Administration Of Levosimendan Research Articles

Levosimendan in Patients with Low Cardiac Output Syndrome After Cardiac Surgery: A Substudy of the Multicenter Randomized CHEETAH Trial

ObjectiveTo test the hypothesis that levosimendan administration to patients with low-cardiac-output syndrome after cardiac surgery is associated with improved long-term (5-year follow-up) outcome. DesignSingle-center subanalysis of the multicenter randomized CHEETAH trial. SettingCardiac surgery department of a tertiary hospital. ParticipantsA total of 134 adult patients requiring hemodynamic support for cardiac index <2.5 L/min/m2 after cardiac surgery with cardiopulmonary bypass (CPB). InterventionsPatients were randomized (1:1 ratio) to receive levosimendan (continuous infusion with starting dose of 0.05 μg/kg/min) or placebo, in addition to standard inotropic care. Measurements and Main ResultsThe primary endpoint was long-term mortality (1-5 years) after randomization. Secondary outcomes were the following: hemodynamic parameters, need for inotropic support (VIS), acute kidney injury (AKI), need for renal-replacement therapy, duration of mechanical ventilation, ICU and hospital stay, 30-day mortality. No significant between-group difference in long-term mortality (5-year) was observed (hazard ratio, 1.59; 95% CI, 0.81 to 3.11; P = 0.17). There were no significant differences in secondary outcomes, except for the difference in the mean pulmonary artery pressure at 4-6 hours after randomization, which was lower in the levosimendan group (24 [21.8, 28] mmHg versus placebo 26 [22.2, 33] mmHg, p = 0.019). ConclusionsAmong patients requiring hemodynamic support after cardiac surgery with CPB, perioperative levosimendan infusion does not affect long-term survival (1-5 years) compared with placebo. Levosimendan also had no effect on major clinical outcomes such as AKI, ICU stay, hospital stay, 30-day mortality.

Intravenous Levosimendan versus Inhalational Milrinone in the Management of Pulmonary Hypertension during Adult Cardiac Surgery: A Randomized Clinical Trial.

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.

The Efficacy and Safety of Levosimendan in Patients with Advanced Heart Failure: An Updated Meta-Analysis of Randomized Controlled Trials.

Intermittent ambulatory levosimendan administration has been shown in several small randomized controlled trials to benefit patients with advanced heart failure, preventing heart failure rehospitalization and mortality. We aim to investigate the totality of high-quality evidence regarding the efficacy and safety of intermittent levosimendan in advanced heart failure patients. Up to September 2023, we systematically reviewed the randomized controlled trials indexed in PubMed, Embase Cochrane, SCOPUS, and Web of Science. We used mean difference (MD) to estimate the continuous outcomes, and risk ratio (RR) for the dichotomous outcomes with a 95% confidence interval (CI), using the random-effects model. Ultimately, a trial sequential analysis was employed to enhance the reliability of our findings and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework for certainty leveling. Fifteen randomized controlled trials with 1181 patients were included. Intermittent levosimendan was significantly associated with an improved left ventricular ejection fraction compared with placebo (MD 6.39 [95% CI 3.04-9.73], P = 0.002; I2 = 75, P = 0.0005), with cumulative z-score of change after ≤ 1 week passing the monitoring boundaries, favoring the levosimendan, but did not cross the required information size. Additionally, levosimendan reduced the all-cause mortality rate (RR 0.60 [95% CI 0.40-0.90], P = 0.01; I2 = 9, P = 0.36). However, we found no difference between levosimendan and placebo in all-cause rehospitalization rate (RR 0.75 [95% CI 0.46-1.22], P = 0.25; I2 = 70, P = 0.04), event-free survival rate (RR 0.97 [95% CI 0.72-1.30], P = 0.84; I2 = 63, P = 0.03), or any adverse event (RR 1 [95% CI 0.73-1.37], P = 1.00, I2 = 0%, P = 0.70). In patients with advanced heart failure, intermittent levosimendan significantly improved left ventricular ejection fraction, brain natriuretic peptide values, and all-cause mortality rate. Levosimendan use is not associated with a change in rehospitalization or event-free survival. PROSPERO identifier number (CRD42023487838).

EFFECTS OF LEVOSIMENDAN ON DIAPHRAGMATIC DYSFUNCTION IN PATIENTS WITH SEPSIS.

Objective: In this study, our aim was to examine the effects of levosimendan on diaphragmatic dysfunction in patients with sepsis, as well as assess its impact on respiratory muscle contractility and the outcome of weaning. Methods: This was a single-blind, randomized, controlled trial. Patients with diaphragmatic dysfunction and failure of spontaneous breathing trials (SBTs) were randomly and equally assigned to the experimental and control groups. The experimental group received levosimendan at a loading dose of 6 μg/kg for 10 min, followed by a continuous infusion at 0.2 μg/kg/min. The control group received an equivalent dose of a placebo. The preadministration and postadministration respiratory mechanics parameters of the patients were recorded. Evaluation of the effect of levosimendan on patients with sepsis-induced diaphragm dysfunction comprised arterial blood gas analysis as well as ultrasound measurements of diaphragm excursion (DE), diaphragm thickness (DT), diaphragm thickening fraction (TFdi), and diaphragm-rapid shallow breathing index (D-RSBI). Results: Forty-four patients were enrolled in the study. We found that postadministration of levosimendan, the patients' tidal volume (GCSMV) increased, whereas the D-RSBI decreased, and the partial pressure of carbon dioxide (PACO 2 ) decreased when compared to the preadministration levels. Additionally, following levosimendan administration, patients showed increased DE and pressure support (PS) when compared to before administration (1.14 ± 0.177 vs. 1.22 ± 0.170 cm and 0.248 ± 0.03 vs. 0.284 ± 0.06, respectively) and decreased D-RSBI (22.76 ± 6.14 vs. 20.06 ± 6.04, respectively), all of which were statistically significant ( P < 0.05). In contrast, in the control group of patients, there were no statistically significant differences in the postadministration levels of DE, TFdi, and D-RSBI as compared to the preadministration period ( P > 0.05). Furthermore, in terms of weaning outcomes, we did not find any statistically significant difference in the number of patients in the two groups who eventually underwent weaning ( P = 0.545). Conclusion: In this study, we found that levosimendan enhanced diaphragm contractile function. However, further investigations are required to explore its effect on weaning outcomes in patients undergoing mechanical ventilation.

Impact of early levosimendan administration in patients with decompensated chronic heart failure on oxidative stress parameters — the rationale and study design

Impact of early levosimendan administration in patients with decompensated chronic heart failure on oxidative stress parameters — the rationale and study design

Cerebral Hemodynamics and Levosimendan Use in Patients with Cerebral Vasospasm and Subarachnoid Hemorrhage: An Observational Perfusion CT-Based Imaging Study.

Delayed cerebral ischemia associated with cerebral vasospasm (CVS) in aneurysmal subarachnoid hemorrhage significantly affects patient prognosis. Levosimendan has emerged as a potential treatment, but clinical data are lacking. The aim of this study is to decipher levosimendan's effect on cerebral hemodynamics by automated quantitative measurements of brain computed tomography perfusion (CTP). We conducted a retrospective analysis of a database of a neurosurgical intensive care unit. All patients admitted from January 2018 to July 2022 for aneurysmal subarachnoid hemorrhage and treated with levosimendan for CVS who did not respond to other therapies were included. Quantitative measurements of time to maximum (Tmax), relative cerebral blood volume (rCBV), and relative cerebral blood flow (rCBF) were automatically compared with coregistered CTP before and after levosimendan administration in oligemic regions. Of 21 patients included, CTP analysis could be performed in 16. Levosimendan improved Tmax from 14.4s (interquartile range [IQR] 9.1-21) before treatment to 7.1s (IQR 5.5-8.1) after treatment (p < 0.001). rCBV (94% [IQR 79-103] before treatment and 89% [IQR 72-103] after treatment, p = 0.63) and rCBF (85% [IQR 77-90] before treatment and 87% [IQR 73-98] after treatment, p = 0.98) remained stable. The subgroup of six patients who did not develop cerebral infarction attributed to delayed cerebral ischemia showed an approximately 10% increase (rCBV 85% [IQR 79-99] before treatment vs. 95% [IQR 88-112] after treatment, p = 0.21; rCBF 81% [IQR 76-87] before treatment vs. 89% [IQR 84-99] after treatment, p = 0.4). In refractory CVS, levosimendan use was associated with a significant reduction in Tmax in oligemic regions. However, this value remained at an abnormal level, indicating the presence of a persistent CVS. Further analysis raised the hypothesis that levosimendan causes cerebral vasodilation, but other studies are needed because our design does not allow us to quantify the effect of levosimendan from that of the natural evolution of CVS.

The Year in Hungarian Cardiology 2023: Heart failure

The year 2023 proved to be a productive period with many remarkable scientific papers published from Hungary in the field of heart failure (HF). Our aim with this brief review is to highlight the results of the most prominent landmark randomized clinical trials as well as other relevant influential publications with significant contribution from Hungarian authors. Several clinical trials were published in 2023 with the primary focus on optimizing medical management. Papers described the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in HF in association with renal dysfunction, COVID-19 infection, and evaluating their economic impact. A comprehensive manuscript analysed the geographic differences in patient characteristics, treatments, and outcomes in the PARADISE-MI trial population. With regards to glucagon-like peptide-1 (GLP-1) receptor agonists, the STEP-HFpEF landmark clinical trial reported a favourable effect for semaglutide in patients with HFpEF and obesity. The intermittent administration of levosimendan did not improve post-hospitalization clinical stability in a population with advanced HF. In the field of cardiac resynchronization therapy (CRT), results of the BUDAPEST-CRT Upgrade trial was published in the European Heart Journal. This was the first prospective, randomized controlled trial to demonstrate that CRT upgrade in patients with intermittent or permanent RV pacing and HFrEF reduces morbidity and mortality. Several papers focused on the greater field of cardiomyopathies, including medical therapies, diuretic use, and cardiotoxicity. Finally, it is important to mention that an issue of Cardiologia Hungarica was published that was entirely dedicated to HF.

Levosimendan: efficacy and safety in pediatric heart failure treatment.

The objective of this study was to assess the effectiveness and safety of levosimendan as an alternative treatment for pediatric patients with decompensated heart failure unresponsive to conventional inotropes and to emphasize its role in enhancing cardiovascular stability. A total of 15 pediatric patients with decompensated heart failure, stemming from acute fulminant myocarditis (53.3%) and post-congenital heart disease surgery complications (46.7%), received levosimendan. The evaluation focused on adverse effects, respiratory support requirements, and concurrent inotropic medication use during levosimendan treatment. Key cardiovascular parameters were assessed at 0, 6, 12, and 24 h post-levosimendan infusion. Levosimendan administration significantly improved key cardiovascular metrics. Left ventricular ejection fraction increased notably from 45±14.8% to 58±15.6% at 24 h (p<0.001). Systolic and diastolic blood pressures rose significantly, with systolic increasing from 79 (68-90) to 98 (89-109) mmHg and diastolic from 47 (40-57) to 66 (54-76) mmHg by 24 h (p<0.001). Heart rate decreased from 162 (111-175) to 132 (99-148) bpm (p=0.02), and lactate levels significantly decreased from 4.15 (2.3-6.5) to 1.85 (0.8-2.6) mmol/L within 6 h (p<0.001). Levosimendan demonstrates its significance in managing pediatric heart failure, indicating its safety and potential to enhance cardiac outcomes by reducing reliance on traditional inotropes.

Determinants of exercise performance in heart failure patients with extremely reduced cardiac output and left ventricular assist device.

The evaluation of exercise capacity and cardiac output (QC) is fundamental in the management of patients with advanced heart failure (AdHF). QC and peak oxygen uptake (VO2) have a pivotal role in the prognostic stratification and in the definition of therapeutic interventions, including medical therapies and devices, but also specific treatments such as heart transplantation and left ventricular assist device (LVAD) implantation. Due to the intertwined relationship between exercise capacity and daily activities, exercise intolerance dramatically has impact on the quality of life of patients. It is a multifactorial process that includes alterations in central and peripheral haemodynamic regulation, anaemia and iron deficiency, pulmonary congestion, pulmonary hypertension, and peripheral O2 extraction. This paper aims to review the pathophysiological background of exercise limitations in HF patients and to examine the complex physiology of exercise in LVAD recipients, analysing the interactions between the cardiopulmonary system, the musculoskeletal system, the autonomic nervous system, and the pump. We performed a literature review to highlight the current knowledge on this topic and possible interventions that can be implemented to increase exercise capacity in AdHF patients-including administration of levosimendan, rehabilitation, and the intriguing field of LVAD speed changes. The present paper confirms the role of CPET in the follow-up of this peculiar population and the impact of exercise capacity on the quality of life of AdHF patients.

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.

Perioperative Application of Levosimendan Optimizes Postoperative Renal Function and Organ Perfusion in Patients with Severe Heart Failure.

Background: Renal dysfunction and impaired organ perfusion are common concerns following cardiac surgery. Levosimendan, a calcium sensitizer inotropic drug, is investigated in this study for its potential to improve postoperative renal function and organ perfusion in patients with low preoperative ejection fraction and severe myocardial dysfunction after cardiac surgery. Methods: A retrospective analysis was conducted on 314 patients with preoperative heart failure who underwent cardiac surgery. Among them, 184 patients received perioperative adjunctive therapy with levosimendan, while 130 patients with similar characteristics received conventional treatment. Results: The perioperative administration of levosimendan resulted in a significantly lower need for renal replacement therapy (p < 0.001) and improvements in the serum creatinine levels, glomerular filtration rate, and creatinine clearance. Similarly, the C-reactive protein levels, blood pH, and lactic acid levels showed comparable improvements. Conclusions: The use of levosimendan was associated with a significant enhancement in postoperative renal function and a reduction in the need for renal replacement therapy. Furthermore, it resulted in a decrease in the extent of organ malperfusion. Postoperative inflammatory reactions and metabolic balance also exhibited improvements.

Prophylactic use of levosimendan in preoperative setting for surgical repair of congenital heart disease in children.

Low cardiac output syndrome (LCOS) is a significant cause of morbidity and the leading cause of mortality after pediatric cardiac surgery. Levosimendan has been shown safe and effective in pediatrics to treat LCOS. We aimed to review our local strategy with preoperative prophylactic Levosimendan infusion to minimize LCOS after heart surgery in identified high-risk patients. Retrospective monocentric study. As there is no reliable cardiac output measurement in children, we recorded hemodynamic parameters as surrogates of cardiac output after extracorporeal circulation through an electronic patient survey system at different time points. Seventy-two children received Levosimendan before surgery between 2010 and 2019. As expected, most patients were newborns and infants with prolonged open-heart surgeries. Median cardiopulmonary bypass time was 182 [137-234] min, and aortic clamping time was 95 [64-126] min. The postoperative hemodynamic parameters, vasoactive-inotropic score, and urine output remained stable throughout the first 48 h. Only a tiny portion of the patients had combined surrogate markers of LCOS with a maximal median arterial lactate of 2.6 [1.9-3.5] mmol/L during the first six postoperative hours, which then progressively normalized. The median arterio-venous difference in oxygen saturation was 31 [23-38] % between 12 and 18 h post-surgery and gradually decreased. The median venous-to-arterial CO2 difference was the highest at 10 [7-12] mmHg between 12 and 18 h post-surgery. Nine patients (13%) required extracorporeal membrane oxygenation. No patient required dialysis or hemofiltration. Mortality was 0%. Before congenital heart surgery, preoperative prophylactic administration of Levosimendan seems effective and safe for decreasing occurrence and duration of LCOS in high-risk children.

Early administration of LEvosimendan in Patients witH decompensAted chroNic hearT failure (ELEPHANT) study. Rationale and protocol of the study

Early administration of LEvosimendan in Patients witH decompensAted chroNic hearT failure (ELEPHANT) study. Rationale and protocol of the study

Monitoring of Levosimendan Administration in Patients with Pulmonary Hypertension Undergoing Cardiac Surgery and Effect of Two Different Dosing Schemes on Hemodynamic and Echocardiographic Parameters.

The perioperative management of patients with pulmonary hypertension (PH) undergoing cardiac surgery represents one of the most challenging clinical scenarios. This fact mainly depends on the relationship existing between PH and right ventricular failure (RVF). Levosimendan (LS) is an inodilator that might be an effective agent in the treatment of PH and RVF. The aim of this study was to examine the impact of the duration of cardiopulmonary bypass (CPB) on the therapeutic drug monitoring of LS and to evaluate the effect of preemptive administration of LS on perioperative hemodynamic and echocardiographic parameters in cardiac surgical patients with preexisting PH. In this study, LS was administered in adult patients undergoing cardiac surgery before CPB in order to prevent exacerbation of preexisting PH and subsequent right ventricular dysfunction. Thirty cardiac surgical patients with preoperatively confirmed PH were randomized to receive either 6 μg/kg or 12 μg/kg of LS after the induction of anesthesia. The plasma concentration of LS was measured after CPB. In this study, a low sample volume was used combined with a simple sample preparation protocol. The plasma sample was extracted by protein precipitation and evaporated; then, the analyte was reconstituted and detected using specific and sensitive bioanalytical liquid chromatography with mass spectrometry (LC-MS/MS) methodology. The clinical, hemodynamic, and echocardiographic parameters were registered and evaluated before and after the administration of the drug. A fast bioanalytical LC-MS/MS methodology (a run time of 5.5 min) was developed for the simultaneous determination of LS and OR-1896, its main metabolite in human plasma. The LC-MS/MS method was linear over a range of 0.1-50 ng/mL for LS and 1-50 ng/mL for its metabolite OR-1896. Measured plasma concentrations of LS were inversely related to the duration of CPB. LS administration before CPB during cardiac surgery was effective in reducing pulmonary artery pressure and improving hemodynamic parameters after CPB, with a more pronounced and durable effect of the drug at the dose of 12 μg/kg. Additionally, administration of LS at a dose of 12 μg/kg in cardiac surgical patients with PH before CPB improved right ventricular function. LS administration decreases pulmonary artery pressure and may improve right ventricular function in patients with PH undergoing cardiac surgery.

Treatment with levosimendan in an experimental model of early ventilator-induced diaphragmatic dysfunction.

Mechanical ventilation (MV) is a life-saving approach in critically ill patients. However, it may affect the diaphragmatic structure and function, beyond the lungs. Levosimendan is a calcium sensitizer widely used in clinics to improve cardiac contractility in acute heart failure patients. In vitro studies have demonstrated that levosimendan increased force-generating capacity of the diaphragm in chronic obstructive pulmonary disease patients. Thus the aim of this study was to evaluate the effects of levosimendan administration in an animal model of ventilator-induced diaphragmatic dysfunction (VIDD) on muscle contraction and diaphragm muscle cell viability. Sprague-Dawley rats underwent prolonged MV (5 hours). VIDD+Levo group received a starting bolus of levosimendan immediately after intratracheal intubation and then an intravenous infusion of levosimendan throughout the study. Diaphragms were collected for ex vivo contractility measurement (with electric stimulation), histological analysis and Western blot analysis. Healthy rats were used as the control. Levosimendan treatment maintained an adequate mean arterial pressure during the entire experimental protocol, preserved levels of autophagy-related proteins (LC3BI and LC3BII) and the muscular cell diameter demonstrated by histological analysis. Levosimendan did not affect the diaphragmatic contraction or the levels of proteins involved in the protein degradation (atrogin). Our data suggest that levosimendan preserves muscular cell structure (cross-sectional area) and muscle autophagy after 5 hours of MV in a rat model of VIDD. However, levosimendan did not improve diaphragm contractile efficiency.

Ultrasound assessment of diaphragmatic dysfunction and its improvement with levosimendan in patients with chronic obstructive pulmonary disease

Diaphragmatic Dysfunction (DD) is a clinical condition in which the diaphragm becomes weak or paralyzed, because of muscle strength reduction. It can be due to muscular issues or loss of proper innervation, but, also, to pulmonary hyperinflation or air trapping, such as in Chronic Obstructive Pulmonary Disease (COPD). DD impacts on COPD induced dyspnea, determining its progressive worsening, but levosimendan, an inodilator better known as Ca2+ sensitizer, may limit this phenomenon and diaphragmatic ultrasound assessment can be useful in monitoring its effect. Here, we show the case of a 77-year-old woman admitted to the Emergency department for acute exacerbation of chronic dyspnea in COPD, related to right ventricular failure and DD, which did not respond to medical therapy and non-invasive mechanical ventilation but did experience a favorable outcome after intravenous administration of levosimendan.

Levosimendan Reverses Cardiac Malfunction and Cardiomyocyte Ferroptosis During Heart Failure with Preserved Ejection Fraction via Connexin 43 Signaling Activation.

In recent decades, the occurrence of heart failure with preserved ejection fraction (HFpEF) has outweighed that of heart failure with reduced ejection fraction by degrees, but few drugs have been demonstrated to improve long-term clinical outcomes in patients with HFpEF. Levosimendan, a calcium-sensitizing cardiotonic agent, improves decompensated heart failure clinically. However, the anti-HFpEF activities of levosimendan and underlying molecular mechanisms are unclear. In this study, a double-hit HFpEF C57BL/6N mouse model was established, and levosimendan (3 mg/kg/week) was administered to HFpEF mice aged 13 to 17 weeks. Different biological experimental techniques were used to verify the protective effects of levosimendan against HFpEF. After four weeks of drug treatment, left ventricular diastolic dysfunction, cardiac hypertrophy, pulmonary congestion, and exercise exhaustion were significantly alleviated. Junction proteins in the endothelial barrier and between cardiomyocytes were also improved by levosimendan. Among the gap junction channel proteins, connexin 43, which was especially highly expressed in cardiomyocytes, mediated mitochondrial protection. Furthermore, levosimendan reversed mitochondrial malfunction in HFpEF mice, as evidenced by increased mitofilin and decreased ROS, superoxide anion, NOX4, and cytochrome C levels. Interestingly, after levosimendan administration, myocardial tissue from HFpEF mice showed restricted ferroptosis, indicated by an increased GSH/GSSG ratio; upregulated GPX4, xCT, and FSP-1 expression; and reduced intracellular ferrous ion, MDA, and 4-HNE levels. Regular long-term levosimendan administration can benefit cardiac function in a mouse model of HFpEF with metabolic syndromes (namely, obesity and hypertension) by activating connexin 43-mediated mitochondrial protection and sequential ferroptosis inhibition in cardiomyocytes.

Levosimendan in patients undergoing extracorporeal membrane oxygenation after cardiac surgery: an emulated target trial using observational data

BackgroundRetrospective cohorts have suggested that levosimendan may facilitate the weaning of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). We therefore studied this clinical question by emulating a randomized trial with observational data.MethodsAll patients with refractory postcardiotomy cardiogenic shock and assisted with VA-ECMO, admitted to a surgical intensive care unit at La Pitié-Salpêtrière Hospital between 2016 and 2019, were eligible. To avoid immortal-time bias, we emulated a target trial sequentially comparing levosimendan administration versus no levosimendan administration in patients treated with VA-ECMO. The primary outcome was time to successful ECMO weaning. The secondary outcomes were 30-day and 1-year mortality. We performed a multivariable analysis to adjust for confounding at baseline.ResultsTwo hundred and thirty-nine patients were included in the study allowing building a nested trials cohort of 1434 copies of patients. No association of levosimendan treatment and VA-ECMO weaning was found (HR = 0.91, [0.57; 1.45], p = 0.659 in multivariable analysis), or 30-day mortality (OR = 1.03, [0.52; 2.03], p = 0.940) and 1-year mortality (OR = 1.00, [0.53; 1.89], p = 0.999).ConclusionsUsing the emulated target trial framework, this study did not find any association of levosimendan treatment and ECMO weaning success after postcardiotomy cardiogenic shock. However, the population of interest remains heterogeneous and subgroups might benefit from levosimendan.

Intermittent inotropic support with levosimendan in advanced heart failure as destination therapy: The LEVO-D registry.

Patients with advanced heart failure (AHF) who are not candidates to advanced therapies have poor prognosis. Some trials have shown that intermittent levosimendan can reduce HF hospitalizations in AHF in the short term. In this real-life registry, we describe the patterns of use, safety and factors related to the response to intermittent levosimendan infusions in AHF patients not candidates to advanced therapies. Multicentre retrospective study of patients diagnosed with advanced heart failure, not HT or LVAD candidates. Patients needed to be on the optimal medical therapy according to their treating physician. Patients with de novo heart failure or who underwent any procedure that could improve prognosis were not included in the registry. Four hundred three patients were included; 77.9% needed at least one admission the year before levosimendan was first administered because of heart failure. Death rate at 1year was 26.8% and median survival was 24.7 [95% CI: 20.4-26.9] months, and 43.7% of patients fulfilled the criteria for being considered a responder lo levosimendan (no death, heart failure admission or unplanned HF visit at 1year after first levosimendan administration). Compared with the year before there was a significant reduction in HF admissions (38.7% vs. 77.9%; P<0.0001), unplanned HF visits (22.7% vs. 43.7%; P<0.0001) or the combined event including deaths (56.3% vs. 81.4%; P<0.0001) during the year after. We created a score that helps predicting the responder status at 1year after levosimendan, resulting in a score summatory of five variables: TEER (+2), treatment with beta-blockers (+1.5), Haemoglobin >12g/dL (+1.5), amiodarone use (-1.5) HF visit 1year before levosimendan (-1.5) and heart rate >70b.p.m. (-2). Patients with a score less than -1 had a very low probability of response (21.5% free of death or HF event at 1year) meanwhile those with a score over 1.5 had the better chance of response (68.4% free of death or HF event at 1year). LEVO-D score performed well in the ROC analysis. In this large real-life series of AHF patients treated with levosimendan as destination therapy, we show a significant decrease of heart failure events during the year after the first administration. The simple LEVO-D Score could be of help when deciding about futile therapy in this population.