Dimlich R V, Kaplan J, Timerding B L, Van Ligten P F
Department of Emergency Medicine, University of Cincinnati College of Medicine, Ohio 45267-0769.
Ann Emerg Med. 1989 Nov;18(11):1162-71. doi: 10.1016/s0196-0644(89)80053-8.
In shock, the presence of hyperlactatemia is prognostic of a failure to survive. An experimental model of stroke that combines bilateral carotid ligation and bleeding to a mean arterial pressure of 50 mm Hg induces hyperlactatemia like that associated with tissue hypoperfusion of hemorrhagic shock. In previous nonsurvival studies with this model, post-ischemic treatment of fed rats with 25 mg/kg of sodium dichloroacetate (DCA) was effective in lowering brain tissue lactate but did not significantly affect the ischemia-induced increase in serum lactate measured after 30 minutes of ischemia followed by 30 minutes of reperfusion. Investigators using other animal models treated hyperlactatemia associated with tissue hypoperfusion successfully with a DCA dose of more than 25 mg/kg. Our goal was to determine the effect of a higher dose of DCA on serum lactate in the model of cerebral ischemia with systemic hypotension that we had used in previous studies. The previously unstudied dose-response also was evaluated in our study. Rats that had been fed ad libitum were assigned randomly to either a real or sham (control) ischemic group. Immediately after 30 minutes of ischemia and subsequent reinfusion of blood or after 30 minutes of sham ischemia, rats received DCA (0, 25, 50, 100, 200, or 300 mg/kg). Comparisons were made of blood values measured at the end of equilibration before ischemia, after 30 minutes of ischemia, and after 30 minutes of reperfusion. All ischemic rats were hyperlactatemic. Serum lactate levels were not correlated to blood glucose elevation during ischemia. After treatment in both control and ischemic rats, the percentage decrease in serum lactate varied as a logarithmic function of the DCA dose administered. Glucose levels and pH were not affected by DCA treatment at any dose. Because acidemia decreases lactate uptake by the liver, values for acidotic rats were compared with those for nonacidotic rats. Whereas lactate in acidotic rats decreased significantly only when treated with DCA, nonacidotic rats evidenced this decrease regardless of whether they received DCA. We discuss the relationship of these findings to the peak levels of lactate achieved, the resolution of hyperlactatemia, and factors that affect the interpretation of data in therapeutic studies using DCA.
在休克状态下，高乳酸血症的存在预示着生存失败。一种将双侧颈动脉结扎和放血至平均动脉压50 mmHg相结合的中风实验模型会诱发高乳酸血症，类似于与失血性休克组织灌注不足相关的情况。在以往使用该模型的非生存研究中，给喂食的大鼠以25 mg/kg的二氯醋酸钠（DCA）进行缺血后治疗可有效降低脑组织乳酸，但对缺血30分钟后再灌注30分钟时测得的缺血诱导的血清乳酸升高没有显著影响。使用其他动物模型的研究人员用超过25 mg/kg的DCA剂量成功治疗了与组织灌注不足相关的高乳酸血症。我们的目标是确定更高剂量的DCA对我们之前研究中使用的全身性低血压脑缺血模型中血清乳酸的影响。我们的研究还评估了之前未研究过的剂量反应。随意进食的大鼠被随机分配到真实或假手术（对照）缺血组。在缺血30分钟及随后再输血后或假缺血30分钟后，大鼠接受DCA（0、25、50、100、200或300 mg/kg）。对缺血前平衡结束时、缺血30分钟后和再灌注30分钟后测得的血液值进行比较。所有缺血大鼠均出现高乳酸血症。缺血期间血清乳酸水平与血糖升高无关。在对照和缺血大鼠中进行治疗后，血清乳酸下降的百分比随所给予的DCA剂量呈对数函数变化。任何剂量的DCA治疗均未影响血糖水平和pH值。由于酸血症会降低肝脏对乳酸的摄取，因此将酸中毒大鼠的值与非酸中毒大鼠的值进行比较。虽然酸中毒大鼠仅在接受DCA治疗时乳酸才显著下降，但无论是否接受DCA，非酸中毒大鼠均出现这种下降。我们讨论了这些发现与所达到的乳酸峰值水平、高乳酸血症的消退以及影响使用DCA的治疗研究中数据解释的因素之间的关系。
