ProCESS: Protocolized Care for Early Septic Shock (2014)

“In a multicenter trial in the United States, we found that protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes.”

  • The ProCESS Investigators

1. Publication Details

  • Trial Title: A Randomized Trial of Protocol-Based Care for Early Septic Shock
  • Citation: The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693. DOI: 10.1056/NEJMoa1401602
  • Published: May 1, 2014, in The New England Journal of Medicine
  • Author: The ProCESS Investigators
  • Funding: The National Institute of General Medical Sciences.

2. Keywords

  • Sepsis, Septic Shock, Early Goal-Directed Therapy (EGDT), Resuscitation, Protocolized Care, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with early septic shock in the emergency department (Population), does a 6-hour protocol of early goal-directed therapy (EGDT) or a simplified protocol-based standard therapy (Intervention) compared to standard, non-protocolized usual care (Comparison) reduce 60-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The landmark single-center trial by Rivers et al. (2001) showed a dramatic mortality benefit for a complex resuscitation protocol called Early Goal-Directed Therapy (EGDT). This led to the widespread adoption of EGDT in international sepsis guidelines.
  • Knowledge Gap: Despite its inclusion in guidelines, the dramatic findings of the single-center Rivers trial had not been replicated in a large, multicenter setting. There was significant clinical uncertainty about whether the benefits of the full, resource-intensive EGDT protocol were real and generalizable, and whether a simpler protocol could achieve similar results.
  • Proposed Hypothesis: The authors hypothesized that both EGDT and a simplified protocol-based standard therapy would be superior to usual care in reducing 60-day mortality in patients with early septic shock.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial with three arms (used to test the effectiveness of interventions).
  • Setting: 31 academic emergency departments in the United States.
  • Trial Period: Enrollment ran from March 2008 to November 2012.
  • Population:
    • Inclusion Criteria: Adult patients with septic shock, defined by refractory hypotension despite fluids or a lactate level ≥4 mmol/L.
    • Exclusion Criteria: Included contraindications to central venous catheterization and situations where the treating clinician believed a specific protocol was either mandatory or contraindicated.
  • Intervention: Patients were randomized to one of three groups for 6 hours:
  • Protocol-based EGDT: A strict protocol based on the original Rivers trial, requiring a central line for CVP and ScvO2 monitoring and guiding the use of fluids, vasopressors, inotropes, and blood transfusions.
  • Protocol-based Standard Therapy: A simplified protocol that required a central line for CVP monitoring but did not require ScvO2 monitoring or mandate transfusions/inotropes.
  • Usual Care: No resuscitation protocol. All treatment decisions were at the discretion of the treating clinicians.
  • Control: The usual-care group served as the control.
  • Management Common to Both Groups: All patients were managed in the emergency department and ICU according to the standard practices of the participating hospitals.
  • Power and Sample Size: The authors calculated that a sample size of 1350 patients would provide 88% power to detect a 6% absolute risk reduction in mortality between the protocol-based groups and the usual-care group. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80-90% is considered standard).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 60 days.
    • Secondary Outcomes: Included in-hospital and 90-day mortality, duration of organ support, and length of hospital stay.

6. Key Results

  • Enrollment and Baseline: 1341 patients were randomized (439 to EGDT, 446 to protocol-based standard care, and 456 to usual care). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 60-day mortality among the three groups. Mortality was 21.0% in the EGDT group, 18.2% in the protocol-based standard-care group, and 18.9% in the usual-care group.
  • Secondary Outcomes: There were no significant differences between the groups in any of the secondary outcomes, including in-hospital mortality or duration of organ support. Patients in the protocol-based groups did receive more intravenous fluids and more frequent use of vasopressors and dobutamine.
  • Adverse Events: There were no significant differences in the rates of serious adverse events between the groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death among the three groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates for each group.
  • Interpretation of Key Statistic(s):
    • P-value: The p-values for the comparisons of the primary outcome between the groups were not statistically significant.
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized controlled trial design with three arms provided a high level of evidence and allowed for a nuanced comparison of different resuscitation strategies.
  • Generalizability: The pragmatic design across 31 diverse academic emergency departments makes the findings highly generalizable to real-world practice in similar settings.
  • Statistical Power: The study was large and adequately powered to detect a clinically meaningful difference if one existed.
  • Patient-Centered Outcomes: The primary outcome of 60-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded to clinicians, which is a potential source of performance bias.
  • External Validity (Generalizability): The “usual care” provided in the control group was of a very high standard, including rapid administration of antibiotics and fluids. This may have improved outcomes in the control group and reduced the potential for the protocolized arms to show a benefit.
  • Other: The overall mortality rate was much lower than in the original Rivers trial, suggesting the study population or the standard of care had changed significantly over time.

10. Conclusion of the Authors

  • The authors concluded that in patients with septic shock, protocol-based resuscitation (either EGDT or a simplified protocol) did not improve outcomes as compared with usual, non-protocolized care.

11. To Summarize

  • Impact on Current Practice: This trial, along with the concurrent ARISE and ProMISe trials, was practice-changing. It provided strong evidence that the full, complex, and resource-intensive EGDT protocol is not superior to modern, high-quality standard care for septic shock.
  • Specific Recommendations:
    • Patient Selection: For adult patients with early septic shock.
    • Actionable Intervention: The results do not support the routine implementation of the full EGDT protocol or other rigid resuscitation protocols.
  • What This Trial Does NOT Mean: This trial does NOT mean that the core principles of early sepsis care (early recognition, early antibiotics, and adequate fluid resuscitation) are not important. It suggests that these principles had become part of “usual care,” making the additional, complex components of the EGDT protocol unnecessary.
  • Implementation Caveats: The focus of early sepsis resuscitation should be on the timely administration of fluids and antibiotics, with vasopressors as needed, guided by careful clinical assessment rather than rigid physiological targets.

12. Context and Related Studies

  • Building on Previous Evidence: The ProCESS trial (2014) was one of three large, multicenter trials designed to validate the findings of the original single-center EGDT trial by Rivers et al. (2001).
  • Influence on Subsequent Research: The consistent neutral findings of the “big three” sepsis trials (ProCESS, ARISE (2014), and ProMISe (2015)) led to a significant simplification of international sepsis guidelines, moving away from the rigid EGDT protocol and towards a more streamlined approach to early resuscitation.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial did not identify which, if any, individual components of the original EGDT protocol might be beneficial on their own.
  • Future Directions: The results of this trial have shifted the focus of sepsis resuscitation research towards more nuanced questions, such as the optimal type and volume of fluid, and the best way to personalize vasopressor therapy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, seeking to validate a practice that had become a widespread standard of care based on single-center evidence.
  • Methods: The multicenter RCT design with three arms was of high quality. A key strength is that the “usual care” arm represented a high standard of modern sepsis care, making the comparison very relevant. The main methodological weakness is the open-label design.
  • Results: The study reported a clear neutral finding for its primary outcome, with no significant difference in mortality among the three groups. This provides strong evidence against a benefit of rigid, protocolized resuscitation over high-quality usual care.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This trial is a classic example of how a high-quality “negative” trial can be profoundly practice-changing by providing strong evidence to de-adopt a complex and resource-intensive intervention.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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