A Novel Device for Optimal and Personalized Fluid Therapy in Septic Shock Patients

摘要 脓毒性休克是一种严重的疾病，导致器官灌注严重减少， 常见的2期和3期急性肾损伤（阿基）发生在多达60%的患者中， 院内合并症死亡率高达70%，令人震惊。当前败血症生存指南 建议早期积极液体复苏，目标是平均动脉压（MAP≥ 65 mmHg）;但是 积极的复苏通常导致血容量过多。腹内压升高（IAP）， 经常发生在危重患者中，被认为是反映静脉流出的重要参数， 广泛的生理效应，包括与阿基的相关性。因此，腹部灌注压 (APP=MAP-IAP）可以提供最佳目标，以指导血流动力学支持，因为它反映了流入（MAP） 和流出（IAP）灌注。然而，目前的IAP测量方法限制了APP作为一种 血流动力学目标，因为它们容易发生（1）人为错误，限制测量的可重复性，以及（2） 导致导管相关尿路感染的污染。Potrero Medical，Inc.发展 Accuryn监测系统，可准确，自动和数字化地提取生理数据， 实时从膀胱，而不需要外部设备或手动操作。Accuryn收到 年4月，FDA正式批准了IAP、尿量和核心温度测量的510（k）许可。 2016.结合通过标准治疗获得的MAP，Accuryn将使APP靶向 感染性休克患者血流动力学复苏在这项拨款中，使用Accuryn来改善临床 通过IAP监测和APP靶向血流动力学复苏治疗感染性休克患者的结果将 得到验证。我们计划对200名感染性休克患者进行为期24个月的临床试验， 组：（1）监测（正常IAP接受MAP靶向复苏），（2）标准护理MAP组 MAP靶向复苏组（IAP升高组）和APP组（IAP升高组，APP≥ 60 mmHg目标复苏。比较的主要终点是发生率或进展（定义为 与基线水平相比，肌酐和UO的峰值严重程度）。次要终点 包括ICU和医院死亡率、RRT频率和持续时间、尿生物标志物数据、 机械通气、血管加压药支持的平均持续时间和不良事件。独立比较 将（1）证实液体复苏期间IAP升高与脓毒症患者阿基相关， （2）验证APP引导的液体复苏可降低休克患者的发生率或进展， 与MAP引导复苏相比，感染性休克患者中的2期和3阿基。通过这项临床研究，我们 将确认Accuryn器械在复苏期间连续测量IAP和目标APP的需求。 从该资助中收集的数据将使设计一项定义APP的关键III期临床研究成为可能- 靶向血流动力学支持作为脓毒性休克的新护理标准。

Abstract Septic shock is a severe condition resulting in a critical reduction of organ perfusion with consequential and common stage 2 and 3 acute kidney injury (AKI) occurring in as many as 60% of patients and with an alarmingly high in-hospital co-morbid mortality rate of up to 70%. Current Surviving Sepsis Guidelines recommend early aggressive fluid resuscitation targeting mean arterial pressure (MAP≥ 65 mmHg); however aggressive resuscitation commonly results in hypervolemia. Elevated intra-abdominal pressure (IAP), which occurs frequently in critically ill patients, is recognized as a vital parameter reflecting venous outflow that has wide-ranging physiologic effects including an association with AKI. Thus, abdominal perfusion pressure (APP=MAP-IAP) may provide the optimal target to guide hemodynamic support as it reflects both inflow (MAP) and outflow (IAP) perfusion. However, current methods of IAP measurement limit the validation of APP as a hemodynamic target as they are prone to (1) human error, limiting the reproducibility of measurements and (2) contamination resulting in catheter-associated urinary tract infections. Potrero Medical, Inc. has developed the Accuryn Monitoring System, which accurately, automatically and digitally extracts physiological data in real-time from the bladder, without the need for external equipment or manual manipulation. Accuryn received formal 510(k) clearance from the FDA for measurement of IAP, urine output and core temperature in April of 2016. In combination with MAP acquired through standard of care, Accuryn will enable APP-targeted hemodynamic resuscitation in septic shock patients. In this grant, the use of Accuryn to improve clinical outcomes in septic shock patients via both IAP monitoring and APP-targeted hemodynamic resuscitation will be validated. We plan to conduct a 24-month clinical trial with 200 septic shock patients divided among three groups: (1) Monitoring (normal IAP receiving MAP-targeted resuscitation), (2) Standard of Care MAP group (elevated IAP receiving MAP-targeted resuscitation), and (3) APP group (elevated IAP receiving APP≥ 60 mmHg targeted resuscitation. The primary endpoint for comparison will be incidence or progression (defined by peak severity in creatinine and UO compared to baseline levels) of stage 2 and 3 AKI. Secondary endpoints include ICU- and hospital mortality, frequency and duration of RRT, urinary biomarker data, days on mechanical ventilation, mean duration of vasopressor support, and adverse events. Independent comparisons between these groups will (1) verify that elevated IAP during fluid resuscitation is correlated with AKI in septic shock patients and (2) validate that APP-guided fluid resuscitation reduces the incidence or progression of stage 2 and 3 AKI in septic shock patients compared to MAP-guided resuscitation. With this clinical study, we will validate the need for the Accuryn device to continuously measure IAP and target APP during resuscitation. The data collected from this grant will enable the design of a pivotal phase III clinical study defining APP- targeted hemodynamic support as the new standard of care for septic shock.