At the time that BALTI-2 was initiated the only treatment of proven effectiveness for acute respiratory distress syndrome (ARDS) was use of a lung-protective (pressure and volume limited) strategy for mechanical ventilation. There were no additional treatments known to improve outcome. A Cochrane review of pharmacological treatments that included 22 studies of 14 different drugs concluded that ‘Effective pharmacotherapy for acute lung injury (ALI) and ARDS is extremely limited, with insufficient evidence to support any specific intervention’. In 2010 a single trial was published showing a reduction in mortality in ARDS patients treated with neuromuscular blocking agents. This is the only trial that has demonstrated an effective pharmacological treatment for ARDS.
There is currently no recognised pharmacological treatment for ARDS.
The rationale for investigating salbutamol in the treatment of ARDS was that there is good evidence from in vivo and in vitro studies that β2-agonists may have a range of important beneficial effects in ARDS patients. Also, salbutamol is a low-cost treatment when compared to the cost of treating patients in ITU.
The authors reported the following results from the study:
• The risk ratio for death at 28 days in the salbutamol group compared with the placebo group was 1.47 (95% CI 1.03 to 2.08; p = 0.03).
• Salbutamol resulted in a 10.9% (95% CI 1.0% to 20.4%) absolute increase (34.2% vs. 23.3%) in 28-day mortality.
• There was one additional death for every 9.2 (95% CI 4.9 to 100.9) ARDS patients treated with salbutamol (number needed to treat for harm).
• Survival analysis for the primary outcome showed a hazard ratio of 1.56 (95% CI 1.03 to 2.36).
The following study limitations were noted:
• The most notable methodological issue is that the trial was terminated at a smaller sample size than originally intended, on the recommendation of the DMEC, because of excess mortality in the salbutamol group found at an interim analysis. This has a number of potential consequences. First, the precision of treatment effect estimates is inevitably lower than anticipated, because of the smaller sample size. This is likely to make the effects of the intervention on some outcomes less clear than would be the case if the trial had reached its planned sample size. A larger sample size and narrower CIs would probably clarify salbutamol's effects on some outcomes such as mortality in ICU and in hospital. Second, there is a small possibility that the increased risk of death in the salbutamol group was a chance finding, arising because the interim analysis happened to coincide with a time when more deaths had occurred in the salbutamol group. The trial was stopped when < 25% of the planned sample size had been recruited, and the treatment effect of salbutamol could have changed substantially if the trial had continued to recruit up to its original target. The excess of deaths in the salbutamol group might then have been small or non-existent, and it is even possible, though unlikely, that the treatment effect could have been reversed into a benefit for salbutamol. Thus, there is a remote possibility that the early termination of the trial may have led to a beneficial treatment effect being missed.
• A substantial number of earlier studies, including one clinical trial, indicated potential benefit for salbutamol, and there was sufficient clinical interest in β2-agonists to initiate trials in the UK and North America. However, the final result of BALTI-2 was in the opposite direction. This may have occurred partly because of the different outcomes measured by different studies. The early studies were concerned primarily with physiological outcomes, and it is possible that these are simply poor surrogates for substantive clinical outcomes and were inaccurate predictors of salbutamol's effects on mortality. Alternatively, the results on physiological parameters may have been misleading because of chance and bias.
• Previous intensive care trials have found it difficult to achieve high rates of long-term data collection and the experience of BALTI-2 confirms that this is a difficult population to follow-up. Only about 40% of survivors were successfully followed up at 6 and 12 months for quality-of-life outcomes. Obviously, the large number of missing data means that conclusions can only be very tentative because of the risk of bias, but the data suggested that quality of life may be lower at 12 months in the salbutamol group. This was in the same direction as the results for mortality.