Identifying Potential Therapeutic Targets for Abusive Head Trauma

确定虐待性头部创伤的潜在治疗目标

基本信息

批准号：
10468009
负责人：
Beth A Costine-Bartell
金额：
$ 44.9万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10468009
关键词：
Accident and Emergency department Accidents Acute Admission activity Age Antiepileptic Agents Apnea Area Biological Markers Blood Vessels Brain Injuries Brain region Characteristics Child Childhood Childhood Injury Clinical Clinical Management Contralateral Craniocerebral Trauma Critical Care Depressed mood Development Disabled Persons Elements Event Evolution Focal Seizure Functional disorder Future Goals Guidelines Hemorrhage Hospitalization Hospitals Hour Human Hypoventilation Hypoxia Image Impairment Infant Injury Intensive Care Kainic Acid Location Matrix Metalloproteinases Mechanics Metabolic acidosis Modeling Multiple Trauma Neurologic Neurological status Outcome Pattern Pediatric Intensive Care Units Protocols documentation Radiology Specialty Seizures Severities Shaken baby syndrome Subarachnoid Hemorrhage Subdural Hematoma Testing Therapeutic Time Tissues Toddler Trauma Traumatic Brain Injury Up-Regulation X-Ray Computed Tomography age related brain morphology cerebral atrophy clinically relevant disability burden hemisphere damage innovation mortality prevent relating to nervous system severe injury therapeutic target therapy development time interval tissue trauma vasogenic edema

项目摘要

PROJECT SUMMARY The pathophysiology of hemispheric hypodensity is unknown. It is a pattern of brain damage only occurring in young children, often resulting from abuse, where the majority of the hemisphere underlying the subdural hematoma appears hypodense on computed tomography spanning multiple vascular territories. When the subdural hematoma is over one hemisphere, the damage is predominantly unilateral. Recently, we successfully induced unilateral hemispheric hypodensity in piglets developmentally similar to human toddlers by re-creating the clinical characteristics of this injury: mechanical trauma, midline shift, subdural hematoma, seizures, apnea, and hypoventilation. This model results in an age-dependent neurologic impairment, metabolic acidosis, and unilateral hypoxic-ischemic-type injury encompassing most of the cortex underlying the subdural hematoma. The pattern of damage, degree of vasogenic edema, and upregulation of matrix metalloproteinases are age-dependent. The percentage of hemispheric damage is positively correlated with hemorrhage area and seizure duration. Our long-term goal is to understand the age- and injury-specific pathophysiology to develop therapies that halt or inhibit the progression of tissue damage after abusive head trauma. The overall objective in this application is to determine the contribution of seizures and hemorrhage in the development of the damage and if the cascades of injury can be aborted. Our central hypothesis is that the large forces generated from abuse causes extensive tissue damage that is primarily driven by an interplay between focal seizures and hemorrhage and that the resultant damage cascades can be arrested with anti- epileptic drugs. The rationale is that by understanding the pathophysiology and determining if the tissue is salvageable, then therapeutics that potentially halt the damage can be tested. We will test our central hypothesis with two specific aims:1.) Determine the contribution of seizures and hemorrhage to the development of unilateral hemispheric hypodensity; and 2.) Determine if stopping seizures at a time when children present to the emergency department prevents the extensive damage. Our contribution is the first model of hemispheric hypodensity that replicates the potentially synergistic multifactorial injury cascades within comparable developmental stages and brain morphology of human infants and toddlers where the pathophysiology and contribution of seizures can be determined. This approach is innovative as it departs from the status quo of using a single injury to induce “severe traumatic brain injury”; instead, we study the synergistic interplay of multiple injuries and insults and manage 30 hours of critical care using standard pediatric critical care protocols with clinically relevant outcomes. The proposed contribution is significant because age-specific therapies that abort the cascades of the pathophysiology of abusive head trauma might reduce the severity of neural damage and reduce the number of infants that die or are permanently disabled.

项目摘要半球降低的病理生理尚不清楚。这是一种脑损伤的模式幼儿通常是由于虐待而导致的，大多数半球都有下半部的半球跨越多个血管区域的计算机断层扫描中的血肿显得较低。什么时候硬膜下血肿超过一个半球，损伤主要是单侧的。最近，我们成功诱导的仔猪中的单侧半球肌无力与人幼儿相似通过重新创建这种损伤的临床特征：机械创伤，中线移位，硬膜下血肿，癫痫发作，呼吸暂停和渗透率不足。该模型导致依赖年龄的神经系统障碍，代谢性酸中毒和单侧缺氧型损伤包括大多数皮质硬膜下血肿。损伤的模式，加血管水肿程度和基质的上调金属蛋白酶是年龄依赖性的。半球损伤的百分比与出血区域和癫痫发作持续时间。我们的长期目标是了解特定年龄和伤害病理生理学以开发出停止或抑制虐待头后组织损伤进展的疗法创伤。本应用的总体目的是确定癫痫发作和出血的贡献损害的发展以及受伤的级联是否可以流产。我们的核心假设是滥用产生的大力量会造成广泛的组织损伤，主要由相互作用驱动在局灶性癫痫发作和出血之间，可以用抗癫痫药。理由是，通过了解病理生理学并确定组织是否是可以挽救的，然后可以测试可能阻止损害的理论。我们将测试我们的中央具有两个具体目的的假设：1。）确定癫痫发作和出血的贡献单方面半球性低强度的发展；和2.）确定是否在某个时候停止癫痫发作出席急诊室的儿童会防止广泛的损害。我们的贡献是第一个半球性低强度的模型，该模型复制了潜在的协同多因素损伤级联人类婴儿和幼儿的可比发育阶段和大脑形态可以确定病理生理学和癫痫发作的贡献。这种方法是创新的，因为它偏离了使用单个损伤诱发“严重创伤性脑损伤”的现状；相反，我们研究了多重伤害和伤害的协同相互作用，并使用标准管理30小时的重症监护带有临床相关结果的小儿重症监护方案。拟议的贡献很重要因为流产的特定于年龄的疗法是虐待头部创伤的病理生理学减少神经元损害的严重程度，并减少死亡或永久残疾的婴儿数量。