Journal
CRITICAL CARE MEDICINE
Volume 39, Issue 5, Pages 1104-1112Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CCM.0b013e31820eb718
Keywords
sepsis; infection; pneumonia; heparin; treatment; metaregression analysis; animal models
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Funding
- National Institutes of Health, Clinical Center
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Introduction: If thrombosis contributes to sepsis, heparin titrated using activated partial thromboplastin times may be efficacious. We investigated heparin in preclinical models. Methods and Main 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. Conclusion: Coagulopathy with sepsis or other variables, such as type of infectious source, may influence the efficacy of heparin therapy for sepsis. (Crit Care Med 2011; 39:1104-1112)
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