1. Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet 2012;379:229-3512
BACKGROUND: In a previous randomised controlled phase 2 trial (BALTI study), 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. The authors assessed the effects of this intervention on mortality in patients with ARDS.
METHODS: The authors 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 (15µg/kg/hr) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation 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. (Gao Smith et al. 201212
Beta-2 agonists activate Beta-2 receptors on alveolar type-1 and type-2 cells, which increases intracellular cAMP, leading to increased sodium transport and acceleration of alveolar fluid reabsorption. Findings from the β-agonist lung injury trial (BALTI) showed that an infusion of salbutamol caused significant reductions in extravascular lung13
. However, the results of the truncated BALTI-2 trial are very disappointed and sufficient to change practice. Beta-2 agonist treatment in patients with ARDS should be limited to the treatment of clinically important reversible airway obstruction and should not be part of routine care.
2. Randomized, placebo-controlled clinical trial of an aerosolized beta 2-agonist for treatment of acute lung injury. Am J Respir Crit Care Med 2011;184: 561-814
RATIONALE: β2-Adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies.
OBJECTIVES: This clinical trial was designed to test the hypothesis that an aerosolized b2-agonist, albuterol, would improve clinical outcomes in patients with acute lung injury (ALI).
METHODS: We conducted a multicenter, randomized, placebo-controlled clinical trial in which 282 patients with ALI receiving mechanical ventilation were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. The primary outcome variable for the trial was ventilator-free days.
MEASUREMENTS AND MAIN RESULTS: Ventilator-free days were not significantly different between the albuterol and placebo groups (means of 14.4 and 16.6 d, respectively; 95% confidence interval for the difference, -4.7 to 0.3 d; P=0.087). Rates of death before hospital discharge were not significantly different between the albuterol and placebo groups (23.0 and 17.7%, respectively; 95% confidence interval for the difference, -4.0 to 14.7%; P=0.30). In the subset of patients with shock before randomization, the number of ventilator -free days was lower with albuterol, although mortality was not different. Overall, heart rates were significantly higher in the albuterol group by approximately 4 beats/minute in the first 2 days after randomization, but rates of new atrial fibrillation (10% in both groups) and other cardiac dysrhythmias were not significantly different.
CONCLUSIONS: These results suggest that aerosolized albuterol does not improve clinical outcomes in patients with ALI. Routine use of beta 2-agonist therapy in mechanically ventilated patients with ALI cannot be recommended. (National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, et al. 201114
The potential value of aerosolized beta 2-agonist therapy for treatment of acute lung injury has not been tested previously in a phase III, randomized clinical trial. The results of this randomized double-blind clinical trial demonstrate that aerosolized b2-agonist therapy with albuterol did not improve clinical outcomes in patients with acute lung injury. However, the majority of animal studies of ALI demonstrating a benefit used beta2-agonists as a pre-injury treatment. Though treatment role of beta-agonists for ALI has not been proved, the potential role in the prophylactic setting is expected. Several studies are ongoing to investigate this possibility.
3. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA 2011;306:1574-8115
CONTEXT: The omega-3 (n-3) fatty acids docosahexaenoic acid and eicosapentaenoic acid, along with gamma-linolenic acid and antioxidants, may modulate systemic inflammatory response and improve oxygenation and outcomes in patients with acute lung injury.
OBJECTIVE: To determine if dietary supplementation of these substances to patients with acute lung injury would increase ventilator-free days to study day 28.
DESIGN, SETTING, AND PARTICIPANTS: The OMEGA study, a randomized, double-blind, placebo-controlled, multicenter trial conducted from January 2, 2008, through February 21, 2009. Participants were 272 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. All participants had complete follow-up. Twice-daily enteral supplementation of n-3 fatty acids, gamma-linolenic acid, and antioxidants compared with an iso-caloric control. Enteral nutrition, directed by a protocol, was delivered separately from the study supplement.
MAIN OUTCOME MEASURE: Ventilator-free days to study day 28.
RESULTS: The study was stopped early for futility after 143 and 129 patients were enrolled in the n-3 and control groups. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, patients receiving the n-3 supplement had fewer ventilator-free days (14.0 vvs 17.2; P = .02) (difference, -3.2 [95% CI, -5.8 to -0.7]) and intensive care unit-free days (14.0 vs 16.7; P = .04). Patients in the n-3 group also had fewer nonpulmonary organ failure-free days (12.3 vs 15.5; P = .02). Sixty-day hospital mortality was 26.6% in the n-3 group vs 16.3% in the control group (P = .054), and adjusted 60-day mortality was 25.1% and 17.6% in the n-3 and control groups, respectively (P = .11). Use of the n-3 supplement resulted in more days with diarrhea (29% vs 21%; P = .001).
CONCLUSIONS: Twice-daily enteral supplementation of n-3 fatty acids, gamma-linolenic acid, and antioxidants did not improve the primary end point of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful. (Rice et al. 201115
Because artificial nutrition showed potential effects on clinical outcomes in critically ill patients during the last decade, nutrition is now considered therapy not supportive care16
. Therefore, it was unexpected and disappointing that enrollment was suspended early in the OMEGA trial because of perceived futility. There are several possible explanations for these negative results. For example, although all patients in the OMEGA trial received a similar number of calories (but by design a different composition of lipids), the control group received up to 20 g of additional protein per day from the control solution. Delivery of a different amount of protein perhaps favorably influenced outcomes in that group. An alternative explanation is that because continuous administration of these supplements appeared beneficial in prior trials, perhaps the bolus delivery method used in this trial blunted the inflammation modulation effect.