Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease.

BACKGROUND: Short term treatment with corticosteroids does not usually reduce airflow limitation and airway responsiveness in patients with chronic obstructive lung disease. We investigated whether corticosteroids modulate the effects of inhaled salbutamol and ipratropium bromide. METHODS: Ten non-allergic subjects with stable disease were investigated; eight completed the randomised, double blind, three period cross over study. Treatment regimens consisted of 1.6 mg inhaled budesonide a day for three weeks, 40 mg oral prednisone a day for eight days, and placebo. After each period cumulative doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo were administered on separate days until a plateau in FEV1 was reached. A histamine challenge was then performed. RESULTS: At the end of placebo treatment mean FEV1 was 55.5% predicted after inhaled placebo, 67.9% predicted after salbutamol and 64.0% predicted after ipratropium. Compared with the results after the placebo period the FEV1 with salbutamol increased by 0.7% predicted after treatment with budesonide and by 0.7% predicted after treatment with prednisone; the FEV1 with ipratropium increased by 0.7% predicted after budesonide and by 4.8% predicted after prednisone; none of these changes was significant. After placebo treatment the geometric mean PC20 was 0.55 mg/ml after placebo, 1.71 mg/ml after salbutamol and 0.97 mg/ml after ipratropium. Compared with the placebo period the PC20 with salbutamol was increased by 0.86 doubling concentrations after treatment with budesonide, and by 0.67 doubling concentrations after prednisone; the PC20 with ipratropium increased by 0.03 and 0.34 doubling concentrations after budesonide and after prednisone respectively compared with placebo; none of these changes was significant. CONCLUSIONS: In non-allergic subjects with chronic obstructive lung disease short term treatment with high doses of inhaled or oral corticosteroids does not modify the bronchodilator response to salbutamol or ipratropium or the protection provided by either drug against histamine. Salbutamol produces greater protection from histamine induced bronchoconstriction than ipratropium.     

Effect of inhaled procaterol on cough receptor sensitivity to capsaicin in patients with asthma or chronic bronchitis and in normal subjects.

BACKGROUND--To evaluate the effect of inhaled beta 2 adrenergic agonists on the sensitivity of airway cough receptors, the effect of inhaled procaterol on cough induced by aerosolised capsaicin, a stimulant of C fibres, was studied in patients with asthma or chronic bronchitis and in normal subjects. METHOD--Eleven patients with asthma and 10 with chronic bronchitis and 14 normal subjects participated. Increasing concentrations of capsaicin solution were inhaled for 15 seconds by tidal breathing through the mouth at one minute intervals until five or more coughs were elicited, before and 30 minutes after inhalation of 20 micrograms procaterol or placebo (freon gas alone) through a metered dose inhaler. Cough threshold was defined as the lowest concentration of capsaicin that elicited five or more coughs. To evaluate the bronchodilator effect of procaterol and the bronchoconstrictor effect of inhaled capsaicin, forced expiratory volume in one second (FEV1) was measured before and one minute after a capsaicin provocation test. This test was carried out both before and 30 minutes after treatment with procaterol or placebo. RESULTS--The geometric mean value of cough threshold to capsaicin was significantly increased by procaterol and placebo in both groups of patients but not in the control subjects. The increment in the cough threshold was not significantly different between the treatments with procaterol and placebo in each group. FEV1 was significantly increased by procaterol but not by placebo in all three groups. CONCLUSIONS--Inhaled procaterol has no effect on airway cough receptor sensitivity to capsaicin. The attenuation of the cough sensitivity seen after inhalation of procaterol in patients with asthma and bronchitis may result from tachyphylaxis to capsaicin.     

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.     

Thermogenic effect of bronchodilators in patients with chronic obstructive pulmonary disease

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are frequently malnourished and have increased resting energy expenditure (REE). An increase in the work of breathing is generally considered to be the main cause of this hypermetabolism, but other factors may also be implicated. Bronchodilators may decrease the work of breathing by reducing airway obstruction, but beta 2 adrenergic agents have a thermogenic effect. The aim of this study was to determine the effect of salbutamol and ipratropium bromide administration on REE in patients with COPD. METHODS: Thirteen patients (10 men) of mean (SD) age 68.3 (7.3) years and forced expiratory volume in one second (FEV1) 39.0 (17.0)% predicted were studied on three consecutive days. The REE was measured by indirect calorimetry at 30, 60, 120, and 180 minutes after double blind nebulisation of either salbutamol, ipratropium bromide, or placebo in random order. RESULTS: FEV1 increased both after salbutamol and after ipratropium. The difference in the mean response between salbutamol and placebo over 180 minutes was +199 ml (95% CI +104 to +295). The difference in mean response between ipratropium and placebo was +78 ml (95% CI +2 to +160). REE increased after salbutamol but was not changed after ipratropium. The difference in mean response between salbutamol and placebo was +4.8% of baseline REE (95% CI +2.2 to +7.4). Heart rate increased after salbutamol but not after ipratropium. The difference in the mean response between salbutamol and placebo was +5.5 beats/ min (95% CI +2.6 to +8.4). CONCLUSION: Salbutamol, but not ipratropium bromide, induces a sustained increase in the REE of patients with COPD despite a reduction in airway obstruction.


     

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.     

Optimal particle size for beta 2 agonist and anticholinergic aerosols in patients with severe airflow obstruction.

BACKGROUND: The optimal particle size of a beta 2 agonist or anticholinergic aerosol in patients with severe airflow obstruction is unknown. METHODS: Seven stable patients with a mean forced expiratory volume in one second (FEV1) of 37.9% of the predicted value inhaled three types of monodisperse salbutamol and ipratropium bromide aerosols with particle sizes of 1.5 microns, 2.8 microns, and 5 microns, respectively, and a placebo aerosol. The volunteers inhaled 20 micrograms salbutamol and 8 micrograms ipratropium bromide, after which lung function changes were determined and analysed with repeated measurements analysis of variance (ANOVA). RESULTS: Greater improvements in FEV1, specific airway conductance (sGaw) and maximum expiratory flow at 75%/50% of the forced vital capacity (MEF75/50) were induced by the 2.8 microns aerosol than by the other particle sizes. CONCLUSIONS: In patients with severe airflow obstruction the particle size of choice for a beta 2 agonist or anticholinergic aerosol should be approximately 3 microns.     

Effects of methacholine induced bronchoconstriction and procaterol induced bronchodilation on cough receptor sensitivity to inhaled capsaicin and tartaric acid.

BACKGROUND: The direct effect of bronchoconstriction on cough receptor sensitivity is unknown, and the antitussive effect of beta 2 adrenergic agonists in man has been controversial. This study was designed to throw light on these questions. METHODS: The threshold of the cough response to inhaled capsaicin, a stimulant acting on C fibre endings, and tartaric acid, a chemostimulant, was measured before and 10 minutes after inhalation of methacholine, which caused a nearly 20% fall in forced expiratory volume in one second (FEV1), in 14 normal subjects (study 1), and also before and 30 minutes after inhalation of procaterol (30 micrograms), placebo, and saline in eight normal subjects (study 2). Progressively increasing concentrations of capsaicin and tartaric acid solutions were inhaled for 15 seconds by mouth tidal breathing at one minute intervals and cough threshold was defined as the lowest concentration of capsaicin and tartaric acid that elicited five or more coughs. RESULTS: In study 1 the geometric mean values of the cough threshold of response to capsaicin and tartaric acid before methacholine callenge, 2.98 (GSE 1.30) micrograms/ml and 46.6 (1.22) mg/ml, were not significantly different from those of the response to methacholine inhalation, 3.45 (1.33) micrograms/ml and 32.9 (1.37) mg/ml. In study 2 the geometric mean value of the cough threshold of response to capsaicin before inhalation of procaterol (4.61 (GSE 1.84) micrograms/ml) was not different from that after inhalation of procaterol (4.61 (GSE 1.84) micrograms/ml), which had significant bronchodilator effects. The cough threshold was not altered by placebo or saline. CONCLUSIONS: These findings suggest that muscarinic receptor stimulation, bronchoconstriction, beta 2 receptor stimulation, or bronchodilation might have no direct effect on the sensitivity of the cough receptors in normal subjects.     

Effect of oral mexiletine on the cough response to capsaicin and tartaric acid

BACKGROUND: The effect of the orally active local anaesthetic mexiletine on the cough response to two different tussive agents, a C-fibre ending stimulator capsaicin and a chemostimulant tartaric acid, was examined in normal subjects. METHODS: The cough threshold, defined as the lowest concentration of capsaicin (C(5)-CP) or tartaric acid (C(5)-TA) causing five or more coughs, and histamine induced bronchoconstriction were measured three hours after a single oral dose of 300 mg mexiletine or placebo in 14 normal subjects. RESULTS: Mexiletene in a mean (SE) serum concentration of 0.99 (0. 04) microg/ml significantly increased C(5)-TA from a geometric mean (SE) of 32.0 (1.27) mg/ml with placebo to 49.9 (1.34) mg/ml, but C(5)-CP did not differ significantly between treatment with mexiletine (12.2 (1.33) microM) and placebo (14.9 (1.23) microM). CONCLUSIONS: These results suggest that the cough response to capsaicin and tartaric acid may be mediated in part via different neural pathways.     

Effect of bronchodilators on the cough response to inhaled citric acid in normal and asthmatic subjects.

Coughing was induced in seven normal and eight asthmatic subjects by giving successive inhalations of citric acid aerosols of progressively higher concentration (range 0.5-32%). A baseline cough response was obtained on each of four experimental days, and there was no significant difference between days in this respect. Then the subjects received by inhalation either a bronchodilator (salbutamol 5 mg or ipratropium 1 mg) or placebo, in a paired double blind crossover design. A second citric acid run followed and was used for paired drug-placebo comparisons. In the asthmatic subjects the cough response was diminished by both bronchodilators (p less than 0.05), and the cough threshold was significantly higher after ipratropium but not salbutamol. In normal subjects no significant effects were found. Airways calibre was assessed, by an oscillatory technique that measures the resistance of the respiratory system (Siemens Siregnost FD 5), in four of the seven normal and all eight asthmatic subjects. The mean respiratory resistance was higher in asthmatic than in normal subjects, and fell significantly after both bronchodilators. In normal subjects smaller decreases in respiratory resistance occurred, significant only with salbutamol. The simplest hypothesis which explains the results relates change in cough response to altered neuroreceptor sensitivity associated with rapid changes in bronchial calibre.     

Bronchodilatation and the site of airway resistance in severe chronic bronchitis.

Twenty-one patients with severe chronic bronchitis and emphysema (FEV1 less than 1 1) inhaled 80 microgram of the atropine-like agent ipratropium or placebo in a double-blind study and three hours later inhaled 200 microgram salbutamol. After 80 microgram ipratropium, mean FEV1 was significantly greater than after 200 microgram salbutamol (P less than 0.025), but the difference was only 40 ml and the clinical significance of this difference is unproved. There was no correlation between the patient's response to ipratropium and the response to salbutamol. When salbutamol was administered three hours after ipratropium, the FEV1 rose to higher levels than after either agent alone (P less than 0.01). Studies breathing 80% helium/20% oxygen suggest that ipratropium dilates both large and small airways. There was no correlation between the response to helium/oxygen and the response to either bronchodilator. The results suggest that in severe chronic bronchitis and emphysema ipratropium is at least as effective as salbutamol, and that such patients should have reversibility studies with salbutamol alone, ipratropium alone, and after both agents together. The combination of ipratropium and salbutamol may be clinically useful.     

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.     

Evidence for opioid modulation and generation of prostaglandins in sulphur dioxide (SO)2-induced bronchoconstriction.

BACKGROUND: Inhalation of sulphur dioxide (SO2) provokes bronchoconstriction in asthmatic subjects. Cholinergic mechanisms contribute, but other mechanisms remain undefined. The effect of morphine, an opioid agonist, on the cholinergic component of SO2-induced bronchoconstriction was investigated, and the effect of indomethacin, a cyclooxygenase inhibitor, on SO2-induced bronchoconstriction and tachyphylaxis was studied. METHODS: In the first study 16 asthmatic subjects inhaled either ipratropium bromide or placebo 60 minutes before an SO2 challenge on days 1 and 2. On day 3 an SO2 challenge was performed immediately after intravenous morphine. In the second study 15 asthmatic subjects took either placebo or indomethacin for three days before each study day when two SO2 challenges were performed 30 minutes apart. The response was measured as the cumulative dose causing a 35% fall in specific airways conductance (sGaw; PDsGaw35). RESULTS: Ipratropium bromide significantly inhibited SO2 responsiveness, reducing PDsGaw35 by 0.89 (95% CI 0.46 to 1.31) doubling doses. This effect persisted after correction for bronchodilatation induced by ipratropium bromide. The effect of ipratropium bromide and morphine on SO2 responsiveness also correlated (r2 = 0.71). In the second study SO2 tachyphylaxis developed with PDsGaw35 on repeated testing, being reduced by 0.62 (95% CI 0.17 to 1.07) doubling doses. Indomethacin attenuated baseline SO2 responsiveness, increasing PDsGaw35 by 0.5 (95% CI 0.06 to 0.93) doubling doses. CONCLUSIONS: These results suggest that opioids modulate the cholinergic component of SO2 responsiveness and that cyclooxygenase products contribute to the immediate response to SO2.     

Salbutamol prevents the increase of respiratory resistance caused by tracheal intubation during sevoflurane anesthesia in asthmatic children

Asthmatic children having their tracheas intubated with sevoflurane often have an increase in respiratory system resistance (Rrs). In this randomized, placebo-controlled, double-blinded study, we investigated the protective effect of an inhaled beta2-adrenergic agonist. Either salbutamol or placebo was administered 30 to 60 min before anesthesia to 30 mildly to moderately asthmatic children scheduled for elective surgery. Induction was performed with sevoflurane in a mixture of 50% nitrous oxide in oxygen and maintained at 3%, with children breathing spontaneously via a face mask and Jackson-Rees modification of the T-piece. Airway opening pressure and flow were measured before and after insertion of an oral endotracheal tube. Rrs and respiratory system compliance were calculated with multilinear regression analysis. The groups were comparable with respect to age, weight, asthma history, and breathing pattern. Intubation induced a different Rrs response in the two groups: children treated with salbutamol showed a 6.0% (-25.2% to +13.2%) decrease (mean, 95% confidence interval), whereas in the Placebo group there was a 17.7% (+4.4% to +30.9%) increase (P = 0.04). Neither asthma history nor the serum inflammation marker eosinophilic cationic protein was predictive for this response. We conclude that when using sevoflurane in mildly to moderately asthmatic children, a preanesthetic treatment with inhaled salbutamol is protective of an increase in Rrs. IMPLICATIONS: Tracheal intubation with sevoflurane as the sole anesthetic is now often performed in children. It can induce an increase in respiratory system resistance in children with asthma. This study shows that in children with mild to moderate asthma, a preanesthetic treatment with inhaled salbutamol can prevent the increase of respiratory system resistance.     

Effects of inhaled budesonide on spirometric values, reversibility, airway responsiveness, and cough threshold in smokers with chronic obstructive lung disease.

Inhaled corticosteroids are known to reduce respiratory symptoms and airway responsiveness in allergic patients with asthma. The aim of the present randomised, double blind study was to assess the effect of eight weeks' treatment with inhaled budesonide in non-allergic smokers with chronic obstructive lung disease. Twenty four subjects (23 male) entered the study. Their ages ranged from 40 to 70 (mean 57) years, with a mean of 35 (range 9-80) pack years of smoking; the mean FEV1 was 53% (range 32-74%) predicted and geometric mean PC20 (histamine concentration causing a 20% fall in FEV1) 0.96 (range 0.07-7.82) mg/ml. After a two week washout, single blind, placebo period, 12 patients were allocated to treatment with budesonide 1600 microgram/day and 12 to placebo for eight weeks. The only additional drug to be taken was ipratropium bromide "if needed." Twenty one patients completed the study, 10 in the budesonide group and 11 in the placebo group. The standard deviation of the difference between duplicate measurements of PC20 histamine and citric acid cough threshold made two weeks apart was below one doubling dose step. There was a significant reduction in dyspnoea in the budesonide group, but otherwise no change in symptom scores or use of ipratropium bromide over the eight weeks of treatment within or between the two groups. No significant differences in spirometric values, peak expiratory flow, PC20 histamine, or citric acid cough threshold were found between the groups. Although differences were not significant, some of the changes showed a trend in favour of budesonide. Whether a longer observation period would show a significant influence of inhaled corticosteroids in patients with chronic obstructive lung disease remains to be determined.     

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.     

Cholinergic blockade in the prevention of exercise-induced asthma.

The contribution of vagal mechanisms to exercise-induced asthma has been studied in 10 adult asthmatic patients using the anticholinergic drug ipratropium bromide. Exercise tests were performed for eight minutes on a cycle ergometer and each individual's tests were standardised by matching oxygen uptake. Two tests were done on each of three study days, the first being without previous medication, and the second preceded by inhalation of ipratropium bromide, 0.1, or 1 mg or saline placebo given 90 minutes beforehand. The mean falls in FEV1 and PEFR after the initial tests were very similar on the three study days. The mean falls in FEV1 after the second test were 22.3%, 19.5%, and 12.5% with placebo, 0.1 mg, and 1 mg ipratropium bromide respectively. Only the higher dose was significantly better than placebo. The results were also analysed using a protection index to compare the first and second tests each day and 1 mg ipratropium bromide was significantly better than both 0.1 mg and placebo. Similar results were obtained using PEFR. Equal bronchodilatation was produced by the two doses of drug. We conclude that conventional doses of anticholinergic drugs are not effective in preventing exercise-induced asthma, while large doses may do so in the same group of subjects.     

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.     

Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting β2 agonists

BACKGROUND: In vitro the long acting beta2 agonist salmeterol can, in contrast to formoterol, behave as a partial agonist and become a partial antagonist to other beta2 agonists. To study this in vivo, the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting beta2 agonists. METHODS: A randomised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second (FEV1) of 88.4% predicted and median concentration of methacholine provoking a fall in FEV1 of 20% or more (PC(20)) of 0.62 mg/ml at entry. One hour after the last dose of 2 weeks of treatment with formoterol (24 microg twice daily by Turbuhaler), salmeterol (100 microg twice daily by Diskhaler), or placebo a methacholine provocation test was performed and continued until there was at least a 30% decrease in FEV1. Salbutamol (50 microg) was administered immediately thereafter, followed by ipratropium bromide (40 microg) after a further 30 minutes. Lung function was monitored for 1 hour after provocation. RESULTS: There was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment. The dose of methacholine needed to provoke a fall in FEV1 of > or = 30% was higher after pretreatment with formoterol (2.48 mg) than with salmeterol (1.58 mg) or placebo (0.74 mg). The difference between formoterol and salmeterol was statistically significant: 0.7 doubling dose steps (95% CI 0.1 to 1.2, p=0.016). The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs (p<0.0003 for both). Three minutes after inhaling salbutamol the increase in FEV1 relative to the pre-methacholine baseline was 15.8%, 7.3%, and 5.5% for placebo, formoterol and salmeterol, respectively (equivalent to increases of 26%, 14%, and 12%, respectively, from the lowest FEV1 after methacholine). At 30 minutes significant differences remained, but 1 hour after completing the methacholine challenge FEV1 had returned to baseline values in all three treatment groups. CONCLUSION: Formoterol has a greater intrinsic activity than salmeterol as a bronchoprotective agent, indicating that salmeterol is a partial agonist compared with formoterol in contracted human airways in vivo. Irrespective of this, prior long term treatment with both long acting beta2 agonists reduced the bronchodilating effect of an additional single dose of salbutamol equally, indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmeterol. Patients on regular treatment with long acting beta2 agonists should be made aware that an additional single dose of a short acting beta2 agonist may become less effective.     

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.