Abstract P228: Resuscitation with Na+/H+ Exchanger Inhibitor Improves Survival and Neurological Outcomes after Severe Hemorrhagic Shock in Pigs
Background: Severe hemorrhage remains a leading cause of mortality in both military and civilian environments. This study tested the hypothesis that inclusion of Na+/H+ exchanger (NHE-1) inhibitor during severe hemorrhagic shock in pigs improves survival and neurological outcomes from resuscitation.
Methods: 12 anesthetized, instrumented and ventilated male pigs that survived an initial hemorrhage of 40ml/kg for 30 min, were given either 3mg/kg BIIB513 in 25ml Hextend (n=6) or Hextend only (vehicle, n=6). One hour after treatment, all animals were resuscitated with Hextend infusion over 60 minutes. Survival, Overall Performance Category (OPC, 1=normal, 5=death) and Neurologic Deficit Score NDS, 0–10=normal, 100=death) were assessed at 72 h post resuscitation.
Results: Only one of the six vehicle treated animals, survived past resuscitation. This animal was terminated the next day due to the development of severe signs of acute respiratory distress syndrome (ARDS). In contrast, all six animals treated with BIIB513 survived past resuscitation and all but one survived such that they were able to have OPC and NDS evaluations at 72h. These five animals had normal neurological outcomes (OPC: 1.2; NDS: 4.0). This positive result was likely due to the following. NHE-1 inhibition with BIIB513 prevented the development of metabolic acidosis and improved oxygen delivery by 23% in the 1h period following hemorrhage, compared to vehicle treated animals. BIIB513 did not affect hemodynamic parameters during this treatment period, but improved the hemodynamic response to fluid resuscitation showing a 23% increase in mean blood pressure and a 35% increase in coronary perfusion pressure. Finally, BIIB513 treatment increased oxygen carry capacity following resuscitation as evidenced by increased oxygenated hemoglobin ratio, reduced deoxyhemoglobin ratio, and increased mixed venous blood oxygen saturation and oxygen delivery compared to Hextend resuscitation alone..
Conclusion: The present study shows that NHE inhibition with BIIB513 protects from whole body ischemia-reperfusion, facilitates the hemodynamic response and oxygen carry capacity to fluid resuscitation, improves cardiovascular and neurological outcomes, and 72 hour survival.
This research has received full or partial funding support from the American Heart Association, National Center.