title: Effects of histone deacetylase inhibition on 24-hour survival and end-organ injury in a porcine trauma model: a prospective, randomized trial.
abstract: BACKGROUND
  Valproic acid (VPA) is a histone deacetylase inhibitor that has been shown to improve early resuscitation from hemorrhagic shock. We sought to examine whether there is a sustained benefit of VPA in a survival model of severe injury.
  
  
  METHODS
  Yorkshire swine (n = 36) were randomized to three groups as follows: (a) control, (b) VPA (single dose), and (c) VPA (two doses at 12 hours apart). Animals underwent a 35% volume-controlled hemorrhage, followed by aortic cross-clamping for 50-minute duration, at which time VPA (400 mg/kg) was administered intravenously. Animals then underwent protocol guided resuscitation with crystalloid and vasopressor infusions for up to 24 hours. The primary end point was animal survival; secondary end points included hemodynamics, physiology, and histologic evidence of end-organ injury.
  
  
  RESULTS
  Mean duration of survival was significantly longer in the control group (15.8 hours, n = 11) compared with single-dose VPA (12.6 hours, n = 9, p < 0.02). Redosing VPA at 12 hours provided no survival benefit. During cross-clamp, animals that received VPA required significantly less lidocaine compared with the control animals (32.8 mg vs. 159.4 mg, p = 0.03). Animals that received VPA also required significantly greater quantities of intravenous fluids per hour (p < 0.01) and higher epinephrine doses (p = 0.01). VPA administration was associated with earlier evidence of cardiac suppression (decreased cardiac output, increased pulmonary wedge pressures, and systemic vascular resistance; p < 0.05). VPA was associated with renal end-organ histologic protection and improved levels of blood urea nitrogen and creatinine at all time points (p < 0.05).
  
  
  CONCLUSIONS
  Despite previous reports citing improved early outcomes with VPA administration, VPA did not improve resuscitation or mortality in a survival model with severe injury. VPA did show some evidence of prolonged renal protection. No benefit of redosing VPA was identified. VPA had a cardiac depressant effect that may be dose dependent and should be studied further.
authors.affiliation: From the Departments of Surgery (D.W.N., C.R.P., D.P.M., M.J.M.), and Clinical Investigation (S.K.S.), Madigan Army Medical Center, Fort Lewis, Washington.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nelson
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Porta
authors.forename: Derek P
authors.initials: DP
authors.lastname: McVay
authors.forename: Shashikumar K
authors.initials: SK
authors.lastname: Salgar
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Martin
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D006439:Hemodynamics / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D011446:Prospective Studies; D012151:Resuscitation / Q000379:methods*; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D013552:Swine; D016896:Treatment Outcome; D014947:Wounds and Injuries / Q000150:complications* / Q000503:physiopathology
chemical_list: D056572:Histone Deacetylase Inhibitors