The Effect of Early Goal-Directed Therapy on Outcome in Adult Severe Sepsis and Septic Shock Patients: A Meta-Analysis of Randomized Clinical Trials

Abstract

Background: Whether early goal-directed therapy (EGDT) improves outcome in severe sepsis and septic shock remains unclear. We performed a meta-analysis of existing clinical trials to examine whether EGDT improved outcome in the resuscitation of adult sepsis patients compared with control care.

Methods: We searched for eligible studies using MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials, and Web of Science databases. Studies were eligible if they compared the effects of EGDT versus control care on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Data including mortality, sample size of the patients with severe sepsis and septic shock, and resuscitation end points were extracted. Data were analyzed using methods recommended by the Cochrane Collaboration Review Manager 4.2 software. Random errors were evaluated by trial sequential analysis (TSA).

Results: Nine studies compared EGDT with control care, and 5202 severe sepsis and septic shock patients were included. A nonsignificant trend toward reduction in the longest all-cause mortality was observed in the EGDT group compared with control care (relative risk, 0.89; 99% confidence interval, 0.74-1.07; P = 0.10). However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients (relative risk, 0.72; 99% confidence interval, 0.57-0.90; P = 0.0002). TSA indicated lack of firm evidence for a beneficial effect.

Conclusions: In this meta-analysis, a nonsignificant trend toward reduction in the longest all-cause mortality in patients resuscitated with EGDT was noted. However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients. TSA indicated a lack of firm evidence for the results. More powered, randomized controlled trials are needed to determine the effects.

Figure 1.

Flow diagram of the search process and study selection.

Figure 2.

The effects of early goal-directed therapy (EGDT) on mortality in patients with severe sepsis and septic shock. Mortality data were recorded during the data extraction. When there is >1 value about mortality published in the article, the longest complete follow-up was preferentially used for evaluation of all-cause mortality. However, when 28-day or 90-day mortality values were not presented, intensive care unit (ICU) or hospital mortality or mortality at other time points were recorded. Ninety-day mortality was reported by the ARISE study, the ProCESS study, and the ProMISe study. Sixty-day mortality was reported by the study of Rivers et al. Twenty-eight-day mortality was reported by the Yan study. Fourteen-day mortality was reported by the study of Wang et al. In-hospital mortality was reported by the study of Rivers et al, the study of Jones et al, Lu study, ARISE study, ProCESS study, and ProMISe study. ICU mortality was reported by the study of Chen et al, the study of Wang, Yan study, and ARISE study. CI indicates confidence interval; RR, relative risk.

Figure 3.

The effects of early goal-directed therapy (EGDT) on mortality in severe sepsis and septic shock patients with different severity of illness. The severity of illness was reported in each study by the acute physiology and chronic health evaluation II score (APACHE II score), and the data were presented as mean ± SD or medians (interquartile ranges). The distinction between higher severity of illness and less severity was differentiated by us according to the means of APACHE II scores in each article. The APACHE II score of the included patients in 5 trials^,,,, were >20, the remaining 3^,, were <20 or unclear. CI indicates confidence interval; RR, relative risk.

Figure 4.

The effects of goal-directed therapy on mortality in severe sepsis and septic shock patients with and without central venous oxygen saturation. Mortality data were recorded during the data extraction. When there is >1 value about mortality published in the article, the longest complete follow-up was preferentially used for evaluation of all-cause mortality. However, when 28-day or 90-day mortality values were not presented, intensive care unit (ICU) or hospital mortality or mortality at other time points were recorded. Ninety-day mortality was reported by the ARISE study, the ProCESS study, and the ProMISe study. Sixty-day mortality was reported by the study of Rivers et al. Twenty-eight-day mortality was reported by Yan study. Fourteen-day mortality was reported by the study of Wang et al. In-hospital mortality was reported by the study of Rivers et al, the study of Jones et al, Lu study, ARISE study, ProCESS study, and ProMISe study. ICU mortality was reported by the study of Chen et al, study of Wang et al, Yan study, and ARISE study. CI indicates confidence interval; RR, relative risk.

Figure 5.

The effects of early goal-directed therapy (EGDT) on intensive care unit (ICU) length of stay in severe sepsis and septic shock patients. CI indicates confidence interval.

Figure 6.

Trial sequential analysis for a relative risk reduction of all-cause mortality of 9.5% in control group in 9 trials. A required diversity-adjusted information size of 21,342 patients was calculated based on a control event proportion of 9.5%, early goal-directed therapy (EGDT) induced relative risk reduction of mortality of 9.5% suggested by all trials, α = 0.05 two-sided, β = 0.20 (power = 80%). The cumulated Z-curve (blue) crosses the traditional boundary (P = 0.05) but not the trial sequential monitoring boundary, indicating lack of firm evidence for a beneficial effect of EGDT.