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.

Public Health Relevance

Pediatric cardiac arrest is highly fatal and morbid, with current supportive care frequently resulting in poor neurologic outcome for survivors. This proposal will use a real-time beside neurophysiologic tool to promptly diagnose and treat post-arrest non-convulsive seizures and to evaluate for associated adverse events. It will also evaluate the association of non-convulsive seizure burden with neurologic outcome.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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NST-2 Subcommittee (NST)
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Fureman, Brandy E
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Children's Hospital of Philadelphia
United States
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Topjian, Alexis A; Telford, Russell; Holubkov, Richard et al. (2018) Association of Early Postresuscitation Hypotension With Survival to Discharge After Targeted Temperature Management for Pediatric Out-of-Hospital Cardiac Arrest: Secondary Analysis of a Randomized Clinical Trial. JAMA Pediatr 172:143-153
Sánchez Fernández, I; Gaínza-Lein, M; Abend, N S et al. (2018) Factors associated with treatment delays in pediatric refractory convulsive status epilepticus. Neurology 90:e1692-e1701
Kirschen, Matthew P; Snyder, Megan; Winters, Madeline et al. (2018) Survey of Bedside Clinical Neurologic Assessments in U.S. PICUs. Pediatr Crit Care Med 19:339-344
Abend, Nicholas S; Xiao, Rui; Kessler, Sudha Kilaru et al. (2018) Stability of Early EEG Background Patterns After Pediatric Cardiac Arrest. J Clin Neurophysiol 35:246-250
Stinson, Hannah R; Srinivasan, Vijay; Topjian, Alexis A et al. (2018) Failure of Invasive Airway Placement on the First Attempt Is Associated With Progression to Cardiac Arrest in Pediatric Acute Respiratory Compromise. Pediatr Crit Care Med 19:9-16
Gaínza-Lein, Marina; Sánchez Fernández, Iván; Jackson, Michele et al. (2018) Association of Time to Treatment With Short-term Outcomes for Pediatric Patients With Refractory Convulsive Status Epilepticus. JAMA Neurol 75:410-418
Abend, Nicholas S; Wiebe, Douglas J; Xiao, Rui et al. (2018) EEG Factors After Pediatric Cardiac Arrest. J Clin Neurophysiol 35:251-255
Holmberg, Mathias J; Moskowitz, Ari; Raymond, Tia T et al. (2018) Derivation and Internal Validation of a Mortality Prediction Tool for Initial Survivors of Pediatric In-Hospital Cardiac Arrest. Pediatr Crit Care Med 19:186-195
Cornell, Timothy T; Selewski, David T; Alten, Jeffrey A et al. (2018) Acute kidney injury after out of hospital pediatric cardiac arrest. Resuscitation 131:63-68
Lasa, Javier J; Jain, Parag; Raymond, Tia T et al. (2018) Extracorporeal Cardiopulmonary Resuscitation in the Pediatric Cardiac Population: In Search of a Standard of Care. Pediatr Crit Care Med 19:125-130

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