Effect of early goal directed therapy in the treatment of severe sepsis and/or septic shock

Background: Many investigators have reproduced the mortality reduction shown in the original trial of early goal directed therapy (EGDT) in patients with severe sepsis and/or septic shock. Three large randomized controlled trials (RCTs) found neutral results when compared to usual care and a modified form of EGDT. Some have interpreted these studies as a reason to question the efficacy of EGDT.
Objectives: The purpose of this study was to comprehensively examine the effect of EGDT in the treatment of severe sepsis and/or septic shock in the literature.
Methods: A systematic review and meta-analysis of RCTs and prospective studies were performed, which extracted studies from PubMed, Elsevier ScienceDirect, Cochrane, Clinicaltrials.gov, Google Scholar, China Knowledge Resource Integrated Database, and Wanfang Database. The mortality trend in the control group from included studies was analyzed.
Results: Seven RCTs and twelve prospective studies enrolling 3502 EGDT and 3791 usual care participants were included in the analysis. EGDT was found to reduce overall mortality compared to usual care groups. This reduction in mortality was apparent in prospective and randomized control trials conducted before 2010. Over this time period there was a reduction in mortality in patients receiving usual care.
Limitations: This conclusion was limited by the small size of some selected studies and complicated by the long range of time during the conduction of these studies. These studies were further biased because of the lack of blinding and the crossover of care between the EGDT and usual care groups.
Conclusions: EGDT significantly reduced mortality in patients with severe sepsis and/or septic shock over 15 years since its publication. Recent studies examining usual care with EGDT have similar mortality benefit because of the diminished treatment effect. This treatment effect is diminished for multiple reasons. With progress in the management of this disease the benefit of EGDT on overall mortality has become comparable with the usual care for sepsis patients. This is because many of the components of EGDT have been incorporated into usual care protocols. As a result, the conclusion that EGDT is ineffective cannot be made. A more rigorous RCT which adjusts for the factors that narrows the treatment effect between groups is required. Given the current state of sepsis care and equipoise that exist, this would be difficult.

研究背景：诸多研究者已证实，早期目标导向治疗（early goal directed therapy, EGDT）在重症脓毒症和/或感染性休克患者原始试验中展现的死亡率降低效应可被重复验证。三项大型随机对照试验（randomized controlled trials, RCTs）对比常规治疗与改良版EGDT时，得到了中性结果。部分学者据此对EGDT的疗效提出了质疑。
研究目的：本研究旨在全面梳理现有文献中EGDT治疗重症脓毒症和/或感染性休克的疗效。
研究方法：本研究针对随机对照试验与前瞻性研究开展了系统评价与荟萃分析（systematic review and meta-analysis），检索数据库涵盖PubMed、Elsevier ScienceDirect、Cochrane、Clinicaltrials.gov、Google Scholar、中国知识资源总库（China Knowledge Resource Integrated Database）及万方数据库（Wanfang Database）。本研究对纳入研究中对照组的死亡率变化趋势进行了分析。
研究结果：本分析共纳入7项随机对照试验与12项前瞻性研究，共计纳入EGDT组受试者3502例、常规治疗组受试者3791例。结果显示，相较于常规治疗组，EGDT可降低患者总体死亡率。该死亡率降低效应在2010年前开展的前瞻性研究与随机对照试验中尤为显著。在此时间段内，接受常规治疗的患者死亡率亦呈下降趋势。
研究局限：本研究结论存在一定局限性：部分纳入研究的样本量较小，且各项研究的开展时间跨度较大，增加了结果解读的复杂性。此外，由于未实施盲法，且EGDT组与常规治疗组间存在治疗方案交叉，上述研究进一步存在偏倚风险。
研究结论：自EGDT问世后的15年间，其可显著降低重症脓毒症和/或感染性休克患者的死亡率。近期对比EGDT与常规治疗的研究中，二者的死亡率获益趋于一致，这是因为EGDT的治疗效应已有所减弱。该治疗效应减弱可归因于多方面因素：随着脓毒症诊疗方案的不断完善，EGDT对总体死亡率的获益已与常规治疗相当，这是由于EGDT的诸多核心环节已被纳入常规诊疗规范。因此，无法得出EGDT无效的结论。未来仍需开展更为严谨的随机对照试验，对缩小组间治疗效应差异的相关因素进行校正。鉴于当前脓毒症诊疗现状及临床均衡（equipoise）问题，开展此类试验颇具难度。