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。它影响了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， 关于脓毒症治疗的量和时机的有限经验数据阻碍了改善护理。这与其他急性疾病形成鲜明对比，例如急性冠状动脉综合征，标准化，及时，严格的护理导致了结果的大幅改善，并为更好的临床和转化研究铺平了道路。我们已经为这个中心的建议聚集了一个多学科的研究小组和领先机构的联盟。我们的目标是解决总体假设，即在脓毒症和脓毒性休克的初始管理中存在“黄金时间”，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局。我们的努力利用了Rivers等人最近的一项“概念验证”试验的结果。他们在一项单中心随机试验中证明，与常规治疗相比，6小时的方案复苏可显著改善急诊科（艾德）早期感染性休克患者的死亡率。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，以及该方案的所有要素是否都是必要的，特别是使用中心静脉导管插入术和输血。里弗斯方案的明显成功也引发了关于复苏技术影响结果的机制的问题。而且，在美国广泛实施协议复苏的后勤和经济限制方面存在重要问题。我们将通过一项大型多中心试验直接解决这些问题。我们将1950例因感染性休克到艾德就诊的受试者随机分为3组（650例/组）：“Rivers”方案;更简单、创伤性更小的方案（使用食管多普勒监测，不输血）;常规护理。将使用关于指南传播的最佳证据实施方案。我们在3个综合子项目下组织了我们的工作。子项目#1（临床疗效）将进行试验，并测试与常规治疗相比，方案化治疗是否能改善死亡率，以及是否需要完整的Rivers方案。子项目#2（作用机制）将测量与脓毒症相关的器官功能障碍（细胞缺氧、氧化应激、炎症和凝血/血栓形成）有关的四种基本途径的仔细选择的循环标志物随时间的浓度，并测试方案复苏是否 降低这些标志物的表达以及这些方案的临床功效是否与降低的 这些标记的表达。次级项目3（成本和成本效益）将衡量增加的成本， 资源使用的协议复苏，并确定价值，或成本效益，替代战略。 这些子项目由3个核心支持：管理、人类受试者以及数据管理和分析。 该项目将产生新的，重要的，全面的临床，生物学和实用方面的数据， 标准迅速严格的复苏治疗败血性休克我们的发现将帮助科学家，临床医生，家庭和 政策制定者，并将立即影响重症患者的护理。由于美国死于败血症的人数与急性心肌梗死的人数相似，因此拟议的研究对该国的公共卫生具有巨大影响，并且与NIH最近对转化研究的重视一致。

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.