A Low Blood Volume Platform for Recurrent Anticoagulation and Kidney Monitoring during Continuous Renal Replacement Therapy in Critically Ill Children

摘要 持续肾脏复发性抗凝和肾脏监测的低血容量平台 危重患儿的替代治疗 (快速通道SBIR PA-20-260) 急性肾损伤(AKI)的特征是肾脏的充分吸收能力突然下降。 保持电解质、酸碱和液体平衡。住进重症监护病房的儿童中，高达30%的儿童 AKI和AKI的存在独立地与住院时间的延长和更高的 死亡率。连续性肾脏替代疗法(CRRT)已成为首选的透析方式 对于危重儿童，并正在变得越来越普遍的新生儿和幼儿(10公斤以下) Aki和先天性肾功能衰竭。经常监测(每天2-6次)抗凝治疗(肝素， 肝素等)、肾功能(尿素)和电解质成分(钾、磷等)。是必要的 在CRRT过程中。现有的实验室检查需要大量的血量，累积失血量 常规的血液检查会导致医源性贫血。大多数危重新生儿(90%的危重新生儿 低出生体重儿和58%的早产儿)在出生期间需要输注红细胞 新生儿重症监护病房(NICU)是由于频繁抽血造成的。 为了满足对新生儿和儿童CRRT监测的快速、低容量血液测试的关键需求， 我们将在我们的近患者数字微流控(DMF)平台上开发一个由四种检测组成的小组，以提供 全面分析抗凝剂量、肾功能和磷平衡。我们的创新 系统将同时检测抗Xa因子(抗FXA)、活化部分凝血活酶时间(APTT)、血液 尿素氮(BUN)和磷来自&lt；50微克L的全血输入。从全血中分离血浆 (对所有四种化验都是必要的)将在试剂盒上自动进行，以便于在患者附近进行检测。通过 结合四种技术复杂的分析(通常送到实验室的不同部分，如血液学和 化学)变成单一的自动化测试，我们可以减少从样品到答案的时间和所需的人员时间 进行每一次单独化验，可以显著减少复发所需的累积血量 全程监测CRRT治疗。 我们在这个快速通道项目上的合作者包括儿科急性护理肾病的先驱 最近的出版物描述了新生儿CRRT的新方法。项目的第一阶段将建立 通过开发DMF抗FXA、aPTT、BUN和磷测试平台的可行性 足够的分析和临床表现的分析和演示。第二阶段将结合四种化验方法 到结果的时间不到15分钟的多重反应，评估分析性能和 每项检测的临床一致性，并对系统进行现场领导用户测试，以确定可靠性和 可用性。我们的最终产品最初将投放市场，用于接受CRRT的新生儿和儿科患者。 二级市场将包括接受心脏手术或其他手术的儿童和成人患者。 与肾功能衰竭、毒素清除和液体超滤有关。

ABSTRACT A Low Blood Volume Platform for Recurrent Anticoagulation and Kidney Monitoring during Continuous Renal Replacement Therapy in Critically Ill Children (Fast-Track SBIR PA-20-260) Acute kidney injury (AKI) is characterized by a sudden decrease in the ability of the kidneys to adequately maintain electrolyte, acid-base, and fluid balance. Up to 30% of children admitted to intensive care units develop AKI and the presence of AKI is independently associated with increased length of hospitalization and higher rates of mortality. Continuous renal replacement therapy (CRRT) has emerged as the preferred dialysis modality for critically ill children and is becoming increasingly common for newborns and small children (under 10 kg) with AKI and congenital kidney failure. Frequent monitoring (2-6 times a day) of anticoagulant therapy (heparin, heparinoids, etc.), kidney function (urea), and electrolyte composition (potassium, phosphorus, etc.) is necessary during the course of CRRT. Existing laboratory tests require large blood volumes, and the cumulative blood loss from routine bloodwork contributes to iatrogenic anemia. The majority of critically ill newborns (90% of extremely low birth weight infants and 58% of premature infants) will require red blood cell transfusions during their time in the neonatal intensive care unit (NICU) as a result of frequent blood draws. To meet the critical unmet need for rapid, low volume blood tests for CRRT monitoring in newborns and children, we will develop a panel of four assays on our near-patient digital microfluidic (DMF) platform to provide comprehensive profiling of anticoagulation dosing, kidney function, and phosphorus balance. Our innovative system will simultaneously measure anti-factor Xa (anti-FXa), activated partial thromboplastin time (aPTT), blood urea nitrogen (BUN), and phosphorus from < 50 µL of whole blood input. Plasma separation from whole blood (necessary for all four assays) will be automated on the cartridge to facilitate testing near the patient. By combining four technically complex assays (typically sent to different sections in a lab such as hematology and chemistry) into a single automated test, we can reduce sample-to-answer time and personnel time needed to perform each individual assay, and can significantly reduce the cumulative volume of blood required for recurrent monitoring over the full course of CRRT therapy. Our collaborators on this Fast-Track project include pioneers in pediatric acute care nephrology with multiple recent publications describing novel approaches to CRRT in newborns. Phase I of the project will establish feasibility of the proposed testing platform through development of DMF anti-FXa, aPTT, BUN, and phosphorus assays and demonstration of sufficient analytical and clinical performance. Phase II will combine the four assays into a multiplexed reaction with a time-to-result of under 15 minutes, evaluate the analytical performance and clinical concordance of each assay, and conduct onsite lead user testing of the system to establish reliability and usability. Our final product will initially be marketed for use in newborn and pediatric patients undergoing CRRT. Secondary markets will include both pediatric and adult patients undergoing cardiac surgery or other procedures associated with kidney failure, toxin removal, and ultrafiltration of fluid.