Publication

• Title: Goal-directed resuscitation for patients with early septic shock
• Acronym: ARISE
• Year: 2014
• Journal published in: New England Journal of Medicine
• Citation: Peake SL, Delaney A, Bailey M, et al; ARISE Investigators; ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-1506.

Context & Rationale

• Background

  Early goal-directed therapy (EGDT) (a 6-hour, haemodynamic protocol using CVP, MAP and ScvO₂ targets with prespecified fluids, vasoactive therapy, transfusion and inotropes) was popularised after a single-centre study reported improved survival in severe sepsis and septic shock.¹
  Over the subsequent decade, sepsis care in emergency departments evolved (earlier lactate measurement, earlier antimicrobials, more systematic early resuscitation), raising uncertainty about whether invasive protocol targets still added incremental benefit beyond contemporary usual care.
  ARISE was designed in parallel with other large international trials to harmonise definitions, interventions, and outcomes, enabling robust cross-trial synthesis and improving generalisability beyond the original single-centre experience.²
• Research Question/Hypothesis

  In adults presenting to the emergency department with early septic shock (or sepsis with severe hypoperfusion), does protocolised EGDT delivered over 6 hours reduce 90-day all-cause mortality compared with usual care?
• Why This Matters

  EGDT is resource-intensive (specialised staff, invasive lines, blood products/inotropes), and can drive system-wide pathway design; a definitive multicentre effectiveness estimate was needed to justify (or retire) mandated ScvO₂/CVP-driven bundles in modern practice.
  The trial’s focus on early emergency department care directly targeted the “golden hours” where resuscitation decisions are most likely to influence downstream organ failure and mortality.

Design & Methods

• Research Question: Does 6-hour EGDT (with mandatory central venous access and ScvO₂-guided targets) reduce 90-day all-cause mortality compared with usual clinician-directed care in early septic shock?
• Study Type: Multicentre, randomised, parallel-group, open-label, investigator-initiated effectiveness trial conducted primarily in emergency departments (51 centres in Australia and New Zealand, plus centres in Finland, Hong Kong and Ireland).
• Population:
  • Setting/timing: Emergency department presentation; eligibility required onset within 6 hours of ED presentation; randomisation required within 2 hours of meeting the final eligibility criterion.
  • Key inclusion: Suspected or confirmed infection; ≥2 systemic inflammatory response syndrome criteria; plus either (a) refractory hypotension (systolic blood pressure <90 mmHg or mean arterial pressure <65 mmHg) after at least 1000 mL intravenous fluid within 60 minutes, or (b) blood lactate ≥4.0 mmol/L; antimicrobials commenced before randomisation.
  • Key exclusions: Pregnancy; acute pulmonary oedema; acute coronary syndrome; acute stroke; seizure; primary cardiac dysrhythmia; primary haemorrhagic shock; burn injury; transfer from another hospital; limitation of medical treatment; imminent death or expected survival <90 days; inability to deliver the assigned intervention within the required timeframe.
• Intervention:
  • EGDT for 6 hours: Mandatory central venous catheter with continuous ScvO₂ monitoring (and arterial catheter), protocolised targets and actions.
  • Targets/actions (hierarchical): Optimise oxygenation (SpO₂ ≥93%); then CVP target (≥8 mmHg if not ventilated; ≥12 mmHg if ventilated) with repeated fluid challenges; then MAP 65–90 mmHg with vasopressors/vasodilators; then ScvO₂ ≥70% using red-cell transfusion (if haematocrit <30%) and/or dobutamine if ScvO₂ remained low despite CVP and MAP targets.
  • Delivery model: Trained staff used a standardised algorithm; intervention commenced promptly after randomisation and continued for 6 hours.
• Comparison:
  • Usual care: Resuscitation and monitoring at clinician discretion with no mandated targets and no requirement for continuous ScvO₂ monitoring.
  • Co-interventions: Antimicrobials and supportive care (ventilation, vasopressors, renal replacement therapy) as per local practice; ICU admission decisions were clinician-led.
• Blinding: Open-label (blinding not feasible for invasive monitoring and protocolised actions); primary endpoint (90-day mortality) is objective, reducing detection bias for the main outcome.
• Statistics: Prespecified statistical analysis plan published before trial completion.³ Planned total sample size 1600 to detect a 7.6% absolute reduction in 90-day mortality (assumed 38% in usual care to 30.4% with EGDT; 20% relative risk reduction) with 90% power at a two-sided 5% significance level (allowing for ~5% withdrawal/loss); primary analysis by intention-to-treat.
• Follow-Up Period: 90 days (primary endpoint: all-cause mortality at day 90).

Key Results

This trial was not stopped early. A single prespecified interim analysis at ~50% recruitment used an O’Brien–Fleming early-stopping boundary (P<0.005); enrolment continued to the planned sample size.³

• Primary outcome: 90-day mortality was virtually identical (18.6% vs 18.8%), with the confidence interval excluding any large survival advantage from EGDT.
• Process intensity: EGDT substantially increased invasive monitoring and protocol-driven interventions (e.g., ScvO₂ catheter 90.4% vs 0.4%; dobutamine 15.4% vs 2.6%; transfusion 13.6% vs 7.0%) without measurable improvements in organ support use, ICU/hospital length of stay, or mortality.
• Subgroups: No evidence of clinically meaningful heterogeneity across prespecified strata (examples: age <65 years OR 1.24 (95% CI 0.83–1.85) vs ≥65 years OR 0.85 (95% CI 0.61–1.18); P for interaction 0.15).

Internal Validity

• Randomisation and allocation concealment: Centralised randomisation with site stratification and variable block size (concealment preserved until allocation).³
• Post-randomisation exclusions / missing primary outcome: Randomised: 796 to EGDT and 804 to usual care; excluded from the primary outcome analysis: 4/796 in EGDT (1 lost to follow-up; 3 declined delayed consent) and 8/804 in usual care (1 lost to follow-up; 6 declined delayed consent; 1 withdrew prior consent); analysed for primary outcome: 792 vs 796.
• Performance/detection bias: Open-label design introduces potential performance bias (clinicians aware of assignment); however, the primary outcome (all-cause mortality) is objective and less prone to ascertainment bias.
• Protocol adherence (intervention fidelity): In EGDT, achievement of key targets at 6 hours was high: SpO₂ 99.6%, CVP 88.9%, MAP 94.1%, ScvO₂ 95.3%.
• Baseline comparability: Groups were closely matched (examples: age 62.7 ± 16.4 vs 63.1 ± 16.5 years; APACHE II score 15.4 ± 6.5 vs 15.8 ± 6.5; lactate 6.9 ± 3.2 vs 6.7 ± 3.0 mmol/L; pre-randomisation IV fluids 2515 ± 1244 vs 2591 ± 1331 mL).
• Timing: Randomisation occurred early (median 2.8 h vs 2.7 h from ED presentation); eligibility required antimicrobials commenced before randomisation (minimising confounding from delayed antibiotics).
• Dose and separation of the variable of interest: Clear separation in the “EGDT package”, especially monitoring and protocol-driven therapies: ScvO₂ catheter 717/793 (90.4%) vs 3/798 (0.4%); central venous catheter 709/793 (89.4%) vs 494/798 (61.9%); dobutamine 122/793 (15.4%) vs 21/798 (2.6%); red-cell transfusion 108/793 (13.6%) vs 56/798 (7.0%); IV fluid 0–6 h 1964 ± 1415 vs 1713 ± 1401 mL (all P<0.001).⁴
• Crossover: Minimal crossover for the defining EGDT component (continuous ScvO₂ monitoring 0.4% in usual care), supporting interpretability of the treatment contrast.
• Heterogeneity: Multicentre and international conduct increases clinical heterogeneity; nonetheless, prespecified subgroup analyses did not show convincing effect modification (e.g., refractory hypotension subgroup OR 0.92 (0.67–1.26) vs no refractory hypotension OR 1.11 (0.72–1.69); P for interaction 0.50).
• Outcome assessment and statistical rigour: Primary endpoint prespecified; analysis plan published pre-completion; interim monitoring prespecified; achieved target sample size, but the observed control mortality (~19%) was markedly lower than the design assumption (38%), limiting power to detect small absolute mortality reductions.

Conclusion on Internal Validity: Overall, internal validity appears strong: randomisation and concealment were robust, intervention fidelity and separation were clear for key EGDT elements, follow-up was near-complete, and the primary endpoint was objective; the principal threats are the open-label design and a lower-than-anticipated event rate (reducing power for modest effects).

External Validity

• Population representativeness: Patients reflected a contemporary ED septic shock cohort in high-income health systems (older adults, moderate severity by APACHE II, high lactate and/or fluid-refractory hypotension, substantial pre-randomisation resuscitation).
• System context: Sites had established emergency/ICU pathways, access to invasive monitoring, blood products, vasopressors and critical care capacity; “usual care” likely exceeds resuscitation capability in some resource-limited settings.
• Applicability: Findings generalise well to ED-based septic shock care in similarly resourced systems where early sepsis recognition and resuscitation are already embedded; applicability is less certain where baseline usual care is delayed or where ICU transfer/logistics differ materially.

Conclusion on External Validity: External validity is good for modern high-resource emergency/critical care systems, but extrapolation to low-resource environments (or to settings without timely antimicrobials, lactate testing, vasopressors, or ICU access) should be cautious.

Strengths & Limitations

• Strengths: Large multicentre international trial; clinically meaningful primary endpoint at 90 days; high adherence to EGDT targets; strong separation for the defining monitoring/therapy components; prespecified analysis plan published before trial completion; minimal crossover for ScvO₂ monitoring.
• Limitations: Open-label design; post-randomisation exclusions driven by delayed consent (small but present); control mortality far lower than anticipated (reducing ability to detect small absolute benefits); protocol embedded CVP/ScvO₂ targets that have limited physiological specificity and may not represent best-in-class haemodynamic monitoring strategies.

Interpretation & Why It Matters

• EGDT vs modern usual care

  ARISE showed that mandatory ScvO₂-guided, CVP/MAP-targeted resuscitation in the first 6 hours does not improve survival when compared with contemporary usual care that already provides early antimicrobials, fluids, and vasoactive support.
• What “works” in early sepsis care

  The trial supports an interpretation that the beneficial “signal” attributed to EGDT in earlier eras may have reflected timely recognition and early resuscitation rather than the specific invasive targets (ScvO₂, CVP) and protocol-mandated transfusion/inotrope steps.
• Resource stewardship

  EGDT increased invasive procedures and exposure to transfusion/inotropes without outcome benefit, sharpening the rationale for prioritising timely, evidence-based components (early antimicrobials, appropriate fluids, vasopressor therapy to a MAP target) over mandatory ScvO₂/CVP-driven bundles.

Controversies & Subsequent Evidence

• Correspondence focused on interpretation in the context of falling sepsis mortality: Contemporary management in both arms (substantial pre-randomisation fluids and early ICU-level care) likely reduced the incremental effect size available to be detected, and lowered event rates compared with earlier eras; this was explicitly debated in post-publication correspondence.⁵
• Convergent negative trials: ProCESS (United States) and ProMISe (United Kingdom) similarly found no mortality benefit from protocolised EGDT-like strategies over usual care in early septic shock.⁶⁷
• Patient-level synthesis: The PRISM individual patient data meta-analysis (integrating ARISE, ProCESS, and ProMISe) demonstrated no mortality benefit of EGDT and supported the conclusion that invasive goal-directed targets are not required for effective early septic shock resuscitation in similar settings.⁸
• Meta-analytic estimates: Contemporary meta-analyses incorporating the post-2014 trials reinforce the absence of a clinically important mortality reduction attributable to EGDT over usual care in high-resource environments.⁹
• Costs and value: A within-trial economic evaluation reported that EGDT increased mean costs and was not cost-effective at conventional willingness-to-pay thresholds in the Australian context.¹⁰
• Guideline evolution: Modern international sepsis guidelines emphasise early antimicrobials, lactate assessment, fluids, and vasopressors to achieve a MAP target, and no longer recommend mandatory ScvO₂-guided EGDT protocols for routine septic shock resuscitation in the manner of Rivers-era bundles.¹¹
• High-end critique in emergency medicine literature: Formal journal commentary highlighted that the “trio of trials” reframed EGDT as an implementation strategy for timely resuscitation rather than a necessary set of invasive physiological targets.¹²

Summary

• In early septic shock managed in contemporary high-resource emergency departments, EGDT did not reduce 90-day mortality compared with usual care (18.6% vs 18.8%).
• EGDT increased protocol-driven interventions and invasive monitoring (ScvO₂ monitoring, transfusion, dobutamine, vasopressor use) without improvement in organ support, ICU/hospital length of stay, or survival.
• Post-randomisation exclusions were small and related mainly to delayed-consent refusal; primary outcome follow-up was near-complete (792/796 vs 796/804 analysed).
• Prespecified subgroup analyses did not identify a subgroup with clear benefit from EGDT.
• Subsequent trials, individual patient data synthesis, and guidelines have aligned around early resuscitation without mandatory ScvO₂/CVP-targeted protocols.

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.
• 2014ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693.
• 2014Peake SL, Delaney A, Bailey M, et al; ARISE 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; ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301-1311.
• 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.

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.
• 2015Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe era. Intensive Care Med. 2015;41:1549-1560.
• 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 L, 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.

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 programme. Intensive Care Med. 2010;36(2):222-231.
• 2014Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med. 2014;42(8):1749-1755.
• 2015Levy MM, Rhodes A, Phillips GS, et al. Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. Crit Care Med. 2015;43(1):3-12.
• 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.

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.
• 2021Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11):e1063-e1143.
• 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.
• 2017Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552.
• 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.

Notes

• ARISE tests the incremental value of invasive goal-directed targets (CVP/ScvO₂ with mandated transfusion/inotrope steps) on top of early contemporary resuscitation; it does not argue against early recognition, early antimicrobials, timely fluids, or vasopressors where indicated.

Overall Takeaway

ARISE is a landmark because it displaced Rivers-era mandatory ScvO₂/CVP-driven EGDT as a default strategy for early septic shock resuscitation in modern, high-resource emergency care. It demonstrated that contemporary usual care achieves comparable survival with fewer protocol-mandated invasive procedures and haemoglobin/inotrope-driven interventions, shifting the field towards prioritising timely core resuscitation actions rather than specific invasive physiological targets.

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.Huang DT, Angus DC, Barnato AE, et al. Harmonizing international trials of early goal-directed resuscitation for severe sepsis and septic shock: methodological convergence of ProCESS, ARISE, and ProMISe. Intensive Care Med. 2013;39(10):1760-1775.
• 3.Delaney A, Peake SL, Bellomo R, et al. Australasian Resuscitation In Sepsis Evaluation trial statistical analysis plan. Emerg Med Australas. 2013;25(5):406-415.
• 4.ARISE Investigators; ANZICS Clinical Trials Group. Supplementary appendix to: Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014.
• 5.Peake SL, Delaney A, Bailey M, et al. Goal-directed resuscitation in septic shock. N Engl J Med. 2015;372(2):190-191.
• 6.ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693.
• 7.Mouncey PR, Osborn TM, Power GS, et al; ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301-1311.
• 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.Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe era. Intensive Care Med. 2015;41:1549-1560.
• 10.Higgins AM, Peake SL, Bellomo R, et al. Clinical and economic outcomes from goal-directed resuscitation for early septic shock: a within-trial cost-effectiveness analysis of the ARISE trial. Crit Care Resusc. 2021;23(3):263-272.
• 11.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.
• 12.Crager SE. Taking the “Goal-Directed” Out of Early Goal-Directed Therapy. Ann Emerg Med. 2015;66(1):13-15.