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Complete Journal Club Article
The ProCESS Investigators. "A Randomized Trial of Protocol-Based Care for Early Septic Shock". NEJM. 2014. online first(online):11.
PubMed Full text PDF

Clinical Question

In patients with severe sepsis in the Emergency Department dose protocol-based resuscitation improve outcomes


No mortality or morbidity benefit was found with protocol-based resuscitation compared to bedside care in patients with severe sepsis.

Major Points

  • This multicenter randomized trial assigned patients 1341 patients to protocol EGDT (Early Goal Directed Therapy), protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions or usual care which was not standardized. The data was analyzed with intention to treat to determine in protocolized treatment of sepsis had a mortality benefit as was shown in the original Rivers Trial. No significant 60 or 90 day mortality benefit was found to the protocol therapy and greater hospital resources such as ICU admissions were found in the protocol based groups.
  • There as an increased use of vasopressors, dobutamine, and blood transfusions in the protocol EGDT group. There was more volume given within 6 hours in the protocol-based standard therapy group. The EGDT group received more vasopressors and dobutamine, and blood transfusions than the other two groups.
  • Ultimately sepsis care is improving with 2001 Rivers Trial morality of (30-40%) to this trial (18%).[1]

One important contribution of the ProCESS trial is the evidence it provides regarding the ongoing role of early recognition of and antibiotic treatment for sepsis in improving survival...The ProCESS trial identifies early recognition of sepsis, early administration of antibiotics, early adequate volume resuscitation, and clinical assessment of the adequacy of circulation as the elements we should focus on to save lives. The publication of the ProCESS trial launches the era of early recognition and treatment in the management of sepsis.

—Craig M. Lilly, M.D, Editorial: The ProCESS Trial — A New Era of Sepsis Management


Study Design

  • Multicenter Randomized trial of 1241 patients (439 in protocol-based EGDT, 446 in protocol based standard therapy, and 456 in the usual-care group)
  • The same physician led team implemented the EGDT and protocol based standard therapies
  • The resuscitation guidelines were published in the supplemental document
  • 31 Academic Hospitals
  • Intention to treat statistical analysis
  • Primary Outcome: All cause in hospital mortality at 60 days


Inclusion Criteria

  • Emergency Department Patients with suspected sepsis within 12 hour of ED arrival and 2 hours within detection of septic shock
  • ≥18 years old
  • Two SIRS Criteria
  • Refractory Hypotension((SBP <90 mmHg or required vasopressors to maintain SBP≥90 mmHg after an IV fluid challenge) ) OR
  • Serum Lactate ≥ 4 mmol/L

Participating Hospitals were required to have:

  1. >40,000 annual ED visits
  2. Use lactate as a screening measure for shock
  3. Not have a routine resuscitation protocol for septic shock
  4. Follow the Surviving Sepsis Campaign guidelines for non resuscitation aspects of care
  5. Not use ScvO2 catheters routinely

Exclusion Criteria

  • Primary CVA
  • Acute Coronary Syndrome
  • Acute Pulmonary Edema
  • Status Asthmaticus
  • Major Cardiac Arrhythmia
  • Acute GI Hemmorrhage
  • Seizure
  • Drug Overdose
  • Burn or Trauma
  • Immediate surgical requirement
  • CD4 count < 50/mm2
  • Advanced directive restricting protocol
  • Central Venous Catheter contraindication
  • Likelihood of refusing a blood transfusion
  • Resuscitation deemed futile
  • Participation in another interventional study
  • Pregnancy
  • Transfer to outside hospital

Patient Characteristics

Protocol Based EGDT group (n=439)

  • Age: 60 years old
  • Male: 52.8%
  • From nursing home: 14.6%
  • Top sepsis sources:
    • Pneumonia 31.9%
    • UTI 22.8%
    • Intraabdominal 15.7%
    • Unknown 13.0%
    • Skin/soft tissue 5.7%
  • Physiologic measurements:
    • SBP: 100.2 mmHg
    • Lactate: 4.8 mmol/L
    • APACHE II: 20.8
  • Positive blood culture: 31.7%
  • Criteria for entry: Refractory hypotension 55.6%, elevated lactate 59.0%
  • Time to randomization:
    • From arrival in ED: 197 minutes
    • From meeting inclusion criteria: 72 minutes

Protocol-Based Standard Therapy (n=446)

  • Age: 61 years old
  • Male: 56.5%
  • From nursing home: 16.1%
  • Top sepsis sources:
    • Pneumonia 34.1%
    • UTI 20.2%
    • Intraabdominal 12.8%
    • unknown 10.5%
    • Skin/soft tissue 7.4%
  • Physiologic measurements:
    • SBP: 102.1 mmHg
    • Lactate: 5 mmol/L
    • APACHE II: 20.6
  • Positive blood culture: 28.3%
  • Criteria for entry: Refractory hypotension 53.8%, elevated lactate 59.2%
  • Time to randomization:
    • From arrival in ED: 185 minutes
    • From meeting inclusion criteria: 66 minutes

Protocol-Based Standard Therapy (n=456)

  • Age: 62 years old
  • Male: 57.9%
  • From nursing home: 16.%
  • Top sepsis sources:
    • Pneumonia 33.1%
    • UTI 20.6%
    • Intraabdominal 11.2%
    • unknown 14.5%
    • Skin/soft tissue 8.3%
  • Physiologic measurements:
    • SBP: 99.9 mmHg
    • Lactate: 4.9 mmol/L
    • APACHE II: 20.7
  • Positive blood culture: 28.7%
  • Criteria for entry: Refractory hypotension 53.3%, elevated lactate 60.7%
  • Time to randomization:
    • From arrival in ED: 181 minutes
    • From meeting inclusion criteria: 69 minutes


  • Randomization to either:
    • Protocol based EGDT [3]
    • Protocol based Standard Therapy [4]
    • Non Protocol Based Usual care


Intention to treat analysis of all cause mortality of Protocol EGDT, Protocol based Standard Therapy, and Physician Directed Usual Care

Primary Outcomes

All-cause in-hospital mortality at 60 days
EGDT: 21.0%
Protocol based Standard Therapy: 18.2%
Usual Care: 18.9%

Secondary Outcomes

All-cause mortality at 90 days
EGDT: 31.9%
Protocol based Standard Therapy: 30.8%
Usual Care: 33.7%

Subgroup analysis

Use of Hospital Resources
EGDT: 91.3%
Protocol based Standard Therapy: 85.4%
Usual Care: 86.2%

Criticisms & Further Discussion

  • Since sepsis education has advanced significantly since the 2001 Rivers Trial, the equalization of mortality may be due to the similar level of care given to patients regardless of protocol.
  • A direct comparison cannot be made between the protocol EGDT group and the Rivers Trial because of greater severity of illness and persistence of shock.


  • Scvo2 monitoring equipment for the study was loaned to the sites by Edwards Lifesciences, but the company had no other role in the study.
  • University of Pittsburgh Clinical Research, Investigation, and Systems Modeling of Acute IllnessCenter managed all the data
  • Funded by the National Institute of General Medical Sciences
  • ClinicalTrials.gov: NCT00510835


  1. Rivers E, et al. "Early Goal Directed Therapy in the Treatment of Severe Sepsis and Septic Shock". The New England Journal of Medicine. 2001. 345(19):1368-1377
  2. www.nejm.org/doi/full/10.1056/NEJMe1402564
  3. Supplementary Appendix - EGDT flowsheet
  4. Supplementary Appendix - Standard Therapy flowsheet

Supplemental Publication