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室（ICU）的主要死因，也是美国第十大死因。由于住院时间延长、治疗方案昂贵和发病率高，目前每年花费170亿美元治疗脓毒症（每次发病约50，000美元）。及时发现和采取行动对于成功的诊断和治疗结果至关重要。脓毒症的早期诊断已被证明可以通过适当的治疗增加患者的生存率，并减少住院时间/费用。不幸的是，目前诊断脓毒症的方法是不理想的，因为它们依赖于症状的检测（例如，发烧、呼吸急促、心率不齐），只有在感染发展到危险水平（晚期）后才变得明显。该项目的目标是开发新的分析方法，以测量抽取血液中生理相关的一氧化氮和亚硝基硫醇浓度，以促进早期干预。尽管先前的文献清楚地显示了由于脓毒症导致血液中一氧化氮和亚硝基硫醇水平的显著升高（> 10倍基础值），但是这些分析物在早期脓毒症发作之前和进展期间的实时变化是未知的。我们的假设是，基于身体对导致败血症的病原体的免疫应答，这些分析物在败血症的临床体征之前发生变化。事实上，免疫细胞（例如，巨噬细胞）响应于细菌而释放一氧化氮，根据细菌负荷具有增加的幅度。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脓毒症筛查的新范式。通过拟议的研究，我们将开发新的，可微型化的传感平台，能够测量小血容量中的一氧化氮和亚硝基硫醇。然后在适当的脓毒症动物（猪）模型中评价这些分析物的时间变化，以确定其预测值。

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.