Levosimendan In Cardiac Surgery Research Articles

Influence of timing of Levosimendan administration on outcomes in cardiac surgery.

Though a subgroup analysis has shown improved survival for patients suffering severely reduced ventricular function undergoing coronary artery bypass grafting, RCTs were not able to demonstrate overall beneficial effects of perioperative Levosimendan in cardiac surgery. This might be due to Levosimendan's pharmacokinetics reaching a steady-state concentration only 4-8 h after administration. Thus, this study now analysed the influence of timing of Levosimendan administration on perioperative outcome in cardiac surgery patients preoperatively presenting with severely reduced ventricular function and therefore considered at high-risk for intra- or postoperative low cardiac output syndrome. We hypothesized that prolonged preoperative Levosimendan administration ("preconditioning") would reduce mortality. All adult patients undergoing cardiac surgery between 2006 and 2018 perioperatively receiving Levosimendan were included in this retrospective, observational cohort study (n = 498). Patients were stratified into 3 groups: Levosimendan started on the day prior to surgery ("preop"), Levosimendan started on the day of surgery ("intraop") or post ICU admission ("postop"). After propensity score matching (PSM) was performed, outcomes defined according to proposed standard definitions for perioperative outcome research were compared between groups. After PSM, there were no significant differences in patients' characteristics, comorbidities and type/priority of surgery between groups. Compared to intraop or postop Levosimendan treatment, preop treated patients had significantly lower in-hospital-mortality (preop vs. intraop. vs. postop = 16,7% vs. 33,3% vs. 42,3%), duration of mechanical ventilation and rate of continuous renal replacement therapy. Prolonged preoperative treatment with Levosimendan of cardiac surgery patients preoperatively presenting with severely reduced left ventricular function might be beneficial in terms of postoperative outcome. Our results are in line with recent experts' recommendations concerning the prolonged perioperative use of Levosimendan. We strongly recommend that future randomized trials include this "preconditioning" treatment as an experimental arm.

The efficacy and safety of prophylactic use of levosimendan on patients undergoing coronary artery bypass graft: a systematic review and meta-analysis.

Prophylactic use of levosimendan in cardiac surgery remains controversial and no meta-analysis has been done exclusively about that in patients undergoing coronary artery bypass graft (CABG) surgery. We conducted this systematic review and meta-analysis of levosimendan in CABG using PubMed, Embase, Scopus, and Cochrane Library (till April 20, 2018). Two-hundred and forty manuscripts were identified and 21 randomized trials (1727 patients in total) investigating the effect of levosimendan on the patients undergoing CABG surgery were finally included in this analysis. We found that levosimendan was an effective, well-tolerated inotropic agent in CABG, which was associated with a significantly reduced mortality rate [odds ratio (OR) 0.43, 95% confidence interval (CI) (0.26, 0.71), p = 0.001, I2 = 0%] and postoperative atrial fibrillation [OR 0.50, 95% CI (0.26, 0.97), p = 0.04, I2 = 76%], but a higher incidence of hypotension [OR 2.26, 95% CI (1.05, 4.85), p = 0.04, I2 = 79%]. Subgroup analyses revealed that such a benefit was mainly observed in the isolated CABG, the preoperative administration, with-bolus and on-pump subgroups. More high-quality and well-designed prospective studies are needed to confirm or disprove our findings in future.

What's New in Cardiopulmonary Bypass

This is a narrative review of recent articles (mainly published in 2017 and 2018) related to the conduct of cardiopulmonary bypass (CPB) that should be of interest to the cardiac anesthesiologist. Some of the topics covered include recent guidelines on temperature management, anticoagulation, perfusion practice, use of transesophageal echocardiography during CPB, optimal mean arterial pressure, vasoplegia, bleeding, perioperative anemia, post-cardiac surgery transfusion, acute kidney injury, delirium and cognitive decline, CPB during pregnancy, lung management, radial-to-femoral artery pressure gradients during CPB, prophylactic perioperative intra-aortic balloon pump, del Nido cardioplegia, antibiotic prophylaxis, and use of levosimendan in cardiac surgery. The review concludes with a perspective on the effect of these development on the practice of cardiac anesthesia.

Perioperative use of levosimendan in cardiac surgery. Hungarian recommendation

Low output syndrome significantly increases morbidity and mortality of cardiac surgery and lengthens the durations of intensive care unit and hospital stays. Its treatment by catecholamines can lead to undesirable systemic and cardiac complications. Levosimendan is a calcium sensitiser and adenosine triphosphate (ATP)-sensitive potassium channel (IK,ATP) opener agent. Due to these effects, it improves myocardium performance, does not influence adversely the balance between O2 supply and demand, and possesses cardioprotective and organ protective properties as well. Based on the scientific literature and experts' opinions, a European recommendation was published on the perioperative use of levosimendan in cardiac surgery in 2015. Along this line, and also taking into consideration cardiac surgeon, anaesthesiologist and cardiologist representatives of the seven Hungarian heart centres and the children heart centre, the Hungarian recommendation has been formulated that is based on two pillars: literature evidence and Hungarian expert opinions. The reviewed fields are: coronary and valvular surgery, assist device implantation, heart transplantation both in adult and pediatric cardiologic practice. Orv Hetil. 2018; 159(22): 870-877.

Use of Levosimendan in Cardiac Surgery: An Update After the LEVO-CTS, CHEETAH, and LICORN Trials in the Light of Clinical Practice

:Levosimendan is a calcium sensitizer and adenosine triphosphate–dependent potassium channel opener, which exerts sustained hemodynamic, symptomatic, and organ-protective effects. It is registered for the treatment of acute heart failure, and when inotropic support is considered appropriate. In the past 15 years, levosimendan has been widely used in clinical practice and has also been tested in clinical trials to stabilize at-risk patients undergoing cardiac surgery. Recently, 3 randomized, placebo-controlled, multicenter studies (LICORN, CHEETAH, and LEVO-CTS) have been published reporting on the perioperative use of levosimendan in patients with compromised cardiac ventricular function. Taken together, many smaller trials conducted in the past suggested beneficial outcomes with levosimendan in perioperative settings. By contrast, the latest 3 studies were neutral or inconclusive. To understand the reasons for such dissimilarity, a group of experts from Austria, Belgium, Finland, France, Germany, Italy, Switzerland, and Russia, including investigators from the 3 most recent studies, met to discuss the study results in the light of both the previous literature and current clinical practice. Despite the fact that the null hypothesis could not be ruled out in the recent multicenter trials, we conclude that levosimendan can still be viewed as a safe and effective inodilator in cardiac surgery.

Perioperative levosimendan in cardiac surgery: A systematic review with meta-analysis and trial sequential analysis.

Several studies suggested beneficial effects of perioperative levosimendan on postoperative outcome after cardiac surgery. However, three large randomized controlled trials (RCTs) have been recently published and presented neutral results. We performed a systematic review with meta-analysis and trial sequential analysis (TSA) to assess benefits and harms of perioperative levosimendan therapy in cardiac surgery. Electronic databases were searched up to September 2017 for RCTs on preoperative levosimendan versus any type of control. The Cochrane methodology was employed. We calculated odds ratio (OR) or Risk Ratio (OR) and 95% confidence interval (CI) using fixed-effects meta-analyses and we further performed TSA. We included data from 40 RCTs and 4246 patients. Pooled analysis of 5 low risk of bias trials (1910 patients) showed no association between levosimendan and mortality (OR 0.86 [95% CI, 0.62, 1.18], p=0.34, TSA inconclusive), acute kidney injury, need of renal replacement therapy, myocardial infarction, ventricular arrhythmias, and serious adverse events, but an association with higher incidence of supraventricular arrhythmias (RR 1.11 [95% CI, 1.00, 1.24], p=0.05, TSA inconclusive) and hypotension (RR 1.15 [95% CI, 1.01, 1.30], p=0.04, TSA inconclusive). Analysis including all 40 trials found that levosimendan was associated with lower postoperative mortality (OR 0.56 [95% CI, 0.44, 0.71], p<0.00001, TSA conclusive), acute kidney injury, and renal replacement therapy, and higher incidence of hypotension. There is not enough high-quality evidence to neither support nor discourage the systematic use of levosimendan in cardiac surgery.

Surgery: Neutral results for levosimendan in cardiac surgery.

Surgery: Neutral results for levosimendan in cardiac surgery.

Levosimendan in Cardiac Surgery: Is it all Gold that Glitters?

Levosimendan in Cardiac Surgery: Is it all Gold that Glitters?

Perioperative use of levosimendan in cardiac surgery

&lt;div data-canvas-width="623.7918644546122"&gt;It is known that low cardiac output in patients undergoing cardiac surgery is associated with organ dysfunction and mortality in the postoperative period. Catecholamines have been the standard therapy for many years, although they carry substantial risks for adverse cardiac and systemic effects, and have been reported to be associated with increased mortality. On the other hand, the calcium sensitiser and potassium channel opener levosimendan has been shown to improve the cardiac function with&lt;/div&gt;&lt;div data-canvas-width="623.8018800588713"&gt;no imbalance in oxygen consumption, and to have protective effects in other organs. Several clinical trials have found beneficial effects of cardiogenic and non-cardiogenic perioperative use of levosimendan. The aim of this article was to describe the mechanism of levosimendan action, as well as to overview the current data regarding its clinical application.&lt;/div&gt;&lt;div data-canvas-width="623.8018800588713"&gt;&lt;span&gt;&lt;br /&gt;&lt;/span&gt;&lt;/div&gt;&lt;div data-canvas-width="623.8018800588713"&gt;&lt;span&gt;Received 22 April 2015. Accepted 18 June 2015.&lt;/span&gt;&lt;/div&gt;&lt;div data-canvas-width="311.3250427845475"&gt; &lt;/div&gt;&lt;div data-canvas-width="311.3250427845475"&gt; &lt;/div&gt;

EComment. Preoperative levosimendan administration in cardiac surgery patients

According to its dual mode of action, levosimendan is both a calcium sensitizer, hence enhancing myocardial contractility without increasing the concentration of intracellular calcium, and a potassium adenosine triphosphate(ATP)-dependent channel opener, leading to vasodilation, which reduces left ventricular afterload and improves blood flow to vital organs [1]. Levosimendan exerts vasodilatory and possible anti-ischaemic and cardioprotective effects by opening of the ATP-dependent potassium-channel. Levosimendan may facilitate weaning from cardiopulmonary bypass (CPB) by both its inotropic and lusitropic properties. It enhances both systolic and diastolic left and right ventricular performance [1]. Levosimendan has a half-life of 1 hour, meaning that it is quickly eliminated from plasma. However, it has an active metabolite (OR-1896), which is formed by intestinal bacteria. OR-1896 has a similar haemodynamic profile to its parent compound, but a longer half-life of 70-80 hours. These pharmacokinetic features provide plausible explanations for the prolonged haemodynamic effects of levosimendan metabolites, which last for up to 7-9 days after discontinuation of a 24-h infusion of levosimendan [2]. We read with great interest the paper by Angadi et al. [3], regarding levosimendan use in paediatric cardiac surgey patients. They suggest that levosimendan is beneficial in improving cardiac performance and reducing the left ventricular afterload. It is promising as a rescue drug on the named-patient basis for a potential clinical benefit in low cardiac ouput syndrome (LCOS) and postcardiac surgeries. We agree with their implications and also would like to add a short comment on preoperative levosimendan administration. Currently, the use of levosimendan in cardiac surgery has gradually increased and is studied more in adults than in children. In cardiac surgery patients, candidates to receive levosimendan include low preoperative left ventricular ejection fraction (LVEF)(<35%), high-risk patients (emergency operation, decompensated heart failure), weaning failure from CPB, scheduled for mechanical assist device (intra-aortic balloon pump/left ventricular assist device), or postoperative LCOS [1]. Levosimendan is often used to improve peri- and postoperative haemodynamics to reduce morbidity and hospital stay. Levosimendan may be administered preoperatively, intraoperatively (before, during, or after CPB), or postoperatively. The timing depends on the logistic utilities of the hospital and the haemodynamic target [1]. Current dosing regimes use levosimendan perioperatively. However, during CPB, there is hypoperfusion in the hepatosplenic region, which may affect intestinal function. Thus, patients receiving levosimendan perioperatively may not have the active metabolite OR-1896. In our retrospective study [4] we reported early results of 18 patients receiving preoperative levosimendan that underwent coronary artery bypass grafting (CABG) with LVEF of 35% or less. Levosimendan infusion was given at a rate of 0.2 microgram/kg/min without a loading dose. It started 12 h before surgey. There was no in-hospital mortality. Levosimendan infusion was tolerated well in all patients. There were significant amelioration in haemodynamic parameters and diuresis. All patients showed no stormy postoperative recovery. In the prospective randomized study by Leppikangas et al. [5], levosimendan improved haemodynamics during the 4 day postoperative period, when infused a day before surgery. The formation of metabolites was documented for this 4 day postoperative period. We think that preoperative levosimendan administration may improve haemodynamic function and clinical outcome in patients with poor left ventricular function undergoing CABG. Conflict of interest: none declared

Levosimendan Reduces Cardiac Troponin Release After Cardiac Surgery: A Meta-analysis of Randomized Controlled Studies

The authors performed a meta-analysis to investigate the effects of levosimendan in cardiac surgery. Inotropic drugs have never shown beneficial effects on outcome in randomized controlled studies, with the possible exception of levosimendan. A meta-analysis. Hospitals. A total of 139 patients from 5 randomized controlled studies were included in the analysis. None. Four investigators independently searched BioMedCentral and PubMed. Inclusion criteria were random allocation to treatment, and comparison of levosimendan versus control performed on cardiac surgery patients. Exclusion criteria were duplicate publications, nonhuman experimental studies, and no outcome data. The endpoint was postoperative cardiac troponin release. Levosimendan was associated with a significant reduction in cardiac troponin peak release (weighted mean difference = 2.5 ng/dL [-3.86, -1.14], p = 0.0003) and in time to hospital discharge (weighted mean difference = -1.38 days [-2.78, 0.03], p = 0.05). No other relevant outcome (mortality, myocardial infarction, atrial fibrillation, time on mechanical ventilation, and intensive care unit stay) was improved in those patients receiving levosimendan. Levosimendan has cardioprotective effects, resulting in reduced postoperative cardiac troponin release.

Application of levosimendan in cardiac surgery

Patients suffering from ventricular dysfunction after cardiac surgery with cardiopulmonary bypass (CPB) often require positive inotropic support. The use of conventional inotropic agents is limited in clinic because of their increasing myocardial oxygen consumption and/or proarrhythmia. Levosimendan, a member of new class (calcium sensitizer) of inotropic agents, enhances cardiac contractility via increasing calcium sensitization of contractile proteins, and produces vasodilation and anti-ischemia effect by opening KATP channel. The available clinical evidences show that levosimendan is effective for treatment of cardiac surgical patients with high perioperative risk or compromised left ventricular function, and rescues patients with difficulties in weaning from CPB. Key words: calcium sensitizer; levosimendan; cardiac surgery

Levosimendan in Cardiac Surgery: A Unique Drug for the Treatment of Perioperative Left Ventricular Dysfunction or Just Another Inodilator Searching for a Clinical Application?

Paul S. Pagel, MD, PhD The myofilament calcium (Ca ) sensitizers are a class of positive inotropic, vasodilating drugs (“inodilators”) that augment myocardial contractility by increasing the Ca sensitivity of the contractile apparatus without altering intracellular Ca concentration (1). Ca sensitizers (including levosimendan, pimobendan, sulmazole, EMD 57033, and MCI-154) have received considerable attention for the treatment of acute and chronic congestive heart failure because, unlike 1-adrenoceptor agonists or cardiac phosphodiesterase (PDE) III inhibitors that stimulate cyclic adenosine monophosphate (cAMP)mediated signaling and increase intracellular Ca concentration, these drugs do not adversely affect myocardial oxygen supply-demand relations (2), produce cardiotoxicity, or predispose to the development of arrhythmias (3). Levosimendan was developed over a decade ago, and based on a large body of accumulated experimental and clinical evidence, appears to be the most promising of these drugs. Levosimendan has already been approved for the treatment of acute exacerbation of chronic heart failure in several European countries following European Society of Cardiology guidelines (4,5). The drug is currently undergoing Phase III clinical trials in the United States (REVIVE study) to evaluate its utility for the acute or chronic management of heart failure, and has received “fast-track” status from the Food and Drug Administration. The mechanisms by which levosimendan enhances the inotropic state and produces vasodilation have been extensively studied (1). Briefly, levosimendan binds to the regulatory protein troponin C (TnC) (6) and stabilizes the Ca -bound conformation of TnC, thereby allowing unopposed interaction between actin and myosin filaments and enhancing the rate and extent of myocyte contraction (7). A unique feature of levosimendan-TnC binding is its dependence on intracellular Ca concentration that facilitates the interaction between TnC and Ca during systole, while simultaneously allowing Ca to dissociate from the protein during diastole (8). This Ca -dependence of TnC binding prevents deleterious abnormalities in relaxation that would otherwise be expected to occur (9). Preservation of lusitropic function is also facilitated by the PDE-inhibiting properties of levosimendan that occur at higher doses of the drug (10). Levosimendan-induced systemic, pulmonary, and coronary vasodilation occurs as a result of at least three distinct mechanisms. Levosimendan opens several types of potassium (K ) channels (including voltagedependent, ATP-sensitive, and Ca -activated forms) in conductance and resistance vessels, actions that reduce intracellular Ca concentration in vascular smooth muscle (11). Levosimendan induces Ca desensitization of the contractile apparatus in vascular smooth muscle that does not contain TnC independent of intracellular Ca concentration (12). PDE inhibition may also play a role in vasodilation produced by higher doses of the drug. Unlike other inotropic drugs, levosimendan may exert important antiischemic effects by virtue of its actions as a KATP channel opener. Levosimendan From the Anesthesia Service, the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin. Accepted for publication December 7, 2006. Address correspondence to Paul S. Pagel, MD, PhD, Clement J. Zablocki Veterans Affairs Medical Center, Anesthesia Service, 5000 W. National Ave., Milwaukee, WI 53295. Address e-mail to paul.pagel@med.va.gov. Copyright © 2007 International Anesthesia Research Society DOI: 10.1213/01.ane.0000256864.75206.6d

Levosimendan in cardiac surgery

Levosimendan in cardiac surgery