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.     

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.     

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.     

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.     

Assessment of reversibility of airway obstruction in patients with chronic obstructive airways disease.

Spirometry before and after an inhaled beta agonist or a course of oral prednisolone is widely used to detect reversible airflow limitation in patients with chronic obstructive lung disease. How many of these patients have a response and how the response to beta agonists relates to the response to corticosteroids is not clear. In 127 outpatients (mean (SD) FEV1 0.92 (0.38) 1) who had a clinical diagnosis of chronic obstructive lung disease (continuous breathlessness for more than six months and an FEV1/forced vital capacity (FVC) ratio less than 60%) and who appeared to be stable, the change in FEV1 was measured after salbutamol 200 micrograms from a metered dose inhaler and 5 mg from a nebuliser. Symptoms and spirometric values were recorded before and after two weeks of oral prednisolone 30 mg. Reversibility was defined as a response in FEV1 of 15% or more from baseline alone and as a 15% change and a minimum increase of at least 200 ml. The latter gave results that showed greater internal consistency between the drug regimens. On the basis of this criterion 56 patients (44%) had no response to salbutamol or prednisolone, 71 responded to salbutamol (including all 27 steroid responders), and 25 patients had a response to salbutamol 5 mg but not to 200 micrograms. In general, the largest increase in FEV1 after salbutamol occurred in the subjects with greatest improvement after prednisolone. Subjects showing a response in FEV1 after two weeks' prednisolone had a fall in total symptom score, unlike those who had no response to any treatment or a response to salbutamol only. These data show that reversibility in response to beta agonists is common in patients diagnosed on clinical grounds as having stable chronic obstructive lung disease, that it can be substantial, and that it is best detected by using a larger dose of salbutamol. Salbutamol responders were those most likely to improve after a trial of oral prednisolone. Allowance should be made for the variability of FEV1 in the calculation of the percentage response at low baseline values (less than 1 litre).     

Nifedipine enhances the bronchodilator effect of salbutamol.

Ten male asthmatic volunteers each inhaled two puffs (200 micrograms) of salbutamol on two separate days 30 minutes after double blind oral administration of either 20 mg nifedipine or identical placebo. FEV1 was recorded before and at intervals for four hours after inhalation of salbutamol. Overall the FEV1 was significantly greater during the four hour period after premedication with nifedipine (p less than 0.025) and the difference between the effects of placebo and nifedipine was greatest four hours after salbutamol (p less than 0.005). These results suggest that nifedipine prolongs the bronchodilator action of salbutamol in vivo.     

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.     

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.     

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.     

Prostaglandin F2 alpha enhancement of capsaicin induced cough in man: modulation by beta 2 adrenergic and anticholinergic drugs.

The effect of inhaled prostaglandin (PG) F2 alpha on the response to the inhaled tussive agent capsaicin was investigated in normal subjects. Seven subjects inhaled three breaths of four doses of capsaicin (0.3, 0.6, 1.2, and 2.4 nmol) before and immediately after inhaling PGF2 alpha (0.1 mumol) or placebo (0.15M NaCl) on separate days. The numbers of capsaicin induced coughs were greater after PGF2 alpha (mean 42.3 coughs) than after 0.15M sodium chloride (30.1). Visual analogue scores (0-10 on a 10 cm continuous scale) showed that capsaicin was more irritant after PGF2 alpha than after saline. Total respiratory resistance (Rrs), measured by the forced oscillation technique, was unaltered throughout the study. A double blind, placebo controlled study of the effects of inhaled salbutamol (200 micrograms, 0.6 mumol) and ipratropium bromide (40 micrograms, 0.1 mumol) on cough induced by capsaicin (2.4 nmol) and by PGF2 alpha (0.1 mumol) and on PGF2 alpha augmented, capsaicin induced coughing was performed in seven subjects. Neither drug had any effect on capsaicin induced coughing. Salbutamol reduced coughing due to PGF2 alpha (mean 7.7 coughs after salbutamol, 9.3 after placebo) but ipratropium bromide did not (mean 6.9 coughs after ipratropium bromide, 6.6 after placebo). Salbutamol also inhibited the augmentation of the capsaicin induced cough that followed inhalation of PGF2 alpha (mean augmentation 1.9 coughs after salbutamol, 4.1 after placebo), whereas ipratropium bromide did not (augmentation 1.7 coughs after ipratropium bromide, 2.7 after placebo). No changes in Rrs were seen after PGF2 alpha or either drug. Thus salbutamol reduces PGF2 alpha induced cough and the augmentation of capsaicin induced cough that follows PGF2 alpha.     

Salmeterol, a new long acting inhaled beta 2 adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients.

Salmeterol is a new inhaled beta 2 adrenoceptor agonist, which has been shown in animal experiments to produce a more prolonged bronchodilator effect than currently available beta 2 adrenoceptor agonists. It was studied in eight adult asthmatic patients. Each patient received on separate test days salbutamol 200 micrograms and salmeterol 50, 100, and 200 micrograms according to a randomised, double blind, crossover design. FEV1, peak expiratory flow (PEF), heart rate, blood pressure, and tremor were recorded in the clinic for six hours after drug inhalation; PEF was recorded for a further six hours at home. All three doses of salmeterol produced peak increases in FEV1 (mean 0.5-0.8 l) and PEF (71-100 l/min) similar to those produced by salbutamol 200 micrograms (0.5 l and 74 l/min). After salbutamol FEV1 and PEF had returned to baseline within six hours, but after all three doses of salmeterol more than half of the maximum bronchodilator effect remained after 12 hours. The effects of salbutamol and the two lower doses of salmeterol (50 and 100 micrograms) on cardiovascular measurements and on tremor were similar, whereas after salmeterol 200 micrograms there was a small decrease in diastolic blood pressure and an increase in heart rate and tremor. Thus inhaled salmeterol has a long acting bronchodilator action in asthmatic patients. This effect may be of value in the treatment of asthma, particularly in patients with nocturnal symptoms.     

A randomised controlled comparison of tiotropium nd ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group

BACKGROUND: A study was undertaken to evaluate and compare the efficacy and safety of tiotropium and ipratropium during long term treatment in patients with stable chronic obstructive pulmonary disease (COPD). METHODS: 288 patients of mean (SD) age 65 (8) years and forced expiratory volume in one second (FEV(1)) 41 (12)% predicted participated in a 14 centre, double blind, double dummy, parallel group study and were randomised after a run in period of two weeks to receive either tiotropium 18 microg once daily from a dry powder inhaler (HandiHaler; two thirds of patients) or ipratropium 40 microg four times daily from a metered dose inhaler (one third of patients) for a period of 13 weeks. Outcome measures were lung function, daily records of peak expiratory flow (PEF), and the use of concomitant salbutamol. FEV(1) and forced vital capacity (FVC) were measured one hour before and immediately before inhalation (mean value of the two measurements on test day 1 was the baseline value while on all other test days it was known as the trough FEV(1) and FVC), and 0.5, 1, 2, 3, 4, 5, and 6 hours after inhalation of the study drug on days 1, 8, 50, and 92. RESULTS: During treatment tiotropium achieved a significantly greater improvement than ipratropium (p<0.05) in trough, average, and peak FEV(1) levels and in trough and average FVC levels. The trough FEV(1) response on days 8, 50, and 92 ranged between 0.15 l (95% CI 0.11 to 0.19) and 0.16 l (95% CI 0.12 to 0.20) for tiotropium and between 0.01 l (95% CI -0.03 to 0.05) and 0.03 l (95% CI 0.01 to 0. 07) for ipratropium. The trough FVC response on days 8, 50, and 92 ranged between 0.34 l (95% CI 0.28 to 0.40) and 0.39 l (95% CI 0.31 to 0.47) for tiotropium and between 0.08 l (95% CI 0.00 to 0.16) and 0.18 l (95% CI 0.08 to 0.28) for ipratropium. On all test days tiotropium produced a greater improvement in FEV(1) than ipratropium starting three hours after inhalation (p<0.05). During treatment weekly mean morning and evening peak expiratory flow (PEF) was consistently better in the tiotropium group than in the ipratropium group, the difference in morning PEF being significant up through week 10 and in evening PEF up through week 7 of treatment (p<0.05). The use of concomitant salbutamol was also lower in the tiotropium group (p<0.05). The only drug related adverse event was dry mouth (tiotropium 14.7%, ipratropium 10.3% of patients). CONCLUSIONS: Tiotropium in a dose of 18 microg inhaled once daily using the HandiHaler was significantly more effective than 40 microg ipratropium four times daily in improving trough, average, and peak lung function over the 13 week period. The safety profile of tiotropium was similar to ipratropium. These data support the use of tiotropium as first line treatment for the long term maintenance treatment of patients with airflow obstruction due to COPD.     

Assessment of bronchodilatation after spontaneous recovery from a histamine challenge in asthmatic children.

BACKGROUND: It would be convenient to be able to measure airway responsiveness to histamine and to bronchodilator drugs on the same day, but whether this can be done reliably is unknown. METHODS: The effect of a prior histamine challenge on the bronchodilator response to salbutamol after spontaneous recovery of FEV1 to 95% of the prechallenge level was studied in two groups of asthmatic children. Fourteen children inhaled 400 micrograms salbutamol after spontaneous recovery from a histamine challenge, followed by a further 100 micrograms salbutamol 20 minutes later. In a second group of eight asthmatic children the study was repeated with 800 micrograms salbutamol, followed by a further 200 micrograms 20 minutes later. RESULTS: After histamine challenge FEV1 returned to baseline in 70 minutes or less on all occasions. The FEV1 20 minutes after 400 micrograms salbutamol was significantly lower after the histamine challenge than on the control day. After the further 100 micrograms salbutamol FEV1 values were similar after the histamine challenge and on the control day. FEV1 values after 800 micrograms salbutamol and the further 200 micrograms dose were not influenced by a prior histamine challenge. CONCLUSIONS: In children with stable asthma in whom FEV1 has returned to baseline after a histamine challenge the FEV1 achieved after 800 micrograms salbutamol is not affected by the histamine challenge. Histamine and bronchodilator responsiveness can thus be assessed reliably on the same day in patients with stable asthma. This has clear advantages for patient care.     

The protective effect of a beta 2 agonist against excessive airway narrowing in response to bronchoconstrictor stimuli in asthma and chronic obstructive lung disease.

Beta 2 agonists reduce airway hypersensitivity to bronchoconstrictor stimuli acutely in patients with asthma and chronic obstructive lung disease. To determine whether these drugs also protect against excessive airway narrowing, the effect of inhaled salbutamol on the position and shape of the dose-response curves for histamine or methacholine was investigated in 12 patients with asthma and 11 with chronic obstructive lung disease. After pretreatment with salbutamol (200 or 400 micrograms) or placebo in a double blind manner dose-response curves for inhaled histamine and methacholine were obtained by a standard method on six days in random order. Airway sensitivity was defined as the concentration of histamine or methacholine causing a 20% fall in FEV1 (PC20). A maximal response plateau on the log dose-response curve was considered to be present if two or more data points for FEV1 fell within a 5% response range. In the absence of a plateau, the test was continued until a predetermined level of severe bronchoconstriction was reached. Salbutamol caused an acute increase in FEV1 (mean increase 11.5% predicted in asthma, 7.2% in chronic obstructive lung disease), and increase in PC20 (mean 15 fold in asthma, fivefold in chronic obstructive lung disease), and an increase in the slope of the dose-response curves in both groups. In subjects in whom a plateau of FEV1 response could be measured salbutamol did not change the level of the plateau. In subjects without a plateau salbutamol did not lead to the development of a plateau, despite achieving a median FEV1 of 44% predicted in asthma and 39% in chronic obstructive lung disease. These results show that, although beta 2 agonists acutely reduce the airway response to a given strength of bronchoconstrictor stimulus, they do not protect against excessive airflow obstruction if there is exposure to relatively strong stimuli. This, together with the steepening of the dose-response curve, could be a disadvantage of beta 2 agonists in the treatment of moderate and severe asthma or chronic obstructive lung disease.     

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.


     

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.     

Protective effect of drugs on histamine-induced asthma.

Controlled standardised histamine inhalation tests were carried out in 21 asthmatics to determine the degree of non-specific bronchial hyperreactivity with and without prior treatment with several anti-asthmatic drugs. A significant protective effect was produced by inhaled salbutamol, 200 microgram, ingested salbutamol, 4 mg, inhaled Sch1000, 40 microgram inhaled atropine sulphate, 290 microgram, and ingested choline theophylinate (200 or 400 mg) producing serum theophylline levels over 10 mg/l. Inhaled salbutamol was consistently the most effective and was significantly better than the other drugs. The protective effect between the other four was not significantly different. Drug side-effects occurred only with the ingested drugs. No significant protection was detected after ingested choline theophyllinate producing serum theophylline levels of less than 10 mg/l, inhaled sodium cromoglycate, 20 mg given once or six-hourly for one week, or ingested ascorbic acid, 1 gram.     

Diurnal variation in airflow obstruction in chronic bronchitis.

Twelve patients fulfilling strict criteria for chronic obstructive bronchitis recorded serial peak expiratory flow rates (PEFR) five times daily for a two-week period. Despite a 9.2% improvement in forced expiratory volume in one second (FEV1) with ipratropium bromide, and an 11.3% improvement with ipratropium bromide plus salbutamol, the inherent diurnal variation in PEFR while on no medication was greater than the improvement caused by either bronchodilator. In the group as a whole, the difference between the highest and the lowest daily PEFR over the two weeks was 24% of the mean daily value. Using cosinor analysis, 10 of the 12 patients showed a significant rhythm in PEFR with a computed mean amplitude between highest and lowest readings of 8.6% of the mean daily value. This is no greater than that found in normal subjects, but is considerably less than the variation in PEFR in patients with bronchial asthma.     

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.     

Bronchodilator reversibility to low and high doses of terbutaline and ipratropium bromide in patients with chronic obstructive pulmonary disease.

BACKGROUND--There is uncertainty regarding the use of monotherapy or combination therapy with beta 2 agonists and anticholinergic drugs in patients with chronic obstructive pulmonary disease (COPD). The measurement of forced expiratory volume in one second (FEV1) or relaxed vital capacity (RVC) in the assessment of reversibility in these patients has also caused considerable debate. METHODS--Twenty seven patients with COPD were evaluated on two occasions. Patients received the following treatments in sequence: (sequence 1) low dose terbutaline 500 micrograms, high dose terbutaline 5000 micrograms, low dose ipratropium 40 micrograms, high dose ipratropium 200 micrograms; (sequence 2) low dose ipratropium 40 micrograms, high dose ipratropium 200 micrograms, low dose terbutaline 500 micrograms, high dose terbutaline 5000 micrograms. RVC, FEV1 and FVC were measured at baseline and 30 minutes after successive treatments. RESULTS--Values for FEV1 at baseline on the first and second study days were not significantly different: 0.90 (0.87-0.93) 1 v 0.90 (0.87-0.93) 1. Likewise, baseline values for RVC and FVC were not different. The number of patients showing a greater than 330 ml overall improvement in RVC was 20 of 27 for sequence 1 and 22 of 27 for sequence 2; similar trends were observed for FEV1 and FVC. For all three parameters there was a significant difference between mean responses to low and high doses of terbutaline when the latter was given as the first drug in sequence 1. When ipratropium was given first in sequence 2 there was, however, no significant improvement with high dose terbutaline over and above the response to low dose terbutaline. The latter effect was more noticeable with RVC than with either FEV1 or FVC. The total bronchodilator response at the end of each sequence was similar whether ipratropium was given first or second. CONCLUSIONS--The measurement of RVC, FEV1, and FVC were equally effective at picking up those patients who had a significant overall bronchodilator response to combined therapy with inhaled beta 2 agonist and anticholinergic medication. There was no significant benefit of adding a higher dose of terbutaline when ipratropium bromide had been given previously, particularly when using RVC as the parameter of response.