An improved clinically relevant sepsis model in the conscious rat

Objective: To develop an improved small animal experimental paradigm that more 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 sepsis produced by intraperitoneal implantation of a fibrin clot containing Escherichia coli in conscious, antibiotic-treated rats. Measurements and Main Results: Similar to human sepsis, the implanted, infected clot (LD₅₀ = 5-7 x 10⁸ colony forming units/mL, n = 6) elevated cardiac index (>7% vs. sterile clot, p < .05, at 4 hrs), whereas mean arterial pressure and heart rate remained unaffected. The total peripheral resistance index and stroke volume index tended to decrease and increase, respectively. In contrast, an intravenous bolus injection of endotoxin (LD₅₀ of E. coli lipopolysaccharide = 5.6 mg/kg, n = 7), the most commonly used sepsis model, 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 volume index (p < .01). The infectious peritonitis model also displayed dose- dependent 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 minimally elevated serum tumor necrosis factor-α level (145 vs. 12 ± 6 pg/mL in controls, p < .05). Conclusion: This rodent model of antibiotic- treated, intra-abdominal infection features key characteristics of clinical sepsis. Although the hyperdynamic response observed in septic patients undergoing resuscitation was not clearly elicited, this paradigm better mimics clinical sepsis compared with the commonly used endotoxin model. Thus, utilization of this paradigm may provide additional opportunities to explore mechanisms of sepsis and to examine novel therapeutics.