Inducing metabolic suppression in severe hemorrhagic shock: pilot study results from the biochronicity project.

BACKGROUND: 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 PI3-kinase inhibition (PI3-KI) would produce metabolic suppression without worsening organ injury or systemic physiology. METHODS: Twenty swine were studied using LY294002 (LY), a non-selective PI3-KI: Animals were assigned to Trauma only (TO, N=3); DMSO 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. RESULTS: Baseline values were similar amongst the groups. Compared with the TO group, the LYO group had reversible decreases in HR, MAP, cardiac output (CO), oxygen consumption, and carbon dioxide production. Compared with TO, LY+T showed sustained decreases in HR (113 vs. 76, p=.03), MAP (40 vs. 31 mmHg, p=.02), and CO (3.8 vs. 1.9 L/min, p=.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=.012) and LYO (119 vs 225 ml/min, p=.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=.043) and LYO (114 vs. 195 ml/min, p=.034) groups. There was no worsening of acidosis (lactate 6.4 vs. 8.3 mmol/L, p=0.4) or other endpoints. IL6 showed a significant increase in LY+T when compared to TO at 6 hours (60.5 vs. 2.47, p=.043). TNF[alpha] and IL1[beta] were decreased and IL10 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. CONCLUSIONS: PI3-KI 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. (C) 2016 Lippincott Williams & Wilkins, Inc.

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