Effect of nitric oxide delivery via cardiopulmonary bypass circuit on postoperative oxygenation in adults undergoing cardiac surgery (NOCARD trial): a randomised controlled trial.

BACKGROUND: Cardiac surgery involving cardiopulmonary bypass induces a significant systemic inflammatory response, contributing to various postoperative complications, including pulmonary dysfunction, myocardial and kidney injuries. OBJECTIVE: To investigate the effect of Nitric Oxide delivery via the cardiopulmonary bypass circuit on various postoperative outcomes. DESIGN: A prospective, single-centre, double-blinded, randomised controlled trial. SETTING: Rabin Medical Centre, Beilinson Hospital, Israel. PATIENTS: Adult patients scheduled for elective cardiac surgery were randomly allocated to one of the study groups. INTERVENTIONS: For the treatment group, 40 ppm of nitric oxide was delivered via the cardiopulmonary bypass circuit. For the control group, nitric oxide was not delivered. OUTCOME MEASURES: The primary outcome was the incidence of hypoxaemia, defined as a p a O2 /FiO 2 ratio less than 300 within 24 h postoperatively. The secondary outcomes were the incidences of low cardiac output syndrome and acute kidney injury within 72 h postoperatively. RESULTS: Ninety-eight patients were included in the final analysis, with 47 patients allocated to the control group and 51 to the Nitric Oxide group. The Nitric Oxide group exhibited significantly lower hypoxaemia rates at admission to the cardiothoracic intensive care unit (47.1 vs. 68.1%), P  = 0.043. This effect, however, varied in patients with or without baseline hypoxaemia. Patients with baseline hypoxaemia who received nitric oxide exhibited significantly lower hypoxaemia rates (61.1 vs. 93.8%), P  = 0.042, and higher p a O2 /FiO 2 ratios at all time points, F (1,30) = 6.08, P  = 0.019. Conversely, this benefit was not observed in patients without baseline hypoxaemia. No significant differences were observed in the incidence of low cardiac output syndrome or acute kidney injury. No substantial safety concerns were noted, and toxic methaemoglobin levels were not observed. CONCLUSIONS: Patients with baseline hypoxaemia undergoing cardiac surgery and receiving nitric oxide exhibited lower hypoxaemia rates and higher p a O2 /FiO 2 ratios. No significant differences were found regarding postoperative pulmonary complications and overall outcomes. TRIAL REGISTRATION: NCT04807413.

Protected cardiac surgery: strategic mechanical circulatory support to improve postcardiotomy mortality.

PURPOSE OF REVIEW: To examine the evolving landscape of cardiac surgery, focusing on the increasing complexity of patients and the role of mechanical circulatory support (MCS) in managing perioperative low cardiac output syndrome (P-LCOS). RECENT FINDINGS: P-LCOS is a significant predictor of mortality in cardiac surgery patients. Preoperative risk factors, such as cardiogenic shock and elevated lactate levels, can help identify those at higher risk. Proactive use of MCS, rather than reactive implementation after P-LCOS develops, may lead to improved outcomes by preventing severe organ hypoperfusion. The emerging concept of "protected cardiac surgery" emphasizes early identification of these high-risk patients and planned MCS utilization. Additionally, specific MCS strategies are being developed and refined for various cardiac conditions, including AMI-CS, valvular surgeries, and pulmonary thromboendarterectomy. SUMMARY: This paper explores the shifting demographics and complexities in cardiac surgery patients. It emphasizes the importance of proactive, multidisciplinary approaches to identify high-risk patients and implement early MCS to prevent P-LCOS and improve outcomes. The concept of protected cardiac surgery, involving planned MCS use and shared decision-making, is highlighted. The paper also discusses MCS strategies tailored to specific cardiac procedures and the ethical considerations surrounding MCS implementation.

Efficacy of perioperative prophylactic administration of corticosteroids in pediatric cardiac surgeries using cardiopulmonary bypass: a systematic review with meta-analysis.

An updated systematic review with meta-analysis comparing perioperative prophylactic administration of corticosteroids with placebo in pediatric cardiac surgeries using cardiopulmonary bypass was conducted. The Cochrane Central Register of Controlled Trials and MEDLINE (via PubMed) were searched for relevant randomized controlled trials published between January 1, 2000, and February 14, 2023. The primary outcome was postoperative in-hospital mortality. Secondary outcomes were duration of mechanical ventilation, length of intensive care unit and hospital stay, postoperative low cardiac output syndrome, and adverse events. A total of 11 studies were included in the meta-analysis. Corticosteroid administration did not decrease postoperative in-hospital mortality compared with placebo (relative risk, 0.69; 95% confidence interval, 0.40-1.17). Subgroup analyses according to the type of corticosteroids and neonates revealed that corticosteroids did not decrease postoperative in-hospital mortality. In the trial sequential analysis, the last point in the z-curve was within the futility borders. Although the duration of mechanical ventilation (mean difference, -5.54 h; 95% confidence interval (CI), -9.75 - -1.34) and incidence of low cardiac output syndrome (relative risk, 0.75; 95% CI, 0.59 - 0.96) decreased with corticosteroid administration, it did not affect the length of intensive care unit (mean difference, -0.28 days; 95% CI, -0.74 - 0.17) and hospital stay (mean difference, -0.59 days; 95% CI, -1.31 - 0.14). In conclusion, perioperative prophylactic corticosteroid administration in pediatric cardiac surgeries using cardiopulmonary bypass did not decrease postoperative in-hospital mortality compared with placebo. According to the trial sequential analysis results, additional randomized controlled trials assessing mortality are not required. PROSPERO REGISTRY NUMBER: CRD 42023391789.

Levosimendan in paediatric cardiac anaesthesiology: A systematic review and meta-analysis.

BACKGROUND: Low cardiac output syndrome (LCOS) after congenital cardiac surgery has an incidence of up to 25%. Preventing and treating LCOS is of pivotal importance as LCOS is associated with excess morbidity and mortality. OBJECTIVES: This systematic review assesses the safety and efficacy of peri-operative levosimendan administration in the setting of paediatric cardiac surgery. DESIGN: Systematic review of randomised controlled trials. Meta-analyses were performed on efficacy and exploratory outcomes. DATA SOURCES: Literature was searched in the following databases (MEDLINE, EMBASE, Web of Science and CENTRAL) from inception to July 2021. ELIGIBILITY CRITERIA: Randomised controlled trials comparing levosimendan with other inotropes or placebo in children younger than 18 years of age undergoing cardiac surgery. RESULTS: Nine studies enrolling a total of 539 children could be included in the systematic review. All trials study the prophylactic administration of levosimendan in comparison with placebo ( n   =  2), milrinone ( n  = 6) or dobutamine ( n   =  1). Levosimendan dosing varied considerably with only three studies using a loading dose. Levosimendan reduced the incidence of LCOS [risk ratio (RR) 0.80] [95% confidence interval (CI), 0.40 to 0.89, P  = 0.01] and increased cardiac index (MD 0.17 l min -1  m -2 ) (95% CI, 0.06 to 0.28, P  = 0.003) without affecting other outcomes (mortality, ICU length of stay, hospital length of stay, duration of mechanical ventilation, serum lactate, central venous oxygen saturation, serum creatine or acute kidney injury). CONCLUSION: The prophylactic use of levosimendan in children undergoing cardiac surgery reduced the incidence of LCOS and increased cardiac index compared with other inotropes or placebo. This effect did not translate into an improvement of other clinical endpoints.

Effect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery: The NITRIC Randomized Clinical Trial.

Importance: In children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation). Objective: To determine the effect of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children undergoing surgery for congenital heart disease. Design, Setting, and Participants: Double-blind, multicenter, randomized clinical trial in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands. A total of 1371 children younger than 2 years undergoing congenital heart surgery were randomized between July 2017 and April 2021, with 28-day follow-up of the last participant completed on May 24, 2021. Interventions: Patients were assigned to receive nitric oxide at 20 ppm delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care cardiopulmonary bypass without nitric oxide (n = 685). Main Outcomes and Measures: The primary end point was the number of ventilator-free days from commencement of bypass until day 28. There were 4 secondary end points including a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels. Results: Among 1371 patients who were randomized (mean [SD] age, 21.2 [23.5] weeks; 587 girls [42.8%]), 1364 (99.5%) completed the trial. The number of ventilator-free days did not differ significantly between the nitric oxide and standard care groups, with a median of 26.6 days (IQR, 24.4 to 27.4) vs 26.4 days (IQR, 24.0 to 27.2), respectively, for an absolute difference of -0.01 days (95% CI, -0.25 to 0.22; P = .92). A total of 22.5% of the nitric oxide group and 20.9% of the standard care group developed low cardiac output syndrome within 48 hours, needed extracorporeal support within 48 hours, or died by day 28, for an adjusted odds ratio of 1.12 (95% CI, 0.85 to 1.47). Other secondary outcomes were not significantly different between the groups. Conclusions and Relevance: In children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery. Trial Registration: anzctr.org.au Identifier: ACTRN12617000821392.

[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.

Clinical efficacy of levosimendan vs milrinone in preventing low cardiac output syndrome following pediatric cardiac surgery.

Background: Prophylactic milrinone is commonly used to prevent Low Cardiac Output Syndrome (LCOS) after pediatric cardiac surgery. This study compares the use of levosimendan with milrinone when used as the primary inotrope following pediatric cardiac surgery. Subjects and Methods: Forty infants undergoing corrective surgery for congenital heart disease were recruited during the study and randomized into two groups (group L and group M). During rewarming, a loading dose of levosimendan or milrinone was administered followed by a 24-hour infusion of the chosen inotrope. Echocardiographic variables were measured postoperatively. Statistical analysis was done with SPSS-20 computer package. Association between the variables was found by independent t test. P < 0.05 was considered statistically significant. Results: Mean age and weight of the patient in Group L was 8.55 ± 5.83 months and 6.05 ± 2.09 kgs, while that in group M was 6.85 ± 3.57 months and 5.26 ± 2.11 kgs. 4 patients (20%) treated with levosimendan had LCOS in comparison with 6 (30%) patients in those treated with milrinone. Echocardiographic parameters in both groups L and M were comparable (cardiac index 3.47 ± 0.76 vs 3.72 ± 1.05 L/min/m2, EF 66.10 ± 7.82% vs 59.34 ± 10.74%, stroke volume index 25.4 ± 6.3 vs 27.74 ± 10.35 mL/m2). The duration of ventilation, ICU stay and hospital stay were lesser in group L (12.75 ± 9.69, 35.95 ± 12.11, 119.10 ± 46.397 vs 23.60 ± 22.03, 51.20 ± 29.92, 140.20 ± 52.65 hours). Conclusions: The incidence of LCOS was lesser in those patients treated with levosimendan, when compared with those treated with milrinone. Cardiac index and stroke volume index were comparable between the two groups. Thus, levosimendan provides a non-inferior alternative to milrinone when used as the primary inotrope following pediatric cardiac surgery.

[Individualized use of levosimendan in cardiac surgery]. / Individualisierter Einsatz von Levosimendan in der Herzchirurgie.

BACKGROUND: Levosimendan is a cardiac inotrope that augments myocardial contractility without increasing myocyte oxygen consumption. Additionally, levosimendan has been shown to exhibit anti-inflammatory, antioxidative, and other cardioprotective properties and is approved for treatment of heart failure. Recent studies indicated that these beneficial effects can be achieved with doses lower than the standard dose of 12.5 mg. Patients with preoperatively diagnosed left ventricular ejection fraction (LVEF) ≤40% received 1.25 mg levosimendan after induction of anesthesia. After surgery, administration of low-dose levosimendan was repeated until cardiovascular stability was achieved. OBJECTIVE: This study aimed to evaluate if pharmacological preconditioning with 1.25 mg levosimendan in patients with LVEF ≤40% altered the postoperative need for inotropic agents, the incidence of newly occurring atrial fibrillation, renal replacement therapy, mechanical circulatory support and 30-day mortality. The cumulative dosage of levosimendan was recorded to assess the required dosage in the context of individualized treatment. MATERIAL AND METHODS: This retrospective study included patients with preoperatively diagnosed LVEF ≤40% who underwent cardiac surgery at this institution between January 2015 and December 2018 and who received 1.25 mg levosimendan after induction of anesthesia to prevent postoperative low cardiac output syndrome. Based on echocardiography results, invasive hemodynamic monitoring, and central venous or mixed venous oxygen saturation and lactate clearance, repetitive doses of levosimendan in 1.25 mg increments could be postoperatively administered until cardiovascular stability was achieved. The results were compared to the current literature. RESULTS: We identified 183 patients with LVEF <40% who received pharmacological preconditioning with 1.25 mg levosimendan. Maximum doses of epinephrine, incidence of atrial fibrillation, need for renal replacement therapy and 30-day mortality were found to be below the published rates of comparable patient collectives. In 73.2% of patients, a cumulative dosage of 5 mg levosimendan or less was considered sufficient. CONCLUSION: The presented concept of pharmacological preconditioning with 1.25 mg levosimendan followed by individualized additional dosing in cardiac surgery patients with preoperative LVEF ≤40% suggests that this concept is safe, with possible advantages regarding the need of inotropic agents, renal replacement therapy, and 30-day mortality, compared to the current literature. Individualized treatment with levosimendan to support hemodynamics and a timely reduction of inotropic agents needs further confirmation in randomized trials.

Coronary revascularisation in cardiac amyloidosis.

We present a case of coronary artery bypass grafting in a 78-year-old man with triple vessel disease and concomitant cardiac amyloidosis. Postoperatively, he developed a profound low cardiac output state and multiorgan failure. He died 3 weeks following surgery. Bypass surgery is rarely performed in patients with cardiac amyloidosis, and there is little in the literature regarding outcomes. The few published cases present a bleak picture, and hence percutaneous coronary intervention should always be preferred.

Preconditioning with levosimendan reduces postoperative low cardiac output in moderate-severe systolic dysfunction patients who will undergo elective coronary artery bypass graft surgery: a cost-effective strategy.

BACKGROUND: Patients with moderate-severe systolic dysfunction undergoing coronary artery bypass graft have a higher incidence of postoperative low cardiac output. Preconditioning with levosimendan may be a useful strategy to prevent this complication. In this context, design cost-effective strategies like preconditioning with levosimendan may become necessary. METHODS: In a sequential assignment of patients with Left Ventricle Ejection Fraction less than 40%, two strategies were compared in terms of cost-effectiveness: standard care (n = 41) versus preconditioning with Levosimendan (n = 13). The adverse effects studied included: postoperative new-onset atrial fibrillation, low cardiac output, renal failure and prolonged mechanical ventilation. The costs were evaluated using deterministic and probabilistic sensitivity analysis, and Monte Carlo simulations were performed. RESULTS: Preconditioning with levosimendan in moderate to severe systolic dysfunction (Left Ventricle Ejection Fraction < 40%), was associated with a lower incidence of postoperative low cardiac output in elective coronary artery bypass graft surgery 2(15.4%) vs 25(61%) (P < 0.01) and lesser intensive care unit length of stay 2(1-4) vs 4(3-6) days (P = 0.03). Average cost on levosimendan group was 14,792€ while the average cost per patient without levosimendan was 17,007€. Patients with no complications represented 53.8% of the total in the levosimendan arm, as compared to 31.7% in the non-levosimendan arm. In all Montecarlo simulations for sensitivity analysis, use of levosimendan was less expensive and more effective. CONCLUSIONS: Preconditioning with levosimendan, is a cost-effective strategy preventing postoperative low cardiac output in patients with moderate-severe left ventricular systolic dysfunction undergoing elective coronary artery bypass graft surgery.

Levosimendan Reduces Mortality and Low Cardiac Output Syndrome in Cardiac Surgery.

BACKGROUND: There has been conflicting evidence concerning the effect of levosimendan on clinical outcomes in patients undergoing cardiac surgery. Therefore, we performed a systematic review and conducted this meta-analysis to provide evidence for/against the administration of levosimendan in cardiac surgery patients. METHODS: We performed a meta-analysis from literature search in PubMed, EMBASE, and Cochrane Library. Only randomized controlled trials comparing the administration of levosimendan in cardiac surgery patients with a control group (other inotrope, standard therapy/placebo, or an intra-aortic balloon pump) were included. In addition, at least one clinical outcome had to be mentioned: mortality, myocardial infarction, low cardiac output syndrome (LCOS), acute kidney injury, renal replacement therapy, atrial fibrillation, prolonged inotropic support, length of intensive care unit, and hospital stay. The pooled treatment effects (odds ratio [OR], 95% confidence intervals [CI]) were assessed using a fixed or random effects model. RESULTS: The literature search retrieved 27 randomized, controlled trials involving a total of 3,198 patients. Levosimendan led to a significant reduction in mortality (OR: 0.67; 95% CI: 0.49-0.91; p = 0.0087). Furthermore, the incidence of LCOS (OR: 0.56, 95% CI: 0.42-0.75; p < 0.0001), acute kidney injury (OR: 0.63; 95% CI: 0.46-0.86; p = 0.0039), and renal replacement therapy (OR: 0.70; 95% CI: 0.50-0.98; p = 0.0332) was significantly decreased in the levosimendan group. CONCLUSION: Our meta-analysis suggests beneficial effects for the prophylactic use of levosimendan in patients with severely impaired left ventricular function undergoing cardiac surgery. The administration of levosimendan was associated with a reduced mortality, less LCOS, and restored adequate organ perfusion reflected in less acute kidney injury.

Developmental Pharmacokinetics and Age-Appropriate Dosing Design of Milrinone in Neonates and Infants with Acute Kidney Injury Following Cardiac Surgery.

BACKGROUND AND OBJECTIVE: Milrinone is used for the prevention of low cardiac output syndrome in pediatric patients after cardiac surgery. Milrinone is mainly eliminated by the kidneys; however, there is limited information on milrinone pharmacokinetics in infants who have acute kidney injury (AKI). The aim of this study was to develop a milrinone population pharmacokinetic model in neonates and infants with or without AKI. The developed milrinone pharmacokinetic model was utilized for a Monte Carlo simulation analysis to identify age-appropriate dosing regimens in neonates and infants. METHODS: Population pharmacokinetic analysis was performed with a total of 1088 serum milrinone concentrations obtained from 92 infants as part of a prospective clinical study in neonates and infants following cardiac surgery (ClinicalTrials.gov identifier NCT01966237). AKI stages were determined based on the Kidney Injury Improving Global Outcomes (KDIGO) Clinical Practice Guideline within the first three postoperative days. RESULTS: A two-compartment model was found to adequately describe the pharmacokinetic data. Allometrically scaled body weight, AKI stages, and maturation function were identified as significant predictors of milrinone clearance. The proposed dosing regimens for milrinone continuous infusions were determined based on a target concentration attainment of simulated steady-state concentration and covered three age groups across 0-12 months of age for each AKI stage. CONCLUSION: This study provides a milrinone population pharmacokinetic model in neonates and infants and captures the developmental changes in clearance. Age-appropriate dosing regimens were determined based on the simulation analysis with the developed pharmacokinetic model. The findings will facilitate model-informed precision dosing of milrinone in infants with or without AKI.

Infused cardioplegia index: A new tool to improve myocardial protection. A cohort study. / Índice de cardioplejía infundida: una nueva herramienta en la protección miocárdica. Un estudio de cohortes.

BACKGROUND: Strategies for cardio-protection are essential in coronary artery bypass graft surgery. The authors explored the relationship between cardioplegia volume, left ventricular mass index and ischemia time by means of the infused cardioplegia index and its relationship with post-operative low cardiac output syndrome. DESIGN: All patients undergoing coronary artery bypass graft surgery between January 2013 and December 2015 were included. Low cardiac output syndrome was defined according to criteria of the SEMICYUC's consensus document. The perioperative factors associated with low cardiac output syndrome were estimated, and using a ROC curve, the optimum cut-off point for the infused cardioplegia index to predict the absence of low cardiac output syndrome was calculated. RESULTS: Of 360 patients included, 116 (32%) developed low cardiac output syndrome. The independent risk predictors were: New York Heart Association Functional Classification (OR 1.8 [95% CI=1.18-2.55]), left ventricle ejection fraction (OR 0.95 (95% CI=0.93-0.98]), ICI (OR 0.99 [95% CI=0.991-0.996]) and retrograde cardioplegia (OR 1.2 [95% CI=1.03-1.50]). The infused cardioplegia index showed an area under the ROC curve of 0.77 (0.70-0.83; P<.001) for the absence of postoperative low cardiac output syndrome using the optimum cut-off point of 23.6ml·min-1(100g/m2 of LV)-1. CONCLUSIONS: The infused cardioplegia index presents an inverse relationship with the development of post-operative low cardiac output syndrome. This index could form part of new strategies aimed at optimising cardio-protection. The total volume of intermittent cardioplegia, especially that of maintenance, should probably be individualised, adjusting for ischemia time and left ventricle mass index.

Prophylactic use of levosimendan in pediatric patients undergoing cardiac surgery: a prospective randomized controlled trial.

BACKGROUND: The administration of levosimendan prophylactically to patients undergoing cardiac surgery remains a controversial practice, and few studies have specifically assessed the value of this approach in pediatric patients. This study therefore sought to explore the safety and efficacy of prophylactic levosimendan administration to pediatric patients as a means of preventing low cardiac output syndrome (LCOS) based upon hemodynamic, biomarker, and pharmacokinetic readouts. METHODS: This was a single-center, double-blind, randomized, placebo-controlled trial. Patients ≤ 48 months old were enrolled between July 2018 and April 2019 and were randomly assigned to groups that received either placebo or levosimendan infusions for 48 h post-surgery, along with all other standard methods of care. LCOS incidence was the primary outcome of this study. RESULTS: A total of 187 patients were enrolled, of whom 94 and 93 received levosimendan and placebo, respectively. LCOS incidence did not differ significantly between the levosimendan and placebo groups (10 [10.6%] versus 18 [19.4%] patients, respectively; 95% confidence interval [CI] 0.19-1.13; p = 0.090) nor did 90-day mortality (3 [3.2%] versus 4 [4.3%] patients, CI 0.14-3.69, p = 0.693), duration of mechanical ventilation (median, 47.5 h and 39.5 h, respectively; p = 0.532), ICU stay (median, 114.5 h and 118 h, respectively; p = 0.442), and hospital stay (median, 20 days and 20 days, respectively; p = 0.806). The incidence of hypotension and cardiac arrhythmia did not differ significantly between the groups. Levels of levosimendan fell rapidly without any plateau in plasma concentrations during infusion. A multiple logistic regression indicated that randomization to the levosimendan group was a predictor of LCOS. CONCLUSIONS: Prophylactic levosimendan administration was safe in pediatric patients and had some benefit to postoperative hemodynamic parameters, but failed to provide significant benefit with respect to LCOS or 90-day mortality relative to placebo. TRIAL REGISTRATION: Name of the registry: Safety evaluation and therapeutic effect of levosimendan on the low cardiac output syndrome in patients after cardiopulmonary bypass. TRIAL REGISTRATION NUMBER: ChiCTR1800016594. Date of registration: 11 June 2018. URL of trial registry record: http://www.chictr.org.cn/index.aspx.

Levosimendan versus placebo in cardiac surgery: a systematic review and meta-analysis.

The aim of this meta-analysis was to review all published randomized clinical trials comparing levosimendan versus placebo in patients undergoing cardiac surgery. PubMed, EMBASE and the Cochrane library database of clinical trials were searched for prospective randomized clinical trials investigating the perioperative use of levosimendan versus placebo in patients undergoing adult cardiac surgery from 1 May 2000 to 10 April 2017. Binary outcomes from individual studies were analysed to compute individual and pooled risk ratios (RRs) with pertinent 95% confidence intervals (CIs). Fourteen randomized clinical trials with a total of 2243 patients were included in this review. Overall meta-analysis results demonstrated that levosimendan was associated with a significant reduction in 30-day mortality (RR = 0.71, 95% CI = 0.53-0.95; P = 0.023). Subgroup analysis showed that this benefit was confined to the moderate and low ejection fraction studies (RR = 0.44, 95% CI = 0.27-0.70; P < 0.001), whereas no benefit was observed in the preserved ejection fraction studies (RR = 1.06, 95% CI = 0.72-1.56; P = 0.78). Levosimendan also reduced the risk of renal replacement therapy (RR = 0.66, 95% CI = 0.47-0.92; P = 0.015) and low cardiac output (RR = 0.40, 95% CI = 0.22-0.73; P = 0.003). No significant differences were detected, between the levosimendan group and the placebo group, in terms of risk of myocardial injury (RR = 0.90, 95% CI = 0.69-1.17; P = 0.44), intensive care unit stay (weighted mean differences = -0.57, 95% CI = -1.15 to 0.01; P = 0.055) and the use of ventricular assist device (RR = 0.42, 95% CI = 0.07-2.63; P = 0.35). In conclusion, levosimendan was associated with a reduced risk of mortality, renal replacement therapy and low cardiac output syndrome in patients undergoing cardiac surgery.

Effects of levosimendan on mortality in patients undergoing cardiac surgery: A systematic review and meta-analysis.

PURPOSE: We sought to determine the impact of levosimendan on mortality following cardiac surgery based on large-scale randomized controlled trials (RCTs). METHODS: We searched PubMed, Web of Science, Cochrane databases, and ClinicalTrials.gov for RCTs published up to December 2017, on levosimendan for patients undergoing cardiac surgery. RESULTS: A total of 25 RCTs enrolling 2960 patients met the inclusion criteria; data from 15 placebo-controlled randomized trials were included for meta-analysis. Pooled analysis showed that the all-cause mortality rate was 6.4% (71 of 1106) in the levosimendan group and 8.4% (93 of 1108) in the placebo group (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.55-1.04; P = 0.09). There were no significant differences between the two groups in the rates of myocardial infarction (OR: 0.91; 95% CI, 0.68-1.21; P = 0.52), serious adverse events (OR: 0.84; 95% CI, 0.66-1.07; P = 0.17), hypotension (OR: 1.69; 95% CI, 0.94-3.03; P = 0.08), and low cardiac output syndrome (OR: 0.47; 95% CI, 0.22-1.02; P = 0.05). CONCLUSION: Levosimendan did not result in a reduction in mortality in adult cardiac surgery patients. Well designed, adequately powered, multicenter trials are necessary to determine the role of levosimendan in adult cardiac surgery.

Characterization of the Glucocorticoid Receptor in Children Undergoing Cardiac Surgery.

OBJECTIVES: Postoperative administration of corticosteroids is common practice for managing catecholamine refractory low cardiac output syndrome. Since corticosteroid activity is dependent on the glucocorticoid receptor, we sought to characterize glucocorticoid receptor levels in children undergoing cardiac surgery and examined the association between glucocorticoid receptor levels and cardiovascular dysfunction. DESIGN: Prospective observational cohort study. SETTING: Large, tertiary pediatric cardiac center. SUBJECTS: Children undergoing corrective or palliative cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A prospective observational cohort study was conducted in 83 children with congenital heart disease. Total glucocorticoid receptor levels were measured in the peripheral WBCs using flow cytometry. In addition, blood samples were collected for total cortisol levels. The primary outcome studied was the time to being inotrope free. An increase in glucocorticoid receptor level from postoperative day 1 to postoperative day 3 was associated with a longer time to being inotrope free (hazard ratio, 0.49 [0.29-0.81]; p = 0.01) in the univariate analysis. This association remained significant after adjusting for age, weight, cardiopulmonary bypass time, cross clamp time, Risk Adjustment for Congenital Heart Surgery-1 score, and postoperative steroid use (hazard ratio, 0.53 [0.29-0.99]; p = 0.05). Postoperative day 3 glucocorticoid receptor level showed a trend to have longer time to being inotrope free (hazard ratio, 0.66 [0.42-1.02]; p = 0.0.06). The cortisol levels minimally increased during the study duration and did not correlate with glucocorticoid receptor levels. CONCLUSIONS: Increasing glucocorticoid receptor levels in peripheral WBCs of children undergoing cardiac surgery are associated with a longer time to being inotrope free. Cortisol levels minimally increased during the study duration. These results suggest that exposure to high-dose perioperative corticosteroids may suppress the hypothalamic-pituitary-adrenal axis leading to increase in glucocorticoid receptor levels in response to a low cortisol environment. Further studies are required to better delineate the interplay between glucocorticoid receptor levels, cortisol levels, corticosteroid exposure, and postoperative inotropic requirements.

Prevention of Low Cardiac Output Syndrome After Pediatric Cardiac Surgery: A Double-Blind Randomized Clinical Pilot Study Comparing Dobutamine and Milrinone.

OBJECTIVES: Dobutamine and milrinone are commonly used after open-heart surgery to prevent or treat low cardiac output syndrome. We sought to compare efficacy and safety of these drugs in pediatric patients. DESIGN: Prospective, single-center, double-blinded, randomized clinical pilot study. SETTING: Tertiary-care university children's hospital postoperative pediatric cardiac ICU. PATIENTS: After written consent, 50 consecutive patients (age, 0.2-14.2 yr; median, 1.2 yr) undergoing open-heart surgery for congenital malformations were included. INTERVENTIONS: After cardiopulmonary bypass, a continuous infusion of either dobutamine or milrinone was administered for the first 36 postoperative hours. Maximum dose: dobutamine 6 µg/kg/min, milrinone 0.75 µg/kg/min. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in demographic data, complexity of surgery, and intraoperative characteristics between the two study groups (dobutamine vs milrinone). Efficacy was defined as need for additional vasoactive support, which did not differ between groups (dobutamine 61% vs milrinone 67%; p = 0.71). Sodium nitroprusside was used more often in the dobutamine group (42% vs 13%; p = 0.019). Systolic blood pressure showed a trend toward higher values in the dobutamine group, whereas both drugs increased heart rate early postoperatively. Echocardiography demonstrated a consistently good cardiac function in both groups. Central venous oxygen saturation, serum lactate levels, urine output, time to chest tube removal, length of mechanical ventilation, ICU, and hospital stay were similar in both groups. Both drugs were well tolerated, no serious adverse events occurred. CONCLUSIONS: Dobutamine and milrinone are safe, well tolerated, and equally effective in prevention of low cardiac output syndrome after pediatric cardiac surgery. The hemodynamic response of the two drugs is comparable. In uncomplicated cases, a trend toward the more cost-saving dobutamine might be anticipated; however, milrinone demonstrated a trend toward higher efficacy in afterload reduction.