在猪创伤性脑损伤、出血和多发伤的致死模型中优化丙戊酸的剂量。
Dose optimization of valproic acid in a lethal model of traumatic brain injury, hemorrhage, and multiple trauma in swine.
机构信息
From the Department of Surgery (B.E.B., A.M.W., I.S.D., N.J.G., K.C., A.Z.S., R.L.O., U.F.B., B.L., R.M.R., Y.L., H.B.A.), and Department of Clinical Pharmacy (M.P.P.), University of Michigan, Ann Arbor, Michigan.
出版信息
J Trauma Acute Care Surg. 2019 Nov;87(5):1133-1139. doi: 10.1097/TA.0000000000002460.
BACKGROUND
Trauma is a leading cause of death, and traumatic brain injury is one of the hallmark injuries of current military conflicts. Valproic acid (VPA) administration in high doses (300-400 mg/kg) improves survival in lethal trauma models, but effectiveness of lower doses on survival is unknown. This information is essential for properly designing the upcoming clinical trials. We, therefore, performed the current study to determine the lowest dose at which VPA administration improves survival in a model of lethal injuries.
METHODS
Swine were subjected to traumatic brain injury (10-mm cortical impact), 40% blood volume hemorrhage, and multiple trauma (femur fracture, rectus crush, and Grade V liver laceration). After 1 hour of shock, animals were randomized (n = 6/group) to four groups: normal saline (NS) resuscitation; or NS with VPA doses of 150 mg/kg (VPA 150) or 100 mg/kg (VPA 100) administered over 3 hours or 100 mg/kg over 2 hours (VPA 100 over 2 hours). Three hours after shock, packed red blood cells were given, and animals were monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test.
RESULTS
Without resuscitation, all of the injured animals died within 5 hours. Similar survival rates were observed in the NS (17%) and VPA 100 (0%) resuscitation groups. Survival rates in the 100-mg/kg VPA groups were significantly (p < 0.05) better when it was given over 2 hours (67%) compared to 3 hours (0%). 83% of the animals in the VPA 150 group survived, which was significantly higher than the NS and VPA 100 over 3 hours groups (p < 0.05).
CONCLUSION
A single dose of VPA (150 mg/kg) significantly improves survival in an otherwise lethal model of multiple injuries. This is a much lower dose than previously shown to have a survival benefit and matches the dose that is tolerated by healthy human subjects with minimal adverse effects.
LEVEL OF EVIDENCE
Therapeutic, level V.
背景
创伤是导致死亡的主要原因之一，而创伤性脑损伤是当前军事冲突中标志性的损伤之一。大剂量（300-400mg/kg）丙戊酸（VPA）给药可提高致死性创伤模型的存活率，但较低剂量对存活率的影响尚不清楚。这些信息对于正确设计即将进行的临床试验至关重要。因此，我们进行了本研究，以确定 VPA 给药可提高致死性损伤模型存活率的最低剂量。
方法
猪接受创伤性脑损伤（10mm 皮质撞击）、40%血容量出血和多发伤（股骨骨折、直肌挤压伤和 V 级肝裂伤）。休克 1 小时后，动物随机（n=6/组）分为四组：生理盐水（NS）复苏；或 NS 联合 VPA 剂量 150mg/kg（VPA 150）或 100mg/kg（VPA 100），分别在 3 小时内或 2 小时内（VPA 100 分 2 次）给药。休克后 3 小时给予浓缩红细胞，再监测 4 小时。使用 Kaplan-Meier 和对数秩检验评估存活率。
结果
未经复苏，所有受伤动物均在 5 小时内死亡。NS（17%）和 VPA 100（0%）复苏组的存活率相似。100mg/kg VPA 组在 2 小时内（67%）给药的存活率明显（p<0.05）优于 3 小时内（0%）给药。VPA 150 组 83%的动物存活，明显高于 NS 和 VPA 100 组（p<0.05）。
结论
单次剂量 VPA（150mg/kg）可显著提高多发伤致死性模型的存活率。这是一个比以前显示有生存获益的剂量低得多的剂量，与最小不良反应的健康人体受试者可耐受的剂量相匹配。
证据水平
治疗，V 级。
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