Early lactate clearance-guided therapy in patients with sepsis: a meta-analysis with trial sequential analysis of randomized controlled trials.

Abstract

Dear Editor, Sepsis represents a global problem with high economic burden for health care systems. Since 2002, the Surviving Sepsis Campaign has recommended early quantitative resuscitation for patients with severe sepsis and septic shock with a recent update [1]. However, the optimal goals for quantitative resuscitation remain uncertain. Lactate clearance, defined by the change of lactate levels between two points in time, as a more rapid and less costly parameter, has the potential to be such a promising goal for quantitative resuscitation. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of early lactate clearance-guided therapy on mortality and other outcomes in patients with sepsis. We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials to identify RCTs that evaluated the effect of early lactate clearance-guided therapy on clinical outcomes in adults with sepsis. The search terms used were ‘‘lactate clearance’’, and ‘‘sepsis’’, or ‘‘severe sepsis’’ or ‘‘septic shock’’. We used the Cochrane collaboration tool to assess risk of bias, and the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach to evaluate the quality of evidence. The primary outcome was all-cause mortality. Secondary outcomes included length of hospital stay and length of intensive care unit (ICU) stay. We calculated risk ratios (RRs) or mean differences (MDs) and 95 % confidence intervals (CIs) using a randomeffects model. A two-tailed p value less than 0.05 was considered a significant level except for where a certain p value has been given. All statistical analyses were performed using RevMan 5.2 (Nordic Cochrane Centre). We conducted trial sequential analysis (TSA) using a diversityadjusted required information size calculated from an alpha error of 0.05, a beta error of 0.20, a control event proportion obtained from the results of the meta-analysis, and a relative risk reduction of 20 % in all-causes mortality, using standard software TSA version 0.9 Beta (http://www.ctu.dk/tsa). Four RCTs enrolling 547 patients were included in the meta-analysis [2–5]. The main characteristics of the four included RCTs are presented in Table 1 in the Electronic Supplementary Material (ESM). Assessment of the risk of bias is summarized in Table 2 (ESM). Overall, two RCTs were categorized as at lower risk of bias [2, 3], and two as at unclear risk of bias [4, 5]. Data on primary outcome were provided in all four trials (547 patients) [2–5]. Early lactate clearance-guided therapy was associated with a reduction in mortality (RR 0.65, 95 % CI 0.49–0.85, p = 0.002, I = 0 %, Fig. 1). TSA showed that 34.5 % of the required information size of 1586 patients were accrued. The cumulative z curve crossed the conventional boundary for benefit but did not cross the trial sequential monitoring boundary for benefit, showing that currently cumulative evidence is inconclusive, as shown in Fig. 3 (ESM). For secondary outcomes, early lactate clearance-guided therapy had no effect on length of hospital stay (weighted mean difference, WMD –0.13 days, 95 % CI –4.58 to 4.31, three RCTs [2, 3, 5]) and length of ICU stay (WMD –1.54 days, 95 % CI –3.22 to 0.15, four RCTs [2–5]), as shown in Fig. 2 (ESM). The GRADE evidence