Inhaled frusemide and exercise-induced bronchoconstriction in children with asthma.

BACKGROUND--Nebulised frusemide has been shown to be protective against bronchoconstricting stimuli in adult asthmatic subjects and against cold air challenge in children. Animal studies suggest that inhaled frusemide may be more effective in the young. METHODS--A double blind placebo, controlled, crossover study on the effect on exercise of pretreatment with frusemide (20 mg) from a metered dose inhaler via a large volume spacer (Volumatic) was performed in 12 asthmatic children. Exercise testing consisted of eight minutes of running on a treadmill in an environmentally controlled laboratory. RESULTS--Deterioration in lung function was less after frusemide than after the placebo exercise tests. The mean (95% CI) maximum percentage falls in forced expiratory volume in one second (FEV1) were 14.4% (7.7 to 21.0) for placebo and 5.7% (2.3 to 9.0) for frusemide. CONCLUSIONS--Inhaled frusemide via a metered dose inhaler reduces exercise-induced bronchoconstriction in children.     

Inhibition of sodium metabisulphite induced bronchoconstriction by frusemide in asthma: role of cyclooxygenase products.

BACKGROUND--Inhaled frusemide inhibits airway responses to sodium metabisulphite and other indirect bronchial challenges in asthma by undetermined mechanisms which may relate to its ability to stimulate prostaglandin release. Inhalation of sodium metabisulphite provokes indirect bronchoconstriction, possibly by activating sensory nerves. To investigate the role of cyclooxygenase products in the airway actions of frusemide and sodium metabisulphite, the effects of a potent cyclooxygenase inhibitor, flurbiprofen, alone and in combination with frusemide were investigated against airway responsiveness to sodium metabisulphite. METHODS--In a double blind double placebo controlled study, 12 mild asthmatic subjects attended on four occasions to undergo three inhalation challenges with sodium metabisulphite. A baseline challenge was performed one hour before oral intake of flurbiprofen 200 mg or matched placebo, and two hours before inhalation of frusemide 40 mg or matched placebo. A second challenge was performed immediately after inhalation of frusemide (two hours after flurbiprofen) with a further challenge three hours later. The log concentration provoking a 20% fall in FEV1 (log PC20) was used to assess airway responsiveness to sodium metabisulphite. RESULTS--Frusemide caused an immediate 1.9 doubling dose protection and a lesser 0.7 doubling dose protection at three hours. This protection was enhanced by flurbiprofen at both time points to 2.7 (early) and 1.9 (late) doubling doses. In addition, flurbiprofen alone significantly reduced airway responsiveness to sodium metabisulphite by 1.1 doubling doses at both two and five hours. CONCLUSIONS--The generation of bronchoprotective prostaglandins is unlikely to underlie the inhibitory action of frusemide against airway responsiveness to sodium metabisulphite. Endogenous contractile prostaglandins within the airways may be involved in the bronchoconstrictor response to sodium metabisulphite.     

The airway microvasculature and exercise induced asthma.

It has been proposed that exercise induced asthma is a result of "rapid expansion of the blood volume of peribronchial plexi" (McFadden ER, Lancet 1990;335:880-3). This hypothesis proposes that the development of exercise induced asthma depends on the thermal gradient in the airways at the end of hyperpnoea. The events that result in exercise induced asthma are vasoconstriction and airway cooling followed by reactive hyperaemia. We agree that the airway microcirculation has the potential for contributing to the pathophysiology of exercise induced asthma. We do, however, question whether reactive hyperaemia, in response to airway cooling, is the mechanism whereby hyperpnoea provokes airways obstruction in asthmatic patients. Further, we question whether vasoconstriction accompanies dry air breathing and whether an abnormal temperature gradient and rapid rewarming of the airways are prerequisites for exercise induced asthma. From published experiments we conclude that dry air breathing is associated with vasodilation and increase in airway blood flow rather than vasoconstriction and a decrease in blood flow to the airways. We propose that the stimulus for the increase in airway blood flow is an increase in osmolarity of the airway submucosa. This osmotic change is caused by the movement of water to the airway lumen in response to evaporative water loss during hyperpnoea. The increase in airway blood flow may occur directly or indirectly by the osmotic release of mediators. Exercise induced asthma is most likely to be due to the contraction of bronchial smooth muscle caused by the same mediators. Whether it is enhanced or inhibited by alterations in airway blood flow is not yet established in man.     

Effect of cetirizine on exercise induced asthma.

The effect of oral and inhaled cetirizine, a potent and specific H1 receptor antagonist, was studied in patients with exercise induced asthma. Twelve patients (five male; mean age 35.2 years) were given oral placebo or cetirizine 10 mg twice daily for one week, double blind and in randomised order, and exercised on a treadmill for six to eight minutes at a submaximal work load two hours after the final dose. There was no significant change in baseline FEV1 after treatment and cetirizine failed to inhibit exercise induced bronchoconstriction (maximum falls in FEV1 28% and 27% of baseline). In a further eight patients (four male; mean age 40.8 years) the effect of 1 ml cetirizine (5 and 10 mg/ml) given through a Wright nebuliser was compared with that of placebo in a double blind trial. The fall in FEV1 after exercise was reduced after both concentrations of cetirizine by 15.2% of baseline after 5 mg/ml and by 10.2% after 10 mg/ml, compared with 23.7% after placebo. In two patients cetirizine had no effect. In a further study cetirizine (10 mg/ml) given by inhalation displaced the geometric mean PC20 histamine 13.1 fold to the right by comparison with placebo. The reason for the difference between the effects of oral and of inhaled cetirizine on exercise asthma is not clear but may be related to differences in local concentration in the airway.     

Attenuation of exercise induced asthma by local hyperthermia.

BACKGROUND: Prior treatment with local hyperthermia has been shown to prevent mast cell degranulation and leucocyte histamine release, and to reduce mortality and cellular infiltrates in a model of acute lung injury. Local hyperthermia is effective in reducing the symptoms of the common cold and perennial and seasonal allergic rhinitis, nasal patency also being improved in rhinitis. It is possible that these effects are mediated by common anti-inflammatory mechanisms, and that this treatment may be effective in the treatment of asthma. The effect of prior local hyperthermia on the response to exercise challenge and histamine bronchoprovocation was therefore examined. METHODS: In a randomised, double blind, placebo controlled, crossover study, 10 asthmatic subjects with exercise induced asthma used machines delivering 40 1/minute of fully humidified air at either 42 degrees C (active treatment) or 31 degrees C (placebo treatment) for 30 minutes' tidal breathing. For each pretreatment, at two week intervals they underwent exercise challenges starting one and 24 hours after starting the inhalations. After a further two weeks the protocol was repeated with histamine substituted for the exercise challenges. RESULTS: The mean (SE) maximum percentage fall in forced expiratory volume in one second (FEV1) was significantly lower one hour after treatment with air at 42 degrees C (30.8% (3.1%)) than after treatment with air at 31 degrees C (22.3% (2.9%)). There was no significant effect on exercise challenge at 24 hours, or on histamine challenge at either time point, though there were nonsignificant trends towards protection with exercise at 24 hours and with histamine at one hour. CONCLUSION: In asthmatic subjects the response to exercise challenge is significantly attenuated one hour after treatment with local hyperthermia. This treatment warrants further investigation in the treatment of clinical asthma and other inflammatory disorders.     

Refractory period following induced asthma: contributions of exercise and isocapnic hyperventilation.

To compare the refractory period that follows exercise and isocapnic hyperventilation, 10 asthmatic children performed two pairs of challenge tests in random order at least six hours apart. In pair A a hyperventilation challenge was followed by an exercise challenge and in pair B the order was reversed. Both pairs of tests were done while the children were breathing cold dry air. Tests were matched in terms of work load, ventilation, and end tidal carbon dioxide tension (PCO2). The mean percentage fall in FEV1 (delta FEV1) after the first challenge (hyperventilation) of pair A and the first challenge (exercise) of pair B were the same (30% (SEM 2%)) and 30% (4%) respectively). The mean delta FEV1 of the exercise test following hyperventilation in pair A and of hyperventilation following exercise in pair B was 22% (4%) and 18% (4%) respectively. Both these latter results were significantly lower than the respective delta FEV1 when the challenge was the first test of the pair. Although the mean refractoriness index (reduction in induced asthma in the second test of each pair compared with the first test) was greater when exercise was the first challenge, the difference was not significant.     

Cross refractoriness between sodium metabisulphite and exercise induced asthma.

BACKGROUND--Exercise and inhaled sodium metabisulphite are thought to cause bronchoconstriction in asthma through different mechanisms. The response to both stimuli becomes refractory with repeat challenge. The mechanism of refractoriness is unclear, although depletion of mast cell derived mediators or neurotransmitters has been suggested. Recent studies suggest a common mechanism involving release of inhibitory prostaglandins. If this is true, exercise and sodium metabisulphite induced bronchoconstriction should show cross refractoriness. METHODS--Thirteen subjects with mild asthma and previously established exercise and sodium metabisulphite induced bronchoconstriction performed two sodium metabisulphite challenges (giving a single dose previously shown to cause a 20% fall in FEV1) on one study day, and two exercise tests on another. The second challenge proceeded after recovery (FEV1 > 95% baseline) from the first. Subjects then attended on two further occasions when an exercise test was performed after sodium metabisulphite and a sodium metabisulphite challenge after exercise. RESULTS--When expressed as the percentage reduction in the area under the change in percentage FEV1 curve over 20 minutes (AUC) the response to exercise was reduced by a mean 62.3% (95% CI 46.5% to 78.1%) following a first exercise challenge, and by 50.7% (95% CI 27.8% to 73.6%) following a sodium metabisulphite challenge. The response to a sodium metabisulphite challenge was reduced by a mean of 80.2% (95% CI 68.9% to 91.5%) when it followed a sodium metabisulphite challenge, and by 37.3% (95% CI 15.1% to 59.5%) following an exercise challenge. CONCLUSION--This study shows some cross refractoriness between exercise and sodium metabisulphite induced bronchoconstriction, in keeping with a partially shared mechanism of refractoriness.     

Circulating catecholamines in exercise and hyperventilation induced asthma

Plasma noradrenaline, adrenaline, and cyclic 3'5' AMP (cAMP) were measured in seven asthmatic patients with known exercise-induced bronchospasm and six matched non-atopic control subjects during a standard treadmill exercise test and then during matched isocapnic hyperventilation. Normal subjects showed a 5.5 fold rise in noradrenaline and a 3.2 fold rise in adrenaline during exercise compared with a 2.1 fold rise in noradrenaline and no significant rise in adrenaline in asthmatics who all developed bronchoconstriction after exercise (mean fall in peak flow rate 28.4 +/- 5.8%). Plasma cAMP rose 1.4 fold in controls but showed no significant rise in asthmatics. This reduced sympatho-adrenal response to exercise in asthmatics is difficult to explain. The failure of circulating catecholamines to rise and stimulate beta adrenoceptors on the mast cell may facilitate the release of bronchoconstrictor mediators. Matched hyperventilation produced bronchospasm in asthmatics (mean fall in peak flow rate 29.0 +/- 4.4%) but no change in catecholamines in either group suggesting that circulating catecholamines have no direct role in exercise-induced bronchospasm but may play a permissive role via the mast cell.     

Platelet activation during exercise induced asthma: effect of prophylaxis with cromoglycate and salbutamol.

Peak expiratory flow (PEF) and plasma concentrations of platelet factor 4 and beta thromboglobulin were measured before and after exercise in nine asthmatic patients and 12 non-asthmatic volunteers. Exercise was preceded by administration in random order of either placebo, salbutamol 200 micrograms, or sodium cromoglycate 2 mg from a pressurised inhaler. In control subjects there were minimal changes in PEF and plasma concentrations of platelet factor 4 and beta thromboglobulin. In the asthmatic patients the typical changes in PEF were seen on exercise; plasma concentrations of platelet factor 4 and beta thromboglobulin rose significantly in parallel, the rise preceding the fall in PEF. The changes in peak flow and platelet activation induced by exercise were attenuated by prior administration of salbutamol or cromoglycate. These results indicate that exercise induced asthma is associated with a rise in platelet release products similar to that observed in antigen induced asthma.     

Dose-response study of nebulised nedocromil sodium in exercise induced asthma.

Ten patients with exercise induced asthma, in whom inhaled nedocromil sodium 4 mg by metered dose inhaler attenuated the exercise fall in forced expiratory volume in one second (FEV1) by at least 40%, participated in a double blind dose response study to compare the protective effect of nedocromil sodium given 15 minutes before exercise challenge via a nebuliser (Wright) in concentrations of 0.5, 5, 10, and 20 mg/ml with that of placebo (saline). Response was assessed as the maximum fall in FEV1 after the patient had run on a treadmill for six to eight minutes. Plasma concentrations of nedocromil sodium were measured at the time of challenge. After exercise challenge the mean (SEM) maximum percentage falls in FEV1 were 30.3 (1.6) for the control run and 28.0 (4.1) after placebo. The percentage fall was attenuated by pretreatment with all concentrations of nedocromil sodium to 12.8 (2.8), 11.2 (2.1), 12.8 (2.1), and 14.1 (3.5) for the 0.5, 5, 10, and 20 mg/ml concentrations respectively (p less than 0.001). There were no significant differences between the different nedocromil concentrations. Mean plasma concentrations of nedocromil were proportional to dose. Thus concentrations of nebulised nedocromil sodium that ranged from 0.5 to 20 mg/ml gave a similar degree of protection (50-60%) against exercise induced asthma. This appears to be the maximum protection that can be achieved with nedocromil sodium and is similar to the protection obtained with 4 mg nedocromil administered by metered dose aerosol.     

Hyperventilation-induced asthma: evidence for two mechanisms.

The mechanism by which airway cooling induces airflow obstruction in asthmatic subjects has not yet been established. Using a pair of isocapnic hyperventilation challenges, with a 40-minute interval, we looked for the presence of a refractory period in 19 asthmatic patients (aged 9-18 years). The subjects fell into two groups. The eight in the "non-refractory" group showed less than a 25% reduction in response to the second challenge, but the 11 in the "refractory" group showed at least a 35% reduction. Twelve subjects also performed a hyperventilation challenge after cholinergic blockade with inhaled ipratropium bromide. In five, in whom no refractoriness after hyperventilation was seen, there was a significant protection from cholinergic blockade (p less than 0.05). In these a vagal (cholinergic) reflex seems likely. The remaining seven, who had a refractory period, received no significant protection from cholinergic blockade and therefore no evidence for the presence of any cholinergic mechanism. We conclude that two mechanisms are responsible for hyperventilation-induced asthma, one of which is a vagal reflex while mediator release may be the other.     

Airway response to methacholine during exercise induced refractoriness in asthma.

To investigate the mechanisms contributing to refractoriness in exercise induced asthma a methacholine challenge test was performed 30 minutes before and 30 minutes after two exercise tests 45 minutes apart. Exercise was performed by 12 asthmatic patients while they were breathing cold air. There was a smaller airway response to the second exercise test than to the first, though there was wide variation between subjects. The response to the second methacholine challenge was reduced in some patients but showed no significant change overall. Refractoriness to exercise induced asthma positively correlated with a reduced response to methacholine. These data suggest that mediator depletion does not fully explain refractoriness.     

Circulating adrenaline and noradrenaline concentrations during exercise in patients with exercise induced asthma and normal subjects.

A failure of the usual increase in plasma adrenaline and noradrenaline concentrations during submaximal exercise has been suggested as a contributory cause of exercise induced asthma. Six normal subjects and six asthmatic patients underwent a standard graded maximal exercise test. Measurements of oxygen consumption, minute ventilation, exercise time, blood lactate concentration, and heart rate indicated that the two groups achieved similarly high work loads during exercise. Mean FEV1 fell by 20% in asthmatic patients after exercise. Basal plasma adrenaline concentrations (nmol/l) increased in normal subjects from 0.05 to 2.7 and in asthmatic patients from 0.12 to 1.6 at peak exercise. Noradrenaline concentrations (nmol/l) increased in normal subjects from 2.0 to 14.3 and in asthmatic patients from 1.9 to 13.7 at peak exercise. The increases in adrenaline and noradrenaline in the asthmatic patients did not differ significantly from the increases in normal subjects. Thus a reduced sympathoadrenal response to exercise seems unlikely to be an important mechanism in the pathogenesis of exercise induced asthma.     

Dose-response effect of sodium cromoglycate pressurised aerosol in exercise induced asthma.

The effects of 2, 10, and 20 mg of sodium cromoglycate delivered by aerosol were compared with those of placebo in a double blind study in 11 patients with extrinsic and exercise induced asthma. The effect of nebulised sodium cromoglycate delivered through a Wright nebuliser (estimated dose 12 mg) was also studied. Patients exercised on a treadmill for six to eight minutes at submaximal work loads on five days, 30 minutes after inhaling placebo or sodium cromoglycate. The FEV1 was recorded before treatment, before exercise, and up to 30 minutes after exercise. Mean baseline values of FEV1 before and after placebo or sodium cromoglycate did not differ significantly on the five days. After exercise the mean (SEM) maximal percentage fall in FEV1 after placebo; 12 mg sodium cromoglycate nebuliser solution; and 2, 10, and 20 mg sodium cromoglycate aerosol were 31.1 (3.8); 9.4 (2.1); and 19.4 (4.6), 13.7 (3.5), and 9.4 (1.9). Sodium cromoglycate inhibited exercise induced asthma at all doses used; the protective effect of the aerosol increased from 2 to 20 mg. The protective effect of 20 mg sodium cromoglycate aerosol was similar to that seen with 12 mg nebulised solution. Our results suggest that the effect of sodium cromoglycate aerosol in exercise induced asthma is dose related.     

Induction of bronchial hypersensitivity: evidence for a role for prostaglandins.

Bronchial hyper-responsiveness is a particular feature of asthma, but also occurs in normal subjects after a viral upper respiratory tract infection or ozone inhalation. Such stimuli would be expected to result in the release of chemical mediators of inflammation. In this study, the effects of one of these, prostaglandin F2 alpha (PGF2 alpha), on the response of normal subjects to inhaled histamine has been investigated. Nine normal volunteers took 10 inhalations of increasing concentrations of PGF2 alpha at 15-minute intervals from a Wright's nebuliser under standard conditions until a change in sGaw could be detected. The next lowest serial dilution of PGF2 alpha was subsequently inhaled by each subject every 15 min for 90 min to ensure the absence of a cumulative effect. Inhalation dose-response curves to histamine diphosphate were constructed on two separate occasions using the same standardised technique. Doses were administered every 15 min and sGaw determined five minutes after each. On one occasion each dose of histamine was immediately preceded by the non-active test dose of PGF2 alpha and on the second by saline as placebo. The study was performed double-blind and in random order. After pretreatment with PGF2 alpha the histamine dose-response curve was significantly shifted to the left in a parallel fashion (p less than 0.001). There was a significant decrease in the doses of histamine required to cause a 20% fall in sGaw (p less than 0.0015) but no significant change in the slopes of the dose-response regression lines, indicating that bronchial muscle sensitivity rather than reactivity had been predominantly affected.     

Laser acupuncture in children and adolescents with exercise induced asthma

BACKGROUND: Laser acupuncture, a painless technique, is a widely used alternative treatment method for childhood asthma, although its efficacy has not been proved in controlled clinical studies. METHODS: A double blind, placebo controlled, crossover study was performed to investigate the possible protective effect of a single laser acupuncture treatment on cold dry air hyperventilation induced bronchoconstriction in 44 children and adolescents of mean age 11.9 years (range 7.5-16.7) with exercise induced asthma. Laser acupuncture was performed on real and placebo points in random order on two consecutive days. Lung function was measured before laser acupuncture, immediately after laser acupuncture (just before cold dry air challenge (CACh)), and 3 and 15 minutes after CACh. CACh consisted of a 4 minute isocapnic hyperventilation of -10 degrees C absolute dry air. RESULTS: Comparison of real acupuncture with placebo acupuncture showed no significant differences in the mean maximum CACh induced decrease in forced expiratory volume in 1 second (27.2 (18.2)% v 23.8 (16.2)%) and maximal expiratory flow at 25% remaining vital capacity (51.6 (20.8)% v 44.4 (22.3)%). CONCLUSIONS: A single laser acupuncture treatment offers no protection against exercise induced bronchoconstriction in paediatric and adolescent patients.