The effect of goal-directed therapy on mortality in patients with sepsis - earlier is better: a meta-analysis of randomized controlled trials

Introduction The Surviving Sepsis Campaign guidelines recommend goal-directed therapy (GDT) for the early resuscitation of patients with sepsis. However, the findings of the ProCESS (Protocolized Care for Early Septic Shock) trial showed no benefit from GDT for reducing mortality rates in early septic shock. We performed a meta-analysis to integrate these findings with existing literature on this topic and evaluate the effect of GDT on mortality due to sepsis. Methods We searched the PubMed, Embase and CENTRAL (Cochrane Central Register of Controlled Trials) databases and reference lists of extracted articles. Randomized controlled trials comparing GDT with standard therapy or usual care in patients with sepsis were included. The prespecified primary outcome was overall mortality. Results In total, 13 trials involving 2,525 adult patients were included. GDT significantly reduced overall mortality in the random-effects model (relative risk (RR), 0.83; 95% confidence interval (CI), 0.71 to 0.96; P =0.01; I2 = 56%). Predefined subgroup analysis according to the timing of GDT for resuscitation suggested that a mortality benefit was seen only in the subgroup of early GDT within the first 6 hours (seven trials; RR, 0.77; 95% CI, 0.67 to 0.89; P =0.0004; I2 = 40%), but not in the subgroup with late or unclear timing of GDT (six trials; RR, 0.92; 95% CI, 0.69 to 1.24; P =0.59; I2 = 56%). GDT was significantly associated with the use of dobutamine (five trials; RR, 2.71; 95% CI, 1.20 to 6.10; P =0.02). Conclusions The results of the present meta-analysis suggest that GDT significantly reduces overall mortality in patients with sepsis, especially when initiated early. However, owing to the variable quality of the studies, strong and definitive recommendations cannot be made. Electronic supplementary material The online version of this article (doi:10.1186/s13054-014-0570-5) contains supplementary material, which is available to authorized users.


Introduction
Sepsis is a systemic response to infection, which may progress to severe sepsis and septic shock [1]. Severe sepsis and septic shock represent global problems with a high economic burden. In the United States, more than 750,000 people experience severe sepsis each year, with a short-term mortality of 20% to 30%, reaching up to 50% when shock is present [2,3]. Therefore, numerous therapeutic strategies that aimed at reducing mortality in these patients have been investigated. However, most of them have not led to significant reductions in mortality [4]. Goal-directed therapy (GDT) has been shown to substantially improve clinical outcomes in surgical patients [5]. Two important aspects of a GDT protocol include early initiation of the therapeutic measures, together with specific (hemodynamic) targets. The Surviving Sepsis Campaign guidelines recommend GDT for the early resuscitation of patients with sepsis [1], which is based largely upon the results of the Rivers et al. trial, in which the researchers reported a 16% absolute reduction in mortality among patients with severe sepsis or septic shock who received early GDT compared to standard therapy [6]. However, in a recent study, this approach was challenged [7], with no benefit shown when GDT was compared to standard therapy. However, initiating therapy early rather than late in the course of critical illness remains a logical clinical goal. In the context of this situation, we systematically reviewed all trials of GDT in patients with sepsis and performed a meta-analysis, focusing on the early initiation of the protocol and its effect on mortality.

Methods
Ethical approval and patient consent were not required, because we conducted a meta-analysis of previously published studies. We followed the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions to carry out the study [8] and follow the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement to report our meta-analysis [9].

Inclusion criteria
We included trials with the following characteristics: 1. Population: Adult patients with one or more of the following characteristics were eligible for inclusion: sepsis, severe sepsis or septic shock. Adults were defined as being of a legal age for consent in the country where the trial was conducted. Studies that included sepsis secondary to noninfectious causes were excluded. 2. Intervention: The intervention had to be GDT, defined as an explicit protocol encompassing the use of hemodynamic monitoring and manipulation of hemodynamic parameters to achieve predetermined hemodynamic endpoints. 3. Control: The control group had to have received standard therapy or usual care. 4. Outcomes: The overall mortality rate had to be the outcome measured. 5. Type of study: The studies had to be randomized controlled trials (RCTs).
We included studies that randomized a mixed population of critically ill patients when a septic subpopulation that met our inclusion criteria was defined; that is, the patients with sepsis constituted a subgroup of the trial population.

Data extraction
We extracted data using a standardized data collection form. Discrepancies in collected data were addressed through team consensus. The following information was extracted from each trial: first author, year of publication, number of patients (GDT and control), study population, clinical setting, goals in GDT and control groups, timing of GDT, mortality endpoint, study design (patient selection and concealment) and outcome data (overall mortality and dobutamine use).

Outcomes and definitions
The prespecified primary outcome was overall mortality. If the study authors reported mortality at one time point, we used the only data used for analysis. If the study authors reported mortality at more than one time point, we used hospital mortality preferentially. Secondary outcomes included overall mortality in the earlyinitiated GDT (that is, within the first 6 hours) versus GDT and dobutamine use initiated later.

Assessment of risk of bias
We used the Cochrane Collaboration tool to assess the risk of bias of individual study and with bias domains across studies [8,10]. Two investigators (WJG and FW) subjectively reviewed all studies and assigned a value of "high," "low" or "unclear" to the following domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. Trials with high risk of bias for any one or more key domains were considered to be at high risk of bias. Trials with low risk of bias for all key domains were considered to be at low risk of bias. Otherwise, they were considered to have an unclear risk of bias [10].

Statistical analysis
We estimated the relative risk (RR) with 95% confidence interval (CI) for dichotomous outcomes. Statistical heterogeneity across studies was tested by using the I 2 statistic [11,12]. Heterogeneity was suggested if the P-value was ≤0.10. I 2 values of 0 to 24.9%, 25% to 49.9%, 50% to 74.9% and 75% to 100% were considered zero, low, moderate and high thresholds for statistical heterogeneity, respectively [11,12]. Clinical heterogeneity could not be excluded, so the more conservative random-effects model [13] (Mantel-Haenszel method) was used. Predefined subgroup analysis was conducted according to the timing of GDT for resuscitation (early being within the first 6 hours versus late or unclear being outside the first 6 hours or unclear timing). In addition, we performed post hoc subgroup analyses according to risk of bias (low versus unclear), sample size (≥100 versus <100) and setting (emergency department versus intensive care unit). We further investigated the influence of a single study on the overall pooled estimate by omitting one study in each step. The potential for bias was assessed by inspection of a funnel plot and Egger's test [14]. The results were considered statistically significant at two-sided P-values <0.05. All statistical analyses were performed using RevMan 5.2 software (The Nordic Cochrane Centre, Copenhagen, Denmark).

Quality of evidence
We evaluated the quality of the evidence by using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach [15]. In addition, the GRADEprofiler 3.6 software (The Nordic Cochrane Centre) was used to create the evidence profile. The GRADE Working Group grades of evidence used were as follows: (1)High quality: Further research is very unlikely to change our confidence in the estimate of effect. (4)Very low quality: We are very uncertain about the estimate.

Risk of bias in included studies
The details of risk of bias are summarized in Figure 2. Five trials were judged to be at low risk of bias [6,7,19,21,22], and eight trials were judged to be at unclear risk of bias [16][17][18]20,[23][24][25][26]. Adequate randomized sequences were generated in eight trials [6,7,[17][18][19]21,22,26], and the investigators in five trials reported appropriate allocation concealment [6,7,19,21,22]. Among the 13 RCTs, none were doubleblinded. However, blinding of patients and clinicians was extremely difficult in these trials to evaluate a complex intervention such as a GDT protocol, and we judged that the primary outcome (that is, overall mortality) was not likely to be influenced by lack of blinding.

Publication bias
We detected no evidence of publication bias by assessing funnel plot either visually ( Figure 5) or statistically (P =0.367 by Egger test).

GRADE profile evidence
We found that GRADE Working Group grades of evidence were low for overall mortality, moderate for mortality in early GDT (within the first 6 hours for resuscitation) and very low for dobutamine use. An additional .doc file shows these data in more detail (see Additional file 1).

Discussion
Our meta-analysis of 13 RCTs showed that GDT was associated with a 17% RR reduction on overall mortality in patients with sepsis. This mortality benefit was present in studies in which GDT was started early, but not when initiated late or when the timing of GDT was unclear. In addition, GDT was significantly associated with dobutamine use.
Despite these findings, the effect of GDT remains a matter of debate, as the most recent and largest trial included in this meta-analysis [7] did not show a difference in mortality, in contrast to many of the preceding studies. This could be due to the effect of the rapid acceptance of the principal interventions of the Rivers et al. study [6] and the subsequent Surviving Sepsis Campaign guidelines, which encompassed all elements of the Rivers study protocol. This is illustrated by the fact that, in the ProCESS (Protocolized Care for Early Septic Shock) trial, all groups received, on average, more than 2 L of fluid prior to randomization and more than 75% of patients received antibiotics before randomization. In addition, the mortality rate was much lower in the ProCESS trial than in preceding trials, possibly reflecting the effect of early diagnosis, fluid resuscitation and initiation of antibiotics on mortality. As the ProCESS trial, like the Rivers et al. study, enrolled patients with sepsis in the emergency department, this effect may have been prominent [27].
Although the current evidence supports the early use of GDT to improve outcomes in patients with sepsis, the optimal goals remain uncertain. Currently, the Surviving Sepsis Campaign guidelines recommend the use of central venous pressure (CVP), mean arterial pressure, urine output and central venous oxygen saturation (ScvO 2 ) as resuscitation goals. However, many of these recommendations have been questioned in recent studies. A recent study [28] was designed to compare the use of lactate clearance to ScvO 2 as a goal of early (up to 6 hours) sepsis resuscitation. No significant difference in mortality was found (17% in the lactate clearance group versus 23% in ScvO 2 group). However, when both normalization of ScvO 2 and a rapid decrease in lactate levels were applied as therapeutic goals in the early resuscitation of a mixed group of critically ill patients, including a large subgroup of sepsis patients, mortality was significantly reduced [29]. In addition, in a recent retrospective study, researchers questioned the CVP endpoint in sepsis resuscitation [30].
Further research is needed before strong and definitive recommendations can be made regarding the effect of   [31]. The results of these ongoing trials should provide further guidance as to the effect of GDT for resuscitation of patients with sepsis.
A major strength of the present meta-analysis is its compliance with the Cochrane handbook methodology recommendations. We conducted an exhaustive literature search that included non-English-language articles. Two authors independently screened all references, included eligible trials, extracted data information, assessed risk of bias and performed statistical analyses. Moreover, we followed the PRISMA statement to report this metaanalysis and evaluated the quality of the evidence by using the GRADE approach.  Because early fluid resuscitation is vital in patients with sepsis, we performed predefined subgroup analyses according to the timing of GDT. We also performed post hoc subgroup analyses according to risk of bias, disease severity, sample size and publication date. These subgroup analyses based on assessment of bias and clinically relevant groups may help health care professionals in clinical decision-making.
Our analysis also has several limitations that must be taken into consideration when interpreting the results. First, most of the included trials had a high risk of bias ( Figure 2). The potential importance of this issue is highlighted by the fact that predefined subgroup analysis comparing mortality estimates between trials with low versus unclear risk of bias suggested the mortality benefit is not clearly apparent among the trials with low risk of bias, although this subgroup difference was not statistically significant (P =0.90). Second, there were some differences in the target populations and protocols of GDT of each study. These factors may have a potential impact on our results and may preclude firm conclusions. Third, different endpoints were used for mortality evaluation. Because this study was a study-level meta-analysis, individual patient data were not included in the analysis; thus, we could not adjust for patient-level confounders.

Conclusions
The evidence suggests that GDT significantly reduces overall mortality in patients with sepsis, especially when initiated early (within the first 6 hours of admission). Until the results of ongoing randomized controlled trials are known, strong and definitive recommendations cannot be made regarding the effect of GDT for resuscitation of patients with sepsis.

Key messages
The Surviving Sepsis Campaign guidelines recommend GDT for the early resuscitation of patients with sepsis, but controversies about its effect remain. The recent ProCESS trial has shown no mortality benefit from GDT in early septic shock. The current evidence, in the aggregate, suggests that GDT significantly reduces overall mortality in patients with sepsis, especially when initiated early (within the first 6 hours of admission). Further research is needed before strong and definitive recommendations can be made regarding the effect of GDT for resuscitation of patients with sepsis, and the optimal goals remain uncertain.

Additional file
Additional file 1: GRADE summary of findings.
Abbreviations ARISE: Australasian Resuscitation in Sepsis Evaluation; CI: Confidence interval; CVP: Central venous pressure; GDT: Goal-directed therapy; GRADE: Grades of Recommendation, Assessment, Development and Evaluation; MAP: Mean arterial pressure; PRISMA: Preferred reporting items for systematic reviews and meta-analyses; ProMISe: Protocolised management in sepsis; RCT: Randomized controlled trial; RR: Relative risk; ScvO 2 : Central venous oxygen saturation.