Protocolized Care for Early Septic Shock (ProCESS)

严重脓毒症是继发于感染的急性器官功能障碍综合征。它影响着75万美国人 年，死亡率为30%。尽管对脓毒症的病理生理学有相当多的了解，但目前的努力是 有关脓毒症治疗的数量和时机的经验数据有限，阻碍了改善护理。这与其他急性疾病形成了鲜明对比，例如急性冠状动脉综合征，在这些疾病中，标准化、及时、严格的护理导致了预后的大幅改善，并为更好的临床和转化性研究铺平了道路。我们已经为这个中心提案聚集了一个由多学科研究人员组成的小组和由领先机构组成的财团。我们的目标是解决最重要的假设，即在脓毒症和感染性休克的初始治疗中有“黄金时段”，在这种情况下，及时、严格、标准化的护理可以减少不必要的下游后果，并改善临床结果。我们的努力利用了Rivers等人最近进行的一项“概念验证”试验的结果。他们在一项单中心随机试验中证明，与常规护理相比，对到急诊科(ED)就诊的早期感染性休克的受试者进行6小时的程序化复苏显著提高了死亡率。虽然这项研究是革命性的，但它没有回答这些发现是否具有普遍性，以及方案的所有要素是否都是必要的，特别是中心静脉插管和输血的使用。Rivers方案的明显成功也引发了人们对复苏技术影响结果的机制的质疑。而且，在美国各地广泛实施程序化复苏存在着重要的后勤和经济限制问题。我们将通过执行一项大型多中心试验直接解决这些问题。我们将1950名因感染性休克而到急诊室就诊的受试者随机分为3组(650例/组)：Rivers方案；一种更简单、侵入性更小的方案(使用食道多普勒监测和不输血)；以及常规护理。将使用关于指南传播的最佳证据来执行协议。我们在3个综合子项目下组织了我们的努力。子项目#1(临床疗效)将进行试验，并测试与常规护理相比，程序化护理是否提高死亡率，以及Full Rivers方案是否必要。子项目2(作用机制)将测量与脓毒症相关器官功能障碍(细胞缺氧、氧化应激、炎症和凝血/血栓形成)有关的四个基本途径中精心挑选的循环标志物随时间的浓度，并测试是否将复苏原始化 减少这些标记物的表达，以及这些方案的临床疗效是否与降低 这些标记的表达。次级项目#3(费用和成本效益)将衡量增量费用和 对程序化复苏的资源使用进行评估，并确定替代战略的价值或成本效益。 这些子项目得到了三个核心的支持：管理、人类主题以及数据管理和分析。 该项目将在临床、生物学和实用性方面产生新的、重要的和全面的数据。 感染性休克的标准、迅速、严格的复苏。我们的发现将帮助科学家、临床医生、家庭和 政策制定者和将立即影响对危重病人的护理。由于美国死于脓毒症的人数与死于急性心肌梗死的人数相似，拟议中的研究对美国的公共卫生具有巨大的影响，并与NIH最近对转化性研究的重视相一致。

Severe sepsis is the syndrome of acute organ dysfunction secondary to infection. It affects 750,000 Americans each year, with a mortality of 30%. Despite considerable understanding of the pathophysiology of sepsis, current efforts to improve care are hampered by limited empiric data regarding the amount and timing of sepsis therapies. This stands in stark contrast to other acute conditions, such as acute coronary syndromes, where standardized, prompt, rigorous care has led to a large improvement in outcome and paved the way for better clinical and translational research. We have amassed for this Center proposal a multidisciplinary group of investigators and consortium of leading institutions. Our goal is to address the overarching hypothesis that there are 'golden hours' in the initial management of sepsis and septic shock where prompt, rigorous, standardized care can reduce unwanted downstream consequences and improve clinical outcomes. Our efforts capitalize on the findings of a recent 'proof-of-concept' trial by Rivers et al. They demonstrated in a single center randomized trial that 6 h of protocolized resuscitation for subjects presenting to the Emergency Department (ED) with early septic shock dramatically improved mortality when compared to usual care. While this study was revolutionary, it left unanswered whether the findings are generalizable and whether all elements of the protocol are necessary, especially the use of central venous catheterization and blood transfusion. The apparent success of the Rivers protocol also prompts questions about the mechanisms by which resuscitation techniques affect outcome. And, there are important questions regarding the logistic and economic constraints to widespread implementation of protocolized resuscitation across the US. We will tackle these questions directly through execution of a large multicenter trial. We will randomize 1950 subjects who present to the ED in septic shock to 3 arms (650/arm): the 'Rivers' protocol; a simpler, less invasive protocol (using esophageal Doppler monitoring and no blood transfusion); and usual care. Protocols will be implemented using best evidence regarding guideline dissemination. We have organized our efforts under 3 integrated subprojects. Subproject #1 (Clinical Efficacy) will conduct the trial and test whether protocolized care improves mortality compared to usual care and whether the full Rivers protocol is necessary. Subproject #2 (Mechanisms of Action) will measure concentrations over time of carefully selected circulating markers of four fundamental pathways implicated in sepsis-related organ dysfunction (cellular hypoxia, oxidative stress, inflammation, and coagulation/thrombosis) and test whether protocolized resuscitation reduces expression of these markers and whether the clinical efficacy of these protocols is associated with reduced expression of these markers. Subproject #3 (Costs and Cost-effectiveness) will measure the incremental costs and resource use of protocolized resuscitation and determine the value, or cost-effectiveness, of the alternative strategies. These subprojects are supported by 3 cores: administration, human subjects, and data management and analysis. This project will generate new, important, and comprehensive data on the clinical, biologic, and pragmatic aspects of standard, prompt, rigorous resuscitation for septic shock. Our findings will aid scientists, clinicians, families and policymakers and will immediately affect care of the critically ill. As the number of Americans dying with sepsis is similar to that of acute myocardial infarction, the proposed study has enormous implications for the public health of the country and is consistent with the recent NIH emphasis on translational research.