Resuscitation using novel impedance threshold devices in pediatrics

描述（由申请人提供）：创伤性损伤和低血容量性休克是全球儿童死亡的主要原因。快速、大量晶体液输注和胸内正压通气复苏策略常增加出血后的发病率和死亡率。在成年猪失血性休克中，即使没有液体复苏，增加胸内负压也能改善血流动力学参数和预后。血管生物学、生理学和组织损伤机制随着儿童从婴儿期到青春期的成熟而变化，并且与成人明显不同。目前尚不清楚恢复血管内容量、预防继发性器官损伤和预防儿童严重失血后可逆性休克进展为不可逆性循环衰竭的最佳方法。我们的中心假设是，胸内压调节（IPR）的使用，提高负胸内压，从而增加前负荷，改善心输出量，提高脑氧合，并延迟或防止可逆性休克进展为不可逆循环衰竭的婴儿和儿童。IPR治疗通过调节无呼吸患者的胸内压起作用。每次正压通气后，它可将胸内压降至低于大气压的水平（-5至-12 cmH 2 O）。降低胸内压将静脉血抽回心脏，降低颅内压，从而增加全身和脑灌注。脑灌注增加是由于继发于较高心输出量的前向血流颅内阻力降低。这种新疗法使用外部真空源来降低胸内压，并根据需要使用开关来进行间歇性正压通气。仔细滴定胸内负压 在迄今为止没有损害证据的情况下优化受益。基于成功的I期研究，证明在儿科猪出血模型中使用IPR技术可改善24小时神经存活率，我们建议在儿科人群中进行仔细对照的临床研究，并测量关键生理变量，包括脑组织氧水平。具体而言，调查人员建议：1）完成开发和510 k清除具有可变真空水平的增强型、小型化儿科专用版本的IPR治疗，其容纳在标准通气回路的呼气支路中以用于临床研究，2）证明胸内压调节（IPR）应用概念证据治疗将导致儿科患者的心脏指数增加：a）败血症患者或B）因先天性心脏病（CHD）（单心室或法洛四联症）接受心脏手术的患者。IPR复苏策略具有成功对抗低血容量性休克和循环衰竭的潜力，低血容量性休克和循环衰竭是全球儿童发病率和死亡率的最常见原因。 公共卫生相关性：创伤性失血性休克是儿童和成人低血压的主要原因。多系统创伤占儿童死亡的50%，最常见的是钝性创伤伴严重血容量不足进展为循环衰竭（CDC Vital Statistics 2003）。每一个因此死亡的儿科病人 在创伤中，有四名幸存者终身残疾（在美国每年约有10万人）。无论病因如何，顽固性心血管虚脱仍然是一个重大的临床挑战，特别是在危重患者中，尽管有传统的液体复苏和血管加压剂。本II期提案的主要目的是在一项精心设计的临床研究中提供概念验证证据，证明胸内压调节（IPR）治疗的应用将导致儿科患者的心脏指数和脑氧合增加：a）脓毒症患者或B）因先天性心脏病（CHD）（单心室或法洛四联症）接受心脏手术的患者。新的方法来治疗这种常见的医疗紧急情况有可能降低与严重低血压相关的高发病率和死亡率。因此，这种新器械有可能成为治疗危及生命的低血压的重要新进展，从而降低儿科发病率和死亡率。

DESCRIPTION (provided by applicant): Traumatic injury and hypovolemic shock are leading causes of death in children worldwide. Rapid, large volume crystalloid infusion and positive intrathoracic pressure ventilation resuscitation strategies often increase morbidity and mortality following hemorrhage. Augmenting negative intrathoracic pressure, even without fluid resuscitation, improves hemodynamic parameters and outcome in adult porcine hemorrhagic shock. Vascular biology, physiology, and tissue injury mechanisms change as the child matures from infancy through adolescence, and are distinctly different from adults. The optimal method to restore intravascular volume, prevent secondary organ damage, and prevent progression of reversible shock to irreversible circulatory collapse following severe blood loss in children is no known. Our central hypothesis is that use of intrathoracic pressure regulation (IPR), enhances negative intrathoracic pressure and thus will augment preload, improve cardiac output, enhance cerebral oxygenation, and delay or prevent the progression of reversible shock to irreversible circulatory collapse for infants and children. IPR therapy works by regulating intrathoracic pressures in non-breathing patients. It lowers intrathoracic pressures to subatmospheric levels (-5 to -12 cmH2O) after each positive pressure ventilation. Lowering intrathoracic pressure draws venous blood back to the heart and lowers intracranial pressure, thereby increasing systemic and cerebral perfusion. Cerebral perfusion is increased by decreased intracranial resistance to forward blood flow secondary to higher cardiac output. This novel therapy uses an external vacuum source to lower intrathoracic pressure and a switch to allow for intermittent positive pressure ventilation, as needed. The negative intrathoracic pressure is carefully titrated to optimize benefit with no evidence of harm to date. Building upon the successful Phase 1 studies that demonstrated improved 24 hour neurological survival when utilizing IPR technology in a pediatric porcine hemorrhage model, we propose to evaluate this innovative therapy in a carefully controlled clinical study in the pediatric population and measure key physiological variables including brain tissue oxygen levels. Specifically, the investigators propose to: 1) complete the development of and 510k clear an enhanced, miniaturized pediatric specific version of IPR therapy with variable vacuum levels that is housed in the expiratory limb of a standard ventilation circuit to be utilized in a clinical study, and 2) demonstrate proof of concep that application of intrathoracic pressure regulation (IPR) therapy will result in an increase in cardiac index in pediatric patients: a) with sepsis or b) who have undergone cardiac surgery for congenital heart disease (CHD) (single ventricle or tetralogy of Fallot). IPR resuscitation strategy has the potential to successfully combat hypovolemic shock and circulatory collapse, the most common cause of morbidity and mortality in children worldwide. PUBLIC HEALTH RELEVANCE: Trauma-induced hemorrhagic shock is the leading cause of hypotension in both children and adults. Multi-system trauma accounts for 50% of deaths occurring in children, most often from blunt trauma with severe hypovolemia progressing to circulatory collapse (CDC Vital Statistics 2003). For every pediatric patient that dies as a result of trauma, there are four survivors who are permanently disabled (approximately 100,000/year in the USA). Regardless of the etiology, intractable cardiovascular collapse continues to be a significant clinical challenge, especially in critically ill patients despite traditional fluid resuscitation and vasopressor agents. The main objective of this Phase 2 proposal is to provide proof of concept evidence in a carefully designed clinical study that application of intrathoracic pressure regulation (IPR) therapy will result in an increase in cardiac index and cerebral oxygenation in pediatric patients: a) with sepsis or b) who have undergone cardiac surgery for congenital heart disease (CHD) (single ventricle or tetralogy of Fallot). New approaches to treatment for this common medical emergency have the potential to reduce the high morbidity and mortality rates associated with severe hypotension. As such, this new device has the potential to be an important new advance in treating life-threatening hypotension and thereby reduce pediatric morbidity and mortality rates.