Levosimendán ambulatorio repetitivo como puente al trasplante cardiaco / Repetitive ambulatory levosimendan as a bridge to heart transplantation

Introducción y objetivos:El levosimendán ambulatorio repetitivo es una opción como puente al trasplante cardiaco (TxC), aunque la evidencia sobre su eficacia y su seguridad es escasa. El objetivo del registro LEVO-T es describir a los pacientes en lista de TxC que reciben levosimendán, sus pautas y los eventos clínicos durante el seguimiento, en comparación con los que no lo reciben. Métodos: Se revisó en retrospectiva a los pacientes en lista de espera para TxC electivo de 14 centros españoles desde 2015 hasta 2020. Resultados: Se incluyó a 1.015 pacientes consecutivos; los 238 (23,4%) que recibieron levosimendán mostraron más ingresos por insuficiencia cardiaca (IC) el año anterior y peor perfil clínico. Las dosis fijas por necesidades clínicas fueron la pauta más frecuente. Dos pacientes (0,8%) presentaron arritmias ventriculares no mortales. No hubo diferencias en hospitalizaciones por IC entre los que comenzaron levosimendán en los primeros 30 días después de inclusión y los que no (el 33,6 frente al 34,5%; p=0,848). De estos últimos, 102 (32,9%) pasaron a levosimendán después de un ingreso por IC, y la tasa de ingresos por IC/mes varió de 0,57 antes del levosimendán a 0,21 después. El análisis mediante emparejamiento por puntuación de propensión no mostró diferencias entre los pacientes con y sin levosimendán en la supervivencia a 1 año tras la inclusión en lista (HR=1,03; IC95%, 0,36-2,97; p=0,958) ni en la supervivencia tras el TxC (HR=0,97; IC95%, 0,60-1,56; p=0,958). Conclusiones: El levosimendán ambulatorio repetitivo como puente al trasplante cardiaco es un tratamiento frecuente y seguro que podría reducir ingresos por IC. (AU)

Introduction and objectives: Repetitive ambulatory doses of levosimendan are an option as a bridge to heart transplantation (HT), but evidence regarding the safety and efficacy of this treatment is scarce. The objective of the LEVO-T Registry is to describe the profile of patients on the HT list receiving levosimendan, prescription patterns, and clinical outcomes compared with patients not on levosimendan. Methods: We retrospectively reviewed all patients listed for elective HT from 2015 to 2020 from 14 centers in Spain. Results: A total of 1015 consecutive patients were included, of whom 238 patients (23.4%) received levosimendan. Patients treated with levosimendan had more heart failure (HF) admissions in the previous year and a worse clinical profile. The most frequent prescription pattern were fixed doses triggered by the patients’ clinical needs. Nonfatal ventricular arrhythmias occurred in 2 patients (0.8%). No differences in HF hospitalizations were found between patients who started levosimendan in the first 30 days after listing and those who did not (33.6% vs 34.5%; P=.848). Among those who did not, 102 patients (32.9%) crossed over to levosimendan after an HF admission. These patients had a rate of 0.57 HF admissions per month before starting levosimendan and 0.21 afterwards. Propensity score matching analysis showed no differences in survival at 1 year after listing between patients receiving levosimendan and those who did not (HR, 1.03; 95%CI, 0.36-2.97; P=.958) or in survival after HT (HR, 0.97; 95%CI, 0.60-1.56; P=.958). Conclusions: Repetitive levosimendan in an ambulatory setting as a bridge to heart transplantation is commonly used, is safe, and may reduce HF hospitalizations. (AU)

Repetitive ambulatory levosimendan as a bridge to heart transplantation.

INTRODUCTION AND OBJECTIVES: Repetitive ambulatory doses of levosimendan are an option as a bridge to heart transplantation (HT), but evidence regarding the safety and efficacy of this treatment is scarce. The objective of the LEVO-T Registry is to describe the profile of patients on the HT list receiving levosimendan, prescription patterns, and clinical outcomes compared with patients not on levosimendan. METHODS: We retrospectively reviewed all patients listed for elective HT from 2015 to 2020 from 14 centers in Spain. RESULTS: A total of 1015 consecutive patients were included, of whom 238 patients (23.4%) received levosimendan. Patients treated with levosimendan had more heart failure (HF) admissions in the previous year and a worse clinical profile. The most frequent prescription pattern were fixed doses triggered by the patients' clinical needs. Nonfatal ventricular arrhythmias occurred in 2 patients (0.8%). No differences in HF hospitalizations were found between patients who started levosimendan in the first 30 days after listing and those who did not (33.6% vs 34.5%; P=.848). Among those who did not, 102 patients (32.9%) crossed over to levosimendan after an HF admission. These patients had a rate of 0.57 HF admissions per month before starting levosimendan and 0.21 afterwards. Propensity score matching analysis showed no differences in survival at 1 year after listing between patients receiving levosimendan and those who did not (HR, 1.03; 95%CI, 0.36-2.97; P=.958) or in survival after HT (HR, 0.97; 95%CI, 0.60-1.56; P=.958). CONCLUSIONS: Repetitive levosimendan in an ambulatory setting as a bridge to heart transplantation is commonly used, is safe, and may reduce HF hospitalizations.

[Levosimendan for preventing low output syndrome in pediatric patients with correction of tetralogy of Fallot]. / Levosimendán para prevenir el síndrome de bajo gasto en pacientes pediátricos con corrección de tetralogía de Fallot.

Background: Tetralogy of Fallot is one of the most frequent cyanotic heart diseases in our country, occupying the second place reported by the national health program 2007- 2012 and its prevalence is around 11%. Patients undergoing correction for tetralogy of Fallot are considered patients with a prolonged ischemic time and a high risk of presenting low cardiac output syndrome. Objective: To compare levosimendan with milrinone to prevent low cardiac output syndrome in patients undergoing tetralogy of Fallot correction. Material and methods: Randomized controlled open, prospective, longitudinal and comparative clinical trial. The sample size consisted of 19 patients, with a 95% confidence level. Group 1: levosimendan 0.1 mcg/kg/min from anesthetic induction. Group 2: conventional management with milrinone 0.5 mcg/kg/min. Results: When comparing the final measurements, it can be observed that the mean arterial pressure of the intervention group (levosimendan) was statistically significant (p = 0.04), both in the intraoperative measurement and in the final measurement. When comparing uresis, we found that the intervention group had a greater amount of uresis (p = 0.03). Regarding lactate, both in the intraoperative measurement (p = 0.002) and in the final measurement (p = 0.02), a lower amount was found in the intervention group. Conclusions: The results in favor of the use of levosimendan were reported, demonstrating the prevention of low cardiac output syndrome.

Introducción: la tetralogía de Fallot es una de las cardiopatías cianóticas más frecuentes de nuestro país, pues ocupa el segundo lugar reportado por el Programa Nacional de Salud 2007-2012 y su prevalencia se sitúa aproximadamente en 11%. Los pacientes sometidos a corrección de tetralogía de Fallot se consideran pacientes con un tiempo de isquemia prolongado y con riesgo alto de presentar síndrome de bajo gasto cardiaco. Objetivo: comparar levosimendán con milrinona para prevenir el síndrome de bajo gasto cardiaco en pacientes operados de corrección de tetralogía de Fallot. Material y métodos: ensayo clínico aleatorizado, controlado, abierto, prospectivo, longitudinal y comparativo. El tamaño de la muestra se estimó en 19 pacientes, con un nivel de confianza del 95%. En el grupo 1 se empleó 0.1 mcg/kg/min de levosimendán desde la inducción anestésica; en el grupo 2 se usó el manejo convencional con milrinona de 0.5 mcg/kg/min. Resultados: al comparar las mediciones finales se pudo observar que la presión arterial media del grupo de intervención (levosimendán) fue estadísticamente significativa (p = 0.04), tanto en la medición transoperatoria como en la medición final. Al comparar la uresis encontramos que el grupo con intervención tuvo mayor cantidad de uresis (p = 0.03). En cuanto al lactato, tanto en la medición transoperatoria (p = 0.002) como en la medición final (p = 0.02) se encontró una menor cantidad en el grupo de intervención. Conclusiones: se reportaron los resultados a favor del uso del levosimendán, pues se demostró que previene el síndrome de bajo gasto cardiaco.

The effect of post-reperfusion levosimendan in an experimental intestinal ischemia-reperfusion model.

BACKGROUND: Levosimendan has been reported to have a positive effect on ischemia-reperfusion injury. Herein, we aimed to evaluate the effects of levosimendan applied after reperfusion in an experimental intestinal injury-reperfusion (IR) model. METHODS: Twenty-one Wistar-albino male rats were separated into three groups: Sham group (n = 7): solely superior mesenteric artery (SMA) was dissected after laparotomy; intestinal ischemia-reperfusion group (IIR, n = 7): SMA was clamped for 60 min and unclamped for 120 min to cause ischemia-reperfusion; IIR + levosimendan group (IIR + L, n = 7): levosimendan was administered in ischemia-reperfusion model. The mean arterial pressures (MAP) were measured in all groups. MAP measurements were performed at the end of stabilization, at the 15th, 30th, and 60th minute of ischemia; at the 15th, 30th, 60th, and 120th minute of reperfusion; and at the end of levosimendan bolus application and when levosimendan infusion concluded. Reperfusion injury was evaluated with tissue malondialdehyde (MDA) and by Chiu score. RESULTS: MAP at 15 min, 30 min, and 60 min of reperfusion was lower in IIR and IIR + L groups compared with basal inter-group measurements. Decline in MAP at 30 min after reperfusion was statistically significant in IIR and IIR + L groups when compared with the sham group. There was no significant difference between MDA levels in the groups. Chiu score was significantly lower in the sham group when compared to IIR and IIR + L groups and higher in IIR when compared to the IIR + L group. CONCLUSION: Levosimendan leads to a decrease in intestinal damage although it did not affect lipid peroxidation and MAP when administered after reperfusion in an experimental intestinal IR model.

Enantiomeric analysis of simendan on polysaccharide-based stationary phases by polar organic solvent chromatography.

Herein, the enantiomeric separation of simendan by high-performance liquid chromatography with ultraviolet detection using polysaccharide-based chiral stationary phases in polar organic mode is described. Three chiral columns (Chiralpak AD-H, Chiralcel OD-H, and Chiralpak AS) were screened using pure methanol and acetonitrile without additives under isocratic conditions. A reversed elution order was observed on the Chiralpak AD-H column when the methanol content in the mobile phase (methanol-acetonitrile mixtures) was above 10%, whereby levosimendan eluted prior to dextrosimendan. Further, it was found that increasing temperature effectively improved the enantioresolution on the Chiralpak AD-H column. Van't Hoff analysis was performed to evaluate the contribution of enthalpy and entropy to the chiral discrimination process. The best enantioseparation (α = 3.00, Rs = 12.85) was obtained on the Chiralpak AD-H column with methanol as the mobile phase at 40°C. Thus, a quantitative method for the resolution of dextrosimendan was established and validated, which could be used as a reference for the determination of dextrosimendan in levosimendan products.

Impact of levosimendan on cardiac function ,plasma BNP and serum cytokine levels in AHF patients／ / 心血管康复医学杂志

To observe therapeutic effect of levosimendan on acute heart failure (AHF) and its impact on cardiac function ,levels of brain natriuretic peptide (BNP) ,high sensitive C reactive protein (hsCRP) ,tumor necro‐sis factor (TNF)‐α and interleukin (IL)‐6. Methods :A total of 148 AHF patients treated in our hospital from Jan 2016 to Jan 2018 were randomly and equally divided into dobutamine group and levosimendan group ,both groups re‐ceived corresponding medication based on routine treatment for 21d.Cardiac function ,levels of plasma BNP ,serum hsCRP ,TNF‐α and IL‐6 ,6min walking distance (6MWD) before and after treatment ,total effective rate and inci‐dence of adverse reactions were observed and compared between two groups .Results :Total effective rate of levosi‐mendan group was significantly higher than that of dobutamine group (83. 78% vs.68.92%) , P＝0.033. Compared with dobutamine group after treatment , there were significant rise in LVEF [ (49. 98 ± 3. 68 )% vs.(52.17 ± 3.82)%] ,stroke volume [SV ,(67. 52 ± 5. 79) ml vs.(69. 48 ± 5. 83) ml] and 6MWD [ (328.46 ± 31.62) m vs. (396.75 ± 31.89) m] ,and significant reductions in left ventricular end systolic dimension [ (54. 12 ± 8.64) mm vs. (51.31 ± 8.26) mm] ,left ventricular end diastolic dimension [(65.25 ± 8. 86) mm vs.(62.14 ± 8.57) mm] ,levels of plasma BNP [ (572.59 ± 89. 62) mg／ml vs .(351.78 ± 81. 41) mg／ml] ,serum TNF‐α [ (24. 68 ± 5.83) ng／L vs. (21.05 ± 5. 39) ng／L] ,IL‐6 [(21.36 ± 4. 51) ng／L vs.(18.29 ± 4.34) ng／L] and hsCRP [(4. 89 ± 2. 15) ng／L vs. (3. 06 ± 1.47) ng／L] in levosimendan group , P＜0. 05 or ＜0. 01. There was no significant difference in incidence rate of adverse reactions during treatment between two groups , P＝0.690. Conclusion :Compared with dobutamine , levosimendan possesses more significant therapeutic effect on AHF .It can more significantly improve cardiac func‐tion ,exercise capacity and reduce cytokine levels in these patients .

Misinterpretation of the sublingual microcirculation during therapy with levosimendan.

There is increasing evidence in the literature that preoperative treatment with levosimendan optimizes cardiopulmonary haemodynamics in patients scheduled for the implantation of a Left Ventricular Assist Device (LVAD). The present case report describes changes in sublingual microcirculation using incident dark field video microscopy in a patient, who received a continuous infusion of 0.5 mg/h levosimendan 12 h before LVAD implantation. Despite no evident macrohaemodynamic or metabolic changes, there was a dramatic reduction in total vessel density and perfused vessel density suggesting a deterioration of microcirculation according to the consensus conference criteria in vessels smaller than 20 µm in diameter. However, the microcirculation of all visible vessels (regardless of diameter) was maintained. This potential misinterpretation is explained by a levosimedan-induced vasodilation and the subsequent reduction of the percentage of vessels with a diameter smaller than 20 µm. Physicians should carefully consider this pitfall of applying the consensus conference criteria in vasodilator-treated patients.

Protective effects of levosimendan and ulinastain on the isolated rabbit heart / 中华胸心血管外科杂志

ObjectiveLevosimendan,a new calcium ion sensitizer,is currently used in the treatment of heart failure and as an option for patients with injury to the left heart or at high risk for surgery.The study tried to evaluate the effects of levosimendan and ulinastain for protecting myocardium from ischemia-reperfusion (I/R) injury to the isolated immature rabbit hearts and investigate the possible mechanism.MethodsFifty New Zealand long-ear white immature rabbits were anesthetized and heparinized.Their hearts were rapidly removed and mounted on modified Langendorff apparatus.A left ventricle pressure monitoring line was inserted through the left atrial and mitral valve.The hearts were equilibrated with oxygenated K-H solution at 37℃ for 10 minutes.The rabbit hearts were randomly divided into 5 groups with 10 hearts in each group.Hearts in group C were perfused with K-H solution,in group U were perfused with ulinastain (50000 U/kg),in group LI were perfused with Levosimendan 0.1 μmol/L,in group L2 were perfused with Levosimendan 0.3 μmol/L,and in group L + U were perfused with Ulinastain (50 000 U/kg) and Levosimendan 0.1μmol/L.The hearts were arrested with St-Thomas solution for 30 min.Hearts in each group underwent 30 min-reperfusion with the same solutions after 30 min-global myocardial ischemia.Heart rate ( HR) Jeft ventricular pressure ( LVP) and LVdp/dtMax were monitored.Effluent from coronary sinus was collected at time of ischemia /reperfusion for measuring the concentration of TNF-α,IL-6,CK and cTnI.ResultsLVP and LVdp/dt in group L1,L2 and L + U were better than those in group C and U.But the heart rates in group L2 were higher than in other groups.Concentrations of CK,cTnI,TNF-α and IL-6 in the effluent from coronary sinus at 0、10 and 30 min of reperfusion were significantly lower in group L + U than in the other groups.ConclusionLevosimendan may have the similar effects with ulinastain in reducing the reperfusion injury to the immature myocardium.The protective effect of levosimendan (0.1 μmol/L) in combination with ulinastain (50 000 U/kg) was better than that of levosimendan or ulinastain alone.