Cardiac arrest in infants is a medical emergency requiring rapid resuscitation to restore circulation. However, resuscitation often results in significant brain injury, caused by ischemia/reperfusion injury. Only 36% of infants (<1yr old) treated for out-of-hospital cardiac arrest and 69% of infants that suffer in-hospital cardiac arrest are successfully resuscitated. These infants currently have no therapeutic options to limit brain injury. The current standard treatment for post-cardiac arrest brain injury is therapeutic hypothermia. Unfortunately, recent studies demonstrated that use of therapeutic hypothermia in pediatric cardiac arrest patients does not provide significant benefit beyond what is achieved with controlled normothermia. A safe and effective neuroprotective intervention that specifically targets reperfusion injury would fill a critical unmet need in the treatment of these vulnerable patients. Our molecular studies on mitochondria uncovered a novel method to non-invasively modulate mitochondrial function during reperfusion and reduce brain injury following resuscitation from cardiac arrest. Indeed, our studies have, for the first time: (i) identified two wavelengths of near infrared light (NIR) that specifically and reversibly reduce mitochondrial respiration by acting on cytochrome c oxidase (COX); (ii) documented that NIR, applied at the time of reoxygenation, is neuroprotective in rodent and swine models of infant and pediatric cardiac arrest/resuscitation; and (iii) developed a NIR-delivery system capable of providing therapeutic doses to patients up to 1 year old. Based on these data, we propose to produce the clinical Light Utilizing COX- Inhibitory Device (LUCID), a medical device that will safely deliver therapeutic NIR to the infant brain. To achieve this goal, Phase I will focus on device development and validation of LUCID in 3 experimental aims: "¢ Develop LUCID engineered for clinical use (Aim 1). "¢ Evaluate safety and efficacy of LUCID (Aim 2). "¢ LUCID clinical trial development and HUD and IDE approval (Aim 3). Phase II will utilize the LUCID clinical device and execute the "LUCID Therapy for Infant Cardiac Arrest" (LUTICA) clinical trial (Aim 4). This proposal combines multi-disciplinary expertise, compelling preliminary data, and state-of-the-art resources available to our team to address a significant health problem in a highly vulnerable patient population.
Public Health Relevance Statement: Interrupted blood flow to the brain during cardiac arrest initiates progressive brain injury in resuscitated infants, and this neurologic injury is a significant contributor to the death and disability. We have discovered that treatment with specific wavelengths of infrared light, applied non-invasively following resuscitation, substantially reduces the production of free radicals and brain damage. We have developed a device capable of providing this therapy to children up to 1 year old and we propose to produce and validate the clinical device, then conduct a small clinical trial to assess the impact of treatment on neurologic function in infant cardiac arrest patients.
Project Terms: Achievement; Achievement Attainment; American Heart Association; Blood Circulation; Bloodstream; Circulation; Brain; Brain Nervous System; Encephalon; Cardiopulmonary Resuscitation; cardiac resuscitation; heart resuscitation; Brain Ischemia; Ischemic Encephalopathy; Child; 0-11 years old; Child Youth; Children (0-21); youngster; Clinical Engineering; Clinical Trials; cytochrome c oxidase; Cytochrome Oxidase; Electron Transport Complex IV; Ferrocytochrome c Oxygen Oxidoreductase; Cessation of life; Death; Electroencephalography; EEG; Enzymes; Enzyme Gene; Foundations; Free Radicals; Goals; Grant; Health; Heart Arrest; Asystole; Cardiac Arrest; Cardiac Surgery procedures; Cardiac Surgery; Cardiac Surgical Procedures; Heart Surgical Procedures; heart surgery; Hospitals; natural hypothermia; Hypothermia; Infant; Ischemia; Laboratories; Light; Photoradiation; Medical Device; Methods; Mitochondria; mitochondrial; Neurologic function; Neurological function; nervous system function; Nervous System Physiology; Neurological Examination; Neurologic Examination; O element; O2 element; Oxygen; Patents; Legal patent; Patients; Actinotherapy; Light Therapy; Photoradiation Therapy; light treatment; Phototherapy; Production; reperfusion; Reperfusion Therapy; Ischemia-Reperfusion Injury; Reperfusion Damage; Reperfusion Injury; Research; Research Resources; Resources; respiratory mechanism; Respiration; Resuscitation; Safety; Scalp; Scalp structure; Software; Computer software; Technology; Temperature; Testing; Time; Tissues; Body Tissues; Translating; Generations; Measures; Mediating; Custom; Reactive Oxygen Species; Active Oxygen; Oxygen Radicals; Pro-Oxidants; Guidelines; base; improved; Clinical; Phase; Neurologic; Neurological; disability; pediatric; Childhood; Blood flow; Oxidases; Head circumference; Acquired brain injury; brain damage; brain-injured; Brain Injuries; Therapeutic; Investigation; Source; System; restoration; biocompatibility; biomaterial compatibility; success; neuroprotection; Animal Models and Related Studies; model of animal; model organism; Animal Model; novel; Devices; ischemic brain damage; Ischemic Brain Injury; Nervous System Injuries; Nervous System damage; Neurological Damage; Neurological Injury; Neurological trauma; neurotrauma; Nervous System Trauma; cytochrome c oxidase II; cytochrome C oxidase subunit II; neurocognitive test; portability; Intervention Strategies; interventional strategy; Intervention; 1 year old; 1 year of age; age 1 year; aged 1 year; aged one year; one year of age; one year old; Therapeutic Uses; Address; Dose; Data; device development; instrument development; Device or Instrument Development; Interruption; Preclinical Models; Pre-Clinical Model; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Enrollment; enroll; Rodent Model; Small Business Technology Transfer Research; STTR; Validation; Preparation; Molecular; Development; developmental; pre-clinical; preclinical; cost; design; designing; Neurocognitive Deficit; IQ Deficit; intelligence quotient deficit; neurocognitive decline; neurocognitive impairment; clinical efficacy; infant brain injury; brain injury in infants; wound; tissue wound; wounding; wounds; Neurological outcome; Neurologic outcome; Coupled; innovation; innovate; innovative; Impairment; multidisciplinary; prototype; patient population; standard care; standard treatment; verification and validation; Institutional Review Boards; IRB; IRBs; Medical emergency; clinical translation; first-in-human; first in man; out-of-hospital cardiac arrest; porcine model; pig model; piglet model; swine model; waveguide
