An improved clinically relevant sepsis model in the conscious rat

Objective: To develop an improved small animal experimental paradigm that m ore closely mimics human sepsis. Design: Prospective, randomized, controlled animal study, Setting: Medical school research laboratory. Subjects: Male Sprague-Dawley rats (280-320 g). interventions: We monitored the hemodynamic, hematologic, and biochemical consequences of abdominal se psis produced by intraperitoneal implantation of a fibrin clot containing E scherichia coli in conscious, antibiotic-treated rats. Measurements and Main Results:Similar to human sepsis, the implanted, infec ted clot (LD50 = 5-7 x 10(8) colony forming units/mL, n = 6) elevated cardi ac index (>7% vs. sterile clot, p < .05, at 4 hrs), whereas mean arterial p ressure and heart rate remained unaffected. The total peripheral resistance index and stroke volume index tended to decrease and increase, respectivel y. in contrast, an intravenous bolus injection of endotoxin (LD50 of E. col i lipopolysaccharide = 5.6 mg/kg, n = 7), the most commonly used sepsis mod el, induced profound hypodynamic responses manifested by a 27% decrease (vs , endotoxin vehicle, p < .01) in cardiac index, a 28% increase in the total peripheral resistance index (p < .01), and a 33% decrease in the stroke Vo lume index (p <.01). The infectious peritonitis model also displayed dose-d ependent thrombocytopenia (<61%, p < .05), leukopenia (<60%, p < .05), and mortality rate (50% at 5-7 x 108 colony forming units/mL, p < .05) with a m inimally elevated serum tumor necrosis factor-alpha level (145 vs. 12 +/- 6 pg/mL in controls, p < .05). Conclusion: This rodent model of antibiotic-treated, intraabdominal infecti on features key characteristics of clinical sepsis. Although the hyperdynam ic response observed in septic patients undergoing resuscitation was not cl early elicited, this paradigm better mimics clinical sepsis compared with t he commonly used endotoxin model. Thus, utilization of this paradigm may pr ovide additional opportunities to explore mechanisms of sepsis and to exami ne novel therapeutics.