Resuscitation using novel impedance threshold devices in pediatrics

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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 not known. Our central hypothesis is that breathing through an impedance threshold device (ITD) or, in apneic patients, use of the intrathoracic pressure regulator (ITPR), 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. The goal of this proposal is to demonstrate the proof of concept of a novel resuscitative strategy for hypovolemic shock in pediatrics that improves outcomes. The strategy involves the use of an impedance threshold device (ITD) in spontaneously breathing infants and children and the intrathoracic pressure regulator (ITPR) in patients requiring assisted ventilation. Both lower intrathoracic pressures and thereby enhance venous return and cardiac output while simultaneously lowering intracranial pressures. This phase 1 investigation proposes to: 1) determine the optimal ITD "cracking pressure" in a pediatric model of hemorrhagic shock, 2) demonstrate proof of concept of the impedance threshold valve in pediatric swine by evaluating the device in an established pediatric porcine model of hemorrhagic shock for its ability to: a) improve hemodynamics, and b) increase the 24-hour survival rate, and 3) demonstrate proof of concept of the intrathoracic pressure regulator (ITPR) in ventilator dependent pediatric swine by evaluating the prototype in an established piglet model of hemorrhagic shock for its ability to: a) improve hemodynamics, b) increase the 24-hour survival rate, and c) be used without adverse events, specifically the occurrence of atelectasis. An optimal ITD and ITPR resuscitation strategy has a great potential to successfully combat hypovolemic shock and circulatory collapse, the most common cause of morbidity and mortality in children worldwide.