EBQ:ProMISe Trial

incomplete Journal Club Article

Mouncey PR, Osborn TM, Power GS, et al. "Trial of Early, Goal-Directed Resuscitation for Septic Shock". NEJM. 2015. 14(372):1301-1311.
PubMed Full text

Clinical Question

Is there a different between EGDT versus “usual care” in 90-day mortality?

Conclusion

Using EGDT did not lead to an improved outcomes.

Major Points

• Mortality was no different at 90-days 29.5% vs 29.2%
• Slight increase is SOFA score at the first 6 hours in the EGDT group (assessment of organ dysfuction)
• Slight increase in length of stay in the ICU

Study Design

Pragmatic, open, multicenter, parallel-group, randomized, controlled trial

Population

56 hospitals in the UK from Feb 2, 2011 to Jul 24, 2014 (29% teaching hospitals)

Patient Demographics

• Highlights
  • Only significant difference was age (66.4 vs 64.3)
  • ~58% male
  • ~55% had refractory hypotension
  • ~64% had hyperlactatemia

Inclusion Criteria

• ≥18 years of age
• Within 6 hours of presenting to ED
• Known or presumed infection
• 2 or more SIRS criteria
• Refractory hypotension (<90 SBP or <65 MAP after 1L IVF trial) or hyperlactatemia (≥4.0)

Exclusion Criteria

• Age <18yrs
• Known pregnancy
• Primary diagnosis of:
  • CVA, Acute pulmonary edema, Status asthmaticus, Major cardiac arrhythmia, Seizure, Drug overdose, Burn or trauma
• GI bleeding
• Known AIDS
• Requirement for immediate surgery
• DNR or advanced directives restricting the protocol
• Contraindication to central line or blood transfusion
• Transfer

Interventions

• Radomization within 2 hours after meeting criteria

Group 1 – EGDT (n=623)

• Airway/breathing
• Central line with oximetric port
• Sedation, analgesia, and/or paralysis
• IVF per CVP
• Vasoactive agents per MAPs
• Transfusion and inotrope agents per ScvO2
• Reassess

Group 2 – Usual Care (n=620)

• Typical care provided at clinician's discretion
• Restricted usag of ScvO2 monitoring

Outcomes

Primary Outcome

• All-cause mortality at 90 days
  • 29.5% vs 29.2% (p=0.90)

Secondary Outcomes

Findings with Significant Differences

• SOFA score at 6hr
  • 6.4 vs 5.6 (p<0.001)
• Receipt of advanced cardiac support
  • 37.0 vs 30.9 (p=0.026)
• LOS in ICU
  • 2.6 vs 2.2 (p=0.005)

Findings with Non Significant Differences=

• SOFA score at 72hrs
• Receipt of advanced respiratory, or renal support and when it started
• Days free of the above advance support
• LOS in ED and hospital
• Duration of survival
• All-cause mortality at 28 days, hospital discharge, and 1yr
• Health related quality of life, resource use, and cost at 90d and 1yr

Criticisms & Further Discussion

• There was a trend towards being more cost effective with usual-care ($17,647 vs $16,239, p=0.26).
• The usual-care group still had a large portion of arterial lines and central lines. If we eliminate ScvO2 monitoring, the protocol becomes essentially guidelines for care.
• Expected mortality in this group 40% while actual mortality was 29%. This matches closely with the 30.5% found in the Rivers 2001 EGDT Trial. This is the first time these numbers have been replicated as the US ProCESS Trial had a mortality rate of 18.9% at 60 days (compared to 30-46% as expected) and the Australia/New Zealand ARISE Trial had mortality 18.8% at 90 days (compared to 38% anticipated).

Funding

The NIHR Health Technology Assessment (HTA) Programme (07/37/47) is supported the central coordination of the trial through the ICNARC CTU, and the local site start up costs. This includes dedicated local research nurses and the economic evaluation.