REVIEW ARTICLE Paul G. Barash, MD Giovanni Landoni, MD Section Editors Perioperative Use of Levosimendan: Best Practice in Operative Settings Wolfgang Toller, MD,* Lars Algotsson, MD,† Fabio Guarracino, MD,‡ Christoph Hörmann, MD,§ Johann Knotzer, MD, Andreas Lehmann, MD,¶ Angela Rajek, MD,# Markku Salmenperä, MD,** Uwe Schirmer, MD,†† Luigi Tritapepe, MD,‡‡ Florian Weis, MD,§§ and Giovanni Landoni, MD¶¶ L EVOSIMENDAN HAS BEEN USED in clinical practice since 2000, especially in the care of heart-failure patients. It probably is the most studied inotropic agent ever, with 83 randomized controlled trials published about adult critically ill patients 1 (PubMed search updated January 6, 2012). The mo- lecular mechanisms of levosimendan action recently have been described in detail elsewhere 2 and are based on, but not limited to, the Ca 2+ -sensitizing effect in the cardiac myofilaments. Pleiotropic effects include activation of adenosine triphospha- te–sensitive sarcolemmal K + channels of smooth muscle cells (linked to vasodilation) and activation of adenosine triphospha- te–sensitive K + channels in cardiovascular mitochondria (in- volved in a cardioprotective effect). The active long-lived me- tabolite OR-1896, also an inodilator, 3,4 allows the cardiovascular effects of levosimendan to persist up to 7 to 9 days after the discontinuation of a 24-hour infusion of the drug. 5 In the last 10 years, a growing body of literature has been published on levosimendan, showing a constant interest in the effects of this drug. Scopus retrieval of levosimendan citations (updated on January 6, 2012) shows that, after a steep increase related to the introduction of this drug in the clinical practice, the number of articles (defined as manuscripts that contain levosimendan in the title, abstract, or keywords) has stabilized at more than 150 per year (Fig 1) with one fourth of the publications using levosimendan in the perioperative setting. The inotropic efficacy of levosimendan is dose dependent and equal or superior to any of the other commercially avail- able inotropic agents. However, the widespread use of levosi- mendan is limited by the noticeably higher cost compared with catecholamines and other inodilators. Thus, its use is reason- able when an improvement in clinically relevant endpoints (eg, survival) or a reduction in other hospital costs (eg, length of hospital stay) can be shown. In this regard, evidence-based medicine suggests that levo- simendan is the only inotropic agent that might reduce mortal- ity in critically ill patients. 1 A meta-analysis of 45 randomized, controlled trials (levosimendan v any comparator) showed an overall mortality rate of 17.4% (507/2,915) among levosimen- dan-treated patients and 23.3% (598 of 2,565) in the control group (risk ratio = 0.80 [confidence intervals 0.72, 0.89], p  0.001, number needed to treat [NNT] = 17). The reduction in mortality was more impressive in the studies performed in cardiac surgery. Patients undergoing cardiac surgery presum- ably benefit more from the use of levosimendan because they usually have transient perioperative stunning and not a terminal form of heart failure. The growing interest for the perioperative use of levosimen- dan also can be extrapolated from http://www.clinicaltrials.gov in which 4 of the 7 active registered studies focus on periop- erative patients (search updated on January 6, 2012). Recently, the first international consensus conference on mortality reduc- tion in cardiac anesthesia and intensive care included levosi- mendan among the 8 ancillary (nonsurgical) drugs/techniques/ strategies that might reduce mortality in cardiac surgery. 6 The present document has been developed on the basis of the current literature and from a consensus opinion reached by From the *Department of Anesthesiology and Intensive Care Med- icine, Medical University of Graz, Graz, Austria; †Department of Anesthesiology and Intensive Care, Faculty of Medicine, Lund Univer- sity, Lund, Sweden; ‡Cardiothoracic Anaesthesia and Intensive Care Unit, Cardiothoracic Department, University Hospital of Pisa, Pisa, Italy; §Division of Anesthesia and Intensive Care Medicine, Landesklinikum St.Pölten, St.Pölten, Austria; Institute of Anesthesiol- ogy and Intensive Care Medicine II, Klinikum Wels-Grieskirchen, Wels, Austria; ¶Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany; #Department of Anesthesiology and General Intensive Care, Vienna General Hospital, University of Vienna, Vienna, Austria; **Depart- ment of Anesthesiology and Intensive Care Medicine, Helsinki Univer- sity Hospital, Helsinki, Finland; ††Institute of Anesthesiology, Heart and Diabetes Center North Rhine-Westphalia, University Clinic Ruhr- University Bochum, Bad Oeynhausen, Germany; ‡‡Department of An- esthesiology and Intensive Care, Sapienza University of Rome, Rome, Italy; §§Clinic for Anesthesiology, Klinikum Großhadern, Munich, Germany; Department of Anesthesia and Intensive Care, Università Vita-Salute San Raffaele, Milan, Italy; and ¶¶Maieutics Foundation, Milan, Italy. Address reprint requests to Giovanni Landoni, MD, Department of Cardiothoracic Anesthesia and Intensive Care, Istituto Scientifico San Raffaele, Via Olgettina 60, Milano 20132, Italy. E-mail: landoni.giovanni@hsr.it © 2012 Elsevier Inc. All rights reserved. 1053-0770/xx0x-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2012.04.007 Key words: cardioprotection, inodilator, cardiac surgery, hemody- namic, consensus guidelines, levosimendan, anesthesia, intensive care 1 Journal of Cardiothoracic and Vascular Anesthesia, Vol xx, No x (Month), 2012: pp xxx