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

项目摘要/摘要 败血症定义为宿主对感染的失调反应，导致75000名儿童患有败血症 美国每年的住院人数和全球50%的儿科住院死亡人数。尽管 多个试验，没有针对成人或儿童脓毒症的靶向治疗，以及及时的支持性护理 抗生素和液体复苏仍然是治疗的主要手段。液体疗法是脓毒症的基石 复苏，尽管液体的选择仍然存在争议。最近在成人中进行的试验表明， 30天内使用平衡晶体的主要不良肾脏事件(MAKE30)，如乳酸林格氏症 (LR)，相对于生理盐水(NS)。MAKE30是一个包含持久性肾脏的复合终点 功能障碍、开始透析或死亡。像LR这样的平衡解决方案的组成更类似于 正常的人血清，而NS与肾功能较差有关，尽管尚不清楚 机械装置。虽然许多儿科败血症的治疗是从成人推断出来的，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为问题。因此，要具体评估 LR或NS复苏是否改善儿童MAKE30：BALANCES的实用儿科试验 在脓毒症中进行了与正常生理盐水对照(即时给药)，计划登记8800人 孩子们。然而，异质性导致了败血症的负面试验，因为一些治疗方法在某些情况下有效。 病人对其他人无效。为了缓解这种异质性，已经提出了针对这两种风险的生物标记物。 具有共同病理生理学的亚型的分层和鉴定。我们的研究，题为《发现 脓毒症平衡盐水与正常盐水对照试验的合适亚型(快速推注)，将评估 用于即刻团注试验中LR与NS治疗效果的异质性。利用我们集团的 在生物标记物定义的风险分层和子表型方面有丰富的经验，我们将测量血浆 随机收集800名儿童的生物标志物并评估液体分配的不同影响 使用两个独立的基于生物标记物的死亡率预测模型(目标1)对跨风险层的MAKE30进行研究。 此外，我们将在对受试者分层后测试流体分配对MAKE30的不同影响 根据两个生物标记物定义的炎症亚型之一(目标2)。最后，我们将利用这一点 生物库将通过测量液体选择和MAKE30之间的标记来研究液体选择和MAKE30之间的潜在机制 内皮细胞(血管生成素-2)和内皮细胞糖萼(Syndecan-1)损伤(目标3)。这些目标将 评估已建立的基于生物标记物的策略对预后(目标1)和预测性浓缩的效用 (目标2)利用正在进行的儿科脓毒症试验的战略，这是随机分析的必要分析 在不同的危重病综合征中进行的试验。目标的成功完成将提供 儿童脓毒症个体化液体复苏的证据和建立概念证据数据 纳入基于生物标记物的方法，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.