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NHE1 inhibition improves tissue perfusion and resuscitation outcome after severe hemorrhage.
MedLine Citation:
PMID:  22878146     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Dongmei Wu; Kristina Russano; Irene Kouz; William M Abraham
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-31
Journal Detail:
Title:  The Journal of surgical research     Volume:  -     ISSN:  1095-8673     ISO Abbreviation:  J. Surg. Res.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-8-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376340     Medline TA:  J Surg Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Affiliation:
Division of Neonatology, Department of Research, Mount Sinai Medical Center, Miami Beach, Florida; The WCU Program, Department of BIN Fusion Technology, Chonbuk National University, Korea.
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