Treatment of porcine sepsis with high-dose antithrombin III reduces tissueedema and effusion but does not increase risk for bleeding

We evaluated the effectiveness of antithrombin III (AT III) infusions desig ned to achieve supraphysiologic plasma levels of this serine protease inhib itor in preventing vascular permeability and disseminated intravascular coa gulation in a pig model of sepsis. In addition, we determined whether high AT III doses were associated with increased bleeding risk. Sepsis was induc ed in 18 pigs by injection of lipopolysaccharide (LPS) (0.25 mug/kg per h f or 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 co ntrols (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 s ignificantly increase bleeding risk as determined by organ hemorrhage. An a dditional assessment of AT III's bleeding risk [skin bleeding time (SBT)] w as 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 alon e produced a dose-dependent increase in SBT, but AT III alone did not. Addi tion of AT III 120/5 to heparin did not induce a further increase in bleedi ng time over heparin alone. These results indicate that administration of A T III in doses designed to achieve very high plasma concentrations signific antly ameliorates symptoms of sepsis-induced vascular leakage and dissemina ted intravascular coagulation without increasing bleeding risk. (C) 2001 Li ppincott Williams & Wilkins.