Finding Appropriate Subtypes in a Trial of Balanced versus nOrmaL Saline FlUid in Sepsis

项目概要/摘要 脓毒症是一种宿主对感染的反应失调， 美国每年的住院人数和全世界50%的住院儿科死亡人数。尽管 多项试验中，没有针对成人或儿童脓毒症的靶向治疗， 抗生素和液体复苏仍然是治疗的主要手段。液体治疗是脓毒症的基础 复苏，虽然液体的选择仍然存在争议。最近的成人试验显示， 使用平衡晶体（如乳酸林格氏液）30天内（MAKE 30）发生的重大肾脏不良事件 (LR)，相对于生理盐水（NS）。MAKE 30是一个复合终点，包括持续性肾脏 功能障碍、开始透析或死亡。平衡溶液（如LR）的组成更类似于 正常人血清，而NS与肾功能恶化相关，尽管通过不清楚的 机制等虽然大部分儿科败血症管理是从成人推断的，但儿童有明显的 流行病学和结果概况，使成人数据的应用成问题。因此，具体评估 无论是LR还是NS复苏都能改善儿童的MAKE 30， 与正常生理盐水在脓毒症中的作用（PRoMPT BOLUS）进行比较，计划入组8，800例 孩子然而，异质性导致了脓毒症的阴性试验，因为在某些情况下治疗有效。 病人对其他人无效。为了减轻这种异质性，已经提出了生物标志物用于两种风险 具有共同病理生理学的亚表型的分层和鉴定。我们的研究， 在脓毒症患者中进行的平衡盐水与非正常盐水（FAST BOLUS）试验中的适当亚型将评估 PRoMPT BOLUS试验中LR与NS治疗效果的异质性。利用我们集团的 基于生物标志物定义的风险分层和亚表型的丰富经验，我们将测量血浆 在随机分组时收集的800名儿童的生物标志物，并评估液体分配的差异效应 使用两个独立的基于生物标志物的死亡率预测模型（Aim 1），在风险分层中对MAKE 30进行评估。 此外，我们将在对受试者进行分层后，检验液体分配对MAKE 30的不同影响 根据两种生物标志物定义的炎性亚表型之一（Aim 2）。最后，我们将利用这个 生物样本库，通过测量以下指标来研究液体选择和MAKE 30之间的潜在机制： 内皮细胞（血管生成素-2）和内皮糖萼（多配体蛋白聚糖-1）损伤（Aim 3）。这些目标将 评估已建立的基于生物标志物的预后（目标1）和预测富集策略的效用 (Aim 2）利用正在进行的儿科败血症试验的策略，这是随机化的必要分析。 在异质性危重病综合征中进行的试验。成功完成目标将提供 儿科脓毒症患者个性化液体复苏的证据，并建立 结合基于生物标志物的方法，以减少未来试验中的异质性。

PROJECT SUMMARY/ABSTRACT Sepsis, defined as a dysregulated host response to infection, is responsible for 75,000 childhood hospitalizations annually in the United States and 50% of inpatient pediatric deaths worldwide. Despite multiple trials, there are no targeted therapies for adult or pediatric sepsis, and supportive care with timely antibiotics and fluid resuscitation remains the mainstay of therapy. Fluid therapy is a cornerstone of sepsis resuscitation, although the choice of fluid remains controversial. Recent trials in adults showed lower rates of major adverse kidney events within 30 days (MAKE30) with balanced crystalloid, such as lactated Ringer’s (LR), relative to normal saline (NS). MAKE30 is a composite endpoint incorporating persistent kidney dysfunction, initiation of dialysis, or death. Balanced solutions like LR have a composition more similar to normal human serum, whereas NS has been associated with worse kidney function, albeit via unclear mechanisms. While much of pediatric sepsis management is extrapolated from adults, children have a distinct epidemiology and outcome profile, making application of adult data problematic. Thus, to specifically assess whether LR or NS resuscitation improves MAKE30 in children, the PRagMatic Pediatric Trial of Balanced versus nOrmaL Saline FlUid in Sepsis (PRoMPT BOLUS) was undertaken, with planned enrollment of 8,800 children. However, heterogeneity has contributed to negative trials in sepsis, as therapies effective in some patients are ineffective in others. To mitigate this heterogeneity, biomarkers have been proposed for both risk stratification and identification of sub-phenotypes with shared pathophysiology. Our study, entitled Finding Appropriate Subtypes in a Trial of Balanced versus nOrmaL Saline FlUid in Sepsis (FAST BOLUS), will assess for heterogeneity of treatment effect of LR versus NS in the PRoMPT BOLUS trial. Leveraging our group’s extensive experience with biomarker-defined risk stratification and sub-phenotyping, we will measure plasma biomarkers in 800 children collected at randomization and assess the for differential effects of fluid assignment on MAKE30 across risk strata using two separate biomarker-based mortality prediction models (Aim 1). Additionally, we will test for differential effects of fluid assignment on MAKE30 after stratifying subjects according to one of two biomarker-defined inflammatory sub-phenotypes (Aim 2). Lastly, we will leverage this biobank to investigate potential mechanisms between fluid choice and MAKE30 by measuring markers of endothelial cell (angiopoietin-2) and endothelial glycocalyx (syndecan-1) damage (Aim 3). These Aims will assess the utility of established biomarker-based strategies for prognostic (Aim 1) and predictive enrichment (Aim 2) strategies by leveraging an ongoing pediatric sepsis trial, which is a necessary analysis of randomized trials conducted in heterogeneous critical illness syndromes. Successful completion of the Aims will provide evidence for personalized fluid resuscitation in pediatric sepsis and establish proof of concept data for incorporation of biomarker-based methods to reduce heterogeneity in future trials.