From the Departments of Surgery (D.W.N., C.R.P., D.P.M., M.J.M.), and Clinical Investigation (S.K.S.), Madigan Army Medical Center, Fort Lewis, Washington.
J Trauma Acute Care Surg. 2013 Dec;75(6):1031-9. doi: 10.1097/TA.0b013e31829d01bf.
Valproic acid (VPA) is a histone deacetylase inhibitor that has been shown to improve early resuscitation from hemorrhagic shock. We sought to examine whether there is a sustained benefit of VPA in a survival model of severe injury.
Yorkshire swine (n = 36) were randomized to three groups as follows: (a) control, (b) VPA (single dose), and (c) VPA (two doses at 12 hours apart). Animals underwent a 35% volume-controlled hemorrhage, followed by aortic cross-clamping for 50-minute duration, at which time VPA (400 mg/kg) was administered intravenously. Animals then underwent protocol guided resuscitation with crystalloid and vasopressor infusions for up to 24 hours. The primary end point was animal survival; secondary end points included hemodynamics, physiology, and histologic evidence of end-organ injury.
Mean duration of survival was significantly longer in the control group (15.8 hours, n = 11) compared with single-dose VPA (12.6 hours, n = 9, p < 0.02). Redosing VPA at 12 hours provided no survival benefit. During cross-clamp, animals that received VPA required significantly less lidocaine compared with the control animals (32.8 mg vs. 159.4 mg, p = 0.03). Animals that received VPA also required significantly greater quantities of intravenous fluids per hour (p < 0.01) and higher epinephrine doses (p = 0.01). VPA administration was associated with earlier evidence of cardiac suppression (decreased cardiac output, increased pulmonary wedge pressures, and systemic vascular resistance; p < 0.05). VPA was associated with renal end-organ histologic protection and improved levels of blood urea nitrogen and creatinine at all time points (p < 0.05).
Despite previous reports citing improved early outcomes with VPA administration, VPA did not improve resuscitation or mortality in a survival model with severe injury. VPA did show some evidence of prolonged renal protection. No benefit of redosing VPA was identified. VPA had a cardiac depressant effect that may be dose dependent and should be studied further.
丙戊酸（VPA）是一种组蛋白去乙酰化酶抑制剂，已被证明可改善失血性休克的早期复苏。我们试图研究 VPA 在严重创伤的生存模型中是否具有持续的益处。
将约克夏猪（n = 36）随机分为三组：（a）对照组，（b）VPA（单次剂量）和（c）VPA（12 小时间隔两次剂量）。动物经历了 35%容量控制的出血，随后进行主动脉夹闭 50 分钟，此时静脉内给予 VPA（400mg/kg）。然后，动物接受晶体和血管加压素输注的方案指导复苏，持续长达 24 小时。主要终点是动物的存活率；次要终点包括血流动力学、生理学和终末器官损伤的组织学证据。
与单次剂量 VPA（12.6 小时，n = 9，p <0.02）相比，对照组的平均存活时间明显更长（15.8 小时，n = 11）。VPA 再给药 12 小时没有提供生存益处。在夹闭期间，接受 VPA 的动物所需的利多卡因明显少于对照组动物（32.8mg 对 159.4mg，p = 0.03）。接受 VPA 的动物还需要每小时输注更多的静脉液体（p <0.01）和更高剂量的肾上腺素（p = 0.01）。VPA 给药与更早的心脏抑制证据相关（心输出量降低、肺楔压升高和全身血管阻力升高；p <0.05）。VPA 与肾脏终末器官的组织学保护相关，并在所有时间点改善血尿素氮和肌酐水平（p <0.05）。
尽管先前有报道称 VPA 给药可改善早期结果，但 VPA 在严重创伤的生存模型中并未改善复苏或死亡率。VPA 确实显示出一些延长肾脏保护的证据。没有发现再给 VPA 剂量的益处。VPA 具有心脏抑制作用，可能与剂量有关，应进一步研究。
