this study was to assess the effects of zafirlukast 20 mg and 80 mg twice daily compared with placebo on exercise challenges performed at 2 and 8 hours after the last dose of regular administration. METHODS: Twenty-four adult patients with stable asthma taking beta(2)-agonists, inhaled corticosteroids, or both received treatment with zafirlukast (20 mg and 80 mg) and placebo. The patients were treated twice daily for 14 days in a randomized, double-blind, 3-way cross-over fashion, with a 7-day washout period between each treatment. Exercise challenges were performed at 2 and 8 hours after the morning dose on day 14. FEV(1) was measured before exercise and at set intervals after exercise until it returned to within 7% of its baseline value. RESULTS: Both zafirlukast treatments significantly reduced EIB, as measured by the area under the FEV(1) time curve after the 2-hour (P <.001) and 8-hour (P <.001) exercise challenges and maximum fall in FEV(1) at the 2-hour challenge (P <.001). The comparison at 8 hours between treatments was affected by the unexpected finding that EIB was less in the placebo group after the 8-hour challenge than after the 2-hour challenge, as measured by the within-group change in the maximum fall in FEV(1) (P <.001) and the area under the FEV(1) time curve (P =.0023). CONCLUSION: Regular zafirlukast treatment protects against EIB for at least 8 hours after regular dosing. A refractory period, which may be caused by exercise-induced leukotriene release, may last for up to 6 hours after the initial response to exercise.     

Rimiterol and the prevention of exercise-induced asthma

The potential for rimiterol to protect athletes from exercise-induced asthma (EIA) has not been fully established. Ten athletes with asthma (15 to 30 years of age) undertook 8 minutes of submaximal exercise (80% of anaerobic threshold) on the treadmill ergometer, once after inhaling rimiterol and once after inhaling a placebo. Treatment with all bronchodilator drugs was stopped for the 12 hours preceding each exercise test. Two puffs (400 micrograms) of rimiterol or placebo were administered in a double-blind crossover manner 2 minutes before each exercise test. Lung function measurements were made before exercise and immediately, 5, 10, 15, 20, 25, and 30 minutes after completion of exercise. The results of a two-way analysis of variance revealed significant (p less than 0.01) difference in the FEV1 scores obtained after rimiterol inhalation and placebo inhalation, 5, 10, 15, 20, 25, and 30 minutes after cessation of exercise. After inhalation of rimiterol, there were no significant changes in FEV1. After inhaling the placebo, significant reductions (p less than 0.01) in FEV1 occurred after cessation of exercise (5, 10, 15, and 20 minutes). All subjects exhibited EIA after placebo, and none after rimiterol. The mean maximum drop after exercise in FEV1 after inhalation of rimiterol (2.807 +/- 5.55) and placebo (24.54 +/- 8.4) was significantly different (t = 6.849). It was concluded that inhalation of rimiterol 2 minutes before exercise afforded significant protection from EIA in all subjects tested.     

The kinin system in exercise-induced asthma

Seventeen asthmatic children, nine with and eight without exercise-induced asthma (EIA), and nine control non-asthmatic children were studied in an attempt to discern possible associations between the activity of the kinin system and EIA. Pulmonary function tests and clinical check-up were performed before and after 6 min of free-range running. Concomitant blood tests revealed a consistent elevation of the kallikrein levels following the exercise challenge in all experimental groups. However, only in the EIA positive group did this elevation exceed the normal laboratory range (16 +/- 7.0 mu/ml). Prekallikrein levels both before and after exercise did not exceed in any group the normal laboratory values. The findings thus suggest that provocation of EIA is associated with a certain threshold of kallikrein level below which no such symptoms are observed. EIA may be triggered only when kallikrein levels are in excess.     

Endogenous adrenergic modification of exercise-induced asthma

To determine if endogenous adrenergic activity could modify the obstructive response to exercise in subjects with asthma, we had 10 subjects undergo two bouts of cycle ergometry under controlled inspired air conditions while peak expiratory flow rates and plasma catecholamines were serially recorded. The second challenge of each pair was timed to coincide with the height of the bronchospasm induced by the first. A similar protocol was undertaken with isocapnic hyperventilation to serve as a control. The initial exercise produced bronchodilatation followed by bronchoconstriction when exercise ceased. During the second challenge, the obstruction resolved totally, only to recur once more when the subjects stopped work. Plasma concentrations of norepinephrine exactly mirrored the fluctuations in pulmonary mechanics, rising with bronchodilatation and falling with bronchoconstriction. The pattern with hyperventilation differed from exercise in that there was no significant increase in norepinephrine during the challenges. To determine if norepinephrine could abolish the bronchial narrowing produced by exercise, and, as a result, possibly account for the changes in mechanics that we observed, we performed a second study in which eight subjects were administered an aerosol of this compound to inhale during an episode of exercise-induced asthma. As with the endogenous elevation, exogenously administered norepinephrine also totally abolished the attack. These data demonstrate that the sympathoadrenal activity that occurs with repetitive exercise in subjects with asthma can materially influence the severity of exercise-induced asthma.     

Incidence of exercise-induced asthma in children

The incidence of exercise-induced asthma (EIA) was studied in 134 asthmatic and 102 nonasthmatic atopic children and compared to that in 56 nonatopic children. Pulmonary function tests measuring forced vital capacity (FVC) and 1-sec forced expiratory volume (FEV₁) were performed on each child prior to and serially for 20 min following free running exercise. The incidences of EIA among the asthmatic and atopic nonasthmatic children were 63% and 41%, respectively. This phenomenon is widespread among allergic children and cannot be accurately predicted from the history. A simple and easily performed outpatient procedure is described for the diagnosis of EIA.