Intrathoracic Pressure Regulator for Resuscitation

描述（由申请人提供）：本SBIR II期申请的目标是继续开发和评价胸内压力调节器（ITPR），预期用于增加循环和血压，临床上显著的低血压状态，包括心脏骤停和感染性休克。这种新型非侵入性设备插入患者和患者通气装置之间的标准呼吸回路中。它的功能是在每次正压通气后，将呼气阶段的胸内压降低到低于大气压的水平。胸内压的降低（通常降低至-7至-9 mmHg）在胸腔内相对于身体的其余部分产生真空，从而a）显著增强血液返回心脏，并因此增加心输出量和血压，以及B）独特地降低颅内压，从而增加脑灌注。1期临床前研究表明，使用ITPR治疗心脏骤停和失血性休克时，生存率和神经系统结局显著改善，且无不良反应。最近在患有术中低血压的人类中进行的试点研究为这种创新技术具有显著临床益处的潜力提供了支持。基于我们最近在该器械方面取得的重大进展，包括在心脏骤停、出血性休克和感染性休克动物模型中的研究，本研究的具体目的包括：1）证明在心脏骤停患者中应用CPR和主动ITPR设备将增加关键生理参数的临床概念的证据，包括平均股动脉收缩压和舒张压、氧饱和度，和呼气末二氧化碳值; 2）证明了临床概念的证据，即在经历a）一般腹部手术和B）肝切除手术的患者中应用主动ITPR将增加关键血液动力学参数，包括当与使用假ITPR时的血液动力学值相比时的收缩期和舒张期动脉血压和平均动脉压;以及3）通过以下方式改进装置设计以满足当前和未来的临床需求：a）设计和制造ITPR装置的商业版本，其可以容易地插入麻醉回路中或连接到复苏器袋和真空源，所述真空源包括压力计、快速脱离和重新接合装置的装置并包括气体采样端口; B）设计、制造和台架测试能够提供3个治疗阶段的ITPR（eITPR）的增强版本的原型：在吸气阶段的正压呼吸，在呼气相的第一部分期间的胸内负压，然后呼气末正压（PEEP）c）在肺损伤的动物模型中评价商业形式的ITPR和eITPR对肺功能的长期作用。一项积极的心肺复苏试验将产生一种新的工具，仅在美国，每年就可以帮助挽救数万人的生命。积极的术中研究有望降低医院内外继发于失血和其他危及生命原因的严重低血压患者的发病率和死亡率。此外，目标3b和3c中提出的拟议产品增强工作将提供一种治疗患有基础肺部疾病的ITPR治疗患者的方法，从而显著扩展这种新型无创治疗方式对临床显著和危及生命的低血压的潜在临床价值。 公共卫生相关性：尽管在治疗创伤性损伤导致的危及生命的低血压患者方面取得了进展，但创伤仍然是1至44岁美国人的头号死亡原因，也是总体死亡的第四大原因。这些伤害的经济后果估计为400亿美元的直接成本和每年超过4000亿美元的生产寿命年。本II期提案的主要目的是在两项精心设计的临床研究中提供概念证据证明，一种新型器械胸内压力调节器（ITPR）可以快速抵消严重低血压的影响。因此，这种新设备有可能成为治疗危及生命的低血压的重要新进展，从而降低平民和军事死亡率。

DESCRIPTION (provided by applicant): The goal of this SBIR Phase 2 application is to continue the development and evaluation the intrathoracic pressure regulator (ITPR), intended to increase circulation and blood pressure clinically significant states of hypotension, including cardiac arrest and septic shock. This novel non-invasive device is inserted within a standard respiratory circuit between the patient and a means to ventilate the patient. It functions by decreasing intrathoracic pressure during the expiratory phase to subatmospheric levels after each positive pressure ventilation. The decrease in intrathoracic pressure, typically to -7 to -9 mmHg, creates a vacuum within the thorax relative to the rest of the body thereby a) significantly enhancing blood return to the heart and consequently increasing cardiac output and blood pressure and b) uniquely lowering intracranial pressure thereby increasing cerebral perfusion. Phase 1 pre-clinical studies demonstrated significantly improved survival and neurological outcome without adverse effects when using the ITPR to treat cardiac arrest and hemorrhagic shock. Recent pilot studies in humans with intra-operative hypotension provide support for the potential for this innovative technology to have a significant clinical benefit. Building further upon our recent and significant progress with this device including studies in animal models of cardiac arrest, hemorrhagic shock, and septic shock, the specific aims of this research include: 1) demonstrate proof of clinical concept that application of CPR and an active ITPR device in cardiac arrest patients will augment key physiological parameters including mean femoral systolic and diastolic arterial blood pressure, oxygen saturation, and end tidal carbon dioxide values when compared to patients treated with a sham ITPR device and CPR; 2) demonstrate proof of clinical concept that application of an active ITPR in patients undergoing a) general abdominal surgery and b) hepatic resection surgery will augment key hemodynamic parameters including systolic and diastolic arterial blood pressure and mean arterial pressure when compared hemodynamic values when a sham ITPR is used; and 3) refine the device design to address current and future clinical needs by: a) designing and manufacturing a commercial version of the ITPR device that can be easily inserted into an anesthesia circuit or attached to a resuscitator bag and vacuum source that includes a manometer, a means to quickly disengage and reengage the device and includes a gas sampling port; b) designing, manufacturing, and bench testing a prototype of an enhanced version of the ITPR (eITPR) capable of providing 3 phases of therapy: positive pressure breath during the inspiratory phase, negative intrathoracic pressure during the first portion of the expiratory phase and then positive end expiratory pressure (PEEP) during the secondary portion of the expiratory phase; and c) evaluating the long-term effects of the commercial version of the ITPR and the eITPR on lung function in an animal model of lung injury. A positive CPR trial would result in a new tool to help save tens of thousands more lives per year after cardiac arrest in the US alone. Positive intra-operative studies promise to decrease morbidity and mortality for patients inside and outside the hospital with severe hypotension secondary to blood loss and other life-threatening causes. In addition, the proposed product enhancement work proposed in Aim 3b and 3c will provide a means to treat patients with ITPR therapy who have underlying pulmonary disease, thereby significantly expanding the potential clinical value of this novel non-invasive treatment modality for clinically significant and life-threatening hypotension. PUBLIC HEALTH RELEVANCE: Despite advances in the treatment of patients with life-threatening hypotension from traumatic injuries, trauma remains the number one cause of death among Americans between the ages of 1 and 44 and the fourth leading cause of death overall. The economic consequence of these injuries is estimated at 40 billion dollars in direct costs and over 400 billion dollars per year in productive life years. The main objective of this Phase 2 proposal is to provide proof of concept evidence in two carefully designed clinical studies that a novel device, the intrathoracic pressure regulator (ITPR), can rapidly counteract the effects of severe hypotension. As such, this new device has the potential to be an important new advance in treating life-threatening hypotension and thereby reduce civilian and military mortality rates.