The effects of glycemic control on post-traumatic brain metabolism

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Animal studies have demonstrated a disturbance in oxidative and glucose metabolism after traumatic brain injury (TBI), with depression of metabolism being a significant feature. Our recent human studies have demonstrated two related findings: 1) There is a prolonged period of metabolic depression after brain injury and 2) extracellular glucose concentrations are frequently low during this metabolic depression. The duration and extent of low extracellular glucose concentration are independent predictors of neurologic outcome. At the same time, many experimental and clinical studies have demonstrated that systemic hyperglycemia adversely affects outcome after human TBI. Hence, the current standard of care requires the use of insulin to maintain nomoglycemia. However, little is known about the effects of glycemic control on brain metabolism nor the potential adverse effects of limiting glucose supply through strict glycemic control after TBI. We have demonstrated that insulin results in reduction in extracellular glucose and an increase in extracellular glutamate (Vespa, 2006) suggesting a possible adverse effect. Thus, there exists a controversy about on how best to manage systemic glucose concentrations in TBI. Given the potential therapeutic implications, there is a profound need to better understand the effects of glycemic control on brain metabolism after TBI. This project proposes to study the null hypothesis that limitation of glucose availability (serum glucose concentrations) reduces the rates of cerebral glucose and oxidative metabolism, by using a controlled insulin infusion to achieve normal serum glucose concentrations (80-110 mg/dl). In addition, we propose to test a secondary hypothesis that reduction of serum glucose to normal concentrations will result in microdialysis markers of metabolic distress in post-traumatic brain injured patients using a combined within-subjects and randomized cross over study design. This project is intricately inter-related with projects 1, 2 and 4 of this PPG.