Bronchial responsiveness to hyperventilation in children with asthma: inhibition by ipratropium bromide.

Isocapnic hyperventilation dose response curves were constructed for 11 asthmatic children before and after pretreatment with placebo or ipratropium bromide, 40-1500 micrograms given by inhalation, on three separate days. The response before and after placebo was highly reproducible (within subject coefficient of variation 7.5%, 18%, and 22% for intervals of two hours, within two weeks, and over two weeks). It was independent of baseline lung function. Complete protection against hyperventilation induced asthma was achieved by ipratropium bromide 40 micrograms in six children and by 200 micrograms or more in a further four. The remaining child was unaffected by any dose of ipratropium up to 1500 micrograms. The dose of ipratropium required for protection was better related to the subjects' requirement for regular medication than to their sensitivity to hyperventilation or baseline lung function.     

Sodium cromoglycate and ipratropium bromide in exercise-induced asthma.

In thirteen patients with extrinsic asthma the effects of placebo, sodium cromoglycate, ipratropium bromide, and ipratropium bromide plus sodium cromoglycate were studied in a random double-blind fashion to assess their inhibitory action in exercise-induced asthma (EIA). Exercise testing consisted of steady state running on an inclined treadmill for up to eight minutes. In eight of the 13 patients studied the baseline ratio of expiratory flow at 50% vital capacity (VC) breathing helium-oxygen (V50He) to V50air was over 1.20 and they were called responders; the remaining five patients were called non-responders. There was a significantly lower baseline maximum mid-expiratory flow rate (MMEF) in non-responders (P less than 0.02) as compared to responders but no difference in forced expiratory volume in one second (FEV1) or forced vital capacity (FVC). Sodium cromoglycate (P less than 0.02), ipratropium bromide (P less than 0.01), and ipratropium bromide plus spdium cromoglycate (P less than 0.01) all significantly inhibited the percentage fall in FEV1 after exercise in the responders. Ipratropium bromide had no preventive action on non-responders, unlike sodium cromoglycate (P less than 0.05) and ipratropium bromide plus sodium cromoglycate (P less than 0.02). It is postulated that mediator release is an important factor in development of EIA in most extrinsic asthmatics, whereas cholinergic mechanisms are relevant only in those patients in whom the main site of airflow obstruction is in the large central airways.     

Relative efficacy of nebulised ipratropium bromide and fenoterol in acute severe asthma

In a double-blind, randomised, controlled clinical trial of 145 patients with acute asthma, the efficacy of nebulised 4-hourly ipratropium bromide plus 4-hourly fenoterol (group I, 50 patients), 2-hourly fenoterol (group II, 50 patients) and 4-hourly fenoterol (group III, 45 patients) was assessed. All patients received an optimal infusion of aminophylline and 81 patients (27 in each group) received hydrocortisone for clinical indications. It was found that cholinergic side-effects in group I were not more common than in group II. Tremor was more common in group II. Assessment of bronchodilator efficacy was confined to the 81 patients whose therapy included hydrocortisone. Peak expiratory flow rate, forced expiratory volume in 1 second, and forced vital capacity were expressed as a percentage of predicted for each individual and the mean values for each group plotted. It was found that the response rate, as assessed by the area under the curve, was significantly more rapid in group I compared with both group II (P less than 0.001) and group III (P less than 0.005). These findings were consistent for all three lung function measurements. However, there was no significant difference in the responses between group II and group III. It is concluded that adding ipratropium bromide to conventional regimens is likely to benefit patients with acute asthma.     

Effect of lignocaine, sodium cromoglycate, and ipratropium bromide in exercise-induced asthma

Eight patients with exercise-induced asthma participated in a single-blind trial comparing the protective effects of inhaled lignocaine (estimated dose 48 mg), sodium cromoglycate (estimated dose 12 mg), and ipratropium bromide (estimated dose 120 μg). Saline was used as control. Effects were assessed from the mean maximal percentage fall in forced expiratory volume in one second (FEV₁) and maximal mid-expiratory flow rates (MMFR) after they had run on a treadmill for eight minutes. There was no significant change in baseline FEV₁ or MMFR before each agent was given. Saline, lignocaine, and sodium cromoglycate did not alter the mean baseline FEV₁ or MMFR significantly. Ipratropium caused bronchodilatation with an increase of 16·3% in the mean FEV₁ (p<0·001) and of 43·4% in the mean MMFR (p<0·05). After exercise the maximal percentage falls in FEV₁ (means and SEM) after saline, lignocaine, sodium cromoglycate, and ipratropium bromide were 38·1% (5·0), 34·5% (6·1), 11·3% (3·7), and 19·3% (7·4) respectively. Similarly, the mean maximal falls in MMFR after saline, lignocaine, sodium cromoglycate, and ipratropium bromide were 54·4% (5·2), 52·9% (7·7), 23·6% (6·6), and 32·1% (10·5) respectively. The inhibitory effects of sodium cromoglycate and ipratropium bromide were significant whereas lignocaine failed to produce an effect. These results suggest that mediator release is an important factor in exercise-induced asthma and that in some patients the effects of the mediators may be on the postsynaptic muscarinic receptors. Local anaesthesia of sensory vagal receptors, on the other hand, does not prevent exercise asthma and these receptors do not appear to have any important role in exercise-induced bronchoconstriction.     

Effects of allergy and age on responses to salbutamol and ipratropium bromide in moderate asthma and chronic bronchitis.

The bronchodilating responses to 400 micrograms salbutamol and 80 micrograms ipratropium bromide were studied in 188 patients with chronic bronchitis (n = 113) or asthma (n = 75) and mild to moderate airflow obstruction (forced expiratory volume in one second (FEV1) above 50% but below 2 SD of predicted value) in a crossover study on two days a week apart. Both the patients with asthma and the patients with chronic bronchitis varied considerably in their responses to the salbutamol and the ipratropium bromide. The mean increase in FEV1 in the subjects with asthma was higher after salbutamol (0.371 or 18% of the prebronchodilator value) than after ipratropium bromide (0.26 1 or 13%). In chronic bronchitis there was no difference between the increase in FEV1 after salbutamol (0.161 or 7%) and after ipratropium bromide (0.191 or 8%). When patients were categorised into those with a better response to salbutamol 400 micrograms and those with a better response to ipratropium bromide 80 micrograms, patients with chronic bronchitis responded better in general to ipratropium bromide whereas asthmatic patients responded better to salbutamol. The response pattern was also related to allergy and age, allergic patients and patients under 60 being more likely to respond better to salbutamol 400 micrograms than non-allergic patients and older patients, who benefited more from ipratropium bromide 80 micrograms. The response pattern was not related to sex, smoking habits, lung function, bronchial reactivity, respiratory symptoms, or number of exacerbations during the preceding year.     

Exercise-induced asthma and cardiovascular fitness in asthmatic children.

BACKGROUND: The role of physical training in the management of children with exercise-induced asthma is controversial. A study was undertaken to determine whether a relationship could be found between the occurrence of exercise-induced asthma and the degree of cardiovascular fitness in asthmatic children. METHODS: Twenty eight children aged 6-13 with mild to moderate asthma and dyspnoea during or after physical exercise were tested. All patients had a basal forced expiratory volume in one second (FEV1) of > 80% predicted. Twelve patients were taking corticosteroid maintenance medication by inhalation and 16 were not. Two exercise tests were performed on a treadmill to assess peak oxygen consumption rate (VO2max) and the percentage decrease in FEV1 after exercise. RESULTS: There was no correlation between the VO2max and the percentage decrease in FEV1. Patients not taking steroids showed a greater fall in FEV1 than those receiving corticosteroid medication (mean fall in FEV1 28.7% versus 6.6%). Four of the 12 children treated with steroids and two of the 16 children not taking steroids had a level of cardiovascular fitness lower than the 5th percentile for healthy Dutch children. CONCLUSION: Normal cardiovascular fitness does not prevent exercise-induced asthma.     

Ipratropium bromide in children with asthma

Eighteen children between 6 and 14 years of age with perennial asthma were studied over two four-week treatment periods. Ipratropium bromide, given in addition to their current treatment, was compared with placebo using a double-blind crossover technique. The period of treatment with ipratropium was associated with a significant reduction in symptoms during both day and night and significantly higher morning peak expiratory flow rates.     

Site of action of ipratropium bromide and clinical and physiological determinants of response in patients with asthma.

It has been suggested that in normal subjects inhaled anticholinergic agents have a preferential dilating effect on large central airways. We therefore studied 21 patients with asthma to see if response to inhaled ipratropium bromide was related to the initial central or peripheral site of major airway narrowing. Fourteen out of 21 patients with asthma increased their Vmax more than 10% after ipratropium but when assessed by air and helium/oxygen (He/O2) flow-volume curves, responders and non-responders to He/O2 breathing were divided equally between those who benefited from the drug, and those who did not. There were no significant differences in percentage improvement in Vmax between initial responders, and initial non-responders to He/O2 breathing. Furthermore the results from air and He/O2 flow-volume curves suggest that, contrary to some previous reports (not in asthmatics), inhaled ipratropium has a generalised action throughout the airways. There were no differences in severity of airflow obstruction, nor in age, sex, smoking history, or atopic status between those who benefited from ipratropium and those who did not. However, those improving after the drug had a significantly longer history of asthma than those who did not.     

Dose related effects of salbutamol and ipratropium bromide on airway calibre and reactivity in subjects with asthma.

The relationship between change in airway calibre and change in airway reactivity after administration of bronchodilator drugs has been investigated by comparing the effect of increasing doses of inhaled salbutamol and ipratropium bromide on the forced expiratory volume in one second (FEV1), specific airways conductance (sGaw), and the dose of histamine causing a 20% fall in FEV1 (PD20) in six subjects with mild asthma. On each of 10 occasions measurements were made of baseline FEV1, sGaw, and PD20 after 15 minutes' rest, and followed one hour later, when the FEV1 had returned to baseline, by a single nebulised dose of salbutamol (placebo, 5, 30, 200 and 1000 micrograms) or ipratropium (placebo, 5, 30, 200 and 1000 micrograms) given in random order. Measurements of FEV1, sGaw, and PD20 were repeated 15 minutes after salbutamol and 40 minutes after ipratropium. Salbutamol and ipratropium caused a similar dose related increase in FEV1 and sGaw, with a mean increase after the highest doses of 0.76 and 0.69 litres for FEV1 and 1.15 and 0.96 s-1 kPa-1 for sGaw. Salbutamol also caused a dose related increase in PD20 to a maximum of 2.87 (95% confidence interval 2.18-3.55) doubling doses of histamine after the 1000 micrograms dose, but ipratropium bromide caused no significant change in PD20 (maximum increase 0.24 doubling doses, 95% confidence interval -0.73 to 1.22). Thus bronchodilatation after salbutamol was associated with a significantly greater change in airway reactivity than a similar amount of bronchodilatation after ipratropium bromide. This study shows that the relation between change in airway reactivity and bronchodilatation is different for two drugs with different mechanisms of action, suggesting that change in airway calibre is not a major determinant of change in airway reactivity with bronchodilator drugs.     

Effects of ipratropium bromide and fenoterol aerosols in pulmonary emphysema.

In patients with radiological evidence of pulmonary emphysema the bronchodilator drugs fenoterol and ipratropium bromide produced a considerable increase in vital capacity and reduction in residual volume. The response to fenoterol was virtually complete 15 minutes after administration, but after ipratropium bromide vital capacity was still increasing at 60 minutes. The change in vital capacity was slightly greater with a combination of the two drugs than with either used alone. Changes in FEV1 and peak flow rate were small.     

Influence of age on response to ipratropium and salbutamol in asthma.

We studied the differential response to inhaled salbutamol and ipratropium of 29 asthmatic patients, 18 intrinsic, 11 extrinsic, using peak expiratory flow rate (PEFR), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC). Thirty minutes after a theoretically maximally bronchodilating dose of salbutamol (400 microgram) or ipratropium (80 microgram), second doses frequently caused further bronchodilatation. We suspect that second doses may reach bronchi untouched by the first inhalation. Analysis of variance showed a powerful intrinsic versus extrinsic effect, and there were clearly differences between patients in their response to treatment (patient versus drug interaction) but these differences were not removed by dividing the patients into intrinsic and extrinsic groups. Results for the group as a whole favoured salbutamol, but examination of individual results by a pattern-recognition technique showed ipratropium equally effective in eight patients and more effective in three. All patients with a definite predominant salbutamol response were less than 40 years old. The response to salbutamol declined significantly with age, whereas that to ipratropium did not. In general in patients aged less than 40 years salbutamol is the drug of choice. With advancing age, and the apparent decline of beta-adrenergic responsiveness, the initially comparatively small response to ipratropium becomes relatively more important and may predominate. In older patients ipratropium, or continued therapy with both drugs, may be preferable.     

Budesonide and terbutaline or terbutaline alone in children with mild asthma: effects on bronchial hyperresponsiveness and diurnal variation in peak flow.

The effects of treatment with budesonide (200 micrograms twice daily) and terbutaline (500 micrograms four times daily) has been compared with the effects of placebo and terbutaline in 27 children with mild asthma, aged 7-14 years, in a double blind, randomised placebo controlled study over eight weeks. Bronchial responsiveness (PC20 histamine), lung function, the amplitude of diurnal variation in peak expiratory flow (PEF), and symptom scores were measured. Baseline FEV1 was over 70% predicted and PC20 histamine less than 8 mg/ml. Twelve children were treated with budesonide and terbutaline and 15 with placebo and terbutaline. After four and eight weeks of treatment the change in PC20 was significantly greater after budesonide and terbutaline than after terbutaline alone by 2.1 (95% CI 0.5-3.8) and 1.3 (95% CI 0.1-2.5) doubling doses respectively. Mean FEV1 did not change in either group. The change in afternoon and nocturnal PEF was significantly greater after budesonide and terbutaline than after terbutaline alone. The amplitude of diurnal variation in PEF did not change significantly in either group. Peak flow reversibility decreased in the budesonide group. There were no differences between treatments for cough and dyspnoea, but wheeze improved in the budesonide group. The children with mild asthma treated with budesonide and terbutaline showed improvement in bronchial responsiveness, afternoon and nocturnal PEF, and symptoms of wheeze and a fall in peak flow reversibility by comparison with those who received terbutaline alone.     

Comparison of the efficacy of preservative free ipratropium bromide and Atrovent nebuliser solution.

The paradoxical bronchoconstriction observed with commercially available isotonic ipratropium bromide nebuliser solution (Atrovent) in patients with asthma results from an adverse reaction to the preservatives, benzalkonium chloride and ethylenediaminetetra-acetic acid (EDTA). The airway response to inhaled Atrovent and preservative free ipratropium bromide nebuliser solutions has been examined in a double blind study. On separate occasions 30 asthmatic subjects inhaled 2 ml of the solutions and airway calibre was measured in terms of FEV1 for 45 minutes. Atrovent nebuliser solution provoked a greater than 20% fall in FEV1 in five of the 30 subjects, whereas this did not occur after preservative free ipratropium bromide. Inhalation of the preservative free solution resulted in more rapid and greater overall bronchodilatation than Atrovent, with mean maximum increases in FEV1 of 29.2% and 18.5% respectively. It is concluded that the risk of paradoxical bronchoconstriction with ipratropium bromide is considerably reduced by removal of benzalkonium chloride and EDTA and that preservative free ipratropium bromide is a more potent bronchodilator than the currently available Atrovent solution.     

Assessment of the clinical usefulness of nebulised ipratropium bromide in patients with chronic airflow limitation.

The effect of adding nebulised ipratropium bromide to bronchodilator treatment was studied in 20 patients with severe chronic airflow limitation. Maintenance theophylline with or without a steroid preparation was continued and comparison made between placebo, nebulised salbutamol, and a combination of nebulised salbutamol and ipratropium. Although the mean FEV1 values showed the combination to produce a small but significant increase in peak bronchodilatation over the effect of salbutamol alone, there were eight patients in whom no clinically useful improvement occurred. The remaining 12 patients did obtain clinically useful improvement in the magnitude or the duration of bronchodilatation (or both) as a result of the added ipratropium. The conclusion is that individual patients with chronic airflow limitation responded to the addition of nebulised ipratropium bromide in a variable way. Patients who could obtain additional benefit from ipratropium need to be identified by an appropriate reversibility study before its inclusion in their bronchodilator treatment.     

Comparison of the effects of inhaled ipratropium bromide and salbutamol on the bronchoconstrictor response to hypocapnic hyperventilation in normal subjects.

A double blind, placebo controlled comparison was made of the effects of nebulised ipratropium bromide (0.05 and 0.5 mg) and salbutamol (0.25 and 2.5 mg) on lung function and the airway response to hyperventilation in eight normal subjects. Both agents at both doses caused similar baseline bronchodilatation, confirming the presence of resting bronchomotor tone. The overall mean increases as percentages of control were 33% in specific airway conductance (sGaw), 10% in maximal flow after expiration of 50% of vital capacity, and 3.7% in FEV1. Hypocapnia (mean end tidal carbon dioxide tension 2.2 kPa) was produced by three minutes of voluntary hyperventilation and resulted in a mean fall in sGaw of 0.49 s-1 kPa-1 (20%). After inhalation of 0.25 mg salbutamol hypocapnic hyperventilation still produced a mean fall in sGaw of 0.55 s-1 kPa-1, whereas salbutamol 2.5 mg reduced this response to 0.15 s-1 kPa-1 (6%). After both doses of ipratropium the decrease in sGaw caused by hyperventilation was similar to the control. This suggests that bronchoconstriction in response to hypocapnic hyperventilation in normal subjects is not mediated via a cholinergic reflex.     

The effect of aerosol ipratropium bromide and salbutamol on exercise tolerance in chronic bronchitis.

In a double-blind placebo controlled trial in 24 patients fulfilling the MRC criteria for chronic bronchitis, ipratropium bromide 40 microgram and salbutamol 200 microgram produced similar and significant (P less than 0.001) increases in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). A greater increase in FEV1 and FVC was seen when both drugs were used together, but this increase did not differ significantly from that produced by either drug alone. Salbutamol increased 12-minute walking distance significantly (P less than 0.001) by 62 +/- 15 metres, whereas the increase of 43 +/- 15 metres observed after ipratropium was not significant (P less than 0.05). With both drugs in combination 12-minute walking distance increased by 72 +/- 15 metres, but this change was not significantly different from that observed with salbutamol alone. If aerosol bronchodilators in the doses used in this study are to be given with a view to improving exercise tolerance in such patients than salbutamol would appear to be the aerosol of choice.     

Failure of allopurinol to modify urinary composition in enteric hyperoxaluria

Conventional treatment of enteric hyperoxaluria (EHO) consists of dietary restriction of oxalate and fat and correction of its underlying cause whenever possible. Recent work suggests that allopurinol reduces the incidence of urolithiasis and the urinary excretion of both oxalate and uric acid in patients without intestinal disease. We have assessed the effect of allopurinol, 300 mg daily for 2 weeks, on urine biochemistry in patients with EHO due to small bowel Crohn's disease and/or resections. Compliance with treatment was confirmed by a fall in plasma uric acid in every patient. Allopurinol failed to alter 24 h urinary oxalate excretion or oxalate concentration. There were also no significant changes in the urinary excretion of glycollate (like oxalate, a breakdown product of glyoxylate), citrate, magnesium or calcium, each of which was at the lower end of the normal range before and during treatment with allopurinol. It appears unlikely that allopurinol will prove useful in the prevention of urolithiasis in patients with EHO.     

Effect of ipratropium bromide on mucociliary clearance and pulmonary function in reversible airways obstruction.

The effects of (a) regular use for one week and (b) a single dose of a synthetic anticholinergic (ipratropium bromide) on lung mucociliary clearance and as a bronchodilator was ascertained in a controlled, double-blind, cross-over study in 12 patients with reversible airways obstruction (mean increase in FEV after isoprenaline: 17% range 10-50%). Two puffs from a metered dose inhaler of either placebo (propellants only) or drug (40 microgram) were administered four times a day for one week (regular use), and mucociliary clearance was measured, by radioaerosol tracer, at the end of each treatment period and after a control period in which no treatment was given. On the mornings of the measurements after the placebo and drug periods one final dose (single dose) of ipratropium (40 microgram) or placebo was given 2.5 hours before the start of the test. There was no statistically significant difference between the three mean mucociliary clearance curves (control, placebo, and drug) for the group; however, there was a significantly greater penetration towards the periphery of the lung of the tracer in the test after drug administration compared with the other two. This increased penetration was attributed to bronchodilatation caused by the drug. Ipratropium bromide does not appear to impair mucociliary clearance, and it acts an effective bronchodilator.     

Effect of oral prednisolone on response to salbutamol and ipratropium bromide aerosols in patients with chronic airflow obstruction.

We examined the bronchodilator responses to inhalation of salbutamol (200 micrograms) and of ipratropium bromide (40 micrograms) in the morning and in the afternoon before and during a course of oral prednisolone (40 mg daily) in 15 patients with chronic, partly reversible airflow obstruction. Bronchodilatation was assessed by measuring serial peak expiratory flow rates (PEFR) for six hours after aerosol drug administration and calculating the area under the time-response curves. Eleven patients were found to be corticosteroid resistant in not attaining a baseline bronchodilatation of at least 25% during corticosteroid treatment. These patients also failed to show any enhancement of their bronchodilator responses to either salbutamol or ipratropium bromide during prednisolone administration. We therefore conclude that there is no rationale for giving or continuing corticosteroid treatment in known steroid-resistant patients in the hope of nevertheless potentiating their bronchodilator responses to salbutamol or ipratropium bromide.     

Effect of four weeks'' high dose ipratropium bromide treatment on lung mucociliary clearance.

In a randomised, double blind crossover study the effect of high dose ipratropium bromide (200 micrograms three times daily given by metered dose inhaler for four weeks) on lung mucociliary clearance and on the wet weight and mean apparent viscosity of sputum was compared with that of placebo. Six smokers, six ex-smokers, and three non-smokers (12 men and three women, median age 60 years) were studied. Eight subjects had chronic obstructive lung disease (median FEV1 46% predicted) and seven had asthma (FEV1 70% predicted). Seven subjects produced sputum regularly, two of whom had asthma. Clearance of secretions was measured by an inhaled radioaerosol technique. The number of coughs and the wet weight, radioactive content, and mean apparent viscosity of sputum produced during the six hour observation period were recorded, as was the mean wet weight of sputum produced during the last two 24 hour periods ending each treatment. Comparison with placebo showed that treatment with high dose ipratropium bromide was associated with a significant increase in the penetration index of inhaled particles, but there was no significant change in alveolar deposition of particles or in tracheobronchial clearance, uncorrected or corrected for sputum expectorated. The wet weight of sputum produced, its radioactive content, and mean apparent viscosity were similar after treatment with ipratropium bromide and placebo. These results show that high dose inhaled treatment with the synthetic anticholinergic bronchodilator ipratropium bromide for four weeks is not associated with detectable modification of the clearance of secretions from the lungs, or of sputum volume or viscosity.