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
Overview
Dr. Ghadimi is a cardiothoracic anesthesiologist, intensivist (ICU doctor), researcher, educator, and director of the clinical research unit in the Department of Anesthesiology at Duke Health. He has published over 100 peer-reviewed manuscripts, book chapters, online reviews, and editorials. His expertise involves the perioperative and intensive care management of patients undergoing cardiac and noncardiac surgery, with a special focus on the treatment of bleeding and inflammation related to shock and mechanical circulatory support and on the modification of pulmonary circulation to optimize end-organ blood flow.
Clinical Education
Dr. Ghadimi is a medical school graduate of Boston University School of Medicine, completed his internship in general surgery at the University of California Irvine Medical Center and Long Beach Veterans Affairs Medical Center and completed clinical anesthesiology residency at the Allegheny Health Network in Pittsburgh, Pennsylvania. He completed advanced clinical fellowship specialization in adult Critical Care Medicine (surgical focus) and Cardiothoracic Anesthesiology at the University of Pennsylvania Health System in Philadelphia, Pennsylvania.
Expertise
Dr. Ghadimi's expertise and instruction spans across the cardiothoracic operating rooms and cardiothoracic surgical ICU environments. His expertise includes perioperative hemostasis & thrombosis, critical care of the heart or lung transplant recipient, and critical care for the patient on mechanical circulatory support, which may include extracorporeal life support (ECMO) or ventricular assist devices/systems.
Research Education
Dr. Ghadimi is a clinical and translational researcher and holds a Master in Health Sciences (M.H.Sc.) from the Duke-NIH Clinical Research Training Program.
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.
Adam David DeVore
Adam D. DeVore, MD, MHS
Dr. DeVore is a cardiologist and Associate Professor of Medicine in the Department of Medicine, Division of Cardiology, at Duke University School of Medicine. His clinical interests include caring for patients and families with heart failure, including those with left ventricular assist devices and heart transplants. He is involved in and leads multiple large studies of patients with heart failure at both Duke University Medical Center and the Duke Clinical Research Institute. He currently serves as the medical director of the Duke Heart Transplant program.
He attended medical school at the University of Chicago Pritzker School of Medicine and completed internal medicine residency at Brigham and Women’s Hospital. He then pursued cardiology training at Duke University and solidified his interests in clinical research and heart failure. He completed a research fellowship at the Duke Clinical Research Institute and a Masters of Health Sciences in Clinical Research before completing an advanced heart failure fellowship at Duke University.
The overarching goals of his research are to advance the current understanding of heart failure through clinical trials as well as develop an evidence base for implementation strategies that addresses the gap between heart failure trial results and clinical practice. For example, he has served on the Steering Committees for large clinical trials, including PIONEER-HF and SPIRRIT-HFpEF. Dr. DeVore also published the first clinical trial conducted within the American Heart Association’s Get With The Guidelines-Heart Failure program, a registry-based cluster randomized trial of quality improvement interventions. He was also the principal investigator for CONNECT-HF, a large-scale, pragmatic, cluster-randomized trial at 161 sites in the US evaluating heart failure quality improvement initiatives. Outside of his work on heart failure, Dr. DeVore is married with 4 children and spends his time corralling them all and coaching youth baseball.
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
Carmelo Alessio Milano
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