Abstract 13657: Induced Hypothermia Improves a Novel Array of Metabolic Outcomes After Mouse Hemorrhagic Shock

Abstract

Introduction: Hemorrhagic shock results in myocardial dysfunction which involves impaired aerobic metabolism leading to energy depletion (ATP and NAD) and lactate production. Prior studies demonstrated that hypothermia (TH) protects heart against HS injury and is associated with decreased metabolic activity and energy demand. We hypothesized that TH protection is result of preservation of energy substrates in tissues via reduced release into blood. Methods: Mice underwent arterial bleed (2.25 ml/100 g over 10 min) and were randomized to normothermia (NT, 37 ± 0.5 °C) and hypothermia (TH, 33 ± 0.5 °C) groups. MAP was then maintained at 35 ± 5 mmHg for 90 min. Resuscitation was initiated by reinfusion of shed blood plus L-lactate Ringer’s solution. TH was induced at 30 min of shock and maintained for 2 h. Hearts were collected at Sham, shock 5, 15, 30 and 90 min (S5, S15, S30 and S90 respectively), and the end of resuscitation (R180). Tissue and blood ATP, NAD, the inflammatory markers PBEF and tissue sorbitol were measured. Tissue content of ATP, NAD and the NAD synthesizing enzyme nicotinamide phosphoribosyltransferase (Nampt) were also measured. Results: Compared to NT, TH improved survival (33% vs. 83%, p < 0.5). In the NT group, ATP, NAD and Nampt were released into blood during shock with resuscitation, with significant attenuation by TH. In contrast, tissue levels of ATP and NAD were significantly higher than blood and were reduced during shock, with restoration to baseline levels in mice that survived to R180. Tissue sorbitol concentrations were increased during shock, were reduced by hypothermia and returned to baseline levels at R180 in mice that survived. Conclusions: Hemorrhagic shock resulted in rapid depletion of ATP and NAD, an effect attenuated by TH, as measured by increased release from muscle tissue into blood. This work identifies a novel array of metabolic markers potentially important to hemorrhagic shock outcome.