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Metabolic effects of sodium dichloroacetate in endotoxemic minipigs
Abstract:
Lactic acidosis is significant in the pathophysiology of endotoxicosis. By increasing the activity of pyruvate dehydrogenase, sodium dichloroacetate (DCA) decreases lactate production and may be useful as a therapy for endotoxic shock. Five (n = 5) 50-80-kg Yucatan minipigs were fitted with jugular, portal, hepatic vein, and carotid artery catheters, and hepatic artery and portal vein flow cuffs to quantitate transhepatic kinetics of glucose, lactate, and insulin. Three days later, they were placed in slings, and a primed-continuous intravenous infusion of 3-tritiated glucose was initiated to monitor whole body glucose kinetics. Following a 3-hour control period, an intravenous infusion of E. coli endotoxin (LPS) was administered at 15 micrograms/kg/hr for 6 hours. After 1 hour of LPS infusion, DCA was administered as a primed (30 mg/kg)-continuous (30 mg/kg/hr) intravenous infusion for 5 hours. These DCA-treated endotoxemic minipigs (group DE) were compared statistically to a group (n = 8) of minipigs given endotoxin only (group E). Group DE arterial lactate concentrations eventually decreased (19.2 +/- 1.0 mg/dl) significantly (P less than or equal to 0.05) below group E (39.3 +/- 7.7 mg/dl) in the last hour of DCA infusion. The progressive hypoglycemia of group DE decreased below that of group E and became significantly (P less than or equal to 0.05) lower in the last hour of the experiment (33.6 +/- 11.5 vs 50.6 +/- 10.0 mg/dl, respectively) due to decreased hepatic gluconeogenesis as evidenced by a lower relative rate of appearance (%Ra) of glucose and decreased hepatic glucose output and lactate extraction. A large relative decrease in pancreatic output of insulin in group DE contributed to the lower serum insulin levels than group E throughout the treatment period. Lethality in group DE (60%) was unaltered from that of group E (67%). Despite its ability to decrease arterial lactate concentrations, DCA alone does not appear to be an effective treatment for endotoxicosis.