Levosimendan Administration In Patients Research Articles

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

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.

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.

Predictors of diuresis response to levosimendan administration in patients with acute heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Levosimendan, a calcium sensitizer and potassium channel-opener, is appreciated for its effects on systemic and pulmonary hemodynamic and for the relief of symptoms in acute heart failure (AHF). Positive effects of levosimendan on renal function have been also described. The aim of the present analysis was to assess the predictors of the diuresis response to levosimendan administration in high risk acute heart failure patients. Methods We analysed 34 consecutive patients admitted with high risk AHF to one centre and treated in intensive cardiac care unit. Levosimendan was administered on top of other treatment as a 24-hour infusion of 12.5 mg total dose except for 7 patients (1 patient - terminated earlier due to intolerance, 5 patients – 48h infusion, 1 patient - 72h infusion). Decision of levosimendan administration was based on clinical status and left to attending physician. Diuresis and diuretic dosage before (24 hours) and after levosimendan infusion (48 hours) were taken into account for the present study. Results The AHF was primary of cardiac origin in all patients. In 6 (18%) it was due to recent acute myocardial infarction. In-hospital mortality was 24%. Median length of hospitalization was 26 days (range 6 to 107 days). Mean age of the patients was 66 ± 12 years, 25 (74%) were men. Mean INTERMACS score was 3.4 ± 1.4 with wet-cold clinical profile present in 13 (38%) of patients. Mean left ventricle ejection fraction (LVEF) was 27 ± 13%, mean NTproBNP was 17176 ± 12464 pg/ml, and mean eGFR 48 ± 22 ml/min/1.73m2. At the time of levosimendan administration patients had background treatment with catecholamines (mean number per patient 1.4 ± 1.1, range 0-3) and with diuretics (mean dosage of furosemide 167 ± 102 mg/24h, range 20-500). 48-hours diuresis after levosimendan administration varies from 950 to 11300 ml (mean 4307 ± 2418 ml). It was significantly lower in patients with cold-wet profile (2646 ± 1335 vs. 5335 ± 2381 ml in other clinical profiles, p = 0.0002). Additionally, 48-hour diuresis was negatively correlated with age (r=-0.46, p = 0.0062) and the number of background catecholamines (r=-0.47, p = 0.0047), and not significantly with the furosemide dosage (r=-0.28, p = 0.10) – figure. No association with diuresis was found for LVEF, NTproBNP, and eGFR. In multiple regression analysis (model R2 = 0.63, p = 0.0085) both older age (p = 0.026) and cold-wet profile (p = 0.0074) were significant predictors of poor diuresis after levosimendan administration. Conclusion Older age and cold-wet profile were significant predictors of poor diuresis response to levosimendan administration in high risk acute heart failure patients. Although concomitant catecholamines and high diuretic dosage use cloud also be markers of non-responders to levosimendan in terms of diuresis. Abstract Figure

Seguridad y eficacia de la utilización de levosimendán sin dosis de carga en una unidad de falla cardiaca especializada

Objetivo: evaluar la eficacia y seguridad del uso de levosimendán en pacientes con falla cardiaca severa crónica descompensada con signos evidentes de bajo gasto, e indicación de utilización de inotrópico, utilizando el medicamento sin dosis de carga, con una mayor concentración y en infusión continua hasta completar la dosis de 12.5 miligramos en total. 
 Metodología: estudio retrospectivo, descriptivo. Se evaluaron los cambios en la presión arterial media, desarrollo de arritmias o muerte durante la infusión y clase funcional I (NYHA) antes y dos meses después de recibir el medicamento. 
 Resultados: se observó cambio en la clase funcional durante el seguimiento a dos meses. La infusión del medicamento fue bien tolerada y no se observaron efectos adversos significativos durante la hospitalización. La presión arterial media antes de la infusión fue 71± 21.6 vs 75 ± 20.9 mmHg 24 horas después, y 71 ± 21.6 vs 71.6 ± 21.4 mmHg 48 horas después. Ningún paciente presentó arritmias inducidas por el inotrópico y se presentó solamente una muerte (4.7%) por sepsis. 
 Conclusiones: el presente reporte es una experiencia inicial que sugiere que la administración de la infusión de levosimendan sin bolo inicial disminuye la incidencia de hipotensión y arritmias en los pacientes con falla cardiaca y puede emplearse en un servicio de hospitalización diferente a la Unidad de Cuidado Intensivo con seguridad 

Levosimendan for patients with heart failure undergoing major oncological surgery: A randomised blinded pilot study.

Background and Aims:Cardiovascular diseases and cancer are among the leading causes of mortality worldwide. The aim of this study is to evaluate the efficacy and safety of preoperative administration of levosimendan in patients with chronic heart failure (CHF) scheduled for major abdominal oncologic surgery.Methods:This study included 60 patients with abdominal malignancy, ejection fraction (EF) <35% and CHF scheduled for surgery under isoflurane-fentanyl anaesthesia and were managed in the surgical intensive care unit perioperatively. They were randomised to receive levosimendan infusion (n = 30) at a dose of 0.1 μg/kg/min or placebo (n = 30) for 24 hours before surgery.Results:The risk of hypotension (RR: 0.40, 95% CI: 0.19-0.83) or decompensated heart failure (RR: 0.31, 95% CI: 0.12-0.76) was significantly lower in the levosimendan group. The ejection fraction, cardiac index and stroke volume index were significantly higher in the levosimendan group after surgery (P < 0.001). Duration of postoperative ventilation and hospital stay were significantly shorter in the levosimendan group (P < 0.001) while the frequency of dysrhythmia, deterioration of renal function and sepsis was comparable.Conclusion:In patients with low EF <35% and CHF, administration of levosimendan for 24 hours before major abdominal oncologic surgeries may reduce the risk of hypotension and decompensated heart failure and may improve cardiac function.

Efficacy of levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery: a Meta-analysis

Objective To explore the effect of levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery. Methods Databases including PubMed, EMBASE and Cochrane database were systematically queried to identify randomized controlled trial (RCT) research regarding levosimendan treatment for patients with left ventricular dysfunction undergoing cardiac surgery published from inception to July 2017. Meta-analysis was performed using RevMan 5.3. Relevant outcomes included early mortality, acute kidney injury, need for renal replacement therapy, hypotension and arrhythmia. Results Nine literatures with a total of 1 464 participants were included, with 736 patients in levosimendan group and 728 patients in control group respectively. Compared with control drugs, levosimendan reduced early mortality [odds ratio (OR)=0.5, 95% confidence interval (CI): 0.31-0.81, P=0.004], the incidence of acute kidney injury (OR=0.5, 95%CI: 0.32-0.78, P=0.003) and renal replacement therapy (OR=0.54, 95%CI: 0.32-0.90, P=0.03) in patients undergoing cardiac surgery, but did not affect the incidence of hypotension and arrhythmias (OR=1.29, 95%CI: 0.83-1.99, P=0.26. OR=0.65, 95%CI: 0.32-1.35, P=0.25). Conclusions Perioperative administration of levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery may improve patient′s prognosis and reduce complications. The scope of this study is small, so more high quality RCT research are needed to provide more conclusive evidence regarding the benefit of this drug. Key words: Levosimendan; Cardiac insufficiency; Cardiac surgery; Mortality; Acute kidney injury

Efficacy and safety of intermittent intravenous outpatient administration of levosimendan in patients with advanced heart failure: the LION-HEART multicentre randomised trial.

The LION-HEART study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial evaluating the efficacy and safety of intravenous administration of intermittent doses of levosimendan in outpatients with advanced chronic heart failure. Sixty-nine patients from 12 centres were randomly assigned at a 2:1 ratio to levosimendan or placebo groups, receiving treatment by a 6-hour intravenous infusion (0.2 μg/kg/min without bolus) every 2 weeks for 12 weeks. The primary endpoint was the effect on serum concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) throughout the treatment period in comparison with placebo. Secondary endpoints included evaluation of safety, clinical events and health-related quality of life (HRQoL). The area under the curve (AUC, pg.day/mL) of the levels of NT-proBNP over time for patients who received levosimendan was significantly lower than for the placebo group (344 × 103 [95% Confidence Interval (CI) 283 × 103 -404 × 103 ] vs. 535 × 103 [443 × 103 -626 × 103 ], p = 0.003). In comparison with the placebo group, the patients on levosimendan experienced a reduction in the rate of heart failure hospitalisation (hazard ratio 0.25; 95% CI 0.11-0.56; P = 0.001). Patients on levosimendan were less likely to experience a clinically significant decline in HRQoL over time (P = 0.022). Adverse event rates were similar in the two treatment groups. In this small pilot study, intermittent administration of levosimendan to ambulatory patients with advanced systolic heart failure reduced plasma concentrations of NT-proBNP, worsening of HRQoL and hospitalisation for heart failure. The efficacy and safety of this intervention should be confirmed in larger trials.

Rehospitalization after intermittent levosimendan treatment in advanced heart failure patients: a meta-analysis of randomized trials.

AimsIntermittent levosimendan administration has been suggested to improve survival in patients with advanced heart failure (AdHF). Quality of life is a key issue for AdHF patients and is negatively affected by frequent hospitalizations.Methods and resultsCENTRAL, Google Scholar, MEDLINE/PubMed, Scopus, and the Cochrane Central Register of clinical trials (updated 15/1/2017) were searched for randomized controlled trials investigating the effect of intermittent levosimendan administration in patients with AdHF. The primary outcome was the number of patients requiring rehospitalization 3 months after the end of treatment. A total of 319 patients from six trials were included. Overall pooled analysis showed that the use of levosimendan was associated with a significant reduction in the number of rehospitalizations at 3 months: 33/207 (16%) vs. 39/113 (35%), risk ratio 0.40, 95% confidence interval 0.27–0.59, P < 0.001, I 2 = 0%. This result was confirmed by sensitivity analyses.ConclusionsWithin the limitations of this meta‐analysis including also studies in which endpoints were not independently adjudicated and not clearly specified, repetitive or intermittent administration of levosimendan for patients with AdHF was associated with a reduction in the rehospitalization rate at 3 months. Large, high‐quality randomized controlled trials are needed to confirm this finding.

Intracoronary administration of levosimendan in patients with acute coronary syndromes and decreased left ventricular ejection fraction undergoing coronary artery bypass graft surgery

In cardiac surgery patients, intracoronary (IC) administration of levosimendan can provide optimal drug spread, enabling ef-fective manifestation of favorable drug effects and avoiding potentially harm-ful systemic hypotension. This could be beneficial in acute coronary syndromes (ACS) with decreased left ventricular ejec-tion fraction (LVEF). We present ten cases of IC administration of levosimendan in ACS manifested as ST segment elevation myocardial infarction, non-ST segment el-evation myocardial infarction or unstable angina pectoris. All patients underwent coronary artery bypass graft (CABG) sur-gery, performed as an “off-pump” or “on-pump”/“off-clamp” procedure (latter one with the use of cardiopulmonary bypass on the beating heart). Levosimendan was ad-ministered as an IC bolus (125-250 μg) in each coronary artery graft (2-3 grafts). In-travenous (IV) levosimendan infusion con-tinued (0.1-0.2 μg•kg-1•min-1) after graft placements (24-48 h), with IV infusion of norepinephrine (0.1 mg•ml-1), if needed. Cardiac function was assessed using LVEF (%) (Teicholz), thermodilution cardiac in-dex (CI) (ml•m-2), and systemic vascular resistance (SVR) (dynes•sec•cm-5). Nonparametric Wilcoxon signed-ranks test [presented as median (MED) with interquartile range (IQR)] indicated a sig-nificant difference between preoperative vs. immediate postoperative CI, SVR, and LVEF in all cases [2.2 (1.9-2.5) vs. 3.1 (2.9-3.4) ml•m-2, 1173.0 (1062.7-1278.2) vs. 882.5 (763.5-993.0) dynes•sec•cm-5, 44.5 (36.0-46.7) vs. 53.5 (45.7-59.2) %, respec-tively] (P=0.005), i.e. IC administration of levosimendan was associated with prompt improvement of intraoperative hemody-namics and cardiac contractility. IC ad-ministration of levosimendan may be a promising alternative method for improv-ing decreased cardiac function in acute cardiac ischemia, besides necessary surgi-cal revascularization.

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.

A comparison of two approaches for intraoperative levosimendan administration in cardiac surgical patients with severe left ventricle dysfunction

It is proved that levosimendan administration improves overall outcome and reduces mortality in high risk cardiac patients. However up to now there is no optimal scheme of its use in intraoperative settings. To compare two approaches of levosimendan administration in patients with left ventricle ejectionfraction less than 35% who underwent cardiac surgery. After approval by the local ethics Committee, 40 patients older than 18 years with severe preoperative left ventricular dysfunction (left ventricle ejection fraction less than 35%), who were planned for cardiac surgery operation with cardiopulmonary bypass and cardioplegia were randomly assigned to two groups of 20 patients each. In group I (n=20) infusion of levosimendan started intraoperatively after induction of anesthesia, a loading dose of 6 mg/kg with subsequent injection of a dose of 0.1 μg/kg/minfor 24 hours. In group 2 (n=20) bolus of levosimendan 24 μg/kg was injected 15 min before aortic clamping. Anesthesia and methods of cardiopulmonary bypass in the groups did not differ Results. We got thefavorable clinical results in a group of 'full" levosimendan dose (12.5 mg as a daily infusion with an, initial bolus of 6 mg/kg just after the induction of anesthesia) in terms ofreduction of the total dose ofsympathomimetics andpostoperative troponin T level in comparison with the group where levosimendan was administered as a single bolus. (24 mg/kg) 15 minutes prior to aortic clamping. Based on these data it can be assumed that the use of prolonged infusion of levosimendan in a dosage of 12.5 mg is preferable to a single bolus 24 μg/kg.

Levosimendan for Prevention of Acute Kidney Injury After Cardiac Surgery: A Meta-analysis of Randomized Controlled Trials

Levosimendan has been shown to confer direct renoprotection in renal endotoxemic and ischemia-reperfusion injury and could increase renal blood flow in patients with low-cardiac-output heart failure. Results from clinical trials of levosimendan on acute kidney injury (AKI) following cardiac surgery are controversial. A random-effect meta-analysis was conducted based on evidence from PubMed, EMBASE, and Cochrane Library. Adult patients undergoing cardiac surgery. Randomized controlled trials comparing the renal effect of levosimendan versus placebo or other inotropic drugs during cardiac surgery. Perioperative levosimendan continuous infusion at a rate of 0.1 to 0.2μg/kg/min following a loading dose (6-24μg/kg) for 24 hours or only 1 loading dose (24μg/kg) within 1 hour. AKI, need for renal replacement therapy, mechanical ventilation duration, intensive care unit stay during hospitalization, and postoperative mortality (in-hospital or within 30 days). 13 trials with a total of 1,345 study patients were selected. Compared with controls, levosimendan reduced the incidence of postoperative AKI (40/460 vs 78/499; OR, 0.51; 95% CI, 0.34-0.76; P=0.001; I(2)=0.0%), renal replacement therapy (22/492 vs 49/491; OR, 0.43; 95% CI, 0.25-0.76; P=0.002; I(2)=0.0%), postoperative mortality (35/658 vs 94/657; OR, 0.41; 95% CI, 0.27-0.62; P<0.001; I(2)=0.0%), mechanical ventilation duration (in days; n=235; weighted mean difference, -0.34; 95% CI, -0.58 to -0.09; P=0.007], and intensive care unit stay (in days; n=500; weighted mean difference, -2.2; 95% CI, -4.21 to -0.13; P=0.04). Different definitions for AKI among studies. Small sample size for some trials. Perioperative administration of levosimendan in patients undergoing cardiac surgery may reduce complications. Future trials are needed to determine the dose effect of levosimendan in improving outcomes, especially in patients with decreased baseline kidney function.

Rationale and Design of a Randomized, Double-Blind, Placebo Controlled Multicenter Trial to Study Efficacy, Security, and Long Term Effects of Intermittent Repeated Levosimendan Administration in Patients with Advanced Heart Failure: LAICA study

BackgroundAdvanced heart failure (HF) is associated with high morbidity and mortality; it represents a major burden for the health system. Episodes of acute decompensation requiring frequent and prolonged hospitalizations account for most HF-related expenditure. Inotropic drugs are frequently used during hospitalization, but rarely in out-patients. The LAICA clinical trial aims to evaluate the effectiveness and safety of monthly levosimendan infusion in patients with advanced HF to reduce the incidence of hospital admissions for acute HF decompensation.MethodsThe LAICA study is a multicenter, prospective, randomized, double-blind, placebo-controlled, parallel group trial. It aims to recruit 213 out-patients, randomized to receive either a 24-h infusion of levosimendan at 0.1 μg/kg/min dose, without a loading dose, every 30 days, or placebo.ResultsThe main objective is to assess the incidence of admission for acute HF worsening during 12 months. Secondarily, the trial will assess the effect of intermittent levosimendan on other variables, including the time in days from randomization to first admission for acute HF worsening, mortality and serious adverse events.ConclusionsThe LAICA trial results could allow confirmation of the usefulness of intermittent levosimendan infusion in reducing the rate of hospitalization for HF worsening in advanced HF outpatients.

Levosimendan treatment of severe acute congestive heart failure refractory to dobutamine/milrinone in children

Levosimendan is a novel positive inotropic agent which, improves myocardial contractility through its calcium-sensitizing action, without causing an increase in myocardial oxygen demand. Also, by opening ATP-sensitive potassium channels, it causes vasodilatation with the reduction in both afterload and preload. Because of the long half-life, its effects last for up 7 to 9 days after 24-hour infusion. We presented three patients 2, 15 and 17 years old. All the patients had severe acute deterioration of the previously diagnosed chronic heart failure (dilatative cardiomyopathy; univentricular heart with bidirectional Glenn anastomosis and restrictive bulboventricular foramen; bacterial endocarditis on artificial aortic valve with severe stenosis and regurgitation). Signs and symptoms of severe heart failure, cardiomegaly (cardio-thoracic index 0.65) and left ventricular dilatation (end-diastolic diameter z-score 2.6; 4.1 and 4.0) were confirmed on admission. Also, myocardial contractility was poor with ejection fraction (EF - 27%, 25%, 35%), fractional shortening (FS - 13%, 11%, 15%) and stroke volume (SV - 40, 60, 72 mL/m2). The treatment with standard intravenous inotropic agents resulted in no improvement but in clinical deterioration. Thus, standard intravenous inotropic support was stopped and levosimendan treatment was introduced. All the patients received a continuous 24-h infusion 0.1 microg/kg/min of levosimendan. In a single patient an initial loading dose of 11 microg/kg over 10 min was administrated, too. Levosimendan treatment resulted in both clinical and echocardiography improvement with the improved EF (42%, 34%, 44%), FS (21%, 16%, 22%) and SV (59, 82, 93 mL/m2). Hemodynamic improvement was registered too, with the reduction in heart rate in all the treated patients from 134-138 bpm before, to less than 120 bpm after the treatment. These parameters were followed by the normalization of lactate levels. Nevertheless, left ventricular end-diastolic diameter did not change after the levosimendan treatment. Our initial experience demonstrates that administration of levosimendan in patients with severe chronic heart failure not responsive to standard intravenous inotropic treatment might result in a significant clinical and hemodynamic improvement and that, in selected patients, it might be life saving. According to our best knowledge patients presented are the first pediatric patients treated with levosimendan in our country.

Safety and efficacy of levosimendan administration in patients with heart failure and coexisting atrial fibrillation

Safety and efficacy of levosimendan administration in patients with heart failure and coexisting atrial fibrillation

Clinical Experience With Levosimendan in the Emergency Department of a Tertiary Care Hospital

The efficacy and safety of levosimendan administration in patients with acute heart failure admitted to intensive care units has been well established. However, no information is available on the drug's beneficial effects in emergency departments. We studied 40 patients with acute heart failure who showed no or only partial improvement after conventional treatment and who received levosimendan during the period 2005-2006. The patients' mean age was 76 (9) years. The most common etiology was ischemic heart disease, and 85% of patients were in New York Heart Association (NYHA) class III or IV. The clinical response was favorable in 82% of patients, while adverse effects occurred in 18%. Some 70% were admitted to the emergency department short-stay unit. These findings indicate that levosimendan can be used safely and effectively in hospital emergency departments.

Anti-Inflammatory and Anti-Apoptotic Effects of Levosimendan in Decompensated Heart Failure: A Novel Mechanism of Drug-Induced Improvement in Contractile Performance of the Failing Heart

Recent experimental and clinical observations indicate that over-expression of pro-inflammatory cytokines is actively implicated to chronic heart failure progression through their cytotoxic and negative inotropic effects. Calcium-sensitizing agents, such as levosimendan, promotes inotropy by stabilizing troponin C in a configuration that enhances the calcium sensitivity of cardiac myofilaments, preserving also diastolic relaxation. Levosimendan also opens ATP-dependent potassium channels in peripheral vessels, leading to vasodilatation. Large scale randomized clinical trials have shown that levosimendan administration in patients with severe heart failure due to left ventricular systolic dysfunction results in favorable hemodynamic changes, symptomatic benefit, and a reduction in short-term morbidity and mortality. This review describes current knowledge about novel cellular mechanisms associated with beneficial effects of levosimendan on cardiac contractile performance, focusing mainly on its immunomodulatory and anti-apoptotic properties. Levosimendan-induced improvement in contractile reserve and clinical status of severe heart failure patients, seems to be related with the reduction of major pro-inflammatory cytokines (TNF-alpha, IL-6) and soluble apoptosis signaling molecules Fas/Fas Ligand. Modulation of pro-inflammatory and pro-apoptotic pathways into the failing heart by levosimendan may be an additional pathophysiologic mechanism that prevents further clinical and hemodynamic consequences of abnormal immune responses in decompensated heart failure and beneficially affects the progression of the syndrome.