title: Randomized, blinded, placebo-controlled trial of tissue factor pathway inhibitor in porcine septic shock.
abstract: This study tested the hypothesis that tissue factor pathway inhibitor (TFPI) would improve mortality and morbidity evoked by peritonitis-induced bacteremia in pigs. Secondarily, it sought to determine if TFPI treatment would attenuate cardiodynamic abnormalities produced by this septic model. 32 pigs were chronically instrumented with intracardiac transducers to measure left ventricular pressure and diameter, pulmonary and aortic pressures, and cardiac output. At least 5 days after surgery to implant transducers, basal cardiovascular readings and blood samples were obtained. Using a randomized, blinded study design, either purified, reconstituted TFPI (1 mg/kg bolus, 10 mg/kg/min for 48 h), placebo (arginine buffer), or saline was administered to pigs immediately after Escherichia coli 0111.B4 (3.0-11 x 10(9) colony-forming U/kg)-laden fibrin clots were implanted intraperitoneally, producing peritonitis and bacteremia. Pigs did not receive antibiotics or supportive therapy. No significant differences in primary or secondary endpoints were noted between the arginine and saline groups, so these data were combined into a control group (N = 20). 5 of 12 TFPI pigs survived (42%), while 5 of 20 control pigs survived (25%); this difference was not significant (p = .714, Fisher's exact test). TFPI treatment augmented cardiac output in surviving pigs, but did not affect any other cardiovascular performance variable (heart rate, % diameter shortening, or systemic and pulmonary vascular resistance). In controls, peritonitis induced rapid increase in plasma tumor necrosis factor-alpha (428 +/- 771 to 5,933 +/- 559 pg/mL at 2 h) and interleukin-8 (180 +/- 153 to 1,393 +/- 145 pg/mL at 2 h). TFPI treatment significantly attenuated cytokine responses to sepsis, reducing peak tumor necrosis factor-alpha to 2,103 +/- 813 pg/mL and reducing peak interleukin-8 levels to 534 +/- 211 pg/mL at 2 h (p < .05, Tukey test, two-way ANOVA). In conclusion, TFPI treatment attenuated important mediator components of the inflammatory response but did not provide significant survival benefit.
authors.affiliation: Department of Medicine, Rush Presbyterian St. Luke's Medical Center, Chicago, Illinois 60612, USA. rgoldfar@rush.edu
authors.forename: R D
authors.initials: RD
authors.lastname: Goldfarb
authors.forename: D
authors.initials: D
authors.lastname: Glock
authors.forename: K
authors.initials: K
authors.lastname: Johnson
authors.forename: A A
authors.initials: AA
authors.lastname: Creasey
authors.forename: C
authors.initials: C
authors.lastname: Carr
authors.forename: R J
authors.initials: RJ
authors.lastname: McCarthy
authors.forename: M
authors.initials: M
authors.lastname: Matushek
authors.forename: I
authors.initials: I
authors.lastname: Akhter
authors.forename: G
authors.initials: G
authors.lastname: Trenholme
authors.forename: J E
authors.initials: JE
authors.lastname: Parrillo
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D016209:Interleukin-8 / Q000097:blood; D008074:Lipoproteins / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D010919:Placebos; D011897:Random Allocation; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality*; D016037:Single-Blind Method; D015996:Survival Rate; D013552:Swine; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D016209:Interleukin-8; D008074:Lipoproteins; D010919:Placebos; D014409:Tumor Necrosis Factor-alpha; C051928:lipoprotein-associated coagulation inhibitor