title: Inducing metabolic suppression in severe hemorrhagic shock: Pilot study results from the Biochronicity Project.
abstract: Suspended animation-like states have been achieved in small animal models, but not in larger species. Inducing metabolic suppression and temporary oxygen independence could enhance survivability of massive injury. Based on prior analyses of key pathways, we hypothesized that phosphoinositol-3-kinase inhibition would produce metabolic suppression without worsening organ injury or systemic physiology.
  
  
  
  Twenty swine were studied using LY294002 (LY), a nonselective phosphoinositol-3-kinase inhibitor. Animals were assigned to trauma only (TO, n = 3); dimethyl sulfoxide only (DMSO, n = 4), LY drug only (LYO, n = 3), and drug + trauma (LY + T, n = 10) groups. Both trauma groups underwent laparotomy, 35% hemorrhage, severe ischemia/reperfusion injury, and protocolized resuscitation. Laboratory, physiologic, cytokine, and metabolic cart data were obtained. Histology of key end organs was also compared.
  
  
  
  Baseline values were similar among the groups. Compared with the TO group, the LYO group had reversible decreases in heart rate, mean arterial pressure, cardiac output, oxygen consumption, and carbon dioxide production. Compared with TO, LY + T showed sustained decreases in heart rate (113 vs. 76, p = 0.03), mean arterial pressure (40 vs. 31 mm Hg, p = 0.02), and cardiac output (3.8 vs. 1.9 L/min, p = 0.05) at 6 hours. Metabolic parameters showed profound suppression in the LY + T group. Oxygen consumption in LY + T was lower than both TO (119 vs. 229 mL/min, p = 0.012) and LYO (119 vs. 225 mL/min, p = 0.014) at 6 hours. Similarly, carbon dioxide production was decreased at 6 hours in LY + T when compared with TO (114 vs. 191 mL/min, p = 0.043) and LYO (114 vs. 195 mL/min, p = 0.034) groups. There was no worsening of acidosis (lactate 6.4 vs. 8.3 mmol/L, p = 0.4) or other endpoints. Interleukin 6 (IL-6) showed a significant increase in LY + T when compared with TO at 6 hours (60.5 vs. 2.47, p = 0.043). Tumor necrosis factor α and IL-1β were decreased, and IL-10 increased in TO and LY + T at 6 hours. Markers of liver and kidney injury were no different between TO and LY + T groups at 6 hours.
  
  
  
  Phosphoinositol-3-kinase inhibition produced metabolic suppression in healthy and injured swine without increasing end-organ injury or systemic physiologic markers and demonstrated prolonged efficacy in injured animals. Further study may lead to targeted therapies to prolong tolerance to hemorrhage and extend the "golden hour" for injured patients.
authors.affiliation: From the Department of Surgery, Madigan Army Medical Center, Fort Lewis, Washington (G.E.B., K.K.S., R.R.S., M.J.E., S.S., M.J.M.); Department of Clinical Investigation, Madigan Army Medical Center, Fort Lewis, Washington (S.T.M.); the Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington (C.C.K., M.B.R.); and Department of Pathology, Madigan Army Medical Center, Fort Lewis, Washington (Z.S.H.).
authors.forename: George E
authors.initials: GE
authors.lastname: Black
authors.forename: Kyle K
authors.initials: KK
authors.lastname: Sokol
authors.forename: Robert R
authors.initials: RR
authors.lastname: Shawhan
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Eckert
authors.forename: Shashikumar
authors.initials: S
authors.lastname: Salgar
authors.forename: Shannon T
authors.initials: ST
authors.lastname: Marko
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Hoffer
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Keyes
authors.forename: Mark B
authors.initials: MB
authors.lastname: Roth
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Martin
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002302:Cardiac Output; D002867:Chromones / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D009025:Morpholines / Q000627:therapeutic use*; D010101:Oxygen Consumption; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000378:metabolism* / Q000628:therapy*; D013552:Swine
chemical_list: D002867:Chromones; D016207:Cytokines; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one