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-3beta (Glycogen synthase kinase 3beta), 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.
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-3beta (Glycogen synthase kinase 3beta), 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.
Authors: Nikolaos Zacharias; Elizabeth A Sailhamer; Yongqing Li; Baoling Liu; Muhammad U Butt; Fahad Shuja; George C Velmahos; Marc de Moya; Hasan B Alam Journal: Resuscitation Date: 2010-10-30 Impact factor: 5.262
Authors: Ashley R Kochanek; Eugene Y Fukudome; Yongqing Li; Eleanor J Smith; Baoling Liu; George C Velmahos; Marc deMoya; David King; Hasan B Alam Journal: J Surg Res Date: 2011-07-05 Impact factor: 2.192
Authors: Aaron M Williams; Umar F Bhatti; Isabel S Dennahy; Kiril Chtraklin; Panpan Chang; Nathan J Graham; Basil M Baccouche; Shalini Roy; Mohammed Harajli; Jing Zhou; Vahagn C Nikolian; Qiufang Deng; Yuzi Tian; Baoling Liu; Yongqing Li; Gregory L Hays; Julia L Hays; Hasan B Alam Journal: J Vis Exp Date: 2018-08-24 Impact factor: 1.355
Authors: Eugene Y Fukudome; Ashley R Kochanek; Yongqing Li; Eleanor J Smith; Baoling Liu; Tareq Kheirbek; Jennifer Lu; Kyuseok Kim; Kristopher Hamwi; George C Velmahos; Hasan B Alam Journal: J Surg Res Date: 2010-05-07 Impact factor: 2.192
Authors: Aaron M Williams; Isabel S Dennahy; Umar F Bhatti; Ben E Biesterveld; Nathan J Graham; Yongqing Li; Hasan B Alam Journal: Shock Date: 2019-09 Impact factor: 3.454
Authors: Pramod K Dash; Sara A Orsi; Min Zhang; Raymond J Grill; Shibani Pati; Jing Zhao; Anthony N Moore Journal: PLoS One Date: 2010-06-30 Impact factor: 3.240