Pressor Choice Influences Protection Of Autoregulation in Brain Injury

 描述（由申请方提供）：低血压和低脑灌注压（CPP，平均动脉压[MAP]减去颅内压[ICP]）与低脑血流量（CBF）、脑缺血和创伤性脑损伤（TBI）后不良结局相关。TBI是儿童和年轻人与伤害有关的死亡的主要原因，男孩和4岁以下儿童的结果特别差。脑外伤后脑自动调节功能常受损，并伴有低血压和高颅内压，导致预后不良。目前的2012年儿科指南建议将CPP保持在40 mm Hg以上，并指出最佳CPP的年龄相关连续性在40至65 mm Hg之间。将CPP维持在这些水平内通常通过使用血管加压药来增加MAP/CPP并优化CBF来管理。然而，临床上用于升高TBI后MAP的血管加压药，如苯肾上腺素（Phe）、肾上腺素（EPI）和去甲肾上腺素（NE），在对CPP、CBF、自动调节和TBI后结局的影响方面尚未进行充分比较，并且几乎对其作用机制一无所知。由于伦理方面的考虑限制了儿童TBI的机制研究，我们使用了一个建立的猪模型的液压冲击损伤（FPI），以获得更好的了解TBI的血管加压机制。与人类一样，猪也有脑回，对TBI敏感，新生和幼年猪与儿童和年轻的成年人相对应。FPI后脑血流动力学受损和自动调节紊乱是由内皮素-1（ET-1）的年龄依赖性增加和肾上腺素（PG）的减少引起的。本实验观察到，苯肾上腺素（Phe）可预防雌性新生猪脑自动调节功能的损害，但可加重雄性新生猪脑自动调节功能的损害。与FPI后女性新生儿ET-1的最小增加相比，男性ET-1的增加与这种差异性结果有关。挑衅性的初步数据表明，与新生猪相比，受损的自动调节在FPI后的雄性和雌性幼猪中受到Phe的同等保护。这些数据表明，TBI后升压支持的选择差异影响保护的自动调节作为一个功能的年龄和性别。总体假设是，血管加压素差异影响TBI后的自动调节保护，这些差异可归因于年龄和性别依赖性的脑扩张剂（PGE 2，ADM）和脑收缩剂（ET-1）比例的调节。目标是：#1。比较Phe、EPI和NE全身给药对雄性和雌性猪TBI后脑血流动力学和自动调节的影响，作为年龄的函数。#2：比较Phe、EPI和NE影响猪TBI后脑血流动力学和自动调节的机制，作为年龄和性别的函数。第三名：确定Phe、EPI和NE诱导的脑血流动力学调节的功能意义以及TBI后猪的自动调节的保护作用作为年龄和性别的函数。

 DESCRIPTION (provided by applicant): Hypotension and low cerebral perfusion pressure (CPP, mean arterial pressure [MAP] minus intracranial pressure [ICP]) are associated with low cerebral blood flow (CBF), cerebral ischemia, and poor outcomes after traumatic brain injury (TBI). TBI is the leading cause of injury related death in children and young adults, with boys and children under 4 years having particularly poor outcomes. Cerebral autoregulation is often impaired after TBI and with concomitant hypotension and high ICP, lead to poor outcome. Current 2012 Pediatric Guidelines recommend maintaining CPP above 40 mm Hg, noting that an age-related continuum for the optimal CPP is between 40 and 65 mm Hg. Maintaining CPP within these levels is often managed by the use of vasopressors to increase MAP/CPP and optimize CBF. However, vasopressors clinically used to elevate MAP after TBI, such as phenylephrine (Phe), epinephrine (EPI), and norepinephrine (NE) have not sufficiently been compared regarding effect on CPP, CBF, autoregulation, and outcomes after TBI and virtually nothing is known about their mechanisms of action. Since ethical considerations constrain mechanistic studies in children with TBI, we have used an established porcine model of fluid percussion injury (FPI) to gain greater understanding of vasopressor mechanism in TBI. Like humans, pigs have gyrencephalic brains, are sensitive to TBI, and newborn and juvenile pigs correspond with children and young adult humans. Impaired cerebral hemodynamics and disturbed autoregulation post FPI is caused by an age dependent increase in endothelin-1 (ET-1) and decrease in prostaglandins (PG). We observed that the vasopressor phenylephrine (Phe) prevented in female but exacerbated impairment of cerebral autoregulation in male newborn pigs. This differential outcome related to an increase in ET-1 in males compared to a minimal increase in ET-1 in female newborns after FPI. Provocative Preliminary Data indicate that, in contrast to newborn pigs, impaired autoregulation is equivalently protected by Phe in male and female juvenile pigs after FPI. These data suggest that pressor support choice after TBI differentially influences protection of autoregulation as a function of both age and sex. The overarching hypothesis is that vasopressors differentially influence protection of autoregulation after TBI and these differences are attributable to age- and sex-dependent modulation of cerebral dilator (PGE2, ADM) and cerebral constrictor (ET-1) ratios. The Aims are: # 1. Compare the effect of systemic administration of Phe, EPI, and NE on cerebral hemodynamics and autoregulation after TBI in male and female pigs as a function of age. # 2: Compare the mechanism by which Phe, EPI, and NE impacts cerebral hemodynamics and autoregulation after TBI in pigs as a function of age and sex. #3: Determine the functional significance of Phe, EPI, and NE induced modulation of cerebral hemodynamics and protection of autoregulation after TBI in pigs as a function of age and sex.