Early management of sepsis with emphasis on early goal directed therapy: AME evidence series 002

Introduction

The Sepsis-3.0 consensus defined sepsis as “life-threatening organ dysfunction caused by dysregulated host response to infection” and it is clinically determined based on sequential organ dysfunction assessment (SOFA) score ≥2 points (1). The term “sepsis” in Sepsis-3.0 corresponds to the term “severe sepsis” in 2012 SSC guidelines (2). However, Sepsis-3.0 has not been fully validated and most studies included in this review employed the term “severe sepsis”. In the review, we adopted the term “severe sepsis” to make it consistent with existing literature. There is general consensus that early recognition and timely treatment largely determine outcome of sepsis and septic shock (3-5). Early recognition refers to the prompt identification of patients presenting with an acute systemic inflammatory response to infection. Depending on sepsis onset, this may occur in the emergency department (ED), ICU, general ward or even during the pre-hospital phase (6). Sepsis unleashes various heterogeneous systemic reactions which interfere with many physiological pathways to finally assault and harm organs. Except for hemodynamic and organ support, there is no “ready-made” treatment for sepsis. Current sepsis management therefore focuses primarily on early goal directed therapy (EGDT) and/or bundle treatment. EGDT promotes prompt recognition of sepsis followed by starting up a treatment “bundle” within the first 3 to 6 hours following diagnosis. Because of methodological issues, several recent large multicenter studies failed to demonstrate a beneficial effect of EGDT as compared to usual care. Yet, the conceptual framework underlying EGDT is still considered as the cornerstone for the early management of sepsis and septic shock (7,8).

Early goal directed therapy (EGDT)

Clinical application of an EGDT protocol was first reported in a single-center study, recruiting patients on arrival at the ED (3). Compared with standard care, EGDT decreased mortality rate by 16%. Basically, EGDT aimed to obtain distinct resuscitation goals [i.e., central venous pressure (CVP) =8–12 mmHg; mean arterial pressure (MAP) =65–90 mmHg; urinary output >0.5 mL/kg/hour; central venous oxygen saturation (ScvO₂) >70% within the first six hours] (Figure 1). The EGDT protocol comprised infusion of colloids and crystalloid fluids to increase effective circulatory volume, vasopressor administration to raise MAP and, as needed, blood cell transfusion, inotropes, mechanical ventilation or curarization to ensure a correct balance between oxygen supply and consumption. During the following years, the EGDT concept was progressively expanded to incorporate interventions such as early initiation of antibiotics, adequate source control, and more elaborated fluid and hemodynamic resuscitation measures. EGDT was also the subject of both experimental and observational studies and became a widely accepted treatment approach. The Surviving Sepsis Campaign (SSC) guidelines proclaimed some components of EGDT as the standard treatment for patients with sepsis and septic shock (2,9). However, the beneficial effect of EGDT has been challenged by several large trials (10,11), which will be discussed in the following sections.

Figure 1 Typical structured protocol for early goal directed therapy (the workflow was drawn according to study protocols of included RCTs). CVC, central venous catheter; CVP, central venous pressure; ITBVI, intrathoracic blood volume index; RBC, red blood cell; MAP, mean arterial pressure; SAP, systolic arterial pressure; Lac, lactate; LCR, lactate clearance rate; UO, urine output; Hb, hemoglobin; JVP, jugular venous pressure; Hct, hematocrit.

Literature search

We conducted a systematic literature review to investigate the efficacy of EGDT on patient-important outcomes. Only original studies involving human subjects were included. An electronic PubMed search was performed using the following strategy and key words: (((((sepsis[Title/Abstract]) OR septic[Title/Abstract]) OR bacteremia[Title/Abstract]) AND Clinical Trial[ptyp])) AND (((early goal[Title/Abstract]) OR goal directed therapy[Title/Abstract]) AND Clinical Trial[ptyp]).

The initial search yielded 38 citations. Additional screening identified ten randomized controlled trials (RCTs) that specifically investigated the efficacy of EGDT (Table 1). Manual review of the references accompanying these publications detected three more studies that fulfilled screening criteria. Finally, 13 RCTs (Table 1) and 12 systematic reviews and meta-analyses on EGDT were identified for the review (Table 2).

Table 1 Randomized controlled trials assessing the effect of EGDT on clinical outcomes
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Table 2 Systematic reviews and meta-analysis investigating the effect of EGDT
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Main findings

EGDT was found to significantly benefit mortality as compared with standard care in 5 of the 13 studies (3,15,17,27,35). Of these, four were performed in China and one was the Rivers seminal study. There was significant heterogeneity among included RCTs and subgroup analysis showed that the heterogeneity could be explained by some factors (I²=64%, P=0.02). For example, the beneficial effect of EGDT was influenced by the economic status of the involved research centers and only confirmed in studies from low-income countries [RR: 0.78 (0.67–0.91) vs. 0.93 (0.83–1.06) for low- and high-income countries respectively] (26). A trial by Chen et al. was conducted in a population with lower socio-economic status and less access to hospital care, which reported significantly lower mortality rate in the treatment group (29.5% vs. 49.0%; P=0.007) (17). However, the study by Andrews et al. was also performed in low-income country, but it reported higher mortality rate in the EGDT group (64.2% vs. 60.7%; P>0.05). Thus, the impact of economic status on the effect of EGDT remains inconclusive.

Another explanation for the heterogeneity among RCTs is the baseline mortality risk of enrolled subjects. Since the first introduction of EGDT by Rivers, its implementation in clinical practice had markedly improved management of sepsis and probably explained the significant reduction in mortality over the last ten years (Table 1) (36-38). Control patients in the three recently published large clinical trials (ProMISe, ARISE and ProCESS, also called “a trio of trials”) literally received “standard” care, but might well have been treated according to EGDT principles (8,10,12,13). Note that EGDT also implies extensive “bundled” treatments including immediate fluid resuscitation, early and adequate source control and/or initiation of antibiotics, and tailored use of vasopressors, inotropes and blood transfusion (39). Although study protocols dictated that the control group was not guided by ScvO₂ monitoring but directed by the treating physician, many components of the SSC bundle could have been introduced (35,40), which may explain why no significant difference was found between standard and EGDT-driven care. As an example, baseline ScvO₂ in these studies was higher than 70% in most of patients, which may reflect an aggressive medical therapy before randomization or the inclusion of less severe patients than in the Rivers study. Measuring lactate clearance is as efficient as ScvO₂ (41), and the availability of lactate clearance in the control arm results in similar outcomes between the two groups.

However, only the Rivers study reported a highly significant beneficial effect of EGDT on patient outcome. Importantly, mortality rate in the Rivers’ control population (49.2%) was much higher than in the ProMISe (29.2%), ARISE (18.8%) and ProCESS (18.9%) controls. It is conceivable that a potential EGDT effect was confounded by this low baseline mortality. Jiang and colleagues showed that the beneficial effects of EGDT were only observed in the oldest studies (RR: 0.52; 95% CI: 0.37–0.73), which support the notion that the control group in recent trials had probably been treated in accordance with EGDT precepts (Figure 2) (33). Interestingly, Simpson and colleagues employed meta-regression analysis to investigate the effect of control group mortality, initial APACHE score, year of publication, and use of central venous catheters in the usual care group on heterogeneity of trial outcomes reported in all meta-analyses of EGDT. They found that the baseline or control group mortality rate explains a significant portion of the heterogeneity (R² =0.57; P=0.042) (32).

Figure 2 Forest plot showing pooled effects of EGDT on mortality outcome. Subgroup analysis showed that old trials were more likely to report beneficial effect than new trials. EGDT, early goal directed therapy. The figure was from the reference (33).

Interestingly, observational studies generally reported better efficacy of EGDT than RCTs (40,42-50). Three of the ten systematic review and meta-analyses reported evidence of significant EGDT benefit (30,31,34), yet were probably biased by including observational studies. Even adjustment for confounders may not exclude the impact of numerous unmeasured factors on the results. In contrast to RCTs, observational studies tend to overestimate treatment effects (51). Also, observational studies mostly are explicitly or implicitly data- rather than hypothesis-driven. Statistical analysis is not predefined but performed after reviewing the data which may lead to multiple testing and selective reporting (52). Furthermore, the conduct of studies cannot be explicitly monitored with validated methodology. Thus, observational studies offer preliminary information with low level of evidence. Others argue that RCTs impose the Hawthorne effect that the control group is improved as compared with normal clinical circumstances (53).

EGDT setting

In the Rivers study, septic shock was regarded as an emergency department study and EGDT was applied immediately after ED admission. The care provided included the use of lactate and ScvO₂, which were completely blinded to the ICU clinicians. The three most recent RCTs (ProMISe, ARISE and ProCESS) were not blinded as the patients were in the ICU within 2 hours of presentation and the longitudinal care of using lactate and ScvO₂ was not blinded (10,12,13). It is possible that the EGDT effect can be diminished by the lack of blinding and the use of numerous principles of EGDT in all treatment groups (8).

In contrast, several Chinese studies in ICU patients all reported better survival in EGDT receivers (16-20). EGDT practice in ICU is conceptually less attractive because substantial time may be lost between arrival in the ED and transfer to the ICU. The critical 3- to 6-hour resuscitation window may be neglected or inadvertently allowed to pass. However, timely EGDT can be performed in patients who enter the ICU directly from the hospital ward or operating room. Based on our experience, a mixed ICU receives half of patients from the ED and the other half from the ward and operating theatre (54). Unfortunately, EGDT studies did not report the time from onset of septic shock to ED and/or ICU admission, because it was difficult or even impossible to determine (24,26,29). Thus, the benefit of EGDT performed in the ED can be confounded by the time between disease onset and ED arrival. In other words, the beneficial effect of EGDT can be diminished by delayed ED arrival and initiation of systemic treatment. Postsurgical patients and patients entering the ICU from hospital wards may benefit more from promptly applying EGDT. Moreover, more accurate appreciation of the time span between sepsis onset and ICU admission provides room for improvement and assessment of EGDT practice in this particular population. However, the impact of timing of EGDT on mortality remains speculative. Preliminary evidence demonstrates that mortality reduction has been observed even with significant delays (up to 12 hours) in initiating EGDT (55-58).

Compliance with Surviving Sepsis Campaign (SSC) bundle

Unlike the negative results from recently published RCTs, most observational studies demonstrated that SSC bundle adherence was associated with a reduced mortality rate (9,59-74), but without significantly increasing medical cost (75). Over a 7.5-year period running from 2005 till 2012, Levy et al. found that compliance to the SSC bundle resulted in a 25% relative mortality risk reduction (76). For less “compliant” sites, hospital mortality rates dropped 0.7% per site for every three months of participation in an educational program (77). Other observational and quasi-experimental studies reported similar results (40,55,78-92). When EGDT was incorporated into a clinical pathway for the treatment of severe sepsis and septic shock, hospital mortality could be decreased (93). Due to the importance of adherence to EGDT bundle, studies investigated factors associated with compliance (94,95). These studies showed that body temperature, experience of nurses and physicians, cryptic shock, serum lactate levels and ED crowding all affected adherence (94,96).

An important distinction between RCTs exploring EGDT and observational studies applying the SSC bundle is that the latter included somewhat different components than recommended in EGDT. Another important difference lies in the management of control groups. Over time, the level of care in the control groups has probably been upgraded, introducing a Hawthorne effect. Taken together, the management of these patients perhaps does not reflect usual clinical practices, resulting in large difference between observational studies and RCTs. In fact, the SSC bundle not only underscores early use of antibiotics, obtaining blood cultures and measuring lactate, and setting resuscitation goals at CVP >8 mmHg, MAP >65 mmHg and ScvO₂ >70%, but also included lung protective ventilation, administration of steroids, tight glucose control and, initially, adjunctive treatment with drotrecogin alfa (a drug that is no longer marketed) (79). The SSC bundle thus represents a frame that allows comprehensive measures to act in concert to enhance the positive effect of each individual component. The effect of a single intervention could indeed become easily corrupted by a low signal-to-noise ratio precluding any valuable statistical interpretation (97). Importantly, mortality of sepsis and septic shock is markedly reduced when physicians are engaged in an educational and quality improvement programs that incorporates all systemic components recommended by the SCC guideline (91,98-100). High-level evidence of the effectiveness of the SSC bundle can only be obtained by conducting a RCT. However, such trial defies ethical standards since it would potentially deprive patients in the control group of evidence-based care. Yet, based on the consistently positive results and the large effect size (OR: 0.66, 95% CI: 0.61–0.72; k=48, N=434,447) reported in observational studies (79), implementation of the SSC bundle to treat sepsis and septic shock is highly recommended.

The importance of early recognition of sepsis

In some studies, delayed initiation of EGDT was associated with improved outcome, compared with non-compliance, suggesting that late initiation is better than no initiation (56-58). However, these studies included initiation of EGDT more than 12 hours after diagnosis in the definition of non-compliance. Delays of this magnitude have been associated with increased risk of death (101). Another study showed that inability to achieve early resuscitation goals (OR: 1.94, 95% CI: 1.0–3.51) was associated with increased 28-day mortality rate (102). Thus, prompt initiation of EGDT is still recommended for septic shock (103-108), and many efforts have been made to improve early recognition and treatment of septic shock (109). However, early recognition of severe sepsis and septic shock, albeit crucial for EGDT efficacy, remains elusive in clinical practice. For example, the Rivers’ study criteria dictated that EGDT maneuvers had to be completed within 6 hours after ED admission (3). However, this 6-hour time window obviously could not have been the same to all patients, who were septic for an unspecified time period before ED admission. Tools that reliably detect early community-acquired sepsis are warranted and are the topic of intensive research. Meanwhile, there are studies focusing on early recognition of sepsis in hospitalized patients (110-112). As mentioned before, this patient population may be identified more easily and thus become more amenable for straightforward EGDT. The SEPSIS KILL program aimed to provide interventions within 60 minutes after onset of sepsis in hospitalized patients, which was shown to be effective in reducing mortality (113).

Studies investigating the impact of automated electronic sepsis alert systems on clinical outcome produced inconsistent results (Table 3) (112). Two RCTs failed to show a beneficial effect of such alert systems (114,118). In contrast, a before-after study showed that applying an alert system resulted in a decreased mortality (117). Time to completion of the resuscitation bundle was not influenced by the use of an electronic alert system (118). Of note is that SIRS criteria, which are challenged for lack of specificity, were mainly used as alerting threshold (120). A new definition of sepsis (Sepsis-3), incorporating an adapted organ dysfunction (quick SOFA) score to identify sepsis in an early phase has recently been released (1,121). The consensus conference recommended that the quick SOFA that includes altered mental status, fast respiratory rate and low blood pressure should be widely diffused in order to improve the early detection of sepsis. More recently, Churpek and colleagues demonstrated that both the Modified Early Warning System (MEWS) and the National Early Warning System (NEWS) demonstrate higher predictive ability for mortality or prolonged ICU stay than qSOFA (122). Trials to investigate whether electronic alerting systems based on Sepsis-3 or other measures will fine-tune sepsis management and improve relevant patient-important outcomes are awaited. Recognition of sepsis with automated sepsis alert systems is not necessarily coupled with initiating the SSC bundle, so it remains to be proven whether triggering SSC bundle therapy by automated sepsis alert systems improves clinical outcomes.

Table 3 Studies investigating the effectiveness of automated electronic sepsis alert systems
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Conclusions

Sepsis is a heterogeneous syndrome and thus unlikely to respond to a single treatment. Within this context, EGDT has been introduced as an interesting approach characterized by early recognition and prompt initiation of a structured treatment algorithm. Initially, EGDT targeted a CVP >8 mmHg, a MAP >65 mmHg, a diuresis >0.5 mL/kg/hour and a ScvO₂ >70%. Thereafter, EGDT was progressively expanded by adding lactate (clearance) as a supplementary goal and including interventions such as early and adequate source control and/or antibiotic use, low tidal volume mechanical ventilation, and steroid administration (123). Such expanded EGDT algorithm is incorporated in the SSC bundle. Current evidence supports the idea that EGDT may benefit ICU patients more than ED subjects because of a better knowledge of the time window between diagnosis of sepsis and start of treatment. Several observational studies have reported a beneficial effect of SSC bundle adherence on patient-important outcomes but this was not confirmed by recent large RCTs. This is due to a progressive decrease of mortality over time in patients receiving “standard” care which probably implicitly implies more adequate resuscitation. Taken together, early awareness of sepsis and upfront initiation of the SSC bundle remain imperative for improving the fate of severely septic patients.

Acknowledgements

We would like to thank Prof. Emanuel Rivers (Department of Emergency Medicine, Henry Ford Hospital, Wayne State University, Detroit, MI, USA) for his invaluable suggestions on this manuscript drafting.

Funding: The study was supported by Zhejiang Medical Science and Technology projects (2015117919) and Zhejiang Provincial Science and technology projects (2013C33G2010401). The funder has no role in the design and conduct of the review.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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