Endotoxin Tolerance Variation over 24 h during Porcine Endotoxemia: Association with Changes in Circulation and Organ Dysfunction

Endotoxin tolerance (ET), defined as reduced inflammatory responsiveness to endotoxin challenge following a first encounter with endotoxin, is an extensively studied phenomenon. Although reduced mortality and morbidity in the presence of ET has been demonstrated in animal studies, little is known about the temporal development of ET. Further, in acute respiratory distress syndrome ET correlates to the severity of the disease, suggesting a complicated relation between ET and organ dysfunction. Eighteen pigs were subjected to intensive care and a continuous endotoxin infusion for 24 h with the aim to study the time course of early ET and to relate ET to outcome in organ dysfunction. Three animals served as non-endotoxemic controls. Blood samples for cytokine analyses were taken and physiological variables registered every third hour. Production of TNF-alpha, IL-6, and IL-10 before and after endotoxin stimulation ex vivo was measured. The difference between cytokine values after and before ex vivo LPS stimulation (Delta-values) was calculated for all time points. Delta TNF-alpha was employed as the principal marker of ET and lower Delta TNF-alpha values were interpreted as higher levels of ET. During endotoxin infusion, there was suppression of ex vivo productions of TNF-alpha and IL-6 but not of IL-10 in comparison with that at 0 h. The ex vivo TNF-alpha values followed another time concentration curve than those in vivo. Delta TNF-alpha was at the lowest already at 6 h, followed by an increase during the ensuing hours. Delta TNF-alpha at 6 h correlated positively to blood pressure and systemic vascular resistance and negatively to cardiac index at 24 h. In this study a temporal variation of ET was demonstrated that did not follow changes in plasma TNF-alpha concentrations. Maximal ET occurred early in the course and the higher the ET, the more hyperdynamic the circulation 18 h later.