DESCRIPTION (provided by applicant): Candidate: Brian W. Roberts, MD is an Assistant Professor of Emergency Medicine at the Cooper Medical School of Rowan University. Dr. Roberts completed his emergency medicine residency, as well as a Resuscitation Research Fellowship at Cooper University Hospital, under Dr. Stephen Trzeciak, the primary mentor on this K23 application. The proposed research project and K23 application are the culmination of six years of collaboration between Dr. Roberts and Dr. Trzeciak. Career goals: The long-term career goal described in this application is to ultimately become an independent investigator that has the skills necessary to design and perform multi-center studies, which advance the field of resuscitation science. This transition to clinical investigator independence will be reached through the immediate goals described in the career development plan in this K23 application and include: (1) rigorous didactic training by completion of the Master of Science in Clinical Research and Translational Medicine (MSCRTM) program at Temple University, (2) a mentorship plan, which clearly delineates key roles, and monitoring of specific objectives for each mentor/advisor, and (3) conducting a high-quality, multi-center, clinically relevant study of partial pressure of arterial carbon dioxid (PaCO2) derangements and ventilation strategies in post-cardiac arrest patients. The skills developed through this career development plan will be utilized to generate an independent application for federal funding (R01) in the final years of this K23 award. Research project Background: Almost two-thirds of post-cardiac arrest patients die in the hospital and the majority of survivors are functionally dependent secondary to anoxic brain injury. Finding new approaches to attenuate brain injury after return of spontaneous circulation (ROSC) is a high priority for resuscitation science. PaCO2 is a major regulator of cerebral blood flow, and PaCO2 derangements are known to worsen clinical outcomes after some forms of brain injury. There is currently a paucity of data on the subject of PaCO2 regulation after cardiac arrest. Our overarching hypothesis is that exposure to PaCO2 derangements after ROSC is associated with worsened neurological disability and cognitive deficits in patients resuscitated from cardiac arrest. Objectives: To test if PaCO2 derangements following ROSC from cardiac arrest are associated with (1) worsened neurological disability at hospital discharge and (2) worsened neuropsychological deficits among survivors at 180 days, as well as to test for the optimal post-ROSC mechanical ventilation settings [minute ventilation (MV)] that reliably achieve an optimal PaCO2 on the first post-ROSC arterial blood gas analysis. Methods/environment: The proposed study will be performed using the infrastructure of an ongoing National Heart, Lung, and Blood Institute (NHLBI)-sponsored cardiac arrest study (R01HL112185) that is led by the mentor on this application and conducted in an established research network that the mentor co-founded [Emergency Medicine Shock Research Network (EMShockNet)]. PaCO2 after ROSC will be prospectively measured and the Modified Rankin Scale (mRS) (a well-validated scale of neurological disability ranging from 0=no disability and asymptomatic to 6=death) will be determined at hospital discharge. Multivariable logistic regression will be used to test the association between the degree and duration of hypocapnia/hypercapnia and poor neurological outcome (defined as a mRS ≥3). Neuropsychological testing will be performed across multiple domains (attention, reasoning, immediate and delayed memory, verbal fluency, executive function) at 180 days after ROSC and the association between hypocapnia/hypercapnia and neuropsychological deficits will be tested. Finally, we will record initial post-ROSC ventilator settings and test the associations between prescribed MV and the optimal PaCO2 range. Significance: This project will generate new, critically important knowledge about a fundamental element of post-cardiac arrest care. If the hypothesis is confirmed, this project will (1) establish PaCO2 derangement as an independent predictor of neurological injury after ROSC and (2) define the optimal PaCO2 range and initial post-ROSC mechanical ventilation settings that rapidly achieve the optimal PaCO2 range for use in a future clinical trial of PaCO2 optimization to reduce neurological injury after cardiac arrest. Thus the project proposed here represents a critical step towards the development of a meaningful change in post-ROSC supportive care that would be simple, scalable and generalizable to post-cardiac arrest patients worldwide.

PUBLIC HEALTH RELEVANCE: If the Hypotheses of the proposed project are confirmed and an optimal range of partial pressure of arterial carbon dioxide (PaCO2) is determined, we will have identified a potential intervention (i.e. optimization of PaCO2 through mechanical ventilation strategies) to attenuate the neurological injury associated with post- cardiac syndrome. The relevance to public health includes: (1) decrease in neurological injury among post- cardiac arrest patients and (2) decrease in the healthcare resources utilized for long-term care of patients with neurological injury. Mechanical ventilation is already a standard component of post-cardiac arrest care, making optimization of PaCO2 a simple, low-cost, and generalizable intervention to improve outcomes among post- cardiac arrest patients globally.