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

Authors: Emanuel Rivers, M.D., M.P.H.; Bryant Nguyen, M.D.; Suzanne Havstad, M.A.; Julie Ressler, B.S.; Alexandria Muzzin, B.S.

Journal: The New England Journal of Medicine, 2001, Volume 345, Issue 19

Type of Study: Randomized controlled trial

DOI/PMID: N Engl J Med. 2001;345:1368-77.

Quick Reference Summary

Early goal-directed therapy (EGDT) significantly reduces in-hospital mortality in patients with severe sepsis or septic shock (30.5% vs. 46.5% deaths in the standard therapy group, P=0.009).

EGDT patients demonstrated improved hemodynamic parameters and organ function, with notable differences in central venous oxygen saturation (70.4% vs. 65.3%, P<0.001) and APACHE II scores (13.0 vs. 15.9, P<0.001).

Core Clinical Question

Question: Does early goal-directed therapy applied in the emergency department reduce in-hospital mortality compared to standard therapy in patients presenting with severe sepsis or septic shock?

PICO Elements:

• Population: Adults with severe sepsis or septic shock
• Intervention: Early goal-directed therapy (EGDT)
• Comparison: Standard therapy
• Outcome: In-hospital mortality

Background

Disease or Condition Overview

Severe sepsis and septic shock are life-threatening conditions marked by systemic inflammatory response leading to organ dysfunction.

Prior Data on the Topic

• Previous studies indicate that aggressive hemodynamic optimization significantly affects outcomes in critically ill patients, though results have been mixed.
• Earlier interventions in sepsis care may yield better health outcomes; delayed treatment correlates with higher mortality rates.
• Current standard of care: Standardized resuscitation approaches including fluid resuscitation and broad-spectrum antibiotics, typically initiated upon intensive care unit admission.
• Knowledge gaps addressed by study: The effectiveness of initiating goal-directed therapy in the emergency department setting and its impact on in-hospital mortality.
• Study rationale: Investigate if EGDT could enhance early intervention outcomes beyond traditional methods, targeting reduced mortality and improved organ function.

Methods Summary

• Study Design: Prospective, randomized, partially blinded trial.
• Setting and Time Period: Emergency department of an 850-bed urban academic tertiary care hospital from March 1997 to March 2000.
• Population Characteristics: 263 adults (mean age ~66 years, 50% male) with severe sepsis and septic shock.
• Inclusion/Exclusion Criteria: Included adults meeting SIRS criteria with systolic BP <90 mm Hg or lactate ≥4 mmol/L; excluded pregnancy, certain acute conditions, and do-not-resuscitate status.
• Intervention Details: Initial 6-hour treatment protocol focused on fluid resuscitation and hemodynamic optimization through the use of central venous catheterization.
• Control/Comparison Group Details: Standard therapy administered at clinician discretion.
• Primary and Secondary Outcomes: In-hospital mortality, hemodynamic parameters, organ dysfunction scores.
• Statistical Analysis Approach: Kaplan-Meier survival estimates, Chi-square tests, ANCOVA, and mixed models for longitudinal data analysis.
• Sample Size Calculations: Achieved adequate power to detect a 15% reduction in mortality with 260 patients.
• Ethics and Funding Information: Approved by the institutional review board; supported by Henry Ford Health Systems Fund and device manufacturers.

Detailed Results

Participant Flow and Demographics

263 patients randomized: 130 to EGDT and 133 to standard treatment.

Completion: 236 patients completed the protocol (intention-to-treat analysis).

Primary Outcome Results

EGDT reduced in-hospital mortality significantly.

Secondary Outcome Results

Improved hemodynamic status, lower lactate levels, reduced organ dysfunction scores in the EGDT group.

Subgroup Analyses

Greater benefit noted specifically in patients with septic shock.

Adverse Events/Safety Data

Overall rates of adverse reactions were similar between the groups.

Authors' Conclusions

Primary Conclusions

Early goal-directed therapy significantly reduces mortality rates in patients with severe sepsis and septic shock when initiated in the emergency department.

Authors' Interpretation of Results

The effectiveness of early hemodynamic optimization suggests potential changes in how sepsis is managed from initial presentation.

Clinical Implications Stated by Authors

Implementation of EGDT could lead to better patient outcomes and should be considered as a standard practice in emergency settings.

Future Research Recommendations

Further studies to confirm these benefits across diverse patient populations and settings.

Literature Review

Previous Studies and Meta-Analyses

• Gattinoni et al. (1995) found that goal-directed therapy did not improve outcomes when used after ICU admission. N Engl J Med. 1995;333:1025-32.
• Hayes et al. (1994) reported high mortality associated with aggressive hemodynamic therapy initiated in ICU settings. N Engl J Med. 1994;330:1717-22.

Contrasting Methodological Quality

This study's early intervention in sepsis contrasts with others that had delayed treatments leading to poorer outcomes. (N Engl J Med. 1995;333:1025-32.)

Comparisons with Guidelines

Crit Care Med 1999;27:639-60 recommends hemodynamic assessments in high-risk sepsis patients, aligning with findings from this trial.

This Trial's Contribution

This study demonstrates that initiating goal-directed therapy before ICU admissions can improve survival in septic shock patients, confirming findings from previous observational studies.

N Engl J Med. 1994;330:1717-22.

Critical Analysis

A. Strengths

• Randomization and blinding enhance internal validity.
• Early intervention in a real-world emergency setting increases external validity.

B. Limitations

• Single-center study, limiting generalizability.
• Lack of long-term outcomes data beyond 60 days.

C. Literature Context

Previous studies highlight varying impacts of timing in goal-directed therapies, suggesting earlier might correlate to better outcomes as demonstrated here.

Clinical Application (Updated)

The findings from the original EGDT study by Rivers et al. demonstrated significant mortality benefits when implemented in 2001. However, subsequent trials such as ProCESS (2014), ARISE (2014), and ProMISe (2015) failed to replicate these mortality reductions when compared to modern usual care, which already incorporates many principles of early sepsis management (e.g., timely antibiotics and fluid resuscitation).

Current evidence supports a more flexible approach to managing severe sepsis and septic shock. Protocolized EGDT is no longer considered mandatory for improving survival; instead, focus has shifted to individualized, goal-directed resuscitation based on dynamic monitoring of clinical response and standardized elements of sepsis management.

In clinical practice today, early recognition and rapid initiation of care—rather than adherence to rigid protocols like EGDT—are the key determinants of improved outcomes. Practitioners should prioritize the principles of the Surviving Sepsis Campaign, which emphasize early fluid resuscitation, antibiotics within the first hour, hemodynamic monitoring, and source control.

How to Use This Information in Practice (Updated)

Practitioners should integrate the following strategies based on current guidelines and evidence:

1. Rapid Recognition:
   • Use screening tools such as qSOFA and SIRS criteria to identify patients at risk of sepsis early, especially in emergency department settings.
2. Immediate Action:
   • Administer broad-spectrum antibiotics and begin fluid resuscitation promptly, ideally within the first hour of sepsis recognition.
   • Tailor fluid therapy based on frequent reassessment of hemodynamic status and organ perfusion.
3. Hemodynamic Support:
   • Use dynamic markers such as stroke volume variation or lactate clearance, rather than central venous oxygen saturation or central venous pressure alone, to guide resuscitation efforts.
   • Initiate vasopressors (e.g., norepinephrine) early in cases of persistent hypotension to maintain a mean arterial pressure (MAP) of at least 65 mm Hg.
4. Source Control:
   • Quickly identify and eliminate the source of infection through surgical or procedural interventions, as clinically indicated.
5. Avoid Over-Resuscitation:
   • Monitor for signs of fluid overload, and transition to a more conservative fluid strategy once initial perfusion goals are achieved.
6. Interprofessional Collaboration:
   • Engage a multidisciplinary team to ensure adherence to sepsis bundles and rapid escalation of care when needed.

Implementation Consideration:

While EGDT as initially proposed is no longer the gold standard, its legacy underscores the importance of early intervention and aggressive treatment for sepsis. By adhering to the updated guidelines and principles of early sepsis care, clinicians can achieve similar—or better—survival outcomes without the complexity of rigid EGDT protocols.