Comparative Effectiveness and Safety of Intermittent, Repeated, or Continuous Use of Levosimendan, Milrinone, or Dobutamine in Patients With Advanced Heart Failure: A Network and Single-Arm Meta-analysis.

ABSTRACT: The aim of this study was to synthesize the available evidence regarding differences in the long-term safety and efficacy of intermittent, repeated, or continuous palliative inotropic therapy among patients with advanced heart failure. We systematically searched the PubMed, Embase, and Cochrane Library electronic databases, with a cutoff date of November 23, 2023, for studies reporting outcomes in adult patients with advanced heart failure treated with intermittent, repeated, or continuous levosimendan, milrinone, or dobutamine. Forty-one studies (18 randomized controlled trials and 23 cohort studies) comprising 5137 patients met the inclusion criteria. The results of the network meta-analysis of randomized controlled trials showed that levosimendan had significant advantages over milrinone or dobutamine in reducing mortality and improving left ventricular ejection fraction. A single-arm meta-analysis also indicated that levosimendan had the lowest mortality and significantly improved B-type brain natriuretic peptide and left ventricular ejection fraction. Regarding safety, hypotension events were observed more frequently in the levosimendan and milrinone groups. However, the current evidence is limited by the heterogeneity and relatively small sample size of the studies.

Novel inhaled pulmonary vasodilators in adult cardiac surgery: a scoping review.

PURPOSE: 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. SOURCE: We searched Embase and MEDLINE for relevant articles from 1947 to 2022. PRINCIPAL FINDINGS: 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. CONCLUSION: 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. STUDY REGISTRATION: Open Science Framework ( https://osf.io/z3k6f/ ); first posted 21 July 2022.

RéSUMé: OBJECTIF: L'hypertension pulmonaire (HTP) est une cause fréquente de mortalité postopératoire en chirurgie cardiaque généralement traitée par des thérapies inhalées conventionnelles, en particulier le monoxyde d'azote et la prostacycline. Les thérapies alternatives comprennent la milrinone et le lévosimendan inhalés, qui suscitent de plus en plus d'intérêt dans la recherche et sont de plus en plus utilisés en clinique car ils peuvent réduire les coûts tout en permettant une administration plus facile. Nous avons cherché à réaliser une étude de portée afin d'évaluer la base de données probantes concernant l'utilisation de ces deux nouveaux vasodilatateurs inhalés comme intervention pour l'HTP en chirurgie cardiaque. SOURCES: Nous avons cherché des articles pertinents dans Embase et MEDLINE de 1947 à 2022. CONSTATATIONS PRINCIPALES: Nous avons identifié 17 études incluant 969 patient·es. Les études incluses montrent que la milrinone et le lévosimendan inhalés sont des vasodilatateurs pulmonaires sélectifs possédant des avantages potentiels allant de la facilité de sevrage de la circulation extracorporelle à la réduction de la dysfonction ventriculaire. Néanmoins, les données de haute qualité sont limitées, et la conception des études et les comparateurs sont extrêmement hétérogènes, ce qui limite la validité potentielle et la généralisabilité des résultats. CONCLUSION: Les résultats de cette étude de portée suggèrent que la milrinone et le lévosimendan pourraient être des solutions de rechange efficaces aux traitements inhalés actuels pour le dysfonctionnement cardiaque dans un contexte d'HTP. Néanmoins, les études randomisées se sont concentrées sur des agents spécifiques et des mesures cohérentes des résultats sont nécessaires pour mieux valider les promesses de ces agents à un stade précoce. ENREGISTREMENT DE L'éTUDE: Open Science Framework ( https://osf.io/z3k6f/ ); première publication le 21 juillet 2022.

Safety of Levosimendan in Pediatric Patients: An Up-to-Date Systematic Review.

BACKGROUND: The potential risks associated with the use of levosimendan in the pediatric population has not been systematically evaluated. This study aimed to review the available evidence regarding the safety of this treatment. METHODS: Bio Med Central, PubMed, Embase, and the Cochrane Central Register of clinical trials were searched for studies describing levosimendan administration in the pediatric population in any setting. Relevant studies were independently screened, selected, and their data extracted by two investigators. The authors excluded: reviews, meta-analyses, as well as basic research and trials involving patients >18 years old. The primary outcome was the number and the type of adverse side effects reported during levosimendan administration. RESULTS: The updated systematic review included 48 studies, enrolling a total of 1,271 pediatric patients who received levosimendan as treatment (790 patients in the 11 studies that reported side effects). The primary adverse effects of levosimendan administration were hypotension and cardiac arrhythmias, particularly tachycardia. Hypotension occurred in approximately 28.9% of patients, while arrhythmia occurred in about 12.3% of patients. Meta analysis of RCTs revealed a rate of all-cause mortality of 2.0% (8 out of 385) in the levosimendan group compared to 3.9% (15 out of 378) in the control group (dobutamine, milrinone or placebo) (risk ratio [RR] = 0.55; 95% confidence interval [CI] = 0.25-1.21; P = 0.14; I2 = 0%) CONCLUSIONS: Hypotension and cardiac arrhythmia are the most reported side effects of levosimendan in pediatric patients. However, adverse events remain underreported, especially in randomized trials.

Hemodynamic Effects of Levosimendan in Outpatients With Advanced Heart Failure: An Echocardiographic Pilot Study.

ABSTRACT: Infusions of levosimendan delivered in ambulatory/outpatient settings have been shown to improve quality of life and reduce hospitalizations in patients with advanced heart failure (HF). The aim of this pilot study was to evaluate the effects of ambulatory infusion of levosimendan on echocardiographic markers of perfusion, congestion, and cardiovascular efficiency. Thirty patients with diagnosed advanced HF underwent ambulatorial infusion of levosimendan at a total dose of 6.25 mg as a part of a repetitive biweekly treatment strategy with the inotrope. Standardized transthoracic echocardiography and Doppler examinations, were performed 1 hour before and 48 hours after completion of ambulatory infusion. At 48 hours after ambulatory infusion of levosimendan, a significant increase in the stroke volume (37.47 ± 12.38 mL/beat vs. 45.47 ± 14.48 mL/beat; P < 0.05) and cardiac output (2.64 ± 0.66 L/min vs. 3.26 ± 0.57 L/min; P < 0.05) occurred. Significant postreductions versus prereductions were also recorded in left atrial pressure (27.37 ± 6.62 mm Hg vs. 22.82 ± 4.17 mm Hg; P < 0.01), mean pulmonary artery pressure (27.69 ± 4.64 mm Hg vs. 23.24 ± 5.32; P < 0.01), and inferior vena cava diameter (23.81 ± 7.63 mm vs. 18.53 ± 4.82 mm; P < 0.01). Significant improvements were noted in the resting cardiac power output (0.46 ± 0.15 watt vs. 0.53 ± 0.22 watt; P < 0.01) and the resting cardiac power index (0.24 ± 0.08 watt/m2 vs. 0.28 ± 0.11 watt/m2; P < 0.01). In outpatients with advanced HF, infusion of levosimendan was associated with hemodynamic responses that may contribute to the clinical benefit previously reported in such patients.

Successful Combination of Landiolol and Levosimendan in Patients with Decompensated Heart Failure.

Tachycardia and supraventricular tachyarrhythmias often impair cardiovascular capacity in patients with decompensated heart failure (dHF) treated with inotropes. Normalization of heart rhythm or rate typically improves diastolic filling and stroke volume (SV). Thus, isochronal administration of an ultra-short-acting and highly selective ß1-blockers, such as landiolol, along with inotropic calcium-sensitizer medications, such as levosimendan, could benefit patients with dHF.We present a case series of three patients with severe dHF and low ejection fraction who were successfully treated with a combination of landiolol and levosimendan. The co-administration of landiolol and levosimendan was well tolerated, improved cardiac function, normalized SV, and enabled the reduction of norepinephrine dosing in all patients. Additionally, the combination improved the vectorcardiographic spatial QRS-T angle and decreased the corrected QT interval. All patients were successfully discharged from the intensive care unit (ICU).A combination of levosimendan and landiolol was safe and well-tolerated. This combination may be a new option for successful treatment of patients with acute dHF complicated by sinus or supraventricular tachycardias.

The Effect of Levosimendan Versus Milrinone on the Occurrence Rate of Acute Kidney Injury Following Congenital Heart Surgery in Infants: A Randomized Clinical Trial.

OBJECTIVES: It has been shown that, in contrast to other inotropic agents, levosimendan improves glomerular filtration rate after adult cardiac surgery. The aim of this study was to investigate the efficacy of levosimendan, compared with milrinone, in preventing acute kidney dysfunction in infants after open-heart surgery with cardiopulmonary bypass. DESIGN: Two-center, double-blinded, prospective, randomized clinical trial. SETTING: The study was performed in two tertiary pediatric centers, one in Sweden (Gothenburg) and one in Finland (Helsinki). PATIENTS: Infants between 1 and 12 months old, diagnosed with Tetralogy of Fallot, complete atrioventricular septal defect or nonrestrictive ventricular septal defect, undergoing total corrective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Seventy-two infants were randomized to receive a perioperative infusion of levosimendan (0.1 µg/kg/min) or milrinone (0.4 µg/kg/min). The infusion was initiated at the start of cardiopulmonary bypass and continued for 26 hours. MEASUREMENTS AND MAIN RESULTS: The primary outcome variable was the absolute value of serum creatinine data on postoperative day 1. Secondary outcomes included the following: 1) acute kidney injury according to the serum creatinine criteria of the Kidney Diseases: Improving Global Outcomes; 2) acute kidney injury with serum creatinine corrected for fluid balance; 3) plasma neutrophil gelatinase-associated lipocalin; 4) cystatin C; 5) urea; 6) lactate; 7) hemodynamic variables; 8) use of diuretics in the PICU; 9) need of dialysis; 10) length of ventilator therapy; and 11) length of PICU stays. There was no significant difference in postoperative serum creatinine between the treatment groups over time (p = 0.65). The occurrence rate of acute kidney injury within 48 hours was 46.9% in the levosimendan group and 39.5% in the milrinone group (p = 0.70). There were no significant differences in other secondary outcome variables between the groups. CONCLUSIONS: Levosimendan compared with milrinone did not reduce the occurrence rate of acute kidney injury in infants after total corrective heart surgery for atrioventricular septal defect, ventricular septal defect, or Tetralogy of Fallot.

Preservation of renal function in cardiac surgery patients with low cardiac output syndrome: levosimendan vs beta agonists.

BACKGROUND: Some studies have been performed to assess the effects of levosimendan on cardiac function when administered to cardiac surgery patients with low cardiac output syndrome (LCOS) in the immediate postoperative period. Levosimendan is an inotropic agent for the treatment of low cardiac output syndrome that seems to have a protective effect on renal function. METHODS: It is a quasi-experimental study. A total of 100 patients with LCOS received either beta-agonists or levosimendan. We assessed the incidence of postoperative kidney failure in cardiac surgery patients. In patients who had kidney failure at diagnosis of LCOS, we examined whether differences existed in the evolution of kidney failure based on the treatment administered for LCOS. The parameters measured included haemodynamics, oxygen supply, and renal function as assessed by the AKI scale. ANOVA, Student's t-test and Wilcoxon or Friedman tests were used. RESULTS: Up to 30% of cardiac surgery patients had kidney failure at diagnosis of LCOS. Kidney failure at discharge from the ICU was more frequent in patients who received beta-agonist drugs as compared to those who received levosimendan (p < 0.05). CONCLUSION: The incidence of kidney failure decreased with the postoperative administration of levosimendan to cardiac surgery patients with LCOS, as compared to beta-agonists. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 46058317. Date of registration: 7/10/2019. Retrospectively registered.

Levosimendan in Cardiac Surgery: Evaluating the Evidence.

Levosimendan, a calcium-sensitizing and Adenosine triphosphate-sensitive potassium channel opening inodilator, has the potential to improve cardiac function without increasing oxygen consumption. The evidence supporting the use of levosimendan in the cardiac surgical perioperative period is not well-established. Recently, large-scale randomized controlled trials studying the utility of levosimendan in cardiac surgery have been conducted. This review examines the physiological and pharmacologic properties of levosimendan and evaluates the literature regarding the use of levosimendan in patients undergoing cardiac surgery.

Intravenous Levosimendan and Vasopressin in New-Onset Acute Pulmonary Hypertension After Weaning from Cardiopulmonary Bypass.

OBJECTIVE: A novel treatment with intravenous levosimendan and vasopressin for new-onset acute pulmonary hypertension after weaning from cardiopulmonary bypass is described. DESIGN: Retrospective analysis of a case series. SETTING: Single-center study. PARTICIPANTS: Nineteen patients undergoing cardiac surgery exhibited new-onset acute pulmonary hypertension with acute right ventricular dysfunction after cardiopulmonary bypass. INTERVENTION: Pulmonary hypertension with acute right heart dysfunction was treated with levosimendan as inodilator therapy and vasopressin combined with norepinephrine for systemic vasopressor therapy. MEASUREMENTS AND MAIN RESULTS: Mean pulmonary artery pressure decreased from 32 ± 9 to 26 ± 6 mmHg (p = 0.039) in the first 24 hours along with an increase in cardiac output (3.2 ± 1 to 4.2 ± 1.1 L/min; p = 0.012) and resolution of lactic acidosis. The ratio between mean pulmonary artery pressure and mean arterial pressure decreased from 1:2 to 1:3, and Wood units decreased from 3 ± 1 to 1.5 ± 2 (p = 0.042). At 30 days after intervention, 3 patients died. CONCLUSION: The combination of levosimendan for inotropic support of the right ventricle in conjunction with its vasodilatory effect on the pulmonary circulation, along with the combination of vasopressin and norepinephrine for systemic vasopressor therapy, may be an effective alternative for the treatment of acute new-onset pulmonary hypertension and acute right heart dysfunction after cardiopulmonary bypass. Although there are many confounding variables in this case series, these findings justify additional sufficiently powered trials.

The efficacy and safety of prophylactic use of levosimendan on patients undergoing coronary artery bypass graft: a systematic review and meta-analysis.

Prophylactic use of levosimendan in cardiac surgery remains controversial and no meta-analysis has been done exclusively about that in patients undergoing coronary artery bypass graft (CABG) surgery. We conducted this systematic review and meta-analysis of levosimendan in CABG using PubMed, Embase, Scopus, and Cochrane Library (till April 20, 2018). Two-hundred and forty manuscripts were identified and 21 randomized trials (1727 patients in total) investigating the effect of levosimendan on the patients undergoing CABG surgery were finally included in this analysis. We found that levosimendan was an effective, well-tolerated inotropic agent in CABG, which was associated with a significantly reduced mortality rate [odds ratio (OR) 0.43, 95% confidence interval (CI) (0.26, 0.71), p = 0.001, I2 = 0%] and postoperative atrial fibrillation [OR 0.50, 95% CI (0.26, 0.97), p = 0.04, I2 = 76%], but a higher incidence of hypotension [OR 2.26, 95% CI (1.05, 4.85), p = 0.04, I2 = 79%]. Subgroup analyses revealed that such a benefit was mainly observed in the isolated CABG, the preoperative administration, with-bolus and on-pump subgroups. More high-quality and well-designed prospective studies are needed to confirm or disprove our findings in future.

Levosimendan differentially modulates electrophysiological activities of sinoatrial nodes, pulmonary veins, and the left and right atria.

INTRODUCTION: Calcium overload increases the risk of atrial fibrillation (AF). Levosimendan, a calcium sensitizer, increases myofilament contractility. Clinical reports suggested that levosimendan might increase AF occurrence, but the electrophysiological effects of levosimendan on AF substrates and triggers (pulmonary veins, PVs) are not clear. METHODS AND RESULTS: Conventional microelectrodes were used to record action potentials (APs) in isolated rabbit PVs, sinoatrial nodes (SANs), the left atrium (LA), and right atrium (RA) before and after application of different concentrations of levosimendan with or without milrinone (a phosphodiesterase [PDE] III inhibitor), and glibenclamide (an ATP-sensitive potassium channel [KATP ] inhibitor). Levosimendan (0.03, 0.1, 0.3, and 1 µM) significantly increased spontaneous rates from 2.1 ± 0.2 to 2.5 ± 0.2, 2.5 ± 0.2, 2.5 ± 0.1, and 2.7 ± 0.2 Hz, respectively, in PVs (n = 10), but had no effects on denudated PVs (n = 9). Additionally, levosimendan significantly induced burst firing and/or triggered beats in intact PVs, but not in denudated PVs. In contrast, levosimendan at 0.3 and 1 µM increased the SAN spontaneous rate. In the presence of milrinone (10 µM), levosimendan (1 µM) did not increase the PV spontaneous activity. Moreover, glibenclamide (100 µM) prevented acceleration of the levosimendan-induced SAN and PV rates. In the LA, levosimendan at 0.3 and 1 µM shortened the AP duration, and increased contractility at 0.03, 0.1, 0.3, and 1 µM. In contrast, levosimendan did not change the RA contractility, and shortened the AP duration only at 1 µM. CONCLUSIONS: Levosimendan increased PV arrhythmogenesis through activating endothelial PDE III and the KATP , and modulating PV tension.

Perioperative Use of Levosimendan Improves Clinical Outcomes in Patients After Cardiac Surgery: A Systematic Review and Meta-Analysis.

Severe postoperative complications can affect cardiac surgery patients. Levosimendan is a novel calcium sensitizer commonly administered after cardiac surgery. However, the patient benefits are controversial. PubMed, Embase, and the Cochrane library were systematically searched for randomized controlled trials comparing levosimendan with control in adult cardiac surgery patients. Twenty-five studies (3247 patients) were included. Pooled data indicated that levosimendan reduced mortality after cardiac surgery [odds ratio (OR) 0.63, 95% confidence interval (CI): 0.47-0.84, P = 0.001]. However, this reduction was restricted to patients with low (<50%) left ventricular ejection fraction (OR 0.49, 95% CI: 0.35-0.70, P = 0.0001). It significantly reduced the incidence of postoperative acute kidney injury (OR 0.55, 95% CI: 0.41-0.74, P < 0.0001) and renal replacement therapy use (OR 0.56, 95% CI: 0.39-0.80, P = 0.002). Moreover, levosimendan significantly shortened the duration of the intensive care unit stay (weighted mean differences -0.49 day, 95% CI: -0.75 to -0.24, P = 0.0002) and mechanical ventilation use (weighted mean differences -2.30 hours, 95% CI: -3.76 to -0.84, P = 0.002). In conclusion, levosimendan reduced the mortality in patients with low left ventricular ejection fraction and decreased the incidence of acute renal injury and renal replacement therapy use. In addition, it shortened the duration of the intensive care unit stay and mechanical ventilation use.

In vitro effects of levosimendan on muscle of malignant hyperthermia susceptible and non-susceptible swine.

BACKGROUND: The calcium sensitizer levosimendan is increasingly used to improve hemodynamics in patients with acutely decompensated heart failure. By binding to cardiac troponin C the conformation of the calcium-troponin C complex is stabilized, which leads to acceleration of actin-myosin crossbrigde formation and increased force generating capacity of muscle fibers. Besides indications in cardiac failure, beneficial effects of levosimendan in skeletal muscle disorders are currently evaluated. The aim of this study was to investigate differential effects of levosimendan on skeletal muscle of pigs with and without susceptibility to malignant hyperthermia (MH) in order to identify possible risks of this emerging drug for patients with predisposition to MH. METHODS: Muscle bundles of 17 pigs (9 MH susceptible (MHS); 8 MH non-susceptible (MHN)) were excised under general anesthesia and examined in the tissue bath with increasing concentrations of levosimendan (0.065; 0.125; 0.5; 1.0; 10 and 50 µg/ml). Baseline tension and twitch force were monitored continuously. Data are presented as median and interquartile range. Statistical evaluation was performed using D'Agostino & Pearson test for normal distribution and student's t test and 2-way ANOVA for differences between the groups. P < 0.05 was considered significant. RESULTS: There were no differences between the groups concerning length, weight, initial twitch force and pre-drug resting tension of the investigated muscle strips. After an initial decrease in both groups, twitch amplitude was significantly higher in MHN (- 3.0 [- 5.2-0.2] mN) compared to MHS (- 7.5 [- 10.8- -4.5] mN) (p = 0.0034) muscle at an applied levosimendan concentration of 50 µg/ml. A marked increase in resting tension was detected following levosimendan incubation with 50 µg/ml in MHS muscle bundles (3.3 [0.9-6.1] mN) compared to MHN (- 0.7 [- 1.3-0.0] mN) (p < 0.0001). CONCLUSIONS: This in vitro investigation revealed the development of significant contractures in muscle bundles of MHS pigs after incubation with levosimendan. However, the effect appeared only at supra-therapeutic concentrations and further research is needed to determine the impact of levosimendan on MHS individuals in vivo.

Levosimendan is superior to epinephrine on coronary flow for lipid-base resuscitation of bupivacaine-induced asystole in the isolated rat heart.

BACKGROUND: Successful resuscitation from asystole induced by bupivacaine requires the reestablishment of a sufficient coronary flow (CF) quickly. This study was designed to test whether levosimendan was superior to epinephrine in the reestablishment of crucial coronary flows after bupivacaine-induced asystole. METHODS: The isolated, perfused, nonrecirculating, Langendorff rat heart preparation was used. Bupivacaine 100 µmol/L was perfused into rat hearts to induce asystole, and then for 3 min thereafter. Three experimental groups were assessed after asystole with infusions as follow: (1) a mixture of 2% lipid emulsion and 40 µmol/L bupivacaine (control group), (2) a mixture of 0.15 µg/mL epinephrine combined with 2% lipid emulsion and 40 µmol/L bupivacaine (epinephrine group), and (3) a mixture of 5 µmol/L levosimendan combined with a 2% lipid emulsion and 40 µmol/L bupivacaine mixture (levosimendan group). Coronary flow (CF), the time to recovery (Trecovery), the number of ventricular arrhythmias, and cardiac function parameters were recorded for 40 min after heartbeat recovery. RESULTS: All hearts in the control, epinephrine and levosimendan groups had heartbeat recovery. The rank order of the mean CF from highest to lowest was the levosimendan group > the epinepgrine group > the control group (P < 0.05). The rank order of Trecovery from shortest to longest was the levosimendan group < the epinephrine group < the control group (P < 0.01). During the recovery phase, isolated rat hearts developed more ventricular arrhythmias in the epinephrine group than in the levosimendan group (P = 0.01). CONCLUSION: Levosimendan is superior to epinephrine in producing higher CFs and faster recovery when reversing bupivacaine-induced asystole in the isolated rat hearts.

Comparison of Levosimendan and Milrinone for ECLS Weaning in Patients After Cardiac Surgery-A Retrospective Before-and-After Study.

OBJECTIVES: Pharmacodynamics suggests that levosimendan might be a valuable inotrope for weaning from extracorporeal life support (ECLS). As there is a paucity of evidence regarding the effectiveness and safety of such an approach, the aim was to report the authors' experiences in ECLS weaning before and after the implementation of levosimendan in clinical practice. DESIGN: Retrospective before-and-after study. SETTING: Cardiac intensive care unit of a university hospital. PARTICIPANTS: A total of 64 patients under ECLS for postcardiotomy cardiac failure, who underwent an ECLS weaning trial. INTERVENTION: Group comparisons between patients treated with levosimendan and patients treated with milrinone were made with the Mann-Whitney U test or the Pearson chi-squared test. Results are given as median (interquartile range) or numbers (percentages). MEASUREMENTS AND MAIN RESULTS: Of 64 patients, 26 (41%) received levosimendan. Successful ECLS weaning was achieved in 24 (92%) and 30 patients (79%) in the levosimendan and milrinone group, respectively (p = 0.18). In the levosimendan group, fewer patients had an intra-aortic balloon pump for weaning (2 [7.7%] v 15 [40%], p = 0.008). The support with norepinephrine was similar in the levosimendan and milrinone groups at the time of ECLS removal (0.06 [0.01-0.11] v 0.07 [0.01-0.16] µg/kg/min, p = 0.64) and 24 hours later (0.06 [0.04-0.09] v 0.04 [0.00-0.09] µg/kg/min, p = 0.15). Twenty-eight days (9/26 (35%) v 14/35 (40%), p = 0.28) and 180 days (13/26 [50%] v 15/34 [44%], p = 0.80) mortalities after ECLS removal were similar in the levosimendan and the milrinone groups. CONCLUSION: Levosimendan enabled ECLS weaning without increasing norepinephrine requirements when compared to a control group receiving milrinone.

The Effect of Inhaled Milrinone Versus Inhaled Levosimendan in Pulmonary Hypertension Patients Undergoing Mitral Valve Surgery - A Pilot Randomized Double-Blind Study.

OBJECTIVE: To compare the effects of inhaled milrinone and levosimendan on pulmonary and systemic hemodynamics in patients with pulmonary hypertension. DESIGN: Prospective, double-blind, randomized controlled study. SETTING: Tertiary care cardiac institute with 650 beds. PARTICIPANTS: The study comprised 150 adult patients with pulmonary hypertension undergoing mitral valve surgery. INTERVENTIONS: Patients were assigned randomly into 1 of the following 3 groups: milrinone (M), levosimendan (L), or control (C); n = 50 per group. In group M, inhaled milrinone (50 µg/kg); in group L, inhaled levosimendan (24 µg/kg); and in group C, normal saline was administered when the patient arrived in the recovery room. Pre-inhalation and post-inhalation hemodynamics (mean arterial pressure [MAP], pulse rate, and systemic vascular resistance [SVR]) were noted until 24 hours of inhalation of the drug. The change in pulmonary artery pressures (pulmonary artery systolic pressure [PASP] and mean pulmonary artery pressure [MPAP]) and the duration for which they remained decreased compared with the control group, were noted. MEASUREMENTS AND MAIN RESULTS: MAP, pulse rate, and SVR were comparable in the 3 groups at various time intervals. PASP and MPAP decreased comparably after inhalation of levosimendan and milrinone. However, they reached levels near the control group values after 2.5 to 3 hours in group L and after 0.5 hours in group M. CONCLUSIONS: Because inhaled levosimendan causes a decrease in PASP and MPAP without causing a decrease in SVR and MAP, the authors conclude that inhaled levosimendan is a selective pulmonary vasodilator. It is as effective as milrinone in reducing pulmonary artery pressures. In addition, it has advantage over inhaled milrinone because it is has a longer duration of action.

Effect of Levosimendan on Renal Outcome in Cardiac Surgery Patients With Chronic Kidney Disease and Perioperative Cardiovascular Dysfunction: A Substudy of a Multicenter Randomized Trial.

OBJECTIVE: Acute kidney injury (AKI) occurs frequently after cardiac surgery. Levosimendan might reduce the incidence of AKI in patients undergoing cardiac surgery. The authors investigated whether levosimendan administration could reduce AKI incidence in a high-risk cardiac surgical population. DESIGN: Post hoc analysis of a multicenter randomized trial. SETTING: Cardiac surgery operating rooms and intensive care units of 14 centers in 3 countries. PARTICIPANTS: The study comprised 90 patients who underwent mitral valve surgery with an estimated glomerular filtration rate <60 mL/min/1.73 m2 and perioperative myocardial dysfunction. INTERVENTIONS: Patients were assigned randomly to receive levosimendan (0.025-0.2 µg/kg/min) or placebo in addition to standard inotropic treatment. MEASUREMENTS AND MAIN RESULTS: Forty-six patients were assigned to receive levosimendan and 44 to receive placebo. Postoperative AKI occurred in 14 (30%) patients in the levosimendan group versus 23 (52%) in the placebo group (absolute difference -21.8; 95% confidence interval -41.7 to -1.97; p = 0.035). The incidence of major complications also was lower (18 [39%]) in the levosimendan group versus that in the placebo group (29 [66%]) (absolute difference -26.8 [-46.7 to -6.90]; p = 0.011). A trend toward lower serum creatinine at intensive care unit discharge was observed in the levosimendan group (1.18 [0.99-1.49] mg/dL) versus that in the placebo group (1.39 [1.05-1.76] mg/dL) (95% confidence interval -0.23 [-0.49 to 0.01]; p = 0.07). CONCLUSIONS: Levosimendan may improve renal outcome in cardiac surgery patients with chronic kidney disease undergoing mitral valve surgery who develop perioperative myocardial dysfunction. Results of this exploratory analysis should be investigated in future properly designed randomized controlled trials.

Ambulatory Intravenous Inotropic Support and or Levosimendan in Pediatric and Congenital Heart Failure: Safety, Survival, Improvement, or Transplantation.

End-stage heart failure (HF) frequently needs continuous inotropic support in hospital and has high morbidity and mortality in absence of heart transplantation. This study reports outcome, efficacy, and safety of continuous ambulatory inotropes (AI) and/or periodic levosimendan (LS) infusions in pediatric HF patients. The study included 27 patients, median age 9.4 (0.1-26.1) years, with severe HF (6 myocarditis, 13 dilated cardiomyopathy, 2 restrictive cardiomyopathy, 6 repaired congenital heart disease). Dobutamine and milrinone AI were administered in 21 patients through a permanent central catheter for median duration 1.0 (0.3-3.7) years. Additionally, 14 AI patients and the remaining 6 study patients received periodic LS infusions for median duration 1.1 (0.2-4.2) years. During median follow-up 2.1 (0.3-21.3) years, 4 patients died of worsening HF after 0.8-2.1 years AI, 6 patients underwent heart transplantation with only 3 survivors, while the rest remained stable out of the hospital with complications 4 line infections treated with antibiotics and 4 catheter reinsertions due to dislodgement. Severe pulmonary hypertension was reversed with AI in 2 patients, allowing successful heart-only transplantation. Therapy with AI was discontinued after 1.4-0.4 years in 6 improved myocarditis and 3 cardiomyopathy patients without deterioration. In conclusion, prolonged AI and/or LS infusions in HF are safe and beneficial even in small infants, allowing stabilization and reasonable social and family life out of the hospital. It may provide precious time for heart transplantation or myocardial remodeling, improvement, and possible discontinuation even after long periods of support.

The favourable alliance between CardioMEMS and levosimendan in patients with advanced heart failure.

AIMS: We report the results of a real-world study based on heart failure (HF) patients' continuous remote monitoring strategy using the CardioMEMS system to assess the impact of this device on healthcare outcomes, costs, and patients' management and quality of life. METHODS AND RESULTS: We enrolled seven patients (69.00 ± 4.88 years; 71.43% men) with HF, implanted with CardioMEMS, and daily remote monitored to optimize both tailored adjustments of home therapy and/or hospital infusions of levosimendan. We recorded clinical, pharmacological, biochemical, and echocardiographic parameters and data on hospitalizations, emergency room access, visits, and costs. Following the implantation of CardioMEMS, we observed a 50% reduction in the total number of hospitalizations and a 68.7% reduction in the number of days in the hospital. Accordingly, improved patient quality of life was recorded with EQ-5D (pre 58.57 ± 10.29 vs. 1 year post 84.29 ± 19.02, P = 0.008). Echocardiographic data show a statistically significant improvement in both systolic pulmonary artery pressure (47.86 ± 8.67 vs. 35.14 ± 9.34, P = 0.022) and E/e' (19.33 ± 5.04 vs. 12.58 ± 3.53, P = 0.023). The Quantikine® HS High-Sensitivity Kit determined elevated interleukin-6 values at enrolment in all patients, with a statistically significant reduction after 6 months (P = 0.0211). From an economic point of view, the net savings, including the cost of CardioMEMS, were on average €1580 per patient during the entire period of observation, while the analysis performed 12 months after the implant vs. 12 months before showed a net saving of €860 per patient. The ad hoc analysis performed on the levosimendan infusions resulted in 315 days of hospital avoidance and a saving of €205 158 for the seven patients enrolled during the observation period. CONCLUSIONS: This innovative strategy prevents unplanned access to the hospital and contributes to the efficient use of healthcare facilities, human resources, and costs.