A Device for the Prevention and Treatment of Multiple Organ Failure in COVID-19 Patients

摘要 多器官功能衰竭(MOF)是重症监护患者发病和死亡的常见原因 重症监护室(ICU)，包括新冠肺炎患者。多器官损伤的预防及后续治疗 应该是ICU的一个重点，被认为在危重病人的支持性护理中特别重要 还有新冠肺炎患者。在预防和治疗MOF的努力中，肠道可能是一个关键的目标，因为它是MOF的驱动力 发展。具体地说，危重疾病有可能影响许多患者的肠道灌注量。 (包括那些有血栓或电击伤的人)，这可以推动病理反应 启动系统 炎症反应综合征(SIRS) 导致了MOF。一种新的治疗方法可能是直接腹膜 复苏(DPR)，包括循环的商业腹膜透析液 腹膜腔。DPR可改善组织灌注量，减少细胞缺血。反过来，DPR一直是 广泛证明可以减轻全身炎症反应综合征，增加终末器官的血流量，并相应减少损伤 提高失血性休克(HS)临床前小动物模型的存活率。此外，重要的临床 DPR的好处已经在1)改善了需要手术治疗的患者的康复 腹部灾难(创伤、脓毒症和坏死性小肠结肠炎)和2)显著增加 从脑死亡、心脏跳动的捐赠者身上移植器官。然而，与伤害相关的并发症的风险 腹膜腔入路是DPR临床应用的重要障碍，尤其是对不稳定、危重的患者 需要在床边快速、安全地放置腹膜导尿管的病人。带来 DPR对ICU的好处，TheraNova开发了多器官衰竭治疗(MOFT)。MOFT 有两个功能：1)通过使用专有的腹膜进入系统，安全、快速地进入床边 (PAS)，以及2)通过使用灌肠控制器(LC)的自主DPR。在前期工作中，我们有 证明1)降低了组织损伤的风险，2)及时进入腹膜，3)循证置入 指导，以及4)持续、自主的腹膜灌洗。此修订应用程序的目标是验证 在转化为临床使用之前，MOFT在临床相关和可重复性的动物模型中。首先，我们将 通过优化MOFT PAS控制器来实现三种基于证据的模式，从而提高设备利用率 在一个集中枢纽内提供指导(目标1)。然后，我们将对HS猪进行随机对照研究 示范安全有效的腹膜通路模式(目标2.1)和DPR治疗预防 肠源性全身炎症和器官损伤(目标2.2)。成功完成这项拟议的工作将 提供足够的证据，以便向FDA申请调查设备豁免。然后我们将启动试点 ICU的临床研究，并特别关注患有新冠肺炎的危重患者。

Abstract Multiple organ failure (MOF) is a common cause of morbidity and mortality for individuals in the intensive care unit (ICU) including those suffering from COVID-19. Prevention of multiorgan injury and subsequent treatment should be a focus in the ICU, and is thought to be especially important in supportive care of critically ill patients and COVID-19 patients. In efforts to prevent and treat MOF, the gut may be a key target as it is a driver of MOF development. Specifically, critical illness has the potential to compromise gut perfusion in many patients (including those with embolic or shock insult), which can propel a pathological response initiating systemic inflammatory response syndrome (SIRS) leading to MOF. A novel treatment may be direct peritoneal resuscitation (DPR), which consists of circulating commercially available peritoneal dialysis solution throughout the peritoneal cavity. DPR improves tissue perfusion and reduces cellular ischemia. In turn, DPR has been extensively proven to attenuate SIRS, increase blood flow in end-organs with corresponding decreased injury and improve survival in preclinical small animal models of hemorrhagic shock (HS). Further, significant clinical benefits of DPR have been demonstrated in 1) improved recovery of patients requiring surgical management of abdominal catastrophe (trauma, sepsis and necrotizing enterocolitis) and 2) significantly increased numbers of organs transplanted from brain dead, heart beating donors. However, the risk of injury-related complications during peritoneal access is a substantial roadblock to the clinical utility of DPR, especially for unstable, critically ill patients, who require peritoneal catheter placement to be quick, safe and conducted at the bedside. To bring the benefits of DPR to the ICU, TheraNova has developed the Multi-Organ Failure Treatment (MOFT). MOFT has two functions: 1) safe, quick bedside access through the use of a proprietary Peritoneal Access System (PAS), and 2) autonomous DPR through the use of a Lavage Controller (LC). In our preliminary work, we have demonstrated 1) attenuated risk of tissue injury, 2) timely peritoneal access, 3) evidence-based insertion guidance, and 4) consistent, autonomous peritoneal lavage. The goal of this revision application is to validate MOFT in a clinically relevant and reproducible animal model before translation to clinical use. First, we will enhance device utility by optimizing the MOFT PAS controller to enable three modalities of evidence-based guidance within a centralized hub (Aim 1). We will then conduct a randomized, controlled study with an HS swine model to demonstrate safe and effective peritoneal access (Aim 2.1) and DPR treatment for the prevention of gut-derived systemic inflammation and organ injury (Aim 2.2). Successful completion of this proposed effort will provide sufficient evidence to file for an Investigational Device Exemption with the FDA. We will then initiate pilot clinical studies in the ICU and focus specifically on critically-ill patients with COVID-19.