• arterial switch operation
• levosimendan
• low birth weight
• low cardiac output syndrome
• milrinone

• Humans
• Milrinone/administration & dosage
• Milrinone/therapeutic use
• Simendan/administration & dosage
• Simendan/therapeutic use
• Retrospective Studies
• Female
• Male
• Cardiotonic Agents/therapeutic use
• Cardiotonic Agents/administration & dosage
• Cardiac Output, Low/etiology
• Cardiac Output, Low/drug therapy
• Cardiac Output, Low/prevention & control
• Transposition of Great Vessels/surgery
• Arterial Switch Operation/adverse effects
• Infant, Newborn
• Infant
• Postoperative Complications/prevention & control
• Treatment Outcome
• Hemodynamics/drug effects
• Echocardiography

• cardiac injury
• cardiac surgery
• heart failure
• levosimendan
• metabolic balance
• organ and tissue perfusion
• renal insufficiency
• systematic inflammatory response

• Acute dialysis quality initiative
• Acute kidney injury
• Acute renal failure
• Hyperthermic intraperitoneal chemotherapy
• Intensive care unit
• Length of stay
• RIFLE

• Levosimendan
• atrial fibrillation
• ejection fraction
• heart failure
• heart rhythm

• aortic stenosis
• heart failure
• inotrope
• levosimendan
• transcatheter valve replacement

• China International Medical Foundation

Acute heart failure (AHF) is associated with high mortality. Levosimendan, an inodilator, has proved to increase cardiac output and exert renoprotective effect in AHF. Our aim was to investigate the efficacy and renoprotective effects of levosimendan in patients with AHF and different renal function.

This is a prospective, observational, multi-center registry. Patients admitted with AHF between June 2020 and May 2022 and treated with levosimendan during the hospital stay were included. Baseline characteristics, laboratory tests, electrocardiogram (ECG), chest X-ray, echocardiography, and treatment were collected. A 5-point Likert scale was used to document patients' baseline dyspnea. The estimated glomerular filtration rate (eGFR) was calculated by means of the Modification of Diet in Renal Disease equation. After levosimendan infusion, patients underwent assessment of degree of dyspnea, and levels of brain-type natriuretic peptide (BNP) /N-terminal pro-BNP (NT-pro BNP), and eGFR repeatedly.

Among 789 AHF patients who received levosimendan treatment in this study, 33.0 % were female, mean age was 64.9 ± 16.8 years, and mean eGFR was 72.6 ± 32.5 ml/min/m². The mean score of dyspnea was 3.0 ± 1.0 using 5-point Likert scale before levosimendan infusion. Dyspnea improved in 68.7% patients at 6h after infusion of levosimendan, and in 79.5% at 24 h. Lower eGFR was associated with lower efficacy rate after 6h infusion (71.7, 70.7, 65.2, and 66.0%, respectively) and after 24 h infusion (80.5, 81.4, 76.2, and 77.8%, respectively). The levels of BNP or NT-pro BNP were also decreased after levosimendan treatment, and in each eGFR category. Levels of eGFR increased from baseline (72.6 ± 32.5 ml/min/m²) to 12–24h (73.8 ± 33.5 ml/min/m²) and 24–72h (75.0 ± 33.4 ml/min/m²) after starting treatment (p < 0.001). However, the eGFR levels increased only in patients with eGFR lower than 90.0 ml/min/m².

In AHF patients who received levosimendan, degree of dyspnea and levels of BNP or NT-pro BNP were significantly improved, especially in patients with higher eGFR levels. However, levosimendan infusion increase eGFR only in AHF patients with renal dysfunction.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been increasingly used in patients with refractory cardiogenic shock (CS) or out-of-hospital cardiac arrest. It is difficult to perform VA-ECMO weaning, which may cause circulatory failure and death. Levosimendan is an effective inotropic agent used to maintain cardiac output, has a long-lasting effect, and may have the potential benefit for VA-ECMO weaning. The study aimed to explore the relationship between the early use of levosimendan and the rate of VA-ECMO weaning failure in patients on VA-ECMO support for circulatory failure.

All patients who underwent VA-ECMO in our hospital for CS between January 2017 and December 2020 were recruited in this cohort study and divided into two groups: without and with levosimendan use. Levosimendan was used as an add-on to other inotropic agents as early as possible after VA-ECMO setting. The primary endpoint was VA-ECMO weaning success, which was defined as survival without events for 24 h after VA-ECMO withdrawl. The secondary outcomes were cardiovascular and all-cause mortality at the 30-day and 180-day follow-up periods post-VA-ECMO initialization.

A total of 159 patients were recruited for our study; 113 patients were enrolled in the without levosimendan-use group and 46 patients were enrolled in the levosimendan-use group. In levosimendan-use group, the patients received levosimendan infusion within 24 h after VA-ECMO initialization. Similar hemodynamic parameters were noted between the two groups. Poorer left ventricular ejection fraction and a higher prevalence of intra-aortic balloon pumping were observed in the levosimendan group. An improved weaning rate (without vs. with: 48.7 vs. 82.6%; p < 0.001), lower in-hospital mortality rate (without vs. with: 68.1 vs. 43.5%; p = 0.007), and 180-day cardiovascular mortality (without vs. with: 75.3 vs. 43.2%; p < 0.001) were also noted. Patients administered with levosimendan also presented a lower rate of 30-day (without vs. with: 75.3 vs. 41.3%; p = 0.034) and 180-day (without vs. with: 77.0 vs. 43.2%; p < 0.001) all-cause mortality.

Early levosimendan administration may contribute to increasing the success rate of VA-ECMO weaning and may help to decrease CV and all-cause mortality.

• GFR
• Levosimendan
• RBF
• medullary oxygenation

• Cardiotonic Agents/pharmacology
• Creatinine/blood
• Glomerular Filtration Rate/drug effects
• Humans
• Kidney/drug effects
• Simendan/pharmacology

The calcium sensitiser levosimendan (SIMDAX; Orion Pharma) has been in clinical use for the management of acute heart failure and a range of related syndromes in many countries around the world for two decades. More recently, levosimendan has become available in China. The authors have examined the profile of levosimendan in clinical trials conducted inside and outside China and grouped the findings under six headings: effects on haemodynamics, effects on natriuretic peptides, effect on symptoms of heart failure, renal effects, effect on survival, and safety profile. Their conclusions are that under each of these headings there are reasonable grounds to expect that the effects and clinical benefits established in trials and with wider clinical use in Europe and elsewhere will accrue also to Chinese patients. Therefore, the authors are confident that global experience with levosimendan provides a reliable guide to its optimal use and likely therapeutic effects in patients in China.

• China
• Levosimendan
• acute heart failure
• calcium sensitisation
• haemodynamics
• randomised controlled trials

• cardiorenal syndrome
• heart failure
• levosimendan
• mortality
• network meta-analysis

• MOST 110-2320-B-039 -020 Ministry of Science and Technology, Taiwan
• DMR-108-023 China Medical University Hospital
• CMU109-S-12 China Medical University, Taiwan

Cardiorenal syndrome (CRS) type 1 is the development of acute kidney injury in patients with acute decompensated heart failure. CRS often results in prolonged hospitalization, a higher rate of rehospitalization, high morbidity, and high mortality. The pathophysiology of CRS is complex and involves hemodynamic changes, neurohormonal activation, hypothalamic-pituitary stress reaction, inflammation, and infection. However, there is limited evidence or guideline in managing CRS type 1, and the established therapeutic strategies mainly target the symptomatic relief of heart failure. This review will discuss the strategies in the management of CRS type 1. Six clinical studies have been included in this review that include different treatment strategies such as nesiritide, dopamine, levosimendan, tolvaptan, dobutamine, and ultrafiltration. Treatment strategies for CRS type 1 are derived based on the current literature. Early recognition and treatment of CRS can improve the outcomes of the patients significantly.

• Cardiorenal syndrome
• Heart failure
• Acute kidney injury
• Renal insufficiency
• Management

• Critical care
• acute heart failure
• adenosine triphosphate-sensitive potassium (KATP) channels
• calcium sensitization
• cardiogenic shock
• levosimendan
• low cardiac output syndrome
• mitochondria

• acute kidney injury and ICU nephrology
• critical illness
• glomerular filtration rate
• hemodynamics
• renal blood flow
• renal oxygen consumption
• renal oxygenation
• respiratory physiologic phenomena
• tubular injury

• acute decompensated heart failure
• inotropic drugs
• levosimendan

• cardiac surgery
• dobutamine
• kidney
• levosimendan
• low cardiac output

Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years.

• Acute heart failure
• advanced heart failure
• haemodynamics
• inodilator
• inotrope
• neurohormone
• regulatory clinical trial

• acute heart failure
• advanced heart failure
• hemodynamics
• inodilator
• inotrope
• neurohormone
• regulatory clinical trial

• Cardiotonic Agents/adverse effects
• Cardiotonic Agents/therapeutic use
• Heart Failure/diagnosis
• Heart Failure/drug therapy
• Heart Failure/mortality
• Heart Failure/physiopathology
• Humans
• Myocardial Contraction/drug effects
• Patient Safety
• Simendan/adverse effects
• Simendan/therapeutic use
• Treatment Outcome
• Vasodilation/drug effects
• Vasodilator Agents/adverse effects
• Vasodilator Agents/therapeutic use

• Acute heart failure
• Dobutamine
• Dopamine
• Glomerular filtration rate
• Levosimendan
• Milrinone
• Renal blood flow
• Renal function

• Orion Pharma

Levosimendan is an inodilator that promotes cardiac contractility primarily through calcium sensitization of cardiac troponin C and vasodilatation via opening of adenosine triphosphate–sensitive potassium (K_ATP) channels in vascular smooth muscle cells; the drug also exerts organ-protective effects through a similar effect on mitochondrial K_ATP channels. This pharmacological profile identifies levosimendan as a drug that may have applications in a wide range of critical illness situations encountered in intensive care unit medicine: hemodynamic support in cardiogenic or septic shock; weaning from mechanical ventilation or from extracorporeal membrane oxygenation; and in the context of cardiorenal syndrome. This review, authored by experts from 9 European countries (Austria, Belgium, Czech republic, Finland, France, Germany, Italy, Sweden, and Switzerland), examines the clinical and experimental data for levosimendan in these situations and concludes that, in most instances, the evidence is encouraging, which is not the case with other cardioactive and vasoactive drugs routinely used in the intensive care unit. The size of the available studies is, however, limited and the data are in need of verification in larger controlled trials. Some proposals are offered for the aims and designs of these additional studies.

• Cardiac surgery
• Cardiopulmonary bypass
• Glomerular filtration rate
• Heart failure, acute
• Milrinone
• Oxygen consumption
• Renal blood flow

• Cardiac surgery
• Kidney
• Levosimendan
• Low cardiac output

• heart failure
• hemodynamic
• inotropic agent
• network meta-analysis

• Cardiotonic Agents/pharmacology
• Cardiotonic Agents/therapeutic use
• Clinical Trials as Topic
• Heart Failure/drug therapy
• Heart Failure/physiopathology
• Hemodynamics/drug effects
• Humans

Cardiotonic drugs mainly include digitalis, catecholamines, phosphodiesterase inhibitors, and calcium sensitizers, which have been successively discovered and applied in clinical practice. However, there are only a few new drugs available in this field, and the selection is very limited. Digitalis, catecholamines, and phosphodiesterase inhibitors increase myocardial contractility by increasing intracellular concentrations of cyclic adenosine monophosphate (cAMP) and Ca²⁺, and this increase in intracellular calcium ion concentration enhances myocardial oxygen consumption and causes arrhythmia. For these reasons, the research focus on positive inotropic agents has shifted from calcium mobilization to calcium sensitization. Intracellular calcium sensitizers are more effective and safer drugs because they do not increase the intracellular concentration of calcium ions. However, only three calcium sensitizers have been fully developed and used in the past three decades. One of these drugs, levosimendan, has multiple molecular targets and exerts its pharmacological effects by not only increasing myocardial contractility, but also enhancing respiratory muscle function and liver and kidney protection, and it is useful for patients with severe sepsis and septic shock. Recently, more than 60 randomized controlled clinical trials of levosimendan have been reported; however, these clinical trials have occasionally shown different findings. This article reviews the research progress of levosimendan in critical illnesses in recent years.

Levosimendan, a calcium sensitizer and potassium channel-opener, is widely appreciated by many specialist heart failure practitioners for its effects on systemic and pulmonary hemodynamics and for the relief of symptoms of acute heart failure. The drug’s impact on mortality in large randomized controlled trials has been inconsistent or inconclusive but, in contrast to conventional inotropes, there have been no indications of worsened survival and some signals of improved heart failure-related quality of life. For this reason, levosimendan has been proposed as a safer inodilator option than traditional agents in settings, such as advanced heart failure. Positive effects of levosimendan on renal function have also been described. At the HEART FAILURE 2018 congress of the Heart Failure Association of the European Society of Cardiology, safe and effective use levosimendan in acute and advanced heart failure was examined in a series of expert tutorials. The proceedings of those tutorials are summarized in this review, with special reference to advanced heart failure and heart failure with concomitant renal dysfunction. Meta-analysis of clinical trials data is supportive of a renal-protective effect of levosimendan, while physiological observations suggest that this effect is exerted at least in part via organ-specific effects that may include selective vasodilation of glomerular afferent arterioles and increased renal blood flow, with no compromise of renal oxygenation. These lines of evidence require further investigation and their clinical significance needs to be evaluated in specifically designed prospective trials.

• Acute heart failure
• Advanced heart failure
• Inodilators
• Inotropes
• Levosimendan
• Renal function

• Acute Disease
• Cardiotonic Agents/adverse effects
• Cardiotonic Agents/therapeutic use
• Chronic Disease
• Congresses as Topic
• Evidence-Based Medicine
• Heart Failure/diagnosis
• Heart Failure/drug therapy
• Heart Failure/mortality
• Heart Failure/physiopathology
• Humans
• Kidney/drug effects
• Kidney/physiopathology
• Myocardial Contraction/drug effects
• Recovery of Function
• Simendan/adverse effects
• Simendan/therapeutic use
• Time Factors
• Treatment Outcome
• Vasodilator Agents/adverse effects
• Vasodilator Agents/therapeutic use

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.

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.

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.

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.

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.

• Acute kidney injury
• atrial fibrillation
• intra-aortic balloon pump
• levosimendan
• off-pump coronary artery bypass grafting

• Levosimendan
• cardiac surgery
• cardioprotection
• inotropic drug
• low cardiac output syndrome
• myth or reality.

• dobutamine
• heart failure
• hemodynamics
• levosimendan
• renal function

• Aged
• Cardio-Renal Syndrome/drug therapy
• Cardiotonic Agents/therapeutic use
• Dobutamine/therapeutic use
• Double-Blind Method
• Female
• Glomerular Filtration Rate
• Heart Failure/complications
• Heart Failure/drug therapy
• Hemodynamic Monitoring
• Hemodynamics
• Humans
• Male
• Middle Aged
• Renal Circulation
• Renal Insufficiency/complications
• Renal Insufficiency/metabolism
• Renal Plasma Flow
• Simendan/therapeutic use
• p-Aminohippuric Acid

• acute kidney injury
• renal hypoxia
• renal ischaemia
• renal medulla

• acute kidney injury
• cardiac surgery
• chronic kidney disease
• hemodynamic support
• inotropes
• levosimendan
• low cardiac output syndrome
• mitral valve surgery

• Cardiac surgery
• Cardiology
• Levosimendan
• Meta-analysis
• Mortality
• Systematic review

• Anti-Arrhythmia Agents/administration & dosage
• Cardiac Surgical Procedures/adverse effects
• Cardiac Surgical Procedures/methods
• Humans
• Hydrazones/administration & dosage
• Perioperative Care/methods
• Postoperative Complications/epidemiology
• Postoperative Complications/prevention & control
• Pyridazines/administration & dosage
• Randomized Controlled Trials as Topic/methods
• Simendan

Small trials suggest that levosimendan is associated with a favorable outcome in patients undergoing cardiac surgery. However, recently published larger-scale trials did not provide evidence for a similar benefit from levosimendan. We performed a meta-analysis to assess the survival benefits of levosimendan in patients undergoing cardiac surgery and to investigate its effects in subgroups of patients with preoperative low-ejection fraction (EF).

We identified randomized clinical trials through 20 April 2017 that investigated levosimendan therapy versus control in patients undergoing cardiac surgery. Individual patient data from each study were compiled. Meta-analyses were performed for primary outcomes, secondary outcomes and serious adverse events, and subgroup analyses according to the preoperative EF of enrolled patients were also conducted. The risk of bias was assessed using the Cochrane risk-of-bias tool.

Seventeen studies involving a total of 2756 patients were included. Levosimendan therapy was associated with a significant reduction in 30-day mortality (RR 0.67; 95% CI, 0.49 to 0.93; p = 0.02) and reduced the risk of death in single-center trials (RR 0.49; 95% CI, 0.30 to 0.79; p = 0.004) and in subgroup trials of inferior quality (RR 0.39; 95% CI, 0.17 to 0.92; p = 0.02); however, in multicenter and in high-quality subgroup-analysis trials, no significant difference in mortality was observed between patients who received levosimendan therapy and controls (p > 0.05). However, in high-quality subgroup trials, levosimendan therapy was associated with reduced mortality in patients in a preoperative low-EF subgroup (RR 0.58; 95% CI, 0.38 to 0.88; p = 0.01). Similarly, only patients in the preoperative low-EF subgroup benefited in terms of reduced risk of renal replacement therapy (RR 0.54; 95% CI, 0.34 to 0.85; p = 0.007). Furthermore, levosimendan therapy was associated with a significant reduction in intensive care unit (ICU) length of stay (MDR −17.19; 95% CI, −34.43 to −2.94; p = 0.02).

In patients undergoing cardiac surgery, the benefit of levosimendan in terms of survival was not shown in multicenter or in high-quality trials; however, levosimendan therapy was associated with reduced mortality in patients with preoperative ventricular systolic dysfunction.

The online version of this article (doi:10.1186/s13054-017-1848-1) contains supplementary material, which is available to authorized users.

• Cardiac surgery
• Levosimendan
• Meta-analyses
• Mortality

• Aged
• Cardiac Output, Low/prevention & control
• Cardiopulmonary Bypass
• Cardiotonic Agents/adverse effects
• Cardiotonic Agents/therapeutic use
• Catecholamines/administration & dosage
• Coronary Artery Bypass/adverse effects
• Double-Blind Method
• Female
• Heart-Assist Devices
• Humans
• Hydrazones/adverse effects
• Hydrazones/therapeutic use
• Infusions, Intravenous
• Intention to Treat Analysis
• Male
• Middle Aged
• Postoperative Complications/prevention & control
• Premedication
• Pyridazines/adverse effects
• Pyridazines/therapeutic use
• Renal Replacement Therapy
• Simendan
• Stroke Volume/drug effects
• Treatment Failure