EGDT: Early Goal-Directed Therapy in Sepsis (2001)

“We conclude that early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.”

  • Emanuel Rivers, M.D., M.P.H., et al.

1. Publication Details

  • Trial Title: Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock
  • Citation: Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377. DOI: 10.1056/NEJMoa010307
  • Published: November 8, 2001, in The New England Journal of Medicine
  • Author: Emanuel Rivers, M.D., M.P.H.
  • Funding: The William Beaumont Hospital Research Institute; Edwards Lifesciences.

2. Keywords

  • Sepsis, Septic Shock, Early Goal-Directed Therapy (EGDT), Resuscitation, Central Venous Oxygen Saturation (ScvO2), Randomized Controlled Trial

3. The Clinical Question

  • In adult patients presenting to the emergency department with severe sepsis or septic shock (Population), does a 6-hour protocol of early goal-directed therapy (EGDT) (Intervention) compared to standard resuscitation (Comparison) reduce in-hospital mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Severe sepsis and septic shock were known to have extremely high mortality rates. It was understood that early and aggressive resuscitation was important, but there was no standardized, evidence-based protocol to guide this resuscitation in the crucial first hours of care.
  • Knowledge Gap: It was unknown if a complex, physiology-based protocol that targeted specific hemodynamic goals, including a measure of oxygen delivery (central venous oxygen saturation, ScvO2), would be superior to standard, non-protocolized care.
  • Proposed Hypothesis: The authors hypothesized that a 6-hour protocol of early goal-directed therapy would be superior to standard care in reducing mortality in patients with severe sepsis and septic shock.

5. Study Design and Methods

  • Design: A single-center, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: The emergency department of a single, large tertiary care hospital in the United States (Henry Ford Hospital).
  • Trial Period: Enrollment ran from March 1997 to March 2000.
  • Population:
    • Inclusion Criteria: Adult patients presenting to the emergency department with severe sepsis or septic shock, defined by suspected infection plus signs of hypoperfusion (e.g., systolic BP < 90 mm Hg after a fluid challenge, or lactate > 4 mmol/L).
    • Exclusion Criteria: Included age <18 years, pregnancy, and an absolute contraindication to central venous catheterization.
  • Intervention: A 6-hour EGDT protocol. This involved placing a central venous catheter to continuously monitor central venous pressure (CVP) and ScvO2. The protocol guided the use of fluids (to a CVP target of 8-12 mm Hg), vasopressors (to a MAP target of 65-90 mm Hg), and, if the ScvO2 remained <70%, red-cell transfusions (to a hematocrit ≥30%) and dobutamine infusions.
  • Control: Standard therapy. Patients received a central line, but ScvO2 was not measured. All treatment decisions regarding fluids, vasopressors, and other therapies were at the discretion of the treating clinicians.
  • Management Common to Both Groups: All patients were admitted to the ICU from the emergency department.
  • Power and Sample Size: The authors calculated that a sample size of 260 patients would be required to have 80% power to detect a 15% absolute risk reduction in in-hospital 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: In-hospital mortality.
    • Secondary Outcomes: Included 28-day and 60-day mortality, and organ dysfunction scores.

6. Key Results

  • Enrollment and Baseline: 263 patients were randomized (130 to EGDT and 133 to standard therapy). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: In-hospital mortality was dramatically lower in the EGDT group: 40 of 130 patients (30.5%) in the EGDT group died, compared with 60 of 133 patients (46.5%) in the standard-therapy group (p=0.009).
  • Secondary Outcomes: 28-day and 60-day mortality were also significantly lower in the EGDT group. During the first 6 hours, patients in the EGDT group received significantly more intravenous fluids and more dobutamine infusions.
  • Adverse Events: The incidence of major complications was similar between the two 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: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.009 for the primary outcome is well below the 0.05 threshold, indicating that the observed difference in mortality is highly statistically significant and very unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 46.5% – 30.5% = 16.0%.
      • Clinical Meaning: For every 100 patients treated with the EGDT protocol, 16 additional deaths were prevented.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.16 = 6.25, which is rounded down to 6.
      • Clinical Meaning: You would only need to treat 6 patients with the EGDT protocol to prevent one additional death.
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: The randomized, controlled design was a major strength and provided a high level of evidence for a novel, complex intervention.
  • Patient-Centered Outcomes: The primary outcome of in-hospital mortality is a robust and patient-centered endpoint.
  • Novelty: The trial introduced a groundbreaking, physiology-driven, protocolized approach to a previously chaotic phase of care.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias. The fact that the study was conducted at a single center with a highly motivated research team is a major limitation.
  • External Validity (Generalizability): The very high mortality rate in the standard-care group (46.5%) was much higher than in many other centers at the time, which may have exaggerated the benefit of the intervention. The resource-intensive nature of the protocol (requiring continuous ScvO2 monitoring) made it difficult to implement in all settings.
  • Other: As a “bundled” intervention, it is impossible to know which specific component of EGDT was responsible for the benefit.

10. Conclusion of the Authors

  • The authors concluded that early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock and should be the standard of care.

11. To Summarize

  • Impact on Current Practice: This was one of the most influential critical care trials ever published. It single-handedly changed the culture of sepsis care worldwide, shifting the focus to aggressive, protocol-based resuscitation in the first hours of illness. The EGDT protocol was incorporated into the international Surviving Sepsis Campaign guidelines for over a decade.
  • Specific Recommendations:
    • Patient Selection: For adult patients presenting to the emergency department with severe sepsis or septic shock.
    • Actionable Intervention: At the time, the trial supported the implementation of the full 6-hour EGDT protocol.
    • Expected Benefit: This intervention was shown to prevent approximately one death for every 6 patients treated.
  • What This Trial Does NOT Mean: As later trials showed, this trial did NOT mean that all the complex and invasive components of EGDT (like mandatory central lines for ScvO2 monitoring) were necessary to achieve good outcomes.
  • Implementation Caveats: The EGDT protocol is resource-intensive and requires significant training and coordination.

12. Context and Related Studies

  • Building on Previous Evidence: The Rivers et al. trial (2001) was a landmark study that provided the first high-quality evidence for a specific, protocolized approach to sepsis resuscitation.
  • Influence on Subsequent Research: The dramatic and controversial findings of this single-center trial led directly to the design of three very large, multicenter trials—ProCESS (2014), ARISE (2014), and ProMISe (2015)—to attempt to replicate its findings. These later trials failed to show a benefit of the full EGDT protocol over modern, high-quality usual care, leading to a simplification of sepsis guidelines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial left the key question of whether its remarkable findings were replicable in other, multicenter settings.
  • Future Directions: The entire subsequent decade of sepsis resuscitation research, culminating in the “big three” trials (ProCESS, ARISE, ProMISe), can be seen as the future direction that followed from this pivotal but ultimately controversial study.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and deadly condition with a novel, structured intervention.
  • Methods: The randomized controlled design was a strength. However, the single-center, unblinded design and the unusually high mortality in the control group are major methodological limitations that raise significant concerns about the internal and external validity of the findings.
  • Results: The study reported a very large and statistically significant mortality benefit (NNT of 6). This dramatic effect size is a key reason why the trial was so influential, but also a reason for skepticism, as such large effects are rare in critical care and are often smaller in subsequent, larger trials.
  • Conclusions and Applicability: While the authors’ conclusion was a fair reflection of their data, the profound limitations of the study design meant that the findings required external validation before being accepted as dogma. The trial is a classic example of a seminal, hypothesis-generating study that rightfully changed the culture of care but whose specific protocol was later shown to be unnecessary when its core principles were incorporated into usual care.

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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