The following departmental faculty were awarded competitive and non-competitive research grants during calendar year 2015.
Miles Berger, MD, PhD and Ankeet Udani, MD from the Anesthesiology Department and Sarah Wingfield, PhD from Geriatrics have been awarded a Geriatrics-for-Specialists Initiative grant from the American Geriatrics Society for their project, “Educating Anesthesia Residents to Improve Perioperative Care for the Elderly.” This $30,000 one-year grant will allow the doctors to develop and determine the efficacy of an educational toolkit for anesthesia residents in improving postoperative outcomes in elderly patients. It will also provide these educational tools for free on the internet for all anesthesia providers to use in improving postoperative outcomes for the nearly 16 million older Americans who undergo anesthesia and surgery each year.
Additionally, Dr. Berger was given the Dennis W. Jahnigen Career Development award in further support of the GEMSSTAR R03 award he received earlier this year from the National Institutes of Health. This additional $25,000 award will be used to supplement the GEMSSTAR R03 project, “The Significance of Perioperative Changes in CSF Tau Levels in the Elderly.” This is a competitive awards program and funding is only provided to applicants who successfully compete for a GEMSSTAR award.
Joern Karhausen, MD, Assistant Professor in the Cardiac Division of Anesthesiology who has been awarded a one-year, $414,362 NIH High Priority, Short-Term Project Award (R56) from the National Heart, Lung, and Blood Institute entitled, “Platelet/Mast Cell Interactions as Determinants of End-Organ Injury in Cardiac Surgery.”
Dr. Karhausen and his collaborators propose to clarify causal effects between mast cell activation and platelet aggregation during deep hypothermic circulatory arrest (DHCA) and define the implications of platelet/mast cell interactions for end-organ injury. In addition, they aim to define the impact of perioperative mast cell activation on end-organ injury in patients undergoing DHCA. In doing so, they will address crucial feedback from the scientific review of their recent R01 application in order to successfully reapply for federal funding. A team of experts in the fields of mast cell (Dr. Soman Abraham, Dept. of Pathology), platelets (Dr. Wolfgang Bergmeier, UNC), animal models of cardiopulmonary bypass (Dr. Ma Qing, Anesthesiology) and clinical statistics and epidemiology (Dr. Miklos Kertai, Anesthesiology) provide strong support for successful completion.
Miles Berger, MD, PhD, and colleagues in the Anesthesiology Department have been awarded an NIH grant from the National Institute of Aging, R03 grant #AG050918-01, for the project entitled, “The Significance of Perioperative Changes in CSF tau levels in the Elderly.” This two-year grant will provide $75,000 per year for enrolling an arm of non-surgical control individuals matched for age, education and gender to the surgical patients already being enrolled in the MADCO-PC trial (Markers of Alzheimer’s Disease and neuroCognitive Outcomes after Perioperative Care).
This GEMSSTAR (Grants for Early Medical/Surgical Specialists’ Transition to Aging Research) grant will also be accompanied by additional professional development funding for Dr. Berger from FAER (the Foundation for Anesthesia Education and Research).
Michael Manning, MD, PhD, Assistant Professor in the Division of Cardiothoracic Anesthesiology, has been awarded a two-year, $150,000 International Anesthesia Research Society (IARS) 2015 Mentored Research Award for his project entitled, “Mechanisms In the Development of Post Operative Atrial Fibrillation.”
Postoperative atrial fibrillation (POAF) occurs in 40%-60% of patients and is the most common complication following cardiac surgery; it is associated with increased length of stay, stroke, and both short- and long-term mortality. While some moderately effective treatments for POAF are available, there are no prevention strategies. Given the aging population and the related increase in cardiac surgeries, development of prevention strategies is necessary to reduce the impact of POAF.
A key factor in POAF development may be inflammation. The exact mechanism by which inflammation influences POAF is unknown, however, one potential mediator is angiotensin II (AngII). Following acute myocardial infarction, local production of AngII as part of the local inflammatory response has been shown to induce atrial remodeling and shorten the atrial effective refractory period. Blocking AngII signaling with angiotensin receptor blockers decreases inflammation-related damage after myocardial infarction. Although multiple similarities exist between the inflammatory processes of acute myocardial infarction and cardiac surgery, it has not been directly evaluated in postoperative inflammation or as a factor in POAF.
The central hypothesis is AngII is produced within the myocardium in association with CPB and ischemia/reperfusion (CPB-I/R), and triggers the pro-inflammatory and pro-fibrotic arrhythmogenic mechanisms underlying the acute development of POAF following cardiac surgery. Using both animal and human studies, Dr. Manning will focus on the mechanism of AngII production during CPB and the role of AngII in perioperative cardiac inflammation while determining whether AngII functions as a primary modulator or secondary regulator in the inflammatory cascade leading to POAF. The objective of these studies is to deconstruct the major cellular contributors of inflammation and identify pharmacologically modifiable points in the pathway to allow new interventions to prevent POAF and improve patient outcomes. Mihai Podgoreanu, MD, Associate Professor with tenure, Division Chief of Cardiothoracic Anesthesiology, will be mentoring Dr. Manning during this project.
Congratulations to Nathan Waldron, MD, CA-2 Resident, along with his mentor Joseph Mathew, MD, MBA, MHSc, Jerry Reves, MD, Professor of Cardiac Anesthesiology and Chairman, Department of Anesthesiology, on their one-year, $75,000 Research Fellowship Grant from the Foundation for Anesthesia Education and Research (FAER) for their proposal entitled, “Temporary autonomic blockade to prevent atrial fibrillation after cardiac surgery.”
Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery, and is associated with increased morbidity, mortality, and hospital length of stay (LOS), resulting in greater healthcare costs. Despite intensive study, the incidence of POAF is essentially unchanged (»40%) over the last twenty years, suggesting that new therapeutic approaches are urgently needed. While the autonomic nervous system is implicated in the pathogenesis of atrial fibrillation, there are few strategies to prevent POAF targeted at autonomic modulation. In this study, the investigators intend to determine whether autonomic modulation via botulinum toxin injected in the epicardial fat pads is efficacious and safe for decreasing POAF after cardiac surgery.
Congratulations to Joern Karhausen, MD, Assistant Professor in the Cardiac Division of Anesthesiology who has been awarded a three-year, $231,000 Mid-Atlantic Affiliate Winter 2015 Scientist Development Grant from the American Heart Association (AHA) entitled, “Platelets as regulators of inflammation and tissue injury after cardiac surgery.”
Platelet activation is a prominent event during cardiac surgery and previous works have shown that blunting platelet responses can improve perioperative outcomes. Based on strong preliminary data, Dr. Karhausen proposes that platelets can initiate inflammatory responses within the small vessels embedded in organ tissues. Specifically, Dr. Karhausen provides, for the first time, evidence that platelets directly activate perivascular mast cells, a cell type known to rapidly launch powerful inflammatory and tissue injurious responses (e.g., in asthma or anaphylaxis). The hypothesis is that platelets and mast cells work together to propagate inflammation and tissue injury, and that modifying this interaction provides a unique opportunity to improve organ protection during cardiac surgery. In their experiments, the investigators will define platelet/mast cell interactions by in vivo imaging of the microvascular interface and fluorescent labeled platelets and mast cells. Next, they aim to identify the mast cell-activating platelet factor(s) by combining state of the art proteomic analysis of the platelet secretome with comprehensive testing of mast cell responses. Lastly, the investigators will pursue the strong translational opportunities of the proposed mechanism by characterizing the impact of modifying mast cell and platelet responses on the inflammatory and tissue injurious responses observed in a pre-clinical model of cardiopulmonary bypass circulation and circulatory arrest. A team of experts in the fields of mast cell (Dr. Soman Abraham, Dept. of Pathology), animal models of cardiopulmonary bypass (Dr. Ma Qing, Anesthesiology), and clinical statistics and epidemiology (Dr. Miklos Kertai, Anesthesiology) provide strong support for successful completion.
David S. Warner, MD, Director of the Multidisciplinary Neuroprotection Laboratories received a 2-year $793,750 NIH Exploratory/Development Research Grant (R21) from the National Institute of Neurological Disorders and Stroke entitled,“Xenon as a Therapeutic Experimental Intracerebral Hemorrhage.”
Intracerebral hemorrhage (ICH) is a form of stroke. There is little treatment option other than supportive care. Xenon (Xe) is an inert gas which has undergone intensive preclinical investigation in models of brain injury and is currently being investigated as an adjunct to hypothermia for treatment of anoxic/asphyxia brain injury in humans. It has few side effects and is available for human use. We found Xe improves neurologic outcome from experimental ICH and offers major advantages to the injured brain. It has rapid BBB penetration, modulates the NMDA glycine recognition site without psychotomimetic effects, and has negligible effects on intracranial pressure and cardiovascular function. We recently investigated Xe in a rodent transient focal ischemic stroke model. While post-ischemic Xe improved short-term outcome, long-term outcome was improved only when Xe was combined with reduction of brain temperature to 36°C. This offered sufficient clinical relevance to lead us to explore the effect of Xe in two different mouse ICH models. While the goal was to rule out a potential adverse effect of Xe in ICH should Xe be applied clinically prior to imaging for ischemic stroke, we were surprised that to the contrary, Xe repeatedly improved both histologic and functional ICH outcome and decreased brain water content and microglial activation. The goal of the project is to subject Xe to a sequence of rigorous preclinical studies specifically designed to advance Xe to human ICH trials.
Noa Segall, PhD, Assistant Professor of Anesthesiology and Human Factors Engineer in the Human Simulation and Patient Safety Center, received a 5-year $1,246,724 AHRQ Health Services Research Project (R01) entitled, “Effect of Monitoring System Design on Response Time to Cardiac Arrhythmias.” To increase the potential for timely detection and treatment of cardiac events, hospitals have implemented a number of different cardio-respiratory monitoring systems for patients who meet at-risk criteria. However, decisions regarding how to structure and staff monitoring systems have historically been made with very little supporting evidence. We propose to use simulation to identify and test determinants of effective cardiac monitoring. The knowledge to be gained will inform the development of evidence-based monitoring standards. The application of such standards is expected to improve survival after in-hospital cardiac arrest.
Ian J. Welsby, MB BS, Associate Professor in the Cardiac Division, received a new 5-year $1,227,568 NIH Research Grant as a Co-PI on a Multiple PI application through Mayo Clinic and Dr. Daryl J. Kor from the National Heart, Lung, & Blood Institute (NHLBI) for their research project R01HL121232-01 entitled, “Point of Care Red Blood Cell (RBC) Washing to Prevent Transfusion-Related Pulmonary Complications.” At present, there are no effective strategies for the prevention of complications following red blood cell (RBC) transfusion. Although the mechanisms that underlie these complications remain incompletely defined, soluble biological response modifiers (BRMs) residing within the RBC storage solution are believed to play an important role. Point-of-care washing of allogeneic RBCs prior to transfusion may remove these BRMs, thereby mitigating their impact on postoperative respiratory complications. The objective of this project is to evaluate the feasibility, safety, efficacy, and clinical impact of point-of-care washing for allogeneic leukocyte-reduced (LR) RBCs using the FDA-approved Continuous AutoTransfusion System (CATS).
Zhen-Zhong Xu, PhD, of the Sensory Plasticity and Pain Research Group in Division of Basic Sciences, received a new 2-year $436,628 Exploratory/Developmental Research Grant Award (R21) from the National Institute of Neurological Disorders and Stroke (NINDS) for his research project entitled, “Treating Chemotherapy-Induced Neuropathic Pain by Targeted Silencing of A-Fibers.” Chemotherapy-induced peripheral neuropathy and neuropathic pain are the dose-limiting toxicity for many commonly used classes of anti-cancer agents. Studies have shown that mechanosensitive A-fibers contribute to neuropathic pain and targeted silencing of A-fibers could be an effective treatment for neuropathic pain induced by chemotherapy. In this project, we propose to address how to treat chemotherapy-induced neuropathic pain by targeted silencing of A-fibers. We believe this research will help develop new therapy for treating neuropathic pain in patients with CIPN.
We would like to congratulate Karthik Raghunathan, MD, MPH, who was recently awarded a 3-year, $779,000 Patient Safety Center of Inquiry (PSCI) grant at the VA for his study entitled, “Reduction of Perioperative Opioid-Related Adverse Events and Prolonged use of Opioids Following Surgery.” The project is focused on improving the safe prescription of opioids in the perioperative period and on preventing adverse drug events related to perioperative use of opioids. The proposal will leverage the VA Corporate Data Warehouse (CDW, which contains millions of surgical cases) to identify and implement best practices at individual VA Medical Centers in collaboration with colleagues at the San Francisco and Palo Alto VA Medical Centers. Funding will begin October 1, 2015.