Safety and efficacy of levosimendan in patients with cardiac amyloidosis.

BACKGROUND: Patients with cardiac amyloidosis (CA) often experience heart failure (HF) episodes. No evidence is available on inotropic therapy. This study aims to fill this gap by examining the safety and efficacy of levosimendan. METHODS: We retrieved all HF patients receiving ≥1 levosimendan infusion from 2013 to 2023. CA patients were matched with HF patients without CA (controls) based on sex, age, and left ventricular ejection fraction (LVEF). The response to levosimendan was measured as changes in daily urinary output, body weight, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR). RESULTS: CA patients (median age 77 years, 73% men, 59% with ATTR-CA) and controls were compared. Levosimendan infusion was stopped because of hypotension in 2 cases with CA and (in 1 case) worsening renal function, and in 2 controls because of ventricular tachycardia episodes and (in 1 case) hypotension. CA patients showed a trend toward increased daily urinary output (p = 0.078) and a significant decrease in body weight (p < 0.001), without significant changes in NT-proBNP (p = 0.497) and eGFR (p = 0.732). Both CA patients and controls displayed similar changes in urinary output, weight, and eGFR, but NT-proBNP decreased more significantly among controls (p < 0.001). No differences were noted in rehospitalization rates, but CA patients experienced higher mortality at 6 and 12 months (p = 0.003 and p = 0.001, respectively). CONCLUSIONS: Levosimendan appears safe for CA patients needing inotropic support. The diuretic response and weight decrease during hospitalization were comparable between CA patients and matched HF patients, despite the greater mortality of CA patients after discharge.

Effect of levosimendan on ventricular remodelling in patients with left ventricular systolic dysfunction: a meta-analysis.

Heart failure is the final stage of several cardiovascular diseases, and the key to effectively treating heart failure is to reverse or delay ventricular remodelling. Levosimendan is a novel inotropic and vasodilator agent used in heart failure, whereas the impact of levosimendan on ventricular remodelling is still unclear. This study aims to investigate the impact of levosimendan on ventricular remodelling in patients with left ventricular systolic dysfunction. Electronic databases were searched to identify eligible studies. A total of 66 randomized controlled trials involving 7968 patients were included. Meta-analysis results showed that levosimendan increased left ventricular ejection fraction [mean difference (MD) = 3.62, 95% confidence interval (CI) (2.88, 4.35), P < 0.00001] and stroke volume [MD = 6.59, 95% CI (3.22, 9.96), P = 0.0001] and significantly reduced left ventricular end-systolic volume [standard mean difference (SMD) = -0.52, 95% CI (-0.67, -0.37), P < 0.00001], left ventricular end-diastolic volume index [SMD = -1.24, 95% CI (-1.61, -0.86), P < 0.00001], and left ventricular end-systolic volume index [SMD = -1.06, 95% CI (-1.43, -0.70), P < 0.00001]. In terms of biomarkers, levosimendan significantly reduced the level of brain natriuretic peptide [SMD = -1.08, 95% CI (-1.60, -0.56), P < 0.0001], N-terminal pro-brain natriuretic peptide [SMD = -0.99, 95% CI (-1.41, -0.56), P < 0.00001], and interleukin-6 [SMD = -0.61, 95% CI (-0.86, -0.35), P < 0.00001]. Meanwhile, levosimendan may increase the incidence of hypotension [risk ratio (RR) = 1.24, 95% CI (1.12, 1.39), P < 0.0001], hypokalaemia [RR = 1.57, 95% CI (1.08, 2.28), P = 0.02], headache [RR = 1.89, 95% CI (1.50, 2.39), P < 0.00001], atrial fibrillation [RR = 1.31, 95% CI (1.12, 1.52), P = 0.0005], and premature ventricular complexes [RR = 1.86, 95% CI (1.27, 2.72), P = 0.001]. In addition, levosimendan reduced all-cause mortality [RR = 0.83, 95% CI (0.74, 0.94), P = 0.002]. In conclusion, our study found that levosimendan might reverse ventricular remodelling when applied in patients with left ventricular systolic dysfunction, especially in patients undergoing cardiac surgery, decompensated heart failure, and septic shock.

Effect of levosimendan on renal function in background of left ventricular dysfunction: a meta-analysis of randomized trials.

OBJECTIVE: Levosimendan, an inotrope, is widely used in the management of heart failure (HF) and cardiac surgery, but it remains uncertain whether levosimendan can improve renal function in patients with left ventricular dysfunction (LVD). METHODS: PubMed, Embase, and Cochrane CENTRAL from the inception to June 2020 were systematically screened for randomized controlled trials (RCTs) to investigate whether levosimendan offers kidney-related advantages in cardiovascular patients with LVD. We pooled the effects using a random-effect model. RESULTS: Twenty-eight studies enrolling 5069 patients were included. Levosimendan reduced the sCr (SMD -0.28, 95% CI (-0.48, -0.09), P = 0.005, I2 = 52.5%, high quality) and the risk of ARF (relative risk 0.75, 95%CI (0.60, 0.95), P = 0.017, I2 = 11.3%, moderate-quality) in patients with LVD compared with control group. The reduction of sCr was more pronounced in patients with a relatively higher baseline sCr level. For secondary outcomes, levosimendan therapy was associated with the improvement of GFR (SMD 0.32, 95%CI (-0.05, 0.68), P = 0.092, I2 = 55.1%, low-quality) and urine output (SMD 0.42, 95%CI (0.06, 0.79), P = 0.024, I2 = 50.0%, very low-quality), but there was no significant reduction in BUN (SMD -0.14, 95%CI (-0.97, 0.70), P = 0.774, I2 = 77.9%, very low-quality). CONCLUSIONS: Levosimendan might improve renal function of patients with LVD.

Use of Levosimendan as bridge therapy to surgical correction of post-infarction ventricular septal defect: a case report.

OBJECTIVE: Ventricular septal defect (VSD) is an uncommon but frequently fatal complication following acute myocardial infarction. In medically treated patients, mortality rates exceed 90%, while the surgical repair is associated with better outcomes, even though optimal surgical timing is still under debate. CASE REPORT: We present the case of a 78-years-old man with no previous remarkable cardiological history admitted to our Emergency Department with the diagnosis of anterior ST-elevation myocardial infarction and significant reduction of left ventricular ejection fraction. The emergency coronary angiography showed sub-occlusion of the left anterior descending coronary artery, treated with stent implantation. The post-procedural echocardiography unveiled the presence of an apical VSD with a large left-to-right shunt, significant right ventricular overload and dysfunction. An intra-aortic balloon pump (IABP) was positioned and, after Heart Team evaluation, a delayed surgical approach was planned. As a bridge to the intervention Levosimendan infusion was administered, on top of IABP support, and a significant improvement in bi-ventricular function and pressure profiles was obtained. Cardiac surgery was successfully performed 9 days after the admission without periprocedural complications. CONCLUSIONS: This unique case supports the use of Levosimendan as a valid pharmacological strategy for perioperative management of VSD.

Effect of Preoperative Infusion of Levosimendan on Biomarkers of Myocardial Injury and Haemodynamics After Paediatric Cardiac Surgery: A Randomised Controlled Trial.

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 (DO2) was significantly higher at 12 h and 24 h after surgery (mean difference [95% CI] 627.70 ml/min/m2 [122.34-1162.67] and 832.35 ml/min/m2 [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' DO2 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.

A simple procedure in a complex patient: perioperative takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TTC) is a rare but life-threatening condition that is still not completely understood. Characterised by rapidly reversible ventricular dysfunction without any prior coronary artery disease, it can imitate a myocardial infarction and lead to death if not managed appropriately. This report examines a case of intraoperative cardiac arrest in a patient with no previous cardiac disease, and discusses the factors that may have precipitated this event, as well as the ways of distinguishing the cause of the arrest based on clinical course and investigations, eventually leading to a diagnosis of TTC.

Long-term outcome of perioperative low cardiac output syndrome in cardiac surgery: 1-year results of a multicenter randomized trial.

PURPOSE: Perioperative myocardial dysfunction occurs frequently in cardiac surgery, and is a risk factor for morbidity and mortality. Levosimendan has been suggested to reduce mortality of patients with perioperative myocardial dysfunction. However, long-term outcome data on its efficacy in cardiac surgery are lacking. MATERIALS AND METHODS: Cardiac surgery patients with perioperative myocardial dysfunction were randomized to levosimendan or placebo, in addition to standard inotropic care. One-year mortality data were collected. RESULTS: We randomized 506 patients (248 to levosimendan 258 to placebo). At 1-year follow-up, 41 patients (16.5%) died in the levosimendan group, while 47 (18.3%) died in the placebo group (absolute risk difference -1.8; 95% CI -8.4 to 4.9; P = .60). Female sex, history of chronic obstructive pulmonary disease, previous myocardial infarction, serum creatinine, hematocrit, mean arterial pressure, and duration of cardiopulmonary bypass were independently associated with 1-year mortality. CONCLUSIONS: Levosimendan administration does not improve 1-year survival in cardiac surgery patients with perioperative myocardial dysfunction. One-year mortality in these patients is 17%. Six predictive factors for long-term mortality were identified. STUDY REGISTRATION NUMBER: NCT00994825 (ClinicalTrials.gov).

Impact of Perioperative Levosimendan Administration on Risk of Bleeding After Cardiac Surgery: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Levosimendan, a calcium sensitizer and potassium channel opener, has been demonstrated to improve myocardial function without increasing oxygen consumption and to show protective effects in other organs. Recently, a prospective, randomized controlled trial (RCT) revealed an association between levosimendan use and a possible increased risk of bleeding postoperatively. Levosimendan's anti-platelet effects have been shown in in vitro studies. Current studies do not provide sufficient data to support a relation between perioperative levosimendan administration and increased bleeding risk. PURPOSE: Our goal was to investigate the relation between perioperative levosimendan administration and increased bleeding risk using a meta-analysis study design. METHODS: The PubMed, Ovid, EMBASE and Cochrane Library databases were searched for relevant RCTs before July 1, 2019. The outcome parameters included reoperation secondary to increased bleeding in the postoperative period, the amount of postoperative recorded blood loss, and the need for transfusion of packed red blood cells (RBCs) and other blood products. RESULTS: A total of 1160 patients in nine RCTs (576 in the levosimendan group and 584 in the control group) were included according to our inclusion criteria. Analysis showed that perioperative levosimendan administration neither increased the rate of reoperation secondary to bleeding nor increased the amount of postoperative chest tube drainage when compared with the control group. In terms of blood product transfusion, levosimendan did not influence the requirement for RBC transfusion, platelet transfusion nor fresh frozen plasma (FFP) transfusion. Levosimendan also did not shorten or prolong the aortic cross-clamp time or the cardiopulmonary bypass time. CONCLUSION: The analyzed parameters, including reoperations due to bleeding, postoperative chest drainage and the requirement for blood products, revealed that levosimendan did not increase postoperative bleeding risk. More studies with a larger sample size are needed to address a more reliable conclusion due to study limitations.

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.

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.

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.

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.

Levosimendan in patients with low cardiac output syndrome undergoing cardiac surgery: A systematic review and meta-analysis.

Levosimendan is an inotropic agent that has been shown in small studies to treat low cardiac output syndrome in cardiac surgery. However, large randomised controlled trials (RCTs) have been recently published and presented neutral results. We sought to determine the effect of levosimendan on mortality in adults with low ejection fraction undergoing cardiac surgery. We searched different databases: Medline, Embase, Cochrane Central Register of Controlled Trials, and clinical trial registries. We included RCTs comparing events in the levosimendan versus placebo in adult patients with ejection fraction ≤ 35% undergoing cardiac surgery. Outcomes were mortality at 30-day, mortality beyond 30-day, acute kidney injury and myocardial infarction. Five trials with a total of 1519 patients were selected. Four trials were rated as low risk of bias. Our meta-analysis showed no significant difference between levosimendan versus placebo mortality at 30-day [odds radio (OR): 0.62; 95% confidence intervals (CI): 0.32 to 1.20; I2 = 33%; high quality evidence] and mortality beyond 30-day (OR: 0.71; 95% CI: 0.46 to 1.11; I2 = 0%). Similarly, there were no significant differences between the levosimendan versus placebo in the incidence of acute kidney injury (OR: 0.61, 95% CI: 0.33-1.13) and myocardial infarction (OR: 0.41, 95% CI: 0.08 to 1.22). The current evidence suggests that levosimendan is not associated with significantly reduced mortality in patients with reduced ejection fraction undergoing cardiac surgery.

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.

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.

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.

Inhaled levosimendan versus intravenous levosimendan in patients with pulmonary hypertension undergoing mitral valve replacement.

CONTEXT: Inhaled levosimendan may act as selective pulmonary vasodilator and avoid systemic side effects of intravenous levosimendan, which include decrease in systemic vascular resistance (SVR) and systemic hypotension, but with same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function. AIM: The aim of this study was to compare the effect of inhaled levosimendan with intravenous levosimendan in patients with pulmonary hypertension undergoing mitral valve replacement. SETTINGS AND DESIGN: The present prospective randomized comparative study was conducted in a tertiary care hospital. SUBJECTS AND METHODS: Fifty patients were randomized into two groups (n = 25). Group A: Levosimendan infusion was started immediately after coming-off of cardiopulmonary bypass and continued for 24 h at 0.1 mcg/kg/min. Group B: Total dose of levosimendan which would be given through intravenous route over 24 h was calculated and then divided into four equal parts and administered through inhalational route 6th hourly over 24 h. Hemodynamic profile (pulse rate, mean arterial pressure, pulmonary artery systolic pressure [PASP], SVR) and RV function were assessed immediately after shifting, at 1, 8, 24, and 36 h after shifting to recovery. STATISTICAL ANALYSIS USED: Intragroup analysis was done using paired student t-test, and unpaired student t-test was used for analysis between two groups. RESULTS: PASP and RV-fractional area change (RV-FAC) were comparable in the two groups at different time intervals. There was a significant reduction in PASP and significant improvement in RV-FAC with both intravenous and inhalational levosimendan. SVR was significantly decreased with intravenous levosimendan, but no significant decrease in SVR was observed with inhalational levosimendan. CONCLUSIONS: Inhaled levosimendan is a selective pulmonary vasodilator. It causes decrease in PAP and improvement in RV function, without having a significant effect on SVR.

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.

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.

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.