A previous study (BALTI-1) suggested β-2 agonists may help in ARDS by reducing extravascular lung water. A randomised trial in the UK aimed to recruit 1334 patients to compare intravenous salbutamol infused for seven days with placebo (0.9% saline). However the Data Monitoring and Ethics Committee recommended that the study stop after the second interim analysis of 273 patients because of a significant increase in mortality. It is unclear why salbutamol is harmful, and could be due to lung, cardiovascular, or other metabolic effects, such as activation of the renin-angiotensin aldosterone system affecting fluid balance.
BACKGROUND:In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS.
METHODS:We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged ≥16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 μg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minimisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO2/FiO2) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86.
FINDINGS:We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03-2·08).
INTERPRETATION:Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of β-2 agonist treatment in ventilated patients with this disorder cannot be recommended.
FUNDING:UK Medical Research Council, UK Department of Health, UK Intensive Care Foundation.
Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial
Lancet 379(9812, 21–27 January 2012, Pages 229–235