Metabolomic analysis of survival in carbohydrate pre-fed pigs subjected to shock and polytrauma

• Published in: Molecular bioSystems 2016-04, Vol.12 (5), p.1638-1652
• Main Authors: Witowski, Nancy E, Lusczek, Elizabeth R, Determan, Charles E, Lexcen, Daniel R, Mulier, Kristine E, Wolf, Andrea, Ostrowski, Beverly G, Beilman, Greg J
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers; Cluster Analysis; Diet, Carbohydrate Loading; Disease Models, Animal; Magnetic Resonance Spectroscopy; Metabolome; Metabolomics - methods; Mitochondria - metabolism; Multiple Trauma - metabolism; Multiple Trauma - mortality; Organ Specificity; Resuscitation; Shock, Hemorrhagic - metabolism; Shock, Hemorrhagic - mortality; Swine; Time Factors
• ISSN: 1742-206X; 1742-2051
• DOI: 10.1039/c5mb00637f

Hemorrhagic shock, a result of extensive blood loss, is a dominant factor in battlefield morbidity and mortality. Early rodent studies in hemorrhagic shock reported carbohydrate feeding prior to the induction of hemorrhagic shock decreased mortality. When repeated in our laboratory with a porcine model, carbohydrate pre-feed resulted in a 60% increase in death rate following hemorrhagic shock with trauma when compared to fasted animals (15/32 or 47% vs. 9/32 or 28%). In an attempt to explain the unexpected death rate for pre-fed animals, we further investigated the metabolic profiles of pre-fed non-survivors (n = 15) across 4 compartments (liver, muscle, serum, and urine) at specific time intervals (pre-shock, shock, and resuscitation) and compared them to pre-fed survivors (n = 17). As hypothesized, pre-fed pigs that died as a result of hemorrhage and trauma showed differences in their metabolic and physiologic profiles at all time intervals and in all compartments when compared to pre-fed survivors. Our data suggest that, although all animals were subjected to the same shock and trauma protocol, non-survivors exhibited altered carbohydrate processing as early as the pre-shock sampling point. This was evident in (for example) the higher levels of ATP and markers of greater anabolic activity in the muscle at the pre-shock time point. Based on the metabolic findings, we propose two mechanisms that connect pre-fed status to a higher death rate: (1) animals that die are more susceptible to opening of the mitochondrial permeability transition pore, a major factor in ischemia/reperfusion injury; and (2) loss of fasting-associated survival mechanisms in pre-fed animals.