Abstract 2049: Fluid Resuscitation with Na+/h+ Exchanger Inhibitor Improves Cardiovascular and Metabolic Function in a Pig Model of Uncontrolled Hemorrhagic Shock

Abstract

Uncontrolled hemorrhage remains a leading cause of traumatic death. The aim of this study was to evaluate the effects of Na+/H+ exchanger (NHE) inhibition on enhancing fluid resuscitation outcomes in traumatic hemorrhagic shock, and to investigate the mechanisms related to NHE inhibitor -induced protection and recovery from hemorrhagic shock. Tibia fractures with soft tissue injury were induced in 12 anesthetized instrumented male pigs. The animals underwent hemorrhage of 25ml/kg for 20min, followed by a 4mm abdominal aortic tear with surgical repair after 30minutes. Animals then underwent initial fluid resuscitation with either 15ml/kg Hextend (n=6) or 3mg/kg BIIB513 +15ml/kg Hextend (n=6). Resuscitation occurred over 40 minutes. A second resuscitation was given 4 hours later. Studies were terminated at 6 hours. All animals survived the entire experiment. In both groups , hemorrhage resulted in similar impaired myocardial performance, and severe hemodynamic and metabolic alterations. Compared to resuscitation with Hextend alone, the addition of BIIB513, improved the hemodynamic response to fluid resuscitation showing a 23% increase in mean blood pressure and a 31% increase in blood oxygen content, as well as preventing metabolic acidosis during early resuscitation. Echocardiography analysis showed that NHE-1 inhibition with BIIB513 attenuated the hemorrhage induced myocardial hypercontracture and resulted in a significant 77% increase in stroke index. NHE-1 inhibition also reduced plasma levels of myocardial troponin-I by 88%, attenuated myeloperoxidase activity in the liver by 46%, and improved organ function. Consistent with this was the finding that nuclear factor (NF)-κB phosphorylation, nuclear translocation, and NF-κB DNA binding activity in the liver was attenuated in Hextend + BIIB513 treated animals, compared to Hextend only treated animals. The present study shows that the response to fluid resuscitation after traumatic hemorrhage is improved by the addition of the NHE-1 inhibitor BIIB513. That BIIB513 treatment attenuates NF-κB activation and neutrophil infiltration suggests that this improvement may be related to the reduction in tissue inflammatory injury. This research has received full or partial funding support from the American Heart Association, AHA National Center.