Hemorrhagic shock (HS) is the foremost etiology of early deaths in trauma patients, whereas infections remain the leading cause of late morbidity and mortality. Patients who survive the initial hemorrhage often pass through periods of systemic inflammatory response syndrome (SIRS) and immune dysfunction where they die of infectious complications.1 This combined (“two-hit”) insult creates an exaggerated injury pattern that can lead to multiple-organ failure.2 Goal-directed resuscitation remains important in the management of these patients, but what exactly is the most appropriate early resuscitation strategy remains controversial.3,4 Although fluids are capable of restoring intravascular volume, they have been implicated in worsening of the postshock inflammatory response.4–6 Compared with conventional isotonic crystalloids (such as isotonic sodium choride solution [ISCS]), hypertonic saline (HTS) has several theoretical advantages, including more effective expansion of intravascular volume and a blunting of the inflammatory response.3–5,7,8 However, the largest and the most recent randomized clinical trial has failed to show an overall survival advantage in the patients that were resuscitated with hypertonic fluid.9 In fact, this trial was stopped ahead of schedule owing to an increase in early deaths in the hypertonic group.10 The pathophysiology of sepsis is classically attributed to hyperinflammatory responses that mediate the excessive production of cytokines, which can lead to cellular injury and organ dysfunction.11 We now know that trauma, even in the absence of sepsis, can cause inflammation through multiple mechanisms.12,13 This sterile inflammation/SIRS is often clinically indistinguishable from its infectious counterpart (sepsis and septic shock).14 Traditional treatment strategies have largely been supportive, but recent research has focused on developing more specific treatments that normalize the underlying affected pathways.15 We have shown that shock alters the acetylation status of the cell, which in turn impairs gene transcription and the function of multiple cell survival pathways.16 Acetylation is a rapid and reversible posttranslational protein modification that is controlled by two opposing enzyme families, histone deacetylases (HDACs) and histone acetyl transferases. The balance of acetylation in a cell can be therapeutically altered by a class of drugs called HDAC inhibitors (HDACIs). HDACs remove acetyl groups from lysine residues of the target proteins, and treatment with their inhibitors (HDACIs) can tilt the balance in favor of histone acetyl transferases. This results in increased acetylation, which has been shown to regulate numerous biologic functions, including inflammation and immune responses.15,16 At the molecular level, it has been reported that both hemorrhage and sepsis lead to an imbalance in protein acetylation and that treatment with HDACIs can restore this balance and improve outcomes.17,18 Recently, our team has demonstrated that treatment with a large dose (300 mg/kg) of valproic acid (VPA), which works as an HDACI, can significantly decrease inflammation and improve survival in a lethal two-hit rodent model of hemorrhagic and septic shock (data presented at the 92nd annual meeting of the New England Surgical Society, September 2011). Although effective, this high dose of VPA is associated with increased chances of toxicity, which has prompted us to explore various strategies that could lower the effective dose of the drug. One such approach is to combine VPA with another anti-inflammatory agent, such as HTS, to see if the prosurvival benefits could be achieved at a lower dose. In the present study, we tested the hypothesis that VPA and HTS would work synergistically to attenuate inflammation and improve survival in a rodent two-hit model: HS followed by septic shock from cecal ligation and puncture (CLP). more...