Influence of antithrombin III on coagulation and inflammation in porcine septic shock

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 mu g . kg (-1) . h(-1) of lipopolysaccharide (LPS) over a period of 3 hours. Animals developed systemic inflammation, disseminated intravascular coagulation (DI C), organ failure and cardiovascular abnormalities, namely pulmonary hypert ension and systemic hypotension. Twenty septic pigs were allocated to 2 stu dy groups, treated either with ATIII (n=10) or placebo (n=10). ATIII was ad ministered as a 250-U/kg IV bolus infusion for 30 minutes (-60 to -30 minut es) 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 th e development of a DIG; 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 (TXB2) levels, w hich were 809+/-287 pg/mL in the placebo and 420+/-174 pg/mL in the verum g roup after 6 hours (P<0.02). On the other hand, ATIII had no influence on T NF levels. In a lethal study with an increased dose of LPS (0.5 mu g . 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, chi(2) te st) 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 hypoten sion, was noted in the ATIII group. It was thus concluded that modulation o f the procoagulatory state by substitution of ATIII results in a late benef icial antiinflammatory effect in this model of septic shock.