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)
Mentored Patient-Oriented Research Career Development Award (K23)
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Neurological Sciences Training Initial Review Group (NST)
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Fureman, Brandy E
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Children's Hospital of Philadelphia
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Kirschen, Matthew P; Topjian, Alexis A; Hammond, Rachel et al. (2014) Neuroprognostication after pediatric cardiac arrest. Pediatr Neurol 51:663-668.e2
Topjian, Alexis A; Stuart, Amber; Pabalan, Alyssa A et al. (2014) Greater fluctuations in serum sodium levels are associated with increased mortality in children with externalized ventriculostomy drains in a PICU. Pediatr Crit Care Med 15:846-55
Topjian, Alexis A; Stuart, Amber; Pabalan, Alyssa A et al. (2014) Risk factors associated with infections and need for permanent cerebrospinal fluid diversion in pediatric intensive care patients with externalized ventricular drains. Neurocrit Care 21:294-9
Sutton, Robert M; French, Benjamin; Niles, Dana E et al. (2014) 2010 American Heart Association recommended compression depths during pediatric in-hospital resuscitations are associated with survival. Resuscitation 85:1179-84
Wolfe, Heather; Zebuhr, Carleen; Topjian, Alexis A et al. (2014) Interdisciplinary ICU cardiac arrest debriefing improves survival outcomes*. Crit Care Med 42:1688-95
Perman, Sarah M; Goyal, Munish; Neumar, Robert W et al. (2014) Clinical applications of targeted temperature management. Chest 145:386-93
Yehya, Nadir; Topjian, Alexis A; Thomas, Neal J et al. (2014) Improved oxygenation 24 hours after transition to airway pressure release ventilation or high-frequency oscillatory ventilation accurately discriminates survival in immunocompromised pediatric patients with acute respiratory distress syndrome*. Pediatr Crit Care Med 15:e147-56
Wagenman, Katherine L; Blake, Taylor P; Sanchez, Sarah M et al. (2014) Electrographic status epilepticus and long-term outcome in critically ill children. Neurology 82:396-404
Topjian, Alexis A; French, Benjamin; Sutton, Robert M et al. (2014) Early postresuscitation hypotension is associated with increased mortality following pediatric cardiac arrest. Crit Care Med 42:1518-23
MacLaren, Robert; Campbell, Jon (2014) The authors reply. Crit Care Med 42:e637-8

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