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Studies and meta-analyses conflict regarding the use of early goal-directed therapy (EGDT) for septic shock. We sought to clarify the conflict by performing a living systematic review and meta-regression.We performed a meta-analysis and explored heterogeneity with meta-regression. We conformed with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and qualified strength of evidence with a Grading of Recommendations Assessment, Development and Evaluation profile.Overall, EGDT did not significantly reduce mortality compared with usual care (relative risk, 0.85; 95% confidence interval, 0.67-1.08); however, heterogeneity was substantial (I2 = 64%; 95% confidence interval, 12%-85%). Illness severity did not correlate with mortality reduction; however, there were significant correlations with control rate mortality and the strategy employed by the control group. Benefit was confined to trials with a control mortality greater than 35%. Compared with monitoring of lactate clearance and central venous pressure, EGDT mortality was higher.The benefit of EGDT is evident in populations with high mortality, in line with reported global mortality rates. In settings with low mortality the recent trials challenge the need for 6-hour goals; however, most patients in these trials met 3-hour resuscitation goals as defined by the Surviving Sepsis Campaign. In settings with higher mortality, EGDT or normalization of lactate/central venous pressure may be viable therapeutic options.