The New England Journal of Medicine MARCH 17, 2015

Trial of Early, Goal-Directed Resuscitation for Septic Shock

Mouncey PR, Osborn TM, Power GS, et al. (The ProMISe Trial Investigators)

Bottom Line

In a large, multicenter, open-label randomized controlled trial, protocolized early goal-directed therapy (EGDT) did not reduce 90-day all-cause mortality compared with usual resuscitation in patients presenting to emergency departments with early septic shock.

Key Findings

1. The primary outcome of 90-day all-cause mortality showed no significant difference between the intervention group and the usual care group (29.5% vs. 29.2%; relative risk, 1.01; 95% confidence interval, 0.85 to 1.20; P=0.90).

2. Patients in the EGDT group received more intensive care, including significantly higher rates of advanced cardiovascular support (37.0% vs. 30.9%; P=0.026), central venous catheterization (92.1% vs. 50.9%), and blood transfusion (8.8% vs. 3.7%).

3. EGDT resulted in increased healthcare costs without demonstrating clinical benefit in terms of quality-adjusted life years (QALYs) or reduction in organ dysfunction.

4. The results were consistent with other large international trials (ProCESS and ARISE), confirming that aggressive protocolized monitoring is not superior to high-quality standard resuscitation in modern clinical practice.

Study Design

Design

RCT

Open-Label

Sample

1,260

Patients

Duration

90 days (and 1 year for economic evaluation)

Median

Setting

Multicenter, England

Population Adult patients presenting to emergency departments with suspected or confirmed infection and signs of early septic shock (refractory hypotension or hyperlactatemia).

Intervention 6-hour protocolized early goal-directed therapy (EGDT) targeting central venous pressure, mean arterial pressure, and central venous oxygen saturation (ScvO2).

Comparator Usual resuscitation according to standard clinical practice within the participating National Health Service (NHS) hospitals.

Outcome All-cause mortality at 90 days after randomization.

Study Limitations

• The trial was open-label, which precluded blinding of clinicians and patients to the assigned resuscitation strategy, potentially introducing assessment bias.

• Usual care in the UK at the time of the study already incorporated many elements of early sepsis management, which likely narrowed the potential treatment effect difference between the two groups.

• The mortality rate in both groups was lower than the initial power calculation had anticipated, which may have limited the ability to detect smaller, yet potentially meaningful, differences in outcomes.

• The trial was conducted in a high-income setting with established emergency and critical care systems, which may limit generalizability to resource-limited settings where standard care is less consistent.

Clinical Significance

The ProMISe trial provides definitive evidence that the rigid application of invasive hemodynamic monitoring and target-driven resuscitation protocols (EGDT) does not improve survival in patients with septic shock when timely standard resuscitation is provided. This study contributed to a major shift in clinical practice guidelines, moving away from resource-intensive invasive monitoring in favor of early, prompt delivery of standard sepsis care bundles.

Historical Context

The study was designed to rigorously test the findings of the influential 2001 single-center trial by Rivers et al., which reported a substantial mortality reduction using 6-hour EGDT. Given the widespread, albeit uneven, adoption of EGDT into international guidelines despite the lack of confirmatory multicenter data, the ProMISe trial, along with the ProCESS and ARISE trials, served as the concluding evidence to re-evaluate the role of protocolized goal-directed resuscitation.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

In the context of the ProMISe trial, what is the physiological rationale for monitoring central venous oxygen saturation (ScvO2) in septic shock, and why might the trial have failed to show a benefit compared to usual care?

Key Response

ScvO2 reflects the balance between systemic oxygen delivery (DO2) and oxygen consumption (VO2). The original 2001 Rivers trial suggested that targeting ScvO2 > 70% reduced mortality. However, ProMISe and related trials showed that by the time of enrollment, many patients in the 'usual care' group already had ScvO2 levels near or above 70% due to early recognition and fluid administration, meaning the physiological deficit the protocol was designed to fix was already being addressed by standard practice.

Resident

The ProMISe trial compared protocolized Early Goal-Directed Therapy (EGDT) to usual care. Based on its findings, which specific interventions from the original 'Rivers Protocol' are no longer recommended as mandatory standards for all patients in early septic shock?

Key Response

The ProMISe trial demonstrated that mandatory invasive monitoring (routine arterial lines and central venous catheters for ScvO2 and CVP) and the protocolized use of dobutamine or blood transfusions to meet specific physiological targets did not improve outcomes. Current management focuses on early antibiotics, fluid resuscitation, and vasopressors if needed, without requiring the rigid, invasive targets of the original EGDT protocol.

Fellow

How do the results of the ProMISe trial, when integrated with the ARISE and ProCESS trials, highlight the 'secular trend' in sepsis mortality, and what does this imply about the generalizability of the original 2001 EGDT findings?

Key Response

The 'Trilogy' of trials (ProMISe, ARISE, ProCESS) showed control group mortality rates around 18-29%, significantly lower than the 46.5% seen in the 2001 Rivers trial. This suggests that the 'usual care' of the 2010s had already incorporated the most effective elements of EGDT (early identification and rapid fluid/antibiotic delivery), rendering the specialized, invasive components of the protocol redundant in modern clinical settings.

Attending

ProMISe was a 'negative' trial for its primary endpoint. Discuss how these results should influence the teaching of 'clinical gestalt' versus 'protocolized bundles' in the management of complex, heterogeneous syndromes like septic shock.

Key Response

The findings suggest that for many patients, the bedside judgment of experienced clinicians (usual care) is equivalent to a rigid protocol. This reinforces the teaching point that while 'bundles' ensure a minimum standard of care (antibiotics/fluids), they should not replace physiological reasoning. It shifts the focus from 'meeting numbers' (like CVP) to 'personalized resuscitation' based on dynamic assessments of perfusion.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ProMISe trial included a detailed prospectively defined economic evaluation. How does the finding of 'increased costs with no difference in QALYs' impact the translation of such research into health policy compared to a trial that only reports clinical mortality?

Key Response

By demonstrating that EGDT was not only clinically non-superior but also more resource-intensive (higher costs for catheters, ICU stays, and staff time), the study provided a robust 'value-based' argument for disinvestment. In systems like the UK's NHS, this economic data is critical for justifying the removal of protocolized mandates from national quality indicators.

Journal Editor

ProMISe was an open-label trial where clinicians in the usual care arm were aware of the trial's existence. What are the potential implications of the 'Hawthorne Effect' in this study design, and how might it lead to a Type II error?

Key Response

The Hawthorne Effect occurs when clinicians improve their 'usual' performance because they are being observed. If the awareness of the trial led the control group to provide more aggressive or timely resuscitation than they would in a non-trial setting, the gap between the intervention and control groups would shrink, potentially masking a true treatment effect of the protocol (a Type II error/false negative).

Guideline Committee

Following the ProMISe trial, the Surviving Sepsis Campaign (SSC) significantly revised its '6-hour bundle.' How does the trial's evidence specifically inform the current recommendation level for using CVP and ScvO2 as primary resuscitation targets?

Key Response

The 2016 and 2021 SSC updates downgraded the importance of CVP and ScvO2, moving them from mandatory targets to optional components of a 'repeated assessment' strategy. Based on the ProMISe findings that these targets did not improve 90-day mortality, the guidelines now emphasize dynamic measures (e.g., skin mottling, capillary refill time, or passive leg raise) over the static, invasive targets used in the original EGDT protocol.

Clinical Landscape

Noteworthy Related Trials

2001

Rivers et al. EGDT Study

n = 263 · NEJM

Tested

Early goal-directed therapy

Population

Patients presenting to the emergency department with severe sepsis or septic shock

Comparator

Standard care

Endpoint

In-hospital mortality

Key result: Early goal-directed therapy resulted in significantly lower in-hospital mortality compared with standard care.

2014

ProCESS Trial

n = 1,341 · NEJM

Tested

Protocol-based early goal-directed therapy

Population

Patients presenting to the emergency department with septic shock

Comparator

Usual care

Endpoint

60-day in-hospital mortality

Key result: The trial found no significant difference in 60-day mortality between protocol-based EGDT and usual care.

2014

ARISE Trial

n = 1,600 · NEJM

Tested

Early goal-directed therapy

Population

Patients with early septic shock in Australasian emergency departments

Comparator

Standard care

Endpoint

90-day all-cause mortality

Key result: Early goal-directed therapy did not result in lower all-cause mortality at 90 days compared with standard care.

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