title: Pharmacologic resuscitation for hemorrhagic shock combined with traumatic brain injury.
abstract: BACKGROUND
  We have previously demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, can improve survival after hemorrhagic shock (HS), protect neurons from hypoxia-induced apoptosis, and attenuate the inflammatory response. We have also shown that administration of 6% hetastarch (Hextend [Hex]) after traumatic brain injury (TBI) decreases brain swelling, without affecting size of the lesion. This study was performed to determine whether addition of VPA to Hex would decrease the lesion size in a clinically relevant large animal model of TBI + HS.
  
  
  METHODS
  Yorkshire swine (42-50 kg) were instrumented to measure hemodynamic parameters, intracranial pressure, and brain tissue oxygenation. A custom-designed, computer-controlled cortical impact device was used to create a TBI through a 20-mm craniotomy: 15-mm cylindrical tip impactor at 4-m/s velocity, 100-millisecond dwell time, and 12-mm penetration depth. Volume-controlled hemorrhage was started (40% blood volume) concurrent with the TBI. After 2 hours of shock, animals were randomized to one of three resuscitation groups (n = 7 per group) as follows: (1) isotonic sodium chloride solution; (2) 6% hetastarch, Hex; and (3) Hex and VPA 300 mg/kg (Hex + VPA). Volumes of Hex matched the shed blood, whereas that of the isotonic sodium chloride solution was three times the volume. VPA treatment was started after an hour of shock. After 6 hours of postresuscitation monitoring, brains were sectioned into 5-mm slices and stained with 2, 3, 5-Triphenyltetrazolium chloride to quantify the lesion size (mm) and brain swelling (percent change compared with uninjured side). Levels of acetylated histone H3 were determined to quantify acetylation, and myeloperoxidase and interleukine-1β (IL-1β) levels were measured as markers of brain inflammation.
  
  
  RESULTS
  Combination of 40% blood loss with cortical impact and a period of shock (2 hours) and resuscitation resulted in a highly reproducible brain injury. Lesion size and brain swelling in the Hex + VPA group (1,989 [156.8] mm, and 19% [1.6%], respectively) were significantly smaller than the isotonic sodium chloride solution group (3,335 [287.9] mm and 36% [2.2%], respectively). Hex alone treatment significantly decreased the swelling (27% [1.6%]) without reducing the lesion size. The number of CD11b-positive cells as well as myeloperoxidase and IL-1 levels in the brains were significantly reduced by the VPA treatment.
  
  
  CONCLUSIONS
  In a combined HS and TBI model, treatment with artificial colloid (Hex) improves hemodynamic parameters and reduces swelling, without affecting the actual size of the brain lesion. Addition of VPA effectively reduces both the size of brain lesion and associated swelling by attenuating the inflammatory response.
authors.affiliation: Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Jin
authors.forename: Michael
authors.initials: M
authors.lastname: Duggan
authors.forename: Ayesha
authors.initials: A
authors.lastname: Imam
authors.forename: Marc A
authors.initials: MA
authors.lastname: Demoya
authors.forename: Martin
authors.initials: M
authors.lastname: Sillesen
authors.forename: John
authors.initials: J
authors.lastname: Hwabejire
authors.forename: Cecilie H
authors.initials: CH
authors.lastname: Jepsen
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.forename: Ali Y
authors.initials: AY
authors.lastname: Mejaddam
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lu
authors.forename: William Michael
authors.initials: WM
authors.lastname: Smith
authors.forename: George C
authors.initials: GC
authors.lastname: Velmahos
authors.forename: Simona
authors.initials: S
authors.lastname: Socrate
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications* / Q000188:drug therapy; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006895:Hydroxyethyl Starch Derivatives / Q000008:administration & dosage / Q000627:therapeutic use*; D007249:Inflammation / Q000517:prevention & control; D007552:Isotonic Solutions / Q000008:administration & dosage / Q000627:therapeutic use; D012151:Resuscitation / Q000379:methods; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000188:drug therapy; D013552:Swine; D014635:Valproic Acid / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D006895:Hydroxyethyl Starch Derivatives; D007552:Isotonic Solutions; D014635:Valproic Acid