Wilson Jeffrey S, Rushing Greg, Johnson Brad L, Kline Jeffrey A, Parker Jaime L, Bowser Andrew, Bandyk Dennis F, Back Martin R
Division of Vascular and Endovascular Surgery, University of South Florida College of Medicine, Tampa, FL, USA.
J Am Coll Surg. 2003 Oct;197(4):591-5. doi: 10.1016/S1072-7515(03)00673-2.
Dichloroacetate (DCA) is a drug that allows pyruvate dehydrogenase to remain active under anaerobic conditions by inhibiting the inactivating enzyme, pyruvate dehydrogenase kinase. We hypothesize that the administration of DCA during acute limb ischemia may have a beneficial effect by reducing the severity of anaerobic metabolism and lessening the irreversible injury.
We studied a rabbit model using unilateral ligation of the iliac artery or femoral artery to evaluate two degrees of ischemia. After 2 hours of hind-limb ischemia, the animals were administered IV DCA (15 mg/kg) or an equivalent volume of saline.
Higher serum lactate levels were seen after high compared to low ligation in control animals consistent with more severe ischemia. DCA treatment significantly reduced serum lactate levels after both high and low ligation. Similarly, the rise in percentage end-tidal CO(2) after reperfusion was less after DCA. All animals regained hind-limb function after the procedure, but ischemia or reperfusion resulted in appreciable muscle necrosis (> 10% area) in 50% of high- and 22% of low-ligation control animals. DCA treatment eliminated significant muscle necrosis in 100% of high-ligation animals. Muscle histology was similar in control and DCA-treated low-ligation animals.
Treatment with DCA during acute arterial occlusion did significantly lower markers of anaerobic metabolism and reduced muscle necrosis in a rabbit model of acute hind-limb ischemia. DCA delivery through collateral blood flow may prolong the ischemia time interval before the onset of irreversible muscle injury and potential limb loss.
二氯乙酸（DCA）是一种药物，通过抑制丙酮酸脱氢酶激酶（使丙酮酸脱氢酶失活的酶），使丙酮酸脱氢酶在无氧条件下保持活性。我们假设在急性肢体缺血期间给予DCA可能通过降低无氧代谢的严重程度和减轻不可逆损伤而产生有益效果。
我们使用兔模型，通过单侧结扎髂动脉或股动脉来评估两种程度的缺血。在下肢缺血2小时后，给动物静脉注射DCA（15mg/kg）或等量的生理盐水。
与低结扎组相比，对照组高结扎组动物血清乳酸水平更高，这与更严重的缺血一致。DCA治疗在高结扎组和低结扎组后均显著降低了血清乳酸水平。同样，DCA治疗后再灌注时呼气末二氧化碳百分比的升高也较小。所有动物术后均恢复了后肢功能，但缺血或再灌注导致50%的高结扎对照组动物和22%的低结扎对照组动物出现明显的肌肉坏死（面积>10%）。DCA治疗使100%的高结扎组动物消除了明显的肌肉坏死。对照组和DCA治疗的低结扎组动物的肌肉组织学相似。
在急性动脉闭塞期间用DCA治疗确实显著降低了急性后肢缺血兔模型中无氧代谢的标志物并减少了肌肉坏死。通过侧支血流输送DCA可能会延长不可逆肌肉损伤和潜在肢体丧失发生前的缺血时间间隔。
