Four Departments, One $3M Grant

Dr. Joseph Mathew & Dr. Charles HughesThe National Institutes of Health and the National Heart, Lung, and Blood Institute have awarded the chairman of Duke Anesthesiology, Dr. Joseph Mathew, and the co-principal investigator, Dr. Charles Hughes, a $3.5 million, five-year R01 award for their project titled, “Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest.”

This research endeavor in the Department of Anesthesiology will bring together the departments of Psychiatry, Cardiac Surgery, Biostatistics and Bioinformatics, as well as external academic institutions such as the University of Pennsylvania and Emory University. Co-investigators include Drs. Jeffrey Browndyke, Joern Karhausen, Yi-Ju Li, Mark Newman, and Wulf Paschen.

The use of deep hypothermia (<20°C) for cerebral protection ushered in the modern era of safe and effective operations on the heart and aorta. In large part due to advanced circulatory management strategies, surgical procedures on the proximal aorta and arch utilizing deep hypothermic circulatory arrest have steadily increased over the last decade. Despite these advances, neurologic complications remain a sobering limitation. Indeed, 7-13 percent of patients endure permanent neurologic dysfunction. In addition, postoperative cognitive decline (POCD) occurs in 36 percent of cardiac surgery patients at six weeks after surgery, and importantly, persists in 42 percent of patients up to five years after surgery and reduces quality of life. Although deep hypothermia has been the standard of care for decades in adult patients requiring circulatory arrest, moderate hypothermia is now more commonly used in many centers. However, this transition to moderate temperatures has been based entirely on observational studies that have not adequately assessed neurological or neurocognitive outcomes.

In the proposed study, the team will test their hypothesis that deep hypothermia (<20°C) during surgical circulatory arrest limits POCD and preserves brain connectivity to a greater degree than moderate hypothermia (24.1°C-28°C) and that low hypothermia (20.1°C-24°C) is non-inferior to deep hypothermia. This proposed study will be the first randomized trial to evaluate the effects of deep vs. low vs. moderate hypothermia during circulatory arrest on neurocognitive function and functional brain connectivity. Preliminary data strongly supports a detrimental effect of moderate hypothermia during circulatory arrest and this study is likely to dramatically alter practice and improve patient safety. This study will also be the first study in humans to assess the role of the small ubiquitin-like modifier conjugation pathway in protecting the brain during cardiac surgery requiring circulatory arrest. This significant study is expected to vertically advance the field of cardiac surgery by revolutionizing our understanding of the effects of hypothermia on neurologic and neurocognitive outcomes, by providing strong evidence for optimal hypothermic temperatures during surgical circulatory arrest, and by identifying new targets for therapeutic intervention to increase the resistance of organs to a transient interruption in blood supply.

Little is more devastating to a patient or the patient’s family than to have a successful operation that prolongs life, but is complicated by cognitive impairment resulting in a diminished quality of life and loss of functional independence. The long-term goal of the multidisciplinary Neurologic Outcome Research Group is to understand the mechanisms underlying neurologic and neurocognitive dysfunction after cardiac surgery, and to reduce the incidence of these devastating outcomes.

Chris KeithFour Departments, One $3M Grant