Publication

• Title: Trial of Early, Goal-Directed Resuscitation for Septic Shock
• Acronym: ProMISe (Protocolised Management in Sepsis)
• Year: 2015
• Journal published in: New England Journal of Medicine
• Citation: Mouncey 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.

Context & Rationale

• Background

  A landmark single-centre ED RCT (Rivers et al., 2001) reported a large mortality reduction with a 6-hour early goal-directed therapy (EGDT) bundle that used CVP/MAP/ScvO₂ targets and triggered blood transfusion and dobutamine.¹
  EGDT was incorporated into international sepsis guidelines and performance-improvement programmes, driving adoption of invasive monitoring and protocolised haemodynamic endpoints.²
  By the early 2010s, “usual care” in many high-income EDs had evolved to include earlier antibiotics, lactate testing, aggressive early fluids, and early vasopressors—raising uncertainty about whether the additional invasive EGDT package still delivered incremental benefit.
• Research Question/Hypothesis

  In adults presenting to ED with early septic shock (or severe sepsis with hyperlactataemia), does a protocolised 6-hour EGDT strategy reduce 90-day all-cause mortality compared with usual resuscitation?
• Why This Matters

  EGDT mandates substantial resources (trained staff, early central/arterial access, specialised catheters) and exposes patients to transfusion/inotrope triggers; determining whether these components improve patient-centred outcomes is essential for guideline credibility, workforce planning, and de-implementation of low-value invasive care.

Design & Methods

• Research Question: Whether protocolised early goal-directed resuscitation for 6 hours reduces 90-day all-cause mortality compared with usual resuscitation in ED patients with early septic shock.
• Study Type: Pragmatic, multicentre, parallel-group randomised controlled trial (1:1 allocation) across 56 UK National Health Service hospitals; ED enrolment with downstream critical care; investigator-initiated; open-label with objective primary outcome; prespecified statistical analysis plan published before database lock.³
• Population:
  • Setting: Emergency departments (with planned critical care admission as clinically indicated); sites were required not to be already delivering routine EGDT and to have capacity for 24/7 enrolment and protocol delivery.⁴
  • Inclusion (core eligibility): Age ≥18 years; suspected or confirmed infection; ≥2 SIRS criteria; and either (a) refractory hypotension (systolic blood pressure <90 mmHg after a 1,000 mL fluid challenge completed within 60 min) or (b) hyperlactataemia (blood lactate ≥4 mmol/L).⁴
  • Timing constraints: Randomisation within 2 hours of meeting inclusion criteria and within 6 hours of ED presentation; initial antimicrobials were started before randomisation.⁴
  • Key exclusions (selected): Age <18; >6 hours since meeting inclusion criteria; transferred from another acute hospital; already in critical care during the current admission; immediate surgery required; clinical decision for comfort measures only / treatment limitation; contraindication to central venous catheterisation or protocol components; pregnancy; other prespecified exclusions (see Supplementary Appendix).⁴
• Intervention:
  • Protocol: 6-hour EGDT bundle delivered immediately after randomisation by trained clinical staff, with structured reassessments and escalation steps (including mandated early central venous and arterial access where feasible).³
  • Targets (hierarchical): CVP ≥8 mmHg (fluids); MAP ≥65 mmHg and/or systolic blood pressure ≥90 mmHg (vasopressors/vasodilators as needed); ScvO₂ ≥70% (blood transfusion to haematocrit/haemoglobin target and/or inotrope [dobutamine] trigger if not achieved).³
  • Permitted co-interventions: Airway/ventilation and sedation/analgesia at clinician discretion; antimicrobials and source control as per usual practice (but initiated prior to randomisation).⁴
• Comparison:
  • Usual resuscitation: Non-protocolised haemodynamic management at clinician discretion (no mandated CVP/ScvO₂ targets, transfusion trigger, or dobutamine algorithm), delivered within the same ED/critical care systems and time windows.⁴
• Blinding: Open-label (protocol delivery not feasibly blinded); primary outcome (mortality) is objective and ascertainable via routine follow-up, limiting detection bias for the primary endpoint.
• Statistics: Sample size 1,260 to detect an 8% absolute mortality reduction (40% to 32%) with 90% power at a two-sided 5% significance level; primary analysis by intention-to-treat with prespecified regression adjustment/sensitivity analyses as detailed in the published statistical analysis plan.³
• Follow-Up Period: Primary endpoint assessed at 90 days; additional follow-up for health-related quality of life and resource use through 90 days (and longer-term follow-up described in prespecified analyses).³

Key Results

This trial was not stopped early. Recruitment continued to the prespecified sample size.

• There was no signal of benefit for the primary endpoint (90-day mortality 29.5% vs 29.2%; RR 1.01; 95% CI 0.85 to 1.20; P=0.90).
• EGDT achieved clear treatment separation, increasing invasive monitoring and triggered therapies (e.g., dobutamine 18.1% vs 2.4%; red-cell transfusion 8.8% vs 3.7%).
• Economic outcomes showed higher mean costs without QALY gain over 90 days (£12,414 vs £11,424; QALYs 0.054 vs 0.054).

Internal Validity

• Randomisation and allocation concealment: Central randomisation with site stratification; allocation was concealed until enrolment/randomisation, limiting selection bias.
• Post-randomisation exclusions/withdrawals: In the EGDT arm, 2/630 requested removal of all data, 2/630 were later deemed ineligible, and 2/630 withdrew before 90 days; in the usual resuscitation arm, 2/630 requested removal of all data, 3/630 were later deemed ineligible, and 6/630 withdrew before 90 days.⁴
• Blinding/performance bias: Open-label delivery makes co-intervention and clinician-behaviour bias plausible for process measures (organ support, line placement), but the primary outcome (mortality) is robust to ascertainment bias.
• Baseline comparability and illness severity: Groups were similar at baseline; mean age 66.4 ± 15.3 vs 64.3 ± 16.3 years; APACHE II 18.7 ± 6.1 vs 18.0 ± 6.4; randomisation occurred early (median 2.5 h from ED presentation in both groups), and most patients had already received substantial pre-randomisation fluids (median 2,000 mL [IQR 1,500–2,500] in both groups).
• Timing and delivery fidelity: Eligibility required randomisation within 2 h of meeting criteria and within 6 h of ED presentation, and protocol delivery was time-limited to 6 h, reducing “late” enrolment bias and focusing on early resuscitation effects.
• Separation of the variable of interest (treatment intensity and haemodynamic approach): During the initial 6 h, EGDT vs usual resuscitation achieved clear separation: IV fluids 2,226 ± 1,443 mL vs 2,022 ± 1,271 mL (mean diff 204 mL; 95% CI 45 to 364; P=0.01); vasopressor infusion 53.3% vs 46.6% (RR 1.14; 95% CI 1.03 to 1.26; P=0.01); red-cell transfusion 8.8% vs 3.7% (RR 2.39; 95% CI 1.49 to 3.83; P<0.001); dobutamine 18.1% vs 2.4% (RR 7.50; 95% CI 4.43 to 12.70; P<0.001); central venous catheter insertion 92.1% vs 50.9% (RR 1.81; 95% CI 1.70 to 1.92; P<0.001).
• Crossover/contamination: “Usual resuscitation” included high use of central venous access (50.9%) and arterial lines (59.6%), implying that the trial primarily tested mandatory ScvO₂-guided triggers and protocolised escalation rather than simply the presence/absence of invasive lines.
• Outcome assessment and statistical rigor: Primary endpoint was prespecified, objective, and analysed intention-to-treat; prespecified sensitivity analyses for missing primary outcome data and subgroup analyses were reported in the Supplementary Appendix.⁴
• Subgroup/interaction evidence: Prespecified subgroup analyses (e.g., by age quartile, MEDS quartile, SOFA quartile) did not demonstrate clinically persuasive effect modification for 90-day mortality in the Supplementary Appendix (interaction tests not supporting a consistent “responsive” subgroup).⁴
• Harms signal: Overall serious adverse events were similar (4.8% vs 4.2%), but EGDT necessarily increased exposure to procedures and triggers (central venous catheterisation, transfusion, inotropes), which are plausible pathways for non-mortality harms; SAE categories are reported in the Supplementary Appendix.⁴

Conclusion on Internal Validity: Moderate-to-strong. Randomisation and outcome objectivity support a credible null mortality effect, and protocol separation was substantial; open-label delivery and overlap in invasive monitoring between groups mainly threaten interpretation of non-mortality/process endpoints rather than the primary outcome.

External Validity

• Population representativeness: Adult ED patients with early septic shock or severe sepsis with lactate ≥4 mmol/L in a high-income national health system; mortality (about 29% at 90 days) reflects contemporary high-resource care rather than the higher mortality assumed in the original power calculation.
• Health-system context: The intervention required trained staff, early invasive monitoring, and protocol-driven transfusion/inotrope triggers; these elements may be difficult to implement in resource-limited settings, and baseline usual care may differ substantially.
• Applicability: Findings generalise best to settings where early antibiotics, early fluids and early vasopressors are already routine; they are less directly transportable to contexts with delayed recognition, restricted access to vasopressors, or limited critical care capacity (where “usual care” is not comparable).
• Case-mix exclusions: Exclusions (e.g., late presentations >6 h after meeting criteria, immediate surgical need, treatment limitation, pregnancy, contraindications to catheterisation) constrain generalisability to those groups.

Conclusion on External Validity: Generalisability is high for high-income ED/ICU systems with mature sepsis pathways and lower for systems with constrained resources or markedly different baseline practices.

Strengths & Limitations

• Strengths: Large pragmatic multicentre RCT in a national health system; early enrolment window targeting the biologically plausible treatment period; clear protocol separation; objective primary endpoint; prespecified statistical analysis plan; integrated economic evaluation.
• Limitations: Open-label delivery; substantial overlap in invasive monitoring between arms (reducing contrast for some components); mortality lower than assumed in sample size calculation (reducing power for small effect sizes); intervention tested a specific CVP/ScvO₂-targeted algorithm (including transfusion/dobutamine triggers) which may not represent “best possible” contemporary haemodynamic resuscitation.

Interpretation & Why It Matters

• Clinical implication

  In a modern high-income ED/ICU system, a mandatory EGDT bundle (with CVP/ScvO₂ targets and transfusion/inotrope triggers) did not improve mortality or organ dysfunction trajectories compared with clinician-led usual resuscitation, despite greater procedural and therapeutic intensity.
• What the trial actually “tested”

  Because usual care already delivered substantial early resuscitation (e.g., pre-randomisation fluids 2,000 mL median; early randomisation at 2.5 h median), ProMISe primarily tested the incremental value of invasive, target-driven triggers (transfusion and dobutamine guided by ScvO₂/CVP) rather than the broader principle of early recognition and prompt treatment.
• Value-based care

  EGDT increased mean 90-day costs without improving QALYs, reinforcing a shift away from routine ScvO₂-based invasive protocols in settings where timely antibiotics, fluids, and vasopressors are already standard.

Controversies & Subsequent Evidence

• Concordant “three-trial” evidence base: ProMISe’s null result aligned with ProCESS and ARISE (both 2014), collectively undermining the premise that routine, invasive ScvO₂-targeted EGDT improves outcomes over contemporary usual care in high-income settings.⁶⁷
• Interpretation clarified in correspondence: Published correspondence emphasised that these trials occurred in an era where “usual care” had already incorporated early sepsis management (antibiotics, early fluids, early vasopressors), so the remaining question was the incremental value (and harms) of mandated invasive monitoring and algorithm-triggered transfusion/inotrope use.⁵
• Physiological critique: Editorial commentary highlighted limitations of fixed CVP targets and ScvO₂-driven triggers as proxies for adequate perfusion and argued for dynamic assessment rather than rigid endpoints; it also underscored that trials of “protocolised care” can become trials of “more invasive care” when baseline resuscitation is already prompt and aggressive.⁹
• Higher-level synthesis: An individual patient-data meta-analysis of ProCESS, ARISE, and ProMISe found no mortality benefit from EGDT across evaluated patient subgroups, supporting de-adoption of routine ScvO₂-guided EGDT in similar systems.⁸
• Guideline evolution: Contemporary Surviving Sepsis Campaign guidance moved away from mandatory ScvO₂/CVP-targeted EGDT, emphasising prompt antimicrobials, early fluids and vasopressors, lactate measurement, and dynamic markers of perfusion—an evolution strongly informed by these trials.¹⁰
• Extended programme report: A detailed NIHR Health Technology Assessment report of ProMISe provided expanded clinical and economic analyses and similarly concluded that EGDT increased costs without clear outcome benefit in the NHS context.¹¹

Summary

• In UK ED patients with early septic shock/severe sepsis (n=1,260), protocolised 6-hour EGDT did not reduce 90-day mortality versus usual resuscitation (29.5% vs 29.2%).
• EGDT produced strong separation in treatment intensity (e.g., dobutamine 18.1% vs 2.4%; transfusion 8.8% vs 3.7%; CVC 92.1% vs 50.9%).
• There was no improvement in early or later organ dysfunction (SOFA at 6 h or 72 h) and no QALY gain at 90 days.
• Mean 90-day costs were higher with EGDT (£12,414 vs £11,424), supporting de-adoption of routine invasive EGDT where contemporary usual care is timely and aggressive.
• Together with ProCESS and ARISE, ProMISe helped shift guidelines from fixed CVP/ScvO₂ targets toward earlier fundamentals (antibiotics, fluids, vasopressors) and dynamic perfusion assessment.

Overall Takeaway

ProMISe showed that, in a modern high-income emergency and critical care system, adding a rigid 6-hour EGDT algorithm (including routine invasive monitoring and ScvO₂-triggered transfusion/inotrope therapy) does not improve survival or organ outcomes compared with clinician-led usual resuscitation. Its concordant null result with ProCESS and ARISE reframed “early goal-directed therapy” as largely unnecessary when the fundamentals of early sepsis care are already delivered reliably and promptly.

Bibliography

• 1.Rivers 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.
• 2.Dellinger 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.
• 3.Mouncey PR, Osborn TM, Power GS, et al. Protocolised Management In Sepsis (ProMISe): Statistical analysis plan. Crit Care Resusc. 2013;15(4):311-317.
• 4.Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. Supplementary Appendix. N Engl J Med. 2015.
• 5.Mouncey PR, Osborn TM, Power GS, et al. Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med. 2015;373(6):576-578.
• 6.ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693.
• 7.ARISE Investigators; ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-1506.
• 8.PRISM Investigators. Early, goal-directed therapy for septic shock — a patient-level meta-analysis. N Engl J Med. 2017;376(23):2223-2234.
• 9.De Backer D. Early goal-directed therapy: do we have a definitive answer? Intensive Care Med. 2016;42(6):1048-1050.
• 10.Evans 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.
• 11.Mouncey PR, Osborn TM, Power GS, et al. Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed therapy for septic shock. Health Technol Assess. 2015;19(97):1-150.