Novel diagnostic and stratification tools for septic shock

感染性休克的新型诊断和分层工具

• 批准号: 8970115
• 负责人: HECTOR R. WONG
• 金额: $ 30.07万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970115
• 关键词: APACHE II; APACHE III; Address; Adult; Age; Biological; Biological Markers; Blood; Blood Transfusion; Caring; Catheters; Child; Childhood; Clinical; Clinical Trials; Collaborations; Conduct Clinical Trials; Country; Coupled; Data; Diagnosis; Disease; Enrollment; Failure; Foundations; Funding; Future; Goals; Grant; Heterogeneity; Hospital Mortality; Intervention; Measures; Modeling; Organ failure; Outcome; Pathway interactions; Patient Selection; Patients; Plasma; Population Study; Probability; Procedures; Proteins; Protocols documentation; Public Health; Relative (related person); Research; Research Personnel; Resuscitation; Risk; Sample Size; Sampling; Sepsis; Septic Shock; Stratification; Study Subject; Syndrome; System; Technology; Testing; Time; United States National Institutes of Health; Vasopressins; Venous; base; design; improved; innovation; meetings; mortality; novel; novel diagnostics; novel strategies; programs; public health relevance; repository; standard care; three-arm study; tool; transcriptomics; translational study; treatment as usual; trial design

 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.

 描述（由适用提供）：在成年人和儿童中，败血性休克仍然是全球公共卫生问题。败血性休克是一种异质综合征，而不是离散的疾病实体。基线死亡率风险广泛可变，使其成为进行介入临床试验的主要混杂因素。当前的试验设计包括低基线死亡率风险的患者，他们不太可能从标准护理以外的新干预措施中受益，以及具有极高基线死亡率风险的患者即使有新的干预措施也可能超出救助。这可以稀释对实验干预的效果大小，该干预措施对具有重大但可改变的死亡率风险的这些极端之间的患者受益。这是该领域的重要且未满足的临床差距是缺乏特异性化败血性休克的稳健分层工具。该提案旨在直接解决这一差距。我们已经得出并验证了小儿败血症生物标志物风险模型（Persevere）。基于广泛的，面向发现的转录组学研究，将包含的生物标志物客观地选择。值得注意的是，生物标志物是在血室中测量的蛋白质，并在满足败血性休克的临床标准时测量。我们最近在来自三个不同国家的881名受试者中使用相同方法来得出并验证了成年人的风险分层模型。成人的化粪池冲击信息和分层技术（Assist）的表现都优于Apache II和III。与我们的初步数据一致，我们建议一种辅助应用是更好地告知患者进行介入临床试验的选择。在此竞争性修订中，我们将通过对早期败血性冲击（过程）试验的协议化护理进行事后，风险分层的分析来测试这一概念。该工艺试验将1,341名具有败血性休克的成年人随机分配为三种早期复苏策略之一：基于方案的早期目标治疗（EGDT）；基于方案的标准疗法不需要放置中央静脉导管，肌力的给药或血液传播；或通常的护理。该过程试验的一个重要组成部分是在多个时间点进行生物样品的库，再加上广泛的临床注释。根据彼此，该过程试验产生了最广泛，最现代的临床和生物学存储库，其中包括成人败血性休克。在与过程调查人员的合作中，我们将检验以下假设：相对于通常的护理，相对于通常的护理患者，方案护理的潜在益处取决于辅助估计的基线死亡率风险。重点，竞争性的修订是弥合两个创新的，NIH资助的败血症研究计划，以解决该领域的主要差距。这项高度集中的努力将为在不久的将来提供更广泛的合作奠定基础。该目标的主要交付是直接检验的概念，即基线死亡率基于风险是进行介入性休克的介入临床试验的有效手段。