Severe hemorrhage from traumatic injury is a major causative factor in almost half of these deaths on the battlefield, especially during the early period (<2h) after injury. Intervention with low-volume fluid resuscitation is increasingly preferred than more aggressive fluid replacement. We evaluated the use of a Na+/H+ exchanger (NHE) inhibitor, as a cardioprotective adjunct therapy to low-volume resuscitation in a rat model of traumatic hemorrhagic shock. Methods: Femur fracture with soft tissue injury was induced in 28 anesthetized male rats. The animals were then bled via the carotid artery to maintain a mean arterial pressure of 40 mmHg for 20 minutes. Groups: 1) no therapy; 2) 15 ml/kg Hextend infusion over 40 minutes; 3) 3 mg/kg BIIB513 (NHE-1 inhibitor) + 15 ml/kg Hextend infusion over 40 minutes. After 4 hours, the animals who survived received a second infusion of Hextend. The experiment was terminated at 6 hours after initial resuscitation. Data are reported as mean ± SD. Results: All animals in the no therapy group died within 2 hours. Compared to Hextend infusion alone, the addition of NHE-1 inhibition with BIIB513, improved the hemodynamic response to fluid resuscitation (Fig 1), increased blood oxygen content, prevented metabolic acidosis, and improved 6 hour survival (42% in Hextend group vs 80% in BIIB513 + Hextend group). NHE-1 inhibition also resulted in reduced plasma levels of TNF-α, ICAM-1 and C-reactive protein, and attenuated neutrophil infiltration in the liver. Conclusion: NHE-1 inhibition with BIIB513 improved the hemodynamic response to fluid resuscitation, attenuated tissue inflammatory mediators, and most importantly improved survival.