title: Synergistic effects of fresh frozen plasma and valproic acid treatment in a combined model of traumatic brain injury and hemorrhagic shock.
abstract: BACKGROUND
  Traumatic brain injury (TBI) and hemorrhagic shock (HS) are major causes of trauma-related deaths and are especially lethal as a combined insult. Previously, we showed that early administration of fresh frozen plasma (FFP) decreased the size of the brain lesion and associated swelling in a swine model of combined TBI+HS. We have also shown separately that addition of valproic acid (VPA) to the resuscitation protocol attenuates inflammatory markers in the brain as well as the degree of TBI. The current study was performed to determine whether a combined FFP+VPA treatment strategy would exert a synergistic effect.
  
  
  METHODS
  Yorkshire swine (42-50 kg) were instrumented to measure hemodynamic parameters, intracranial pressure, and brain tissue oxygenation. TBI was created through a 20-mm craniotomy using a computer-controlled cortical impactor: 15-mm cylindrical tip impactor at 4 m/s velocity, 100 ms dwell time, and 12-mm penetration depth. The TBI was synchronized with the initiation of volume-controlled hemorrhage (40 ± 5% of total blood volume). After a 2-hour period of shock, animals were randomized to 1 of 3 resuscitation groups (n = 5 per group): (1) 0.9% saline (NS); (2) FFP; and (3) FFP and VPA 300 mg/kg (FFP+VPA). The resuscitative volume for FFP was equivalent to the shed blood, whereas NS was 3 times this volume. VPA treatment was started 1 hour after hemorrhage. Animals were monitored for 6 hours post-resuscitation. At this time the brains were harvested, sectioned into 5-mm slices, and stained with 2,3,5-triphenyltetrazolium chloride to quantify the lesion size (mm(3)) and brain swelling (percent change compared with the uninjured side).
  
  
  RESULTS
  The combined TBI+HS model resulted in a highly reproducible brain injury. Lesion size and brain swelling (mean value ± standard error of the mean) in the FFP+VPA group (1,459 ± 218 mm(3) and 13 ± 1%, respectively) were less than the NS group (3,285 ± 131 mm(3) [P < .001] and 37 ± 2% [P < .001], respectively), and the FFP alone group (2,160 ± 203 mm(3) [P < .05] and 22 ± 1% [P < .001], respectively).
  
  
  CONCLUSIONS
  In a large animal model of TBI+HS, early treatment with a combination of FFP and VPA decreases the size of brain lesion and the associated swelling.
authors.affiliation: Department of Surgery, Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
authors.forename: Ayesha M
authors.initials: AM
authors.lastname: Imam
authors.forename: Guang
authors.initials: G
authors.lastname: Jin
authors.forename: Michael
authors.initials: M
authors.lastname: Duggan
authors.forename: Martin
authors.initials: M
authors.lastname: Sillesen
authors.forename: John O
authors.initials: JO
authors.lastname: Hwabejire
authors.forename: Cecilie H
authors.initials: CH
authors.lastname: Jepsen
authors.forename: Danielle
authors.initials: D
authors.lastname: DePeralta
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lu
authors.forename: Marc A
authors.initials: MA
authors.lastname: deMoya
authors.forename: Simona
authors.initials: S
authors.lastname: Socrate
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000503:physiopathology / Q000628:therapy*; D005260:Female; D006439:Hemodynamics; D010949:Plasma; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000503:physiopathology / Q000628:therapy*; D013552:Swine; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D014635:Valproic Acid