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Purpose Myocardial dysfunction is common in sepsis but optimal treatment strategies are unclear. The inodilator, levosimendan was suggested as a possible therapy; however, the levosimendan to prevent acute organ dysfunction in Sepsis (LeoPARDS) trial found it to have no benefit in reducing organ dysfunction in septic shock. In this study we evaluated the effects of levosimendan in patients with and without biochemical cardiac dysfunction and examined its non-inotropic effects. Methods Two cardiac biomarkers, troponin I (cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and five inflammatory mediators were measured in plasma from patients recruited to the LeoPARDS trial at baseline and over the first 6 days. Mean total Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were compared between patients with normal and raised cTnI and NT-proBNP values, and between patients above and below median values. Results Levosimendan produced no benefit in SOFA score or 28-day mortality in patients with cardiac dysfunction. There was a statistically significant treatment by subgroup interaction ( p  = 0.04) in patients with NT-proBNP above or below the median value. Those with NT-proBNP values above the median receiving levosimendan had higher SOFA scores than those receiving placebo (mean daily total SOFA score 7.64 (4.41) vs 6.09 (3.88), mean difference 1.55, 95% CI 0.43–2.68). Levosimendan had no effect on the rate of decline of inflammatory biomarkers. Conclusion Adding levosimendan to standard care in septic shock was not associated with less severe organ dysfunction nor lower mortality in patients with biochemical evidence of cardiac dysfunction.

Purpose Respiratory muscle weakness frequently develops in critically ill patients and is associated with adverse outcome, including difficult weaning from mechanical ventilation. Today, no drug is approved to improve respiratory muscle function in these patients. Previously, we have shown that the calcium sensitizer levosimendan improves calcium sensitivity of human diaphragm muscle fibers in vitro and contractile efficiency of the diaphragm in healthy subjects. The main purpose of this study is to investigate the effects of levosimendan on diaphragm contractile efficiency in mechanically ventilated patients. Methods In a double-blind randomized placebo-controlled trial, mechanically ventilated patients performed two 30-min continuous positive airway pressure (CPAP) trials with 5-h interval. After the first CPAP trial, study medication (levosimendan 0.2 µg/kg/min continuous infusion or placebo) was administered. During the CPAP trials, electrical activity of the diaphragm (EA di ), transdiaphragmatic pressure ( P di ), and flow were measured. Neuromechanical efficiency (primary outcome parameter) was calculated. Results Thirty-nine patients were included in the study. Neuromechanical efficiency was not different during the CPAP trial after levosimendan administration compared to the CPAP trial before study medication. Tidal volume and minute ventilation were higher after levosimendan administration (11 and 21%, respectively), whereas EA di and P di were higher in both groups in the CPAP trial after study medication compared to the CPAP trial before study medication. Conclusions Levosimendan does not improve diaphragm contractile efficiency.

To investigate the effects of sacubitril valsartan sodium combined with levosimendan on improving cardiac and renal functions in patients with CRS. 90 patients with the cardiorenal syndrome who were hospitalized in our hospital from February 2020 to February 2022 were selected and divided into two groups, the control group, and the joint group, according to both single and double number methods, with 45 cases in each group. Patients who met the diagnostic criteria for CRS, were older than 18 years of age, had NYHA class II to IV, and had stage 1 or 2 chronic kidney disease were included in the study. Patients with severe hypersensitivity to the drugs used in this test, haemodynamic instability, combined hyperthyroidism, malignancy, severe pulmonary hypertension, cardiogenic shock, malignant arrhythmias and pregnant women were excluded. Among them, the control group was treated with sacubitril valsartan sodium alone, and the joint group was treated with levosimendan supplemented with the treatment method of the control group. The treatment effect, the improvement of cardiac and renal function, and the incidence of adverse reactions were compared between the two groups of CRS patients, and the prognostic effect was followed up 6 months after treatment. The total effective rate of treatment in the joint group was 95.56%, which was significantly higher than that in the control group of 80.00%, and the difference was statistically significant by using χ2 test (P < .05). After treatment, LVEF, LVEDD, and NT-proBNP levels in both groups were significantly improved compared with those before treatment (P < .05), and the improvement effect of each index in the joint group was more significant than that in the control group (P < .05). After treatment, the levels of SCr, BUN, and UA in both groups were significantly lower than those before treatment (P < .05), and the levels of each index in the joint group were significantly lower than those in the control group, statistical analyses showed significant differences (P < .05) using t test. The incidence of adverse effects such as tachycardia, premature ventricular contractions, heart failure, and myocardial ischaemia was 22.22% in the combined group, which was significantly lower than 42.22% in the control group, and the difference in the total incidence between the two groups was statistically significant by χ2 test (P < .05). One case of malignant arrhythmia and five cases of recurrence of heart failure occurred 6 months after surgery in the combined group, which were significantly lower than the eight and twelve cases in the control group. Sacubitril valsartan sodium combined with levosimendan can significantly improve the therapeutic effect of CRS, with significant improvement in cardiac and renal function of CRS patients, and its incidence of adverse effects and long-term prognostic effects are lower than those of sacubitril valsartan sodium alone. This combination therapy offers a promising new direction for CRS management, warranting further investigation in larger, multicenter trials.

Objective The aim was to test the hypothesis that preoperative infusion of levosimendan would decrease patients’ cardiac biomarker profiles during the immediate postoperative stage (troponin I and B-type natriuretic peptide levels) more efficiently than placebo after cardiopulmonary bypass. Methods In a randomised, placebo-controlled, double-blinded study, 30 paediatric patients were scheduled for congenital heart disease surgery. 15 patients (50%) received prophylactic levosimendan and 15 patients (50%) received placebo from 12 h before cardiopulmonary bypass to 24 h after surgery. Results Troponin I levels were higher in the placebo group at 0, 12, and 24 h after cardiopulmonary bypass, although the mean differences between the study groups and the 95% confidence intervals (CIs) for troponin I levels did not present statistically significant differences at any of the three time points considered (mean differences [95% CIs] − 3.32 pg/ml [− 19.34 to 12.70], − 2.42 pg/ml [− 19.78 to 13.95], and − 79.94 pg/ml [− 266.99 to 16.39] at 0, 12, and 24 h, respectively). A similar lack of statistically significant difference was observed for B-type natriuretic peptide (mean differences [95% CIs] 36.86 pg/dl [− 134.16 to 225.64], − 350.79 pg/dl [− 1459.67 to 557.45], and − 310.35 pg/dl [− 1505.76 to 509.82]). Lactic acid levels were significantly lower with levosimendan; the mean differences between the study groups and the 95% CIs for lactate levels present statistically significant differences at 0 h (− 1.52 mmol/l [− 3.19 to − 0.25]) and 12 h (− 1.20 mmol/l [− 2.53 to − 0.10]) after cardiopulmonary bypass. Oxygen delivery (DO 2 ) was significantly higher at 12 h and 24 h after surgery (mean difference [95% CI] 627.70 ml/min/m 2 [122.34–1162.67] and 832.35 ml/min/m 2 [58.15 to 1651.38], respectively). Conclusions Levosimendan does not significantly improve patients’ postoperative troponin I and B-type natriuretic peptide profiles during the immediate postoperative stage in comparison with placebo, although both were numerically higher with placebo. Levosimendan, however, significantly reduced lactic acid levels and improved patients’ DO 2 profiles. These results highlight the importance of this new drug and its possible benefit with regard to myocardial injury; however, evaluation in larger, adequately powered trials is needed to determine the efficacy of levosimendan. Trial registry number : EudraCT 2012-005310-19.

Background Acute kidney injury (AKI) is a common and serious complication after cardiac surgery, and current strategies aimed at treating AKI have proven ineffective. Levosimendan, an inodilatating agent, has been shown to increase renal blood flow and glomerular filtration rate in uncomplicated postoperative patients and in patients with the cardiorenal syndrome. We hypothesized that levosimendan through its specific effects on renal vasculature, a preferential vasodilating effect on preglomerular resistance vessels, could improve renal function in AKI-patients with who did not have clinical indication for inotropic support. Methods In this single-center, double-blind, randomized controlled study, adult patients with postoperative AKI within 2 days after cardiac surgery, who were hemodynamically stable with a central venous oxygen saturation (ScvO 2 ) ≥ 60% without inotropic support were eligible for inclusion. After randomization, study drug infusions, levosimendan (n = 16) or placebo (n = 13) were given for 5 h. A bolus infusion of levosimendan (12 µg/kg), were given for 30 min followed by 0.1 µg/kg/min for 5 h. Renal blood flow and glomerular filtration rate were measured using infusion clearance of para-aminohippuric acid and a filtration marker, respectively. As a safety issue, norepinephrine was administered to maintain mean arterial pressure between 70–80 mmHg. Intra-group differences were tested by Mann–Whitney U-tests, and a linear mixed model was used to test time and group interaction. Results Twenty-nine patients completed the study. At inclusion, the mean serum creatinine was higher in the patients randomized to levosimendan (148 ± 29 vs 127 ± 22 µmol/L, p  = 0.030), and the estimated GFR was lower (46 ± 12 vs 57 ± 11 ml/min/1.73 m 2 , p  = 0.025). Levosimendan induced a significantly ( p  = 0.011) more pronounced increase in renal blood flow (15%) compared placebo (3%) and a more pronounced decrease in renal vascular resistance (− 18% vs. − 4%, respectively, p  = 0.043). There was a trend for a minor increase in glomerular filtration rate with levosimendan (4.5%, p  = 0.079), which did differ significantly from the placebo group ( p  = 0.440). The mean norepinephrine dose was increased by 82% in the levosimedan group and decreased by 29% in the placebo group ( p  = 0.012). Conclusions In hemodynamically stable patients with AKI after cardiac surgery, levosimendan increases renal blood flow through renal vasodilatation. Trial registration NCT02531724, prospectly registered on 08/20/2015. https://clinicaltrials.gov/ct2/show/NCT02531724?cond=AKI&cntry=SE&age=1&draw=2&rank=1

Pulmonary hypertension (PH) is a common cause of postoperative mortality in cardiac surgery that is commonly treated with conventional inhaled therapies, specifically nitric oxide and prostacyclin. Alternative therapies include inhaled milrinone and levosimendan, which are receiving more research interest and are increasing in clinical use as they may cut costs while allowing for easier administration. We sought to conduct a scoping review to appraise the evidence base for the use of these two novel inhaled vasodilators as an intervention for PH in cardiac surgery. We searched Embase and MEDLINE for relevant articles from 1947 to 2022. We identified 17 studies including 969 patients. The included studies show that inhaled milrinone and levosimendan are selective pulmonary vasodilators with potential benefits ranging from ease of weaning from cardiopulmonary bypass to reduction in ventricular dysfunction. Nevertheless, high-quality data are limited, and study design and comparators are extremely heterogeneous, limiting the potential validity and generalizability of findings. The findings of this scoping review suggest that milrinone and levosimendan may be effective alternatives to current inhaled therapies for cardiac dysfunction in the setting of PH. Nevertheless, randomized trials have focused on specific agents and consistent outcome measures are needed to better validate the early-stage promise of these agents. Open Science Framework ( https://osf.io/z3k6f/ ); first posted 21 July 2022.

There remains ongoing controversy and debate regarding the effect of levosimendan on weaning from mechanical ventilation in critical ill patients relying on ventilator. The objective of this study is to assess the specific effect of levosimendan on weaning from mechanical ventilation and to ascertain whether levosimendan can indeed improve the prognosis. This meta-analysis was proactively registered on PROSPERO platform. The PubMed, Web of Science, Embase, ScienceDirect and Cochrane were searched from inception to June 2024. The primary outcome of interest was duration of mechanical ventilation. Secondary outcomes included mortality rates, as well as length of stay in both intensive care unit (ICU) and the hospital. Six studies (n = 1069 patients) were included in the analysis ultimately. In relation to the primary outcome, the findings revealed that patients who received levosimendan experienced a significantly earlier successful weaning from mechanical ventilation compared to those who did not receive the medication [Mean Difference (MD) = −1.86 (95 %CI, −2.71 to −1.01, P < 0.01]. For the secondary outcomes, levosimendan was associated with a notable in both length of ICU stay [MD = -36.89 (95 %CI, −70.68 to −3.11, P < 0.01] and the total in-hospital stay [MD = -51.77 (95 %CI, −92.34 to −11.20, P < 0.01]. Levosimendan did not demonstrate a statistically effect in reducing mortality rates [Relative Risk(RR) =0.65 (95 %CI, 0.27 to 1.57, P = 0.40]. Levosimendan helps patients weaning from mechanical ventilation occuring earlier and reduces length of stay (ICU and hospital), but does not affect mortality. •Levosimendan helps patients weaning from mechanical ventilation.•Levosimendan helps shorten the length of stay.•There is no significant effect on mortality reduction.•This meta-analysis is more comprehensive and reliable.

Levosimendan exerts positive inotropic and vasodilatory effects. Currently, its effects on right heart function remain uncertain. This systematic review and meta-analysis is intended to illustrate the impacts of levosimendan on systolic function of the right heart in patients with heart dysfunction. We systematically searched electronic databases (PubMed, the Cochrane Library, Embase and Web of Science) up to November 30, 2020, and filtered eligible studies that reported the impacts of levosimendan on right heart function. Of these, only studies whose patients suffered from heart dysfunction or pulmonary hypertension were included. Additionally, patients were divided into two groups (given levosimendan or not) in the initial research. Then, RevMan5.3 was used to conduct further analysis. A total of 8 studies comprising 390 patients were included. The results showed that after 24 h of levosimendan, patients’ right ventricular fractional area change [3.17, 95% CI (2.03, 4.32), P < 0.00001], tricuspid annular plane systolic excursion [1.26, 95% CI (0.35, 2.16), P = 0.007] and tricuspid annular peak systolic velocity [0.86, 95% CI (0.41, 1.32), P = 0.0002] were significantly increased compared to the control group. And there is an increasing trend of cardiac output in levosimendan group [1.06, 95% CI (− 0.16, 2.29), P = 0.09 ] .Furthermore, patients’ systolic pulmonary arterial pressure [− 5.57, 95% CI (− 7.60, − 3.54), P < 0.00001] and mean pulmonary arterial pressure [− 1.01, 95% CI (− 1.64, − 0.37), P = 0.002] were both significantly decreased, whereas changes in pulmonary vascular resistance [− 55.88, 95% CI (− 206.57, 94.82), P = 0.47] were not significant. Our study shows that in patients with heart dysfunction, levosimendan improves systolic function of the right heart and decreases the pressure of the pulmonary artery.

Acute mesenteric ischemia (AMI) is a life-threatening condition characterised by oxidative stress, inflammation, apoptosis, and necrosis of intestinal epithelial cells. Different drugs with vasoactive, antioxidant, and anti-inflammatory properties have been used to treat AMI. Levosimendan is a drug with proven anti-ischemic effects used in the management of acute congestive heart failure. This study evaluated the protective effects of levosimendan pretreatment on intestinal, as well as lung, heart, and kidney tissue in a rat model of mesenteric artery ischemia/reperfusion (I/R) injury. Male Wistar rats (N = 24) were divided into four groups: control, I/R, levosimendan (LS) 1 mg/kg i.p, and LS + I/R (1 mg/kg i.p. 30 min before injury). I/R by itself caused elevation of oxidative markers (thyobarbituric acid reactive species (TBARS), hydrogen peroxide (H2O2), super oxide anjon radical (O2−), and nitrogen dioxide (NO2−)), induced inflammation (macrophage infiltration and Interleukin-6 (IL-6) production), and apoptosis (nuclear factor kappa light-chain enhancer of activated B cells (NF-κB), cleaved caspase-3 (CC3), and terminal deoxy-nucleotidyl transferase (TdT)-mediated dUTP nick end labelling (TUNEL)). Levosimendan pretreatment significantly reduced oxidative stress markers and enhanced antioxidant defences (catalase (CAT), reduced glutathione (GSH), and superoxide dismutase (SOD)). Histological analysis revealed reduced mucosal damage and preserved goblet cells in intestinal tissue. Similar protective effects of levosimendan were observed in other organs such as lung, heart, and kidney. Immunohistochemistry showed reduced epithelial apoptosis and upregulation of antioxidant and anti-inflammatory proteins. These findings highlight levosimendan’s ability to protect mesenteric I/R tissue injury and multi-organ damage by suppressing oxidative stress, inflammation, and apoptosis, emphasising its therapeutic potential in clinical settings.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been increasingly used over the last decade in patients with refractory cardiogenic shock. ECMO weaning can, however, be challenging and lead to circulatory failure and death. Recent data suggest a potential benefit of levosimendan for ECMO weaning. We sought to further investigate whether the use of levosimendan could decrease the rate of ECMO weaning failure in adult patients with refractory cardiogenic shock. METHODS: We performed an observational single-center cohort study. All patients undergoing VA-ECMO from January 2012 to December 2018 were eligible and divided into two groups: group levosimendan and group control (without levosimendan). The primary endpoint was VA-ECMO weaning failure defined as death during VA-ECMO treatment or within 24 h after VA-ECMO removal. Secondary outcomes were mortality at day 28 and at 6 months. The two groups were compared after propensity score matching. P \\textless 0.05 was considered statistically significant. RESULTS: Two hundred patients were analyzed (levosimendan group: n = 53 and control group: n = 147). No significant difference was found between groups on baseline characteristics except for ECMO duration, which was longer in the levosimendan group (10.6 ± 4.8 vs. 6.5 ± 4.7 days, p \\textless 0.001). Levosimendan administration started 6.6 ± 5.4 days on average following ECMO implantation. After matching of 48 levosimendan patients to 78 control patients, the duration of ECMO was similar in both groups. The rate of weaning failure was 29.1% and 35.4% in levosimendan and control groups, respectively (OR: 0.69, 95%CI: 0.25-1.88). No significant difference was found between groups for all secondary outcomes. CONCLUSION: Levosimendan did not improve the rate of successful VA-ECMO weaning in patients with refractory cardiogenic shock. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04323709 .