Increase in plasma succinate is associated with aerobic lactate production in a model of endotoxic shock

The Krebs or tricarboxylic acid (TCA) cycle plays a key role in the regulation of immune responses and adaptations to hypoxia that occur during sepsis. Although the concentrations of some of these intermediates have been reported to be increased in large cohorts of septic patients, a detailed analysis of their changes during sepsis is still lacking. Here, we investigated the plasma concentrations of several TCA intermediates in a swine model of endotoxic shock and the relationship between these TCA cycle intermediates and lactate production. Nine female swine were administered lipopolysaccharide to induce endotoxic shock, while four females served as controls. Plasma samples were collected at three time points: baseline, 3 and 6 h after lipopolysaccharide administration. Control samples were collected at parallel time points. Quantification of TCA intermediates, lactate and pyruvate was performed by high-performance liquid chromatography. Oxygen-derived variables were obtained by gas analysis of arterial and venous samples. The endotoxic shock group showed a significant increase in lactate, accompanied by stability of oxygen-derived variables and a low lactate:pyruvate ratio, indicative of aerobic conditions. Of all the TCA intermediates analysed, only citrate and succinate showed significant increases compared with controls. Furthermore, the changes in lactate were determined, in part, by the changes in succinate concentration. The increase in succinate concentrations was associated with the increase in lactate in global aerobic conditions. Our results suggest a potential role for succinate as a biomarker of aerobic lactate production.