Preoperative Levosimendan in Patients With Severe Left Ventricular Dysfunction Undergoing Isolated Coronary Artery Bypass Grafting: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To verify the impact of preoperative levosimendan on patients with severe left ventricular dysfunction (ejection fraction <35%) undergoing isolated coronary artery bypass grafting. DESIGN: A meta-analysis. SETTING: Hospitals. PARTICIPANTS: The authors included 1,225 patients from 6 randomized controlled trials. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors performed a meta-analysis of trials that compared preoperative levosimendan with placebo or no therapy, reporting efficacy and safety endpoints. Statistical analyses used mean differences and risk ratios (RR), with a random effects model. Six studies were included, comprising 1,225 patients, of whom 615 (50.2%) received preoperative levosimendan, and 610 (49.8%) received placebo/no therapy. Preoperative levosimendan showed a lower risk of all-cause mortality (RR 0.31; 95% CI 0.16-0.60; p < 0.01; I2 = 0%), postoperative acute kidney injury (RR 0.44; 95% CI 0.25-0.77; p < 0.01; I2 = 0%), low-cardiac-output syndrome (RR 0.45; 95% CI 0.30-0.66; p < 0.001; I2 = 0%), and postoperative atrial fibrillation (RR 0.49; 95% CI 0.25-0.98; p = 0.04; I2 = 85%) compared to control. Moreover, levosimendan significantly reduced the need for postoperative inotropes and increased the cardiac index at 24 hours postoperatively. There were no differences between groups for perioperative myocardial infarction, hypotension, or any adverse events. CONCLUSION: Preoperative levosimendan in patients with severe left ventricular dysfunction undergoing isolated coronary artery bypass grafting was associated with reduced all-cause mortality, low-cardiac-output syndrome, acute kidney injury, postoperative atrial fibrillation, and the need for circulatory support without compromising safety.

Extending the 'host response' paradigm from sepsis to cardiogenic shock: evidence, limitations and opportunities.

Recent clinical and research efforts in cardiogenic shock (CS) have largely focussed on the restoration of the low cardiac output state that is the conditio sine qua non of the clinical syndrome. This approach has failed to translate into improved outcomes, and mortality has remained static at 30-50%. There is an unmet need to better delineate the pathobiology of CS to understand the observed heterogeneity of presentation and treatment effect and to identify novel therapeutic targets. Despite data in other critical illness syndromes, specifically sepsis, the role of dysregulated inflammation and immunity is hitherto poorly described in CS. High-dimensional molecular profiling, particularly through leukocyte transcriptomics, may afford opportunity to better characterise subgroups of patients with shared mechanisms of immune dysregulation. In this state-of-the-art review, we outline the rationale for considering molecular subtypes of CS. We describe how high-dimensional molecular technologies can be used to identify these subtypes, and whether they share biological features with sepsis and other critical illness states. Finally, we propose how the identification of molecular subtypes of patients may enrich future clinical trial design and identification of novel therapies for CS.

Discontinuation of Intravenous Catecholamine by Oral Ivabradine in a Patient with Decompensated Heart Failure with Low Cardiac Output Syndrome.

Ivabradine has been shown to improve heart failure with sinus tachycardia by reducing the heart rate without affecting left ventricular systolic function or blood pressure. Here we report a case of a catecholaminedependent patient, New York Heart Association (NYHA) class IV, LVEF of 18%, and low cardiac output, who was able to discontinue intravenous catecholamine by oral administration of ivabradine.

Predictors and associated clinical outcomes of low cardiac output syndrome following cardiac surgery: insights from the LEVO-CTS trial.

AIMS: High-risk cardiac surgery is commonly complicated by low cardiac output syndrome (LCOS), which is associated with high mortality. There are limited data derived from multi-centre studies with adjudicated endpoints describing factors associated with LCOS and its downstream clinical outcomes. METHODS AND RESULTS: The Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial evaluated prophylactic levosimendan vs. placebo in patients with a reduced ejection fraction undergoing coronary artery bypass grafting (CABG) and/or valve surgery. We conducted a pre-specified analysis on LCOS, which was characterized by a four-part definition. We constructed a multivariable logistical regression model to evaluate risk factors associated with LCOS and performed Cox proportional hazards modelling to determine the association of LCOS with 90-day mortality. A total of 186 (22%) of 849 patients in the LEVO-CTS trial developed LCOS. The factors most associated with a higher adjusted risk of LCOS were pre-operative ejection fraction [odds ratio (OR) 1.26; 95% confidence interval (CI): 1.08-1.46 per 5% decrease] and age (OR 1.13; 95% CI: 1.04-1.24 per 5-year increase), whereas isolated CABG surgery (OR 0.44, 95% CI: 0.31-0.64) and levosimendan use (OR 0.65; 95% CI: 0.46-0.92) were associated with a lower risk of LCOS. Patients with LCOS had worse outcomes, including renal replacement therapy at 30-day (10 vs. 1%) and 90-day mortality (16 vs. 3%, adjusted hazard ratio of 5.04, 95% CI: 2.66-9.55). CONCLUSION: Low cardiac output syndrome is associated with a high risk of post-operative mortality in high-risk cardiac surgery.

Comprehensive and Safe Decongestion in Acutely Decompensated Heart Failure.

PURPOSE OF THE REVIEW: Progressive intravascular, interstitial, and alveolar fluid overload underlies the transition from compensated to acutely decompensated heart failure and loop diuretics are the mainstay of treatment. Adverse effects and resistance to loop diuretics received much attention while the contribution of a depressed cardiac output to diuretic resistance was downplayed. RECENT FINDINGS: Analysis of experience with positive inotropic agents, especially dobutamine, indicates that enhancement of cardiac output is not consistently associated with increased renal blood flow. However, urinary output and renal sodium excretion increase likely due to dobutamine-mediated decrease in renal and systemic reduced activation of sympathetic nervous- and renin-angiotensin-aldosterone system. Mechanical circulatory support with left ventricular assist devices ascertained the contribution of low cardiac output to diuretic resistance and the pathogenesis and progression of kidney disease in acutely decompensated heart failure. Diuretic resistance commonly occurs in acutely decompensated heart failure. However, failure to resolve fluid overload despite high doses of loop diuretics should alert to the presence of a low cardiac output state.

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.

[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.

Indonesian Study: Triiodothyronine for Infants Less than 5 Months Undergoing Cardiopulmonary Bypass.

This study evaluates the efficacy and safety of oral triiodothyronine on time to extubation for infants less than 5 months undergoing heart surgery in Indonesia, and primarily relates to patients in emerging programs with high malnutrition and mortality. In this randomized, double-blind, placebo-controlled trial, oral triiodothyronine (T3, Tetronine®) 1 µg/kg-body weight/dose or placebo (saccharum lactis) was administered via nasogastric tube every 6 h for 60 h to treatment group. A total of 120 patients were randomized into T3 (61 patients) and placebo (59 patients) groups. The majority of the patients had moderate to severe malnutrition (55.83%) with a high post-operative mortality rate of 23.3%. The T3 group showed significantly higher serum FT3 levels from 1 until 48 h post cross-clamp removal (p < 0.0001), lower incidence of low cardiac output syndrome at both 6 h (28 [45.9%] vs. 39 [66.1%] patients, p = 0.03, OR 2.3, 95% CI: 1.10-4.81) and 12 h after cross-clamp removal (25 [41.7%] vs. 36 [63.2%], p = 0.02, OR 2.40, 95% CI: 1.14-5.05). Although not statistically significant, the treatment group had shorter median (IQR) intubation time (2.59 [1.25-5.24] vs. 3.77 [1.28-6.64] days, p = 0.16, HR 1.36, 95% CI: 0.88-2.09)] and lower mortality (10 [16.4%] vs. 18 [30.5%], p = 0.07]. Patients with Aristotle score < 10.0 (low risk) receiving T3 had faster extubation than placebo patients (p = 0.021, HR of 1.90, 95% CI: 1.10-3.28) and were significantly less likely to require CPR or experience infection (p = 0.027, OR 8.56, 95% CI:0.99-73.9 and p = 0.022, OR 4.09 95% CI: 1.16-14.4, respectively). Oral T3 supplementation reduced overall incidence of low cardiac output syndrome and significantly reduced the time to extubation in low-risk patients. Therefore, prophylactic oral T3 administration may be beneficial in these patients.Trial Registration: ClinicalTrials.gov NCT02222532.

Effect of Levosimendan Treatment in Pediatric Patients With Cardiac Dysfunction: An Update of a Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Levosimendan increasingly has been used to treat heart failure and cardiac dysfunction in pediatric patients. Currently, there is only limited evidence that this drug positively affects outcomes. The authors' aim was to investigate the effects of levosimendan on hemodynamic parameters and outcomes in pediatric patients in all clinical settings. The study design was a systematic review of randomized and nonrandomized studies. Randomized clinical trials (RCTs) were included in a meta-analysis. The primary outcome of the meta-analysis was the effect of levosimendan on central venous oxygen saturation (ScvO2) and lactate values as surrogate markers of low-cardiac-output syndrome. The study setting was any acute care setting. Study participants were pediatric patients (age <18 years) receiving levosimendan, and the intervention was levosimendan versus any control treatment. The authors identified 44 studies published from 2004 to 2020, including a total of 1,131 pediatric patients. Nine studies (enrolling 547 patients) were RCTs, all performed in a pediatric cardiac surgery setting. Three RCTs were judged to carry a low risk of bias. In the RCTs, levosimendan administration was associated with a significant improvement of ScvO2 (p = 0.03) and a trend toward lower postoperative lactate levels (p = 0.08). No differences could be found for secondary outcomes. Levosimendan use in pediatric patients is not associated with major side effects and may lead to hemodynamic improvement after cardiac surgery. However, its impact on major clinical outcomes remains to be determined. Overall, the quality of evidence for levosimendan use in pediatric patients is low, and further high-quality RCTs are needed.

Eficacia y seguridad de milrinona en pacientes pediátricos con síndrome de bajo gasto cardíaco postoperatorio de cardiopatía congénita (incluido el trasplante cardíaco) / Efficacy and safety of milrinone in pediatric patients with postoperative low cardiac output syndrome of congenital heart disease (including heart transplantation)

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de milrinona en pacientes pediátricos con síndrome de bajo gasto cardíaco (SBGC) en el periodo postoperatorio de cardiopatía congénita. El síndrome de bajo gasto cardíaco (SBGC) ocurre cuando la función de eyección del corazón es insuficiente para mantener un flujo sanguíneo adecuado para satisfacer la demanda de oxígeno de los tejidos del cuerpo. El SBGC es la principal causa de morbilidad y mortalidad en el estado postoperatorio de pacientes pediátricos con cardiopatías. En Estados Unidos, en el 2004, se reportó que el 25% de niños con cardiopatías desarrolló SBGC luego de una cirugía cardíaca. No existe consenso sobre los parámetros para el diagnóstico del SBGC en la población pediátrica. Algunos de estos parámetros son: valores altos o incremento rápido del lactato en sangre, disminución en la producción de orina, incremento de la diferencia entre la temperatura periférica y la temperatura corporal central, bajo gasto cardíaco, alto requerimiento de inotrópicos y fracción de eyección menor a 40 %. En EsSalud, se cuenta con agentes simpaticomiméticos como: adrenalina, dopamina, y dobutamina para el tratamiento del SBGC postoperatorio en población pediátrica (incluidos los pacientes con trasplante cardíaco). Sin embargo, los especialistas consideran que milrinona, podría ofrecer mayor beneficio en el tratamiento de pacientes pediátricos con SBGC postoperatorio de cardiopatía congénita (incluido el trasplante cardíaco). METODOLOGÍA: La búsqueda de la literatura científica se realizó con el objetivo de identificar evidencia sobre la eficacia y seguridad de milrinona, en comparación con el tratamiento convencional (dopamina, adrenalina, dobutamina), en pacientes pediátricos con SBGC postoperatorio de cardiopatía congénita (incluido el trasplante cardíaco). La búsqueda de la evidencia se realizó en las bases de datos bibliográficas: PubMed, Lilacs y The Cochrane Library. Adicionalmente, se revisó la evidencia generada por grupos internacionales que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica, tales como The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH), Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Quality and Efficiency in Health Care (IQWiG), Scottish Medicines Consortium (SMC), Haute Autorité de Santé (HAS), Institute for Clinical and Economic Review (ICER), y Comissão nacional de incorporação de tecnologías no sus (CONITEC). También se realizó una búsqueda manual en las bases The Guidelines International Network (G-I-N), el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), y se colectó información sobre el medicamento de interés del presente dictamen en las páginas web de la European Medicines Agency (EMA), y Food and Drug Administration (FDA). Finalmente, se realizó una búsqueda manual en el portal ClinicalTrials.gov del National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o que aún no hayan sido publicados. RESULTADOS: Se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: En el presente documento, se evaluó la mejor evidencia científica disponible en relación con la eficacia y seguridad de milrinona en comparación con el tratamiento convencional (dopamina, adrenalina, dobutamina), en pacientes pediátricos con SBGC postoperatorio de cardiopatía congénita (incluido el trasplante cardíaco). La búsqueda de la literatura científica identificó tres GPC, el estudio pivotal de milrinona y un ensayo clínico no aleatorizado. Las GPC elaboradas por Sarris et al. y de Kantor et al., coinciden en recomendar fuertemente el uso de medicamentos inotrópicos para mejorar el gasto. la guía de Alphonso et al. recomienda el uso de medicamentos inodilatadores o vasodilatadores para mejorar el gasto cardiaco, sin mencionar algún medicamento en particular. El ECA PRIMACORP de fase III, doble-ciego y pivotal de milrinona, evaluó la eficacia y seguridad del uso de milrinona en comparación con placebo, para prevenir el desarrollo del SBGC en pacientes pediátricos. En otras palabras, este estudio no analizó el uso de milrinona en pacientes con el SBGC instaurado (como tratamiento del SBGC), población objetivo del presente dictamen. El estudio elaborado por Duggal et al, evaluó el efecto de milrinona en pacientes pediátricos con SBGC postoperatorio. El estudio reportó una mejora de la función biventricular, pero no se encontraron diferencias en las tasas de eyección cardiacas. Sin embargo, las limitaciones de su diseño, como la falta de un grupo control, impiden que se pueda asegurar que estos resultados se deben al uso de milrinona. La evidencia sugerida por los especialistas de EsSalud, correspondiente a un artículo de revisión y tres estudios que analizaron los patrones de prescripciones de medicamentos para el tratamiento o prevención del SBGC en pacientes pediátricos, no permite conocer si milrinona es más eficaz o seguro que las alternativas disponibles en EsSalud (dopamina, adrenalina, dobutamina) y/o no brindan información sobre el uso de milrinona en niños con SBGC. Por lo expuesto, el Instituto de Evaluaciones de Tecnologías en Salud e Investigación ­ IETSI no aprueba el uso de milrinona en pacientes pediátricos con SBGC postoperatorio de cardiopatía congénita (incluido el trasplante cardíaco).

Usefulness of Tolvaptan for the Postoperative Control After Kidney Transplantation in a Patient With Cardiac Hypofunction: A Case Report.

BACKGROUND: Kidney transplantation in patients with cardiac hypofunction is challenging. Even if the surgery is successfully performed, these patients may suffer from low output cardiac function. We report the case of a patient with severe cardiac hypofunction who developed heart failure (HF) complicated with low output cardiac function, which markedly improved after the administration of tolvaptan, after successful living kidney transplantation. CASE PRESENTATION: A 70-year-old man was diagnosed with chronic renal failure of unknown etiology 4 years previously, for which hemodialysis was initiated. Three years previously, percutaneous coronary intervention was performed because of acute myocardial infarction. Since then, he had been hospitalized for the control of HF. He was referred to our department because he wished to undergo kidney transplantation. We decided to perform the transplantation after determining that he could tolerate the operation. On postoperative day 6, however, his urine discharge volume suddenly declined, leading to an increase in his body weight despite administration of an adequate amount of furosemide, and he was diagnosed with acute HF. The patient's condition markedly improved after the introduction of tolvaptan. CONCLUSION: To our knowledge, this is the first report of improvement in postoperative HF after tolvaptan administration. Although numerous kidney transplantations have been performed at our institute, it is relatively rare that we decide to operate in a patient with severe cardiac hypofunction.

Circulating cyclic adenosine monophosphate concentrations in milrinone treated paediatric patients after congenital heart surgery.

BACKGROUND: Milrinone is a phosphodiesterase type 3 inhibitor that results in a positive inotropic effect in the heart through an increase in cyclic adenosine monophosphate. The purpose of this study was to evaluate circulating cyclic adenosine monophosphate and milrinone concentrations in milrinone treated paediatric patients undergoing congenital heart surgery. METHODS: Single-centre prospective observational pilot study from January 2015 to December 2017 including children aged birth to 18 years. Milrinone and circulating cyclic adenosine monophosphate concentrations were measured at four time points through the first post-operative day and compared between patients with and without low cardiac output syndrome, defined using clinical and laboratory criteria. RESULTS: Fifty patients were included. Nine (18%) developed low cardiac output syndrome. For all patients, 22% had single ventricle heart disease. The density and distribution of cyclic adenosine monophosphate concentrations varied between those with and without low cardiac output syndrome but were not significantly different. Milrinone concentrations increased in all patients. Paired t-tests demonstrated an increase in circulating cyclic adenosine monophosphate concentrations during the post-operative period among patients without low cardiac output syndrome. CONCLUSIONS: In this prospective observational study, circulating cyclic adenosine monophosphate concentrations increased in those without low cardiac output syndrome during the first 24 post-operative hours and milrinone concentrations increased in all patients. Further study of the utility of cyclic adenosine monophosphate concentrations in milrinone treated patients is necessary.

[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.

Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome.

BACKGROUND: Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) are potentially life-threatening complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery. While there is solid evidence for the treatment of other cardiovascular diseases of acute onset, treatment strategies in haemodynamic instability due to CS and LCOS remains less robustly supported by the given scientific literature. Therefore, we have analysed the current body of evidence for the treatment of CS or LCOS with inotropic and/or vasodilating agents. This is the second update of a Cochrane review originally published in 2014. OBJECTIVES: Assessment of efficacy and safety of cardiac care with positive inotropic agents and vasodilator agents in CS or LCOS due to AMI, HF or after cardiac surgery. SEARCH METHODS: We conducted a search in CENTRAL, MEDLINE, Embase and CPCI-S Web of Science in October 2019. We also searched four registers of ongoing trials and scanned reference lists and contacted experts in the field to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials (RCTs) enrolling patients with AMI, HF or cardiac surgery complicated by CS or LCOS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures according to Cochrane standards. MAIN RESULTS: We identified 19 eligible studies including 2385 individuals (mean or median age range 56 to 73 years) and three ongoing studies. We categorised studies into 11 comparisons, all against standard cardiac care and additional other drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo; enoximone versus dobutamine, piroximone or epinephrine-nitroglycerine; epinephrine versus norepinephrine or norepinephrine-dobutamine; dopexamine versus dopamine; milrinone versus dobutamine and dopamine-milrinone versus dopamine-dobutamine. All trials were published in peer-reviewed journals, and analyses were done by the intention-to-treat (ITT) principle. Eighteen of 19 trials were small with only a few included participants. An acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements occurred in nine of 19 trials. In general, confidence in the results of analysed studies was reduced due to relevant study limitations (risk of bias), imprecision or indirectness. Domains of concern, which showed a high risk in more than 50% of included studies, encompassed performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events. All comparisons revealed uncertainty on the effect of inotropic/vasodilating drugs on all-cause mortality with a low to very low quality of evidence. In detail, the findings were: levosimendan versus dobutamine (short-term mortality: RR 0.60, 95% CI 0.36 to 1.03; participants = 1701; low-quality evidence; long-term mortality: RR 0.84, 95% CI 0.63 to 1.13; participants = 1591; low-quality evidence); levosimendan versus placebo (short-term mortality: no data available; long-term mortality: RR 0.55, 95% CI 0.16 to 1.90; participants = 55; very low-quality evidence); levosimendan versus enoximone (short-term mortality: RR 0.50, 0.22 to 1.14; participants = 32; very low-quality evidence; long-term mortality: no data available); epinephrine versus norepinephrine-dobutamine (short-term mortality: RR 1.25; 95% CI 0.41 to 3.77; participants = 30; very low-quality evidence; long-term mortality: no data available); dopexamine versus dopamine (short-term mortality: no deaths in either intervention arm; participants = 70; very low-quality evidence; long-term mortality: no data available); enoximone versus dobutamine (short-term mortality RR 0.21; 95% CI 0.01 to 4.11; participants = 27; very low-quality evidence; long-term mortality: no data available); epinephrine versus norepinephrine (short-term mortality: RR 1.81, 0.89 to 3.68; participants = 57; very low-quality evidence; long-term mortality: no data available); and dopamine-milrinone versus dopamine-dobutamine (short-term mortality: RR 1.0, 95% CI 0.34 to 2.93; participants = 20; very low-quality evidence; long-term mortality: no data available). No information regarding all-cause mortality were available for the comparisons milrinone versus dobutamine, enoximone versus piroximone and enoximone versus epinephrine-nitroglycerine. AUTHORS' CONCLUSIONS: At present, there are no convincing data supporting any specific inotropic or vasodilating therapy to reduce mortality in haemodynamically unstable patients with CS or LCOS. Considering the limited evidence derived from the present data due to a high risk of bias and imprecision, it should be emphasised that there is an unmet need for large-scale, well-designed randomised trials on this topic to close the gap between daily practice in critical care of cardiovascular patients and the available evidence. In light of the uncertainties in the field, partially due to the underlying methodological flaws in existing studies, future RCTs should be carefully designed to potentially overcome given limitations and ultimately define the role of inotropic agents and vasodilator strategies in CS and LCOS.

An evidence-based review of the use of vasoactive and inotropic medications in post-operative paediatric patients after cardiac surgery with cardiopulmonary bypass from 2000 to 2020.

BACKGROUND: Infants with moderate-to-severe CHD frequently undergo cardiopulmonary bypass surgery in childhood. Morbidity and mortality are highest in those who develop post-operative low cardiac output syndrome. Vasoactive and inotropic medications are mainstays of treatment for these children, despite limited evidence supporting their use. METHODS: To help inform clinical practice, as well as the conduct of future trials, we performed a systematic review of existing literature on inotropes and vasoactives in children after cardiac surgery using the PubMed and EMBASE databases. We included studies from 2000 to 2020, and the patient population was defined as birth - 18 years of age. Two reviewers independently reviewed studies to determine final eligibility. RESULTS: The final analysis included 37 papers. Collectively, selected studies reported on 12 different vasoactive and inotropic medications in 2856 children. Overall evidence supporting the use of these drugs in children after cardiopulmonary bypass was limited. The majority of studies were small with 30/37 (81%) enrolling less than 100 patients, 29/37 (78%) were not randomised, and safety and efficacy endpoints differed widely, limiting the ability to combine data for meta-analyses. CONCLUSION: Vasoactive and inotropic support remain critical parts of post-operative care for children after cardiopulmonary bypass surgery. There is a paucity of data for the selection and dosing of vasoactives and inotropes for these patients. Despite the knowledge gaps that remain, numerous recent innovations create opportunities to rethink the conduct of clinical trials in this high-risk population.

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).

Effects of levosimendan on ventriculo-arterial coupling and cardiac efficiency in paediatric patients with single-ventricle physiology after surgical palliation: retrospective study.

OBJECTIVES: The use of levosimendan for paediatric patients with low cardiac output after congenital heart surgery has been recently described. We sought to evaluate ventriculo-arterial coupling (VAC) and other ventricular energetic parameters before and after 72 h from levosimendan start in infants with single-ventricle physiology and cardiac failure after palliation with Norwood or hybrid procedures. METHODS: In this single-centre retrospective study, 9 consecutive patients affected by hypoplastic left heart syndrome-like anatomy were retrospectively analysed. Systolic elastance, diastolic elastance, arterial elastance, VAC and cardiac mechanical efficiency were calculated by measuring, through 2-dimensional echocardiography, end-systolic volume and end-diastolic volume and by recording mean arterial pressure and central venous pressure. RESULTS: The median (range) weight and age were 2.8 (2.3-6) kg and 16.5 (6-116) days, respectively. After 72 h from levosimendan start, end-systolic volume significantly decreased (-1 ml, -3.2 to -0.1, P = 0.007), whereas mean arterial pressure and end-diastolic volume remained stable. Heart rate showed a significant decrease (-28 beats/min, -41 to 22, P = 0.008). Systolic elastance (2.9 mmHg/ml, 0.4-5.4, P = 0.008), arterial elastance (-5.9, -24 to -0.5, P = 0.038), VAC (-0.86, -1.5 to -0.16, P = 0.009) and cardiac mechanical efficiency (0.18, 0.03-0.22, P = 0.008) differences also showed significant modifications. CONCLUSIONS: In a small case series of patients with single-ventricle physiology, levosimendan showed to improve contractility and optimize VAC, with a reduction of heart rate. Monitoring of VAC and ventricular energetics can be an interesting aspect to improve the management of heart failure in infants with univentricular anatomy.