Early goal-directed therapy in the treatment of severe sepsis and septic shock

Rivers. NEJM 2001; 345:1368-1377. doi:10.1056/NEJMoa010307

Clinical Question

• In adults with severe sepsis or septic shock, does the use of early goal-directed therapy (EGDT) reduce the mortality?

Design

• Randomised controlled trial
• Computer-generated blocks of 2 to 8
• Concealed allocation
• No blinding of clinicians, study personnel or patients
• Power calculation: sample size of 260 required with 80% power and 0.05 alpha error rate to detect absolute reduction in mortality of 15% (expected baseline not specified)
• Intention-to-treat analysis

Setting

• Single academic tertiary hospital in Detroit, USA
• March 1997 to March 2000

Population

• Inclusion: Severe sepsis or septic shock
  • ≥ 2 SIRS features, and either
  • systolic BP ≤ 90 mmHg after crystalloid fluid of 20 to 30 ml/kg over 30 minutes, or
  • blood lactate ≥ 4 mmol/l
• Exclusion: age under 18 years; pregnancy; other acute neurological, cardiac, gastrointestinal or respiratory pathology; contraindications to central catheterisation; uncured cancer; immunosupression; limitations defined for active care
• 268 randomised with 236 completing study

Intervention

• Early goal-directed therapy for 6 hours
  • Remained in ED for 6 hours and protocolised therapy managed by an emergency physician, two residents and three nurses
  • Oxygen ± intubation and mechanical ventilation
  • Central venous and arterial catheterisation
  • Central venous catheter (Edwards Lifesciences) capable of measuring continuous ScvO₂ 
  • 500 ml fluid boluses until CVP 8–12 mmHg
  • Vasopressors or vasodilators until MAP 65–90 mmHg
  • If ScvO₂ < 70%
    • Transfused red cells until haematocrit ≥ 30%
    • If still ScvO₂ < 70%
      • Dobutamine 2.5–20 µg/kg/min until ScvO₂ > 70%
      • Dobutamine limited or reduced if MAP < 65 mmHg or pulse > 120 /min

Control

• Usual care for 6 hours without protocol
  • Treatment at the discretion of the clinician and patient admitted to ICU as soon as possible after consult and lines inserted
  • Oxygen ± intubation and mechanical ventilation
  • Central venous and arterial catheterisation
  • Targets defined but without treatment algorithm:
    • CVP ≥ 8–12 mmHg
    • MAP ≥ 65 mmHg
    • Urine output ≥ 0.5 ml/kg/hr

Outcome

• Primary outcome: in-hospital mortality was statistically and clinically significantly better in the EGDT intervention group compared to the usual care control group.
  • 30.5% vs 46.5% p = 0.009
• Secondary outcome: subgroup analyses all favoured EDGT
  • severity of sepsis
  • 28-day and 60-day mortality
  • cause of in-hospital death (sudden cardiovascular collapse and multi-organ failure)
• Tertiary data collection:
  • The EGDT group received more fluid over the early 6-hour period but there was no difference in total fluid over 72 hours
  • More red-cell transfusions were given to the EGDT group
  • Early inotropic use was more prevalent in the EGDT group (not statistically different over complete 72-hour period)
  • Vasopressor use was more prevalent in the usual care group
  • Intubation and ventilation was more prevalent in the usual care group

Authors’ Conclusions

• “goal-directed therapy provided at the earliest stages of severe sepsis and septic shock… has significant short-term and long-term benefits.”

Strengths

• Adequate trial design for the clinical question
• 90% completed the study – a drop-out / lost-follow-up rate that is well below the primary outcome rate

Weaknesses

• Single centre study
• Intervention was a bundle of care, and individual components cannot be investigated separately
• Usual care control group had a higher than average mortality rate
• In-hospital mortality as an outcome measure has its limitations, as some patients will go to institutions or home to die soon after
• Lead author is a paid consultant for manufacturer of ScvO₂-measuring central catheter, and has registered “early goal-directed therapy” and “EGDT” as his trademarks!