Origin of Endotoxemia Influences the Metabolic Response to Endotoxin in Dogs

Abstract

Different routes of endotoxin administration have been used to mimic inflammatory and metabolic responses observed during sepsis. Because the origin of endotoxemia may affect the reactions to endotoxin, we compared the induction of tumor necrosis factor (TNF), interleukin-6 (IL-6), hormones, and glucose production after endotoxin (1.0 μg/kgEscherichia coli0111:B4) administration into a peripheral (n= 8) versus the portal (n= 8) vein in anesthetized dogs. Prior to endotoxin, a laparotomy was performed for cannulation of hepatic vessels. To evaluate the effects of surgery and anesthesia, we also studied the effects of peripheral endotoxin administration in six awake dogs. The rate of appearance of glucose was measured by primed continuous infusion of [6,6-2H2]glucose. In anesthetized dogs, arterial concentrations of TNF and IL-6 increased after endotoxin administration (P< 0.01 vs basal; NS between groups). Net hepatic TNF production was increased after endotoxin administration (peripheral vs portal endotoxin administration: 533 ± 177 vs 2135 ± 1127 ng/min, bothP< 0.05 vs basal; NS between groups). Net hepatic IL-6 production was stimulated only after portal endotoxin delivery (from 86 ± 129 to 4740 ± 1899 ng/min,P< 0.05; NS between groups). Although there were no differences in neuroendocrine activation, portal endotoxin administration resulted in decreased glucose production compared with peripheral administration (13.6 ± 0.9 vs 16.8 ± 1.2 μmol/kg·min,P< 0.05). In contrast to anesthetized dogs, endotoxin increased glucose production considerably in awake dogs from 13.8 ± 1.2 to 24.2 ± 3.2 μmol/kg·min (P< 0.05;P< 0.05 vs anesthetized dogs). The contribution of anesthesia and surgery increased the endotoxin-induced IL-6 response by ∼350% compared with the effect of endotoxin in awake dogs (P< 0.01). In conclusion, there are no major differences in the responses to endotoxin between peripherally treated and portally treated dogs, except for differences in glucose production. Portal delivery compared with systemic delivery of endotoxin alters hepatic metabolism through nonendocrine mechanisms, reflected in decreased glucose production. The inflammatory, endocrine, and metabolic effects of endotoxin are altered by the combination of surgery and anesthesia.