Effect of endotoxin shock on the clearance of lidocaine and indocyanine green in the perfused rat liver

Endotoxin administration and cecal ligation and puncture produce significan t hepatocellular dysfunction when studied in vivo. Specific factors that ar e present in vivo after endotoxin administration and cecal ligation and pun cture, such as alterations in liver blood flow, circulating mediators, and hypoxia, can alter hepatic function. In this study, we used an isolated per fused liver to evaluate the effects of in vivo administration of endotoxin on hepatic function using indocyanine green (ICG) as a global marker of fun ction and lidocaine and its metabolite, MEGX, as specific markers of the CY P450 enzyme system. Endotoxin (Escherichia coli; 45 mg/kg i.p.) was adminis tered to rats followed by a 6-h monitoring before preparation of the isolat ed in situ perfused liver. Livers from control and endotoxin groups receive d either ICG (control, n = 6; endotoxin, n = 5) or lidocaine (control, n = 8; endotoxin, n = 8). A separate group of rats (n = 6) received cimetidine (an inhibitor of the CYP450 enzyme system) at a dose of 80 mg/kg daily for 3 days. Livers were perfused via the portal vein by using a single-pass sys tem with a balanced salt solution 6 h after receiving either endotoxin or s aline or 24 h after receiving the last dose of cimetidine. After a 40-min s tabilization period, ICG or lidocaine was infused via the portal vein until steady-state concentrations were reached in the venous outflow. The total hepatic clearance and intrinsic hepatic clearance for ICG and lidocaine wer e unchanged in the livers obtained from endotoxin-treated rats. This model could adequately detect CYP450 inhibition because cimetidine-treated rats h ad significantly lower initial MEGX concentrations (0.63 +/- 0.03 mg/L) com pared with control (0.77 +/- 0.03 mg/L) and endotoxin-treated (0.74 +/- 0.0 4 mg/L) rats. Septic livers had significantly higher initial hepatic oxygen consumption (HVO2) than did control livers (45 rc 3 mu L/min/g vs 82 +/- 9 mu L/min/g). The HVO2 remained higher in the septic livers and significant ly increased throughout the study, which demonstrated that the livers remai ned viable and functional. These data indicate that there is no detectable hepatocellular dysfunction after endotoxin shock using ICG, lidocaine, and MEGX in the isolated perfused liver; therefore the dysfunction reported fro m in vivo studies may be reversible when the liver is removed from the shoc ked environment.