Objective: Neutrophil elastase is believed to be an important mediator of acute lung injury. Sivelestat (ONO-5046, Elaspol) is a small molecular weight inhibitor of neutrophil elastase. The primary objectives of this study were to determine whether sivelestat would reduce 28-day all-cause mortality or increase the number of ventilator-free days (days alive and free from mechanical ventilation from day 1 to day 28) compared with placebo in mechanically ventilated patients with acute lung injury. Design: Multiple-center, double-blind, placebo-controlled trial administering a continuous infusion of sivelestat at a dose of 0.16 mg·kg -1 ·hr -1 . Setting: One hundred and five institutions in the United States, Canada, Belgium, Spain, Australia, and New Zealand. Patients: A total of 492 mechanically ventilated patients with acute lung injury. Interventions: Patients were randomized in a 1:1 fashion to sivelestat or placebo. Study drug was administered as a continuous infusion for the duration of mechanical ventilation plus 24 hrs for a maximum of 14 days. All patients were managed using low tidal volume mechanical ventilation. Measurements and Main Results: The study was stopped prematurely at the recommendation of an external Data and Safety Monitoring Board, which noted a negative trend in long-term mortality rate. Final analysis revealed no effect of sivelestat on the primary end points of ventilator-free days (day 1-day 28) or 28-day all-cause mortality. There were 64 deaths in each treatment group within the 28-day study period, and the mean number of ventilator-free days was 11.4 and 11.9 in the sivelestat and placebo treatment groups, respectively (p = .536). There was no evidence of effect on measures of pulmonary function, including Pa0 2 /Fl0 2 , static lung compliance, and time to meeting weaning criteria. There was no difference in adverse events or serious adverse events between treatment groups. A comparison of the Kaplan-Meier 180-day survival curves showed no difference between treatment groups (p = .102), but there was an increase in 180-day all-cause mortality in the sivelestat treatment group compared with the placebo group (p = .006. Conclusions: Intravenous sivelestat had no effect on 28-day all-cause mortality or ventilatar-free days in a heterogeneous acute lung injury patient population managed with low tidal volume mechanical ventilation.
|Journal||Critical Care Medicine|
|Publication status||Published - 1 Aug 2004|
- Acute lung injury
- Acute respiratory distress syndrome
- Mechanical ventilation
- Neutrophil elastase