Intrathoracic Pressure Regulator for Resuscitation

描述(由申请人提供)：该SBIR第二阶段应用的目标是继续开发和评估胸腔内压力调节器(ITPR)，旨在增加循环和血压临床显著的低血压状态，包括心脏骤停和感染性休克。这种新的非侵入性设备被插入到患者和用于患者通风的装置之间的标准呼吸回路中。它的作用是在每次正压通气后，将呼气相的胸腔内压降低到大气层下的水平。胸内压的降低，通常为-7至-9毫米汞柱，在胸腔内产生相对于身体其他部分的真空，从而a)显著增加血液回流到心脏，从而增加心输出量和血压，以及b)独特地降低颅内压，从而增加脑血流。第一阶段临床前研究显示，当使用ITPR治疗心脏骤停和失血性休克时，显著改善了存活率和神经预后，没有不良反应。最近对患有术中低血压的人类进行的先导性研究支持了这项创新技术具有显著临床益处的潜力。这项研究的具体目的包括：1)证明在心脏骤停、失血性休克和感染性休克动物模型研究的基础上，我们最近在该设备上取得的重大进展的基础上，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，包括平均股动脉收缩和舒张压、血氧饱和度和呼气末二氧化碳分压，与使用假ITPR设备和CPR的患者相比；2)证明临床概念，即在接受a)普通腹部手术和b)肝切除手术的患者中应用主动ITPR将增强关键的血流动力学参数，包括当使用假ITPR时比较血流动力学数值时的收缩和舒张压以及平均动脉压；以及3)改进装置设计以满足当前和未来的临床需求：a)设计和制造商业版本的ITPR装置，该装置可以容易地插入麻醉电路或连接到复苏器袋和真空源，包括压力计、快速脱离和重新接触装置的装置，并包括气体采样端口；B)设计、制造和在试验台上测试能够提供3个治疗阶段的增强型ITPR(EITPR)的原型：吸气期的正压呼吸，呼气期第一部分的胸腔内负压，然后呼气期第二部分的呼气末正压(PEEP)；以及c)在肺损伤动物模型中评估商业版本的ITPR和eITPR对肺功能的长期影响。一项积极的CPR试验将产生一种新的工具，仅在美国就能帮助挽救每年心脏骤停后数万人的生命。积极的术中研究有望降低医院内外因失血和其他危及生命的原因而继发严重低血压的患者的发病率和死亡率。此外，目标3b和3c中建议的产品增强工作将提供一种方法来治疗患有潜在肺部疾病的ITPR治疗患者，从而显著扩大这种新的非侵入性治疗模式对临床意义重大和危及生命的低血压的潜在临床价值。 公共卫生相关性：尽管创伤性低血压患者的治疗取得了进展，但在1岁至44岁的美国人中，创伤仍然是头号死因，也是第四大死因。这些伤害造成的经济后果估计为400亿美元的直接成本和每年超过4000亿美元的生产寿命年。这项第二阶段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，证明一种新型设备--胸腔内压力调节器(ITPR)可以迅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，从而降低平民和军人的死亡率。

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.