Meta-analysis of the Safety and Efficacy of Levosimendan for Cardiac Insufficiency in Infants and Children

Summary

This meta-analysis of 16 studies suggests that levosimendan has a favorable safety profile in infants and children with cardiac insufficiency and is associated with an early, time-dependent reduction in lactate levels—an indicator of tissue hypoxia and impaired perfusion—without increasing the risk of adverse events.

Abstract

This meta-analysis aimed to evaluate the safety and efficacy of levosimendan for cardiac insufficiency in infants and children, conducted in accordance with PRISMA guidelines and a PROSPERO-registered protocol. Databases including PubMed, Web of Science, Embase, and the Cochrane Library were searched up to October 6, 2024. A total of 276 initial records were screened, and 16 studies (10 randomized controlled trials and 6 retrospective observational studies) were ultimately included. Meta-analyses using Stata and RevMan revealed that at 6 h post-intervention, levosimendan significantly reduced heart rate (WMD=-7.60, 95% CI [-15.16,-0.04]), mean arterial pressure (WMD=-4.04, 95% CI [-6.5,-1.58]), and lactate levels (SMD=-0.29, 95% CI [-0.58,-0.00]) compared with the control group. However, no significant effects on these three indices were observed at 12 or 24 h. Levosimendan showed no significant impacts on central venous pressure, oxygen saturation, B-type natriuretic peptide, ejection fraction, or length of hospitalization. It also did not increase the risks of acute kidney injury, arrhythmia, mortality, or pneumonia, and no publication bias was detected. In conclusion, levosimendan has a favorable safety profile in this pediatric population. Beneficial effects were observed early, mainly manifested by improvements in hypoxia-related indicators and reductions in heart rate and blood pressure within 6 h, without increasing adverse event risk, and the effects were limited to this early 6-h time point.

Introduction

Cardiac insufficiency is a complex clinical syndrome defined by structural or functional cardiac abnormalities that impair the heart’s ability to fill and eject blood¹. This results in insufficient tissue perfusion and an impaired capacity to meet the body’s metabolic demands, rendering it a leading cause of clinical mortality in pediatric populations². In infants and children, the etiology of cardiac insufficiency differs markedly from that in adults, with congenital heart disease and severe myocarditis as the primary pathogenic factors^3,4. Due to their unique physiological characteristics, the safety and efficacy of cardiovascular drugs in this population require further investigation⁵.

Digitalis is a first-line conventional agent for pediatric cardiac insufficiency, as it augments cardiac contractility to alleviate clinical symptoms⁶. However, pediatric patients exhibit increased sensitivity to digitalis, which complicates dose titration and elevates the risk of drug toxicity and adverse effects⁷. Levosimendan strengthens cardiac contraction by increasing the sensitivity of systolic myofibrils to calcium⁸. This unique mechanism prevents excessive myocardial oxygen consumption, and its broader therapeutic concentration range relative to digitalis supports its potential utility for the management of cardiac insufficiency in neonates and children⁹.

Most current research on levosimendan has focused on adult populations^10,11. Silvetti et al.¹² (2022) conducted a systematic review and meta-analysis (44 studies up to 2020) focusing on pediatric cardiac surgery, reporting improved central venous oxygen saturation (ScvO₂, p=0.03) and a trend toward lower lactate levels (p=0.08) but lacking time-stratified analysis and high-quality evidence. The same team’s 2024 systematic review only addressed safety (hypotension: 28.9%; arrhythmia: 12.3%) without exploring efficacy or age-specific pharmacokinetics¹³. Lapere et al.¹⁴ included 9 randomized controlled trials (RCTs) solely in pediatric cardiac surgery, confirming a reduced incidence of cardiac output syndrome but lacking time-stratified analysis and in-depth assessment of hypoxia-related indicators. Emara et al.¹⁵ performed a GRADE-assessed comparison of levosimendan and milrinone in cardiac surgery patients (adults + pediatrics, 17 studies up to 2024) but found no significant efficacy or safety differences, with no time-stratified analysis or focus on hypoxia-specific indicators (e.g., lactate) in pediatric cardiac insufficiency.

This meta-analysis innovatively conducts time-stratified subgroup analyses at 6, 12, and 24 h post-intervention, includes newly published clinical studies through October 6, 2024, and assesses multiple hypoxia-related metabolic indicators (lactate levels) and the favorable safety profile of levosimendan. To our knowledge, this is the first meta-analysis to systematically characterize the time-dependent early efficacy of levosimendan in pediatric cardiac insufficiency and comprehensively evaluate the drug’s favorable safety profile in this population. The primary hypothesis is that levosimendan exhibits time-dependent early efficacy and a favorable safety profile in the treatment of pediatric cardiac insufficiency, and this study aims to provide evidence-based support for its clinical application.

Protocol

This meta-analysis was based on previously published clinical studies and did not involve human subjects, specimen collection, or experimental interventions, with ethical approval not required in accordance with international and national research ethics guidelines. This is a prescriptive meta-analysis protocol registered in PROSPERO (CRD420261335583) and fully compliant with the PRISMA reporting guidelines for systematic reviews and meta-analyses, for the systematic evaluation of the safety and efficacy of levosimendan in the treatment of cardiac insufficiency in infants and children. The protocol was initiated on September 1, 2024, as the procedural beginning, with the literature search concluding on October 6, 2024, as the definitive endpoint, and all subsequent research procedures completed within the time frame specified by the protocol. The meta-analysis follows four sequential core procedural steps: database searching, literature screening and data extraction, study quality assessment, and statistical analysis. A standardized workflow was adopted for statistical analyses, with raw data collated and normality tested in Microsoft Excel, heterogeneity tests and meta-analysis performed in Stata, and forest plots generated and publication bias assessed in RevMan, in this sequential order.

Search criteria
The study design was based on the Population, Intervention, Comparison, Outcome (PICO) framework, with the population, intervention, comparison, outcome measures, and study type defined in detail as follows. The study population comprised patients diagnosed with cardiac insufficiency, including neonates, infants, and children. The intervention adopted was levosimendan treatment, administered at standard doses or according to protocol-specified regimens, as per the included studies. The control groups received other positive inotropic agents or a placebo.

The primary and secondary outcome measures included heart rate, blood pressure, oxygen saturation, lactate level, pH value, ejection fraction, B-type natriuretic peptide (BNP) level, urine output, length of hospital stay, mortality, and adverse events. Eligible study types were RCTs and retrospective observational studies.

The predefined exclusion criteria included animal studies and non-original research, such as narrative reviews, systematic reviews, meta-analyses, and case reports. Data from non-peer-reviewed sources without full-text availability (e.g., conference abstracts, dissertations) were also excluded, as were duplicate publications with overlapping data or identical study populations across multiple articles. Additionally, studies lacking specific effect sizes (e.g., weighted mean difference, standardized mean difference, relative risk) and their corresponding 95% confidence intervals (95% CIs) were excluded from the analysis.

Search databases
Literature searches were conducted in PubMed, Web of Science, Embase, and the Cochrane Library, covering the period from the establishment of each database to October 6, 2024. The detailed search strategy for each database is presented in Supplementary Table S1.

Data extraction and quality assessments
Two independent researchers screened the literature, extracted relevant data, and evaluated the methodological quality of the included studies using predefined inclusion and exclusion criteria. If discrepancies arose, the researchers resolved them through discussion or by consulting a third independent researcher. Data extraction was conducted after full-text review, covering the following information: sample size, age distribution, and outcome measures of both the experimental (levosimendan) and control groups. For continuous variables, the mean and standard deviation (SD) were extracted. For dichotomous variables, the number of participants with and without the outcome of interest was recorded.

The methodological quality of the included studies was evaluated using the Cochrane Risk of Bias tool. This tool assessed six key domains of bias, including bias arising from random sequence generation, bias due to allocation concealment, bias due to blinding of participants, investigators, and outcome assessors, bias due to incomplete outcome data, bias due to selective outcome reporting, and other potential sources of bias. Based on the evaluation results, studies were categorized into three levels of bias risk: low risk (all six domains met the relevant low-bias criteria), moderate risk (partial domains met the relevant low-bias criteria), and high risk (key domains failed to meet the relevant low-bias criteria). Studies judged to have a high risk of bias were excluded from the present analysis.

Statistical analysis
Meta-analyses were performed using Stata and RevMan software. For continuous variables, the mean and SD for each group were extracted directly. When data were reported as median and interquartile range, they were converted to mean and SD using validated computational methods prior to analysis. For dichotomous variables, the numbers of participants with and without the outcome of interest in each group were extracted; if any cell frequency was zero, an arcsine (inverse chord) transformation was applied to correct for zero-cell frequencies before statistical analysis.

Statistical heterogeneity across included studies was assessed using the Cochran’s Q test and the I² statistic. Statistical heterogeneity was categorized as moderate (I² < 50%) or high (I² ≥ 50%), with the Cochran’s Q-test P-value used for complementary assessment. A fixed-effects model was employed if no significant statistical heterogeneity was detected; otherwise, a random-effects model was used. Publication bias was evaluated via Egger’s test and Begg’s test. If significant publication bias was identified, the trim-and-fill method was applied to quantify its potential impact on the Meta-analysis results.

Results

Literature search and characteristics of included studies
This study initially identified 276 records from four databases (PubMed, Web of Science, Embase, Cochrane Library). Eighty-four duplicate records were removed, and the remaining articles were screened against predefined inclusion and exclusion criteria, with 176 articles failing to meet the criteria excluded. Finally, 16 articles were included in the qualitative and quantitative syntheses. The detailed literature screening process is illustrat...

Discussion

Pediatric cardiac insufficiency is strongly associated with congenital heart disease and fulminant myocarditis and is a major cause of cardiogenic shock and mortality in children³. Traditional positive inotropic agents (e.g., catecholamines, phosphodiesterase inhibitors) are associated with increased mortality, whereas digitalis has a narrow therapeutic window. Pediatric patients' increased sensitivity to digitalis further elevates the risk of toxicity and adverse effects³³

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Excel Office Software 2019	Microsoft Corporation	https://www.microsoft.com/microsoft-365/excel	Data collation and normality verification
RevMan Analysis Software 5.4	The Cochrane Collaboration	https://training.cochrane.org/online-learning/core-software/revman	Forest plot generation and publication bias assessment
Stata Statistical Software 18	StataCorp LLC	https://www.stata.com	Heterogeneity tests and meta-analysis implementation