Protocolized Goal-directed Resuscitation of Septic Shock to Prevent AKI

描述(由申请人提供)：根据PAR-07-024，正在进行的主要NIDDK的辅助研究和NHLBI临床研究NIDDK，我们提议进行一项旨在研究脓毒症患者急性肾损伤(AKI)自然病史的研究。超过50%的AKI危重患者存在脓毒症。3美国国立卫生研究院最近资助了一项早期感染性休克的大型治疗试验(P50 GM076659)。这项名为Protocolated Care for早期感染性休克(PROCESS)的试验将19个中心的1935名患者随机分成三个不同的治疗组。从过程队列中研究患者的机会为我们提供了一个历史性的机会，可以在最有可能导致AKI的情况下，进行一项大型自然历史研究，作为广泛的多中心试验的辅助。我们的提案，感染性休克的程序化目标导向复苏预防急性肾损伤(进展AKI)，将检验程序化复苏对AKI发展的影响。我们还试图探索干预效果的潜在机制，并评估肾脏损伤和修复的标记物，以帮助选择患者进行未来的介入试验。为了与美国国立卫生研究院的路线图保持一致，为了了解这项工作的临床实用价值，我们将建立一个考虑生物标志物和临床变量的临床风险预测模型。我们将这些任务组织为三个特定的目标：1.检验协议复苏可以预防或减轻AKI严重程度或持续时间的假设，2.确定哪些病理生理紊乱(炎症、缺血、氧化应激和凝血/血栓形成)与AKI的发生或单独相关，以及3.确定生物标记物是否可以预测AKI和败血症时AKI的恢复。我们研究的一部分将包括家访，我们选择将家访与家长试验分开进行，以避免因辅助研究而招生的任何损失。我们将在出院后重新联系过程受试者，并在三年内在五个时间点跟踪他们。通过研究的这一部分，我们将确定程序化复苏在改善整个队列以及通过生物标记物(生物标记物阳性的AKI)证实AKI的亚群中的长期结果(存活、肾脏恢复、CKD进展减少)方面是否更有效。 公共卫生相关性：急性肾损伤(AKI)的发病率估计约为每百万人口2000人。这项研究将检验最常见的治疗方法(液体)对预防和/或减轻由其最常见原因(脓毒症)引起的AKI的有效性。为了指导未来的研究，该项目还将确定哪些病理生理紊乱与AKI的发生有关，并确定目前可用的生物标记物是否可以预测AKI以及在脓毒症环境下AKI的恢复。

DESCRIPTION (provided by applicant): Under PAR-07-024, Ancillary Studies to Major Ongoing NIDDK and NHLBI Clinical Research Studies NIDDK, we are proposing to conduct a study which aims to examine the natural history of Acute Kidney Injury (AKI) arising in patients with sepsis. Sepsis is found in more than 50% of critically-ill patients with AKI.3 The NIH has recently funded a large therapeutic trial of early septic shock (P50 GM076659). This trial, Protocolized Care for Early Septic Shock (ProCESS), will randomize 1935 patients at 19 centers to three different treatment arms. The opportunity to study patients from the ProCESS cohort presents us with an historic opportunity to prospectively conduct a large natural history study ancillary to an extensive multi-center trial in a setting which is most likely to result in AKI. Our proposal, Protocolized Goal-directed Resuscitation of Septic Shock to Prevent Acute Kidney Injury (ProGReSS AKI), will examine the effect of protocolized resuscitation on the development of AKI. We also seek to explore mechanisms underlying the effect of the intervention and to evaluate markers of renal injury and repair in order to help select patients for future interventional trials. In keeping with the NIH roadmap, in order to understand the clinical utility of this work, we will build a clinical risk prediction model that will consider biomarkers and clinical variables. We have organized these tasks as three specific aims: 1. test the hypothesis that protocolized resuscitation prevents or lessens severity or duration of AKI, 2. determine which pathophysiologic derangements (inflammation, ischemia, oxidative stress, and coagulation/ thrombosis), in combination or individually, are associated with the development of AKI, and 3. determine whether biomarkers can predict AKI and recovery from AKI in the setting of sepsis. Part of our study will include home visits, for which we have opted to separate from the parent trial so as to avoid any loss of enrollment incurred by the ancillary study. We will re-contact ProCESS subjects after discharge from the hospital and follow them at five time points for three years. Through this part of the study, we will determine if protocolized resuscitation is more effective in improving long term outcomes (survival, renal recovery, reduced progression of CKD) in the entire cohort as well as in the subpopulation that has evidence of AKI by biomarkers (biomarker-positive AKI). PUBLIC HEALTH RELEVANCE: The incidence of acute kidney injury (AKI) is estimated at approximately 2000 per million population. This study will examine the effectiveness of the most common treatment (fluids) for the prevention and/or attenuation of AKI resulting from its most common cause (sepsis). To guide future studies, this project will also determine which pathophysiologic derangements are associated with the development of AKI, and determine whether currently available biomarkers can predict AKI and recovery from AKI in the setting of sepsis.