Surviving blood loss without blood transfusion in a swine poly-trauma model
Surviving blood loss without blood transfusion in a swine poly-trauma model
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DOI：
10.1016/j.surg.2009.04.007
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发表时间：
2009-08-01
期刊：
影响因子：
3.8
通讯作者：
Velmahos, George C.
中科院分区：
文献类型：
--
作者：
Alam, Hasan B.;Shuja, Fahad;Velmahos, George C.
背景资料。我们以前已经证明，丙戊酸(VPA)是一种组蛋白去乙酰化酶抑制剂，可以提高致死性失血性休克模型的存活率。本研究在临床相关的多发伤/失血性休克的大型动物模型上，研究VPA治疗是否能提高存活率，以及其保护作用是否通过Akt的生存途径来实现。约克郡猪采用多伤治疗方案，包括：(1)院前股骨骨折，60%出血，休克30min(平均动脉压25-30 mm Hg)，静脉输注154 mM氯化钠(3次失血)：(2)早期医院A-V期肝损伤(模拟先前包含的血肿破裂)，然后肝填塞；(3)治疗/监测期随机分为3个治疗组(n=6~8个/组)：不治疗(对照组)、新鲜全血(FWB)和静脉注射VPA(400 mg/kg，院前给药)。动物，监测4h，以存活为主要终点。对肝组织进行免疫印迹分析。FWB组(n=6)和VPA组(n=7)的存活率(分别为100%和86%)显著高于对照组(n=8)(25%)。该方案出现严重贫血(Hb<；6g/dL)和乳酸酸中毒(乳酸3-5 mmol/L)。酸中毒在输血后有所改善，其他两组酸中毒加重。VPA治疗增加了磷酸化Akt(激活)、磷酸化GSK-3β(糖原合成酶激酶3β)、β-连环蛋白和Bcl2(B细胞白血病/淋巴瘤)。2)蛋白质水平，与对照组相比(P分别为.01、.01、.03和.02)。对照组和FWB组上述蛋白表达水平差异无统计学意义。在高致死性多发伤和失血性休克模型中，不输血的VPA治疗可提高早期存活率。存活的优势不是由于复苏的改善，而是因为细胞对休克的更好耐受性，部分原因是Akt生存途径的保存。(《外科》2009；146：325-33。)
Background. We have demonstrated previously that valproic acid (VPA), a histone deacetylase inhibitor, can improve survival in lethal models of hemorrhagic shock. This study investigated Whether VPA treatment would improve survival in a clinically relevant large animal model of poly-trauma/hemorrhagic shock, and whether the Protective effects are executed through the Akt survival pathway.Methods. Yorkshire swine were subjected to a poly-trauma protocol, including: (1) Pre-hospital phase-Femur fracture, 60% hemorrhage, 30 min of shock (mean arterial pressure [MAP]: 25-30 mmHg), and infusion of 154mM NaCl (3 x shed blood); (2) Early hospital phase A Grade V liver injury (simulating rupture of a previously contained hematoma) followed by liver packing; (3) Treatment/monitoring phase randomization to 3 treatment groups (n = 6-8/group): no treatment (control), fresh whole blood (FWB), and intravenous VPA (400 mg/kg, given during the pre-hospital phase). Animals, were monitored for 4 h, with survival being the primary endpoint. Liver tissue was subjected to Western blot analysis.Results. FWB (n = 6) and VPA treatments (n = 7) significantly increased survival (100% and 86%, respectively) compared to control group (n = 8) (25%). The protocol produced, significant anemia, (Hb < 6 g/dL) and lactic acidosis (lactate 3-5 mmol/L.). Acidosis improved after blood transfusion and worsened in the other two groups. VPA treatment increased phospho-Akt (activated), phospho-GSK-3 beta (Glycogen synthase kinase 3 beta), beta-catenin and Bcl-2 (B-cell leukemia/lymphoma. 2) protein levels, compared to control group (P = .01, .01, .03, and .02, respectively). There was no significant difference in the level of these proteins between the control and FWB groups.Conclusion. Treatment with VPA without blood transfusion improves early survival in a highly lethal poly-trauma and hemorrhagic shock model. The survival advantage is due not to improvement in resuscitation but to better tolerance of shock by the cells, in part due to the preservation of the Akt survival pathway. (Surgery 2009;146:325-33.)