Improving Understanding and Outcomes of Traumatic Brain Injury Using Bidirectional Translational Research

Abstract

Recent clinical trials in traumatic brain injury (TBI) have failed to demonstrate therapeutic effects even when there appears to be good evidence for efficacy in one or more appropriate pre-clinical models. While existing animal models mimic the injury, difficulties in translating promising therapeutics are exacerbated by the lack of alignment of discrete measures of the underlying injury pathology between the animal models and human subjects. To address this mismatch, we have incorporated reverse translation of bedside experience to inform pre-clinical studies in a large animal (pig) model of TBI that mirror practical clinical assessments. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. Cerebral perfusion pressure (CPP) is often normalized by use of vasoactive agents to increase mean arterial pressure (MAP) and thereby limit impairment of cerebral autoregulation and neurological deficits. Vasoactive agents clinically used to elevate MAP to increase CPP after TBI, such as phenylephrine (Phe), dopamine (DA), norepinephrine (NE), and epinephrine (EPI), however, have not been compared sufficiently regarding effect on CPP, autoregulation, and survival after TBI, and clinically, current vasoactive agent use is variable. The cerebral effects of these clinically commonly used vasoactive agents are not known. This review will emphasize pediatric work and will describe bidirectional translational studies using a more human-like animal model of TBI to identify better therapeutic strategies to improve outcome post-injury. These studies in addition investigated the mechanism(s) involved in improvement of outcome in the setting of TBI.

Keywords: age; brain injury; cerebral autoregulation; histopathology; sex; signal transduction; vasopressor.

FIG. 1.

Mechanisms and clinical implications of cardiac dysfunction after neurologic illness. Adapted from Chest. ECG, electrocardiography. Color image is available online.