Temporal analysis of nitric oxide as potential sepsis biomarker

描述（由申请人提供）：脓毒症是非心脏重症监护病房（icu）的主要死亡原因，也是美国第十大死亡原因。由于住院时间延长，治疗方案昂贵，发病率高，目前每年用于治疗脓毒症的费用为170亿美元（每次发病率约为50,000美元）。及时发现和采取行动是成功诊断和治疗结果的关键。早期诊断败血症可通过适当治疗提高患者生存率，减少住院时间/费用。不幸的是，目前诊断败血症的方法并不理想，因为它们依赖于检测症状（例如发烧、呼吸短促、心率不规律），这些症状只有在感染进展到危险水平（晚期）后才会变得明显。该项目的目标是开发新的分析方法，以便测量抽血中与生理相关的一氧化氮和亚硝基硫醇浓度，以促进早期干预。虽然以前的文献清楚地表明，由于败血症，血液中一氧化氮和亚硝基硫醇水平（bbb10倍基础）显著升高，但这些分析物在发病前和早期败血症进展过程中的实时变化尚不清楚。我们的假设是，根据人体对导致败血症的病原体的免疫反应，这些分析物在败血症的临床症状出现之前就发生了变化。事实上，免疫细胞（如巨噬细胞）释放一氧化氮作为对细菌的反应，并根据细菌负荷的增加而增加。因此，我们认为血液中一氧化氮和亚硝基硫醇的测量代表了基于其变化率的败血症筛查的新范式。通过提出的研究，我们将开发新的、小型化的传感平台，能够测量小血容量中的一氧化氮和亚硝基硫醇。这些分析物的时间变化将在适当的动物（猪）败血症模型中进行评估，以确定其预测价值。

DESCRIPTION (provided by applicant): Sepsis is the leading cause of death in non-cardiac Intensive Care Units (ICUs) and the 10th leading cause of death in the U.S. Due to extended hospital stays, expensive treatment protocols, and significant morbidity, $17 billion/year is currently spent treating sepsis (roughly $50,000 per incidence). Prompt detection and action are critical for successful diagnosis and treatment outcomes. Early diagnosis of sepsis has been shown to increase patient survival via appropriate treatment and decrease hospital stays/costs. Unfortunately, current methods of diagnosing sepsis are non-ideal as they rely on the detection of symptoms (e.g., fever, shortness of breath, irregular heart rate) that only become evident after the infection has progressed to dangerous levels (late stages). The goal of this project is t develop new analytical methodology that will allow for the measurement of physiologically relevant nitric oxide and nitrosothiols concentrations in drawn blood to facilitate earlier intervention. Although previous literature clearly shows significant elevations in both nitric oxid and nitrosothiol levels (>10x basal) in blood due to sepsis, the real-time variations in these analytes both before the onset and during the progression of early sepsis are unknown. Our hypothesis is that these analytes change well before the clinical signs of sepsis based on the body's immune response to pathogens that lead to sepsis. Indeed, immune cells (e.g., macrophages) release nitric oxide in response to bacteria, with increasing magnitude according to bacteria burden. As such, we believe that the measurement of nitric oxide and nitrosothiols in blood represents a new paradigm for sepsis screening based on their rate of change. Through the proposed studies we will develop novel, miniturizable sensing platforms capable of measuring nitric oxide and nitrosothiol in small blood volumes. The temporal changes of these analytes will then be evaluated in an appropriate animal (porcine) model of sepsis to determine their predictive value.