Pressor Choice Influences Protection Of Autoregulation in Brain Injury

加压剂选择影响脑损伤中自动调节的保护

• 批准号: 9331755
• 负责人: WILLIAM M ARMSTEAD
• 金额: $ 34.89万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331755
• 关键词: Address; Adolescent; Adult; Affect; Age; Area; Bilateral; Brain; Brain Injuries; Carotid Arteries; Cause of Death; Cerebral Ischemia; Cerebral perfusion pressure; Cerebrovascular Circulation; Cerebrum; Cessation of life; Child; Childhood; Clinical; Data; Dilator; Dinoprostone; Drops; Endothelin-1; Epinephrine; Ethics; Family; Family suidae; Female; Fostering; Guidelines; Histopathology; Homeostasis; Human; Hypotension; Impairment; Injury; Interleukin-6; Intervention; Intracranial Pressure; Investigation; Laser-Doppler Flowmetry; Lead; Link; MAP Kinase Gene; MAPK14 gene; MAPK8 gene; Mediating; Mitogen-Activated Protein Kinases; Modeling; Newborn Infant; Norepinephrine; Outcome; Patients; Phenylephrine; Potassium Channel; Pressor Support; Prostaglandins; Protein Isoforms; Regulation; Research; Research Personnel; Role; Signal Transduction; Testing; Translational Research; Trauma; Traumatic Brain Injury; Up-Regulation; Vasoconstrictor Agents; Vasodilation; adrenomedullin; age related; base; boys; cerebral hemodynamics; disability; experimental study; fluid percussion injury; male; neurovascular unit; pressure; prevent; public health relevance; response; sex; virtual; young adult

 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.

 描述（由适用提供）：低血压和低脑灌注压力（CPP，平均动脉压[MAP]减去颅内压[ICP]）与低脑血流（CBF），大脑缺血和较差的脑部缺血和较差的脑损伤后（TBI）有关。 TBI是儿童和年轻人与受伤有关的主要原因，男孩和儿童在4岁以下的结果特别差。脑自动调节通常会在TBI后受损，并且伴随性低血压和高ICP会导致预后不良。当前的2012年小儿指南建议将CPP保持在40 mm Hg以上，并指出与年龄相关的最佳CPP连续体为40至65 mm Hg。使用加压器来增加MAP/CPP并优化CBF，通常可以管理将CPP保持在这些级别中。然而，在TBI之后用于升高图的加压剂，例如苯肾上腺素（PHE），肾上腺素（EPI）和去甲肾上腺素（NE）（NE）尚未在对CPP，CBF，自动调节和TBI之后的效果以及在TBI之后以及实际上尚未在其机构上的影响方面进行过充分的比较。由于在TBI儿童中的道德考虑约束机械研究以来，我们使用了既定的流体打击乐损伤猪模型（FPI）来对TBI中的加压剂机制有更多了解。像人类一样，猪具有沟渠的大脑，对TBI敏感，新生儿和少年猪与儿童和年轻人相对应。 FPI后FPI后的脑血液动力学受损和自动调节受损是由于内皮素-1（ET-1）的年龄增加而引起的，前列腺素（ET-1）的降低（PG）。我们观察到，雌性新生猪的雌性但加剧了脑自动调节损害的加速器苯肾上腺素（PHE）。与FPI后女性新生儿ET-1的最小增加相比，这种差异结果与男性ET-1的增加有关。挑衅性的初步数据指标表明，与新生儿猪相比，自动调节受损在FPI后在男性和雌性少年猪中受PHE的保护。这些数据表明，TBI之后的训练支持选择对自动调节的保护与年龄和性别的关系不同。总体假设是，加速器对TBI后自动调节的保护有所不同，并且这些差异归因于大脑扩张剂（PGE2，ADM）和大脑收缩（ET-1）比率的年龄和性别依赖性调节。目的是：＃1。比较雄性和雌性猪在TBI后对PHE，EPI和NE对脑血液动力学的影响和自动调节的影响。 ＃2：比较PHE，EPI和NE会影响猪在TBI之后的脑血液动力学和自动调节的机制与年龄和性别的关系。 ＃3：确定PHE，EPI和NE诱导的脑血液动力学调节的功能意义，并保护猪在TBI后对自动调节的保护，这是年龄和性别的函数。