The activity of tissue factor pathway inhibitor in experimental models of superantigen-induced shock and polymicrobial intra-abdominal sepsis

Objectives: To study recombinant human tissue factor pathway inhibitor (rhT FPI) in a superantigen-induced shock model and in a cecal ligation and punc ture (CLP) model of peritonitis in mice. Design: Prospective, randomized, experimental study. Setting: An experimental animal research laboratory. Subjects: Eighty BALB/c mice for the superantigen model, and 56 BALB/c mice for the CLP model. Interventions: In the superantigen-induced shock model, animals received rh TFPI (350 mg/kg) subcutaneously every 12 hrs (n = 30) or saline control (n = 30) for 60 hrs after staphylococcal enterotoxin B (SEB; 10 mug iv) and a sublethal dose of E. coli 0111:B4 lipopolysaccharide (LPS; 75 mug ip). Cont rol groups received SEB alone (n = 10) and LPS alone (n = 10). In the CLP m odel, rhTFPI or saline was given every 8 hrs for 48 hrs by using a 21-gauge needle (n = 9) or 23-gauge needle (n = 14) for CLP. A sham surgery control group (n = 10) was also included. Measurements and Main Results: There was 0% mortality in the SEB and LPS co ntrol groups. The mortality rate was 64% in the saline control group that r eceived both SEB and LPS (19 of 30), whereas the rhTFPI-treated animals had a mortality rate of 20% (6 of 30; p < .01). The rhTFPI-treated group had s ignificantly lower interleukin-6 levels (61.8 +/- 41 pg/mL vs. 285 +/- 63 p g/mL; p < .05) than the control group but no differences in tumor necrosis factor-alpha or interferon-gamma levels. In the CLP experiment, rhTFPI-treated animals did not have any survival adv antage over the control group after the large-bore (21-gauge) needle punctu re. The rhTFPI group had significantly improved 7-day mortality rate after CLP with the small-bore needle (23-gauge; 21.4% [rhTFPI] vs. 71.4% [control ], p < .01). Plasma LPS, interleukin-6, interferon-<gamma>, and tumor necro sis factor-alpha levels were unchanged by rhTFPI treatment, but significant ly reduced LPS (p = .006) and IFN gamma (p = .001) levels were found in the peritoneal fluid. Conclusions:Tissue factor pathway inhibitor significantly improves the mort ality rate in models of superantigen-induced shock and polymicrobial intra- abdominal infection, supporting its potential use in clinical trials for se ptic shack.