Hummel Johanna, Rücker Gerta, Stiller Brigitte
Department of Congenital Heart Defects and Pediatric Cardiology, Heart Center, University of Freiburg, Mathildenstr. 1, Freiburg, Germany, 79106.
Cochrane Database Syst Rev. 2017 Aug 2;8(8):CD011312. doi: 10.1002/14651858.CD011312.pub3.
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.
AUTHORS' 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).
低心排血量综合征仍然是一种严重的并发症，在接受先天性心脏病手术的儿科患者术后过程中，其导致了相当高的发病率和死亡率。低心排血量综合征的标准预防和治疗策略主要基于儿茶酚胺，这些药物虽有效，但有相当多的副作用。左西孟旦作为一种钙增敏剂，通过产生比儿茶酚胺肾上腺素能刺激更节能的心肌收缩力来增强心肌功能。因此，左西孟旦有可能成为心脏直视手术后预防儿科患者低心排血量综合征的标准药物的有益替代品。
综述左西孟旦术后预防性应用对接受先天性心脏病手术的儿科患者预防低心排血量综合征和死亡率的疗效及安全性。
我们于2016年6月通过系统检索CENTRAL、MEDLINE、Embase和Web of Science以及临床试验注册库来识别试验。检查了原始研究和综述文章的参考文献列表以获取更多参考文献。
我们的分析仅纳入了随机对照试验（RCT），这些试验比较了左西孟旦预防性用药与标准药物或安慰剂，研究对象为18岁及以下接受先天性心脏病手术的婴幼儿和儿童。
两位综述作者根据预先定义的方案独立提取数据并评估偏倚风险。我们从纳入研究的所有作者（除一位作者外）处获取了额外信息。我们使用五个GRADE考量因素（研究局限性、效应一致性、不精确性、间接性和发表偏倚）来评估为荟萃分析提供数据的研究对于预设结局的证据质量。我们创建了一个“结果总结”表来总结每个结局的结果和证据质量。
我们纳入了五项随机对照试验，分析中共有212名参与者。所有纳入的参与者均未满五岁。使用GRADE评估，我们发现所有分析结局的证据质量都很低。由于两项研究未设盲，我们评估这两项研究存在执行和检测偏倚的高风险。与标准治疗相比，左西孟旦对死亡率风险无明显影响（风险比（RR）0.47，95%置信区间（CI）0.12至1.82；参与者 = 123；研究 = 3），对低心排血量综合征也无明显影响（RR 0.64，95% CI 0.39至1.04；参与者 = 83；研究 = 2）。纳入的任何研究均未提供关于死亡时间的数据。关于左西孟旦对次要结局的影响没有确凿证据。重症监护病房住院时间（平均差（MD）0.33天，95% CI -1.16至1.82；参与者 = 188；研究 = 4）、住院时间（MD 0.26天，95% CI -3.50至4.03；参与者 = 75；研究 = 2）、机械通气时间（MD -0.04天，95% CI -0.08至0.00；参与者 = 208；研究 = 5）以及机械循环支持或心脏移植风险（RR 1.49，95% CI 0.19至11.37；参与者 = 60；研究 = 2）在两组之间没有明显差异。关于左西孟旦不良反应的已发表数据有限。由于血压值表达的异质性，对左西孟旦最令人担忧的副作用之一低血压进行荟萃分析不可行。
目前的证据水平不足以判断预防性使用左西孟旦是否能预防接受先天性心脏病手术的儿科患者的低心排血量综合征和死亡率。到目前为止，在这种情况下，左西孟旦与标准的正性肌力药物治疗之间未发现显著差异。作者使用GRADE方法将证据质量评估为低。降级的原因是存在严重的偏倚风险（两项RCT未设盲导致执行和检测偏倚）、严重的不一致风险以及严重至极严重的不精确风险（纳入患者数量少，事件发生率低）。
