The in vivo alterations in organ-specific substrate processing and endogenous mediator production induced by endotoxin were investigated in healthy volunteers. An endotoxin bolus (20 U/kg) produced increased energy expenditure, hyperglycemia, hypoaminoacidemia, and an increase in circulating free fatty acids. These changes included increased peripheral lactate and free fatty acid output, along with increased peripheral uptake of glucose. Coordinately, there were increased splanchnic uptake of oxygen, lactate, amino acids, and free fatty acids, and increased splanchnic glucose output. There were no changes in circulating glucagon, or insulin and transient changes in epinephrine and cortisol were insufficient to explain the metabolic changes. Plasma cachectin levels peaked 90 min after the endotoxin infusion, and hepatic venous (HV) cachectin levels (peak 250±50 pg/ml) were consistently higher than arterial levels (peak 130±30 pg/ml, P < 0.05 vs. HV). No interleukin la or 1,8 was detected in the circulation. Circulating interleukin 6, measured by B.9 hybridoma proliferation, peaked 2 h after the endotoxin challenge (arterial, 16±2 U/ml; HV, 21±3 U/ml). The net cachectin efflux (-7 Mg) from the splanchnic organs demonstrates that these tissues are a major site for production of this cytokine. Hence, splanchnic tissues are likely influenced in a paracrine fashion by regional cachectin production and may also serve as a significant source for systemic appearance of this cytokine.

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Intestinal mucosal atrophy, as induced by total parenteral nutrition (TPN) and/or prolonged bowel rest, is hypothesized to enhance bowel endotoxin (LPS) translocation and may alter host responses to infection. To examine the effect of TPN-induced bowel atrophy on the response to LPS, 12 healthy volunteers were randomized to receive either enteral feedings (ENT, n = 6) or seven days of TPN without oral intake (TPN, n = 6). Enteral or TPN feedings were terminated 12 hours before the study period when a constant dextrose infusion (50 mg/kg/hour) was initiated and continued throughout the subsequent study period. After placement of arterial, hepatic vein, and femoral vein catheters, metabolic parameters were determined before and for six hours after an intravenous E. coli LPS challenge (20 U/kg). Subsequent peak levels of arterial glucagon (ENT, 189 +/- 39 pg/mL; TPN, 428 +/- 48; p less than 0.01), arterial epinephrine (ENT, 236 +/- 52 pg/mL; TPN, 379 +/- 49; p less than 0.05) and hepatic venous cachectin/tumor necrosis factor (cachectin/TNF) (ENT, 250 +/- 56 pg/mL; TPN, 479 +/- 136; p less than 0.05) were significantly higher in the TPN group than in the ENT group. The extremity efflux of lactate (ENT, -16 +/- 4 micrograms/min-100cc tissue; TPN, -52 +/- 13; t = 2 hours; p less than 0.05) and of amino acids (ENT, -334 +/- 77 nmol/min-100cc tissue; TPN, -884 +/- 58; t = 4 hours; p less than 0.05) were higher in the TPN subjects after the endotoxin challenge. Circulating C-reactive Protein (CRP) levels measured 24 hours postendotoxin were also significantly higher in the TPN subjects (ENT, 1.7 +/- 0.2 mg/dL; TPN, 3.2 +/- 0.3; p less than 0.01). Hence the counter-regulatory hormone and splanchnic cytokine responses to LPS were enhanced after TPN and bowel rest. This is associated with a magnified acute-phase response, peripheral amino acid mobilization, and peripheral lactate production. Thus antecedent TPN may influence the metabolic alterations seen in infection and sepsis via both an exaggerated counter-regulatory hormone response as well as an enhanced systemic and splanchnic production of cytokines.