Protocolized Care for Early Septic Shock (ProCESS)

提供。严重脓毒症是继发于感染的急性器官功能障碍综合征。它每年影响75万美国人，死亡率为30%。尽管对脓毒症的病理生理学有相当的了解，但目前改善护理的努力受到有关脓毒症治疗的数量和时间的有限经验数据的阻碍。这与急性冠状动脉综合征等其他急症形成鲜明对比，在急性冠状动脉综合征中，标准化、及时、严格的护理大大改善了治疗结果，并为更好的临床和转化研究铺平了道路。为了这个中心的提案，我们聚集了一个多学科的研究小组和领先机构的联盟。我们的目标是解决在脓毒症和脓毒性休克的初始管理中存在“黄金时间”的首要假设，其中及时，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“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，在急诊室（ED）出现早期感染性休克的受试者进行6小时的协议复苏可显著提高死亡率。虽然这项研究是革命性的，但它没有回答这些发现是否可以推广，以及该方案的所有要素是否都是必要的，特别是中心静脉置管和输血的使用。里弗斯协议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化复苏的后勤和经济限制方面存在重要问题。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名脓毒性休克患者随机分为3组（650人/组）：“Rivers”方案；一种更简单、侵入性更小的方案（使用食管多普勒监测，不输血）；还有日常护理。将使用关于指南传播的最佳证据实施方案。我们在三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，协议化护理是否能提高死亡率，以及完整的Rivers协议是否必要。子项目#2（作用机制）将测量精心挑选的与败血症相关器官功能障碍有关的四个基本途径（细胞缺氧、氧化应激、炎症和凝血/血栓形成）的循环标志物随时间的浓度，并测试方案化复苏是否会降低这些标志物的表达，以及这些方案的临床疗效是否与这些标志物的表达减少有关。子项目#3（成本和成本效益）将测量协议化复苏的增量成本和资源使用，并确定替代策略的价值或成本效益。这些子项目由3个核心支持：管理、人类主题以及数据管理和分析。该项目将在脓毒性休克的标准、及时、严格复苏的临床、生物学和实用方面产生新的、重要的和全面的数据。我们的研究结果将有助于科学家、临床医生、家庭和政策制定者，并将立即影响对危重患者的护理。由于美国人死于败血症的人数与死于急性心肌梗死的人数相似，这项拟议的研究对美国的公共卫生有着巨大的影响，并且与最近美国国立卫生研究院对转化研究的重视是一致的。

PROVIDED. 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'(nihroadmap.nih.gov).