title: The effect of heparin administration in animal models of sepsis: a prospective study in Escherichia coli-challenged mice and a systematic review and metaregression analysis of published studies.
abstract: BACKGROUND
  If thrombosis contributes to sepsis, heparin titrated using activated partial thromboplastin times may be efficacious. We investigated heparin in preclinical models.
  
  
  RESULTS
  In unchallenged mice (n = 107), heparin at 100, 500, or 2500 units/kg produced activated partial thromboplastin time levels less than, within, or greater than a prespecified therapeutic range (1.5-2.5 times control), respectively. In animals (n = 142) administered intratracheal Escherichia coli challenge, compared to placebo treatment, heparin at 100, 500, or 2500 units/kg were associated with dose dependent increases in the hazard ratios of death (hazard ratio [95% confidence interval]: 1.08 [0.66, 1.76]; 1.34 [0.80, 2.24]; 3.02 [1.49, 6.10], respectively) (p = .001 for the dose effect). Compared to normal saline challenge, E. coli without heparin (i.e., with placebo) increased the activated partial thromboplastin time (p = .002) close to the therapeutic range. While heparin at 100 and 500 units/kg with E. coli further increased activated partial thromboplastin time (p < .0001 vs. placebo) within or above the therapeutic range, respectively, these did not decrease inflammatory cytokines or lung injury. In metaregression analysis of published preclinical studies, heparin improved survival with lipopolysaccharide (n = 23, p < .0001) or surgically induced infection (n = 14, p < .0001) but not monobacterial (n = 7, p = .29) challenges.
  
  
  CONCLUSIONS
  Coagulopathy with sepsis or other variables, such as type of infectious source, may influence the efficacy of heparin therapy for sepsis.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Sun
authors.forename: Xizhong
authors.initials: X
authors.lastname: Cui
authors.forename: Haresh
authors.initials: H
authors.lastname: Mani
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
authors.forename: Xuemei
authors.initials: X
authors.lastname: Li
authors.forename: Jun-Wu
authors.initials: JW
authors.lastname: Su
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Fitz
authors.forename: Peter Q
authors.initials: PQ
authors.lastname: Eichacker
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D006493:Heparin / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010314:Partial Thromboplastin Time; D011897:Random Allocation; D012016:Reference Values; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality*; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D006493:Heparin