New England Journal of Medicine May 01, 2014

A Randomized Trial of Protocol-Based Care for Early Septic Shock

The ProCESS Investigators

Bottom Line

In adult patients with early septic shock, protocol-based Early Goal-Directed Therapy (EGDT) did not improve 60-day in-hospital mortality compared to protocol-based standard therapy or usual care.

Key Findings

1. There was no significant difference in the primary outcome of 60-day in-hospital mortality among the three groups: 21.0% in the EGDT group, 18.2% in the protocol-based standard-therapy group, and 18.9% in the usual-care group.

2. No significant differences were observed in 90-day mortality, 1-year mortality, or the need for organ support such as mechanical ventilation or renal replacement therapy.

3. Patients assigned to the EGDT group received significantly more intravenous fluids, vasopressors, and blood transfusions during the first 6 hours of resuscitation than those in the usual-care group.

4. Length of intensive care unit (ICU) and hospital stay did not differ significantly across the trial arms.

Study Design

Design

Multicenter RCT

Open-Label

Sample

1,341

Patients

Duration

60 days

Median

Setting

Multicenter, US

Population Adult emergency department patients with early septic shock (defined as suspected infection, ≥2 SIRS criteria, and refractory hypotension or lactate ≥4 mmol/L)

Intervention Protocol-based Early Goal-Directed Therapy (EGDT) requiring central venous catheterization to strictly target central venous pressure (CVP), mean arterial pressure (MAP), and central venous oxygen saturation (ScvO2) for 6 hours

Comparator Protocol-based standard therapy (fluid and vasopressor administration without requiring central lines) or Usual Care (non-protocolized management at the bedside physician's discretion)

Outcome In-hospital mortality from any cause at 60 days

Study Limitations

• The trial utilized an open-label, unblinded design due to the nature of the interventions, which could introduce performance bias, although the primary endpoint of mortality is objective.

• Overall mortality was much lower (~18-21%) than in the original 2001 Rivers trial (~30-46%), reflecting secular improvements in modern baseline care that may have blunted any measurable benefit of specific protocols.

• High baseline compliance with early antibiotics and fluids in the usual care arm (possibly influenced by a Hawthorne effect or execution at academic centers) may limit generalizability to lower-resource settings.

• Strict exclusion criteria, such as patients requiring immediate surgery or presenting with acute bleeding, limit the generalizability to all unselected patients with shock.

Clinical Significance

The ProCESS trial catalyzed a major paradigm shift in sepsis management by demonstrating that strict, invasive EGDT—mandating central venous lines to strictly target central venous pressure (CVP) and central venous oxygen saturation (ScvO2)—does not improve outcomes compared to standard resuscitation. It established that early recognition, timely administration of antibiotics, and adequate fluid resuscitation are the pivotal elements of septic shock survival, effectively reducing unnecessary invasive procedures without compromising patient care.

Historical Context

Following the landmark 2001 single-center trial by Rivers et al., Early Goal-Directed Therapy (EGDT) became the standard of care and a core pillar of the Surviving Sepsis Campaign guidelines. However, concerns grew over the invasiveness, cost, and external validity of EGDT in an era of improving standard emergency care. This led to the funding of three large, harmonized, international randomized trials: ProCESS (USA), ARISE (Australasia), and ProMISe (UK). ProCESS was the first of the three to publish, successfully refuting the necessity of the rigid Rivers protocol and reshaping modern guidelines.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

The Rivers EGDT protocol evaluated in the ProCESS trial mandated monitoring Central Venous Oxygen Saturation (ScvO2). Physiologically, what does ScvO2 represent, and why was it initially targeted to reverse septic shock?

Key Response

ScvO2 reflects the physiological balance between total body oxygen delivery and oxygen consumption. In early sepsis, a low ScvO2 indicates inadequate perfusion and oxygen extraction mismatch, driving the rationale for using transfusions or inotropes to increase oxygen delivery, prevent tissue hypoxia, and avoid multiorgan failure.

Resident

Given that the ProCESS trial demonstrated no mortality benefit of strict EGDT over usual care, how does this change the initial management and monitoring of a patient presenting to the ED with septic shock compared to the traditional Rivers protocol?

Key Response

Residents no longer need to routinely place central venous catheters solely to monitor CVP and ScvO2 or aim for rigid transfusion thresholds (e.g., hematocrit > 30%) in early resuscitation. Management shifts to timely antibiotics, adequate crystalloid fluid resuscitation (e.g., 30cc/kg), and vasopressors to maintain MAP > 65 mmHg using non-invasive or standard monitoring.

Fellow

The control group (usual care) in the ProCESS trial had a significantly lower mortality rate than the control group in the original 2001 Rivers trial. How did 'usual care' for sepsis evolve between these two trials, and how does this phenomenon impact the interpretation of these results?

Key Response

Over the 13 years between trials, 'usual care' improved dramatically due to the widespread adoption of early sepsis recognition, rapid antibiotic administration, and aggressive initial fluid resuscitation promoted by the Surviving Sepsis Campaign. This elevated baseline level of care makes it much harder for a specific, invasive protocol to demonstrate incremental benefit, highlighting the shifting baseline in critical care trials.

Attending

The ProCESS trial found that protocol-based EGDT resulted in higher rates of ICU admission and central venous catheterization without improving survival. From a systems and attending-level perspective, how do these findings influence resource allocation and the prevention of iatrogenic harm?

Key Response

Eliminating the strict EGDT protocol reduces unnecessary invasive procedures, thereby mitigating associated complications like pneumothorax or CLABSI. It also optimizes ICU bed utilization by allowing some appropriately resuscitated patients to be managed with peripheral vasopressors or in step-down units, reinforcing the clinical teaching that more invasive interventions do not inherently equal better care.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ProCESS trial utilized a three-arm design (protocol-based EGDT, protocol-based standard therapy, and usual care). What is the methodological advantage of including both a 'protocol-based standard therapy' arm and a 'usual care' arm, rather than a simple two-arm comparison?

Key Response

A three-arm design isolates the specific effect of the physiological targets (ScvO2, CVP) from the effect of strictly protocolizing care. If EGDT was better than usual care but equal to protocolized standard care, the benefit would be attributed to the protocolization itself. Since all three arms had similar outcomes, it proved that neither the rigid physiological targets nor the strict protocolization provided additional benefit over modern clinical judgment.

Journal Editor

A critical reviewer might argue that the timing of enrollment in the ProCESS trial limits its external validity, as patients had already received significant fluid resuscitation prior to randomization. How does this pre-randomization treatment affect the trial's ability to definitively refute the original EGDT concept?

Key Response

Patients received an average of 2-3 liters of fluid before randomization, meaning they were already partially resuscitated. A rigorous reviewer would flag that EGDT might still have a role in completely unresuscitated patients. The trial actually proves that after early initial fluid loading and antibiotics, further protocolized EGDT offers no additional benefit, rather than entirely invalidating the concept of early aggressive care.

Guideline Committee

Based on the findings of the ProCESS trial, combined with the subsequent ARISE and ProMISe trials, how should the Surviving Sepsis Campaign (SSC) guidelines be updated regarding resuscitation targets, and what level of evidence supports these changes?

Key Response

The convergence of ProCESS, ARISE, and ProMISe provides high-quality evidence to strongly recommend against the routine use of CVP and ScvO2 targets for sepsis resuscitation. Consequently, the SSC guidelines were updated to remove the requirement for these specific hemodynamic targets, instead recommending a generalized target of MAP >= 65 mm Hg and guiding fluid resuscitation through dynamic measures of fluid responsiveness.

Clinical Landscape

Noteworthy Related Trials

2001

Rivers Trial

n = 263 · NEJM

Tested

Early Goal-Directed Therapy (EGDT)

Population

Patients with severe sepsis or septic shock

Comparator

Standard therapy

Endpoint

In-hospital mortality

Key result: EGDT significantly reduced in-hospital mortality compared to standard therapy (30.5% vs 46.5%).

2014

ARISE Trial

n = 1591 · NEJM

Tested

Early Goal-Directed Therapy (EGDT)

Population

Patients with early septic shock

Comparator

Usual care

Endpoint

90-day all-cause mortality

Key result: There was no significant difference in 90-day mortality between the EGDT group and the usual-care group (18.6% vs 18.8%).

2015

ProMISe Trial

n = 1260 · NEJM

Tested

Early Goal-Directed Therapy (EGDT)

Population

Patients with early septic shock

Comparator

Usual resuscitation

Endpoint

90-day all-cause mortality

Key result: EGDT did not reduce all-cause mortality at 90 days compared with usual resuscitation and was associated with increased costs.

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