Introduction: A recent report showed successful management of large diaphyseal segmental bone defects with titanium mesh cages and intramedullary nails. The purpose of the study was a quantitative evaluation of the of the mechanical role of a cylindrical titanium mesh cage and an intramedullary nail when used for the treatment of significant segmental defects of the tibia. Methods: : 28 adult rats after sustaining closed, mid shaft femur fracture, were bled to maintain a mean arterial pressure of 40 mmHg for 20 minutes while monitoring blood oxygen content. 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. Results: All animals in the no therapy group died within 2 hours. Group 3 showed improved hemodynamic response to fluid resuscitation, increased blood oxygen content, prevented metabolic acidosis, and improved 6 hour survival, 42%, compared to group 3, 80%. 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. There were no morhpologic changes found in any of the tissue samples at this early time period. Conclusion: NHE inhibition prevented early death caused by cardiac arrest, and multiple organ failure by inhibiting neutrophil infiltration and NF-(B activation, thereby, reducing systemic inflammation in a model of severe hemorrhagic shock and fracture in a rat.