Traumatic brain injury: Symptoms to systems in the 21st century

Abstract

• No drug therapy has reduced mortality after moderate-to-severe TBI. • Lack of effective drugs may be a consequence of the way we study TBI. • A more integrated systems-based approach may increase animal to human translation and lead to breakthrough treatments. • A revolution is required to better understand how the whole body responds to TBI, identify markers of its progression, and discover new system-acting drugs to treat it. Severe traumatic brain injury (TBI) is a devastating injury with a mortality of ∼ 25–30 %. Despite decades of high-quality research, no drug therapy has reduced mortality. Why is this so? We argue two contributing factors for the lack of effective drug therapies include the use of specific-pathogen free (SPF) animals for translational research and the flawed practice of single-nodal targeting for drug design. A revolution is required to better understand how the whole body responds to TBI, identify new markers of its progression, and discover new system-acting drugs to treat it. In this review, we present a brief history of TBI, discuss its system’s pathophysiology and propose a new research strategy for the 21st century. TBI progression develops from injury signals radiating from the primary impact, which can cause local ischemia, hemorrhage, excitotoxicity, cellular depolarization, immune dysfunction, sympathetic hyperactivity, blood brain barrier breach, coagulopathy and whole-body dysfunction. Metabolic reprograming of immune cells drives neuroinflammation and secondary injury processes. We propose if sympathetic hyperactivity and immune cell activation can be corrected early, cardiovascular function and endothelial-glycocalyx-mitochondrial coupling can be restored, and secondary injury minimized with improved patient outcomes. The therapeutic goal is to switch the injury phenotype to a healing phenotype by restoring homeostasis and maintaining sufficient tissue O 2 delivery. We have been developing a small-volume fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat TBI and have shown that it blunts the CNS-stress response, supports cardiovascular function and reduces secondary injury. Future research will investigate its suitability for human translation

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