title: Prophylactic levosimendan for the prevention of low cardiac output syndrome and mortality in paediatric patients undergoing surgery for congenital heart disease.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 levosimendan groups had shorter length of intensive care unit stays (mean difference (MD) 0.33 days, 95% CI -1.16 to 1.82; participants = 188; studies = 4; I² = 35%), length of hospital stays (0.26 days, 95% CI -3.50 to 4.03; participants = 75; studies = 2), and duration of mechanical ventilation (MD -0.04 days, 95% CI -0.08 to 0.00; participants = 208; studies = 5; I² = 0%). The risk of mechanical circulatory support or cardiac transplantation favoured the levosimendan groups (RR 1.49, 95% CI 0.19 to 11.37; participants = 60; studies = 2). 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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Department of Congenital Heart Defects and Pediatric Cardiology, Heart Center, University of Freiburg, Mathildenstr. 1, Freiburg, Germany, 79106.
authors.forename: Johanna
authors.initials: J
authors.lastname: Hummel
authors.affiliation: Institute for Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Stefan-Meier-Str. 26, Freiburg, Germany, 79104.
authors.forename: Gerta
authors.initials: G
authors.lastname: Rücker
authors.affiliation: Department of Congenital Heart Defects and Pediatric Cardiology, Heart Center, University of Freiburg, Mathildenstr. 1, Freiburg, Germany, 79106.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Stiller
mesh_terms: D001243:Assisted Circulation / Q000706:statistics & numerical data; D002303:Cardiac Output, Low / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D003325:Coronary Care Units / Q000706:statistics & numerical data; D006330:Heart Defects, Congenital / Q000401:mortality / Q000601:surgery*; D006801:Humans; D006835:Hydrazones / Q000627:therapeutic use*; D007902:Length of Stay / Q000706:statistics & numerical data; D011183:Postoperative Complications / Q000401:mortality / Q000517:prevention & control*; D011724:Pyridazines / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012121:Respiration, Artificial / Q000706:statistics & numerical data; D000077464:Simendan
chemical_list: D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan