title: The individual survival benefits of tumor necrosis factor soluble receptor and fluid administration are not additive in a rat sepsis model.
abstract: BACKGROUND
  Tumor necrosis factor (TNF) antagonists [e.g., TNF soluble receptor (TNFsr)] improved survival in preclinical but not clinical sepsis trials. However fluid support-itself beneficial-is standard clinically but rarely employed in preclinical sepsis models. We hypothesized that these therapies may not have additive benefit.
  
  
  RESULTS
  Antibiotic-treated rats (n = 156) were randomized to intratracheal or intravenous Escherichia coli challenges (>LD50) and either placebo or TNFsr and 24 h fluid treatments alone or together. The survival effects of these therapies did not differ significantly comparing challenge routes. When averaged across route, while TNFsr or fluid alone decreased the hazard ratio of death significantly [ln ± standard error (SE): -0.65 ± 0.30 and -0.62 ± 0.30, respectively, p ≤ 0.05], together they did not (p = 0.16). Furthermore, the observed effect of TNFsr and fluid together on reducing the hazard ratio was significantly less than estimated (-0.37 ± 0.29 versus -1.27 ± 0.43, respectively, p = 0.027) based on TNFsr and fluid alone. While each treatment increased central venous pressure at 6 and 24 h, the observed effects of the combination were also less than estimated ones (p ≤ 0.0005).
  
  
  CONCLUSIONS
  The individual survival benefits of TNFsr and fluids were not additive in this rat sepsis model. Investigating new sepsis therapies together with conventional ones during preclinical testing may be informative.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Building 10, Room 2C145, Bethesda, MD 20892, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Qiu
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: Jia
authors.initials: J
authors.lastname: Weng
authors.forename: Steven M
authors.initials: SM
authors.lastname: Banks
authors.forename: Steven
authors.initials: S
authors.lastname: Kern
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Fitz
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Suffredini
authors.forename: Peter Q
authors.initials: PQ
authors.lastname: Eichacker
authors.forename: Xizhong
authors.initials: X
authors.lastname: Cui
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D005440:Fluid Therapy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors*; D018805:Sepsis / Q000401:mortality* / Q000628:therapy*; D015996:Survival Rate
chemical_list: D018124:Receptors, Tumor Necrosis Factor