Randomized Trial of Inhaled Nitric Oxide to Augment Tissue Perfusion in Sepsis

描述（由申请人提供）：败血症是一种常见的破坏性疾病，是危重患者死亡的主要原因。微循环衰竭是脓毒症的关键致病事件，可在脓毒症相关器官功能障碍中发挥重要作用。我们的研究小组和其他研究人员使用正交偏振光谱视频显微镜（一种测量人体微循环流量指数的无创技术）来证明，败血症患者微循环流量受损与多器官衰竭和死亡率有关。目前，还没有专门针对微循环的败血症新疗法。一氧化氮（NO）维持微循环稳态和通畅，特别是当微循环受到损伤时，如败血症时。尽管在脓毒症中一氧化氮在全球范围内上调，但在微循环水平上，器官系统之间和器官系统内一氧化氮的产生是不均匀的，一些微循环单位具有低流量。吸入一氧化氮（iNO）可以有效地将一氧化氮输送到系统微循环，并“打开”这些低流量微循环单元。我们假设在早期目标导向治疗（EGDT）的脓毒症复苏过程中，iNO会增加微循环灌注，微循环流量的增加将导致更有效的复苏和减少器官衰竭。我们的目标是通过一项随机双盲安慰剂对照试验来验证这一假设，以评估iNO在EGDT期间增强微循环灌注指数的能力；(2)改善两个临床重要的结局指标：(a) EGDT期间的乳酸清除率，(b) 24小时序贯器官衰竭评估评分。这个以患者为导向的研究职业发展指导奖的总体目的不仅仅是提供一个成功的研究，更重要的是，一个成功的研究者。PI的最终目标是发展成为一个独立的研究者，在循环性休克患者中进行重要和创新的临床试验。这种指导的研究培训经验将包括一个为期五年的课程，特别侧重于临床试验培训。将有三个不同的元素：1)指导，2)说教式教育，和3)调查。指导团队由许多脓毒症研究领域的知名专家组成，其中包括一位主要导师，他曾进行过美国国立卫生研究院资助的关于脓毒症微血管反应的研究。PI将接受严格的教学计划（临床流行病学理学硕士）的培训，并接受临床试验设计和分析方面的正式准备。最终，这种指导经验将产生一名PI，他将与NIH竞争独立研究经费。该项目将是第一个专门针对败血症患者微循环的随机试验。鉴于脓毒症的发病率和死亡率一直很高（美国每年有215,000人死亡），这种使用新方法评估和治疗脓毒症的临床试验有可能影响许多人的生命，并极大地造福公众健康。

DESCRIPTION (provided by applicant): Sepsis is a common and devastating disease and the leading cause of death in critically ill patients. Microcirculatory failure is a pivotal pathogenic event in sepsis that can play a major role in sepsis-associated organ dysfunction. Our group and others have used orthogonal polarization spectral videomicroscopy, anon- invasive technique of measuring microcirculatory flow indices in human subjects, to demonstrate that impaired microcirculatory flow in sepsis is associated with multi-organ failure and mortality. Currently, there are no novel therapies for sepsis that specifically target the microcirculation. Nitric oxide (NO) maintains microcirculatory homeostasis and patency, especially when the microcirculation sustains an insult as it does in sepsis. Although NO is globally upregulated in sepsis, NO production is heterogeneous between and within organ systems at the microcirculatory level, and some microcirculatory units have low flow. Inhaled nitric oxide (iNO) can deliver NO effectively to the systemic microcirculation and "open" these low-flow microcirculatory units. We hypothesize that iNO will augment microcirculatory perfusion during sepsis resuscitation with early goal-directed therapy (EGDT), and this increase in microcirculatory flow will result in more effective resuscitation and decreased organ failure. We aim to test this hypothesis with a randomized double-blind placebo-controlled trial to evaluate the ability of iNO to (1) augment microcirculatory perfusion indices during EGDT; and (2) improve two clinically important outcome measures: (a) lactate clearance during EGDT, and (b) the Sequential Organ Failure Assessment score at 24 hours. The overall purpose of this Mentored Patient-Oriented Research Career Development Award is not only to deliver a successful investigation, but more importantly, a successful investigator. The PI's ultimate goal is to develop into an independent investigator who conducts important and innovative clinical trials in patients with circulatory shock. This mentored research training experience will consist of a five-year curriculum specifically focused on clinical trials training. There will be three distinct elements: 1) mentoring, 2) didactic education, and 3) investigation. The mentoring team features a number of renowned experts in sepsis research, including a primary mentor who has conducted NIH-funded research on the microvascular response to sepsis. The PI will train in a rigorous didactic program (Masters of Science in Clinical Epidemiology) and receive formal preparation in the design and analysis of clinical trials. Ultimately, this mentored experience will produce a PI who competes for independent research grants from the NIH. This project will be the first randomized trial specifically targeting the microcirculation in sepsis patients. Given the persistently high morbidity and mortality of sepsis (215,000 deaths annually in the U.S.), this type of clinical trial that uses novel methods to evaluate and treat sepsis has the potential to impact numerous lives and substantially benefit public health.