Abstract 2085: NHE1 Inhibition Delays the Onset of Hypovolemic Circulatory Shock
Background: Severe blood loss is a major cause of death occurring within hours of traumatic injury. Na+/H+ exchange (NHE1) activity is an important determinant of the extent of ischemic myocardial injury. The goal of the present study was to test the hypothesis that NHE1 inhibition may delay the onset of hypovolemic circulatory shock, prevent early death due to severe hemorrhage in pigs.
Methods: Moderate to severe hypovolemia was studied in sixteen (25.2 kg) anesthetized male pigs in steps of: 10 ml/kg, 20 ml/kg, 30 ml/kg, 40 ml/kg, 50 ml/kg blood loss, each in 30 minutes intervals. Shed blood resuscitation was started 30 minutes after 50 ml/kg blood loss. The experiment was terminated at 3 hours of resuscitation. Eight pigs were used as saline control. Eight pigs received 3mg/kg BIIB513 (NHE1 inhibitor) 15 minutes before hemorrhage.
Results: Seven control pigs died at 40 to 50 ml/kg blood loss. One control pig survived initial resuscitation, but died soon after. In contrast, all animals treated with NHE1 inhibitor survived the entire protocol. In control animals, cardiac output and mean arterial pressure gradually decreased at each step of blood loss with marked increase in heart rate. Cardiovascular decompensation occurred at 40 ml/kg blood loss. NHE1 inhibition increased oxygen delivery, attenuated cardiovascular decompensation, and delayed the onset of hypovolemic circulatory shock and enabled resuscitation to survival. Echocardiography analysis shows that myocardial ischemic contracture gradually developed with each step of blood loss, as evidenced by a progressive increase of left ventricular wall thickness and a decrease of left ventricular cavity. NHE1 inhibition attenuated ischemic contracture, prevented early death caused by severe hemorrhage.
Conclusion: The present study shows that NHE1 inhibition attenuates ischemic contracture and cardiovascular decompensation, delays the onset of hypovolemic circulatory shock and prevents early death in severe hemorrhage.