title: Low-volume resuscitation from traumatic hemorrhagic shock with Na+/H+ exchanger inhibitor.
abstract: OBJECTIVE
  To evaluate the use of a Na/H exchanger (NHE-1) inhibitor as a cardioprotective adjunct therapy to low-volume resuscitation in two different rat models of traumatic hemorrhagic shock.
  
  
  METHODS
  Experimental, prospective study.
  
  
  METHODS
  Medical center research laboratory.
  
  
  METHODS
  Sprague Dawley male rats.
  
  
  METHODS
  Series 1: femur fracture was induced in anesthetized rats, followed by pressure-controlled hemorrhage (40 mm Hg for 20 minutes) and resuscitation. Groups: 1) no therapy; 2) 15 mL/kg hetastarch; and 3) 3 mg/kg benzamide, N-(aminoiminomethyl)-4-[4-(2-furanylcarbonyl)-1-piperazinyl]-3-(methylsulfonyl), methanesulfonate (BIIB513) (NHE-1 inhibitor) + 15 mL/kg hetastarch infusion over 40 minutes. The experiment was terminated at 6 hours after resuscitation. Series 2: the rats received laparotomy and closure under anesthesia and subsequently remained conscious for the rest of the study. The rats were subjected to volume-controlled hemorrhage (2.5 mL/100 g) followed by resuscitation as described in series 1. The experiment was terminated at 24 hours after resuscitation.
  
  
  RESULTS
  Series 1: all animals in the no-therapy group died within 2 hours. Compared with hetastarch infusion alone, the addition of NHE-1 inhibitor improved the hemodynamic response to fluid resuscitation, increased blood oxygen content, prevented metabolic acidosis, and improved 6-hour survival (42% in hetastarch group vs. 80% in BIIB513 + hetastarch group). NHE-1 inhibition also resulted in reduced plasma levels of tumor necrosis factor-alpha, intercellular adhesion molecule-1, and C-reactive protein, and attenuated neutrophil infiltration in the liver. Series 2: all animals in the no-therapy group died within 4 hours after hemorrhage. Compared with hetastarch infusion alone, the addition of BIIB513 improved 24-hour survival (44% in hetastarch group vs. 78% in BIIB513 + hetastarch group). NHE-1 inhibition also reduced plasma levels alanine aminotransferase at 24 hours after resuscitation.
  
  
  CONCLUSIONS
  NHE-1 inhibition facilitated the hemodynamic response to fluid resuscitation, attenuated tissue inflammatory injury, and organ dysfunction, but most importantly improved survival.
authors.affiliation: Department of Research, Division of Neonatology, Mount Sinai Medical Center, Miller School of Medicine, University of Miami, Miami Beach, FL, USA. dwu@msmc.com
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wu
authors.forename: Hui
authors.initials: H
authors.lastname: Dai
authors.forename: Jaqueline
authors.initials: J
authors.lastname: Arias
authors.forename: Loren
authors.initials: L
authors.lastname: Latta
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
mesh_terms: D000818:Animals; D008297:Male; D008698:Mesylates / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation / Q000379:methods*; D012771:Shock, Hemorrhagic / Q000209:etiology* / Q000628:therapy*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D014947:Wounds and Injuries / Q000150:complications*
chemical_list: D008698:Mesylates; D017923:Sodium-Hydrogen Exchangers; C402725:BIIB 513