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.

项目概要半球低密度的病理生理学尚不清楚，它是一种仅发生在脑部的损伤模式。年幼的儿童，通常是由于虐待造成的，其中大部分半球位于硬膜下当计算机断层扫描时，血肿出现跨越多个血管区域的低密度。硬膜下血肿超过一个半球，损害以单侧为主。成功诱导仔猪单侧半球低密度，其发育与人类幼儿相似通过重新创建这种损伤的临床特征：机械性创伤、中线移位、硬膜下血肿，癫痫发作、呼吸暂停和通气不足，该模型会导致年龄依赖性神经功能障碍，代谢性酸中毒和单侧缺氧缺血型损伤，涵盖大部分皮层硬膜下血肿的损伤模式、血管源性水肿的程度和基质的上调。金属蛋白酶与年龄相关。半球损伤的百分比与年龄呈正相关。我们的长期目标是了解特定年龄和损伤的出血面积和癫痫发作持续时间。病理生理学开发治疗方法，阻止或抑制头部虐待后组织损伤的进展本申请的总体目标是确定癫痫发作和出血的影响。损害的发展以及是否可以中止连锁反应我们的中心假设是滥用产生的巨大力量会导致广泛的组织损伤，这主要是由相互作用引起的局灶性癫痫发作和出血之间的关系，并且由此产生的级联损伤可以用抗- 其基本原理是通过了解病理生理学并确定组织是否存在。可以挽救，然后可以测试可能阻止损害的治疗方法。该假设有两个具体目标：1.) 确定癫痫发作和出血对出现单侧半球低密度；和 2.) 确定癫痫发作是否在以下时间停止：前往急诊室的儿童可以防止大范围的损害，我们的贡献是首要的。半球低密度模型，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较的发育阶段和大脑形态这种方法是创新的，因为它偏离了癫痫发作的病理生理学和贡献。利用单一损伤诱发“严重创伤性脑损伤”的现状；多重伤害和侮辱的协同相互作用，并使用标准管理 30 小时的重症监护具有临床相关结果的儿科重症监护方案所提出的贡献意义重大。因为针对年龄的治疗可能会中止虐待性头部创伤的病理生理学级联反应减轻神经损伤的严重程度并减少死亡或永久残疾的婴儿数量。