title: Early drotrecogin alpha (activated) administration in severe sepsis is associated with lower mortality: a retrospective analysis of the Canadian ENHANCE cohort.
abstract: BACKGROUND
  Early multimodal treatment of severe sepsis, including the use of drotrecogin alfa (activated) (DrotAA) when indicated, is considered essential for optimum outcome. However, predicting which infected patients will progress to severe sepsis and the need for aggressive intervention continues to be problematic. We therefore wished to explore whether there were any potential early markers that might predict improved survival in response to early use of DrotAA in patients with severe sepsis. In particular, in the dynamic setting of severe sepsis, we postulated that changes in markers reflecting evolving rather than baseline clinical status might guide therapy.
  
  
  METHODS
  Data on a cohort of 305 Canadian patients from the open label ENHANCE trial of DrotAA in severe sepsis was retrospectively analyzed to search for potential clinical predictors of outcome in severe sepsis. Patients received a 96-hour infusion of DrotAA and were followed for 28 days. The association between time to treatment and mortality within subgroups defined by dynamic changes in various potential markers was explored.
  
  
  RESULTS
  Mortality at 28 days was 22.6% and the variables of age, time to treatment, and early changes in serum creatinine and platelet count were identified by logistic regression as independent predictors of mortality. Across all age ranges, 28-day mortality was lower when DrotAA was administered within 24 hours of first sepsis-induced organ dysfunction compared to administration after 24 hours for both subgroups of patients defined by changes in platelet count and creatinine within the first day.
  
  
  CONCLUSIONS
  These findings suggest that when indicated, treatment with DrotAA should be initiated as soon as possible, regardless of age.
  
  
  BACKGROUND
  Previous trial registration number: NCT00568893.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Ottawa, The Ottawa Hospital, Ottawa, ON, Canada. rhodder@ottawahospital.on.ca
authors.forename: Richard V
authors.initials: RV
authors.lastname: Hodder
authors.forename: Richard
authors.initials: R
authors.lastname: Hall
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.forename: Harold N
authors.initials: HN
authors.lastname: Fisher
authors.forename: Bobbie
authors.initials: B
authors.lastname: Lee
mesh_terms: D000368:Aged; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D002170:Canada / Q000453:epidemiology; D018450:Disease Progression; D005260:Female; D006305:Health Status Indicators; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D011486:Protein C / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012189:Retrospective Studies; D018805:Sepsis / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D000890:Anti-Infective Agents; D015415:Biomarkers; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated