Valproic acid during hypotensive resuscitation in pigs with trauma and hemorrhagic shock does not improve survival

BACKGROUND: Valproic acid (VPA) has been extensively used for treatment of anxiety and seizure. Recent studies have shown that VPA has cellular protective effects in preclinical models following severe hemorrhage. This study investigated the effects of VPA on coagulation and survival in pigs after traumatic hemorrhage and hypotensive resuscitation. METHODS: Following baseline measurements, femur fracture was performed in 20 anesthetized and instrumented pigs (41 +/- 2 kg), followed by hemorrhage of 55% of the estimated blood volume and a 10-minute shock period. Pigs were then resuscitated for 30 minutes with normal saline (NS) alone (NS group, n = 10, 4mL/kg) or VPA solution (VPA group, n = 10, 90mg/kg, 2 mL/kg of 45mg VPA/mL, plus 2 mL NS/kg). All pigs were then monitored for 2 hours or until death. Hemodynamics were recorded, and blood samples were taken for blood and coagulation analysis (Rotem) at baseline, after hemorrhage, resuscitation, and 2 hours or death. RESULTS: Femur fracture and hemorrhage caused similar reductions in mean arterial pressure and cardiac output, and increase in heart rate in both groups. Resuscitation with NS or VPA did not return these measurements to baseline. No differences were observed in hematocrit, pH, lactate, base excess, or total protein between the groups. Compared with NS, resuscitation with VPA decreased platelet counts and prolonged activated partial thromboplastin time, with no differences in fibrinogen levels, prothrombin time, or any of the Rotem measurements between the two groups. Neither survival rates (NS, 7 of 10 pigs; VPA, 7 of 10 pigs) nor survival times after resuscitation (NS, 97 +/- 40 minutes; VPA, 98 +/- 43 minutes) differed between the groups. CONCLUSION: Following traumatic hemorrhage and hypotensive resuscitation in pigs, VPA provides no benefit toward improving coagulation function or survival times.