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Angus DC, et al. "A randomized trial of protocol-based care for early septic shock". The New England Journal of Medicine. 2014. 370(10):1683-1693.
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Clinical Question

Among patients with early septic shock, is early goal-directed therapy or a novel protocol-based therapy superior to usual care in reducing all-cause in-hospital mortality at 60 days?

Bottom Line

Among patients with early septic shock, there was no difference in all-cause in-hospital mortality at 60 days with management driven by early goal-directed therapy, a novel protocol-based therapy, or usual care.

Major Points

A dramatic shift in the practice of critical care medicine followed the publication of the 2001 Rivers Trial, a single urban-center trial demonstrating that an early goal-directed therapy (EGDT) protocol featuring aggressive resuscitation and early antibiotics led to an absolute risk reduction in mortality of 16% for patients with severe sepsis or septic shock. Resuscitation involved administration of fluids, vasopressors, and packed RBC transfusions guided by MAP, CVP, ScvO2 (which required central line placement), and UOP in the first 6 hours. The following year the international Surviving Sepsis Campaign (SSC) was established to promote evidence-based approaches for reducing mortality from sepsis;[1] its guidelines reflect the EGDT protocol with a grade 1C recommendation.[2] Institutions implementing EGDT-like strategies have reported mortality reductions.[3]

It's impossible to determine which of the EGDT resuscitation interventions conferred survival benefit. Transfusions to maintain a hematocrit of 30 for low ScvO2 is in contrast to the deleterious effects of excessive transfusions in a similar population in the TRICC trial (1999). ScvO2-driven resuscitation itself requires placement of a central venous catheter and did not differ in outcomes driven by lactate in EMSchockNet (2010).[4] CVP has been known to poorly correlate with blood volume in critically ill patients since 1984.[5] A multicenter trial confirming the benefit of the EGDT interventions was lacking.

The 2014 Protocolized Care for Early Septic Shock (ProCESS) multicenter trial randomized 1,341 patients with septic shock to one of three arms: 1. EGDT-like care, 2. a novel protocol-based care using non-invasive monitoring to drive resuscitation, or 3. usual care as directed by the treating physicians (albeit in academic institutions in a closely monitored research setting). The EGDT group received more vasopressors, dobutamine, and blood transfusions than the other two groups. The protocol-based care group received more volume through hour 6 and total volume through hour 72 than the other two groups. At 60 days, 90 days, and 1 year there was no differences in mortality between the three arms. The protocol-based care was associated with higher degree of renal failure. Usual care had a non-significant reduction in heart failure (P=0.06).

The EGDT protocol used here differs from that in the Rivers trial in several ways. Volume resuscitation in this trial started before randomization due to inclusion criteria requiring a fluid challenge. Because of this, the EGDT arm received 44.5% of administered volume until hour 6 before randomization occurred. This resulted in the "early" component of resuscitation lasting longer than the 6 hours in the Rivers trial. Furthermore, timing of non-resuscitation therapies (i.e. antibiotics) were left to the discretion of the investigator though most of the participants received antibiotics before randomization. Finally, in the >10 years since the Rivers trial was published, the practice of critical care medicine has changed considerably given the SSC's emphasis on early identification of and treatment for those with sepsis. The very guidelines driving the standard of care in this field are heavily influenced by the Rivers trial. Indeed, all three groups in this trial received similar volume administration at 6 hours as the EGDT group in the Rivers trial.

The findings of ProCESS were later confirmed in the 2014 ARISE and 2015 ProMISe trials[6] which compared EGDT and usual care in academic and community centers and NHS hospitals, respectively. The true benefit of modern therapies for septic shock may lie in the early identification of those with the condition which would ultimately lead to an early treatment, rather than a specific algorithm.[7]


Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[8]

  • Begin treatment and resuscitation immediately (best practice statement [BPS] are ungraded, strong recommendations)
  • For sepsis-induced hypoperfusion, give ≥30 mL/kg IV crystalloid fluid in the first 3 hours (strong recommendation, low quality evidence)
  • After initial resuscitation, given additional fluids guided by frequent reassessment of status of hemodynamics like HR, BP, PaO2, RR, temp, UOP, noninvasive, and/or invasive monitoring (BPS)
  • Target MAP of 65 mm Hg in patients requiring vasopressors (strong recommendation, moderate quality of evidence
    • Norepinephrine as first line vasopressor (strong recommendation, moderate quality of evidence)
      • Add vasopressin up to 0.03 U/min (weak recommendation, moderate quality of evidence) or epinephrine (weak recommendation, low quality of evidence) to raise MAP to target
      • Can add vasopressin up to 0.03 U/min to decrease norepinephrine dose (weak recommendation, moderate quality of evidence)
  • Suggested guiding resuscitation to normalize lactate in those with lactate elevations (weak recommendation, low quality of evidence)
  • Recommend administration of IV antimicrobials as soon as possible, preferably within 1 hour of recognition (strong recommendation, moderate quality of evidence)


  • Multicenter, randomized, open-label trial
  • N=1,343 (12,707 screened)
    • EGDT (n=439)
    • Protocol-based standard therapy (n=446)
    • Usual care (n=458)
  • Setting: 31 US academic centers
  • Enrollment: 2008-2013
  • Total follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary outcome: All-cause in-hospital mortality at 60 days


Inclusion Criteria

For Research Sites

  • Academic hospitals with >40,000 ED visits annually
  • Use of serum lactate as method for screening for cryptogenic shock
  • Adherence to Surviving Sepsis Campaign guidelines for non-resuscitation aspects of care but no routine resuscitation protocols for septic shock
  • No routine use of ScvO2 catheters

For Participants

  • Patients in the ED >18 years of age meeting ≥2 criteria for SIRS:
    • Temperature >38°C or <36°C
    • HR >90 BMP
    • RR >20 breaths/minute or PaCO2 <32mmHg
    • WBC count >12,000/mm3, <4,000/mm3, or >10% bands/immature forms
  • Refractory hypotension (SBP <90 mmHg or required vasopressors to maintain SBP≥90 mmHg after an IV fluid challenge) or serum lactate ≥4 mmol/L
    • 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
    • Patients did not need to be in shock on arrival
  • Enrollment within 2 hours of earliest detection of shock and within 12 hours of ED arrival

Exclusion Criteria

For Participants

  • 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
  • Enrollment in another interventional study
  • Known pregnancy
  • Transfer from an OSH

Baseline Characteristics

From the EGDT group.

  • Demographics: Age 60 years, male 52.8%, nursing home resident 14.6%
  • Baseline health data:
    • SBP: 100.2 mmHg
    • Lactate: 4.8 mmol/L
    • Charlson comorbidity score: 2.6 (out of 33, higher indicating greater illness burden)
    • APACHE II: 20.8 (out of 71, higher indicating greater illness severity)
  • Sepsis source: Pneumonia 31.9%, UTI 22.8%, intraabdominal 15.7%, skin/soft tissue 5.7%, catheter 2.5%, CNS 0.7%, endocarditis 0.2%, other 6.4%, unknown 13.0%
    • No infection determined after review: 1.1%
  • Positive blood culture: 31.7%
  • Criteria for entry: Refractory hypotension 55.6%, elevated lactate 59.0%
  • Time to randomization:
    • From ED arrival: 197 minutes
    • From meeting study criteria: 72 minutes


  • Open-label randomization to a group:
    • EGDT - A standardized protocol[9] consisting of:
      • Oxygen \B1 intubation followed by insertion of central line with oximetric port
      • 500 mL bolus for CVP <8 mmHg and rebolusing until CVP 8-12 mmHg
      • Following rebolusing, initiation of vasoactive agents if needed to achieve MAP ≥65 and ≤90 mmHg
      • Following MAP goals, if ScvO2 <70% then transfusion of packed RBC to achieve hematocrit >30%, if still <70% then inotropic agents to achieve ScvO2 ≥70%
      • Reassessment of the above steps every 15-30 minutes
    • Standard Therapy - A standardized protocol[10] consisting of:
      • Oxygen ± intubation followed by placement of two large bore ≥18 gauge IVs
      • 500-1000 mL fluid bolus (crystalloids primarily) with minimum initial fluid of 2 liters targeting SBP <100 mmHg or shock index (SI) ≥0.8 unless fluid replete/overloaded or on vasopressors
        • Fluid replete/overload is clinical diagnosis by the treating investigator involving a constellation of a JVD, rales, and decreased oximetry readings
        • SI defined as HR/SBP
      • Isotonic IVF at 250-500 mL/hr
      • If hypoperfused, re-initiate protocol
    • Usual care - Bedside providers direct care
  • All groups were otherwise treated at the discretion of the treating physician, including antibiotic medication choices


Presented as EGDT vs. protocol-based standard therapy vs. usual care. P-values are for three-group comparison with Fisher's exact test unless otherwise specified.

Primary Outcome

All-cause in-hospital mortality at 60 days
21.0% vs. 18.2% vs. 18.9% (individual comparisons P=0.31 to 0.89)

Secondary Outcomes

All-cause mortality
At 90 days: 31.9% vs. 30.8% vs. 33.7% (P=0.66)
At 1 year: No difference
New organ failure in the first week
CV: 61.3% vs. 63.7% vs. 56.1% (P=0.06)
Respiratory: 38.0% vs. 36.5% vs. 32.4% (P=0.19)
Renal: 3.1% vs. 6.0% vs. 2.8% (P=0.04 for worsening in the protocol-based group versus the other two)

Additional Analyses

Duration of organ support
CV: 2.6 vs. 2.4 vs. 2.5 days (P=0.52)
Respiratory: 6.4 vs. 7.7 vs. 6.9 days (P=0.41)
Renal: 7.1 vs. 8.5 vs. 8.8 days (P=0.92)
Hospital resources
Admission to ICU: 91.3% vs. 85.4% vs. 86.2% (P=0.01)
ICU stay: 5.1 vs. 5.1 vs. 4.7 days (P=0.63)
Hospital stay: 11.1 vs. 12.3 vs. 11.3 days (P=0.25)
Discharge placement
Not discharged: 0.7% vs. 1.8% vs. 0.4% (P=0.82)
Long-term acute care facility: 3.6% vs. 4.9% vs. 4.8%
Another acute care hospital: 1.8% vs. 0.4% vs. 1.1%
Nursing home: 16.2% vs. 20.9% vs. 19.3%
Home: 53.8% vs. 50.9% vs. 51.5%
Other/unknown: 3.0% vs. 2.9% vs. 3.9%

Additional Analyses

Interventions before randomization
IV antibiotics: 75.6% v.s 76.9% vs. 76.1% (P=0.91)
Mechanical ventilation: 13.7% vs. 14.6% vs. 13.8% (P=0.93)
Corticosteroids: 9.3% vs. 9.4% vs. 8.3% (P=0.82)
IV fluid administration
Pre-randomization: 2254 vs. 2226 vs. 2083 mL (P=0.15)
Randomization to 6 hours: 2805 vs. 3285 vs. 2279 mL (P<0.0001)
6 to 72 hours: 4428 vs. 4896 vs. 4354 mL (P=0.08)
0 to 72 hours: 7220 vs. 8175 vs. 6633 mL (P<0.0001)
Pre-randomization: 19.1% vs. 16.8% vs. 15.1% (P=0.28)
Randomization to 6 hours: 54.9% vs. 52.2% vs. 44.1% (P=0.003)
6 hours to 72 hours: 19.8% vs. 20.9% vs. 18.0% (P=0.38)
0 to 72 hours: 27.3% vs. 24.0% vs. 22.4% (P=0.05)
Pre-randomization: None in any group
Randomization to 6 hours: 8% vs. 1.1% vs. 0.9% (P<0.0001)
6 hours to 72 hours: 47.6% vs. 46.6% vs. 43.2% (P=0.08)
0 to 72 hours: 60.4% vs. 61.2% vs. 53.7% (P<0.0001)
Blood transfusion
Pre-randomization: 1.1% vs. 1.6% vs. 2.0% (P=0.63)
Randomization to 6 hours: 14.4% vs. 8.3% vs. 7.5% (P=0.001)
6 hours to 72 hours: 4.3% vs. 2.0% vs. 2.2% (P=0.54)
0 to 72 hours: 9.3% vs. 2.5% vs. 2.9% (P=0.22)
Mechanical ventilation
Randomization to 6 hours: 26.4% vs. 24.7% vs. 21.7% (P=0.25)
6 hours to 72 hours: 33.7% vs. 31.4% vs. 27.9% (P=0.16)
0 to 72 hours: 36.2% vs. 34.1% vs. 29.6% (P=0.10)

Subgroup Analysis

There was no difference in analysis of the primary outcome by age, race, sex, infection source, or type of shock. Post-hoc analyses for APACHE II score, serum lactate level, and time to randomization were without interactions.

Adverse Events

Any serious
5.2% vs. 4.9% vs. 8.1% (P=0.32)

There was no reported statistical difference in individual adverse events between the groups.


  • The EGDT arm was preceded by fluid resuscitation, unlike the protocol in the Rivers trial
  • Demographics and disease prevalence differed from that in the Rivers trial
  • Underpowered to detect differences in strategies between different subgroups
  • Unclear if local practices influencing withdrawal of care altered outcomes


  • National Institute of General Medical Sciences, NIH
  • Authors with financial disclosures

Further Reading