Background
Reduced heart function is a potentially fatal complication after heart surgery in infants and children. There are different drugs available for prevention and treatment, but they can trigger serious side effects. Levosimendan is a calcium sensitiser that enhances the heart's pump function. It potentially triggers fewer side effects than conventional medication.
Review question
In this review, we assessed whether the prophylactic use of levosimendan prevented reduced heart function and death in infants and children after surgery for congenital heart disease. We searched different medical literature databases and trial registers that collect information about planned, ongoing, and completed studies. We considered trials in which one group had received levosimendan and a second had received another drug instead, after heart surgery. Two review authors independently screened and collected the data.
Study characteristics
We identified five studies that had a total of 212 patients. All patients were under five years of age. The patients were given levosimendan during or immediately after heart surgery for a duration of 20 to 72 hours. They were monitored for 20 hours to six days. We asked all of the study authors for additional information about their trials. All but one author responded. The evidence is current to June 2016.
Quality of evidence
We found low-quality evidence for all outcomes. This was mainly due to the small number of included patients (high imprecision of results). Thus, all results of the meta-analysis must be viewed with caution.
Key results
The available data revealed no clear difference between levosimendan and conventional medication in preventing reduced heart function and death after heart surgery in the studied population. We also found no clear difference in the length of stay in the intensive care unit. The available data did not allow us to judge whether one of the treatment arms was superior to the other for three secondary outcomes: length of hospital stay, time on mechanical ventilation, need to implant circulatory support devices or the need for cardiac transplantation. Overall, few side effects were reported in any of the groups. We were unable to pool data to generate useful information about the safety of levosimendan.
The current level of evidence is insufficient to judge whether prophylactic levosimendan prevents low cardiac output syndrome and mortality in paediatric patients undergoing surgery for congenital heart disease. So far, no significant differences have been detected between levosimendan and standard inotrope treatments in this setting.
The authors evaluated the quality of evidence as low, using the GRADE approach. Reasons for downgrading were serious risk of bias (performance and detection bias due to unblinded setting of two RCTs), serious risk of inconsistency, and serious to very serious risk of imprecision (small number of included patients, low event rates).
Low cardiac output syndrome remains a serious complication, and accounts for substantial morbidity and mortality in the postoperative course of paediatric patients undergoing surgery for congenital heart disease. Standard prophylactic and therapeutic strategies for low cardiac output syndrome are based mainly on catecholamines, which are effective drugs, but have considerable side effects. Levosimendan, a calcium sensitiser, enhances the myocardial function by generating more energy-efficient myocardial contractility than achieved via adrenergic stimulation with catecholamines. Thus potentially, levosimendan is a beneficial alternative to standard medication for the prevention of low cardiac output syndrome in paediatric patients after open heart surgery.
To review the efficacy and safety of the postoperative prophylactic use of levosimendan for the prevention of low cardiac output syndrome and mortality in paediatric patients undergoing surgery for congenital heart disease.
We identified trials via systematic searches of CENTRAL, MEDLINE, Embase, and Web of Science, as well as clinical trial registries, in June 2016. Reference lists from primary studies and review articles were checked for additional references.
We only included randomised controlled trials (RCT) in our analysis that compared prophylactic levosimendan with standard medication or placebo, in infants and children up to 18 years of age, who were undergoing surgery for congenital heart disease.
Two review authors independently extracted data and assessed risk of bias according to a pre-defined protocol. We obtained additional information from all but one of the study authors of the included studies. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of evidence from the studies that contributed data to the meta-analyses for the prespecified outcomes. We created a 'Summary of findings' table to summarise the results and the quality of evidence for each outcome.
We included five randomised controlled trials with a total of 212 participants in the analyses. All included participants were under five years of age. Using GRADE, we assessed there was low-quality evidence for all analysed outcomes. We assessed high risk of performance and detection bias for two studies due to their unblinded setting. Levosimendan showed no clear effect on risk of mortality (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.12 to 1.82; participants = 123; studies = 3) and no clear effect on low cardiac output syndrome (RR 0.64, 95% CI 0.39 to 1.04; participants = 83; studies = 2) compared to standard treatments. Data on time-to-death were not available from any of the included studies.
There was no conclusive evidence on the effect of levosimendan on the secondary outcomes. The length of intensive care unit stays (mean difference (MD) 0.33 days, 95% CI -1.16 to 1.82; participants = 188; studies = 4), length of hospital stays (MD 0.26 days, 95% CI -3.50 to 4.03; participants = 75; studies = 2), duration of mechanical ventilation (MD -0.04 days, 95% CI -0.08 to 0.00; participants = 208; studies = 5), and the risk of mechanical circulatory support or cardiac transplantation (RR 1.49, 95% CI 0.19 to 11.37; participants = 60; studies = 2) did not clearly differ between the groups. Published data about adverse effects of levosimendan were limited. A meta-analysis of hypotension, one of the most feared side effects of levosimendan, was not feasible because of the heterogeneous expression of blood pressure values.