title: Addition of low-dose valproic acid to saline resuscitation provides neuroprotection and improves long-term outcomes in a large animal model of combined traumatic brain injury and hemorrhagic shock.
abstract: BACKGROUND
  Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) is highly lethal. In a nonsurvival model of TBI + HS, addition of high-dose valproic acid (VPA) (300 mg/kg) to hetastarch reduced brain lesion size and associated swelling 6 hours after injury; whether this would have translated into better neurologic outcomes remains unknown. It is also unclear whether lower doses of VPA would be neuroprotective. We hypothesized that addition of low-dose VPA to normal saline (NS) resuscitation would result in improved long-term neurologic recovery and decreased brain lesion size.
  
  
  METHODS
  TBI was created in anesthetized swine (40-43 kg) by controlled cortical impact, and volume-controlled hemorrhage (40% volume) was induced concurrently. After 2 hours of shock, animals were randomized (n = 5 per group) to NS (3× shed blood) or NS + VPA (150 mg/kg). Six hours after resuscitation, packed red blood cells were transfused, and animals were recovered. Peripheral blood mononuclear cells were analyzed for acetylated histone-H3 at lysine-9. A Neurological Severity Score (NSS) was assessed daily for 30 days. Brain magnetic resonance imaging was performed on Days 3 and 10. Cognitive performance was assessed by training animals to retrieve food from color-coded boxes.
  
  
  RESULTS
  There was a significant increase in histone acetylation in the NS + VPA-treated animals compared with NS treatment. The NS + VPA group demonstrated significantly decreased neurologic impairment and faster speed of recovery as well as smaller brain lesion size compared with the NS group. Although the final cognitive function scores were similar between the groups, the VPA-treated animals reached the goal significantly faster than the NS controls.
  
  
  CONCLUSIONS
  In this long-term survival model of TBI + HS, addition of low-dose VPA to saline resuscitation resulted in attenuated neurologic impairment, faster neurologic recovery, smaller brain lesion size, and a quicker normalization of cognitive functions.
authors.affiliation: From the Department of Surgery (I.H., T.Ba., B.L., Y.L., T.Bont., T.Bonh., K.C., H.B.A.), and Section of Neuroradiology (A.S.), Department of Radiology, University of Michigan, Ann Arbor, Michigan; Department of Surgical Critical Care (Z.C.), Beijing Hospital Ministry of Health, Beijing; and Department of Cardiothoracic Surgery (H.W.), Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
authors.forename: Ihab
authors.initials: I
authors.lastname: Halaweish
authors.forename: Ted
authors.initials: T
authors.lastname: Bambakidis
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Chang
authors.forename: He
authors.initials: H
authors.lastname: Wei
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.forename: Toby
authors.initials: T
authors.lastname: Bonthrone
authors.forename: Ashok
authors.initials: A
authors.lastname: Srinivasan
authors.forename: Tess
authors.initials: T
authors.lastname: Bonham
authors.forename: Kiril
authors.initials: K
authors.lastname: Chtraklin
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000188:drug therapy*; D003071:Cognition; D004195:Disease Models, Animal; D005260:Female; D006895:Hydroxyethyl Starch Derivatives / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D000066829:Neuroprotection; D011897:Random Allocation; D012151:Resuscitation / Q000379:methods*; D012771:Shock, Hemorrhagic / Q000188:drug therapy*; D012965:Sodium Chloride / Q000494:pharmacology*; D013552:Swine; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D006895:Hydroxyethyl Starch Derivatives; D012965:Sodium Chloride; D014635:Valproic Acid