title: Influence of antithrombin III on coagulation and inflammation in porcine septic shock.
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 microgram. 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 (TXB2) 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 microgram. 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, chi2 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.
authors.affiliation: Centeon Pharma GmbH, 35002 Marburg Medical Clinic, Justus-Liebig-University, 35385 Giebetaen, Germany. Dicknei1@MSMBWMD.Hoechst.com
authors.forename: G
authors.initials: G
authors.lastname: Dickneite
authors.forename: B
authors.initials: B
authors.lastname: Leithäuser
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000032:analysis / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D004211:Disseminated Intravascular Coagulation / Q000517:prevention & control; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy*; D013552:Swine; D013929:Thromboxane B2 / Q000097:blood
chemical_list: D013929:Thromboxane B2; D000990:Antithrombin III