Dose response study of ipratropium bromide aerosol on maximum exercise performance in stable patients with chronic obstructive pulmonary disease.

BACKGROUND: Although the bronchodilating effect of inhaled anticholinergics has been established in patients with chronic obstructive pulmonary disease (COPD), their effects on exercise capacity are still controversial. Previous studies have suggested that the standard dosage hardly affects exercise tolerance, whereas higher doses might elicit an improvement. The aim of the present study was to determine the dose of ipratropium bromide aerosol that improves exercise performance using progressive cycle ergometry in patients with stable COPD. METHODS: Twenty men with stable COPD of mean (SD) age 69.2 (4.6) years and forced expiratory volume in one second (FEV1) 1.00 (0.37) 1 were studied in a randomised double blind manner. Each patient received ipratropium bromide in doses of 240 micrograms, 160 micrograms, 80 micrograms, 40 micrograms, and placebo from a metered dose inhaler (MDI) with an InspirEase spacer on five separate days. Spirometric parameters were assessed before and at 30, 60, 90, and 120 minutes after each inhalation, and pulse rate and blood pressure were also measured immediately before each spirometric measurement. Symptom limited progressive (20 watts/min) cycle ergometer exercise tests were performed 90 minutes after each inhalation. RESULTS: Ipratropium bromide in doses of 160 micrograms and 240 micrograms produced a greater increase in FEV1 than 40 micrograms or 80 micrograms ipratropium bromide at all time points. Doses of 160 micrograms and 240 micrograms ipratropium bromide also produced greater increases in maximal work load and maximal oxygen consumption than placebo, whereas 40 micrograms and 80 micrograms ipratropium bromide did not. There was a weak correlation between the change in FEV1 and the change in maximal work load (r = 0.45). No differences were found in pulse rate or blood pressure between the treatment and placebo groups, and no side effects were noted throughout the study. CONCLUSIONS: A dose of at least four times the standard dose of ipratropium bromide from an MDI with a spacer device was necessary to improve maximal cycle exercise capacity in patients with stable COPD. Although the data from cycle ergometry cannot be directly applied to exercise performed during day to day activities, it is conceivable that the recommended doses of ipratropium bromide do not elicit the optimal clinical benefits.     

Supraventricular tachycardia caused by nebulised ipratropium bromide.

A 71 year old patient developed a supraventricular tachycardia after the administration of nebulised ipratropium bromide.     

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.     

Dose-response comparison of ipratropium bromide from a metered-dose inhaler and by jet nebulisation

The dose-response relationships of the anticholinergic bronchodilator drug ipratropium bromide were studied. Cumulative doses totalling 288 micrograms ipratropium were given by inhalation of a liquid aerosol from a Wright nebuliser to each of 10 patients with stable, moderately severe airflow obstruction. Up to 80% of the maximum achievable bronchodilator response, as assessed by a rise in the patients' mean forced expiratory volume in one second (FEV1), was obtained with a cumulative total dose of 72 micrograms; with additional doses beyond 72 micrograms there was no significant further improvement. In the same patients the effects of administration of cumulative doses of ipratropium to a total of 72 micrograms from a Wright nebuliser were compared with those achieved with a metered-dose inhaler. Bronchodilatation was assessed by measurement of peak expiratory flow rate, FEV1, forced vital capacity, thoracic gas volume and specific airways conductance (sGaw). No significant difference was observed in the response at any dose level between the wet and the dry aerosols. By fitting a curve to the mean values of FEV1 and sGaw an estimate was made of the dose of ipratropium bromide required to produce 99% of the achievable bronchodilator response. For FEV1 this dose was 78 micrograms when ipratropium was inhaled as a nebulised solution from the Wright nebuliser and 82 micrograms when it was inhaled from the metered-dose inhaler; for sGaw the respective values were 54 and 58 micrograms. In these patients with stable airflow obstruction there was no therapeutic advantage in the use of ipratropium bromide as a wet aerosol.     

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.     

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.     

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.     

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.     

异丙托溴铵对全麻病人呼吸力学的影响

目的通过麻醉前吸入异丙托溴铵,观察其对气管插管及机械通气时呼吸力学指标的影响。方法49例择期上腹部手术病人随机分为两组,雾化吸入异丙托溴铵0.5 mg的观察组(27例)和雾化吸入生理盐水的对照组(22例),分别于插管后即刻、插管后10、30及60 min监测呼吸力学指标的变化。结果观察组的气道峰压、呼吸功、吸气阻力和呼气阻力与对照组相比明显降低,而观察组肺顺应性明显高于对照组(P<0.05)。随着时间的延长,两组病人的气道峰压、呼吸功、吸气阻力和呼气阻力在不同时间点有不同程度的上升趋势;顺应性在下降到某一数值后则不再随时间而变化(P<0.05)。结论麻醉前雾化吸入异丙托溴铵,可降低机械通气早期气道峰压、呼吸机所做的呼吸功、吸气阻力及呼气阻力,同时改善肺动态顺应性。     

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.     

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.     

Bronchodilator effects of ipratropium bromide and albuterol sulfate among subjects with tetraplegia

Objective: In addition to lung volume restriction, persons with chronic tetraplegia demonstrate obstructive airway physiology evinced by pharmacologically-induced bronchodilation. We previously found independent evidence that anticholinergic agents (ipratropium bromide; IB) and beta-2 adrenergic agonists (albuterol sulfate; AS) were associated with significant bronchodilation in subjects with tetraplegia as determined via spirometry or body plethysmography. Direct comparison of these two classes of agents has received little attention.

Methods: Twelve subjects with chronic tetraplegia completed single dose treatment on alternate days with nebulized IB or AS. Patients underwent pre- and 30-minute post-bronchodilator spirometry, body plethysmography, and impulse oscillation system (IOS) in accordance with established protocols.

Results: Spirometry and specific airway conductance revealed significant bronchodilator responsiveness following both IB and AS. As determined by increases in specific airway conductance post-bronchodilator, IB tended toward greater bronchodilation than AS (71% vs. 47%). IOS revealed a greater reduction in central airway resistance (R20) following IB compared to AS (22% vs. 9%, P?Conclusion: Among subjects with tetraplegia, both IB and AS elicit significant bronchodilation, although the magnitude of the bronchodilator response is greater following IB. This lends support to theory of overriding cholinergic airway tone in tetraplegia. The IOS findings further suggest that the predominant site of action of IB is upon the larger central airways congruent with findings in able-bodied subjects.     

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.     

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.     

Effect of ipratropium bromide aerosol on respiratory function in patients under ventilator treatment

Twenty patients, 36-78 years old, with a history of chronic obstructive lung disease, and immediately after operation mostly for cardiac disease, were treated with ipratropium bromide (IB, 15 cases) or placebo (5 cases). A metered dose inhaler with a new adapter was used during postoperative ventilator treatment. In the IB group the heart rate did not change, but the inspiratory resistance decreased and the arterial oxygen tension increased. This is considered to indicate an effect not only on large but also on small airways, or an improvement of the ventilation/perfusion relationship. The investigation also demonstrated the practical usefulness of the new adapter.     

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.     

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.     

Failure of ipratropium bromide to modify the diurnal variation of asthma in asthmatic children.

Thirty one children with asthma were given 40 micrograms of ipratropium bromide and identical placebo by inhalation three times a day in a double blind, randomised crossover study to test the ability of an anticholinergic drug to modify the diurnal variation in airway calibre and bronchial reactivity. Subjects measured peak expiratory flow rate approximately eight hourly, before and after inhaled salbutamol, for four week periods. Paired t tests and cosinor analysis were used to assess the diurnal variation in airway calibre from the peak expiratory flow rate recorded before salbutamol and to assess the diurnal variation in bronchodilator responsiveness from the increase in peak expiratory flow rate after salbutamol. Maintenance treatment with ipratropium bromide 40 micrograms three times daily reduced the provocative dose of histamine which caused a 20% fall in FEV1 (geometric mean PD20 = 0.78 v 0.49 mg/ml, p less than 0.05), despite an eight to 12 hour gap between the last dose of ipratropium and histamine challenge. It did not, however, diminish the diurnal variation in airway calibre (mean amplitude = 12.7 v 10.1) or in bronchodilator responsiveness (mean amplitude = 62.4 v 63.5). There was no improvement in the clinical state of subjects while they were taking ipratropium bromide.     

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.     

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.