Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery.
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2023-07
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Abstract
Background
Right ventricular failure (RVF) is a leading driver of morbidity and mortality after major cardiac surgery for advanced heart failure, including orthotopic heart transplantation and left ventricular assist device implantation. Inhaled pulmonary-selective vasodilators, such as inhaled epoprostenol (iEPO) and nitric oxide (iNO), are essential therapeutics for the prevention and medical management of postoperative RVF. However, there is limited evidence from clinical trials to guide agent selection despite the significant cost considerations of iNO therapy.Methods
In this double-blind trial, participants were stratified by assigned surgery and key preoperative prognostic features, then randomized to continuously receive either iEPO or iNO beginning at the time of separation from cardiopulmonary bypass with the continuation of treatment into the intensive care unit stay. The primary outcome was the composite RVF rate after both operations, defined after transplantation by the initiation of mechanical circulatory support for isolated RVF, and defined after left ventricular assist device implantation by moderate or severe right heart failure according to criteria from the Interagency Registry for Mechanically Assisted Circulatory Support. An equivalence margin of 15 percentage points was prespecified for between-group RVF risk difference. Secondary postoperative outcomes were assessed for treatment differences and included: mechanical ventilation duration; hospital and intensive care unit length of stay during the index hospitalization; acute kidney injury development including renal replacement therapy initiation; and mortality at 30 days, 90 days, and 1 year after surgery.Results
Of 231 randomized participants who met eligibility at the time of surgery, 120 received iEPO, and 111 received iNO. Primary outcome occurred in 30 participants (25.0%) in the iEPO group and 25 participants (22.5%) in the iNO group, for a risk difference of 2.5 percentage points (two one-sided test 90% CI, -6.6% to 11.6%) in support of equivalence. There were no significant between-group differences for any of the measured postoperative secondary outcomes.Conclusions
Among patients undergoing major cardiac surgery for advanced heart failure, inhaled pulmonary-selective vasodilator treatment using iEPO was associated with similar risks for RVF development and development of other postoperative secondary outcomes compared with treatment using iNO.Registration
URL: https://www.Clinicaltrials
gov; Unique identifier: NCT03081052.Type
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Ghadimi, Kamrouz, Jhaymie L Cappiello, Mary Cooter Wright, Jerrold H Levy, Benjamin S Bryner, Adam D DeVore, Jacob N Schroder, Chetan B Patel, et al. (2023). Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery. Circulation. 10.1161/circulationaha.122.062464 Retrieved from https://hdl.handle.net/10161/28419.
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Kamrouz Ghadimi
Dr. Kamrouz (Kam) Ghadimi is an experienced cardiovascular acute care specialist (cardiovascular anesthesiology and intensive care), established investigator, physician leader, and associate professor of Anesthesiology and Critical Care at Duke Health.
His clinical practice is rooted in the cardiothoracic surgical ICU and operating rooms. He has broad expertise in all topics involving perioperative cardiovascular medicine and intensive care, including the management of acutely ill patients after surgery or those receiving extracorporeal life support (ECLS/ECMO). His specific area of expertise focuses on the enhancement of blood circulation through the lungs and the reversal of bleeding with prevention of thrombosis after surgery and circulatory life support. He has published original research, invited reviews, and guidance documents in several high-impact multidisciplinary journals and networks, including JAMA, Circulation, BMJ, Journal of the American College of Cardiology, Journal of Heart and Lung Transplantation, and Journal of Thrombosis & Haemostasis. He has also published in anesthesiology specialty journals, including Anesthesia & Analgesia, Anesthesiology, Current Opinion in Anesthesiology, and the British Journal of Anaesthesia. Dr. Ghadimi has served on the Editorial Board for the Journal of Cardiothoracic and Vascular Anesthesia since 2018 and has served as a peer reviewer for more than 30 top-medical journals worldwide.
Over his career, he has developed a global multidisciplinary network of collaborators and colleagues in academic medicine, private practice, larger healthcare systems, and offices of the federal government. He has experience with grant funding from a variety of sponsors, including federal, industry, foundation, philanthropy, and institutional sources. He also holds positions on several other national and international committees aimed at improving cardiovascular health in patients undergoing surgery and post-surgical intensive care. He is a selected task force and writing committee member of the 2024 American College of Cardiology and American Heart Association Perioperative Cardiovascular Guidelines. He has devoted the majority of his career to the service of patients requiring cardiovascular perioperative and surgical intensive care.
In addition to a doctorate in Medicine, Dr. Ghadimi holds a Bachelor’s in Economics from Boston University and a Master’s in Clinical Research from Duke University School of Medicine and the National Institutes of Health. He is also an inventor with patents/patents pending, a medical consultant, a mentor, and an investor. He is a founding member and the original academic director of True Learn, an eLearning company focused on board exam preparation for multiple medical subspecialties. This resource is used by many physicians around the country. Beyond developing an educational platform that has reached several thousand physicians and physicians-in-training, Dr. Ghadimi has formally mentored 22 pre-doctorate and post-doctorate trainees, with several mentees continuing their faculty careers in academic practice. In addition, he serves as a resource for a multitude of other physicians, physicians-in-training, and allied healthcare professionals.
Currently, Dr. Ghadimi serves as Director of the Clinical Research Unit for the Department of Anesthesiology at Duke Health, leading a cohesive, high-performing management team that oversees 45 staff working with Anesthesiology faculty and faculty in other departments to operationalize more than 80 innovative research protocols annually (single- and multi-site studies) to advance the fields of perioperative medicine, intensive care, pain management, and brain and heart health. He is leading digital health and artificial intelligence implementation in research workflow to rapidly leverage capabilities for automation and efficiency with the evolving guidance of cybersecurity compliance. He has also led the expansion of the Human Biospecimen Repository within the Department of Anesthesiology, where participants from prospective studies have generously donated biofluids and tissue for the advancement of disease-specific biology and translational research. Dr. Ghadimi is currently involved in the One Duke Gen precision medicine initiative for Duke Health to catalyze high-impact translational discoveries through expansive data-driven partnerships.
Jerrold Henry Levy
Jerrold Levy is Professor of Anesthesiology, Critical Care, and Surgery (Cardiothoracic) at Duke University Medical Center in Durham, NC. He obtained his medical degree from the University of Miami, where he was an intern in internal medicine, and undertook his residency in the Department of Anesthesiology of the Massachusetts General Hospital and Harvard Medical School in Boston, where he was also Chief Resident, and completed fellowships in both Respiratory ICU and Cardiac Anesthesiology. He previously was Professor, Deputy Chair for Research, and Chief of Cardiothoracic Anesthesiology at Emory University School of Medicine. His clinical and research interests include anticoagulation and its reversal, therapeutic strategies to prevent and treat coagulopathy and acute inflammatory responses in critically ill patients, clinical applications of recombinant and purified protein concentrates to treat bleeding, and pharmacologic approaches to treat shock. He is currently Chair of the Subcommittee on Perioperative and Critical Care Thrombosis and Hemostasis for the International Society of Thrombosis and Hemostasis, Executive Editor of Anesthesiology, and consultant to the FDA‘s Biologic Products Advisory Committee. He is the author of over 450 publications on PubMED, with over 100,000 citations on Google Scholar and a h-index of 95. He is also fluent in French and conversational in Spanish and Japanese.
Jacob Niall Schroder
Sudarshan Rajagopal
I am a physician-scientist with a research focus on G protein-coupled receptor signaling in inflammation and vascular disease and a clinical focus on pulmonary vascular disease, as I serve as Co-Director of the Duke Pulmonary Vascular Disease Center. My research spans the spectrum from clinical research in pulmonary vascular disease, to translational research in cardiovascular disease, to the basic science of receptor signaling.
Our basic science resesarch focuses on understanding and untapping the signaling potential of G protein-coupled receptors (GPCRs) to regulate inflammation in vascular disease. GPCRs are the most common transmembrane receptors in the human genome (over 800 members) and are some of the most successful targets for drug therapies. While it has been known for some time that these receptors signal through multiple downstream effectors (such as heterotrimeric G proteins and multifunctional beta arrestin adapter proteins), over the past decade it has been better appreciated that these receptors are capable of signaling with different efficacies to these effectors, a phenomenon referred to as “biased agonism”. Ligands can be biased, by activating different pathways from one another, and receptors can be biased, by signaling to a limited number of pathways that are normally available to them. Moreover, this phenomenon also appears to be common to other transmembrane and nuclear receptors. While a growing number of biased agonists acting at multiple receptors have been identified, there is still little known regarding the mechanisms underlying biased signaling and its physiologic impact.
Much of our research focuses on the chemokine system, which consists of approximately twenty receptors and fifty ligands that display considerable promiscuity with each other in the regulation of immune cell function in inflammatory diseases. Research from our group and others have shown that many of these ligands act as biased agonists when signaling through the same receptor. We use models of inflammation such as contact hypersensitivity and pulmonary arterial hypertension (PAH). PAH is a disease of the pulmonary arterioles that results in right heart failure and most of its treatments target signaling by GPCRs. We use multiple approaches to probe these signaling mechanisms, including in-house pharmacological assays, advanced phosphoproteomics and single cell RNA sequencing.
Svati Hasmukh Shah
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