Effect of regular inhaled salbutamol on airway responsiveness and airway inflammation in rhinitic non-asthmatic subjects

BACKGROUND: Regular, inhaled beta 2 agonists may increase airway responsiveness in asthmatic subjects. The mechanism is not known but may be via an increase in airway inflammation. A study was undertaken to examine the effect of regular inhaled salbutamol on airway responsiveness to methacholine and hypertonic saline, on the maximal response plateau to methacholine, and on inflammatory cells in induced sputum in rhinitic non-asthmatic subjects. METHODS: Thirty subjects with a baseline maximal response plateau of > 15% fall in forced expiratory volume in one second (FEV1) entered a randomised, placebo controlled, parallel trial consisting of two weeks run in, four weeks of treatment, and two weeks washout. Methacholine challenges were performed at the beginning of the run in period, before treatment, after treatment, and after washout. Hypertonic saline challenges were performed before and after treatment and induced sputum samples were collected for differential cell counting. RESULTS: There was no change in airway responsiveness, maximal response plateau to methacholine, or in induced sputum eosinophils or mast cells. The maximum fall in FEV1 after hypertonic saline increased in the salbutamol group (median change 6.0%, interquartile range (IQR) 11.0) but did not change in the placebo group (median change 1.3%, IQR 5.5). CONCLUSIONS: Regular inhaled salbutamol for four weeks increases airway responsiveness to hypertonic saline but does not alter airway responsiveness to methacholine or cells in induced sputum in non-asthmatic individuals with rhinitis. The relevance of these findings to asthmatic subjects has not been established.


     

Intravenous or inhaled salbutamol in severe acute asthma?

Ten patients with life-threatening attacks of asthma (status asthmatiucus') were treated with salbutamol inhaled by intermittent positive pressure breathing, and their response in terms of rise in peak flow rate was measured. They were then given intravenous salbutamol and any further increment in peak flow was measured. Hydrocortisone treatment was started simultaneously and the responses to salbutamol were re-measured on each of the next three days. Only two patients initially responded to the aerosol, whereas all save one responded to the intravenous drug. The two who responded initially to the aerosol were the two who were able to produce sputum at the time of admission. All patients subsequently responded to the aerosol, and the onset of this response correlated closely with the beginning of sputum production. Sympathominetics should be given parenterally to patients in severe asthma if the response to inhaled drug is reduced or absent.     

Cardiovascular side effects of inhaled salbutamol in hypoxic asthmatic patients

BACKGROUND: Beta-2 adrenoceptor agonists have been associated with sudden death in asthma patients but the cause and underlying mechanism are unclear. Animal experiments indicate that the combination of hypoxia and beta2 agonists may result in detrimental cardiovascular effects. A study was undertaken to investigate the effect of hypoxia on the systemic vascular effects of salbutamol in patients with asthma who are hypoxic by assessing forearm blood flow (FBF) as a measure of peripheral vasodilatation. METHODS: Eight men with mild asthma underwent the following treatments: normoxia + placebo (NP), normoxia + salbutamol (NS), hypoxia + placebo (HP), and hypoxia + salbutamol (HS). The period of mask breathing started at t=0 minutes, lasted for 60 minutes, and at 30 minutes 800 microg salbutamol was inhaled. The experiment was completed 30 minutes after the inhalation (t=60 minutes). For the hypoxia treatment the SpO2 level was 82%. Differences between treatments were sought using factorial ANOVA on percentage change from the pretreatment value. RESULTS: There were no significant differences in blood pressure and potassium levels between the treatments. After 60 minutes the increase in FBF was 13% (95% CI -12 to 39) more for HP treatment than for NP, 21% (95% CI -5 to 46) more for NS than for NP, and 32% (95% CI 7 to 58) more for HS than for HP (p=0.016). The inhalation of salbutamol during hypoxia resulted in a significant increase in FBF of 45% (95% CI 20 to 71) compared with NP (p=0.001). CONCLUSION: Patients with asthma who are hypoxic and inhale beta2 agonists have serious systemic vascular side effects which may be an additional explanation for the association between asthma treatment and sudden death.     

Time course of response to oral and inhaled corticosteroids in non-asthmatic chronic airflow obstruction.

One hundred and twenty one patients considered on clinical grounds to have non-asthmatic chronic airflow obstruction completed a double blind, crossover trial comparing oral prednisolone 40 mg per day with inhaled beclomethasone dipropionate 500 micrograms thrice daily, each given for 14 days, with a 14 day washout period between treatments. The time course of response was analysed for the 57 occasions where there was a significant increase in mean daily peak expiratory flow (PEF) over the treatment period. Mean daily PEF was still rising at day 14 on 12 occasions. After withdrawal of treatment mean daily PEF remained above pretreatments levels for more than two weeks in half the responses analysed. The peak response occurred earlier with inhaled beclomethasone (median 9.5 (range 3-14) days) than with oral prednisolone (median 12 (range 1-14) days), though both treatments produced a response that was sustained for a similar period. The results suggest that a trial of treatment with corticosteroids in this group of patients should last more than 14 days, and that in a study with a crossover design the washout period should be longer than two weeks.     

Dose-response study of inhaled salbutamol powder in chronic airflow obstruction.

Dose-response relationships for salbutamol were studied in eight patients suffering from chronic airflow obstruction with no asthmatic features. Each inhaled, double blind, in randomised order 0, 200, 400, 800, and 1600 micrograms salbutamol on five successive mornings. Before and at intervals up to six hours after the inhalation FEV1, vital capacity, maximum inspiratory and expiratory flow-volume curves, and 12-minute walking distances were measured. Analysis of variance of the results indicated significant dose-response relationships and showed the larger doses to have a longer duration of action. Simple spirometric tests were as useful in providing objective evidence of benefit as maximum inspiratory flows or the 12-minute walking distance.     

Effects of hypothyroidism on bronchial reactivity in non-asthmatic subjects.

The effect of hypothyroidism on non-specific bronchial reactivity was studied in 11 patients without pulmonary disease (mean age 40 (SD 13) years) who had had a total thyroidectomy and radioiodine treatment for thyroid cancer 41 (36) months before the study. All patients when mildly hyperthyroid while having long term thyroxine replacement treatment and once when hypothyroid two weeks after stopping triiodothyronine for the purpose of screening for metastases. Bronchial reactivity was assessed by measuring specific airways conductance (sGaw) after increasing doses of inhaled carbachol (45-1260 micrograms). The dose producing a 35% decrease in sGaw (PD35) was determined from the cumulative log dose-response curve by linear regression analysis. Mean baseline sGaw values were similar when the patients were hypothyroid and when they were hyperthyroid (1.35 (0.36) and 1.41 (0.56) s-1 kPa-1). The interstudy coefficients of variation of baseline sGaw were higher in the thyroid patients than in a euthyroid control group (14% versus 8%). Geometric mean PD35 was lower when the patients were hypothyroid (97 micrograms) than when they were mildly hyperthyroid (192 micrograms). It is concluded that acute hypothyroidism increases non-specific bronchial reactivity in nonasthmatic subjects.     

Asthma control during long term treatment with regular inhaled salbutamol and salmeterol

BACKGROUND: The adverse effects of long term treatment of asthma with the short acting beta agonist fenoterol have been established in both epidemiological and clinical studies. A study was undertaken to investigate the efficacy and safety of long term treatment with salbutamol and salmeterol in patients with mild to moderate bronchial asthma. METHODS: In a two centre double dummy crossover study 165 patients were randomly assigned to receive salbutamol 400 micrograms q.i.d., salmeterol 50 micrograms b.i.d., or placebo via a Diskhaler. All patients used salbutamol as required for symptom relief. The study comprised a four week run in and three treatment periods of 24 weeks, each of which was followed by a four week washout. Asthma control was assessed by measuring mean morning and evening peak expiratory flow rate (PEFR), a composite daily asthma score, and minor and major exacerbation rates. Washout assessments included methacholine challenge and bronchodilator dose response tests. Analysis was by intention to treat. RESULTS: Data from 157 patients were analysed. Relative to placebo, the mean morning PEFR increased by 30 l/min (95% CI 26 to 35) for salmeterol but did not change for salbutamol. Evening PEFR increased by 25 l/min (95% CI 21 to 30) and 21 l/min (95% CI 17 to 26), respectively (p < 0.001). Salmeterol improved the asthma score compared to placebo (p < 0.001), but there was no overall difference with salbutamol. Only daytime symptoms were improved with salbutamol. The minor exacerbation rates were 0.29, 0.88, and 0.97 exacerbations/patient/year for salmeterol, salbutamol and placebo, respectively (p < 0.0001 for salmeterol). The corresponding major exacerbation rates were 0.22, 0.51 and 0.40, respectively (p < 0.03 for salmeterol). For salbutamol the asthma score deteriorated over time (p < 0.01), and the time spent in major exacerbation was significantly longer compared with placebo (12.3 days (95% CI 4.2 to 20.4) versus 8.4 days (95% CI 5.2 to 11.6), p = 0.02). There was no evidence of rebound deterioration in asthma control, lung function, or bronchial hyper-responsiveness following cessation of either active treatment, and no evidence of tolerance to salbutamol or salmeterol. CONCLUSIONS: Regular treatment with salmeterol is effective in controlling asthma symptoms and reduces minor more than major exacerbation rates. Salbutamol was associated with improved daytime symptoms but subtle deterioration in asthma control occurred over time. Salbutamol should therefore be used only as required.     

Corticosteroid trials in non-asthmatic chronic airflow obstruction: a comparison of oral prednisolone and inhaled beclomethasone dipropionate.

One hundred and twenty seven adults considered on clinical grounds to have non-asthmatic chronic airflow obstruction entered a randomised, double blind, placebo controlled, crossover trial comparing the physiological response to inhaled beclomethasone dipropionate 500 micrograms thrice daily with oral prednisolone 40 mg a day, both given for two weeks. One hundred and seven patients completed the study. Response was assessed as change in FEV1 and FVC measured on the last treatment day, and as change in mean peak expiratory flow (PEF) over the final seven days of treatment from home PEF recordings performed five times daily. A full response to treatment was defined as an increase in FEV or FVC, or an increase in mean daily PEF over the final seven days of treatment, of at least 20% from baseline values. An improvement in one measurement of at least 15%, or of 10% in any two measurements, was defined as a partial treatment response. Response to placebo showed a significant order effect, suggesting a carry over effect of active treatment of at least three weeks. Response to active treatment was therefore related to initial baseline values, and compared with placebo by considering responses in the first treatment phase only. A full response to oral prednisolone (16/38) was significantly more common than to placebo (3/35). The number of full responses to inhaled beclomethasone (8/34) did not differ significantly from the number responding to oral prednisolone or placebo in the first treatment phase, though full and partial responses to inhaled beclomethasone (12/34) were significantly more common than those to placebo (4/35). When all three treatment phases were considered 44/107 patients showed a full response to one or both forms of corticosteroid treatment, a response to prednisolone (39) occurring more frequently than to inhaled beclomethasone (26). Only 21 of the 44 responders showed a response to both forms of treatment. Inhaled beclomethasone dipropionate 500 micrograms thrice daily was inferior to oral prednisolone 40 mg per day, but better than placebo, in producing improvement in physiological measurements in patients thought to have nonasthmatic chronic airflow obstruction. It was, however, an effective alternative in over half of those showing a response to prednisolone.     

Acute effects of inhaled salbutamol on the metabolic rate of normal subjects.

BACKGROUND--This study was designed to investigate the contribution of inhaled salbutamol to the increase in resting metabolic rate found in patients with chronic airflow limitation who were receiving bronchodilator therapy. METHODS--The resting metabolic rate of 10 normal subjects (age 20-47 years, weight 42-105 kg, seven men) was studied after inhalations of salbutamol or placebo. An open canopy method of indirect calorimetry was used to measure resting oxygen consumption (VO2) and resting carbon dioxide production (VCO2). Subjects inhaled two, four, eight, or 12 puffs (100 micrograms/puff) of salbutamol or placebo in a double blind manner. Recordings of VO2 and VCO2 were made after inhalation of the four doses of salbutamol or placebo, integrated over one hour, and compared. RESULTS--VO2 and VCO2 increased in a dose dependent manner after inhaled salbutamol with a maximum effect at five minutes after inhalation. After four puffs, VO2 was 203 and 188 ml/kg/h for salbutamol and placebo respectively. After eight puffs, VO2 was 207 and 185 and VCO2 was 167 and 155 ml/kg/h. After 12 puffs, VO2 was 220 and 190 with a VCO2 of 181 and 168 ml/kg/h. Twelve puffs of salbutamol increased the mean (SE) respiratory quotient from 0.85 (0.01) to 0.93 (0.04) at five minutes indicating an increase in ventilation in excess of metabolic demand. Mean heart rate increased in parallel with VO2. CONCLUSION--Inhaled salbutamol significantly increases resting metabolic rate in a dose dependent manner.     

Cardiovascular and hypokalaemic effects of inhaled salbutamol, fenoterol, and isoprenaline.

The cardiovascular and hypokalaemic effects of equal doses of inhaled fenoterol, isoprenaline and salbutamol were compared in eight healthy male volunteers, in a double blind, placebo controlled study. Increasing doses of 400, 600, and 800 micrograms were given from a metered dose inhaler at 15 minute intervals, followed by measurements of heart rate, blood pressure, total electromechanical systole (as a measure of inotropic response), QTc interval, and plasma potassium concentration. After repeated inhalation, fenoterol resulted in significantly greater chronotropic, electrocardiographic, and hypokalaemic effects than either isoprenaline or salbutamol. The maximum inotropic effect of fenoterol was similar to that of isoprenaline.     

Modification of the thermogenic effect of acutely inhaled salbutamol by chronic inhalation in normal subjects.

BACKGROUND--Acute inhalation of clinical doses of salbutamol in normal volunteers increases resting metabolic rate by up to 20% above control values. This study was designed to see if chronic treatment with salbutamol causes a sustained increase in metabolic rate and whether it modifies the acute thermogenic response to the drug. METHODS--The effects of chronic inhaled salbutamol on resting oxygen consumption (VO2) and carbon dioxide output (VCO2) were studied in seven normal subjects (age 20-47 years, weight 52-105 kg, five men). An open canopy method of indirect calorimetry was used to measure VO2, VCO2, and respiratory quotient (RQ). Subjects inhaled two puffs of salbutamol or placebo four times a day in a double blind manner. Measurements of resting VO2 and VCO2 after 10 days of salbutamol were compared with the values after 10 days of placebo and with those taken at the start of the study. At the end of each treatment period subjects inhaled eight puffs (800 micrograms) of salbutamol and the acute effects on VO2, VCO2 and RQ were monitored for one hour. RESULTS--Resting VO2, VCO2, and RQ were not significantly different at the end of the salbutamol and placebo periods but the acute response to eight puffs of salbutamol was abolished by regular inhalation. The mean VO2 integrated over one hour after 800 micrograms salbutamol given acutely was different (241.3 and 210.7 ml/kg/h in the placebo and salbutamol groups respectively). Differences were not significant between placebo and salbutamol groups for changes in VCO2, heart rate, blood pressure, and RQ after acute inhalation. CONCLUSION--Regular treatment with inhaled salbutamol (800 micrograms/day) does not cause a sustained increase in resting metabolic rate but prevents the increase in VO2 that occurs after acute inhalations in normal subjects.     

Airway response to inhaled salbutamol in hyperthyroid and hypothyroid patients before and after treatment.

For many years the development of thyrotoxicosis has been known to cause a deterioration in asthma but the mechanism is unknown. We have studied the effect of thyroid function on airway beta adrenergic responsiveness in 10 hyperthyroid and six hypothyroid subjects before and after treatment of their thyroid disease. Airway adrenergic responsiveness was assessed by measuring specific airway conductance (sGaw) after increasing doses of inhaled salbutamol (10-410 micrograms). After treatment there was no difference in resting FEV1, sGaw, or thoracic gas volume. FVC increased in the hyperthyroid subjects but did not change in the hypothyroid subjects. In the hyperthyroid subjects there was a significant increase in delta sGaw after 35, 60, 110, and 41 micrograms salbutamol; in sGaw after 60, 110, and 410 micrograms salbutamol; and in the area under the salbutamol dose response curve (AUC) after treatment of the thyroid disorder. In the hypothyroid subjects there was a significant reduction in sGaw after 10 and 60 micrograms salbutamol and in the AUC after treatment. When all subjects were considered, there was a negative correlation between the AUC and serum thyroxine values. These findings suggest that an inverse relationship exists between the level of thyroid function and airway beta adrenergic responsiveness.     

Comparison of the relative airways and systemic potencies of inhaled fenoterol and salbutamol in asthmatic patients.

BACKGROUND--There is controversy as to the relative safety of fenoterol and salbutamol. No differences have been found in the relative cardiac beta 1/beta 2 receptor activity of inhaled fenoterol and salbutamol in normal subjects. These initial findings have been extended by comparing the respective potencies of equivalent doses by weight of fenoterol and salbutamol in asthmatic subjects, in terms of airways and systemic responses. METHODS--Eighteen asthmatic patients of mean (SD) age 40 (14) years and a forced expiratory volume in one second (FEV1)% predicted of 56 (14)% (1.97 (0.66)1) were randomised to inhale fenoterol (100 micrograms/puff or 200 micrograms/puff), salbutamol, or placebo (100 micrograms/puff or 200 micrograms/puff) on three separate days. Dose-response curves were constructed using cumulative doses of 100 micrograms, 200 micrograms, 400 micrograms, 1000 micrograms, 2000 micrograms, and 4000 micrograms, and airways and systemic responses were measured 20 minutes after each dose with 40 minute increments. Dose ratios for the relative potency of fenoterol versus salbutamol were calculated from the dose-response curves using regression analysis of parallel slopes. RESULTS--There was no difference in bronchodilator potency between fenoterol and salbutamol (as median dose ratio): FEV1 1.1 (95% CI 0.4 to 4.6). In contrast, dose ratios for systemic responses showed that fenoterol was more potent than salbutamol: serum potassium 3.7 (95% CI 2.0 to 6.0), tremor 5.7 (95% CI 1.4 to 10.2), heart rate 1.6 (95% CI 1.0 to 2.3). At a conventional dose of 200 micrograms the only difference in response between the two drugs was observed for tremor (as mean difference): 0.23 log units (95% CI 0.06 to 0.41 log units). CONCLUSIONS--There was no difference in the bronchodilator potency between fenoterol and salbutamol on a microgram equivalent basis. In contrast, systemic potency was greater with fenoterol, although this difference was not clinically relevant at conventional dosages up to 200 micrograms.     

Corticosteroids and inhaled salbutamol in patients with reversible airway obstruction markedly decrease the incidence of bronchospasm after tracheal intubation

BACKGROUND: In patients with bronchial hyperreactivity, airway instrumentation can evoke life-threatening bronchospasm. However, the best strategy for the prevention of bronchospasm has not been defined. Therefore, in a randomized, prospective, placebo-controlled study, the authors tested whether prophylaxis with either combined salbutamol-methylprednisolone or salbutamol alone (1) improves lung function and (2) prevents wheezing after intubation. METHODS: Thirty-one patients with partially reversible airway obstruction (airway resistance > 180%, forced expiratory volume in 1 s [FEV1] < 70% of predicted value, and FEV1 increase > 10% after two puffs of salbutamol), who were naive to anti-obstructive treatment, were randomized to receive daily for 5 days either 3 x 2 puffs (0.2 mg) of salbutamol alone (n = 16) or salbutamol combined with methylprednisolone (40 mg/day orally) (n = 15). Lung function was evaluated daily. Another 10 patients received two puffs of salbutamol 10 min before anesthesia. In all patients, wheezing was assessed before and 5 min after tracheal intubation. RESULTS: Within 1 day, both salbutamol and salbutamol-methylprednisolone treatment significantly improved airway resistance (salbutamol, 4.3+/- 2.0 [SD] to 2.9+/-1.3 mmHg x s x l(-1); salbutamol-methylprednisolone, 5.5+/-2.9 to 3.4+/-1.7 mmHg x s x l(-1)) and FEV1 (salbutamol, 1.79+/-0.49 to 2.12+/-0.61 l; salbutamol-methylprednisolone, 1.58+/-0.66 to 2.04+/-1.05 l) to a steady state, with no difference between groups. However, regardless of whether single-dose salbutamol preinduction or prolonged salbutamol treatment was used, most patients (8 of 10 and 7 of 9) experienced wheezing after intubation. In contrast, only one patient receiving additional methylprednisolone experienced wheezing (P = 0.0058). CONCLUSIONS:: Pretreatment with either salbutamol alone or salbutamol combined with methylprednisolone significantly and similarly improves lung function within 1 day. However, only combined salbutamol-methylprednisolone pretreatment decreases the incidence of wheezing after tracheal intubation. Therefore, in patients with bronchial hyperreactivity, preoperative treatment with combined corticosteroids and salbutamol minimizes intubation-evoked bronchoconstriction much more effectively than the inhaled beta2-sympathomimetic salbutamol alone.     

Corticosteroid therapy of non-asthmatic chronic obstructive bronchopneumopathies

BASIS OF TREATMENT: Chronic obstructive pulmonary disease (COPD) is a common condition. Medical, and particularly drug, therapy still provides insufficiently effective relief. Corticosteroid treatment relies on the effect of these drugs on the underlying inflammatory mechanisms. Their efficacy has been demonstrated in asthma which exhibits certain features common with COPD. INDICATIONS: Short-term corticosteroid regimens are generally well tolerated. Clinical data favor their use in certain cases of acute decompensation. Long-term systemic regimens are not warranted due to the risk of adverse effects and the difficulty in maintaining appropriate dosages. Inhaled corticosteroids are widely used although the efficacy remains controversial. IMPORTANT DRAWBACKS: Clear evidence of efficacy from large controlled trials is still lacking. The difficulty encountered in obtaining such evidence is an indication of the minimal impact of such treatment and raises the question of its clinical pertinence. Patients exhibiting features similar to those observed in asthma (atopy, eosinophilia, improvement with bronchodilatation, non-smokers...) should be able to benefit from corticosteroids. For others a therapeutic test would be advisable to identify responders who could benefit from a preventive effect on the progression of COPD or associated asthma. A test lasting a few weeks at sufficient dosage is needed for subjective and objective (respiratory function tests) assessment. This costly therapy would not be warranted in non-responders, particularly in light of the expected secondary effects. Current evidence does not point to corticosteroid therapy as the much needed fully effective treatment for COPD.     

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 airway calibre on lung delivery of nebulised salbutamol

BACKGROUND: A study was undertaken to test the hypothesis that airway calibre may alter lung deposition and therefore lung bioavailability of inhaled drugs as a result of narrowed airways reducing peripheral drug delivery. This was evaluated using the early lung absorption profile of salbutamol over the first 30 minutes after inhalation. METHODS: Three groups were compared: (1) 10 normal subjects with mean forced expiratory volume in one second (FEV1) 109.5% predicted and mid forced expiratory flow (FEF25-75) 103.0%, (2) 10 mild asthmatic patients with FEV1 102.0% and FEF25-75 82.6%, and (3) 10 severe asthmatic patients with FEV1 49.2% and FEF25-75 27.5% predicted. Each subject had one study visit where a single dose of nebulised salbutamol was given (40 micrograms/kg) via a Ventstream nebuliser with mouthpiece followed by mouth rinsing. Plasma salbutamol levels were measured at five, 10, 20, and 30 minutes after the end of nebulisation with calculation of maximal (Cmax) and average (Cav) concentration over 0-30 minutes. Systemic beta 2 responses (plasma potassium, tremor and heart rate) and airway responses (FEV1, FEF25-75) were measured before and 30 minutes after nebulisation. RESULTS: For Cav over 0-30 minutes the severe asthmatic patients had a lower plasma salbutamol concentration (1.31 ng/ml) than either the normal subjects (2.40 ng/ml) or those with mild asthma (2.45 ng/ml): normal subjects versus severe asthmatics 95% CI 0.30 to 1.88, mild versus severe asthmatics 95% CI 0.07 to 2.21. Airway responses as delta FEF25-75 were lower in the severe asthmatic subjects (0.30 l/s) than in either the normal subjects (0.69 l/s) or those with mild asthma (0.74 l/s): normal subjects versus severe asthmatic subjects 95% CI 0.09 to 0.88, mild versus severe asthmatics 95% CI 0.04 to 0.93. Values for delta log tremor also showed attenuated responses in those with severe asthma (1.22 mg2/s) compared with normal subjects (2.00 mg2/s) or those with mild asthma (2.02 mg2/s): normal subjects versus those with severe asthma 95% CI -0.02 to 3.30, mild versus severe asthmatics 95% CI 0.02 to 3.30. CONCLUSIONS: These results show that baseline airway calibre significantly alters the early lung absorption profile of salbutamol in patients with severe asthma. This may have implications in terms of optimising dose and delivery of inhaled beta 2 agonists in these patients.