Precision Guidance of Resuscitation and Deresuscitation in Sepsis

脓毒症复苏和复苏的精确指导

• 批准号: 10602712
• 负责人: Jonathan Feldschuh
• 金额: $ 30.5万
• 依托单位: DAXOR CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602712
• 关键词: Adult; Affect; American; Antibiotics; Biological Markers; Blood Plasma Volume; Blood Volume; Blood capillaries; Caring; Cell Volumes; Cessation of life; Chest; Clinical; Clinical Decision Support Systems; Control Groups; Critical Illness; Data; Development; Diagnosis; Diagnostic; Dilution Techniques; Erythrocyte Transfusion; Erythrocytes; Evaluation; Familiarity; Guidelines; Health Personnel; Hematocrit procedure; Hemoglobin; Hospitalization; Hospitals; Hypotension; Hypovolemia; Hypovolemics; Iatrogenesis; Knowledge; Liquid substance; Marketing; Measurement; Measures; Methodology; Methods; Operative Surgical Procedures; Outcome; Patients; Phase; Positioning Attribute; Publications; Randomized; Randomized, Controlled Trials; Recommendation; Respiratory Failure; Resuscitation; Role; Sensitivity and Specificity; Sepsis; Septic Shock; Signs and Symptoms; Small Business Innovation Research Grant; Surrogate Markers; System; Techniques; Technology; Testing; Time; Tracer; Translating; United States; Validation; Vasoconstrictor Agents; Weight; Work; cardiovascular collapse; clinical practice; commercial application; commercialization; comorbidity; cost; design; electric impedance; evidence base; experience; first-in-human; hemodynamics; hypoperfusion; improved; improved outcome; maltreatment; prospective; prototype; randomized trial; septic patients; standard care; success; support tools; technological innovation; tool; treatment as usual; treatment guidelines; usability; user centered design; user-friendly

ABSTRACT Sepsis impacts 1.7 million Americans annually, leading to 270,000 deaths and $62 billion in costs. Most of the sepsis treatment follows the Surviving Sepsis Campaign (SSC) guidelines, consisting of early antibiotics, liberal fluid resuscitation, and vasopressor use in persistent hypotension. However, the fundamental assumption that sepsis universally results in high capillary leak leading to hypovolemia that benefits from aggressive fluid resuscitation, has been refuted by multiple publications suggesting improved outcomes with the administration of less or even no fluid. In fact, other studies have shown that even very restrictive fluid resuscitation might benefit septic shock. Despite these findings, U.S.-based treatment guidelines and CMS requirements are a weight-based fluid administration for all patients, irrespective of actual intravascular fluid status. Thus, there is a significant unmet need for clinically validated sepsis fluid management strategies based on precise, objective assessment of circulating BV. Daxor’s BVA-100, provides 98% accurate quantitative measurement of total blood volume, plasma volume, and red blood cell volume, which it then compares to validated patient-specific norms to provide an accurate measure of intravascular blood volume composition and derangement. A prospective randomized controlled trial (RCT) evaluated the impact of BVA in critically ill surgical patients (n=100) with septic shock, severe sepsis, severe respiratory failure, and/or cardiovascular collapse. In this study access to BVA resulted in a change in treatment in 44% of the time to patients randomized to the BV group and would have resulted in a treatment change in 61% of the patients in the control group. Additionally, the control group received red blood cell transfusions 1.5 ± 2 days later that the BVA group, at which time the abnormality became clinically evident. The preliminary work presented supports Daxor’s hypotheses that (1) sepsis patients are highly heterogeneous with respect to BV and RBCV status implying that (2) standard care decongestion strategies for treating such patients would benefit from BVA as a uniquely precise, objective diagnostic measure of intravascular BV and RBCV derangement. Here, Daxor hypothesizes that fluid management guided by direct quantification of BV status represents a potential paradigm shift in clinical practice, which to date has been based on surrogate markers that lack GS sensitivity and specificity. Transitioning this initial success to clinical acceptance requires the development of a validated, protolyzed methodology for the implementation of BVA, as well as a clinical decision-support system (CDSS) translating BVA results into actionable treatment decisions. The proposed Phase I supports the development of the Sepsis FLO (Sepsis FLuid Optimizer), a CDSS designed to precisely guide BV diagnosis and treatment in sepsis patients. This will be achieved through 1) the development of an alpha prototype through user-centered design; 2) the validation of three functional prototypes through formative usability testing; and 3) the development of a functional beta prototype. In Phase II, the Sepsis- FLO will be further validated in a RCT powered to assess improvements of clinical outcomes versus usual care.

摘要 败血症每年影响170万美国人，导致27万人死亡和620亿美元的成本。大部分 脓毒症治疗遵循生存脓毒症运动（SSC）指南，包括早期抗生素，自由 液体复苏和持续性低血压中血管加压药的使用。然而，基本的假设是， 脓毒症普遍导致高毛细血管渗漏，导致低血容量，其受益于侵袭性液体 复苏，已被多个出版物反驳，表明管理结果改善 更少甚至没有液体。事实上，其他研究表明，即使是非常限制性的液体复苏， 有益于感染性休克。尽管有这些发现，美国-基于治疗指南和CMS要求是一个 对所有患者进行基于体重的液体给药，无论实际血管内液体状态如何。因此，有一个 对基于精确、客观、有效的脓毒症液体管理策略的临床验证的显著未满足需求 评估循环BV。Daxor的BVA-100，提供98%准确的血液总量定量测量 体积、血浆体积和红细胞体积，然后将其与经验证的患者特异性标准进行比较 以提供血管内血容量组成和紊乱的精确测量。一项前瞻性 一项随机对照试验（RCT）评价了BVA对脓毒症外科危重患者（n=100）的影响， 休克、严重脓毒症、严重呼吸衰竭和/或心血管衰竭。在这项研究中，获得BVA 导致随机分配至BV组的患者在44%的时间内改变治疗， 导致对照组中61%的患者改变治疗。此外，对照组接受 比BVA组晚1.5 ± 2天输注红细胞，此时异常变为临床异常 很明显。初步工作支持Daxor的假设，即（1）脓毒症患者高度 BV和RBCV状态的异质性意味着（2）标准治疗缓解充血策略， 治疗这些患者将受益于BVA作为一种独特的精确，客观的诊断措施， 血管内BV和RBCV紊乱。在这里，Daxor假设，由直接指导的液体管理 BV状态的量化代表了临床实践中潜在的范式转变，迄今为止， 缺乏GS敏感性和特异性的替代标志物。将这一初步成功转化为临床 接受需要为BVA的实施开发一种经过验证的、原型化的方法， 以及临床决策支持系统（CDSS），将BVA结果转化为可行的治疗决策。 拟议的第一阶段支持脓毒症FLO（脓毒症流体优化器）的开发，这是一种CDSS， 准确指导脓毒症患者BV的诊断和治疗。这将通过以下方式实现：1） 通过以用户为中心的设计开发alpha原型; 2）验证三个功能原型 通过形成性可用性测试; 3）开发功能性测试原型。在第二阶段，败血症- FLO将在一项有把握度的RCT中进一步验证，以评估与常规治疗相比临床结局的改善。