Vasoactive Agents and Cerebral Outcomes in Brain Injury

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 DESCRIPTION (provided by applicant): Trauma is the leading killer of children and adolescents, and traumatic brain injury (TBI) is the leading cause of pediatric trauma related death, where boys and young children have worse outcomes. When caring for injured children, front line physicians such as surgeons, anesthesiologists, emergency medicine physicians, and intensivists often struggle to prevent and/or expediently correct the unwanted but prevalent hypotension. This is problematic because systemic hypotension causes low cerebral perfusion (cerebral perfusion pressure [CPP] and cerebral blood flow [CBF], resulting in brain ischemia and poor outcomes. Moreover, cerebral autoregulation is impaired after TBI, which prevents brain perfusion during systemic hypotension. Current Level II recommendations are to maintain systolic blood pressure > 70 + 2 (age) and CPP above 40 mmHg. Intravenous vasoactive agents such as phenylephrine (PHE), norepinephrine (NE), dopamine (DA) and epinephrine (EPI), while used to treat hypotension after correction with fluids/ blood products, lack comparison with respect to desired effect. Thus, initial choice of vasoactive agent is largely empiric, and variable. Importantly, vasoactive agents have not been compared vis-à-vis their effect on cerebral outcomes (hemodynamics [CPP] and perfusion [CBF and cerebral autoregulation]) after trauma; virtually nothing is known about their mechanisms or how these mechanisms relate to TBI. Our previous work suggests that knowing which intravenous vasoactive better corrects hypotension is clinically important, vasoactive agents differentially affect the neurovascular unit (NVU), and that the NVU plays an important role in cerebral perfusion and outcomes. Yet, no mechanisms for cerebral perfusion or dysautoregulation have been elucidated in pediatric trauma/TBI. The overarching hypothesis is that commonly used intravenous vasoactive agents have differential mechanistic effects on cerebral outcomes in TBI, and these differences are related to sex and age. The Specific Aims are to: 1) Examine the association between intravenously administered vasoactive agents (PHE, NE, DA, EPI) and cerebral perfusion (hemodynamics and autoregulation) after TBI by age and sex, and 2) Investigate the mechanism by which vasoactive agents (PHE, NE, DA, EPI) affect cerebral hemodynamics and autoregulation after TBI in children by age and sex. The impact of this exploratory R21 study will be to provide new information as to whether and how initial choice of vasoactive agent affects the NVU, cerebral hemodynamics and cerebral perfusion characteristics in pediatric TBI by age and sex.