46 study sites participated in recruitment; a further 25 sites obtained approval to start the trial, but were unable to do so before recruitment was stopped. Recruitment was stopped after the second interim analysis, when the Data Monitoring and Ethics Committee reviewed the results for 273 patients in March, 2010. The RR for the primary outcome at this time was 1·55 (95% CI 1·07–2·24). Therefore, the committee recommended suspension of recruitment to BALTI-2 because of a significant (p=0·02) adverse effect of salbutamol on 28-day mortality, and the 99·8% CI excluded a benefit for salbutamol of the size anticipated in the protocol. Infusion was discontinued in all patients (one receiving salbutamol, two receiving placebo) receiving study drug at that time. The trial steering committee endorsed this recommendation and closed recruitment on March 23, 2010.
shows the trial profile. 326 patients were randomly assigned to receive either salbutamol or placebo. Two patients withdrew consent; no outcome data were available for these patients. The study drug was not given to two patients in the salbutamol group: one patient needed a β blocker between randomisation and starting the drug, the other patient's next of kin refused to have a separate intravenous line inserted for infusion after initially giving consent.
Both groups had similar baseline characteristics (). The median time from randomisation to start of the study infusion was similar in both groups (salbutamol 1·3 h, IQR 0·6–2·5; placebo 1·1 h, 0·6–2·2). Patients in the salbutamol group were more likely to have their infusion stopped early than were those in the placebo group, either because of death (14/161 vs eight of 163), or the development of significant side-effects (47/161 vs 13/163). The duration of infusion was on average 24·5 h (95% CI 12·3–36·7) shorter in the salbutamol group than in the placebo group (mean 114·1 h [SD 62·7] vs 138·6 h [47·9]; ). The risks of patients developing a tachycardia, new arrhythmia, or lactic acidosis severe enough to warrant stopping of the study drug were substantially higher in the salbutamol group than in the placebo group ().
Kaplan-Meier curves for duration of infusions
Primary and secondary outcomes
More patients died 28 days after randomisation in the salbutamol group than in the placebo group (RR 1·47, 95% CI 1·03–2·08; p=0·03; ). Survival analysis of the primary outcome () showed a hazard ratio of 1·56 (95% CI 1·03–2·36). Salbutamol resulted in a 10·9% (95% CI 1·0–20·4) absolute increase in 28-day mortality (). One additional death occurred for every 9·2 (95% CI 4·9–100·9) patients with ARDS given salbutamol. The number of deaths before discharge from either intensive-care unit or hospital did not differ significantly between groups (p=0·10 and p=0·26, respectively; ). We noted an 8·4% (95% CI −1·7 to 18·3) absolute increase in intensive-care unit mortality and a 6·0% (−4·4 to 16·2) increase in hospital mortality in the salbutamol group ().
Kaplan-Meier curves for mortality
Ventilator-free and organ failure-free days in the first 28 days after randomisation were both reduced in the salbutamol group (). We detected no clear differences between the groups in length of stay in intensive-care units and hospitals (). Surviving patients with ARDS in the salbutamol group needed a mean of 3·4 more days (95% CI −0·3 to 7·1) in intensive-care units than did those in the placebo group (). Serious adverse events (other than those recorded as trial outcomes, eg, death) were reported for 13 participants (nine in salbutamol group, four in placebo group). Four of these events were thought to be related to the study drug infusion, and only one was an unexpected effect. Subgroup analyses did not suggest that the effects of salbutamol were modified by any of the variables investigated. For cause (categorical subgrouping variable), the ratio of RRs was 0·96 (95% CI 0·46–2·01). For continuous variables the ratios of odds ratios for each variable investigated were 0·97, 0·93–1·00; p=0·07 for age; 1·02, 0·92–1·14; p=0·66 for severity of hypoxemia; and 1·29, 0·08–22·04; p=0·86 for mortality risk. The analysis suggested weak evidence of a possible interaction effect with age. However, the effect was small and strongly affected by the oldest age stratum (>85 years), in which there were only four patients; therefore, this finding is likely to be due to chance.
Adjustment for baseline variables (age, sex, PaO2/FIO2 ratio, and cause) alone or in combination made no substantial difference to the estimate of the treatment effect of salbutamol or its statistical significance (data not shown). We obtained data for cause of death for 91 of 93 patients who died by day 28 (55/55 in the salbutamol group, 36/38 in the placebo group). Because of the diversity of individual diagnoses, we grouped results for cause of death according to organ system. Diagnoses for the respiratory system were the most common primary cause of death in both groups (28 [51%] patients given salbutamol vs 20 [53%] given placebo), followed by multiorgan failure (12 [22%] vs 14 [37%]). ARDS was recorded on the death certificate for 11 (21%) patients in the salbutamol group, and eight (21%) in the placebo group.