Precision Guidance of Resuscitation and Deresuscitation in Sepsis

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.