Amelioration of lactic acidosis with dichloroacetate during liver transplantation in humans

Abstract

Background: Marked lactic acidosis occurs during orthotopic liver transplantation (OLT), especially during the anhepatic phase. Current standard therapy is NaHCO3, although it may exacerbate intracellular acidosis, increase plasma lactate, and contribute to hypernatremia. Alternatively, dichloroacetate (DCA) stimulates pyruvate oxidation in vivo, reduces plasma lactate, and moderates intracellular acidosis. The aims of this study were to test the efficacy of DCA to control lactic acidosis, reduce the NaHCO3 requirement and incidence of hypernatremia, and stabilize perioperative acid-base homeostasis. Others aims were to examine the DCA pharmacokinetic profile during OLT and the role of lactate metabolism in OLT- associated hyperglycemia. Methods: Patients (n = 66) for OLT were divided into two equal groups to receive or not receive DCA during OLT. DCA 40 mg · kg-1 was infused over 60 min after induction of anesthesia and 4 h later. Plasma DCA concentration was measured by gas chromatography-mass spectroscopy, and pharmacokinetics were assessed by a one-compartment model. Serial arterial blood gases, lactate, Na+, glucose, and hemodynamic measurements were compared, as were intraoperative utilization of blood products, CaCl2, and NaHCO3. Results: Plasma DCA concentration was maintained between 0.28 and 1.18 mM during OLT, with peak concentrations of 0.73 ± 0.06 (mean ± SE) and 1.18 ± 0.09 mM, respectively after the first and second doses. In control patients, plasma lactate was 1.07 ± 0.04 at baseline and 1.20 ± 0.06 before incision and reached a peak of 7.30 ± 0.41 mM after graft reperfusion. In DCA-treated patients, the respective values were 1.07 ± 0.06 (difference not significant), 0.63 ± 0.05 (P < 0.001), and 3.39 ± 0.20 (P < 0.001) mM. Intraoperative changes in arterial blood pH, HCO3-1, and base excess were comparable though less marked in DCA-treated patients, whose NaHCO3 requirement was reduced (0.59 ± 0.36 vs. 2.83 ± 0.53 mEq · kg-1 in control patients, P < 0.001). There was no difference between groups in requirements for CaCl2 or blood products, in intraoperative hemodynamics, in duration of the surgical stages, or in graft ischemia times. Twelve control and 4 DCA-treated patients exhibited a plasma Na+ concentration > 145 mEq/l at completion of surgery (P < 0.05). Hyperglycemia was not attenuated by DCA despite decreased plasma lactate concentration. Sixteen and 28 h after graft reperfusion, when plasma DCA had been eliminated, plasma lactate and degree of metabolic alkalosis did not differ between groups. Conclusions: DCA safely and effectively attenuated lactic acid accumulation and moderated acidosis during OLT. DCA decreased the requirement for NaHCO3 therapy and the incidence of hypernatremia. OLT- associated hyperglycemia did not result from lactate-induced stimulation of hepatic gluconeogenesis. Postoperative metabolic alkalosis was not substantially influenced by lactate metabolism.