Suspension Of Biologic Time In Fatal Traumatic Injury: Preliminary Results From The Biochronicity Project

George E Black, MD, Kyle K Sokol, MD, Robert Shawhan, MD, Matthew J Eckert, MD, Matthew J Martin, MD. Madigan Army Medical Center

Objectives: Biologic time is the idea that energy production and consumption, and the biologic processes they control, are inherently linked to the life span of a cell or organism. Studies in small animals have shown the ability to slow or stop biologic time and induce a state of “suspended animation”. These studies have not been attempted in larger animal models. One of the experimental drugs used in this research is the PI3-kinase inhibitor LY294002. We hypothesized that use of this drug in a hemorrhagic/ischemic porcine trauma model would decrease the metabolic rate of the animals and have potential effects on physiologic, hemodynamic, and certain genomic factors.

Methods: Three study groups were formed. One control group underwent trauma but did not receive drug (Trauma/No Drug), one group received test drug but did not undergo trauma (No Trauma/Drug) and a third group underwent trauma and received drug (Trauma/Drug). All animals in trauma groups underwent laparotomy, 35% hemorrhage, and supraceliac aortic cross-clamping and administration of drug as appropriate followed by reperfusion and resuscitation. Physiologic, metabolic cart (specifically O₂ consumption and CO₂ production) and laboratory data were obtained prior to hemorrhage and at multiple time points during resuscitation. All animals were survived for 6 hours.

Results: When compared with the Trauma/No Drug animals, the animals in the No Trauma/Drug group had initial decreases in heart rate, O₂ consumption and CO₂ production which were not sustained through the 6 hour resuscitation period. The Trauma/Drug animals showed a 35% decrease in heart rate at 6 hours when compared to the Trauma/No Drug animals which had a 10% increase in heart rate at 6 hours. The mean arterial pressure (MAP) at 6 hours in both groups showed a decrease from baseline of approximately 50%. Despite significantly lowered MAP throughout the 6 hour resuscitation course the animals in the Trauma/Drug group showed a steady decline in lactate level. Lactate increased by 15% less than the Trauma/No Drug animals at 6 hours. O₂ consumption in the Trauma/No Drug animals decreased by an average of 6% at 6 hours while in the Trauma/Drug animals this parameter decreased by 31%. Similarly CO₂ production in the Trauma/No Drug animals was decreased by 12.5% on average while the Trauma/Drug animals have shown a 41% average decrease.

Conclusion: While much of our data has yet to be obtained, preliminarily we have shown that LY294002 is effective at decreasing the metabolic rate in animals that have suffered a simulated hemorrhagic/ischemic insult without increasing lactate levels. A majority of battlefield deaths continue to be secondary to large volume hemorrhage. The use of novel agents to decrease metabolic demand and help extend the “golden hour” of trauma could foreseeably buy extra time to help injured soldiers reach definitive care prior to succumbing to their injuries. Further research will be necessary to determine the use and efficacy of this drug for that purpose.