ARISE: EGDT for Septic Shock (2014)

“In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days, as compared with usual care.”

  • The ARISE Investigators and the ANZICS Clinical Trials Group

1. Publication Details

  • Trial Title: Goal-Directed Resuscitation for Patients with Early Septic Shock
  • Citation: The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-Directed Resuscitation for Patients with Early Septic Shock. N Engl J Med. 2014;371(16):1496-1506. DOI: 10.1056/NEJMoa1404380
  • Published: October 16, 2014, in The New England Journal of Medicine
  • Author: The ARISE Investigators
  • Funding: National Health and Medical Research Council of Australia; and others.

2. Keywords

  • Sepsis, Septic Shock, Early Goal-Directed Therapy (EGDT), Resuscitation, 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) (Intervention) compared to standard care (Comparison) reduce 90-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.
  • Proposed Hypothesis: The authors hypothesized that EGDT would be superior to standard care in reducing 90-day mortality in patients with early septic shock.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 51 tertiary and non-tertiary hospitals in Australia, New Zealand, Finland, Hong Kong, and the Republic of Ireland.
  • Trial Period: Enrollment ran from October 2008 to April 2014.
  • Population:
    • Inclusion Criteria: Adult patients presenting to the emergency department with early septic shock, defined by suspected or confirmed infection, evidence of refractory hypotension or hypoperfusion (e.g., lactate ≥4 mmol/L).
    • Exclusion Criteria: Included contraindications to central venous catheterization and situations where the treating clinician believed EGDT was either mandatory or contraindicated.
  • Intervention: Patients received a 6-hour protocol of EGDT, which included the placement of a central venous catheter capable of continuous central venous oxygen saturation (ScvO2) monitoring. The protocol guided the use of fluids, vasopressors, inotropes, and blood transfusions to meet specific physiological targets.
  • Control: Patients received “usual care,” where all treatment decisions, including the type and extent of hemodynamic monitoring, were at the discretion of the treating clinicians.
  • 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 1600 patients would provide 80% power to detect a 7% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included in-hospital mortality, duration of organ support, and length of ICU and hospital stay.

6. Key Results

  • Enrollment and Baseline: 1600 patients were randomized (796 to the EGDT group and 804 to the usual-care group). The baseline characteristics were well-matched.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality. 147 of 794 patients (18.5%) in the EGDT group died, compared with 150 of 800 patients (18.8%) in the usual-care group (p=0.90).
  • Secondary Outcomes: There were no significant differences between the groups in any of the secondary outcomes, including in-hospital mortality, duration of vasopressor support, or length of stay. Patients in the EGDT group did receive more intravenous fluids and more frequent use of 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 between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death at 90 days: 0.98 (95% CI, 0.78 to 1.24; P-value: 0.90).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 0.98.
      • Clinical Meaning: An RR of 0.98 indicates a non-significant 2% lower relative risk of death in the EGDT group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.78 to 1.24.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 22% benefit to a 24% harm.
    • P-value: The p-value of 0.90 is much higher than the 0.05 threshold, indicating the result is not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • 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 blinded outcome assessment provided a high level of evidence and minimized bias.
  • Generalizability: The pragmatic design across 51 diverse hospitals makes the findings highly generalizable to real-world practice.
  • 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 90-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 very aggressive and included early antibiotics and large volumes of fluid, which may have improved outcomes in the control group and reduced the potential for EGDT 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

  • In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days as compared with usual care.

11. To Summarize

  • Impact on Current Practice: This trial, along with the concurrent ProCESS 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, including the mandatory use of a central line for ScvO2 monitoring.
  • 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 the additional, complex components of the EGDT protocol are not necessary.
  • Implementation Caveats: The focus of early sepsis resuscitation should be on the timely administration of fluids and antibiotics, with vasopressors as needed, rather than on achieving specific, complex physiological targets.

12. Context and Related Studies

  • Building on Previous Evidence: The ARISE 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 (ARISE, ProCESS (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 blinded outcome assessment 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.
  • Results: The study reported a clear neutral finding for its primary outcome, with a confidence interval that was centered on the null value. This provides strong evidence against a benefit of the EGDT protocol.
  • 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 to most modern emergency departments and ICUs. 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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