The use of dichloroacetate in the treatment of overwhelming hypoxic acidosis

Abstract

Overwhelming hypoxic acidosis due to poor tissue oxygen delivery from low cardiac output, pulmonary failure, and other causes has devastating effects postoperatively on patient outcome. Whereas conventional therapeutics often can not reverse the downward spiral of these patients, dichloroacetate (DCA) has been shown to be beneficial. This study investigated the metabolic and hemodynamic effects of DCA given after the onset of overwhelming hypoxic acidosis in a canine model. A hypoxically ventilated canine model of severe induced acidosis was established and dogs surviving the development of acidosis were randomized to receive DCA or sodium chloride (NaCI) treatment. Dogs receiving DCA after development of hypoxic lactic acidosis showed no further change in metabolic parameters during the 90-minute treatment period (pH, 7.24 to 7.23; HC0 3, 17.7 to 18 mmol/L; lactate, 2.04 to 1.05 mM/L); whereas animals receiving an equivalent sodium load showed progressive, significant deterioration in all parameters (pH, 7.24 to 7.12; HCO 3, 16.8 to 13.2 mM/L; lactate, 2.05 to 3.55 mM/L). Myocardial blood flow was significantly increased by hypoxia in all dogs. Finally, cardiac output and stroke volume were significantly increased at 90 minutes by DCA versus control. Myocardial oxygen utilization efficiency (LV work/ M VO 2) was improved during DCA treatment. DCA, a carboxylic acid, increases pyruvate dehydrogenase activity, thereby enhancing lactate use as a metabolic substrate. DCA had an ameliorative metabolic effect, and benefitted myocardial performance without a direct inotropic effect. DCA treatment appears to enhance myocardial performance on a metabolic and not primarily inotropic basis, does not increase the “cost” of myocardial work, and warrants further study.