{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T23:07:36Z","timestamp":1768691256241,"version":"3.49.0"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,9,14]],"date-time":"2024-09-14T00:00:00Z","timestamp":1726272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Introduction: The perioperative management of patients with pulmonary hypertension (PH) undergoing cardiac surgery is challenging, mainly due to the potential risk of right ventricular failure (RVF). Levosimendan is a calcium-sensitizing agent that has primarily been used in the treatment of decompensated heart failure. However, recently levosimendan has been shown to be an effective and safe therapeutic strategy for patients with pulmonary arterial hypertension and PH associated with left heart disease. The aim of this study was to investigate the potential utility of the preemptive administration of levosimendan in cardiac surgical patients with preexisting PH and to compare its effectiveness with milrinone, which represents an already established therapeutic option in the management of PH during cardiac surgery. Materials and Methods: In this study, 40 adult cardiac surgical patients with PH were randomly assigned to receive either levosimendan intravenously or milrinone via inhalation in a double-blind fashion prior to a cardiopulmonary bypass (CPB). Hemodynamic and echocardiographic parameters were recorded and evaluated before and after the administration of the drugs. Results and Conclusions: The results of this study demonstrated that both levosimendan and milrinone administered before CPB in cardiac surgical patients with PH may offer protective benefits, reducing pulmonary artery pressure and preventing the exacerbation of PH and RVF. Pulmonary vasodilation attributed to levosimendan is of longer duration and greater magnitude compared to pulmonary vasodilation afforded by milrinone.<\/jats:p>","DOI":"10.3390\/life14091164","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T04:14:07Z","timestamp":1726460047000},"page":"1164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Intravenous Levosimendan versus Inhalational Milrinone in the Management of Pulmonary Hypertension during Adult Cardiac Surgery: A Randomized Clinical Trial"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2021-9494","authenticated-orcid":false,"given":"Panagiotis","family":"Ftikos","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Onassis Cardiac Surgery Center, 176 74 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3161-9941","authenticated-orcid":false,"given":"Georgios","family":"Gkantinas","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Onassis Cardiac Surgery Center, 176 74 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7380-9677","authenticated-orcid":false,"given":"Vlasios","family":"Karageorgos","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Onassis Cardiac Surgery Center, 176 74 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Smirli","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Onassis Cardiac Surgery Center, 176 74 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nektarios","family":"Kogerakis","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Onassis Cardiac Surgery Center, 176 74 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evangelos","family":"Leontiadis","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Onassis Cardiac Surgery Center, 176 74 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7962-040X","authenticated-orcid":false,"given":"Konstantinos","family":"Petsios","sequence":"additional","affiliation":[{"name":"Faculty of Nursing, National and Kapodistrian University of Athens, 115 28 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theofani","family":"Antoniou","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Onassis Cardiac Surgery Center, 176 74 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4890-4642","authenticated-orcid":false,"given":"Kassiani","family":"Theodoraki","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Aretaieion University Hospital, National and Kapodistrian University of Athens, 115 28 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/157340310790231671","article-title":"Pulmonary hypertension in cardiac surgery","volume":"6","author":"Denault","year":"2010","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1093\/ejcts\/ezs043","article-title":"EuroSCORE II","volume":"41","author":"Nashef","year":"2012","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1002\/ehf2.13870","article-title":"A standardized definition for right ventricular failure in cardiac surgery patients","volume":"9","author":"Jabagi","year":"2022","journal-title":"ESC Heart Fail."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Foschi, M., Di Mauro, M., Tancredi, F., Capparuccia, C., Petroni, R., Leonzio, L., Romano, S., Gallina, S., Penco, M., and Cibelli, M. (2017). The Dark Side of the Moon: The Right Ventricle. J. Cardiovasc. Dev. Dis., 4.","DOI":"10.3390\/jcdd4040018"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1097\/ACO.0b013e32835b8be2","article-title":"Perioperative right ventricular dysfunction","volume":"26","author":"Denault","year":"2013","journal-title":"Curr. Opin. Anaesthesiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1801913","DOI":"10.1183\/13993003.01913-2018","article-title":"Haemodynamic definitions and updated clinical classification of pulmonary hypertension","volume":"53","author":"Simonneau","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e029024","DOI":"10.1161\/JAHA.122.029024","article-title":"Revised Definition of Pulmonary Hypertension and Approach to Management: A Clinical Primer","volume":"12","author":"Maron","year":"2023","journal-title":"J. Am. Heart Assoc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/S2213-2600(15)00543-3","article-title":"A global view of pulmonary hypertension","volume":"4","author":"Hoeper","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1053\/j.jvca.2012.07.017","article-title":"Pulmonary hypertension in patients undergoing cardiac surgery: Pathophysiology, perioperative management, and outcomes","volume":"27","author":"Thunberg","year":"2013","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1161\/HYPERTENSIONAHA.119.14330","article-title":"Pulmonary Hypertension Due to Left Heart Disease: Diagnosis, Pathophysiology, and Therapy","volume":"75","author":"Sugito","year":"2020","journal-title":"Hypertension"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1378\/chest.112.3.676","article-title":"Inflammatory response to cardiopulmonary bypass: Mechanisms involved and possible therapeutic strategies","volume":"112","author":"Wan","year":"1997","journal-title":"Chest"},{"key":"ref_12","first-page":"21","article-title":"Cardiopulmonary bypass-induced inflammation: Is it important?","volume":"12","author":"Hill","year":"1998","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3977585","DOI":"10.1155\/2022\/3977585","article-title":"Postoperative Pulmonary Hemodynamics and Systemic Inflammatory Response in Pediatric Patients Undergoing Surgery for Congenital Heart Defects","volume":"2022","author":"Souza","year":"2022","journal-title":"Mediators Inflamm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1378\/chest.122.3.1061","article-title":"Catastrophic cardiovascular adverse reactions to protamine are nitric oxide\/cyclic guanosine monophosphate dependent and endothelium mediated: Should methylene blue be the treatment of choice?","volume":"122","author":"Viaro","year":"2002","journal-title":"Chest"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1620\/tjem.207.51","article-title":"Efficiency of prostacyclin in the treatment of protamine-mediated right ventricular failure and acute pulmonary hypertension","volume":"207","author":"Ocal","year":"2005","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Baron-Stefaniak, J., Leitner, G.C., K\u00fcntzel, N.K.I., Meyer, E.L., Hiesmayr, M.J., Ullrich, R., and Baron, D.M. (2019). Transfusion of standard-issue packed red blood cells induces pulmonary vasoconstriction in critically ill patients after cardiac surgery\u2014A randomized, double-blinded, clinical trial. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0213000"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1097\/ALN.0b013e318246ef77","article-title":"Pulmonary hypertension in lambs transfused with stored blood is prevented by breathing nitric oxide","volume":"116","author":"Baron","year":"2012","journal-title":"Anesthesiology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1161\/CIRCULATIONAHA.106.631549","article-title":"Impact of prosthesis-patient mismatch on survival after mitral valve replacement","volume":"115","author":"Magne","year":"2007","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1093\/ejcts\/ezx167","article-title":"Effect of prosthesis patient mismatch in mitral position on pulmonary hypertension","volume":"52","author":"Ammannaya","year":"2017","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1213\/ane.0b013e31818d8b92","article-title":"The right ventricle in cardiac surgery, a perioperative perspective: II. Pathophysiology, clinical importance, and management","volume":"108","author":"Haddad","year":"2009","journal-title":"Anesth. Analg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"116","DOI":"10.4103\/aca.ACA_123_17","article-title":"Pulmonary hypertension and cardiac anesthesia: Anesthesiologist\u2019s perspective","volume":"21","author":"Sarkar","year":"2018","journal-title":"Ann. Card. Anaesth."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.21037\/cdt-20-426","article-title":"Peri-operative right ventricular dysfunction-the anesthesiologist\u2019s view","volume":"10","author":"Navaratnam","year":"2020","journal-title":"Cardiovasc. Diagn. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Wanner, P.M., and Filipovic, M. (2020). The Right Ventricle-You May Forget it, but It Will Not Forget You. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020432"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1513\/AnnalsATS.201312-446FR","article-title":"Management of acute right ventricular failure in the intensive care unit","volume":"1","author":"Ventetuolo","year":"2014","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1053\/j.jvca.2012.07.020","article-title":"Hemodynamic effects of combination therapy with inhaled nitric oxide and iloprost in patients with pulmonary hypertension and right ventricular dysfunction after high-risk cardiac surgery","volume":"27","author":"Antoniou","year":"2013","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1007\/s00380-017-1023-2","article-title":"A retrospective comparison of inhaled milrinone and iloprost in post-bypass pulmonary hypertension","volume":"32","author":"Theodoraki","year":"2017","journal-title":"Heart Vessel."},{"key":"ref_27","first-page":"192","article-title":"Pilot randomized controlled trial of inhaled milrinone in high-risk cardiac surgical patients","volume":"4","author":"Denault","year":"2014","journal-title":"Surg. Curr. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.jtcvs.2004.09.011","article-title":"Inhaled but not intravenous milrinone prevents pulmonary endothelial dysfunction after cardiopulmonary bypass","volume":"130","author":"Lamarche","year":"2005","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nguyen, A.Q., Denault, A.Y., Th\u00e9oret, Y., and Varin, F. (2023). Inhaled milrinone in cardiac surgical patients: Pharmacokinetic and pharmacodynamic exploration. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-29945-7"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e122994","DOI":"10.5812\/aapm-122994","article-title":"Comparison of Nebulized versus Intravenous Milrinone on Reducing Pulmonary Arterial Pressure in Patients with Pulmonary Hypertension Candidate for Open-cardiac Surgery: A Double-Blind Randomized Clinical Trial","volume":"12","author":"Jorairahmadi","year":"2022","journal-title":"Anesth. Pain. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1093\/eurheartj\/ehi875","article-title":"Evidence-based use of levosimendan in different clinical settings","volume":"27","author":"Colucci","year":"2006","journal-title":"Eur. Heart J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.ijcard.2016.07.202","article-title":"Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper","volume":"222","author":"Farmakis","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"613","DOI":"10.2165\/00003495-200161050-00006","article-title":"Levosimendan","volume":"61","author":"Figgitt","year":"2001","journal-title":"Drugs"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"328","DOI":"10.4103\/aca.ACA_19_18","article-title":"Inhaled levosimendan versus intravenous levosimendan in patients with pulmonary hypertension undergoing mitral valve replacement","volume":"21","author":"Kundra","year":"2018","journal-title":"Ann. Card. Anaesth."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2045894018790905","DOI":"10.1177\/2045894018790905","article-title":"Levosimendan in pulmonary hypertension and right heart failure","volume":"8","author":"Hansen","year":"2018","journal-title":"Pulm. Circ."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s40265-022-01833-w","article-title":"Use of Levosimendan in Patients with Pulmonary Hypertension: What is the Current Evidence?","volume":"83","author":"Masarone","year":"2023","journal-title":"Drugs"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.echo.2020.03.002","article-title":"Guidelines for the Use of Transesophageal Echocardiography to Assist with Surgical Decision-Making in the Operating Room: A Surgery-Based Approach: From the American Society of Echocardiography in Collaboration with the Society of Cardiovascular Anesthesiologists and the Society of Thoracic Surgeons","volume":"33","author":"Nicoara","year":"2020","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.jchf.2021.01.015","article-title":"Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial","volume":"9","author":"Burkhoff","year":"2021","journal-title":"JACC Heart Fail."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s13019-020-01140-z","article-title":"Preconditioning with levosimendan reduces postoperative low cardiac output in moderate-severe systolic dysfunction patients who will undergo elective coronary artery bypass graft surgery: A cost-effective strategy","volume":"15","year":"2020","journal-title":"J. Cardiothorac. Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/s00540-019-02643-3","article-title":"The efficacy and safety of prophylactic use of levosimendan on patients undergoing coronary artery bypass graft: A systematic review and meta-analysis","volume":"33","author":"Wang","year":"2019","journal-title":"J. Anesth."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.1016\/j.jtcvs.2019.06.020","article-title":"Levosimendan in patients with reduced left ventricular function undergoing isolated coronary or valve surgery","volume":"159","author":"Mehta","year":"2020","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"473","DOI":"10.6002\/ect.2020.0342","article-title":"Levosimendan for Treatment of Primary Graft Dysfunction after Heart Transplantation: Optimal Timing of Application","volume":"19","author":"Immohr","year":"2021","journal-title":"Exp. Clin. Transplant."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1002\/ehf2.13427","article-title":"Levosimendan in venoarterial ECMO weaning.  Rational and design of a randomized double blind multicentre trial","volume":"8","author":"Ellouze","year":"2021","journal-title":"ESC Heart Fail."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1177\/1089253206294400","article-title":"Inhaled milrinone: A new alternative in cardiac surgery?","volume":"10","author":"Denault","year":"2006","journal-title":"Semin. Cardiothorac. Vasc. Anesth."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1053\/j.jvca.2023.01.032","article-title":"Levosimendan or Milrinone for Ventricular Septal Defect Repair with Pulmonary Arterial Hypertension","volume":"37","author":"Nag","year":"2023","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1053\/j.jvca.2016.01.015","article-title":"Comparative Effect of Levosimendan and Milrinone in Cardiac Surgery Patients with Pulmonary Hypertension and Left Ventricular Dysfunction","volume":"30","author":"Mishra","year":"2016","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Ftikos, P., Falara, A., Rellia, P., Leontiadis, E., Samanidis, G., Kamperi, N., Piperakis, A., Tamvakopoulos, C., Antoniou, T., and Theodoraki, K. (2023). Monitoring of Levosimendan Administration in Patients with Pulmonary Hypertension Undergoing Cardiac Surgery and Effect of Two Different Dosing Schemes on Hemodynamic and Echocardiographic Parameters. Pharmaceuticals, 16.","DOI":"10.3390\/ph16060815"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/14\/9\/1164\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:56:19Z","timestamp":1760111779000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/14\/9\/1164"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,14]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["life14091164"],"URL":"https:\/\/doi.org\/10.3390\/life14091164","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,14]]}}}