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。我们和其他人使用了正交偏振光谱视频显微镜，一种无创性测量人体微循环血流指数的技术，证明脓毒症患者的微循环血流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脓毒症的新疗法。一氧化氮(NO)维持微循环的动态平衡和通畅性，特别是当微循环持续受损时，就像脓毒症一样。尽管在脓毒症中NO在全球范围内上调，但在微循环水平上，NO在器官系统之间和内部的产生是异质性的，并且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NO输送到全身微循环，并开放这些低流量的微循环单位。我们假设，在败血症早期目标导向治疗(EGDT)中，iNO将增加微循环灌注量，这种微循环血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的能力：(1)在EGDT期间增加微循环灌流指数；(2)改善两项临床上重要的结果指标：(A)EGDT期间的乳酸清除，(B)24小时的序贯器官衰竭评估评分。这个以患者为导向的导师研究职业发展奖的总体目的不仅是提供一个成功的调查，更重要的是，一个成功的调查者。PI的最终目标是发展成为一名独立的研究员，对循环系统休克患者进行重要的创新临床试验。这种有指导的研究培训经验将包括一个专门侧重于临床试验培训的五年课程。将有三个不同的元素：1)指导，2)教育，3)调查。指导团队由许多败血症研究方面的知名专家组成，其中包括一名主要导师，他曾在NIH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的正式准备。最终，这种有指导的经历将产生一名私人投资，他将竞争NIH的独立研究拨款。该项目将是第一个专门针对脓毒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居高不下(美国每年有21.5万人死亡)，这类使用新方法评估和治疗脓毒症的临床试验有可能影响无数人的生命，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.