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

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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.