Nearly 90% of patients who suffer an out-of-hospital cardiac arrest (CA) die. This leading cause of unexpected and sudden death in the US results in an enormous emotional, psychological and financial burden to hundreds of thousands of families and communities across America annually. Relative to the many potentially lethal disease states such as cancer, stroke, sepsis, and trauma, CA survival rates have barely improved since 1960 when manual standard (S) was first described. Over the past 25 years, the applicants have discovered and developed new approaches, techniques and devices to increase cerebral and coronary blood flow and improve neurologically-sound survival after CA. With prior NIH SBIR support they developed the impedance threshold device (ITD), performed animal and clinical trials, and ultimately obtained FDA approval for manual active compression decompression (ACD) plus ITD, the first device ever approved by the FDA to increase the likelihood of survival after CA. Despite this progress, further innovation is needed to substantively improve successful outcomes for more Americans. This application is focused on a new discovery that elevation of the head and thorax during ACD + ITD CPR results in a striking decrease in intracranial pressures and an increase in cerebral and coronary perfusion pressures. These findings, due to the effects of gravity when the head and heart are elevated, have the potential to significantly further enhance cerebral and coronary blood flow and improve overall survivability. The proposed research in an animal model of cardiac arrest is focused on demonstrating proof-of-concept that a new head up CPR device, when used in combination with ACD + ITD CPR, is able to significantly improve blood flow to the heart and brain safely and effectively increase 48-hour survival in an animal model of prolonged CA. We further propose to assess the ergonomics and human factors associated with a light-weight human prototypic head up CPR device in manikins and human cadavers with help of professional firefighters. This novel and approach could increase neurologically-favorable survival rates for >10,000 more Americans annually due to greater blood flow and lower intracranial pressure afforded by gravity-enhanced head up CPR.
Public Health Relevance Statement: Narrative Sudden cardiac arrest is a leading cause of death in the USA, with only 3-20% neurologically intact survival for >350,000 out of hospital non-traumatic cardiac arrest (OHCA) patients each year. 1, 2 Closed-chest standard (S) cardiopulmonary resuscitation (CPR), the current gold standard, has remained largely unchanged since first described in 1960. 3 S-CPR is performed with the entire body in the horizontal plane. 3 While helping many patients, S-CPR is inherently inefficient, generating only 15-30% of normal vital organ perfusion. 3-7 S- CPR can also result in simultaneously high arterial and venous percussion waves to the brain with each compression, creating the potential for harmful increases in intracranial pressure (ICP) with every compression. 8-11 New CPR devices and methods, like active compression decompression (ACD) and the impedance threshold device (ITD) developed by the PI and others over the past 25 years enhance cardio-cerebral perfusion and survival with favorable brain function by a relative 50% versus S-CPR. 4, 5, 12-15 The ACD + ITD combination is only CPR device to date approved by the FDA to increase the likelihood of survival after OHCA. The PI received multiple NIH SBIR awards for the pre-clinical and clinical work on ACD + ITD. In 2015 Zoll Medical bought this technology and recently has started to market it. Despite this progress further innovation is needed as most OHCA patients still die. The centerpiece of this new Phase 1 application is a novel Head Up Position (HUP) device designed to improve neurologically favorable survival after cardiac arrest. HUP CPR increases cardio- cerebral circulation and reduces the potential for brain injury with each chest compression. This Phase 1 application is focused on establishing preclinical proof-of-concept for the HUP CPR device and building the first human prototype for clinical evaluation. The applicants have previously demonstrated that positive and negative changes in intrathoracic pressure during CPR are immediately transmitted to the brain. 8, 10 Changes in intrathoracic pressure can impact cerebral perfusion during cardiac arrest, brain injury and shock. 8, 10 ACD + ITD CPR was developed in part to harness this physiology and improve cardio-cerebral circulation. 10 Building upon ACD + ITD, the applicants discovered the concepts underlying HUP CPR in 2014 when comparing CPR with whole body head up tilt versus whole body head down tilt. 8 HUP CPR involves elevating the heart and the head about 5 and 20 cm, respectively. We have assessed this new idea in animals in cardiac arrest and human cadavers. 8-10, 16, 17 This modest elevation immediately enhances venous drainage from the brain and lowers ICP, lowers right atrial pressures, increases cardiac preload, and redistributes blood flow within the lungs thereby improving respiration and circulation within the lungs. These mechanisms contribute to a clinically significant increase in cardio-cerebral circulation and reduce the potential brain trauma associated with excessively high levels of ICP with each chest compression. Further studies in a human cadaver model demonstrated that HUP CPR immediately reduces ICP and enhances cerebral perfusion pressure. 17 Additional animal studies have also demonstrated that HUP CPR does not work with conventional S-CPR. 8, 9 S-CPR does not provide enough forward flow to pump blood "uphill' with head elevation. 8, 9 In contrast, ACD + ITD CPR provides nearly three times more blood flow to the heart and brain compared with S-CPR, thus making it feasible and practical to perform HUP CPR. 7, 9, 10, 12 Based upon this potential advance the applicants propose to perform a series of proof-of-concept studies to determine if HUP CPR provides superior cerebral blood flow, hemodynamics, and 48 hour neurologically-intact survival rates compared with CPR in the supine position in a pig model of prolonged cardiac arrest. We further propose to build a light weight HUP CPR device prototype and assess its ease of use during manual ACD + ITD CPR and LUCAS + ITD CPR. A successful preclinical safety and effectiveness study will be the basis for the first human evaluation of head up CPR. HUP CPR has the potential to be a major breakthrough in the treatment of cardiac arrest worldwide, especially when integrated into an overall systems-based approach to pre- and post-resuscitation care.
Project Terms: Abdominal; Abdomen; Americas; Animals; Award; Blood Reticuloendothelial System; Blood; Circulation; Bloodstream; Blood Circulation; Blood Gas Analyses; Blood Gas Analysis; Encephalon; Brain Nervous System; Brain; Cadaver; neoplasm/cancer; malignancy; Malignant Tumor; Cancers; Malignant Neoplasms; Carbonic Anhydride; CO2; Carbon Dioxide; heart resuscitation; Cardio-Pulmonary Resuscitation; Cardiopulmonary Resuscitation; Cause of Death; cerebrovascular blood flow; cerebrocirculation; cerebral circulation; cerebral blood flow; brain blood flow; Cerebrovascular Circulation; Clinical Trials; Communities; Sudden Death; Disorder; Disease; Drainage; Drainage procedure; Family; Feasibility Studies; Goals; Gold; Head; Heart; Cardiac Arrest; Asystole; Heart Arrest; atrium; Cardiac Atrium; Atrial; Heart Atrium; Insertion of catheter into heart chamber; Heart Catheterization Pocedure; Heart Catheterization; Cardiac Catheterization; Cardiac Catheterization Procedures; hemodynamics; Hospitals; Modern Man; Human; Intervention Studies; interventions research; interventional study; interventional research; intervention research; Intracranial Pressure; Subarachnoid Pressure; Laboratories; Lower Extremity; Membrum inferius; Lower Limb; Lung; pulmonary; Lung Respiratory System; Manikins; Mannequins; Manuals; Methods; Microspheres; Microbeads; Minnesota; United States National Institutes of Health; National Institutes of Health; NIH; Nervous System Physiology; nervous system function; Neurological function; Neurologic function; Patients; Percussion; Perfusion; Physiology; pressure; Research; Respiration; respiratory mechanism; Resuscitation; Safety; Shock; circulatory shock; Circulatory Collapse; sound; Employee Strikes; Strikes; stroke; cerebrovascular accident; cerebral vascular accident; brain attack; Cerebrovascular Stroke; Cerebrovascular Apoplexy; Cerebral Stroke; Brain Vascular Accident; Apoplexy; Supine Position; Dorsal Position; Survival Rate; Family suidae; suid; porcine; Swine; Suidae; Pigs; Technology; Testing; Time; Universities; Work; Measures; Device Designs; ergonomics; Blinded; Caring; raised intracranial pressure; raised ICP; Intracranial Pressure Increase; Intracranial Pressure Elevation; Elevated Intracranial Pressure; Intracranial Hypertension; Impedance; Electrical Impedance; electric impedance; base; Organ; blood pump; improved; Clinical; Phase; Physiologic; Physiological; Medical; psychological; psychologic; Neurological; Neurologic; Series; Evaluation; Blood flow; cerebral; Cerebrum; Measurement; Head-Down Tilt; Veterinarians; brain-injured; brain damage; Acquired brain injury; Brain Injuries; Gravities; Force of Gravity; light weight; lightweight; Venous; programs; Pupil light reflex; pupillary reflex; pupillary light reflex; Cerebral perfusion pressure; Hour; Techniques; System; Oxygen saturation measurement; Oximetry; Accident and Emergency department; Emergency room; Emergency Department; American; Animal Model; model organism; model of animal; Animal Models and Related Studies; c new; novel; Devices; Human Resources; personnel; Manpower; Positioning Attribute; Position; Chest; Thorax; Thoracic; Thorace; Emotional; Modeling; Traumatic Brain Injury; traumatic brain damage; Brain Trauma; Effectiveness; Interruption; Reproducibility; clinical test; Clinical Testing; Clinical Evaluation; research clinical testing; Small Business Innovation Research; SBIR; Small Business Innovation Research Grant; Process; Coronary; Modification; Cardiac; preclinical; pre-clinical; designing; design; bloodstream infection; blood infection; Sepsis; novel strategy; novel approaches; new approaches; novel strategies; Outcome; Neurological outcome; Neurologic outcome; coronary perfusion; Trauma; innovation; innovative; innovate; clinically significant; clinical significance; prototype; commercialization; FDA approved; preclinical safety
