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

描述（由申请人提供）：脓毒症是一种常见的毁灭性疾病，是危重患者死亡的主要原因。微循环衰竭是脓毒症中的关键致病事件，在脓毒症相关器官功能障碍中起主要作用。我们的小组和其他人已经使用正交偏振光谱视频显微镜，在人类受试者中测量微循环流动指数的非侵入性技术，以证明脓毒症中受损的微循环流动与多器官衰竭和死亡率相关。目前，没有专门针对微循环的脓毒症的新疗法。一氧化氮（NO）维持微循环的稳态和通畅性，特别是当微循环受到脓毒症的损害时。虽然NO在脓毒症中整体上调，但在微循环水平上，NO的产生在器官系统之间和器官系统内是异质的，并且一些微循环单元具有低流量。吸入一氧化氮（iNO）可以有效地将NO输送到全身微循环并“打开”这些低流量微循环单元。我们假设，iNO将增加脓毒症复苏早期目标导向治疗（EGDT）期间的微循环灌注，这种微循环流量的增加将导致更有效的复苏和减少器官衰竭。我们的目的是通过随机双盲安慰剂对照试验来验证这一假设，以评估iNO（1）在EGDT期间增加微循环灌注指数的能力;（2）改善两个临床重要的结果指标：（a）EGDT期间的乳酸清除率，和（B）24小时的序贯器官衰竭评估评分。这个指导以患者为导向的研究职业发展奖的总体目的不仅是提供一个成功的调查，但更重要的是，一个成功的调查。PI的最终目标是发展成为一名独立的研究者，在循环休克患者中进行重要和创新的临床试验。这种指导性的研究培训经验将包括一个为期五年的课程，专门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。该指导团队拥有许多脓毒症研究领域的知名专家，其中包括一位主要导师，他曾对脓毒症的微血管反应进行过NIH资助的研究。PI将接受严格的教学计划（临床流行病学硕士）培训，并接受临床试验设计和分析的正式准备。最终，这种指导的经验将产生一个PI谁竞争独立的研究赠款从NIH。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。鉴于脓毒症的持续高发病率和死亡率（在美国每年有215，000例死亡），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，并大大有益于公众健康。

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.