This application describes a five-year plan that will allow me to achieve independence as an investigator in the field of anesthesia and critical care medicine. My project focuses on the deleterious effects of plasma hemoglobin increased after prolonged cardiopulmonary bypass (CPB). I am an anesthesiologist at Massachusetts General Hospital (MGH) and have a strong background in investigation in critical care research. Dr. Fumito Ichinose, my primary mentor, is professor of anesthesia at Harvard Medical School and cardiac anesthesiologist at the Department of Anesthesia at MGH. His research field focuses on the effects of inhaled nitric oxide and hydrogen sulfide on the cardiovascular system. Dr. Taylor Thompson, my co-mentor, is a pulmonologist at MGH and the Medical Director of the NHLBI-funded PETAL Network Clinical Coordinating Center and served in that capacity for the ARDS Network for 20 years. He is a leader in conducting clinical trials for the critically ill. An advisory committee of senior scientists able to provide additional expert guidance includes Drs. Warren Zapol, Joseph Bonventre, Christopher Stowell and Marc Semigran. The research will be performed at MGH and at Brigham and Women's Hospital. Cardiopulmonary bypass is commonly used during open-heart surgery. However, it has been shown that prolonged (> 90 minutes) CPB is associated with adverse outcomes. Specifically, long CPB has been associated with acute kidney injury (AKI). My hypothesis is that prolonged CPB increases levels of circulating plasma hemoglobin, which depletes plasma nitric oxide, in patients with endothelial dysfunction, in whom the ability to replace nitric oxide is impaired. Administration of 80 part per million NO gas during and up to 24 hours after cardiac surgery will (Aim I) reduce incidence of post-operative AKI (AIM IIa) block the avidity of plasma free Oxy-Hb to consume plasma NO and (Aim IIb) preserve vascular responsiveness to vasodilation, despite the presence of pre-existing endothelial dysfunction. I will test this hypothesis in a randomized, double-blind, controlled clinical trial in 250 patients with endothelial dysfunction, undergoing cardiac surgery requiring prolonged CPB. Patients will be randomized to receive 80 ppm NO or N2 through the membrane oxygenator, while on CPB, and through the mechanical ventilator after weaning from the CPB. During the award period I will attend a Master of Science at Harvard School of Public Health to improve my knowledge and skills in clinical trials design and biostatistics. This research project will enhance both my knowledge in critical care trial conduct and in translational medicine. The exposure to the advices of such experienced mentors, the ?hands-on? experience on clinical research and the formal training will equip me with the critical expertise in the performance of clinical trials in critical care patients.

Public Health Relevance

Acute kidney injury is one of the most common complications after open-heart surgery with prolonged cardiopulmonary bypass and clinical studies have shown the association between the role of hemolysis due to prolonged cardiopulmonary bypass and acute kidney injury. This career development award will support training that I need to become established as an independent investigator with expertise in anesthesia and critical care medicine. The proposed research will help us understand the role of hemolysis and plasma nitric oxide depletion in causing the deleterious effects of prolonged cardiopulmonary bypass and will give us information about a possible therapeutic approach that prevents the complications associated to hemolysis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
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Werner, Ellen
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Massachusetts General Hospital
United States
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