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

AbstractOBJECTIVE:
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 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.
AuthorsBernhardt G Zeiher, Antonio Artigas, Jean-Louis Vincent, Alexei Dmitrienko, Kimberley Jackson, B Taylor Thompson, Gordon Bernard, STRIVE Study Group
JournalCritical care medicine (Crit Care Med) Vol. 32 Issue 8 Pg. 1695-702 (Aug 2004) ISSN: 0090-3493 [Print] United States
PMID15286546 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial)
Chemical References
  • Serine Proteinase Inhibitors
  • Sulfonamides
  • sivelestat
  • Leukocyte Elastase
  • Glycine
Topics
  • Australia (epidemiology)
  • Belgium (epidemiology)
  • Canada (epidemiology)
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Glycine (administration & dosage, adverse effects, analogs & derivatives)
  • Guideline Adherence (statistics & numerical data)
  • Humans
  • Infusions, Intravenous
  • Leukocyte Elastase (antagonists & inhibitors, 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, mortality)
  • Serine Proteinase Inhibitors (administration & dosage)
  • Spain (epidemiology)
  • Sulfonamides (administration & dosage, adverse effects)
  • Survival Analysis
  • Tidal Volume
  • Time
  • Treatment Outcome
  • United States (epidemiology)

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