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What is this summary about? This summary describes the results of a clinical study called MANDALA that was published in the New England Journal of Medicine in 2022. In the MANDALA study, researchers looked at a new asthma rescue inhaler that contains both albuterol and budesonide in a single inhaler (known as albuterol-budesonide , AIRSUPRA™). This summary describes the results for people aged 18 yearsand older who took part in the study.

Background: As asthma symptoms worsen, patients typically rely on short-acting β 2 -agonist (SABA) rescue therapy, but SABAs do not address worsening inflammation, which leaves patients at risk for severe asthma exacerbations. The use of a fixed-dose combination of albuterol and budesonide, as compared with albuterol alone, as rescue medication might reduce the risk of severe asthma exacerbation., Methods: We conducted a multinational, phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of albuterol-budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial. Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide (with each dose consisting of two actuations of 90 μg and 80 μg, respectively [the higher-dose combination group]), a fixed-dose combination of 180 μg of albuterol and 80 μg of budesonide (with each dose consisting of two actuations of 90 μg and 40 μg, respectively [the lower-dose combination group]), or 180 μg of albuterol (with each dose consisting of two actuations of 90 μg [the albuterol-alone group]). Children 4 to 11 years of age were randomly assigned to only the lower-dose combination group or the albuterol-alone group. The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population., Results: A total of 3132 patients underwent randomization, among whom 97% were 12 years of age or older. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group than in the albuterol-alone group (hazard ratio, 0.74; 95% confidence interval [CI], 0.62 to 0.89; P = 0.001). The hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, was 0.84 (95% CI, 0.71 to 1.00; P = 0.052). The incidence of adverse events was similar in the three trial groups., Conclusions: The risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide than with as-needed use of albuterol alone among patients with uncontrolled moderate-to-severe asthma who were receiving a wide range of inhaled glucocorticoid-containing maintenance therapies. (Funded by Avillion; MANDALA ClinicalTrials.gov number, NCT03769090.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: In double-blind, placebo-controlled trials, budesonide-formoterol used on an as-needed basis resulted in a lower risk of severe exacerbation of asthma than as-needed use of a short-acting β 2 -agonist (SABA); the risk was similar to that of budesonide maintenance therapy plus as-needed SABA. The availability of data from clinical trials designed to better reflect clinical practice would be beneficial., Methods: We conducted a 52-week, randomized, open-label, parallel-group, controlled trial involving adults with mild asthma. Patients were randomly assigned to one of three treatment groups: albuterol (100 μg, two inhalations from a pressurized metered-dose inhaler as needed for asthma symptoms) (albuterol group); budesonide (200 μg, one inhalation through a Turbuhaler twice daily) plus as-needed albuterol (budesonide maintenance group); or budesonide-formoterol (200 μg of budesonide and 6 μg of formoterol, one inhalation through a Turbuhaler as needed) (budesonide-formoterol group). Electronic monitoring of inhalers was used to measure medication use. The primary outcome was the annualized rate of asthma exacerbations., Results: The analysis included 668 of 675 patients who underwent randomization. The annualized exacerbation rate in the budesonide-formoterol group was lower than that in the albuterol group (absolute rate, 0.195 vs. 0.400; relative rate, 0.49; 95% confidence interval [CI], 0.33 to 0.72; P<0.001) and did not differ significantly from the rate in the budesonide maintenance group (absolute rate, 0.195 in the budesonide-formoterol group vs. 0.175 in the budesonide maintenance group; relative rate, 1.12; 95% CI, 0.70 to 1.79; P = 0.65). The number of severe exacerbations was lower in the budesonide-formoterol group than in both the albuterol group (9 vs. 23; relative risk, 0.40; 95% CI, 0.18 to 0.86) and the budesonide maintenance group (9 vs. 21; relative risk, 0.44; 95% CI, 0.20 to 0.96). The mean (±SD) dose of inhaled budesonide was 107±109 μg per day in the budesonide-formoterol group and 222±113 μg per day in the budesonide maintenance group. The incidence and type of adverse events reported were consistent with those in previous trials and with reports in clinical use., Conclusions: In an open-label trial involving adults with mild asthma, budesonide-formoterol used as needed was superior to albuterol used as needed for the prevention of asthma exacerbations. (Funded by AstraZeneca and the Health Research Council of New Zealand; Novel START Australian New Zealand Clinical Trials Registry number, ACTRN12615000999538.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: In exacerbations of chronic obstructive pulmonary disease, administration of high concentrations of oxygen may cause hypercapnia and increase mortality compared with oxygen titrated, if required, to achieve an oxygen saturation of 88-92%. Optimally titrated oxygen regimens require two components: titrated supplemental oxygen to achieve the target oxygen saturation and, if required, bronchodilators delivered by air-driven nebulisation. The effect of repeated air vs oxygen-driven bronchodilator nebulisation in acute exacerbations of chronic obstructive pulmonary disease is unknown. We aimed to compare the effects of air versus oxygen-driven bronchodilator nebulisation on arterial carbon dioxide tension in exacerbations of chronic obstructive pulmonary disease., Methods: A parallel group double-blind randomised controlled trial in 90 hospital in-patients with an acute exacerbation of COPD. Participants were randomised to receive two 2.5 mg salbutamol nebulisers, both driven by air or oxygen at 8 L/min, each delivered over 15 min with a 5 min interval in-between. The primary outcome measure was the transcutaneous partial pressure of carbon dioxide at the end of the second nebulisation (35 min). The primary analysis used a mixed linear model with fixed effects of the baseline PtCO 2 , time, the randomised intervention, and a time by intervention interaction term; to estimate the difference between randomised treatments at 35 min. Analysis was by intention-to-treat., Results: Oxygen-driven nebulisation was terminated in one participant after 27 min when the PtCO 2 rose by > 10 mmHg, a predefined safety criterion. The mean (standard deviation) change in PtCO 2 at 35 min was 3.4 (1.9) mmHg and 0.1 (1.4) mmHg in the oxygen and air groups respectively, difference (95% confidence interval) 3.3 mmHg (2.7 to 3.9), p < 0.001. The proportion of patients with a PtCO 2 change ≥4 mmHg during the intervention was 18/45 (40%) and 0/44 (0%) for oxygen and air groups respectively., Conclusions: Oxygen-driven nebulisation leads to an increase in PtCO 2 in exacerbations of COPD. We propose that air-driven bronchodilator nebulisation is preferable to oxygen-driven nebulisation in exacerbations of COPD., Trial Registration: Australian New Zealand Clinical Trials Registry number ACTRN12615000389505 . Registration confirmed on 28/4/15.

Asthma mortality surveys report delays in seeking medical review and overuse of beta-agonist therapy as factors contributing to a fatal outcome. However, the strength of these associations is limited because many asthma deaths are unwitnessed. We undertook a secondary analysis of data from a 24-week randomised controlled trial of 303 patients with high-risk asthma, randomised to combination budesonide/formoterol inhaler according to a single maintenance and reliever therapy regimen or fixed dose budesonide/formoterol with salbutamol as reliever (Standard) regimen. Medication use was measured by electronic monitors. The thresholds for high, marked and extreme beta-agonist use days were defined in the single maintenance and reliever therapy arm as: >8, >12 and >16 actuations of budesonide/formoterol in excess of four maintenance doses, respectively; and in the Standard arm as: >16, >24 and >32 actuations of salbutamol, respectively. Whether a medical review was obtained within 48 h of an overuse episode was determined by review of data collected during the study by participant report. The mean (standard deviation) proportion of days in which high, marked and extreme beta-agonist overuse occurred without medical review within 48 h was 0·94(0·20), 0·94(0·15) and 0·94(0·17), and 0·92(0·19), 0·90(0·26) and 0·94(0·15) for single maintenance and reliever therapy and Standard regimens, respectively. In at least 90% of days, in which beta-agonist overuse occurred, patients did not obtain medical review within 48 h of beta-agonist overuse, regardless of the magnitude of overuse or the inhaled corticosteroid/long-acting beta-agonist regimen., Reliever Inhaler Overuse and Delay in Medical Review in Asthma: In asthma, overuse of beta-agonist reliever medication and delay in seeking medical review in an exacerbation are linked to asthma deaths. Janine Pilcher at the Medical Research Institute of New Zealand, and co-workers, conducted a review of data from a study of 303 adult patients with severe asthma, followed over 24 weeks. The patients were allocated to either a budesonide/formoterol, or a salbutamol inhaler to take for symptom relief, in addition to their maintenance treatment. Inhalers were fitted with electronic monitors, to accurately document every use. In both groups, on 90% of days when an exacerbation requiring excess use of an inhaler occurred, patients did not follow-up with medical professionals within 48 h as advised. Further, in both groups, 'extreme' reliever inhaler use was recorded at least once in around one in four patients.

Background: Fluticasone furoate (FF)/vilanterol (VI) is a once-daily maintenance treatment for asthma and chronic obstructive pulmonary disease. The duration of bronchodilation beyond 24 h has not been determined previously., Methods: Adults aged 18-65 (n = 32), with asthma and reversibility to salbutamol (≥15% and ≥200 mL increase in forced expiratory volume in 1 s [FEV 1 ]) participated in a double-blind, placebo-controlled, crossover study. Patients were admitted to a clinical trials unit for 72 h, and inhaled, in random order, placebo or FF/VI 100/25 mcg via ELLIPTA dry powder inhaler on two occasions 7-14 days apart. FEV 1 was measured at baseline, 15 and 30 min, 1, 2, 4, 12, 24, 36, 48, 60, and 72 h. The differences in change in FEV 1 from baseline between treatments and corresponding two-sided 95% confidence intervals (CI) were calculated at each time point., Findings: FF/VI produced a rapid onset of bronchodilation (adjusted mean difference in change from baseline in FEV 1 versus placebo at 15 min, 252 mL [95% CI 182-322]). Maximum bronchodilation was observed at 12 h (adjusted mean difference in the change from baseline in FEV 1 , 383 mL [95% CI 285-481]). Bronchodilation was maintained throughout the 72-h assessment period (adjusted mean difference in the change in FEV 1 from baseline at 72 h, 108 mL (95% CI 15-200]). FF/VI was well tolerated and no serious side effects were reported., Interpretation: A single dose of FF/VI 100/25 mcg showed evidence of a 72-h bronchodilator duration of action in adults with asthma., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objective: The optimal management of people with asthma with a significant smoking history is uncertain. The aim of this study was to determine whether the efficacy/safety profile of single combination inhaled corticosteroid (ICS)/long acting beta-agonist (LABA) inhaler maintenance and reliever therapy is influenced by smoking status., Methods: We undertook secondary analyses from an open-label 24-week randomized study of 303 high risk adult asthma patients randomized to budesonide/formoterol 200/6-µg-metred dose inhaler for maintenance (two actuations twice daily) and either budesonide/formoterol 200/6-µg-metred dose inhaler one actuation ('single ICS/LABA maintenance and reliever therapy (SMART)' regimen) or salbutamol 100 µg 1-2 actuations for symptom relief ('Standard' regimen). Smoking status was classified in to three groups, as 'current', 'ex' or 'never', and a smoking/treatment interaction term tested for each outcome variable. The primary outcome variable was number of participants with at least one severe exacerbation., Results: There were 59 current, 97 ex and 147 never smokers included in the analyses. The smoking status/treatment interaction term was not statistically significant for any of the outcome measures. With adjustment for smoking status, the number of participants with severe exacerbations was lower with the SMART regimen (OR 0.45, 95% CI: 0.26-0.77, P = 0.004; P value for interaction between smoking status and treatment 0.29)., Conclusion: We conclude that the favourable safety/efficacy profile of the SMART regimen applies to patients with high risk asthma, irrespective of smoking status., (© 2016 Asian Pacific Society of Respirology.)

Background: Predictors of asthma exacerbations, poor asthma control, or extreme β-agonist overuse may be of clinical utility in the management of asthma., Objective: To investigate characteristics that predict subsequent adverse outcomes in asthma., Methods: An independent 24-week, randomized controlled trial of 303 adult patients with asthma who are at risk, which compared the efficacy of SMART (single budesonide-formoterol inhaler as maintenance and reliever therapy) with a fixed-dose regimen with salbutamol as reliever ("Standard"). Inhaled medication use was measured by electronic monitoring. Baseline characteristics that were predictors of subsequent severe asthma exacerbations, poor asthma control (Asthma Control Questionnaire -5 score ≥1.5), and "extreme" β-agonist overuse (>16 budesonide-formoterol actuations/d in SMART and >32 salbutamol actuations/d in Standard) were assessed by multivariate analyses., Results: FEV₁ % predicted (rate ratio [RR] 1.14 [95% CI, 1.03-1.27] per 10% lower), more previous exacerbations (RR 1.15 [95% CI, 1.01-1.31]), Standard therapy (RR 1.62 [95% CI, 1.07-2.47]), and female sex (RR 2.18 [95% CI, 1.29-3.67]) were associated with future severe exacerbations. Asthma Control Questionnaire--5 (regression coefficient 0.20 [95% CI, 0.13-0.27] per 0.5 points higher) and age (regression coefficient 0.09 [95% CI, 0.01-0.17] per decade older) were associated with future poorly controlled asthma. Higher reliever use (RR 1.63 [95% CI, 1.36-1.95] per categorical score in Asthma Control Questionnaire question no. 6), Māori ethnicity (RR 2.20 [95% CI, 1.43-3.38]) and FEV₁ % predicted (RR 1.16 [95% CI, 1.03-1.31] per 10% lower) were associated with future extreme β-agonist overuse., Conclusion: Future severe asthma exacerbations, poor asthma control, and extreme β-agonist overuse are predicted by different baseline clinical and demographic characteristics and management approaches in at-risk asthma., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background and Objective: There are significant health disparities between Māori and non-Māori with asthma, a pattern seen between other ethnic populations. This study investigates outcomes for Māori in a randomized controlled trial (RCT) of combination budesonide/formoterol inhaler therapy in asthma., Methods: This 24-week multicentre RCT recruited 303 adult asthma patients, 44 of whom were Māori. Participants were randomized to the single combination budesonide/formoterol inhaler as maintenance and reliever therapy ('SMART') regimen or 'standard' regimen (combination budesonide/formoterol inhaler for maintenance and salbutamol as reliever). Outcomes included patterns of beta-agonist inhaler use including 'high use' of reliever therapy (>8 actuations of budesonide/formoterol in excess of four maintenance doses per day for SMART and >16 actuations per day of salbutamol for standard). Differences in outcomes for Māori versus non-Māori were assessed using an interaction term between ethnicity and treatment., Results: With adjustment for ethnicity, the SMART group had fewer days of high use (relative rate (RR) 0.57 (95% confidence interval (CI): 0.38-0.85)), days of high use without medical review within 48 h (RR 0.49 (95% CI: 0.32-0.75)) and severe exacerbations (RR 0.54 (95% CI: 0.36-0.81)) compared with standard. The magnitude of the benefit from the SMART regimen was similar in Māori and non-Māori. Regardless of treatment regimen, Māori demonstrated more days of high use, high use without medical review and underuse of maintenance therapy., Conclusions: The SMART regimen has a favourable risk/benefit profile in Māori. Days of high use, days of high use without medical review and underuse of maintenance treatment were greater in Māori, regardless of treatment regimen., (© 2014 Asian Pacific Society of Respirology.)

Background: Beta-agonist overuse is associated with adverse outcomes in asthma, however, the relationships between different metrics of salbutamol use and future risk are uncertain., Objective: To investigate the relationship between metrics of salbutamol use and adverse outcome., Methods: In a 24-week randomized controlled trial of 303 asthma patients at risk of severe exacerbations which compared the efficacy and safety of combination budesonide/formoterol inhaler according to a single inhaler regimen (SMART) with a fixed-dose regimen with salbutamol as reliever ('Standard'), actual medication use was measured by electronic monitoring (Australian New Zealand Clinical Trials Registry Number ACTRN12610000515099). A nested cohort study explored the relationship between metrics of baseline salbutamol use over 2 weeks and future severe asthma exacerbations, poor asthma control (ACQ-5 ≥ 1.5) or 'extreme' salbutamol overuse (> 32 salbutamol actuations/24-h period)., Results: Higher mean daily salbutamol use (per two actuations/day) [Odds ratio (OR) (95% CI) 1.24 (1.06-1.46)], higher days of salbutamol use (per 2 days in 2 weeks) [OR 1.15 (1.00-1.31)] and higher maximal 24-h use (per two actuations/day) [OR 1.09 (1.02-1.16)] were associated with future severe exacerbations. Higher mean daily salbutamol use was associated with future poor asthma control [OR 1.13 (1.02-1.26)]. Higher mean daily salbutamol use [OR 2.73 (1.84-4.07)], number of days of use [OR 1.46 (1.24-1.71)], and maximal daily use [OR 1.57 (1.31-1.89)] were associated with an increased risk of future extreme salbutamol overuse., Conclusion and Clinical Relevance: Electronically recorded frequency of current salbutamol use is a strong predictor of risk of future adverse outcomes in asthma, with average daily use performing the best. These findings provide new information for clinicians considering metrics of salbutamol as predictors of future adverse outcomes in asthma., (© 2013 John Wiley & Sons Ltd.)

Background: The relationship between current asthma symptoms and rescue bronchodilator (reliever) use is uncertain, leading to different recommendations about the preferred reliever metric to use when assessing asthma control. In a 6-month randomized controlled trial of combination budesonide/formoterol as maintenance and reliever therapy versus combination budesonide/formoterol as maintenance treatment with albuterol as reliever, we measured inhaler use by electronic monitoring., Objective: To determine the agreement between current asthma symptoms and different metrics of albuterol use for patients randomly assigned to maintenance budesonide/formoterol treatment., Methods: Data on albuterol use were extracted for the 7-day period before visit 2 (at week 3) from 150 adult patients with asthma. Current asthma symptoms were measured by Asthma Control Questionnaire-5 (ACQ-5) score at the clinic visit., Results: The number of days of albuterol use, the average number of albuterol actuations/day, and the highest number of albuterol actuations/day in the 1-week period were all positively associated with ACQ-5 score (r = 0.41-0.45, P < .001) and had moderate discrimination for well-controlled and not well-controlled asthma (ACQ-5 scores ≤0.75 and ≥1.5, respectively), with receiver operator characteristic area under the curve of 0.80 to 0.82 and 0.70 to 0.77, respectively. Cut points of ≥3 days of albuterol use, average albuterol use of ≥1 actuation/day, and highest albuterol use of ≥4 actuations/day in the 1-week period had 73% sensitivity and 62% specificity, 78% sensitivity and 67% specificity, and 78% sensitivity and 66% specificity, respectively, for predicting an ACQ-5 ≥1.5., Conclusion: Our findings support the use of the number of days of albuterol use, the average number of albuterol actuations per day, and the highest number of albuterol actuations per day over a 1-week period of observation as comparable markers of current asthma control., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Based primarily on extrapolation from adult studies, current pediatric asthma guidelines advise the addition of long-acting beta₂-agonists for children symptomatic on low/moderate-dose inhaled corticosteroids before increasing the corticosteroid dose. This study was designed to compare the effect of combination salmeterol/fluticasone propionate (SFC) with doubling the dose of fluticasone propionate (FP) on specific airway resistance (sR(aw)) in moderate/severe persistent asthmatic children. A double-blind, randomized, controlled study was performed; children with asthma (4-11 years old; sR(aw) > 1.3 kPa·s) were randomized after a 2-week run-in (FP, 100 μg, b.i.d.) to either SFC (50 μg/100 μg b.i.d.) or FP (200 μg b.i.d.) via Diskus (GlaxoSmithKline, Stockley Park, U.K.) for 6 weeks. Lung function (sR(aw)-plethysmography and forced expiratory volume in 1 second [FEV₁]) was measured before run-in, at randomization, after 3 weeks, at the end of 6-week treatment, and after 48-hour washout. Symptom scores and rescue medication use were recorded throughout. Thirty-five children entered run-in and 24 were randomized (mean age, 7.3 ± 2.2 years; 50% boys). All children showed an improvement in sR(aw). After adjusting for age, gender, and baseline sR(aw,) children receiving SFC had a significantly greater improvement in sR(aw) compared with those receiving FP (adjusted means ratio [95% confidence interval {CI}], 0.81 [0.68-0.97]; p = 0.021). There was a significant interaction between treatment and gender (sR(aw), adjusted geometric mean [95% CI ]kPa·s, SFC versus FP: boys, 1.25 [1.10-1.41] [n = 7] versus 1.87 [1.61-2.17] [n = 5]; girls, 1.29 [1.10-1.52] [n = 5] versus 1.29 [1.13-1.47] [n = 7]; p = 0.008). There were no differences in FEV₁, symptoms, or rescue medication use between the groups. Addition of salmeterol provides greater improvement in sR(aw) than doubling the dose of FP in children with moderate/severe persistent asthma.

Background: There is concern that long-acting beta agonist (LABA) drugs may increase the risk of asthma mortality., Methods: A meta-analysis was conducted of asthma deaths in randomised controlled clinical trials from the GlaxoSmithKline database that compared salmeterol with a non-LABA comparator treatment in asthma. The Peto one-step method was used to determine the risk overall (all studies) and in derived datasets based on inhaled corticosteroid (ICS) use., Results: There were 35 asthma deaths in 215 studies with 106,575 subjects. Two studies (SMART and SNS) contributed 30/35 (86%) asthma deaths, the overall findings largely reflecting the characteristics of these studies. The odds ratio for risk of asthma mortality with salmeterol was 2.7 (95% CI 1.4 to 5.3). In 54 placebo controlled studies the risk of death from asthma in patients not prescribed ICS was 7.3 (95% CI 1.8 to 29.4). In 127 studies in which patients were prescribed ICS, the risk of asthma death was 2.1 (95% CI 0.6 to 7.9). In 63 studies in which patients were randomised to receive the combination salmeterol/fluticasone propionate inhaler or ICS, there were no asthma deaths among 22,600 patients., Conclusions: Salmeterol monotherapy in asthma increases the risk of asthma mortality and this risk is reduced with concomitant ICS therapy. There is no evidence that combination salmeterol/fluticasone propionate therapy is associated with an increased risk of asthma mortality, although this interpretation is limited by the low statistical power of available studies.

This article reviews the available evidence as to whether inhaled long acting beta-agonists (LABA) increase the risk of asthma mortality and considers the implications for the use of this treatment in the management of asthma. Randomised controlled trials suggest that LABAs prescribed as monotherapy may increase the risk of asthma death in certain circumstances, such as the unsupervised "off-label" use without concomitant inhaled corticosteroid (ICS) treatment in patients with unstable asthma. However, there is also evidence that the use of LABAs in conjunction with ICS treatment in adult asthma as recommended in current guidelines is not associated with an increased risk of asthma mortality. The only way in which a prescriber can ensure that a patient with asthma takes LABA treatment in conjunction with ICS is through a combination ICS/LABA product, an approach which may have additional therapeutic advantages. We propose that in the management of asthma, a case can now be made to limit the availability of LABAs to combination LABA/ICS therapy.

Objective and Background: To investigate the duration of bronchodilator action of a salmeterol/fluticasone combination (SFC) inhaler when administered in the evening to children with asthma., Design: A double-blind, placebo-controlled, cross-over study., Setting: Hospital inpatient., Subjects: Fourteen children aged between 4 and 11 years with mild to moderate asthma (FEV(1) > 60% predicted) who exhibited a 15% increase in FEV(1) with bronchodilator., Interventions: SUBJECTS inhaled, in random order, either SFC (100/50 microg) or placebo, via accuhaler, at 20.00 hours on two separate occasions with at least 3 days between study days., Outcome Measures: Lung function measurements including FEV(1), PEF, specific airways conductance (sGaw) and maximum expiratory flow at 25-75% of vital capacity were measured at baseline, 2, 12, 16, 20 and 24 h., Results: For all lung function parameters SFC resulted in significantly greater bronchodilation than placebo for at least 20 h after inhalation. At 24 h, the increase in FEV(1) and PEF compared with placebo was 0.08 L (95% confidence interval: -0.18 to 0.02, P = 0.16) and 27 L/min (95% confidence interval: -47 to -6, P = 0.004), respectively., Conclusions: The single administration of SFC via an accuhaler in the evening resulted in significant bronchodilation for at least 20 h in children with asthma.

Background: There is uncertainty as to the dose of inhaled corticosteroids (ICS) at which to start concomitant long acting beta agonist (LABA) treatment in patients with asthma not adequately controlled by ICS alone., Methods: A meta-analysis was carried out of randomised, double blind clinical trials that compared the efficacy of adding salmeterol to moderate doses of ICS (fluticasone propionate 200 mug/day or equivalent) with increasing the ICS dose by at least twofold in symptomatic adult patients with asthma. The main outcome measures were the number of subjects withdrawn from the study due to asthma and the number of subjects with at least one moderate or severe exacerbation., Results: Twelve studies with a total of 4576 subjects met the inclusion criteria for the analyses. The number of subjects withdrawn due to asthma and with at least one moderate or severe exacerbation was higher in the high dose ICS group (odds ratios 1.58, 95% CI 1.12 to 2.24 and 1.35, 95% CI 1.10 to 1.66, respectively). For the secondary outcome variables (forced expiratory volume in 1 second, morning and evening peak expiratory flow, and daytime beta agonist use) there was significantly greater benefit in the salmeterol group., Conclusions: This meta-analysis shows that the addition of salmeterol to moderate doses of ICS (fluticasone 200 mug/day or equivalent) in patients with asthma symptomatic at that dose results in significantly greater clinical benefit than increasing the dose of ICS by twofold or more.

Introduction: The duration of bronchodilator action of the long-acting beta agonist salmeterol when administered in the evening has not been investigated. In this study we have investigated whether a single evening dose of salmeterol, administered from the combination salmeterol/fluticasone (SFC) Accuhaler significantly attenuates the circadian rhythm in airway tone over 24 h., Methods: Eighteen subjects with mild to moderate asthma (mean FEV1 84% predicted) participated in a double-blind, double dummy, placebo controlled, cross-over study. Subjects inhaled, in random order, placebo, salbutamol (200 microg) or SFC (50/100 microg) administered in the evening (2000 h) on three separate occasions. Lung function measurements including FEV1, specific airways conductance (sGaw) and maximum expiratory flow at 25-75% of vital capacity (MEF(25-75%)) were assessed at baseline, at 1 h and subsequently every 4 h post-dose for 24 h., Results: Compared with placebo, SFC significantly improved the three measures of airways function throughout the 24 h period, with a difference in FEV1 at 24 h of 0.24 l (0.00-0.47 l). SFC abolished the biphasic pattern of the circadian rhythm in airway tone. In contrast, salbutamol had a significant bronchodilator action of 4-8 h, depending on the lung function parameter measured., Conclusion: The single evening administration of SFC via the Accuhaler resulted in a duration of bronchodilation of at least 24 h, with the abolition of the accentuated biphasic circadian variation in airway tone observed in asthma.

Objectives: This study investigated the ability of patients to assess when a metered dose inhaler (MDI) is empty., Methodology: A total of 17 patients assessed, by shaking, the number of doses remaining in a salbutamol MDI that had been partially emptied. Another 100 patients were asked to collect all salbutamol MDIs they considered to be empty and would have thrown away. These MDI canisters were weighed and the number of doses that had been used was estimated., Results: Using the 'shaking method', patients overestimated the amount remaining by around 40 doses. The mean number of doses delivered from an MDI labelled to contain 200 doses before it was discarded was 224 (range, 155-289)., Conclusions: These findings confirm that patients are unable to determine when an MDI should be discarded, resulting in insufficient drug delivery at the end of the life of an MDI for the majority of patients, and wastage of the drug for others.

Objectives: Formoterol, a beta(2) agonist with a rapid onset of effect and long duration of action, can be used as maintenance and reliever medication for asthma and COPD. We compared the pulmonary and extra-pulmonary effects of cumulative doses of formoterol and salbutamol in patients with COPD to assess efficacy and safety., Methodology: In a randomized, double-blind, cross-over study, 12 patients with moderate to severe COPD inhaled, via Turbuhaler, 10 doses of formoterol (total metered dose, 120 microg, equivalent to a 90- microg delivered dose), salbutamol (total metered dose 2000 microg) or placebo at 2-min intervals on separate days. The effects on lung function (FEV(1) and PEF), heart rate, blood pressure, oxygen saturation, corrected QT interval (QTc), T-wave height and plasma potassium were assessed before each dose, 15 min after each dose, and at half-hourly intervals for 3 h following the final dose., Results: Inhalation of formoterol or salbutamol resulted in significant improvement in lung function (measured 30 min after the last dose) when compared with placebo. There were no clinically important or statistically significant changes in heart rate, QTc, T-wave height, plasma potassium, oxygen saturation, or systolic and diastolic blood pressures with formoterol or salbutamol. One patient developed ventricular trigeminy after both formoterol and salbutamol. She had had ventricular ectopics on her screening electrocardiogram., Conclusion: Formoterol and salbutamol both produced significant improvement in lung function and were similarly well tolerated in high doses, as might be taken by a patient for relief of COPD symptoms.

Background: Intravenous magnesium can cause bronchodilation in treatment of severe asthma, however its effect by the nebulised route is uncertain. We aimed to assess the effectiveness of isotonic magnesium sulphate as an adjuvant to nebulised salbutamol in severe attacks of asthma., Methods: We enrolled 52 patients with severe exacerbations of asthma presenting to the emergency departments at two hospitals in New Zealand. A severe exacerbation was defined as a forced expiratory volume at 1 s (FEV(1)) of less than 50% predicted 30 min after initial administration of 2.5 mg salbutamol via nebulisation. In this randomised double-blind placebo-controlled trial patients received 2.5 mg nebulised salbutamol mixed with either 2.5 mL isotonic magnesium sulphate or isotonic saline on three occasions at 30 min intervals. The primary outcome measure was FEV(1) at 90 min. Analysis was per protocol., Findings: At 90 min the mean FEV1 in the magnesium group was 1.96 L (95% CI 1.68-2.24) and in the saline group 1.55 L (1.24-1.87). The difference in the mean FEV(1) between the magnesium and saline groups was 0.37 L (0.13-0.61, p=0.003)., Interpretation: Use of isotonic magnesium as an adjuvant to nebulised salbutamol results in an enhanced bronchodilator response in treatment of severe asthma.

With the development of different chlorofluorocarbon (CFC)-free metered dose aerosol and dry powder devices, it is necessary to study and validate the methods used for assessing and comparing their efficacy. This study evaluated the cumulative dose design by determining the bronchodilator response to salbutamol given according to either a high or a low cumulative dose regimen. Adults with asthma (n = 24) were studied in a placebo-controlled, randomized, double-blind, cross-over design. On separate days, cumulative doses of salbutamol (50+50+100+200 or 100+100+ 200+400 or 400+0+0+0 or 0+0+0+0 microg) were given via Turbuhaler with 30 min between doses. The two cumulative dose regimens produced almost identical bronchodilator responses at each time point. The relative dose-potency between the 800- and 400- microg cumulative dose regimens was 0.7 with a 95% confidence interval of 0.5-1.0, excluding the true value of 2. The 400-microg cumulative dose regimen resulted in a higher FEV1 at 115 min than the 400-microg single-dose regimen. There was no difference in the bronchodilator response to the single dose of 50, 100, or 400 microg of salbutamol after either 5 or 25 min. Thus, care should be exercised when using either a cumulative or single-dose design for comparing different beta2-agonists, or different inhalation devices, with respect to their relative dose-potency. In addition, this study provides further evidence that for short-acting beta2-agonists such as salbutamol, lower doses than those normally recommended may be used, and that repeated self-administration of low doses over a period of 60 min may give a better bronchodilator response than a single administration of a high dose.

Background: A case-control study was undertaken to investigate the hypothesis that the use of the long acting beta agonist salmeterol increases the risk of a near-fatal attack of asthma., Methods: The cases comprised admissions to the intensive care unit (ICU) for asthma in 14 major hospitals within the Wessex region in 1992. For each of the cases four age-matched controls were selected from asthma admissions to the same hospital during the same period. Information on prescribed drug therapy for the 48 cases and 185 controls was collected from the hospital admission records., Results: The patients admitted to the ICU had greater chronic asthma severity and had generally been prescribed more asthma drugs than the control admissions to hospital. The relative risk of a near-fatal attack of asthma in patients prescribed inhaled salmeterol was 2.32 (95% CI 1.05 to 5.16), p = 0.04. However, the salmeterol relative risk decreased to 1.42 (95% CI 0.49 to 4.10), p = 0.52 when the analysis was restricted to the more chronically severe patients (those in the subgroup of patients with a hospital admission for asthma in the previous 12 months). These findings suggest that the increased unadjusted relative risk with salmeterol is predominantly due to confounding by severity--that is, the increased relative risk is due to patients with more severe asthma (at greatest risk of a near-fatal asthma attack) being preferentially prescribed salmeterol. This interpretation is supported by the finding in this study that, within the control group (selected from the population of asthmatics requiring hospital admission), salmeterol was preferentially prescribed to the most severe patients (a threefold greater prescription of salmeterol to control patients if they had been admitted to hospital in the 12 months prior to the index admission). There was no increased risk of a near-fatal attack of asthma in patients prescribed a beta agonist by metered dose inhaler (OR 0.75 (95% CI 0.31 to 1.78), p = 0.51). In contrast, the relative risks for beta agonists delivered by nebulisation (OR 3.86 (95% CI 1.99 to 7.50), p < 0.001) and oral theophylline (OR 2.45 (95% CI 1.26 to 4.78), p < 0.01) were increased and did not markedly decrease when the analysis was restricted to the more severe asthmatic subjects., Conclusions: Although these findings are not conclusive, particularly because of the small numbers involved in some subgroup analyses, they suggest that the use of salmeterol by patients with chronic severe asthma is not associated with a significantly increased risk of a near-fatal attack of asthma. If a near-fatal asthma attack is considered to be an intermediate step in a process by which a severe attack of asthma may become fatal, these results would suggest that salmeterol is unlikely to be associated with an increased risk of death, at least by this mechanism.

Study Objective: To compare the maximal extrapulmonary effects of the beta-agonists albuterol and fenoterol in eight healthy volunteers., Subjects and Methods: In this double-blind study, we have examined the maximum cardiac effects (electromechanical systole [QS2I]--a measure of inotropy, heart rate, BP) and metabolic effects (plasma K+ and cyclic adenosine monophosphate [cAMP]) of repeated inhalation of albuternol and fenoterol. In eight healthy volunteers, 400 microg of each drug was administered every 10 min until QS2I and plasma K+ had reached a plateau (+/- 0.1 mmo l/L for K+, and +/- 10 ms for QS2I). The maximum response (Emax) and the dose of albuterol required to produce 50% of the maximum response to fenoterol (ED50F) were calculated., Results: The Emax for fenoterol was significantly greater than albuterol for plasma K+ (-1.4 vs -1.03 mmol/L; p<0.002), QS2I (-71.8 vs 57.5 ms; p=0.047), and cAMP (33.8 vs 18.1 nmol/L; p<0.002). The dose required to produce the ED50f was significantly greater for albuterol than for fenoterol with potency ratios of 1.75, 1.61, and 2.26 for plasma K+, QS2I, and cAMP, respectively. There were no significant differences between fenoterol and albuterol with respect to heart rate (Emax, 44.9 vs 32.5 beats/min; p=0.19; potency ratio, 1.98; p=0.052)., Conclusions: These findings suggest that albuterol behaves as a partial agonist at beta-receptors when compared with fenoterol, and that when inhaled in doses currently recommended for severe asthma, albuterol will result in lesser maximum cardiac and metabolic effects than fenoterol. These findings are consistent with the hypothesis that the property of full receptor agonism may contribute to the increased risk of death associated with fenoterol.

The cardiovascular and metabolic effects of the long-acting beta 2-agonist formoterol were compared with those of salbutamol, fenoterol and placebo in 12 healthy volunteers, using a randomised, double-blind, cross-over design. On the study days, the subjects inhaled either formoterol (24 micrograms), salbutamol (400 micrograms), fenoterol (400 micrograms) or placebo, at 30 min intervals for five doses. Heart rate (HR) total electromechanical systole (Q-S2I) (a measure of inotropy), the corrected QT interval (QTc), systolic and diastolic blood pressure, plasma glucose and plasma potassium (K+) were measured prior to drug administration, 10 min after each inhalation and at 30 min intervals for 3 h after the last inhalation. All of the active agents significantly increased HR, QTc and plasma glucose, and decreased Q-S2I, diastolic blood pressure and plasma K+ compared to placebo. Fenoterol had a significantly greater maximum effect on HR, QTc and Q-S2I than either salbutamol or formoterol. Formoterol and fenoterol caused a similar maximum reduction in plasma K+, greater than that due to salbutamol. We conclude that formoterol is a more selective beta 2-agonist than fenoterol, and has similar cardiovascular effects to salbutamol when inhaled repeatedly by normal volunteers.

We have investigated the cardiovascular and metabolic effects of multiple inhaled doses of salbutamol and hexoprenaline in 12 healthy volunteers. They inhaled 200 micrograms of salbutamol or hexoprenaline at 15 min intervals for 60 min from a metered dose inhaler (total dose 1000 micrograms). We measured heart rate, blood pressure, total electromechanical systole (as a measure of inotropic response), QTc interval on the ECG, and plasma potassium at baseline, 10 min after each inhalation, and 30 and 60 min after the last inhalation. There was no difference in the effects of the two drugs on blood pressure, total electromechanical systole, or QTc interval. Salbutamol significantly increased heart rate compared with hexoprenaline. Hexoprenaline caused a significantly greater fall in plasma potassium compared with salbutamol.

The pulmonary and extrapulmonary effects of two doses of nebulized fenoterol (5 mg) salbutamol (5 mg) and ipratropium bromide (0.5 mg) at 60 min intervals were compared in nine patients with asthma in a double-blind, randomized study. Measurements of heart rate, blood pressure, electromechanical systole (QS2I), QTc interval, FEV1 and plasma potassium were made at baseline and at 15, 30 and 60 min after each nebulization. Both beta-agonists caused significantly greater inotropic (QS2I), chronotropic (HR), electrocardiographic (QTc) and hypokalaemic effects than ipratropium bromide (IB), with fenoterol being more potent than salbutamol. Fenoterol had no greater effect on FEV1 than salbutamol although both were superior to IB. Only the first four subjects had two doses as originally intended, because the second administration of fenoterol resulted in marked cardiovascular effects and hypokalaemia. The observed differences in extrapulmonary effects between fenoterol and salbutamol provide a plausible group of mechanisms which may explain the increased risk of death associated with fenoterol in severe asthmatics.

It has been suggested that the association between inhaled fenoterol and deaths from asthma in New Zealand occurred because patients with unstable asthma were switched to fenoterol after its introduction in 1976. If so, a similar pattern might also have occurred after the introduction of albuterol (salbumatol) in 1969. This hypothesis has been investigated in a case-control study of 17 deaths from asthma during the period from 1969 to 1976 in patients whose ages ranged from 5 to 45 years; as in a previous study in New Zealand, two control groups were used. The inhaled albuterol odds ratio was 0.88 (95% confidence interval, 0.29 to 2.62) using control group A and 1.40 (95% confidence interval, 0.48 to 4.09) using control group B. The major problem with this study is the very small number of cases, but the findings nevertheless indicate that albuterol was not associated with deaths from asthma after its introduction.

In this double blind study, the cardiovascular and hypokalaemic effects of equal doses of inhaled pirbuterol and salbutamol were compared in eight healthy volunteers. Increasing doses of 200, 400, 600 and 800 micrograms (total dose 2000 micrograms) were given from a metered dose inhaler at 15 min intervals, followed by measurement of heart rate, blood pressure, total electromechanical systole (QS2I) (as a measure of inotropic response) and plasma potassium (K+) concentration 15 min after each inhalation. After inhalation of the highest concentration, salbutamol resulted in a greater increase in heart rate (10.5 bpm vs 4.4 bpm, p less than 0.0007), and reduction in QS2I (-25.4 ms vs -9.6 ms, p less than 0.0001) than pirbuterol. There were no significant differences in changes in systolic blood pressure (1.9 mmHg vs 6 mmHg, p = 0.27), diastolic blood pressure (-5.8 mmHg vs -3.9 mmHg, p = 0.64) or plasma K+ (-0.21 mmol/L vs -0.15 mmol/L, p = 0.57). We conclude that the new beta-2 adrenergic agonist pirbuterol is at least as beta-2 selective as salbutamol when administered by repeated inhalation in healthy volunteers.

The cardiovascular effects of equal doses (5 mg) of nebulised fenoterol, salbutamol and terbutaline were compared in 12 healthy individuals in a double-blind, placebo-controlled study. Measurements of heart rate, blood pressure, systolic time intervals, QTc interval and T-wave amplitude were made at baseline and at 15, 30, 45, 60 and 90 minutes after nebulisation. Fenoterol caused significantly greater chronotropic electrocardiographic and inotropic effects than either salbutamol or terbutaline. The peak effects after terbutaline occurred later than those after fenoterol or salbutamol.

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.