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% 对于感染性休克的儿童，目的是增强氧气输送，帮助解决休克，并预防 器官功能障碍。然而，输注红细胞已多次与不良后果有关。 病情危重，暗示伤害。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注指南都使用了血红蛋白 浓度仅为RBC输血决定提供信息。然而，这可能不是决定的最佳方式 何时给休克患者输注红细胞。我们在败血症儿童中的初步数据表明 血流动力学测量更好地识别哪些儿童可能从红细胞输注中受益，哪些儿童 严重的免疫抑制可能会带来更大的输血相关伤害风险。最后，我们的数据显示， 红细胞输注效果可能因红细胞单位的采集、存储和处理方法的不同而有所不同 由此产生的可溶性介体的数量。总而言之，这些数据支持我们的假设，即生理和 血液产物因子将预测感染性休克儿童何时受益于RBC或受到RBC损害 输血。我们研究计划的总体目标是开发一种个性化的医学方法来 感染性休克患儿的红细胞输注。我们这项提案的目标是构建决策支持工具 可用于未来的临床试验，以确定感染性休克的儿童何时应该或不应该 输注红血球。我们的建议使用健壮的机器学习技术，旨在使用非常 大量的动态变量来定义个性化的治疗决策，从而最大化临床结果。 有了这些方法，以及一种不可知的、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，可以考虑比传统上使用的更广泛的临床参数阵列 输血试验。我们将对660名脓毒症儿童进行多中心前瞻性观察研究。 休克以实现以下特定目标：目标1：确定临床、血流动力学和血液 感染性休克儿童的红细胞输注决策应受特定产品因素的影响。 使用电子病历中的数据，我们将使用结果加权学习来构建动态 输血算法，最大限度地减少预测的每日器官功能障碍(PELOD2评分)。目标2：确定 免疫表型预测败血症儿童对输注红细胞的不同反应 令人震惊。我们将收集受试者的连续血液样本，以测量经过验证的炎症性和 免疫功能生物标记物，并检验与红细胞输注相关的结果将不同的假设 对输血前炎症和/或免疫抑制生物标志物水平的影响。我们预计我们的数据将 改变数据驱动RBC输血算法的介入试验设计以转移输血 摆脱以血红蛋白为基础的策略，改善重症败血症儿童的预后。

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.