Transfusion and Organ Dysfunction in Pediatric Septic Shock (TROPICS) study

摘要 全世界每年有近300万儿童死于败血症。红细胞（RBC）输注约50% 的儿童感染性休克，目的是加强氧气输送，帮助解决休克，并防止 器官功能障碍然而，红细胞输注一再与不良结局相关， 严重的疾病，暗示着伤害。对于大多数感染性休克的儿童，我们缺乏数据来确定谁应该或 不应该输血。介入试验和红细胞输血指南使用血红蛋白 浓度单独通知RBC输血决策。然而，这可能不是决定 什么时候给休克病人输红细胞我们在败血症儿童中的初步数据表明， 血液动力学测量可以更好地识别可能受益于红细胞输注的儿童和 严重的免疫抑制可能有更大的输血相关伤害的风险。最后，我们的数据显示， 红细胞输注效果可能因红细胞单位采集、储存和处理方法而异， 得到的可溶性介质的量。总之，这些数据支持我们的假设，即生理和 血液制品因素将预测感染性休克儿童何时受益于红细胞或受到红细胞的伤害 输血我们的研究计划的总体目标是开发个性化的医疗方法， 感染性休克患儿的红细胞输注。我们的目标是建立决策支持工具 可以在未来的临床试验中使用，以确定感染性休克儿童何时应该或不应该 输了红细胞我们的建议使用了强大的机器学习技术，旨在使用一个非常 大量的动态变量来定义个性化的治疗决策，最大限度地提高临床效果。 有了这些方法，以及一个不可知的、数据驱动的方法，最终的决策规则将不受临床医生的影响。 偏差，并且可以考虑比传统上使用的更广泛的临床参数 输血试验我们将对660例败血症患儿进行多中心前瞻性观察研究， 目的1：确定哪些临床、血流动力学和血液动力学参数 产品特异性因素应推动败血性休克儿童的红细胞输注决策。 使用来自电子病历的数据，我们将使用结果加权学习来建立动态的 输血算法，以尽量减少预测的日常器官功能障碍（PELOD 2评分）。目标2：确定 预测脓毒症患儿红细胞输注差异反应免疫表型 冲击.我们将从受试者中收集一系列血液样本，以测量一组经验证的炎症和 免疫功能生物标志物，并检验与RBC输注相关的结局将因 对输血前炎症和/或免疫抑制生物标志物水平的影响。我们希望我们的数据 改变数据驱动的红细胞输血算法的介入性试验设计， 范例远离血红蛋白为基础的战略和改善重症脓毒症儿童的结果。

Abstract Worldwide, nearly 3 million children die each year from sepsis. Red blood cells (RBC) are transfused in ~50% of children with septic shock, with the intent to enhance oxygen delivery, help resolve shock, and prevent organ dysfunction. However, RBC transfusion has repeatedly been associated with adverse outcomes in critical illness, suggesting harm. For most children with septic shock we lack data to identify who should or should not be transfused. Interventional trials and RBC transfusion guidelines have used hemoglobin concentration alone to inform RBC transfusion decisions. However, this is likely not the best way to decide when to transfuse RBCs to a patient with shock. Our preliminary data in septic children suggest that hemodynamic measures better identify children who might benefit from RBC transfusion and that children with severe immune suppression may be at greater risks of transfusion-related harm. Lastly, our data show that RBC transfusion effects likely differ based on RBC unit collection, storage, and processing methods, and resultant quantities of soluble mediators. Together, these data support our hypothesis that physiologic and blood product factors will predict when children with septic shock will benefit from, or be harmed by, RBC transfusion. The overall goal of our research program is to develop a personalized-medicine approach to RBC transfusion in children with septic shock. Our objective for this proposal is to build decision support tools that can be used in future clinical trials to identify when children with septic shock should or should not be transfused with RBCs. Our proposal uses robust machine learning techniques that are designed to use a very large number of dynamic variables to define personalized treatment decisions that maximize clinical outcomes. With these methods, and an agnostic, data-driven approach, the resultant decision rules will be free of clinician bias and can consider a much wider array of clinical parameters than have traditionally been used in transfusion trials. We will conduct a multicenter prospective observational study of 660 children with septic shock to accomplish the following specific aims: Aim 1: Determine which clinical, hemodynamic, and blood product-specific factors should drive RBC transfusion decision-making in children with septic shock. Using data from the electronic medical record, we will use outcome-weighted learning to build dynamic transfusion algorithms to minimize predicted daily organ dysfunction (PELOD2 scores). Aim 2: Identify immune phenotypes that predict differential response to RBC transfusion in children with septic shock. We will collect serial blood samples from subjects to measure a validated panel of inflammatory and immune function biomarkers and test the hypothesis that outcomes related to RBC transfusion will differ based on pre-transfusion levels of biomarkers of inflammation and/or immune suppression. We expect our data to transform the design of interventional trials of data-driven RBC transfusion algorithms to shift the transfusion paradigm away from hemoglobin-based strategies and improve outcomes for critically ill septic children.