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.     

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.     

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.     

Comparison of nebulised salbutamol and ipratropium bromide with salbutamol alone in the treatment of chronic obstructive pulmonary disease.

BACKGROUND--Patients admitted with acute exacerbation of chronic obstructive pulmonary disease (COPD) are often prescribed ipratropium bromide in combination with a beta 2 agonist such as salbutamol. Studies have not shown any benefit in adding ipratropium bromide to salbutamol in acute exacerbations of COPD, but these studies have only assessed patients for 60-90 minutes and short term studies may not predict long term clinical response. Combination therapy with the two drugs was compared with salbutamol alone in the treatment of acute exacerbations of COPD during a hospital admission. METHODS--Seventy patients admitted to hospital with an acute exacerbation of COPD were randomly allocated to receive either nebulised salbutamol 5 mg and ipratropium bromide 500 micrograms, or nebulised salbutamol 5 mg alone (all four times a day) on admission. All other treatment was prescribed at the discretion of the attending physician. Length of stay in hospital and spirometric values on days 1, 3, 7, 14, and discharge were assessed. Patients completed a subjective symptom score each day. RESULTS--There was no difference between the two groups in the mean (SD) length of stay (salbutamol 10.5 (4.7) days, salbutamol + ipratropium bromide 11.8 (4.4) days; 95% CI -1.02 to 3.62). There was no difference in spirometric values on days 1, 3, 7, 14, or discharge between the two groups. The subjective improvement was similar with both treatments. CONCLUSIONS--The routine addition of nebulised ipratropium bromide to salbutamol appears to be of no benefit in the treatment of acute exacerbations of COPD.     

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.     

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.     

A comparison of responses to bronchodilator drugs in chronic bronchitis and chronic asthma

Isoprenaline by inhalation, adrenaline by inhalation, subcutaneous adrenaline, intravenous aminophylline, and subcutaneous atropine were administered to two groups of 18 patients suffering from either chronic bronchitis or chronic asthma using a Latin square design. Prednisolone was then given to both groups of patients for six days. The responses to the drugs were assessed by recording the F.E.V._1·0 before and 20 minutes after the administration of the short-acting drugs and daily during the period of prednisolone therapy. No significant differences were found between the responses to the short-acting antispasmodic drugs in the group of patients suffering from chronic bronchitis and only an insignificant improvement in the mean F.E.V._1·0 occurred during the period of prednisolone administration. Significant differences between mean responses to the anti-spasmodic drugs of the group of patients suffering from chronic asthma were observed. The mean F.E.V._1·0 response following subcutaneous adrenaline was 44%, which was significantly better than the 23·7% improvement after adrenaline inhalation (p=0·005) and the mean improvement in F.E.V._1·0 of 17·1% after subcutaneous atropine sulphate (p=0·001). A dramatic improvement in the mean F.E.V._1·0 of 49·5% occurred after six days of prednisolone administration. It is tentatively suggested that a good response to subcutaneous adrenaline and a poor response to subcutaneous atropine, as judged by improvement in the F.E.V._1·0, may be an indication that a good response to prednisolone can be expected in wheezy patients.     

Direct labelling of ipratropium bromide aerosol and its deposition pattern in normal subjects and patients with chronic bronchitis.

A technique for the direct labelling of ipratropium bromide with bromine-77, with reconstitution of the drug in a metered dose inhaler so as to be identical to the commercial product, was used to study drug deposition patterns in seven normal subjects and seven patients with chronic bronchitis (mean FEV1 32% (SD 12.2%) predicted normal). The gamma camera image of the thorax was divided into a middle zone--the mediastinal zone--and the lung itself into a central zone comprising its medial third and a peripheal zone, the lateral two thirds. Measurements after 10 inhalations of labelled ipratropium bromide showed similar results for the two groups of subjects. The total lung dose inhaled was 11.2% of 203 micrograms and 11.7% of 186 micrograms in the normal subjects and the patients respectively. In contrast to the deposition patterns seen in aerosol studies using steady state inhalation methods, there was no difference in deposition pattern--that is, the distribution between the central and the peripheral lung zones--between the normal subjects and the patients with airways obstruction.     

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.     

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.     

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.     

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.     

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 oral salbutamol and slow-release aminophylline on exercise tolerance in chronic bronchitis.

In a double-blind placebo-controlled trial in 24 patients fulfilling the MRC criteria for chronic bronchitis, oral salbutamol 4 mg and slow-release aminophylline (Phyllocontin) 450 mg produced similar and significant (p less than 0.05) mean increases in forced expiratory volume in one second (FEV1). A significantly greater increase in mean FEV1 and forced vital capacity (FVC) was seen when both drugs were given although there was no statistical evidence of synergistic interaction. Salbutamol significantly increased the mean distance walked in 12 minutes (12MD) (p less than 0.02) by 56 metres and a similar increase of 54 metres (p less than 0.001) was seen after Phyllocontin. With both drugs in combination mean 12MD increased by 51 metres (p less than 0.02 cf placebo), a change not significantly different from that observed with either drug alone. Oral salbutamol and Phyllocontin improve exercise tolerance in chronic bronchitis. The significantly greater changes in FEV1 and FVC resulting from simultaneous administration of the two drugs are not associated with further improvement in exercise tolerance.     

Effects of theophylline and ipratropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease

BACKGROUND—The effects of theophylline oranticholinergic agents on exercise capacity in patients with chronicobstructive pulmonary disease (COPD) remain controversial. The aim ofthe present study was to compare the effect of an oral theophyllinewith an inhaled anticholinergic agent and to examine the effects ofcombined therapy on exercise performance using progressive cycle ergometry.
METHODS—Twenty one men with stable COPD anda mean (SD) forced expiratory volume in one second (FEV₁)of 1.00 (0.40) l were studied. Theophylline (600 or 800 mg daily),ipratropium bromide (160 µg), a combination of both drugs, andplacebo were given in a randomised, double blind, four period crossoverdesign study. Spirometric data, pulse rate, and blood pressure wereassessed before and at 90 and 120 minutes after inhalation. Symptomlimited progressive cycle ergometer exercise tests (20 watts/min) wereperformed 90minutes after each inhalation, and dyspnoea was measuredduring exercise using the Borg scale.
RESULTS—The mean (SD) serum theophyllineconcentration was 18.3 (6.3) µg/ml, and seven patients had sideeffects during treatment with theophylline. Theophylline andipratropium bromide produced greater increases in FEV₁,maximal oxygen consumption, maximal minute ventilation, and severaldyspnoea ratios than placebo. There were no differences betweentheophylline and ipratropium bromide except in maximal heart rate. Acombination of both drugs produced greater improvements in pulmonaryfunction and exercise capacity than either drug alone.
CONCLUSIONS—Both high dose theophylline and highdose ipratropium bromide improved exercise capacity in patients withstable COPD. Although data based on short term effects cannot bedirectly applied to long term therapy, theophylline added to an inhaledanticholinergic agent may have beneficial effects on exercise capacityin patients with COPD.

     

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.     

Differences in responsiveness to hyperventilation and methacholine in asthma and chronic bronchitis.

In a previous study on 27 patients with chronic bronchitis we found that only three developed bronchoconstriction in response to hyperventilation of cold, dry air despite an increased responsiveness to methacholine inhalation. We therefore investigated bronchial responsiveness to hyperventilation with cold, dry air and methacholine in 27 patients with stable asthma who had a similar range of baseline FEV1 values but who developed bronchoconstriction that could be reversed to give an FEV1 more than 70% of the predicted value. Baseline FEV1 was 0.88-3.98 l (37-114% predicted). All but one subject developed bronchoconstriction in response to hyperventilation. There was a linear relationship between baseline FEV1 and response to methacholine (r2 = 0.37, p less than 0.001) and the relationship was significantly different from that found in the bronchitic subjects (F2.50 = 24.94, p less than 0.001). In general, the response to methacholine was greater in the asthmatic than in the bronchitic subjects for any baseline FEV1. The results suggest that there are different mechanisms underlying the increased responsiveness to methacholine in asthma and chronic bronchitis.     

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.     

Some histological changes in chronic bronchitis and asthma

The differences in two groups of patients (24 with chronic bronchitis and 24 with bronchial asthma) were compared by bronchoscopy and bronchial biopsies. The same investigations were carried out on 24 healthy control subjects. The only bronchoscopic difference between the two groups was hypertonicity of the bronchial wall, which was frequent in the asthmatics and absent in the chronic bronchitics. Mucus was scanty and viscous in the asthmatics and more abundant and watery in the chronic bronchitics. Hypersecretion of mucus occurred in both groups. In asthma the mucous hyperplasia affected chiefly the goblet cells. In chronic bronchitis the deeper bronchial glands were affected as well as the goblet cells. In asthma the mucus stained predominantly with the periodic-acid Schiff technique, and was thus presumed to contain much neutral mucopolysaccharide. In chronic bronchitis the mucus was strongly alcian blue positive and was thought to consist largely of acid mucopolysaccharide. Thickening of the basement membrane was almost constant in bronchial asthma and rare in chronic bronchitis. Tissue eosinophilia was very frequent and intense in asthma but infrequent and sparse in chronic bronchitis. Mast cells were degranulated and decreased in number in asthma but increased in number and packed with granules in chronic bronchitis. It is presumed that there is a relation between tissue eosinophilia and degranulation of mast cells. The study confirms that bronchial asthma and chronic bronchitis are two distinct diseases, both with a separate pathology.