The New England Journal of Medicine MAY 01, 2014

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

The ProCESS Investigators

Bottom Line

The ProCESS trial demonstrated that in patients with early septic shock, neither protocol-based early goal-directed therapy (EGDT) nor protocol-based standard therapy resulted in improved 60-day mortality compared to usual care.

Key Findings

1. The 60-day in-hospital mortality was similar across all 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 (P values between 0.31 and 0.89).

2. There were no significant differences in 90-day mortality, 1-year mortality, or the duration of organ support required across the study arms.

3. Patients in the EGDT group received higher amounts of intensive care resources, including more vasopressors, blood transfusions, and dobutamine, compared to the other study arms, despite no clinical benefit.

Study Design

Design

RCT

Open-Label

Sample

1,341

Patients

Duration

60 days

Median

Setting

Multicenter, US academic

Population Adults presenting to the emergency department with early septic shock (refractory hypotension or hyperlactatemia >= 4 mmol/L)

Intervention Protocol-based early goal-directed therapy (EGDT) as per the Rivers protocol

Comparator Protocol-based standard therapy and usual care

Outcome 60-day in-hospital mortality

Study Limitations

• The study was open-label (non-blinded) as it was impossible to blind clinicians to the intervention protocols, which could introduce bias in co-interventions.

• The study was conducted exclusively in academic medical centers, which may limit the generalizability of the findings to community hospital settings with different resource levels.

• The mortality rates observed in the trial (approx. 20%) were significantly lower than the historical mortality rates (approx. 40-50%) upon which the trial's power calculations were initially based.

Clinical Significance

The ProCESS trial significantly shifted the clinical paradigm of sepsis management by demonstrating that a strict, protocol-based EGDT bundle does not confer a mortality advantage over contemporary standard care. It highlights that the critical drivers of improved outcomes in sepsis are early recognition, prompt antibiotic administration, and adequate fluid resuscitation, rather than the adherence to specific, invasive hemodynamic protocols.

Historical Context

Early goal-directed therapy (EGDT) gained widespread acceptance following a 2001 single-center study by Rivers et al., which reported a substantial mortality reduction (approx. 16%) with a standardized protocol. This protocol was subsequently incorporated into international Surviving Sepsis Campaign guidelines. The ProCESS trial, along with the ARISE and ProMISe trials, was conducted to test the generalizability of these findings in more diverse and contemporary practice settings, ultimately challenging the necessity of the full EGDT bundle.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological rationale behind targeting central venous oxygen saturation (ScvO2) in the initial management of septic shock, and why might the ProCESS trial suggest this metric is less critical than previously thought?

Key Response

ScvO2 represents the balance between oxygen delivery and consumption. The 2001 Rivers trial suggested that targeting an ScvO2 >70% reduced mortality; however, the ProCESS trial found that usual care in modern settings—which often already includes early fluids and antibiotics—achieves similar outcomes without the need for invasive ScvO2 monitoring, suggesting that the timing of basic interventions is more important than specific physiological targets.

Resident

In light of the ProCESS trial results, how should a clinician decide between following a strict Early Goal-Directed Therapy (EGDT) algorithm versus 'usual care' when managing a patient with early septic shock in the Emergency Department?

Key Response

The ProCESS trial showed no mortality benefit for protocol-based EGDT or protocol-based standard therapy over usual care. This allows clinicians to exercise bedside judgment, focusing on prompt antibiotic administration and fluid resuscitation without being mandated to place central venous catheters solely for CVP or ScvO2 monitoring, provided the patient is responding to initial therapy.

Fellow

The ProCESS trial, along with ARISE and ProMISE, is often cited as the 'death of EGDT.' How do these findings reconcile with the physiological concept of 'oxygen debt' in early sepsis, and does this mean hemodynamic monitoring has no place in resuscitation?

Key Response

While the trials showed no benefit to a rigid protocol, they also demonstrated that 'usual care' has significantly improved since 2001, often achieving the same physiological goals as EGDT. Hemodynamic monitoring is still vital for patients who do not respond to initial fluid challenges or those with complex comorbidities (e.g., heart failure), but it should be used to guide individualized therapy rather than as a universal requirement for all septic patients.

Attending

How does the evidence from the ProCESS trial change the way we teach sepsis resuscitation to residents, specifically regarding the 'bundle' mentality versus 'individualized' clinical assessment?

Key Response

ProCESS teaches us that the specific 'targets' (CVP, ScvO2) of the original bundles are not the drivers of survival. Instead, the focus of teaching should shift to 'early recognition' and 'prompt source control/antibiotics.' It empowers attendings to teach residents to monitor for clinical signs of perfusion (capillary refill, lactate clearance, urine output) rather than relying on invasive pressure-based measurements that may lead to over-resuscitation.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ProCESS trial utilized a three-arm design to compare two distinct protocols against 'usual care.' From a methodological standpoint, how does the potential for 'provider crossover' or 'behavioral contamination' in the 'usual care' arm affect the internal validity and the ability to detect a treatment effect?

Key Response

In a multicenter trial where clinicians manage patients in all arms, they may subconsciously apply elements of the experimental protocols (e.g., more aggressive fluid monitoring) to the 'usual care' group. This 'Hawthorne Effect' or contamination can narrow the gap between the intervention and control groups, potentially leading to a null result if the trial is not powered to detect very small differences in mortality.

Journal Editor

Considering the median time from ED arrival to randomization in ProCESS was approximately 3 hours, to what extent does 'pre-randomization care' (early fluid and antibiotic administration) represent a lead-time bias or a threat to the trial's ability to evaluate the true efficacy of the EGDT protocol?

Key Response

A critical reviewer would flag that if patients already received significant resuscitation before the 'start' of the protocol, the 'window of opportunity' for EGDT to show benefit may have already closed. This suggests the trial may not be testing EGDT against nothing, but rather testing 'extra' monitoring against 'early successful stabilization,' which significantly impacts the editorial interpretation of the study's impact.

Guideline Committee

Given the results of ProCESS and its sister trials (ARISE and ProMISE), what is the strength of evidence for recommending against the mandatory use of CVP and ScvO2 targets in the Surviving Sepsis Campaign (SSC) guidelines?

Key Response

The 'trilogy' of trials provides Level 1A evidence that protocolized EGDT does not improve survival over usual care in settings where early sepsis recognition is standard. Consequently, the SSC guidelines moved away from mandatory invasive monitoring (CVP/ScvO2) in the 6-hour bundle, instead emphasizing dynamic measures of fluid responsiveness, reflecting the high-quality evidence that rigid, invasive targets provide no incremental benefit.

Clinical Landscape

Noteworthy Related Trials

2001

Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock

n = 263 · NEJM

Tested

Early goal-directed therapy (EGDT) protocol

Population

Patients with severe sepsis or septic shock in the ED

Comparator

Standard care

Endpoint

In-hospital mortality

Key result: EGDT significantly reduced in-hospital mortality compared to standard care in patients with severe sepsis and septic shock.

2014

Arise Trial

n = 1600 · NEJM

Tested

Early goal-directed therapy (EGDT)

Population

Patients presenting to the ED with early septic shock

Comparator

Usual care

Endpoint

All-cause mortality at 90 days

Key result: EGDT did not result in lower 90-day all-cause mortality compared with usual care in patients presenting to the emergency department with early septic shock.

2015

Protocolised Management in Sepsis (ProMISe) Trial

n = 1260 · NEJM

Tested

Protocol-based early goal-directed therapy (EGDT)

Population

Patients with septic shock in the emergency department

Comparator

Standard care

Endpoint

All-cause mortality at 90 days

Key result: Protocol-based resuscitation for patients with early septic shock did not improve outcomes compared to standard care.

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