Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study

Crit Care Med. 2004 Aug;32(8):1695-702. doi: 10.1097/01.ccm.0000133332.48386.85.


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

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 Pao2/Fio2, 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 ventilator-free days in a heterogeneous acute lung injury patient population managed with low tidal volume mechanical ventilation.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Australia / epidemiology
  • Belgium / epidemiology
  • Canada / epidemiology
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Glycine / administration & dosage*
  • Glycine / adverse effects
  • Glycine / analogs & derivatives*
  • Guideline Adherence / statistics & numerical data
  • Humans
  • Infusions, Intravenous
  • Leukocyte Elastase / antagonists & inhibitors*
  • Leukocyte Elastase / blood
  • Male
  • Middle Aged
  • New Zealand / epidemiology
  • Outcome and Process Assessment, Health Care
  • Prospective Studies
  • Respiration, Artificial / statistics & numerical data
  • Respiratory Distress Syndrome / drug therapy*
  • Respiratory Distress Syndrome / mortality*
  • Serine Proteinase Inhibitors / administration & dosage*
  • Spain / epidemiology
  • Sulfonamides / administration & dosage*
  • Sulfonamides / adverse effects
  • Survival Analysis
  • Tidal Volume
  • Time
  • Treatment Outcome
  • United States / epidemiology


  • Serine Proteinase Inhibitors
  • Sulfonamides
  • sivelestat
  • Leukocyte Elastase
  • Glycine