Optimization of brain metabolism using metabolic-targeted therapeutic hypothermia can reduce mortality from traumatic brain injury.

Background: Therapeutic hypothermia is widely used to treat traumatic brain injuries (TBIs). However, determining the best hypothermia therapy strategy remains a challenge. We 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[degrees]C body temperature. Brain and circulatory metabolic pool blood samples were collected at baseline and on days 1, 3, and 7 during the hypothermia treatment, which were selected randomly from a subgroup of MTHT and BTHT groups. The primary outcome was mortality. Using 1HNMR technology, we tracked and located 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 the MTHT and BTHT groups (median age, 42 years; 69.32% males; mean Glasgow Coma Scale 6.17+/-1.02). The mortality was significantly lower in the MTHT than the BTHT group (15.91% vs. 34.09%, p=0.049). From these, 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 based on the model parameters and scores plots. Finally, metabolites representing potential neuroprotective monitoring parameters for hypothermia treatment were identified through 1HNMR metabolomics. Conclusions: MTHT can significantly reduce the mortality of severe TBI patients. Metabolomics research showed that this strategy could effectively improve brain metabolism, suggesting that reducing the metabolic rate to 50-60% should be set as the hypothermia therapy target. Study Type: Randomized Controlled Trial Level of Evidence: I (C) 2017 Lippincott Williams & Wilkins, Inc.

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