Precision Guidance of Resuscitation and Deresuscitation in Sepsis

摘要 败血症每年影响170万美国人，导致27万人死亡，损失620亿美元。大多数 脓毒症的治疗遵循存活脓毒症运动(SSC)指南，包括早期抗生素，自由 液体复苏和血管升压剂在持续性低血压中的应用。然而，基本的假设是 脓毒症通常导致高毛细血管渗漏，导致低血容量，这得益于侵袭性液体。 复苏，已经被多个出版物驳斥，建议改善与政府的结果 液体很少，甚至没有。事实上，其他研究表明，即使是非常严格的液体复苏也可能 有益于感染性休克。尽管有这些发现，美国的治疗指南和CMS要求是一个 无论实际血管内液体状态如何，所有患者均可根据体重进行输液。因此，有一个 基于精确、客观的临床验证脓毒症液体管理策略的重大未得到满足的需求 循环BV的评估。Daxor公司的BVA-100可提供98%准确的全血定量测量 体积、血浆体积和红细胞体积，然后将其与经过验证的患者特定正常值进行比较 以提供血管内血液容量组成和排列紊乱的准确测量。一位潜在的 随机对照试验(RCT)评估BVA对外科危重患者(n=100)脓毒症的影响 休克、严重败血症、严重呼吸衰竭和/或心血管衰竭。在这项研究中，获得BVA 导致随机进入BV组的患者44%的时间改变治疗，并将 导致对照组中61%的患者治疗发生变化。此外，对照组还收到了 红细胞输注比BVA组晚1.5±2天，出现临床异常 很明显。提出的初步工作支持Daxor的假设：(1)脓毒症患者高度 关于BV和RBCV状况的异质性，意味着(2)标准护理缓解充血战略 治疗这类患者将受益于BVA，作为一种独特的准确、客观的诊断手段 血管内BV和RBCV排列紊乱。在这里，Daxor假设流体管理由DIRECT指导 BV状态的量化代表了临床实践中潜在的范式转变，到目前为止，这一转变是基于 缺乏GS敏感性和特异性的替代标记。将这一初步成功转化为临床 接受要求为实施BVA制定一种有效的、原则化的方法，如 以及将BVA结果转化为可操作的治疗决策的临床决策支持系统(CDSS)。 拟议的第一阶段支持开发Sepsis Flo(Sepsis流体优化器)，这是一个设计的CDSS 准确指导脓毒症患者的BV诊断和治疗。这将通过1) 通过以用户为中心的设计开发阿尔法原型；2)验证三个功能原型 通过形成性可用性测试；以及3)开发功能测试版原型。在第二阶段，败血症- FLO将在一项随机对照试验中得到进一步验证，该试验旨在评估临床结果与常规护理相比的改善情况。

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.