Treatment of porcine sepsis with high-dose antithrombin III reduces tissue edema and effusion but does not increase risk for bleeding.
We evaluated the effectiveness of antithrombin III (AT III) infusions designed to achieve supraphysiologic plasma levels of this serine protease inhibitor in preventing vascular permeability and disseminated intravascular coagulation in a pig model of sepsis. In addition, we determined whether high AT III doses were associated with increased bleeding risk. Sepsis was induced in 18 pigs by injection of lipopolysaccharide (LPS) (0.25 microg/kg per h for 3 h). At 90 min after the start of LPS infusion, pigs were randomized (n = 6 per group) to receive either human serum albumin as a placebo, AT III 120/5 (120 U/kg, 30-min bolus + 5 U/kg per h for 240 min), or AT III 250/10 (250 U/kg + 10 U/kg per h). Three additional animals served as negative controls (no LPS, no AT III). Treatment with AT III significantly reduced the amount of effluents in body cavities and fibrin monomers. AT III did not significantly increase bleeding risk as determined by organ hemorrhage. An additional assessment of AT III's bleeding risk [skin bleeding time (SBT)] was carried out in 35 nonseptic pigs treated with either AT III alone (120/5 or 250/10) or in the combination with heparin. Heparin administration alone produced a dose-dependent increase in SBT, but AT III alone did not. Addition of AT III 120/5 to heparin did not induce a further increase in bleeding time over heparin alone. These results indicate that administration of AT III in doses designed to achieve very high plasma concentrations significantly ameliorates symptoms of sepsis-induced vascular leakage and disseminated intravascular coagulation without increasing bleeding risk.
Dickneite
G
G
Pharmacology & Toxicology, Aventis Behring GmbH, Marburg, Germany. Gerhard.Dickneite@aventis.com
Kroez
M
M
D000818:Animals; D000990:Antithrombin III / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001760:Bleeding Time; D002199:Capillary Permeability; D004211:Disseminated Intravascular Coagulation / Q000188:drug therapy; D004487:Edema / Q000188:drug therapy*; D005122:Exudates and Transudates; D006470:Hemorrhage / Q000209:etiology*; D006493:Heparin / Q000008:administration & dosage; D007700:Kinetics; D008070:Lipopolysaccharides; D008297:Male; D009919:Orchiectomy; D010976:Platelet Count; D012307:Risk Factors; D018805:Sepsis / Q000188:drug therapy* / Q000209:etiology; D013552:Swine
D008070:Lipopolysaccharides; D000990:Antithrombin III; D006493:Heparin