A Randomized Trial of Protocol-Based Care for Early Septic Shock

The ProCESS Investigators. N Engl J Med 2014; 370:1683-1693.

Clinical Question

• In adult patients with sepsis, does protocol-based care compared to usual care reduce death within 60 days?

Design

• Randomised, controlled trial of 3 groups in 1:1:1 ratio
• Non-blinded design

Setting

• 31 academic hospitals in US
• March 2008 to May 2013

Population

• Inclusion: adults arriving in the emergency department (ED) with suspected sepsis (refractory hypotension or lactate > 4 mmol/l with two or more SIRS criteria)
• Exclusion: if another primary diagnosis was present, such as acute myocardial infarction
• 12,707 screened of which 1,351 randomised

Intervention

• Early goal-directed therapy (EGDT) group: strict protocolised care (based on Rivers study) for 6 hours with dedicated doctor, nurse and research assistant that provided prompts
• Protocol-based standard therapy group: relaxed protocolised care (based upon published expert opinions) for 6 hours with dedicated doctor, nurse and research assistant that provided prompts

Control

• Usual care group: no extra staffing, with all care as directed by bedside physician for 6 hours. Research assistant collected data but provided no prompting.

Outcome

• Primary outcome: there were no differences in 60-day mortality between groups
  • EGDT 21.0%; Protocol-based standard therapy 18.2%; Usual care 18.9%. (P values 0.31 – 0.89)
• Secondary outcomes: there were no differences in 90-day or 1-year mortality between groups, or markers of significant morbidity.

Authors’ Conclusion

• No significant advantage, with respect to mortality or morbidity, of protocol-based resuscitation over bedside care that was provided according to the treating physician’s judgement.

Strengths

• Well designed, pragmatic method
• Methods and statistical analysis defined and published a priori.
• Recruited adequate numbers as planned for 80% power to detect 6–7% mortality reduction with alpha 0.05.

Weaknesses

• Changed inclusion criteria during trial (reduced fluid bolus required before meeting “refractory hypotension” criteria), but mean volume used was within Rivers’ original definition of 20–30 ml/kg.
• Mortality ~20% but initial power calculation based on 30–46%, therefore interim adjustment made and recruitment target reduced.
• Adherence to protocol was 88.1% in EGDT group and 95.6% in protocol-based standard therapy group. Although pragmatic, this is not perfect and may reduce between group differences.