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

描述（由申请人提供）：在美国，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%的严重孤立性脑外伤患者会发展为急性呼吸窘迫综合征（ARDS）。脑外伤后ARDS的发展与较高的医疗费用和较差的神经预后相关（Holland, 2004, Mascia 2008）。对孤立性脑外伤患者肺损伤的机制知之甚少。这里提出的研究将利用从大量孤立的TBI患者中收集的全面的、前瞻性的数据和血浆标本。我将评估可能导致ARDS发生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ARDS高风险方面的效用。来自小鼠和临床研究的生物学合理性和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，另一个患者特有的因素，暴露于香烟烟雾中，会增加创伤患者随后发生ARDS的风险（Calfee, 2011）。在这里，我们提出验证患者特异性因素的假设，如头部损伤的严重程度（Aim 1a）和暴露于烟草烟雾（Aim 1b），有助于生物学紊乱，随后导致孤立性TBI患者发生ARDS。此外，我们假设炎症、内皮活化和血管通透性的血浆标志物将捕获孤立性TBI中ARDS的因果途径。我们将测量三种潜在的生物标志物，白细胞介素-8 （IL-8）、血管生成素2 （Ang-2）和基质金属蛋白酶-3组织抑制剂（TIMP3），并测试这些血浆蛋白的早期差异预测ARDS后续发展的假设（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等人描述了脑外伤后急性呼吸窘迫综合征的双重打击模型，其中脑外伤使肺内皮更容易受到呼吸机诱导的肺损伤。我们将验证这样的假设，即任何暴露于高潮汐气量通气（bbb10 - 10cc/kg理想体重）与孤立性脑外伤后ARDS风险增加有关（目的3）。我们还将评估暴露于高潮气量机械通气和ARDS的发展是否通过测量生物标志物IL-8、Ang-2和TIMP3的变化介导的共同途径。如果具有特定临床特征且炎症和内皮损伤更严重的患者发生ARDS的风险更高，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，并设计未来的干预措施，旨在改善严重孤立性TBI患者的临床结果。开展这项工作将使我在以患者为导向的科学研究、临床数据分析和科学合作方面建立技能，这将为我在转化研究方面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.