Preoperative Levosimendan Research Articles

Preoperative Levosimendan in Patients With Severe Left Ventricular Dysfunction Undergoing Isolated Coronary Artery Bypass Grafting: A Meta-Analysis of Randomized Controlled Trials

ObjectiveTo verify the impact of preoperative levosimendan on patients with severe left ventricular dysfunction (ejection fraction < 35%) undergoing isolated coronary artery bypass grafting. DesignA meta-analysis SettingHospitals ParticipantsWe included 1,225 patients from six randomized controlled trials. InterventionsNone. Measurements & Main ResultsWe performed a meta-analysis of trials that compared preoperative levosimendan with placebo or no therapy, reporting efficacy and safety endpoints.Statistical analyses used mean differences and risk ratios (RR) with a random effects model. We included six studies comprising 1225 patients, of whom 615 (50.2%) received preoperative levosimendan and 610 (49.8%) received placebo/no therapy. Preoperative levosimendan showed a lower risk of all-cause mortality (RR 0.31; 95% CI 0.16-0.60; p <0.01; I2 = 0%), postoperative acute kidney injury (AKI; RR 0.44; 95% CI 0.25-0.77; p<0.01; I2=0%), LCOS (RR 0.45; 95% CI 0.30-0.66; p<0.001; I2=0%), and postoperative atrial fibrillation (AF; RR 0.49; 95% CI 0.25-0.98; p=0.04; I2=85%) compared to control. Moreover, levosimendan significantly reduced the need for postoperative inotropes and increased the cardiac index at 24 hours postoperative. There were no differences between groups for perioperative myocardial infarction, hypotension, or any adverse events. ConclusionPreoperative levosimendan in patients with severe left ventricular dysfunction undergoing isolated coronary artery bypass grafting was associated with reduced all-cause mortality, low cardiac output syndrome, acute kidney injury, postoperative atrial fibrillation, and the need for circulatory support without compromising safety.

Abstract 17145: Impact of Preoperative Levosimendan in Patients With Severe Heart Failure Undergoing Left Ventricular Assist Device Support: A Meta-Analysis

Introduction: Left ventricular assist devices (LVADs) are frequently employed as a bridge to transplant or destination therapy. The implementation of preventive preoperative measures can have a beneficial impact on the prognosis of patients undergoing LVAD implantation. However, the role of levosimendan in this context remains uncertain. Goals: To evaluate the efficacy of preoperative levosimendan in reducing complications after LVAD implantation. Methods: We systematically searched PubMed, Scopus, and Cochrane Library for studies comparing the use of levosimendan before LVAD implantation vs. standard of care alone in May 2023. Statistical analyses were performed using Review Manager 5.4.1. Heterogeneity was assessed with I2 statistics. Results: Four studies comprising 4032 patients who underwent LVAD implantation were included, of whom 15,2% were on preoperative levosimendan. There was no significant difference between groups in 30-day mortality (OR, 0.95 [95% CI, 0.70-1.28], I2=0%, p=0.73 - Fig. 1A), right ventricular failure (OR, 0.92 [95% CI, 0.47-1.80], I2=69%, p=0.81 - Fig. 1B), or length of intensive care unit (ICU) stay (mean difference, 2.63 [95% CI, -2.07-7.33], I2=92%, p=0.27 - Fig. 1C). Conclusions: In this meta-analysis, the preoperative use of levosimendan was not associated with reduced mortality, right ventricular failure, or length of ICU stay in patients undergoing LVAD implantation.

Preoperative Levosimendan Administration in Heart Transplant Patients with Severe Hepatic and Renal Impairment: A Retrospective Study.

The cardio-renal syndrome and hepatic impairment play a critical role in end-stage heart failure (HF). Levosimendan is an effective inotropic agent used to maintain cardiac output similar to classic cardiotonic like dobutamine/dopamine. This current research aims to investigate the clinical outcomes of levosimendan and dobutamine/dopamine in Chinese heart transplant awaiting patients with severe hepatic or renal impairment. We performed a retrospective analysis of 568 heart transplant awaiting individuals with severe hepatic or renal impairment who treated with levosimendan or dobutamine/dopamine in our institution between January 2015 and December 2020. Univariate Cox proportional hazard models and Kaplan-Meier survival curves were applied. The primary endpoint was defined as death included inhospital mortality and the mortality at 30 days, 90 days, 180 days and 1 year after heart transplantation. There were no significant differences in mortality rate at 30, 90, 180 days and 1 years after heart transplantation between the levosimendan and non-levosimendan groups, or between subgroups of patients with severe hepatic impairment or renal impairment. The results were consistent before and after propensity score matching. In the population with advanced heart failure awaiting heart transplantation, levosimendan did not increase short- or long-term mortality rates after surgery compared to dobutamine/dopamine, regardless of their hepatic or renal function. Severe hepatic or renal impairment were not necessarily considered a contraindication for levosimendan in these patients.

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.

(835) Preoperative Levosimendan to Reduce Risk of Right Ventricular Failure after LVAD Surgery

(835) Preoperative Levosimendan to Reduce Risk of Right Ventricular Failure after LVAD Surgery

Efficacy of levosimendan infusion in patients undergoing a left ventricular assist device implant in a propensity score matched analysis of the EUROMACS registry-the Euro LEVO-LVAD study.

Early right-sided heart failure (RHF) was seen in 22% of recipients of a left ventricular assist device (LVAD) in the European Registry for Patients with Mechanical Circulatory Support (EUROMACS). However, the optimal treatment of post-LVAD RHF is not well known. Levosimendan has proven to be effective in patients with cardiogenic shock and in those with end-stage heart failure. We sought to evaluate the efficacy of levosimendan on post-LVAD RHF and 30-day and 1-year mortality. The EUROMACS Registry was used to identify adults with mainstream continuous-flow LVAD implants who were treated with preoperative levosimendan compared to a propensity matched control cohort. In total, 3661 patients received mainstream LVAD, of which 399 (11%) were treated with levosimendan pre-LVAD. Patients given levosimendan had a higher EUROMACS RHF score [4 (2- 5.5) vs 2 (2- 4); P < 0.001], received more right ventricular assist devices (RVAD) [32 (8%) vs 178 (5.5%); P = 0.038] and stayed longer in the intensive care unit post-LVAD implant [19 (8-35) vs 11(5-25); P < 0.001]. Yet, there was no significant difference in the rate of RHF, 30-day, or 1-year mortality. Also, in the matched cohort (357 patients taking levosimendan compared to an average of 622 controls across 20 imputations), we found no evidence for a difference in postoperative severe RHF, RVAD implant rate, length of stay in the intensive care unit or 30-day and 1-year mortality. In this analysis of the EUROMACS registry, we found no evidence for an association between levosimendan and early RHF or death, albeit patients taking levosimendan had much higher risk profiles. For a definitive conclusion, a multicentre, randomized study is warranted.

Preoperative Levosimendan therapy reduces postoperative right ventricular failure in patients undergoing left ventricular assist device implantation

Perioperative mortality and complications still remain high after left ventricular assist device (LVAD) implantation, especially in highly compromised patient cohorts. Here, we evaluate the effects of preoperative Levosimendan therapy on peri- and postoperative outcomes after LVAD implantation. We retrospectively analysed 224 consecutive patients with LVAD implantation for end-stage heart failure between November 2010 and December 2019 in our centre with regard to short- and longer-term mortality as well as incidence of postoperative right ventricular failure (RV-F). Out of these, 117 (52.2%) received preoperative i.v. Levosimendan therapy within 7 days before LVAD implantation (Levo group). In-hospital, 30-day and 5-year mortality was comparable (in-hospital mortality: 18.8% vs 23.4%, P = 0.40; 30-day mortality: 12.0% vs 14.0%, P = 0.65; Levo vs control group). However, in the multivariate analysis, preoperative Levosimendan therapy significantly reduced postoperative RV-F but increased postoperative vasoactive inotropic score ([RV-F: odds ratio 2.153, confidence interval 1.146-4.047, P = 0.017; vasoactive inotropic score 24 h post-surgery: odds ratio 1.023, confidence interval 1.008-1.038, P = 0.002). These results were further confirmed by 1:1 propensity score matching of 74 patients in each group. Especially in the subgroup of patients with normal preoperative RV function, the prevalence of postoperative RV-F was significantly lower in the Levo- group as compared to the control group (17.6% vs 31.1%, P = 0.03; respectively). Preoperative Levosimendan therapy reduces the risk of postoperative RV-F, especially in patients with normal preoperative RV function without effects on mortality up to 5 years after LVAD implantation.

Effect of levosimendan infusion prior to left ventricular assist device implantation on right ventricular failure

ObjectiveInvestigate the safety and efficacy of preoperative levosimendan in patients undergoing left ventricular assist device (LVAD) implantation.MethodsConsecutive patients who received LVADs (HeartMate-2, 3, HVAD) in a single tertiary medical center (2012–2018). INTERMACS profile 1 patients were excluded. The primary outcome was post-LVAD right ventricular failure (RVF) and inhospital mortality rates. The secondary outcomes included other clinical, echocardiographic and hemodynamic parameters at follow-up.ResultsFinal cohort consisted of 62 patients (40[65%] in the levosimendan group and 22[35%] in the no-levosimendan group). Post-operative RVF rate and inotrope or ventilation support time were similar in the levosimendan and no-levosimendan groups (7.5% vs. 13.6%; P = 0.43, median of 51 vs. 72 h; P = 0.41 and 24 vs. 27 h; P = 0.19, respectively). Length of hospitalization, both total and in the intensive care unit, was not statistically significant (median days of 13 vs. 16; P = 0.34, and 3 vs. 4; P = 0.44, respectively). Post-operative laboratory and echocardiographic parameters and in-hospital complication rate did not differ between the groups, despite worse baseline clinical parameters in the Levosimendan group. There was no significant difference in the in-hospital and long term mortality rate (2.5% vs. 4.5%; P > 0.999 and 10% vs. 27.3% respectively; P = 0.64).ConclusionsLevosimendan infusion prior to LVAD implantation was safe and associated with comparable results without significant improved post-operative outcomes, including RVF.

Prophylactic levosimendan in patients with low ejection fraction undergoing coronary artery bypass grafting: A pooled analysis of two multicentre randomised controlled trials

ObjectivesTo assess the effect of preoperative levosimendan on mortality at day 90 in patients with left ventricular ejection fraction (LVEF) ≤ 40%, and to investigate a possible differential effect between patients undergoing isolated coronary artery bypass grafting (CABG) versus CABG combined with valve replacement surgery. DesignPooled analysis of two multicentre randomised controlled trials (RCT) investigating prophylactic levosimendan versus placebo prior to CABG surgery on mortality at day 90 in patients with LVEF ≤ 40%. A meta-analysis of all RCT investigating the same issue was also conducted. ResultsA cohort of 1084 patients (809 isolated CABG, and 275 combined surgery) resulted from the merging of LEVO-CTS and LICORN databases. Seventy-two patients were dead at day 90. The mortality at day 90 was not different between levosimendan and placebo (Hazard Ratio (HR): 0.73, 95% CI: 0.41–1.28, p = 0.27). However, there was a significant interaction between the type of surgery and the study drug (p = 0.004). We observed a decrease in mortality at day 90 in the isolated CABG subgroup (HR: 0.39, 95% CI: 0.19–0.82, p = 0.013), but not in the combined surgery subgroup (HR: 1.73, 95% CI: 0.77–3.92, p = 0.19). The meta-analysis of 6 RCT involving 1441 patients confirmed the differential effect on mortality at day 30 between the 2 subgroups. ConclusionsPreoperative levosimendan did not reduce mortality in a mixed surgical population with LV dysfunction. However, the subgroup of patients undergoing isolated CABG had a reduction in mortality at day 90, whereas there was no significant effect in combined surgery patients. This finding requires confirmation with a specific prospective trial.

Yüksek Riskli Koroner Arter Hastalarında Profilaktik Levosimendan Kullanımı: Retrospektif Klinik Araştırma

Objective: To investigate the perioperative and postoperative effects of preoperative levosimendan use in coronary artery patients with low ejection fraction (EF) (<40%). Material and Methods: A total of 6,571 coronary bypass patients who were treated at Kartal Koşuyolu High Specialization Training and Research Hospital between 2016 and 2019 were scanned, and 132 patients with preoperative EF below 40% were retrospectively analyzed. The patients were divided into 2 groups as those who received preoperative levosimendan (Group 1: 90 patients) and the control group, who did not receive it at all (Group 2: 42 patients). All of the patients included in the study were onpump coronary bypass patients and excluded off-pump bypass, emergency bypass, and other concomitant procedures. Results: In terms of EF values, improvements over time were significantly different in favor of Group 1 (p<0.043). The duration of the intensive care unit stay in Group 1 was longer (p<0.047). The changes in patients in terms of postoperative venous oxygen saturation over time were found to be statistically positive in favor of Group 1 (p<0.042). Mortality was observed in 5 patients in the postoperative early period (first 30 days), all of whom were from Group 1. However, no statistical difference was observed. Conclusion: Preoperative use of levosimendan in coronary artery patients with low EF improved some hemodynamic parameters; however, it did not make a significant hemodynamic and clinical contribution to surgery success in high-risk patients.

Rationale and Design of a Spanish Mulicenter Randomized Controlled Trial of Use of Preoperative Levosimendan to Reduce Low Cardiac Output Syndrome (LCOS) in Low Ejection Fraction (? 35%) Cardiac Surgery Patients Spanish Randomized Clinical Trial on Sindax (Spartans Study)

Background: Low Cardiac Output Syndrome (LCOS) is a complication that appears in approximately 20%of cardiac surgeries with extracorporeal circulation. This is associated with increased mortality, delayed recovery and prolonged hospital stay. The Spanish Randomized Clinical Trial on Sindax (SPARTANS) aims to demonstrate the effectiveness of the preoperative use of levosimendan in reducing LCOS in patients with poor Left Ventricle Ejection Fraction (LVEF) undergoing elective cardiac surgery. Methods: SPARTANS study is a multicenter, randomized triple-blind, placebo-controlled trial. 300 patients with LVEF ≤ 35%, undergoing elective cardiac surgery will be recruited from 9 Spanish hospitals and randomized into two groups: Preoperative administration of levosimendan or placebo for 24 hours. The study drug will be started as a continuous infusion (0.1 μg/kg/ min) at least 8 hours before surgery. The primary endpoint will be 30-day LCOS. It will be evaluated using any of the following criteria: 1) Postoperated cardiac index ≤ 2.0 L/min/m2, 2) Need to implant a intra-aortic balloon pump/left ventricular assist device, 3) Vasoactive inotropic scale (VIS) >5.5. The secondary end-point will be composite event rate at one year including the following events: death from any cause, need for renal replacement therapy or dialysis and LCOS. The sample size is based on the assumption that levosimendan reduces LCOS by 50%. Conclusion: The effectiveness of levosimendan has not yet been reported with a good evidence in cardiac surgery. We will test the hypothesis that levosimendan reduces LCOS in patients with compromised left ventricular function. Trial registration number: NCT04179604 (ClinicalTrials.gov). Rationale and Design of a Spanish Mulicenter Randomized Controlled Trial of Use of Preoperative Levosimendan to Reduce Low Cardiac Output Syndrome (LCOS) in Low Ejection Fraction (≤ 35%) Cardiac Surgery Patients Spanish Randomized Clinical Trial on Sindax (Spartans Study)

Sol ventrikül fonksiyonları bozulmuş, ejeksiyon fraksiyonu %40’ın altında olan, koroner arter by-pass greft operasyonu yapılacak hastalara verilen levosimendan tedavisinin, kardiyoprotektif etkinliğinin postoperatif olarak değerlendirilmesi

The purpose of this study is to demonstrate the postoperative cardioprotective efficacy of preoperative levosimendan treatment in patients with impaired left ventricular function undergoing coronary by-pass surgery. Materyal and Method: This study was performed prospectively between November 2008 and September 2009 in Eskişehir Osmangazi Univercity Department of Cardiovascular Surgery. Twenty patients with coronary artery disease (CAD) between the ages of 48-78 and ejection fraction (EF) below 40% were included in the study. levosimendan was given to the first group preoperatively(experimental group). Group 2 was the control group. Coronary artery bypass graft (CABG) surgery was performed in all of them. One group received additional levosimendan infusion, preoperatively. Age, comorbidity, cardiopulmonary by-pass (CPB) time, cross clamp (CC) time, patient vessel number, anastomosis number, extubation times, intensive care stay and hospital stay were recorded. Preoperative, postoperative 1st day and postoperative 7th day nt-proBNP values and preoperative and postoperative 15th day ejection fraction (EF) values with echocardiography (ECHO) were measured. The cardioprotective efficacy of the drug was evaluated by comparing the data of the control group and the experimental group. Results: No statistically significant difference was found between the two groups in terms of CPB time, CC time, age, comorbidity, number of sick vessels, number of anastomosis, extubation time, length of stay in intensive care and hospital stay. (P&amp;gt; 0.05). There was no significant difference between the groups in preoperative EF values (P&amp;gt; 0.05). The mean values of EF measurements on the postoperative 15th day were calculated as 39% in the experimental group and 40% in the control group. The increase in EF values was greater in the experimental group. This increase was found to be more significant in the experimental group (P = 0.008). There was a significant difference between the groups in preoperative and postoperative 1st day n-tproBNP values (P &amp;lt;0.05). A significant increase was observed in nt-proBNP values in the groups until the 7th postoperative day. (P &amp;lt;0.001). Although this increase was statistically significant in both groups, it was observed that the increase in the control group was higher. After the nt-proBNP measurements on the postoperative 7th day, there was no significant difference between the two groups (P&amp;gt; 0.05). Conclusion: As a result of this study, it was determined that levosimendan has a positive effect on myocardial protection and contractility in patients with low EF in CABG surgery. Keywords: Levosimendan; coroner by-pass surgery; left ventricle dyusfunction.

P2792Preoperative levosimendan improves survival in patients with low cardiac output syndrome undergoing cardiac surgery: a meta-analysis of randomized controlled trials

Abstract Background and purpose Previous studies and meta-analyses of perioperative levosimendan to improve the outcomes of patients with low cardiac output syndrome (LCOS) undergoing cardiac surgery have given controversial results and the optimal time of infusion of levosimendan remains uncertain. We thus aimed to elucidate the risk/benefit ratio of preoperative levosimendan in a meta-analysis of randomized controlled trials (RCTs). Methods Online databases were searched for RCTs comparing preoperative levosimendan to placebo in patients with LCOS undergoing cardiac surgery until February 2019. Data from retrieved studies were abstracted and analyzed in a comprehensive meta-analysis. Primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction, renal failure/replacement therapy, need for inotropic therapy, need for left ventricular assist devices, ventricular arrhythmia and arterial hypotension. Results As a result of the online database search, six eligible RCTs with 1,326 patients were included in the meta-analysis. Preoperative levosimendan showed a significant reduction in all-cause mortality (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.29–0.83; p&lt;0.01), renal failure/replacement therapy (OR 0.48, CI 0.29–0.80; p&lt;0.01) and need for inotropic therapy (OR 0.24, CI 0.06–0.95; p=0.04) compared to placebo. There were no significant differences in levosimendan vs. placebo concerning the rates of myocardial infarction (OR 0.61, p=0.38), need for left ventricular assist devices (OR 0.38, p=0.1), ventricular arrhythmia (OR 0.7, p=0.33), and arterial hypotension (OR 1.28, p=0.07). Conclusions Preoperative administration of levosimendan may improve survival in patients with low cardiac output syndrome undergoing cardiac surgery. It reduces need for inotropic medical support and renal failure/replace-ment therapy compared to placebo.

Optimization with levosimendan improves outcomes after left ventricular assist device implantation.

The aim of this study was to examine the haemodynamic effects of preoperative levosimendan infusion in patients who underwent left ventricular assist device implantation and evaluate the prognoses. Between May 2013 and October 2018, 85 adult patients who underwent left ventricular assist device implantation were included; 44 and 41 patients suffered from dilated cardiomyopathy and ischaemic cardiomyopathy, respectively. Patients were divided into 2 groups: group A (58 patients) included those who received levosimendan infusion in addition to other inotropes and group B (27 patients) included those who received inotropic agents other than levosimendan. Levosimendan infusion was started at a dose of 0.1 µg⋅kg-1⋅min-1 for a maximum of 48 h without a bolus. The primary outcome was early right ventricular failure (RVF). The secondary outcomes were in-hospital mortality, need for right ventricular assist device, late RVF and recovery of end-organ functions. The safety end points of levosimendan included hypotension, atrial fibrillation, ventricular tachycardia or fibrillation and resuscitated cardiac arrest. Patient characteristics were similar in both groups. No significant differences between groups were observed in the rates of early mortality, RVF, need for right ventricular assist device, cardiopulmonary bypass time and intensive care unit stay. Survival rates at 30 days, 1 year and 3 years and freedom from late RVF were similar between the groups. Administration of levosimendan was safe, generally well-tolerated and not interrupted because of side effects. Levosimendan therapy was well-tolerated in patients who received permanent left ventricular assist devices. Combined preoperative therapy with inotropes and levosimendan significantly improves end-organ functions.

Prophylactic preoperative levosimendan for off-pump coronary artery bypass grafting in patients with left ventricular dysfunction: Single-centered randomized prospective study.

Background:Off-pump coronary artery bypass surgery (OPCAB) is often complicated by hemodynamic instability, especially in patients with prior left ventricular (LV) dysfunction and appropriate choice of inotrope plays a vital role in perioperative management of these patients.Aim and Objective:To study hemodynamic effects and immediate outcome of prophylactic infusion of levosimendan in patients with the LV dysfunction undergoing OPCAB surgery and whether this strategy helps in successful conduct of OPCAB surgery.Materials and Methods:After Institutional Ethics Committee approval, 60 patients posted for elective OPCAB surgery were randomly divided into two groups (n = 30 each). Patients with the LV ejection fraction <30% were included. Study group was started on injection levosimendan (@ 0.1 μg/kg/min) in the previous night before surgery and continued for 24 h including intraoperative period. Hemodynamic monitoring included heart rate, invasive blood pressure, cardiac index (CI), pulmonary capillary wedge pressure (PCWP), pulse oximetry, and arterial blood gases with serum lactates at as T0 (baseline), T1 (15 min after obtuse marginal and/or PDA anastomoses), T2 (at end of surgery), T3 (6 h after surgery in Intensive Care Unit [ICU]), T4 (12 h after surgery), and T5 (24 h after surgery in ICU). Vasopressor was added to maintain mean arterial pressure >60 mmHg. Chi-square/Fisher's exact/Mid P exact test and Student's t-tests were applied for categorical and continuous data.Results:CI was greater and PCWP reduced significantly in Group L during intraoperative and early postoperative period. Serum lactate concentration was lower in patients pretreated with levosimendan. Incidence of postoperative atrial fibrillation (POAF) (36.6 vs. 6.6%; P = 0.01), low cardiac output syndrome (LCOS) (30% vs. 6%; P = 0.02), and acute kidney injury (23.3% vs. 6.7%; P = 0.04) was less in Group L. Three patients (10%) in control group required conversion to cardiopulmonary bypass (CPB) as compared to none in the study group. There was no difference regarding ICU or hospital stay and mortality in both groups.Conclusion:Preoperative levosimendan helps in successful conduct of OPCAB and reduces the incidence of LCOS, POAF, conversion to CPB, and requirement of intra-aortic balloon pump.

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.

Effect of Levosimendan on Low Cardiac Output Syndrome in Patients With Low Ejection Fraction Undergoing Coronary Artery Bypass Grafting With Cardiopulmonary Bypass

Low cardiac output syndrome after cardiac surgery is associated with high morbidity and mortality in patients with impaired left ventricular function. To assess the ability of preoperative levosimendan to prevent postoperative low cardiac output syndrome. Randomized, double-blind, placebo-controlled trial conducted in 13 French cardiac surgical centers. Patients with a left ventricular ejection fraction less than or equal to 40% and scheduled for isolated or combined coronary artery bypass grafting with cardiopulmonary bypass were enrolled from June 2013 until May 2015 and followed during 6 months (last follow-up, November 30, 2015). Patients were assigned to a 24-hour infusion of levosimendan 0.1 µg/kg/min (n = 167) or placebo (n = 168) initiated after anesthetic induction. Composite end point reflecting low cardiac output syndrome with need for a catecholamine infusion 48 hours after study drug initiation, need for a left ventricular mechanical assist device or failure to wean from it at 96 hours after study drug initiation when the device was inserted preoperatively, or need for renal replacement therapy at any time postoperatively. It was hypothesized that levosimendan would reduce the incidence of this composite end point by 15% in comparison with placebo. Among 336 randomized patients (mean age, 68 years; 16% women), 333 completed the trial. The primary end point occurred in 87 patients (52%) in the levosimendan group and 101 patients (61%) in the placebo group (absolute risk difference taking into account center effect, -7% [95% CI, -17% to 3%]; P = .15). Predefined subgroup analyses found no interaction with ejection fraction less than 30%, type of surgery, and preoperative use of β-blockers, intra-aortic balloon pump, or catecholamines. The prevalence of hypotension (57% vs 48%), atrial fibrillation (50% vs 40%), and other adverse events did not significantly differ between levosimendan and placebo. Among patients with low ejection fraction who were undergoing coronary artery bypass grafting with cardiopulmonary bypass, levosimendan compared with placebo did not result in a significant difference in the composite end point of prolonged catecholamine infusion, use of left ventricular mechanical assist device, or renal replacement therapy. These findings do not support the use of levosimendan for this indication. EudraCT Number: 2012-000232-25; clinicaltrials.gov Identifier: NCT02184819.

Rationale and design of the multicenter randomized trial investigating the effects of levosimendan pretreatment in patients with low ejection fraction (≤40 %) undergoing CABG with cardiopulmonary bypass (LICORN study).

BackgroundPatients with a left ventricular ejection fraction (LVEF) of less than 40 % are at high risk of developing postoperative low cardiac output syndrome (LCOS). Despite actual treatments (inotropic agents and/or mechanical assist devices), the mortality rate of such patients remains very high (13 to 24 %). The LICORN trial aims at assessing the efficacy of a preoperative infusion of levosimendan in reducing postoperative LCOS in patients with poor LVEF undergoing coronary artery bypass grafting (CABG).Methods/DesignLICORN study is a multicenter, randomized double-blind, placebo-controlled trial in parallel groups. 340 patients with LVEF ≤40 %, undergoing CABG will be recruited from 13 French hospitals. The study drug will be started after anaesthesia induction and infused over 24 h (0.1 μg/kg/min).The primary outcome (postoperative LCOS) is evaluated using a composite criterion composed of: 1) need for inotropic agents beyond 24 h following discontinuation of the study drug; 2) need for post-operative mechanical assist devices or failure to wean from these techniques when inserted pre-operatively; 3) need for renal replacement therapy. Secondary outcomes include: 1) mortality at Day 28 and Day 180; 2) each item of the composite criterion of the primary outcome; 3) the number of “ventilator-free” days and “out of intensive care unit” days at Day 28.DiscussionThe usefulness of levosimendan in the perioperative period has not yet been documented with a high level of evidence. The LICORN study is the first randomized controlled trial evaluating the clinical value of preoperative levosimendan in high risk cardiac surgical patients undergoing CABG.Trial registration numberNCT02184819 (ClinicalTrials.gov).

Cardiac, renal, and neurological benefits of preoperative levosimendan administration in patients with right ventricular dysfunction and pulmonary hypertension undergoing cardiac surgery: evaluation with two biomarkers neutrophil gelatinase-associated lipocalin and neuronal enolase.

PurposeTo evaluate if the preoperative administration of levosimendan in patients with right ventricular (RV) dysfunction, pulmonary hypertension, and high perioperative risk would improve cardiac function and would also have a protective effect on renal and neurological functions, assessed using two biomarkers neutrophil gelatinase-associated lipocalin (N-GAL) and neuronal enolase.MethodsThis is an observational study. Twenty-seven high-risk cardiac patients with RV dysfunction and pulmonary hypertension, scheduled for cardiac valve surgery, were prospectively followed after preoperative administration of levosimendan. Levosimendan was administered preoperatively on the day before surgery. All patients were considered high risk of cardiac and perioperative renal complications. Cardiac function was assessed by echocardiography, renal function by urinary N-GAL levels, and the acute kidney injury scale. Neuronal damage was assessed by neuron-specific enolase levels.ResultsAfter surgery, no significant variations were found in mean and SE levels of N-GAL (14.31 [28.34] ng/mL vs 13.41 [38.24] ng/mL), neuron-specific enolase (5.40 [0.41] ng/mL vs 4.32 [0.61] ng/mL), or mean ± SD creatinine (1.06±0.24 mg/dL vs 1.25±0.37 mg/dL at 48 hours). RV dilatation decreased from 4.23±0.7 mm to 3.45±0.6 mm and pulmonary artery pressure from 58±18 mmHg to 42±19 mmHg at 48 hours.ConclusionPreoperative administration of levosimendan has shown a protective role against cardiac, renal, and neurological damage in patients with a high risk of multiple organ dysfunctions undergoing cardiac surgery.

Assessing the effect of preoperative levosimendan on renal function in patients with right ventricular dysfunction.

The Acute Kidney Injury Network (AKIN) classification considers SCr values, urea and urine output in order to improve timely diagnose ARF and improve patient prognosis by early treatment. Preoperative levosimendan is a new way for cardiac and kidney protection, we try to evaluate this drug in fifteen patients comparing values of AKIN scale parameters pre and post cardiac surgery in patients with right ventricle dysfunction.