The Risk of Acute Respiratory Distress Syndrome after Severe Isolated Traumatic B

描述（由申请人提供）：美国每年有170万人遭受创伤性脑损伤（TBI），其中52，000人死亡。超过20%的严重、孤立性TBI患者会发展为急性呼吸窘迫综合征（ARDS）。TBI后发生ARDS与较高的医疗保健费用和较差的神经系统结局相关（Holland，2004，Mascia 2008）。目前对孤立性TBI患者肺损伤的机制知之甚少。本文提出的研究将利用全面的、前瞻性收集的数据和从大型孤立TBI患者队列中收集的血浆标本。我将评估可能导致发生ARDS风险的患者特定因素和护理过程的差异，并测试三种候选生物标志物在预测较高的ARDS风险中的效用。有生物相容性和来自小鼠和临床研究的数据支持更严重的头部损伤与ARDS相关的假设。我们的研究小组最近报道，另一个患者特异性因素，暴露于香烟烟雾，赋予创伤患者后续ARDS的更高风险（Calfee，2011）。在这里，我们建议测试的假设，病人的具体因素，如头部损伤的严重程度（目标1a）和暴露于烟草烟雾（目标1b），有助于生物紊乱，随后导致急性呼吸窘迫综合征患者孤立的创伤性脑损伤。此外，我们假设血浆炎症标志物、内皮活化和血管通透性将捕获单独TBI中ARDS的因果通路。我们将测量损伤后立即获得的血浆样本中的三种潜在生物标志物：白细胞介素-8（IL-8）、血管生成素2（Ang-2）和基质金属蛋白酶组织抑制剂-3（TIMP 3），并检验这些血浆蛋白的早期差异预测随后发生的ARDS（目的2）。除了研究到达急诊科时存在的因素外，我们还将确定导致ARDS风险的护理过程。2009年，Mascia等人描述了TBI中ARDS的两次打击模型，其中TBI使肺内皮更容易受到呼吸机诱导的肺损伤的影响。我们将检验以下假设：任何暴露于大潮气量通气（> 10 cc/kg理想体重）与孤立性TBI后ARDS风险增加相关（目标3）。我们还将评估是否暴露于高潮气量机械通气和ARDS的发展是通过测量的生物标志物IL-8、Ang-2和TIMP 3的变化的共同途径介导的。如果具有特殊临床特征和更严重炎症和内皮损伤的患者发生ARDS的风险更高，则本文概述的研究将建立一种在病程早期识别这些高风险患者的方法，并设计旨在改善严重孤立TBI患者临床结局的未来干预措施。开展这项工作将使我能够建立以患者为导向的科学研究，临床数据分析和科学合作的技能，这将为转化研究的职业生涯奠定基础。

DESCRIPTION (provided by applicant): Each year in the United States 1.7 million people sustain Traumatic Brain Injury (TBI) and 52,000 of these patients die. Over 20% of patients with severe, isolated TBI will develop Acute Respiratory Distress Syndrome (ARDS). The development of ARDS after TBI is associated with higher health care costs and worse neurological outcomes (Holland, 2004, Mascia 2008). Little is known about the mechanisms that cause lung injury in patients with isolated TBI. The studies proposed here will take advantage of comprehensive, prospectively collected data and plasma specimens collected from a large cohort of isolated TBI patients. I will evaluate patient specific factors and differences in processes of care that may contribute to the risk of developing ARDS, and to test the utility of three candidate biomarkers in predicting higher risk of ARDS. There is biologic plausibility and data from murine and clinical studies to support the hypothesis that more severe head injury is associated with ARDS. Our research group recently reported that another patient-specific factor, exposure to cigarette smoke, confers a higher risk of subsequent ARDS in trauma patients (Calfee, 2011). Here we propose to test the hypotheses that patient-specific factors, such as the severity of head injury (Aim 1a) and exposure to tobacco smoke (Aim 1b), contribute to the biological derangements that subsequently lead to ARDS in patients with isolated TBI. Furthermore, we hypothesize that plasma markers of inflammation, endothelial activation, and vascular permeability will capture causal pathways of ARDS in isolated TBI. We will measure three potential biomarkers, Interleukin-8 (IL-8), angiopoietin 2 (Ang-2), and tissue inhibitor of matrix metalloproteinase-3 (TIMP3) in plasma samples obtained just after injury and test the hypothesis that early differences in these plasma proteins predict the subsequent development of ARDS (Aim 2). In addition to studying factors that are present upon arrival to the emergency department, we will identify processes of care that contribute to the risk of ARDS. In 2009 Mascia et al. described a two-hit model for ARDS in TBI in which TBI primes the pulmonary endothelium to be more susceptible to ventilator induced lung injury. We will test the hypothesis that any exposure to high tidal volume ventilation (>10cc/kg of ideal body weight) is associated with increased risk of ARDS after isolated TBI (Aim 3). We will also evaluate if exposure to high tidal volume mechanical ventilation and development of ARDS is mediated through a common pathway with changes in measured biomarkers IL-8, Ang-2, and TIMP3. If patients with particular clinical characteristics and more severe inflammation and endothelial injury are at higher risk of ARDS, the studies outlined here will establish a means of identifying these high risk patients early in their course illness and designing future interventions aimed at improving clinical outcomes in patients with severe isolated TBI. Carrying out this work will allow me to build skills in patient-oriented science research, clinical data analysis, and scientific collaborations that will lay the foundation for a career in translational research.