The ProCESS Trial

ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18. PubMed PMID: 24635773. [Full Text] [Supplement]

In patients with septic shock is protocol-based resuscitation superior to usual care, and is a protocol with central hemodynamic monitoring to guide the use of fluids, vasopressors, blood transfusions, and dobutamine superior to a simpler protocol that did not include these elements?

TYPE OF STUDY

• MCRCT
• 31 US academic centers, n=1,343 (12,707 screened)
• open-label (non-blinded) with concealed randomisation
• intention-to-treat analysis

POPULATION

Inclusion criteria

• Patients in the ED >18 years of age meeting ≥2 criteria for SIRS (Standard definition)
• Refractory hypotension (SBP <90 mmHg or required vasopressors to maintain SBP≥90 mmHg after an IV fluid challenge) or serum lactate ≥4 mmol/L
• Patients did not need to be in shock on arrival
• Enrolment within 2 hours of earliest detection of shock and within 12 hours of ED arrival

Exclusion criteria

• Acute cerebral vascular event
• ACS
• Acute pulmonary edema
• Status asthmaticus
• “Major” cardiac arrhythmia
• Active GIB
• Seizure
• Drug overdose
• Burn
• Trauma
• Need for immediate surgery
• CD4 count <50
• Advanced directive that would restrict implementation of the protocol
• Contraindication for central venous catheter
• “High likelihood” of blood transfusion refusal (e.g. Jehovah’s Witness)
• Futility of resuscitation as deemed by treating physician
• Enrolment in another interventional study
• Known pregnancy
• Transfer as inpatient from other hospital

INTERVENTIONS/ COMPARISONS

• early goal directed therapy (EGDT) n=439 (as per Rivers protocol)
  • additional n=6 lost to follow up
• protocol-based standard therapy n=446
  • additional n=2 lost to follow up
• usual care n=458  (at he discretion of the treating physician)
  • additional n=2 lost to follow up

OUTCOMES

Primary outcome

• No difference in in-hospital death at 60 days: EGDT 21%, Protocol 18.2%, Usual care 18.9%

Secondary outcomes

• More ICU admissions in the EGDT group: 91.3%, 85.4%, 86.2%
• No difference in:
  • Death at 90 days: 31.9%, 30.8%, 33.7%
  • Hospital LOS: 11.1d, 12.3d, 11.3d
  • Adverse organ system failures (slight increase in acute renal failure requiring RRT in Protocol group)
  • Adverse Events: 5.2%, 4.9%, 8.1%
  • Disposition destinations

Protocol performance

• Good adherence to Protocols (0-6hrs): EGDT 89.1%, Protocol 95.6%, usual care N/A
• Intravenous Fluids: 96% of fluid was crystalloid with more fluid given in Protocol arm (3.3L) than EGDT (2.8L) or usual care (2.3L)
• Intravenous Antibiotics given in all 3 groups (97%)
• CVP line placement was notably higher, and inserted earlier, with EGDT: EGDT 94%, Protocol 56.5%, Usual care 57.9%;
• Outside of the EGDT group SVO2 rarely measured: Protocol 4%, Usual care 3.5%)
• Vasopressor use was slightly less with usual care: 54.9% EGDT vs 52.2% Protocol vs 44.1% Usual
• Dobutamine was rarely used, but more so in EGDT: : EGDT 8%, Protocol 1.1%, Usual care 0.9%
• Blood transfusion rates higher for EGDT: EGDT14.4%, Protocol 8.3%, Usual 7.5% (the transfusion threshold was Hb <75g/L)

• This study did not find the mortality benefit for EGDT as suggested by the often criticised landmark NEJM article on EGDT by Rivers et al, 2001.
• Good points include: concealed randomisation, good baseline balance, complete follow up and use of patient-orientated outcomes, not funding conflicts
• all sites were academic centers with >40,000 ED visits annually that used lactate to screen for crytogenic sepsis and adhered to the non-resucitation apsects of the Surviving Sepsis Campaign guidelines, but none routinely used ScvO2 catheters prior to this study
• Fluid challenge defined as 20 mL/kg over 30 minutes though after 2010-04 it was modified to 1 liter of fluids over 30 minutes, which may have led to the inclusion of less sick patients
• sequential recruiting was not reported
• study does not apply to non-emergency department patients
• less fluid used in the EGDT group than may would have predicted – overall relatively less fluid than many would have predicted
• 90 day mortality was notably higher than at 60 days
• Simon Finfer (@icuresearch) has noted that the true mortality figures in this study are ~28% at 60d and ~32% at 90d (see here) due to the way the mortality data was censored at hospital discharge.
• required sample size was recalculated at the first interim analysis based on apparent lower mortality rates from sepsis that initially predicted, a smaller sample size was used without loss of power

No benefit for EGDT over a protocolised approach or usual care for severe sepsis.

This study is unlikely to change current practice in Australasia, where the EGDT component of the Surviving Sepsis Campaign Guidelines has not been adopted. The ARISE study by the ANZICS CTG has also recently been completed and will provide more evidence in the Australasian setting. The SSC response is here.