Publication

• Title: A randomized trial of protocol-based care for early septic shock
• Acronym: ProCESS (Protocolized Care for Early Septic Shock)
• Year: 2014
• Journal published in: New England Journal of Medicine
• Citation: The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693.

Context & Rationale

• Background

  Early goal-directed therapy (EGDT), as originally operationalised in Rivers et al, used protocolised haemodynamic targets (central venous pressure, mean arterial pressure, and central venous oxygen saturation) linked to staged interventions including fluids, vasopressors, red-cell transfusion, and dobutamine, and was associated with improved outcomes in a single-centre study.¹
  By the late 2000s, sepsis recognition, lactate testing, timely antimicrobials, and early resuscitation had become more widespread, raising uncertainty about whether the incremental benefit in Rivers’ setting would persist in contemporary, multi-centre practice.
• Research Question/Hypothesis

  In adults with early septic shock identified in the emergency department, does protocol-based resuscitation (EGDT or a less-invasive protocolised standard therapy) reduce 60-day in-hospital mortality compared with usual care, and does EGDT outperform protocolised standard therapy?
• Why This Matters

  EGDT had major resource and workflow implications (central venous catheterisation with oximetry, dedicated staffing, protocol enforcement) and embedded transfusion/inotrope triggers with potential harms; ProCESS tested whether these specific protocol components added value beyond modern early sepsis care.

Design & Methods

• Research Question: Among adults with early septic shock in the emergency department, does protocol-based resuscitation (EGDT or protocolised standard therapy) improve 60-day in-hospital mortality versus usual care, and is EGDT superior to protocolised standard therapy?
• Study Type: Multi-centre, parallel-group, investigator-initiated, open-label, randomised trial (1:1:1), conducted in US emergency departments (31 academic centres).
• Population:
  • Setting: Emergency department patients with early septic shock prior to ICU admission (resuscitation delivered over the first 6 hours after randomisation).
  • Key inclusion: Adults (≥18 years) with suspected infection plus systemic inflammatory response syndrome and either refractory hypotension after a fluid challenge or an initial lactate ≥4.0 mmol/L; randomised within 2 hours of meeting eligibility.
  • Key exclusions: Immediate need for surgery; limitations of therapy (including do-not-resuscitate); contraindications to protocol components; and other protocol-specified exclusions intended to avoid non-sepsis shock states and situations where mandated interventions would be inappropriate.
• Intervention:
  • Protocol-based EGDT (6-hour algorithm): Mandatory central venous catheter with continuous central venous oxygen saturation monitoring; staged targets (CVP, MAP, ScvO₂) linked to protocolised fluids and vasopressors, with escalation to red-cell transfusion and dobutamine when ScvO₂ targets were not met.
  • Core targets and actions: CVP and MAP targets used to guide fluid boluses and vasopressors; low ScvO₂ triggered transfusion to haematocrit target and then dobutamine (per protocol limits), with ongoing reassessment throughout the 6-hour window.
• Comparison:
  • Protocolised standard therapy (6-hour algorithm): Protocol-driven fluids and vasopressors to achieve CVP and MAP goals using a central venous catheter without mandatory ScvO₂ monitoring; transfusion/inotrope use was not mandated by ScvO₂-based triggers.
  • Usual care: Treating clinician-directed care without a trial-mandated resuscitation algorithm; all usual therapies permitted (including central access and vasopressors) at clinician discretion.
• Blinding: Unblinded (treating teams aware of allocation); primary outcome (mortality) is objective, while process measures and discharge destinations could be influenced by unblinded care.
• Statistics: Initially powered for 1,950 patients to detect a ~6–7% absolute mortality reduction with 80% power at a 5% significance level; sample size was re-estimated and reduced to ~1,350 when observed mortality was lower than expected, with a final significance threshold of 0.0494 after one interim analysis; primary analysis was intention-to-treat with hierarchical testing (protocol-based care vs usual care, then EGDT vs protocolised standard therapy if indicated).
• Follow-Up Period: Primary outcome: in-hospital mortality censored at 60 days; secondary mortality follow-up at 90 days and 1 year; additional secondary outcomes included organ failure, duration of organ support, lengths of stay, and discharge disposition at 60 days.

Key Results

This trial was not stopped early. Enrolment was completed after a pre-planned sample-size re-estimation based on lower-than-anticipated event rates.

• Across all three arms, mortality was substantially lower than in early single-centre EGDT-era cohorts, and neither protocolised strategy improved 60-day survival versus usual care.
• The EGDT arm achieved clear separation in invasive monitoring and in ScvO₂-linked interventions (e.g., transfusion and dobutamine), yet this did not translate into improved clinical outcomes.
• The protocolised standard therapy arm performed similarly to usual care and was numerically (but not significantly) lower in mortality than EGDT, undermining the necessity of ScvO₂-driven escalation as a routine requirement.

Internal Validity

• Randomisation and allocation: Centralised, web-based allocation with 1:1:1 assignment; allocation concealment is supported by remote assignment, though blinding after allocation was not feasible.
• Dropout/exclusions: 12,707 screened; 1,351 enrolled; 10 withdrew consent and declined use of data before randomisation; 1,341 were randomised and formed the intention-to-treat cohort.
• Performance/detection bias: Open-label resuscitation could influence non-mortality outcomes and downstream care; however, the primary endpoint (mortality) is robust to detection bias.
• Protocol adherence: Protocol adherence failures were reported in 48/404 (11.9%) in EGDT and 19/435 (4.4%) in protocolised standard therapy; central venous catheter placement was not achieved in 30/439 (6.8%) in EGDT and 6/446 (1.3%) in standard therapy.
• Baseline characteristics: Groups were well balanced and severely ill (baseline APACHE II: 20.8 ± 8.1 vs 20.6 ± 7.4 vs 20.7 ± 7.5; baseline lactate: 4.9 ± 3.2 vs 4.8 ± 3.0 vs 4.9 ± 3.2 mmol/L).
• Timing: Randomisation occurred after substantial early care (time from ED arrival to randomisation: 197 ± 116 vs 185 ± 112 vs 181 ± 97 minutes; pre-randomisation intravenous fluids: 2,254 ± 1,472 vs 2,346 ± 1,387 vs 2,363 ± 1,433 mL; intravenous antibiotics before randomisation: 75.6% vs 76.9% vs 76.1%).
• Dose and separation of the variable of interest: The EGDT arm delivered substantially more invasive monitoring and ScvO₂-linked escalation within 0–6 hours (central venous catheterisation: 93.9% vs 56.3% vs 57.9%; oximetric catheter: 93.3% vs 1.2% vs 2.9%; red-cell transfusion: 14.4% vs 8.3% vs 7.5%; dobutamine infusion: 8.0% vs 1.1% vs 0.9%; intravenous fluids from randomisation to 6 hours: 2,805 ± 1,957 vs 3,285 ± 2,212 vs 2,279 ± 1,881 mL).
• Heterogeneity: Multi-centre implementation increases practice variability, but prespecified subgroup analyses did not demonstrate convincing effect modification by entry criterion (hyperlactataemia vs refractory hypotension) for mortality.
• Crossover/contamination: Usual care included central venous catheterisation in a substantial minority during the first 6 hours (57.9%), narrowing the contrast for “protocolisation” as such; however, ScvO₂ catheter use remained rare (2.9%), preserving contrast for the core EGDT-specific component.
• Outcome assessment: Mortality outcomes are objective; organ failure definitions and discharge dispositions are more sensitive to practice differences but were prespecified.
• Statistical rigour: Prespecified hierarchical testing and an interim analysis with adjusted final alpha were used; sample-size re-estimation was performed because observed event rates were lower than anticipated.

Conclusion on Internal Validity: Overall, internal validity appears moderate-to-strong given centralised randomisation, an intention-to-treat framework, and clear protocol separation in key EGDT components, tempered by open-label care, meaningful “usual care” intensity, and incomplete protocol adherence in a minority.

External Validity

• Population representativeness: Enrolled adults with early septic shock identified in the ED with high lactate and/or refractory hypotension; mean age ~60 years and baseline APACHE II ~21 resemble many high-acuity ED sepsis populations in high-resource systems.
• Setting dependency: Conducted in US academic emergency departments with established capacity for rapid lactate testing, early antimicrobials, and prompt escalation to vasopressors and central access.
• Applicability: Findings are most applicable where early sepsis recognition and prompt initial management are already routine; generalisability may be more limited in settings without rapid diagnostics, staffing, or invasive monitoring resources, or where sepsis care processes are less mature.
• Intervention relevance over time: The specific EGDT triggers (ScvO₂-driven transfusion and dobutamine) are less aligned with contemporary practice in many centres, increasing the relevance of the “protocol vs usual care” question but reducing the direct applicability of the exact Rivers-era algorithm as a package.

Conclusion on External Validity: Generalisability is good for high-resource ED/ICU systems with mature early sepsis pathways, and more limited for resource-constrained environments or systems where baseline early resuscitation and antimicrobial delivery differ substantially.

Strengths & Limitations

• Strengths: Large, multi-centre, pragmatic trial in the ED; early enrolment of high-risk septic shock; three-arm design separating EGDT-specific components from protocolisation per se; strong separation in ScvO₂ monitoring and linked co-interventions; clinically meaningful, objective primary endpoint.
• Limitations: Open-label care; substantial pre-randomisation resuscitation reduced the “incremental” signal detectable by protocol algorithms; usual care intensity was high and partially overlapped with protocol components (central access/vasopressors); protocol adherence failures were non-trivial in EGDT; sample-size re-estimation reflects lower-than-expected event rates and limits power for smaller effects.

Interpretation & Why It Matters

• Clinical practice

  In contemporary ED septic shock care with early antimicrobials and substantial early fluid/vasopressor use, mandatory ScvO₂-guided EGDT (including routine transfusion and dobutamine escalation) does not improve survival compared with clinician-directed care.
• Mechanism-level implication

  Clear separation in ScvO₂ monitoring and its linked interventions, without outcome benefit, argues against ScvO₂-triggered transfusion/inotrope escalation as a default strategy in early septic shock resuscitation.
• Systems-level implication

  ProCESS supports a focus on early recognition and prompt, high-quality basic resuscitation rather than rigid, resource-intensive protocols; this framing was reinforced in contemporaneous editorial interpretation.²

Controversies & Subsequent Evidence

• What ProCESS “actually tested”: Because patients received substantial resuscitation before randomisation (fluids ~2.3 L; antibiotics in ~76%; vasopressors in ~24–29%), ProCESS is best interpreted as testing whether protocolised targets and ScvO₂-linked escalation add benefit beyond contemporary early sepsis care, not whether early resuscitation itself matters.
• Protocolisation vs ScvO₂-driven escalation: The protocolised standard therapy arm (CVP/MAP-driven care without mandated ScvO₂ monitoring) had outcomes similar to EGDT and usual care, suggesting that any benefit of “doing sepsis care early and systematically” can be achieved without mandatory ScvO₂-guided transfusion/dobutamine.
• Triumvirate convergence: The subsequent ARISE and ProMISe trials reported similarly neutral mortality findings for EGDT compared with usual care, supporting a consistent inference across health systems.⁴⁵
• Patient-level synthesis: A later patient-level meta-analysis across ProCESS, ARISE, and ProMISe found no mortality advantage for EGDT over usual care and no compelling subgroup in which EGDT consistently improved outcomes, reinforcing the “no incremental benefit” conclusion at scale.³
• Guideline impact: Modern guideline recommendations no longer require ScvO₂-targeted EGDT; emphasis has shifted towards early antimicrobials, source control, and dynamic haemodynamic assessment rather than fixed CVP/ScvO₂ targets.⁶

Summary

• ProCESS randomised 1,341 ED patients with early septic shock to EGDT, protocolised standard therapy, or usual care.
• There was no mortality benefit at 60 days: 21.0% (EGDT) vs 18.2% (protocolised standard) vs 18.9% (usual care); primary hierarchical comparison protocol vs usual care RR 1.04; 95% CI 0.82 to 1.31; P=0.83.
• EGDT achieved marked separation in invasive monitoring and in ScvO₂-linked interventions (oximetry catheters, transfusion, dobutamine), yet did not improve survival or reduce incident organ failure.
• Usual care in participating centres was already intensive and timely (substantial fluids/antibiotic delivery before randomisation), limiting the plausible incremental effect of rigid protocols.
• Together with ARISE and ProMISe, ProCESS shifted practice away from mandated ScvO₂-based EGDT and towards early recognition plus high-quality foundational resuscitation.

Further Reading

Other Trials

• 2001Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377.
• 2010Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303(8):739-746.
• 2014ARISE Investigators; ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-1506.
• 2015Mouncey PR, Osborn TM, Power GS, et al. Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med. 2015;372(14):1301-1311.
• 2019Hernández G, Ospina-Tascón GA, Damiani LP, et al. Effect of a Peripheral Perfusion–Guided Resuscitation Strategy vs a Lactate Level–Guided Strategy on 28-Day Mortality in Septic Shock (ANDROMEDA-SHOCK). JAMA. 2019;321(7):654-664.

Systematic Review & Meta Analysis

• 2017PRISM Investigators. Early, goal-directed therapy for septic shock — a patient-level meta-analysis. N Engl J Med. 2017;376(23):2223-2234.
• 2016Simpson SQ, Gaines M, Hussein Y, Badgett RG. Early goal-directed therapy for septic shock: a living systematic review. J Crit Care. 2016;36:43-48.
• 2017Park SK, Shin SR, Hur M, et al. Effect of early goal-directed therapy for treatment of severe sepsis and septic shock: a systematic review and meta-analysis. J Crit Care. 2017;38:115-122.
• 2016Jiang LB, Zhang M, Jiang SY, Ma YF. Early goal-directed resuscitation for patients with severe sepsis and septic shock: a meta-analysis and trial sequential analysis. Scand J Trauma Resusc Emerg Med. 2016;24:23.
• 2015Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ProCESS/ARISE/ProMISe era. Intensive Care Med. 2015;41(9):1549-1560.

Observational Studies

• 2006Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596.
• 2010Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. 2010;38(2):367-374.
• 2017Seymour CW, Gesten F, Prescott HC, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med. 2017;376(23):2235-2244.
• 2018Rhee C, Filbin MR, Massaro AF, et al. Association Between Compliance With the National SEP-1 Quality Measure and Clinical Outcomes Among Patients With Sepsis. Crit Care Med. 2018;46(10):1585-1591.
• 2022Townsend SR, Kline JA, Rivera V, et al. National Performance in the Centers for Medicare & Medicaid Services SEP-1 Sepsis Bundle: Relationship With Sepsis Outcomes. Chest. 2022;161(3):651-662.

Guidelines

• 2021Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Intensive Care Med. 2021;47(11):1181-1247.
• 2018Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med. 2018;44(6):925-928.
• 2017Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-377.
• 2016Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810.
• 2013Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med. 2013;41(2):580-637.

Notes

• ProCESS is one of three large pragmatic ED trials (with ARISE and ProMISe) that collectively displaced mandatory ScvO₂-targeted EGDT from routine practice.
• Interpretation should separate the value of early, high-quality sepsis care (widely supported) from the incremental value of rigid haemodynamic targets and ScvO₂-triggered escalation (not supported in ProCESS).

Overall Takeaway

ProCESS demonstrated that, in modern US academic emergency departments where early sepsis care was already intensive, protocol-based EGDT (including ScvO₂-guided transfusion and dobutamine) did not improve survival compared with either a less invasive protocol or clinician-directed usual care. Its core legacy is to reframe “goal-directed” sepsis resuscitation around timely recognition and foundational therapy rather than mandatory invasive monitoring and fixed haemodynamic targets.

Bibliography

• 1Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377.
• 2Angus DC. The ProCESS Trial — A New Era of Sepsis Management. N Engl J Med. 2014;370:1750-1751.
• 3PRISM Investigators. Early, goal-directed therapy for septic shock — a patient-level meta-analysis. N Engl J Med. 2017;376(23):2223-2234.
• 4ARISE Investigators; ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-1506.
• 5Mouncey PR, Osborn TM, Power GS, et al. Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med. 2015;372(14):1301-1311.
• 6Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Intensive Care Med. 2021;47(11):1181-1247.