TY - JOUR
T1 - NHE1 inhibition improves tissue perfusion and resuscitation outcome after severe hemorrhage
AU - Wu, Dongmei
AU - Russano, Kristina
AU - Kouz, Irene
AU - Abraham, William M.
N1 - Funding Information:
This work was supported by USAMRMC Grant W81XWH-06-1-0719 to Dr. Dongmei Wu; and in part by the World Class University Program ( R31-20029 ) and Basic Science Research Program through the National Research Foundation of Korea ( NRF-2012007331 ), funded by the Ministry of Education, Science, and Technology, Republic of Korea .
PY - 2013/5/15
Y1 - 2013/5/15
N2 - Introduction: This study tested the hypothesis that blockade of the pH-regulatory protein, Na+/H+ exchanger (NHE1) during prolonged hemorrhagic shock can protect against whole-body ischemia-reperfusion injury, resulting in improved neurological outcomes. Methods: We used a total of 24 male pigs in this study. We excluded two animals: one because of cardiac arrest after the initial hemorrhage, and the second because of a catheter malfunction for color microspheres. In Series 1, anesthetized pigs underwent an initial hemorrhage of 40 mL/kg for 30 min, and then were given either 3 mg/kg of NHE1 selective inhibitor BIIB513 (n = 6) or vehicle (n = 6). At 1 h after treatment, all animals received fluid resuscitation. We assessed survival and neurologic outcomes 72 h postresuscitation. In Series 2, we measured organ blood flow in a separate group of control (n = 5) and BIIB513-treated pigs (n = 5) undergoing the same experimental paradigm. Results: Five of six control animals failed to be weaned from mechanical ventilation. We killed another control animal the next day because of severe complications. In contrast, all six animals treated with BIIB513 were weaned off the ventilator, and all but one survived the 72-h experimental period with normal neurological outcome. Results showed that NHE1 inhibition with BIIB513 improved blood flow to the brain, heart, and kidney, and prevented the development of metabolic acidosis in the 1-h hypovolemic period. In addition, BIIB513 facilitated the hemodynamic response to fluid resuscitation, increased mixed venous blood oxygen saturation and oxygen delivery, and reduced proinflammatory cytokine release and multiorgan injury compared with vehicle controls. Conclusions: In this study, NHE1 inhibition with BIIB513 improved vital organ blood flow, prevented the development of metabolic acidosis during prolonged hypovolemia, and facilitated the hemodynamic response to fluid resuscitation, resulting in increased survival and normal neurological outcomes.
AB - Introduction: This study tested the hypothesis that blockade of the pH-regulatory protein, Na+/H+ exchanger (NHE1) during prolonged hemorrhagic shock can protect against whole-body ischemia-reperfusion injury, resulting in improved neurological outcomes. Methods: We used a total of 24 male pigs in this study. We excluded two animals: one because of cardiac arrest after the initial hemorrhage, and the second because of a catheter malfunction for color microspheres. In Series 1, anesthetized pigs underwent an initial hemorrhage of 40 mL/kg for 30 min, and then were given either 3 mg/kg of NHE1 selective inhibitor BIIB513 (n = 6) or vehicle (n = 6). At 1 h after treatment, all animals received fluid resuscitation. We assessed survival and neurologic outcomes 72 h postresuscitation. In Series 2, we measured organ blood flow in a separate group of control (n = 5) and BIIB513-treated pigs (n = 5) undergoing the same experimental paradigm. Results: Five of six control animals failed to be weaned from mechanical ventilation. We killed another control animal the next day because of severe complications. In contrast, all six animals treated with BIIB513 were weaned off the ventilator, and all but one survived the 72-h experimental period with normal neurological outcome. Results showed that NHE1 inhibition with BIIB513 improved blood flow to the brain, heart, and kidney, and prevented the development of metabolic acidosis in the 1-h hypovolemic period. In addition, BIIB513 facilitated the hemodynamic response to fluid resuscitation, increased mixed venous blood oxygen saturation and oxygen delivery, and reduced proinflammatory cytokine release and multiorgan injury compared with vehicle controls. Conclusions: In this study, NHE1 inhibition with BIIB513 improved vital organ blood flow, prevented the development of metabolic acidosis during prolonged hypovolemia, and facilitated the hemodynamic response to fluid resuscitation, resulting in increased survival and normal neurological outcomes.
KW - Hemorrhagic shock
KW - Na/H exchanger
KW - Neurological outcomes
KW - Oxygen transport
KW - Resuscitation
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U2 - 10.1016/j.jss.2012.07.026
DO - 10.1016/j.jss.2012.07.026
M3 - Article
C2 - 22878146
AN - SCOPUS:84876413711
VL - 181
SP - E75-E81
JO - Journal of Surgical Research
JF - Journal of Surgical Research
SN - 0022-4804
IS - 2
ER -