Inducing metabolic suppression in severe hemorrhagic shock
| Autor: | Matthew J. Martin, Zachary S. Hoffer, Shannon T. Marko, Matthew J. Eckert, Kyle K. Sokol, George E. Black, Robert R. Shawhan, Shashikumar Salgar, Christopher C. Keyes, Mark B. Roth |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Cardiac output
Resuscitation Mean arterial pressure medicine.medical_specialty Swine Morpholines medicine.medical_treatment Blood Pressure Shock Hemorrhagic Critical Care and Intensive Care Medicine 03 medical and health sciences Oxygen Consumption 0302 clinical medicine Internal medicine Heart rate Animals Medicine Cardiac Output Enzyme Inhibitors Interleukin 6 Phosphoinositide-3 Kinase Inhibitors Acidosis biology business.industry 030208 emergency & critical care medicine medicine.disease Disease Models Animal Cytokine Endocrinology Chromones 030220 oncology & carcinogenesis biology.protein Cytokines Surgery medicine.symptom business Reperfusion injury |
| Zdroj: | Journal of Trauma and Acute Care Surgery. 81:1003-1011 |
| ISSN: | 2163-0755 |
| Popis: | 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 phosphoinositol-3-kinase inhibition would produce metabolic suppression without worsening organ injury or systemic physiology. METHODS 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. RESULTS 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. CONCLUSIONS 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. |
| Databáze: | OpenAIRE |
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