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PHARMACOKINETICS AND METABOLIC EFFECTS OF DICHLOROACETATE IN PATIENTS UNDERGOING CARDIAC SURGERY WITH CARDIOPULMONARY BYPASS

Shangraw, RE MD, PhD; Davis, RF MD

doi: 10.1097/00000539-199802001-00100
Abstracts of Posters Presented at the International Anesthesia Research Society; 72nd Clinical and Scientific Congress; Orlando, FL; March 7-11, 1998: Cardiovascular Anesthesia
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Department of Anesthesthesiology., Oregon Health Sciences University and VAMC, Portland, OR 97201.

Abstract S100

Cardiopulmonary bypass (CPB) has been associated with development of systemic type B lactic acidosis. [1] Further, recovery of cardiac mechanical function after ischemia is compromised by the inhibition of pyruvate dehydrogenase (PDH), an enzyme which catalyzes pyruvate oxidation and limits accumulation of lactic acid. [2] We have previously found that the type B lactic acidosis during orthotopic liver transplantation (OLT) is effectively attenuated by dichloroacetate (DCA), which acts by stimulating PDH activity. [3] By stimulating glucose oxidative flux DCA improves mechanical function of the isolated post-ischemic heart. [2] This study was designed to determine the pharmacokinetics and metabolic effects of DCA during cardiac surgery in humans.

Methods: The protocol was approved by the FDA (IND #35,790); and Portland VAMC IRB. After written informed consent, 26 patients for CABG/valve or re-do CABG were randomized to receive either DCA or placebo DCA (50 mg/kg iv over 30 min) was infused after anesthesia induction, and again (30 mg/kg over 30 min) at 180 min Serial arterial blood samples were taken to determine pH, [HCO3], base excess, [glucose], [lactate] and [DCA]. [DCA] was assayed by gas chromatography-mass spectroscopy. [3] Data were analyzed by ANOVA or unpaired t-test.

Results: Peak [DCA] was 204 +/- 31 (SE) and 176 +/- 25 [micro sign]g/ml after the first and second DCA doses, resp. CBP time was 177 +/- 12 and 154 +/- 11 min in control and DCA-treated patients, resp. Arterial [lactate] rose from a preinduction baseline of 0.639 +/- 0.081 to 2.62 +/- 0.46 mM at 15 min after separation from CPB. Corresponding [lactate] values for DCA-treated patients were 0.820 +/- 0.050 mM (ND) and 1.64 +/- 0.31 mM (p<0.05). Base excess decreased from 1.4 +/- 0.6 mEq/l to a nadir of -1.0 mEq/l during CPB in controls, and from 1.8 +/- 0.6 mEq/l to -1.4 +/- 0.5 during CPB with DCA (ND). Intraoperative NaHCO3 consumption did not differ between groups (74 +/- 16 vs 60 +/- 20 mEq, resp). Baseline [glucose] was 94 +/- 6 mg/dl and increased to 178 +/- 24 mg/dl at the end of CPB in controls. Corresponding values in DCA-treated patients were 99 +/- 9 and 179 +/- 21 mg/dl, resp (ND)

Discussion: DCA was well-tolerated in all patients. Safe and predictable plasma [DCA] can be achieved in patients undergoing cardiac surgery with prolonged CPB. DCA reduces [lactate] in part by increasing myocardial lactate uptake. [2] Lactic acidosis was modest in controls, and DCA had no appreciable effect on acid-base homeostasis. Further work is warranted to assess the positive inotropic effect of DCA in cardiac surgery patients, and to identify a possible subset of these patients susceptible to lactic acidosis who may respond to DCA if the etiology involved inhibition of PDH. [1]

(Support: International Anesthesia Research Society)

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REFERENCES

1. Crit Care Med 1997;25:46-51.
2. Circulation 199591:2071-2079.
3. Anesthesiology 1994;81:1127-1138.
© 1998 International Anesthesia Research Society