A Rat Model of Early Sepsis: Relationships between Gentamicin Pharmacokinetics and Systemic and Renal Effects of Bacterial Lipopolysaccharide Combined with Interleukin-2

抄録

A rat model of early sepsis induced by lipopolysaccharide (LPS) combined with interleukin-2 (IL-2) was developed. The primary aim was to assess the pharmacokinetics of gentamicin and sepsis-induced pathophysiological changes. Moreover, the effects on the glomerular filtration rate and tubular function were studied in septic and control rats. First, an intravenous (i.v.) bolus of LPSIL-2 (1 mg/kg-Pseudomonas aeruginosa, 15 µg/kg IL-2) or saline (controls, C) was administred. The Wistar rats were treated 30 min after LPSIL-2 with gentamicin as a 3 mg/kg i.v. bolus followed 10 min later by an i.v. 170-min infusion (GE, 0.09 mg/kg·min⁻¹). The monitoring of vital functions, biochemistry and GE concentrations was performed. Creatinine clearance was 2–3 times lower and fractional urea excretion was 3–4 times less in septic rats as compared to controls(p<0.05), although urine flow was comparable. Capillary leakage caused a 55% elevation in the volume of distribution (V_c) in the LPSIL+GE group vs. C+GE (p<0.05). The renal CL_ge was less (2.2±0.59 vs. 3.8±0.53 mL/min·kg⁻¹, p<0.05), while the total CL_ge was comparable (5.9±1.5 vs. 6.7±1.1 mL/min·kg⁻¹; p=0.30). In the LPSIL+GE group relative to C+GE, the half-life (t_1/2) was 79% higher (p<0.05) and GE concentrations detected at the end of the study in the plasma and kidney were elevated 2.5-fold (p=0.09) and 2.2-fold (p<0.05), respectively. The model reproduced several consequences of early sepsis like in patients such as capillary leak, a decreased glomerular filtration rate (GFR) and the changes in pharmacokinetics of GE (increased values of V_c and t_1/2 and a drop in renal CL_ge proportional to that of CL_cr). Nonrenal routes which, for the most part, compensate the reduced renal CL_ge in septic rats deserve further study.