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

Abstract

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.

Metabolomics and Precision Medicine in Trauma: The State of the Field

“…Furthermore, decreased lipid synthesis and urea cycle activity in the liver as well as increased hyperglycemia and lactic- and keto-acidosis have been shown to occur after injury (21, 90). These have been noted in fasting and fed states (24, 91, 92). Clinical care can both affect the metabolic response after trauma and be informed by changes in metabolic profiles.…”

“…Traditionally, high-field NMR has been the method of choice in metabolomic investigations (21–23). In fact, most of the published investigations involving the metabolic studies of trauma have relied on 1 H NMR (21–24). NMR is highly quantitative which allows the acquired data to be extremely reproducible.…”

Serum Metabolomics as a Powerful Tool in Distinguishing Trauma from Other Critical Illness Conditions

“…Lacking specific therapies for traumatic injury, early treatment is a key to improving survival. Metabolomics has already been successfully used to identify succinate, an objective biomarker of mortality, to improve triage [20][21][22]. However, new technology needs to be developed to bring succinate detection and quantification to the clinic.…”