Influence of Antithrombin III on Coagulation and Inflammation in Porcine Septic Shock

Abstract

Abstract —The physiological inhibitor of thrombin, antithrombin III (ATIII, Kybernin P) was investigated for its antiinflammatory and anticoagulant effects in a pig model of septic shock. Pigs were infused with a dose of 0.25 μg · kg −1 · h −1 of lipopolysaccharide (LPS) over a period of 3 hours. Animals developed systemic inflammation, disseminated intravascular coagulation (DIC), organ failure and cardiovascular abnormalities, namely pulmonary hypertension and systemic hypotension. Twenty septic pigs were allocated to 2 study groups, treated either with ATIII (n=10) or placebo (n=10). ATIII was administered as a 250-U/kg IV bolus infusion for 30 minutes (−60 to −30 minutes) followed by a single IV bolus of 125 U/kg (t=0) and a second 30-minute infusion of 250 U/kg (120 to 150 minutes). ATIII significantly prevented the development of a DIC; the increase in fibrin monomers (placebo, 11.4±9.1 reciprocal titers, at 6 hours) was completely overcome by ATIII ( P <0.05). ATIII significantly prevented the increase in thromboxane (TXB 2 ) levels, which were 809±287 pg/mL in the placebo and 420±174 pg/mL in the verum group after 6 hours ( P <0.02). On the other hand, ATIII had no influence on TNF levels. In a lethal study with an increased dose of LPS (0.5 μg · kg −1 · h −1 ). A significant reduction in mortality was observed in the ATIII group (0 of 7) compared with the placebo group (4 of 6) ( P <0.05, χ 2 test) a significant reduction of pulmonary hypertension (placebo, 42.0±11.1 mm Hg; ATIII, 23.6±7.5 mm Hg, P <0.05), but no effect on systemic hypotension, was noted in the ATIII group. It was thus concluded that modulation of the procoagulatory state by substitution of ATIII results in a late beneficial antiinflammatory effect in this model of septic shock.