Temporal analysis of nitric oxide as potential sepsis biomarker

描述(申请人提供)：脓毒症是非心脏重症监护病房(ICU)的头号死因，也是美国第十大死因。由于住院时间延长、治疗方案昂贵和严重的发病率，目前每年花费170亿美元治疗脓毒症(每个病例约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。脓毒症的早期诊断已被证明可以通过适当的治疗提高患者的存活率，并减少住院时间/费用。不幸的是，目前诊断败血症的方法并不理想，因为它们依赖于对症状(例如发烧、呼吸急促、心率不齐)的检测，而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，以便能够测量抽出的血液中生理上相关的一氧化氮和亚硝硫醇浓度，以便进行早期干预。尽管以前的文献清楚地表明，由于脓毒症，血液中一氧化氮和亚硝硫醇(&gt；10倍基础)水平显著升高，但这些分析物在早期脓毒症发病前和进展期间的实时变化尚不清楚。我们的假设是，这些分析物在脓毒症临床症状出现之前就会发生变化，这是基于人体对导致脓毒症的病原体的免疫反应。事实上，免疫细胞(如巨噬细胞)会对细菌作出反应，释放一氧化氮，其幅度随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硫醇的测量代表了一种基于它们的变化率进行脓毒症筛查的新范例。通过拟议的研究，我们将开发新的、可微型化的传感平台，能够测量少量血液中的一氧化氮和亚硝硫醇。这些分析物的时间变化将在适当的败血症动物(猪)模型中进行评估，以确定它们的预测价值。

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.