Vasoactive Agents and Cerebral Outcomes in Brain Injury

 描述（由申请人提供）：创伤是儿童和青少年的主要杀手，创伤性脑损伤（TBI）是儿科创伤相关死亡的主要原因，其中男孩和幼儿的结局更糟。当护理受伤的儿童时，一线医生如外科医生、麻醉师、急诊医生和重症监护医生通常努力预防和/或方便地纠正不希望的但普遍存在的低血压。这是有问题的，因为全身性低血压引起低脑灌注（脑灌注压[CPP]和脑血流量[CBF]），导致脑缺血和不良结局。此外，脑自身调节受损后，TBI，这阻止了脑灌注在全身性低血压。目前的II级建议是保持收缩压> 70 + 2（年龄）和CPP高于40 mmHg。静脉内血管活性剂，如苯肾上腺素（PHE）、去甲肾上腺素（NE）、多巴胺（DA）和肾上腺素（EPI），虽然用于治疗液体/血液制品纠正后的低血压，但缺乏预期效果的比较。因此，血管活性剂的初始选择主要是经验性的和可变的。重要的是，尚未比较血管活性药物对创伤后脑结局（血流动力学[CPP]和灌注[CBF和脑自动调节]）的影响;几乎不知道它们的机制或这些机制如何与TBI相关。我们以前的工作表明，了解哪种静脉血管活性药物更好地纠正低血压在临床上很重要，血管活性药物对神经血管单位（NVU）的影响不同，NVU在脑灌注和结局中起着重要作用。然而，在小儿创伤/TBI中，尚未阐明脑灌注或自动调节障碍的机制。总体假设是，常用的静脉血管活性药物对TBI的脑结局具有不同的机制作用，这些差异与性别和年龄有关。具体目标是：1）按年龄和性别检查静脉内施用的血管活性剂（PHE、NE、DA、EPI）与TBI后脑灌注（血流动力学和自动调节）之间的关联; 2）按年龄和性别研究血管活性剂（PHE、NE、DA、EPI）影响儿童TBI后脑血流动力学和自动调节的机制。这项探索性R21研究的影响将是提供关于血管活性药物的初始选择是否以及如何影响儿童TBI的NVU、脑血流动力学和脑灌注特征的新信息。

 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.