Treatment of Lactic Acidosis with Dichloroacetate in Dogs

Abstract

A B S T R A C T Lactic acidosis is a clinical condition due to accumulation of H+ ions from lactic acid, characterized by blood lactate levels >5 mM and arterial pH <7.25. In addition to supportive care, treatment usually consists of intravenous NaHCO3, with a resultant mortality >60%. Dichloroacetate (DCA) is a compound that lowers blood lactate levels under various conditions in both man and laboratory animals. It acts to increase pyruvate oxidation by activation of pyruvate dehydrogenIse. We evaluated the effects of DCA in the treatment of two different models of type B experimental lactic acidosis in diabetic dogs: hepatectomy-lactic acidosis and phenformin-lactic acidosis. The metabolic and systemic effects examined included arterial blood pH and levels of bicarbonate and lactate; the intracellular pH (pHi) in liver and skeletal muscle; cardiac index, arterial blood pressure and liver blood flow; liver lactate uptake and extrahepatic splanchnic (gut) lactate production; and mortality. Effects of DCA were compared with those of either NaCl or NaHCO3. The infusion of DCA and NaHCO3, delivered equal amounts of volume and sodium, although the quantity of NaHCO3 infused (2.5 meq/kg per h) was insufficient to normalize arterial pH.In phenformin-lactic acidosis, DCA-treated animals had a mortality of 22%, vs. 89% in those treated with NaHCO3. DCA therapy increased arterial pH and bicarbonate, liver pHi and cardiac index, with increased This work was presented in part at

Effects of dichloroacetate in the treatment of hypoxic lactic acidosis in dogs.

“…4). Similar findings have been obtained in the diabetic dog (20) and in dogs with phenformin lactic acidosis (14), and it has been suggested that the pyruvate dehydrogenase complex in gut may be fundamentally different from skeletal muscle (21).…”

“…The abdomen was opened via a midline abdominal incision and teflon cannulas were placed in the aorta (Ao) via the femoral artery (FA), in the hepatic portal vein (HPV) via a branch of the splanchnic vein, and in the hepatic vein (HV) via the jugular vein. Blood flow to liver, extrahepatic splanchnic tissues (gut) and skeletal muscle (carcass) was measured by flow measurements in the appropriate vessels as previously described (12)(13)(14). Cardiac output was measured by the thermodilution technique and mean aortic blood pressure was monitored via a catheter through the FA ( 13).…”

Dichloroacetate inhibits glycolysis and augments insulin-stimulated glycogen synthesis in rat muscle.

“…The physiologic significance ofthe decrease in muscle glucose uptake that we found is unclear because the blood glucose of animals or humans given DCA is unchanged or decreased (1,2,8,(28)(29)(30). The hypoglycemic effect ofDCA has been attributed to direct inhibition of hepatic gluconeogenesis (31,32) and to decreased net release ofgluconeogenic precursors from peripheral tissues (28,30,31,33).…”

“…Dichloroacetate (DCA)' has been used to lower the blood lactate concentration in humans and experimental animals with lactic acidosis (1)(2)(3)(4). This effect has been attributed to stimulation of pyruvate dehydrogenase activity, resulting in increased lactic acid oxidation (5)(6)(7).…”

“…This effect has been attributed to stimulation of pyruvate dehydrogenase activity, resulting in increased lactic acid oxidation (5)(6)(7). But, after examining the effects of DCA in hepatectomized dogs with lactic acidosis, Park and Arieff (2) concluded that DCA must have reduced lactate production in extrasplanchnic tissues. More recently, Graf et al.…”