Optimization Metabolic-targeted Therapeutic Hypothermia For Traumatic Brain Injury

Objective: Therapeutic hypothermia is widely used to treat traumatic brain injuries(TBIs).However,how to target hypothermia therapy remains a challenge.This study hypothesized that reducing the metabolic rate,rather than reaching a fixed body temperature,would be an appropriate target,as optimizing metabolic conditions,especially the brain metabolic environment,may enhance neurologic protection.A pilot single-blind randomized controlled trial was designed to test this hypothesis,and a nested metabolomics study was conducted to explore the mechanics thereof.Methods: Severe TBI patients(Glasgow Coma Scale,3-8)were randomly divided into the metabolic-targeted hypothermia treatment(MTHT)group: 50-60% rest metabolic ratio as the hypothermia therapy target,and the body temperature-targeted hypothermia treatment(BTHT)control group: hypothermia therapy target of 32-35°C body temperature.The patients were enrolled in this study if they met the following inclusion criteria: 1)diagnosis of severe TBI;2)Glasgow Coma Scale score of 3-8 and Injury Severity Score ?16;3)age 14-65 years;and 4)?12 hours after brain injury or ?6 hours after emergency brain surgery.The exclusion criteria were as follows: 1)pregnancy or breast-feeding;2)patients with severe chronic illnesses such as severe cardiovascular disease and liver and kidney directive damage or failure;3)severe combined injury or hypothermia(<35°C);4)age<14 years or > 65 years with special metabolic patterns potentially;5)patients with various types of shock;and 6)patients not providing informed consent.Brain and circulatory metabolic pool blood samples were collected at baseline and on days 1,3,and 7 during the hypothermia treatment,which were subgroup randomly selected from the MTHT and BTHT groups,respectively.The primary outcome was mortality.Using proton nuclear magnetic resonance(1HNMR)metabolomics technology,we explored the disturbances of metabolic networks.Results: 88 severe TBI patients were recruited and analyzed from December 2013 to December 2014,44 each were assigned in MTHT and BTHT groups,respectively(median age,42 years;69.32% males;mean Glasgow Coma Scale 6.17±1.02).The mortality was significantly lower in the MTHT vs.BTHT group(15.91% vs.34.09%,P=0.049).8 cases of MTHT and 6 cases from BTHT group were enrolled for metabolomics analysis,which showed a significant difference between the brain and circulatory metabolic patterns in MTHT group on day 7.Finally,metabolites representing potential neuroprotective monitoring parameters for optimized hypothermia treatment were identified through 1HNMR metabolomics.Conclusions: MTHT can significantly reduce the mortality of severe TBI patients.Metabolomics research showed that strategy could effectively improve brain metabolism,suggesting that reducing the metabolic rate to 50-60% should be set as the hypothermia therapy target.