Prompt Diagnosis and Treatment of Subclinical Seizures After Cardiac Arrest

描述（由申请人提供）：Alexis Ann Topjian博士，宾夕法尼亚大学（UPenn）和费城儿童医院（CHOP）的麻醉，重症监护和儿科助理教授，正在重新提交她对指导患者导向研究职业发展奖（K23）的申请。这位候选人将她的努力作为儿科重症监护研究员和早期CCM教员，致力于发展成为以患者为导向的神经科学家。本申请中的拟议调查是她在逮捕后神经科学方面不断增长的经验和专业知识的自然发展。Topjian博士的近期目标是评估一种新的方法，用于实时ICU床边癫痫发作检测和心脏骤停后危重儿童非惊厥性癫痫发作的及时管理。她的长期职业目标是改善儿童心脏骤停后的神经功能结局和生活质量。她渴望成为一名专注于复苏后护理的独立神经科学家。工作环境：职业发展计划和打算进行的研究调查建立在候选人所在机构现有的研究和指导网络的基础上。候选人与她的导师在儿科重症监护室实施了每天24小时/每周7天的神经监测系统，这将作为她进行研究的基础。她将继续在宾夕法尼亚大学临床流行病学和生物统计学中心学习流行病学和高级统计学。她有广泛的统计资源来完成这个项目，并开发未来的研究调查。这种环境与专家指导团队的结合几乎保证了她成为一名独立的复苏神经科学家的成功。研究：每年有8,000多名儿童心脏骤停，导致高死亡率和神经系统发病率。在自主循环恢复后的最初3天内，几乎一半的这些儿童发生非惊厥性癫痫发作（NCS），其中2/3的儿童为非惊厥性癫痫持续状态（NCSE）。由于缺乏严格的监测或及时的EEG解释，NCS和NCSE的识别和治疗可能会延迟（或在进展为临床可检测的体征和症状之前未检测或治疗）。重要的是，长期NCS和静脉抗惊厥药物治疗NCS可能会导致不良反应，最终恶化生存和/或神经系统结局。 本研究的目的是评估一种新的方法，用于实时ICU床旁NCS检测和心脏骤停后危重患儿的NCS管理。 目标1将评估 连续EEG模式（密度谱阵列（DSA））用于床边ICU医生和护士实时检测NCS的诊断准确性（灵敏度、特异性、阳性和阴性预测值）。目的2通过将患者随机分为DSA监测组和标准EEG监测组，评价使用DSA监测和及时治疗与标准EEG监测和治疗儿童心脏骤停后非惊厥性癫痫发作的有效性和安全性。主要疗效结局为至以下时间：1）检测、2）治疗和3）终止NCS。不良结局的主要指标是低血压的强度和持续时间。最后，在目标3中，我们将评估在控制损伤严重程度后，停搏后前三天内较大的NCS负荷是否与停搏后6个月时较差的神经功能结局相关。总结：该计划在这个指导以患者为导向的研究职业发展奖的应用将提供杰出的早期职业经验，上级环境和世界一流的指导，准备候选人成为一名独立的研究者。此外，这些目标的成功实现将为未来的研究提供基础，以确定非惊厥性癫痫发作的实时诊断和及时治疗是否可以减少心脏骤停后危重儿童的短期和长期神经损伤。

DESCRIPTION (provided by applicant): Dr. Alexis Ann Topjian, Assistant Professor of Anesthesia, Critical Care, and Pediatrics at the University of Pennsylvania (UPenn), and the Children's Hospital of Philadelphia (CHOP), is resubmitting her application for the Mentored Patient-Oriented Research Career Development Award (K23). This candidate has focused her efforts as a Pediatric Critical Care Fellow and early CCM faculty member on developing into a patient-oriented neuroscientist. The proposed investigation in this application is a natural progression of her growing experience and expertise in post-arrest neuroscience. Dr. Topjian's immediate goal is to evaluate a novel approach for real-time ICU bedside seizure detection and prompt management of non-convulsive seizures in critically ill children following cardiac arrest. Her long-term career goal is to improve neurologic outcomes and quality of life following pediatric cardiac arrest utilizing. She aspires to become an independent neuroscientist focusing on post-resuscitation care. Environment: The career development plan and the intended research investigation build upon an existing network of research and mentorship already in place at the candidate's institution. The candidate with her mentors has implemented a 24 hour per day/7 days per week Neuro-monitoring system in the pediatric intensive care unit which will serve as the foundation for performing her research. She will continue her coursework at UPenn's Center for Clinical Epidemiology and Biostatistics focusing on epidemiology and advanced statistics. She has extensive statistical resources to complete this project and develop future research investigations. The combination of this environment paired with an expert mentorship team all but guarantees her success as she develops into an independent resuscitation neuroscientist. Research: More than 8,000 children suffer a cardiac arrest each year, resulting in high mortality and neurologic morbidity. During the first 3 days following retur of spontaneous circulation, almost half of these children have non-convulsive seizures (NCS), of whom 2/3 have non-convulsive status epileptics (NCSE). NCS and NCSE identification and treatment may be delayed (or not detected or treated until progression to clinically detectable signs and symptoms) because of lack of rigorous monitoring or timely EEG interpretation. Importantly, both prolonged NCS and intravenous anticonvulsant medications to treat NCS may cause adverse effects, ultimately worsening survival and/or neurologic outcomes. The goal of this specific study is to evaluate a novel approach for real-time ICU bedside NCS detection and prompt NCS management in critically ill children following cardiac arrest. Aim 1 will evaluate the diagnostic accuracy (sensitivity, specificity, positive and negative predictive value) of a continuous EEG modality, Density Spectral Array (DSA), for the real-time detection of NCS by bedside ICU physicians and nurses. Aim 2 will evaluate the efficacy and safety of using DSA monitoring and prompt treatment compared with standard EEG monitoring and treatment for non-convulsive seizures in children post-cardiac arrest by randomizing patients to DSA monitoring or standard EEG monitoring. The primary efficacy outcomes will be time to: 1) detection, 2) treatment and 3) termination of NCS. The primary measure of adverse outcome is the intensity and duration of hypotension. Finally, in Aim 3 we will evaluate if larger NCS burden during the first three days post-arrest is associated with worse neurologic outcome at 6 months post-arrest after controlling for severity of injury. Summary: The plan in this Mentored Patient-Oriented Research Career Development Award application will provide the outstanding early career experience, superior environment and world-class mentorship to prepare the candidate to become an independent investigator. In addition, successful accomplishment of these aims will provide the foundation for future investigations to determine if real-time diagnosis and prompt treatment of non-convulsive seizures can decrease short- and long-term neurologic injury for critically ill children post- cardiac arrest.