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

摘要 感染性休克是一种严重的情况，导致器官灌注量的严重减少，从而导致 常见的2期和3期急性肾损伤(AKI)发生在多达60%的患者中，并伴有 医院内合并症死亡率高达70%，令人震惊。目前尚存的脓毒症指南 建议以平均动脉压(MAP≥65毫米汞柱)为目标的早期积极液体复苏；然而 积极复苏通常会导致高容量血症。腹内压升高(IAP) 常见于危重病人，被认为是反映静脉流出的重要参数 广泛的生理影响，包括与AKI的联系。因此，腹部灌注压 (APP=MAP-IAP)可提供指导血流动力学支持的最佳靶点，因为它反映了两个流入(MAP) 外流(IAP)灌流。然而，目前的IAP测量方法限制了APP作为一种 血流动力学指标，因为它们容易(1)人为错误，限制测量的重复性和(2) 污染导致导尿管相关的尿路感染。Potrero医疗公司已经开发出 Accuryn监护系统，可准确、自动和数字地提取生理数据 实时从膀胱，不需要外部设备或手动操作。Accuryn已收到 年4月FDA正式批准510(K)用于测量IAP、尿量和核心体温 2016年。与通过标准护理获得的地图相结合，Accuryn将启用针对应用程序的 感染性休克患者的血流动力学复苏。在这笔赠款中，Accuryn的使用改善了临床 感染性休克患者通过IAP监测和APP靶向血流动力学复苏的结果将 被证实。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，分为三组。 分组：(1)监测(接受MAP靶向复苏的正常IAP)，(2)标准护理MAP组 (3)APP组(接受APP≥60的提升的IAP 毫米汞柱定向复苏。比较的主要终点将是发生率或进展(已定义 与基线水平相比，AKI阶段2和3的肌酐和UO的峰值严重程度)。次要端点 包括ICU和住院死亡率、RRT频率和持续时间、尿生物标志物数据、 机械通气、血管加压剂支持的平均持续时间和不良事件。独立比较 这些小组之间将(1)证实液体复苏期间升高的IAP与败血症患者的AKI相关 休克患者和(2)证实APP引导的液体复苏减少了 感染性休克患者的2期和3期AKI与MAP引导复苏的比较。通过这项临床研究，我们 将验证Accuryn设备在复苏期间持续测量IAP和目标APP的必要性。 从这笔赠款中收集的数据将使设计一项关键的III期临床研究成为可能，该研究定义了APP- 靶向血流动力学支持作为感染性休克护理的新标准。

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.