Novel diagnostic and stratification tools for septic shock

 描述(由申请人提供)：感染性休克仍然是成人和儿童的世界性公共卫生问题。感染性休克是一种异质性综合征，而不是一个离散的疾病实体。基线死亡风险变化很大，使其成为进行介入临床试验的主要混杂因素。目前的试验设计包括基线死亡风险低的患者，他们不太可能从标准护理以外的新干预措施中受益，以及基线死亡风险极高的患者，即使使用新的干预措施，他们也可能无法挽救。这可以稀释实验干预的效果大小，该实验干预对这两个极端之间的患者有好处，这些患者具有显著的但可修改的死亡风险。因此，该领域一个重要且尚未填补的临床空白是缺乏针对感染性休克的强有力的分层工具。这项提议寻求直接解决这一差距。我们已经推导并验证了儿科败血症生物标记物风险模型(PERSIVE)。Perevere中包含的生物标记物是在广泛的、以发现为导向的转录学研究的基础上客观选择的。值得注意的是，生物标记物是在血腔内测量的蛋白质，在达到感染性休克的临床标准时进行测量。我们最近在来自三个不同国家的881名受试者中使用相同的方法推导并验证了成人风险分层模型。成人感染性休克信息和分层技术(ASSIST)的表现优于APACHE II和APACHE III。与我们的初步数据一致，我们建议ASSIST的一个应用是更好地为介入临床试验的患者选择提供信息。在这项竞争性修订中，我们将通过对早期感染性休克(PROCESS)试验的原始化护理(PROCESS)试验进行临时、风险分层分析来检验这一概念。该过程试验随机将1,341名患有感染性休克的成年人分为三种早期复苏策略之一：基于方案的早期目标定向治疗(EGDT)；基于方案的标准治疗，不需要放置中心静脉导管、肌松药或输血；或常规护理。该过程试验的一个重要组成部分是在多个时间点储存生物样本，并加上广泛的临床注释。因此，该过程试验产生了一个最广泛的，当代可用的成人败血症休克的临床和生物资料库。在与流程调查人员的合作下，我们将检验这样一种假设，即相对于常规护理，感染性休克患者的程序化护理的潜在好处取决于ASSID估计的基线死亡风险。这一重点、竞争性的修订是弥合两个创新的、由NIH资助的脓毒症研究项目的第一步，以解决该领域的主要差距。这种高度集中的努力将为在不久的将来进行更广泛的合作奠定基础。这一目标的主要成果是直接测试基线死亡率风险选择是进行感染性休克介入性临床试验的有效手段这一概念。

 DESCRIPTION (provided by applicant): Septic shock continues to be a worldwide public health problem in both adults and children. Septic shock is a heterogeneous syndrome, not a discrete disease entity. Baseline mortality risk is widely variable, making it a major confounder for the conduct of interventional clinical trials. Current trial designs include patients with low baseline mortality risk who are unlikely to benefit from novel interventions beyond standard care, as well as patients having an extremely high baseline mortality risk who may be beyond salvage even with novel interventions. This can dilute the effect size for an experimental intervention that has benefit for patients between these extremes who have a significant, but modifiable mortality risk. Thus, an important and unmet clinical gap in the field is the lack of a robust stratification tool specific for septic shock. This proposal seeks to directly address this gap. We have derived and validated the Pediatric Sepsis Biomarker Risk Model (PERSEVERE). The biomarkers included in PERSEVERE were selected objectively based on extensive, discovery-oriented transcriptomic studies. Of note, the biomarkers are proteins measured in the blood compartment and are measured at the time of meeting clinical criteria for septic shock. We recently derived and validated the risk stratification model for adults using the same approach in 881 subjects from three different countries. The Adult Septic Shock Information and Stratification Technology (ASSIST) outperform both APACHE II and III. Consistent with our preliminary data, we propose that one application of ASSIST is to better inform the selection of patients for interventional clinical trials. In this competitive revision, we will test this concep by conducting a post hoc, risk-stratified analysis of the Protocolized Care for Early Septic Shock (ProCESS) Trial. The ProCESS Trial randomly allocated 1,341 adults with septic shock into one of three early resuscitation strategies: protocol-based early goal-directed therapy (EGDT); protocol-based standard therapy that did not require placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. An important component of the ProCESS trial was the banking of biological samples at multiple time points, coupled with extensive clinical annotations. Accordingly, the ProCESS trial has generated one the most extensive, contemporary clinical and biological repositories of adult septic shock available. In collaboration with the ProCESS Investigators, we will test the hypothesis that the potential benefits of protocolized care in patients with septic shock, relative to usual care, are dependent on baseline mortality risk as estimated by ASSIST. This focused, competitive revision represents a first step toward bridging two innovative, NIH-funded, sepsis research programs to address major gaps in the field. This highly focused effort will provide the foundation for more extensive collaborations in the near future. The major deliverable of this Aim is a direct test of the concept that baseline mortality risk-based selection is an effective means of conducting interventional clinical trials for septic shock.