Article Identification

  • Article Title: A Randomized Trial of Protocol-Based Care for Early Septic Shock
  • Citation: Yealy, D. M., Kellum, J. A., Huang, D. T., Pike, F., et al. (2014). A Randomized Trial of Protocol-Based Care for Early Septic Shock. The New England Journal of Medicine, 370(18), 1683-1693.
  • DOI: 10.1056/NEJMoa1401602
  • PMID: 24735773

Quick Reference Summary

The ProCESS trial compared protocol-based early goal-directed therapy (EGDT), protocol-based standard therapy, and usual care in 1,341 patients with septic shock across 31 U.S. emergency departments. No significant differences were found in 60-day in-hospital mortality (21.0% vs. 18.2% vs. 18.9%, p=0.83) among the three groups, indicating that protocol-based resuscitation did not improve survival compared to usual care.

Core Clinical Question

Does protocol-based early goal-directed therapy (EGDT) compared to protocol-based standard therapy and usual care reduce 60-day in-hospital mortality in adults presenting with septic shock in emergency departments?

PICO:

  • Population: Adults (>18 years) presenting with septic shock in emergency departments
  • Intervention: Protocol-based early goal-directed therapy (EGDT)
  • Comparison: Protocol-based standard therapy and usual care
  • Outcome: 60-day in-hospital mortality

Background

Disease Overview

Septic shock, a subset of sepsis, is characterized by persistent hypotension requiring vasopressors to maintain mean arterial pressure despite adequate fluid resuscitation, along with elevated serum lactate levels. It is associated with high mortality rates, exceeding 20%, and requires prompt recognition and management in the emergency department (ED).

Prior Data

  • Rivers et al. (2001): Demonstrated that EGDT, involving central venous pressure and oxygen saturation monitoring, significantly reduced mortality in septic shock compared to usual care (30.5% vs. 46.5%).
  • Variability in Sepsis Management Studies: Indicated inconsistent application of sepsis protocols across institutions, impacting patient outcomes negatively.

Current Standard of Care

The Surviving Sepsis Campaign (SSC) guidelines advocate for early recognition and standardized protocols, including timely antibiotic administration, fluid resuscitation, vasopressor support, and source control. EGDT was considered a cornerstone based on early studies but has since been re-evaluated.

Knowledge Gaps Addressed

  • Generalizability: Whether the mortality benefits of EGDT observed in single-center studies are replicable across multiple centers.
  • Component Necessity: Determining if all elements of the EGDT protocol (e.g., central venous catheterization, inotropes, blood transfusions) are essential for improving outcomes.

Study Rationale

Given advancements in sepsis management and potential variability in protocol adherence, the ProCESS trial aimed to validate the effectiveness of EGDT in a multicenter setting and assess whether streamlined protocol-based therapies could achieve similar or better outcomes.

Methods Summary

  • Study Design: Multicenter, randomized, controlled trial
  • Setting and Time Period: 31 emergency departments in the United States, March 2008 – May 2013
  • Population Characteristics: Adult patients (>18 years) diagnosed with septic shock based on at least two systemic inflammatory response syndrome (SIRS) criteria and evidence of hypoperfusion (refractory hypotension or serum lactate ≥4 mmol/L)
  • Inclusion/Exclusion Criteria:
    • Inclusion: Adults with septic shock presenting to ED
    • Exclusion: Immediate surgery required, active gastrointestinal hemorrhage, contraindications to central venous catheterization or transfusion, among others
  • Intervention Details:
    • EGDT Group: Protocol-based monitoring of central venous pressure (CVP) and central venous oxygen saturation (ScvO2), administration of fluids, vasopressors, inotropes, and blood transfusions to achieve specific hemodynamic targets over 6 hours
    • Standard Therapy Group: Protocol-based resuscitation without mandatory placement of central venous catheter, inotropes, or blood transfusions; focus on achieving CVP and mean arterial pressure (MAP) targets
    • Usual Care Group: No specific protocol; care directed by treating physicians without protocol prompts
  • Primary and Secondary Outcomes:
    • Primary Outcome: 60-day in-hospital mortality
    • Secondary Outcomes: 90-day and 1-year mortality, need for organ support, duration of ICU/hospital stay, and adverse events
  • Statistical Analysis Approach: Intention-to-treat analysis with Fisher’s exact test for primary outcome; Kaplan-Meier estimates and log-rank tests for survival analysis; subgroup analyses for predefined stratifications
  • Sample Size Calculations: Initially aimed for 1,950 patients for 80% power to detect a 6-7% mortality reduction; adjusted to 1,350 after interim analyses
  • Ethics and Funding: Approved by institutional review boards at participating sites; funded by the National Institute of General Medical Sciences; no declared conflicts of interest

Detailed Results

Participant Flow and Demographics

A total of 1,351 patients were randomized—439 to EGDT, 446 to Standard Therapy, and 456 to Usual Care—with 1,341 evaluable patients after excluding 10 requests for data removal. Baseline characteristics were well-matched across groups with no significant differences in age, sex, comorbidities, source of sepsis, APACHE II scores, lactate levels, or time to randomization.

Primary Outcome Results

  • 60-Day In-Hospital Mortality:
    • EGDT: 92/439 (21.0%)
    • Standard Therapy: 81/446 (18.2%)
    • Usual Care: 86/456 (18.9%)
  • Relative Risk (Protocol-Based vs. Usual Care): 1.04 (95% CI: 0.82–1.31; P=0.83)
  • Relative Risk (EGDT vs. Standard Therapy): 1.15 (95% CI: 0.88–1.51; P=0.31)

Secondary Outcome Results

No significant differences were observed in 90-day mortality (EGDT 31.9%, Standard Therapy 30.8%, Usual Care 33.7%; P=0.66) or 1-year mortality (P=0.70 for 90-day; P=0.92 for 1-year). Organ support needs were similar across groups with no significant differences in cardiovascular or respiratory failure. Minor differences were noted in renal failure rates (Standard Therapy 6.0%, EGDT 3.1%, Usual Care 2.8%; P=0.04). No significant differences were observed in serious adverse events or subgroup analyses for predefined stratifications.

Results Table

Outcome EGDT Group (N=439) Standard Therapy Group (N=446) Usual Care Group (N=456) P-value
60-Day In-Hospital Mortality 92/439 (21.0%) 81/446 (18.2%) 86/456 (18.9%) 0.83
90-Day Mortality 129/405 (31.9%) 128/415 (30.8%) 139/412 (33.7%) 0.66
1-Year Mortality - - - 0.92
New Renal Failure 12/382 (3.1%) 24/399 (6.0%) 11/397 (2.8%) 0.04
Admission to ICU 401/439 (91.3%) 381/446 (85.4%) 393/456 (86.2%) 0.01
Serious Adverse Events 23/439 (5.2%) 22/446 (4.9%) 37/456 (8.1%) 0.32

Authors' Conclusions

The ProCESS trial demonstrated that, in a multicenter setting within tertiary care hospitals, protocol-based resuscitation strategies (both EGDT and standard therapy) for patients with newly diagnosed septic shock did not result in improved 60-day in-hospital mortality compared to usual care. These findings suggest that the aggressive components of EGDT, such as mandatory central venous catheterization and targeted ScvO2 monitoring, may not be necessary to achieve comparable survival outcomes. The study underscores the effectiveness of contemporary usual care practices and indicates that flexibility in protocol adherence does not compromise patient survival.

Critical Analysis

A. Strengths

  • Multicenter Design: Included 31 diverse U.S. emergency departments, enhancing generalizability across various clinical settings.
  • Large Sample Size: Enrolled 1,341 patients, providing adequate power to detect differences in mortality outcomes.
  • Randomization and Blinding: Utilized centralized web-based randomization and blinded outcome assessment, reducing selection and measurement biases.
  • Comprehensive Outcome Measures: Assessed both short-term and long-term mortality, organ support needs, and adverse events, offering a holistic view of patient outcomes.
  • High Protocol Adherence: Reported high adherence rates in protocol-based groups, ensuring the integrity of intervention implementation.
  • Clear Reporting: Detailed presentation of methods, results, and subgroup analyses, facilitating transparency and reproducibility.

B. Limitations

  • Usual Care Variability: As usual care was not standardized, there could be significant variability in management across different sites, potentially diluting observable effects.
  • Exclusion of Specific Populations: Certain patient groups were excluded (e.g., those requiring immediate surgery or with active hemorrhage), limiting applicability to all septic shock patients.
  • Potential for Unmeasured Confounders: Despite randomization, unmeasured factors influencing outcomes could exist, although balanced baseline characteristics mitigate this risk.
  • Limited Power for Subgroup Analyses: Although the overall sample size was adequate, the study may have been underpowered to detect differences within specific subgroups.
  • Single Time-Centric Intervention: Focused on the first six hours of resuscitation, not accounting for post-resuscitation care quality or interventions beyond this window that could impact mortality.

Literature Review

Literature Review: Protocol-Based Therapy for Septic Shock in Context of Current Guidelines and Supporting Trials

Introduction

The management of septic shock has been a critical focus in emergency and intensive care medicine due to its high mortality and resource utilization. The early goal-directed therapy (EGDT) paradigm, introduced by Rivers et al. in 2001, significantly influenced sepsis protocols by emphasizing strict hemodynamic targets. However, subsequent trials, including the ProCESS study, have questioned the universal applicability and necessity of EGDT's components. This literature review contextualizes the ProCESS trial within recent guidelines, supporting trials, and evolving clinical practices to provide a comprehensive understanding of protocol-based septic shock management as of 2025.

Comparison with the Surviving Sepsis Campaign Guidelines

The Surviving Sepsis Campaign (SSC) continuously updates its guidelines based on emerging evidence. The 2021 SSC guidelines continue to endorse early identification and standardized treatment protocols, including timely antibiotic administration, fluid resuscitation, vasopressor support, and source control. However, nuances have evolved since the initial introduction of EGDT.

Alignment with ProCESS: Both the ProCESS trial and SSC guidelines advocate for early intervention. The ProCESS protocol-based EGDT aligns with SSC’s emphasis on structured care pathways, performance improvement programs, and sepsis screening. However, SSC guidelines have become more flexible regarding specific hemodynamic targets, reflecting findings from multiple trials including ProCESS, ARISE, and ProMISe, which collectively indicated that rigid adherence to EGDT protocols does not significantly outperform usual care in mortality reduction.

Divergence: While SSC guidelines synthesize evidence from various studies to provide adaptable recommendations, the ProCESS trial specifically dissects the efficacy of EGDT’s individual components. The lack of mortality benefit seen in ProCESS suggests that SSC’s broader sepsis bundles, which integrate multiple interventions beyond hemodynamic monitoring, remain relevant and necessary. The SSC has thus shifted towards emphasizing the timely administration of critical therapies rather than strict protocol adherence.

Integration with Supporting Trials

ARISE and ProMISe Trials: The Australasian Resuscitation in Sepsis Evaluation (ARISE) and the Protocolised Management in Sepsis (ProMISe) trials mirrored ProCESS’s objectives across different geographic settings, enrolling participants from Australia and the UK respectively. Similar to ProCESS, both trials found no significant mortality differences between protocol-based EGDT and usual care, reinforcing the notion that contemporary sepsis management adequately addresses hemodynamic goals without the need for invasive monitoring.

VICTAS Trial: The VITAMINS trial explored adjunctive therapies—specifically the combination of vitamin C, thiamine, and hydrocortisone—in septic shock management. The trial found no significant improvement in ventilator- and vasopressor-free days compared to placebo, aligning with ProCESS’s findings that not all protocol components yield mortality benefits. Early termination due to lack of funding potentially limited its power, but the trend echoed that simpler, less invasive protocols can be as effective as more complex ones.

TRISS Trial: Investigating transfusion thresholds in septic shock, the TRISS trial concluded that lower hemoglobin thresholds did not result in higher mortality, despite reduced transfusion rates. This parallels ProCESS’s observation that mandatory transfusion protocols do not necessarily enhance survival outcomes, suggesting that individualized decision-making may be preferable to rigid transfusion protocols.

Pediatric Studies: Pediatric-focused research, such as the study by Akcan Arikan et al., indicated that protocol-driven resuscitation bundles can decrease acute kidney injury and improve outcomes in pediatric septic shock. While ProCESS focused on adults, these findings underscore the potential benefits of protocol adherence in specific populations, highlighting the need for age-tailored sepsis management strategies.

Telemedicine Interventions: Studies like that of Mohr et al. have demonstrated that provider-to-provider telemedicine can enhance adherence to sepsis bundle care in rural community hospitals. This adds another layer of applicability to ProCESS’s findings, suggesting that in settings where usual care might lack standardized protocols, telemedicine-supported protocols could bridge gaps in care quality.

Biomarker Analyses: Secondary analyses of ProCESS data, such as those by Kellum et al., examined the relationship between resuscitation strategies, biomarker trajectories, and outcomes. These analyses revealed heterogeneity in treatment effects based on baseline inflammatory profiles, indicating that personalized medicine approaches could optimize sepsis management beyond one-size-fits-all protocols.

Comprehensive Synthesis of Findings

  • Protocol-Based vs. Usual Care:
    • The ProCESS, ARISE, and ProMISe trials collectively suggest that protocol-based EGDT does not significantly reduce mortality compared to usual care in adult septic shock patients.
    • Usual care has evolved to incorporate many elements initially championed by EGDT, potentially explaining the lack of additional benefit from strict protocol adherence.
  • Component Necessity:
    • Trials targeting specific protocol components (e.g., central venous catheterization, transfusion thresholds, adjunctive therapies) often find no significant improvement in outcomes, supporting a more flexible, individualized approach to sepsis management.
  • Supporting Trials’ Consistencies:
    • The lack of mortality benefits in VICTAMINS and TRISS aligns with ProCESS’s findings, questioning the added value of certain invasive or adjunctive interventions within sepsis care protocols.
  • Contextual Applicability:
    • Telemedicine interventions improving protocol adherence in community settings hint at the potential for technology-integrated protocols to enhance care quality where usual practices may lag.
    • Pediatric studies emphasize that protocol benefits may vary across patient populations, necessitating tailored strategies.
  • Biomarker Insights:
    • Biomarker analyses suggest that patient-specific factors (e.g., inflammatory profiles) might influence the effectiveness of protocol-based interventions, advocating for precision medicine in sepsis management.
  • Guideline Evolution:
    • SSC guidelines have adapted to reflect the cumulative evidence, moving towards flexible, evidence-based bundles rather than rigid EGDT protocols, ensuring recommendations remain applicable across diverse clinical settings.

Gaps and Future Directions

  • Personalized Sepsis Management: Further studies are needed to explore how patient-specific biomarkers and physiological profiles can inform individualized treatment protocols, potentially enhancing outcomes beyond standardized approaches.
  • Long-Term Outcomes: Existing trials focus primarily on short- to mid-term mortality. Research should investigate long-term functional outcomes and quality of life post-septic shock to provide a comprehensive assessment of resuscitation strategies.
  • Implementation Science: Understanding barriers to protocol adherence in various settings, especially in low-resource or high-variance environments, is crucial. Implementation science studies can identify strategies to optimize protocol integration without compromising flexibility.
  • Adjunctive Therapies: While trials like VICTAMINS have not demonstrated benefits of certain adjunctive therapies, ongoing research into novel interventions (e.g., immunomodulators, advanced hemodynamic monitoring technologies) could yield breakthroughs in sepsis management.
  • Telemedicine and Remote Protocols: Expanding telemedicine interventions to more diverse settings and evaluating their impact on sepsis outcomes could democratize high-quality sepsis care, especially in underserved regions.
  • Pediatric Sepsis Protocols: Building on pediatric studies, more research is needed to develop and validate age-specific sepsis protocols that address the unique physiological and clinical needs of children.

Integration with Current Guidelines (2025)

The ProCESS trial, along with subsequent studies, has significantly influenced SSC guidelines by demonstrating that strict protocol adherence to EGDT does not confer additional mortality benefits over evolved usual care practices. The SSC has thus refined its recommendations to focus on key sepsis management pillars—early recognition, timely antibiotics, appropriate fluid and vasopressor use—while allowing clinicians flexibility in achieving hemodynamic targets based on individual patient needs. This evolution reflects an evidence-based balance between standardized care and clinical judgment, ensuring guidelines are both rigorous and adaptable.

Clinical Application

The ProCESS trial reinforces that strict protocol-based EGDT does not significantly reduce mortality in septic shock patients compared to evolved usual care, which already incorporates many vital elements of sepsis management. Clinicians should continue to adhere to Surviving Sepsis Campaign guidelines, emphasizing early recognition and timely administration of antibiotics and fluids, while employing clinical judgment to tailor interventions based on individual patient responses. Specific patient populations, such as those with lower baseline inflammatory biomarkers, may benefit from more structured protocols, suggesting a need for personalized sepsis management strategies. Implementation considerations include ensuring adequate training, resource allocation, and potentially integrating telemedicine support to enhance protocol adherence in diverse clinical environments.

How To Use This Info In Practice

Practitioners should utilize the ProCESS trial findings to support a flexible, evidence-based approach to septic shock management, integrating key elements of standardized care protocols while maintaining the ability to adapt interventions based on individual patient needs and clinical judgment. Aligning with most up-to-date guidelines, clinicians should focus on early identification, timely antibiotic therapy, appropriate fluid resuscitation, and vasopressor support, recognizing that rigid protocol adherence may not be necessary for improving patient outcomes.