title: Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial.
abstract: BACKGROUND
  Activation of the coagulation system and depletion of endogenous anticoagulants are frequently found in patients with severe sepsis and septic shock. Diffuse microthrombus formation may induce organ dysfunction and lead to excess mortality in septic shock. Antithrombin III may provide protection from multiorgan failure and improve survival in severely ill patients.
  
  
  OBJECTIVE
  To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock.
  
  
  METHODS
  Double-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted from March 1997 through January 2000.
  
  
  METHODS
  A total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30 000 IU in total over 4 days) or a placebo (1% human albumin).
  
  
  METHODS
  All-cause mortality 28 days after initiation of study medication.
  
  
  RESULTS
  Overall mortality at 28 days in the antithrombin III treatment group was 38.9% vs 38.7% in the placebo group (P =.94). Secondary end points, including mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin III and placebo groups. In the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n = 698), the 28-day mortality was nonsignificantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (P =.08). This trend became significant after 90 days (n = 686; 44.9% for antithrombin III group vs 52.5% for placebo group; P =.03). In patients receiving antithrombin III and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001).
  
  
  CONCLUSIONS
  High-dose antithrombin III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin.
authors.affiliation: Brown University School of Medicine, Infectious Disease Division, Memorial Hospital of Rhode Island, 111 Brewster St, Pawtucket, RI 02860, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Warren
authors.forename: A
authors.initials: A
authors.lastname: Eid
authors.forename: P
authors.initials: P
authors.lastname: Singer
authors.forename: S S
authors.initials: SS
authors.lastname: Pillay
authors.forename: P
authors.initials: P
authors.lastname: Carl
authors.forename: I
authors.initials: I
authors.lastname: Novak
authors.forename: P
authors.initials: P
authors.lastname: Chalupa
authors.forename: A
authors.initials: A
authors.lastname: Atherstone
authors.forename: I
authors.initials: I
authors.lastname: Pénzes
authors.forename: A
authors.initials: A
authors.lastname: Kübler
authors.forename: S
authors.initials: S
authors.lastname: Knaub
authors.forename: H O
authors.initials: HO
authors.lastname: Keinecke
authors.forename: H
authors.initials: H
authors.lastname: Heinrichs
authors.forename: F
authors.initials: F
authors.lastname: Schindel
authors.forename: M
authors.initials: M
authors.lastname: Juers
authors.forename: R C
authors.initials: RC
authors.lastname: Bone
authors.forename: S M
authors.initials: SM
authors.lastname: Opal
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use*; D000990:Antithrombin III / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology* / Q000517:prevention & control*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D012772:Shock, Septic / Q000150:complications* / Q000188:drug therapy*; D016019:Survival Analysis; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications / Q000188:drug therapy; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control
chemical_list: D000925:Anticoagulants; D015842:Serine Proteinase Inhibitors; D000990:Antithrombin III; D006493:Heparin