Article Identification

• Title: Goal-Directed Resuscitation for Patients with Early Septic Shock (ARISE Trial)
• Authors: The ARISE Investigators and the ANZICS Clinical Trials Group
• Journal: The New England Journal of Medicine
• Year: 2014
• Volume: 371
• Pages: 1496-1506
• DOI: 10.1056/NEJMoa1404380

Quick Reference Summary

• In this multicenter trial of 1600 patients, early goal-directed therapy (EGDT) did not reduce 90-day all-cause mortality compared with usual care among adults presenting to the emergency department with early septic shock (EGDT 18.6% vs. usual care 18.8%; p=0.90).
• Although the EGDT group received more intravenous fluids, vasopressors, and inotropes in the first six hours, there was no significant difference in survival time, organ support duration, or length of hospital stay.

Core Clinical Question

In adults presenting to the emergency department with early septic shock (Population), does a protocolized EGDT bundle including continuous ScvO2 monitoring (Intervention), compared with usual care (Comparison), reduce 90-day all-cause mortality (Outcome)?

Background

• Disease or Condition Overview:
  • Sepsis and septic shock remain major causes of morbidity and mortality worldwide, though mortality rates have been declining over the past two decades.
  • Early recognition and prompt treatment with fluids, vasopressors, and antibiotics are central to sepsis management.
• Prior Data on the Topic:
  • Rivers et al. (2001) reported improved survival with an EGDT protocol, but concerns arose regarding applicability of these single-center findings to broader settings.
  • The ProCESS trial (2014) in the United States found no mortality benefit of protocol-based EGDT versus usual care, prompting questions about whether or which elements of EGDT remain vital.
• Current Standard of Care:
  • Current Surviving Sepsis Campaign guidelines emphasize early antibiotic administration, fluid resuscitation, and hemodynamic support, though continuous ScvO2 monitoring is no longer a universal recommendation.
  • By 2025, many emergency departments and ICUs worldwide use locally adapted sepsis bundles focusing on rapid antibiotic therapy, ongoing hemodynamic monitoring, and routine lactate clearance targets, rather than strict EGDT protocols.
• Knowledge Gaps Addressed by This Study:
  • Conflicting data on whether strict protocolized EGDT improves outcomes compared to usual care.
  • The influence of EGDT on long-term survival, resource use, and practice outside the U.S. academic environment.
• Study Rationale: To test EGDT versus usual care in diverse Australasian centers, including both metropolitan and rural hospitals, given uncertainty about EGDT’s international generalizability.

Methods Summary

• Study Design: Prospective, multicenter, parallel-group, randomized controlled trial (RCT) of EGDT vs. usual care.
• Setting and Time Period: Conducted in 51 tertiary and nontertiary hospitals in Australia, New Zealand, and several other countries (Finland, Hong Kong, Republic of Ireland) from October 2008 to April 2014.
• Population Characteristics: 1600 adults with suspected infection, ≥2 systemic inflammatory response criteria, and early septic shock (refractory hypotension or lactate ≥4 mmol/L) within 6 hours of ED presentation.
• Inclusion/Exclusion Criteria:
  • Inclusion: Adults (≥18 years) with severe sepsis or septic shock in the ED, requiring randomization within 2 hours of meeting shock criteria.
  • Exclusion: Included patients whose immediate treatment goals conflicted with the trial (e.g., comfort measures only) or >6 hours since shock onset.
• Intervention Details:
  • EGDT group received arterial and central venous catheters (with continuous ScvO2 monitoring) and protocol-based resuscitation (fluids, vasopressors, inotropes, RBC transfusions) over 6 hours, targeting predefined hemodynamic and oxygenation goals (ScvO2 ≥70%, CVP 8-12 mmHg, MAP ≥65 mmHg).
• Control/Comparison Group: Usual care group: No mandated advanced hemodynamic monitoring or protocol for EGDT; all other treatments (fluids, vasopressors) were directed by the treating team, without ScvO2 guidance.
• Primary and Secondary Outcomes:
  • Primary: 90-day all-cause mortality.
  • Secondary: 28-day, hospital, and ICU mortality; organ support duration; length of stay; adverse events.
• Statistical Analysis Approach: Intention-to-treat analysis using Fisher’s exact test for the primary outcome. Subgroup analyses explored pre-specified variables (e.g., APACHE II score, hypotension, lactate level).
• Sample Size Calculations: 1600 patients provided 85–90% power (α=0.05) to detect a 7.6% absolute risk reduction in mortality.
• Ethics and Funding Information: Approved by Monash University and local ethics committees. Funded by the National Health and Medical Research Council of Australia and the Alfred Foundation; ScvO2 monitors loaned by Edwards Lifesciences.

Detailed Results

• Participant Flow and Demographics:
  • 796 patients in EGDT group, 804 in usual care; mean ages, severity (e.g., APACHE II 20–22 range), and baseline fluid volumes (~2.5 L) were similar.
  • ~70% had refractory hypotension, ~46% had lactate ≥4.0 mmol/L.
• Primary Outcome Results:
  • 90-day mortality: EGDT 18.6% vs. usual care 18.8% (absolute difference, –0.3 percentage points; 95% CI, –4.1 to 3.6; p=0.90).
  • No significant difference in survival curves between groups (HR ~1.0).
• Effect Sizes, Confidence Intervals, and Significance: Relative risk ~0.99 (95% CI, ~0.79 to 1.25), indicating no mortality advantage for EGDT.
• Secondary Outcome Results:
  • Hospital mortality, ICU mortality, organ support duration (mechanical ventilation, vasopressors), and length of stay were similar between groups.
  • EGDT group showed higher use of vasopressors (66.6% vs. 57.8%; p<0.001), RBC transfusions (13.6% vs. 7.0%; p<0.001), and dobutamine (15.4% vs. 2.6%; p<0.001) during the first 6 hours.
• Subgroup Analyses: No mortality benefit was identified in any predefined subgroup (e.g., by age, hypotension, lactate level).
• Adverse Events/Safety Data: Comparable rates of adverse events (~7% EGDT vs. ~5% usual care; p=0.15).

Results Table (Key Outcomes)

NS denotes not significant; **denotes absolute difference in percentage points.

Authors' Conclusions

• The authors concluded that, in a broadly representative population of patients with early septic shock, EGDT did not reduce 90-day all-cause mortality compared to usual care.
• They suggest that routine incorporation of EGDT protocols with mandatory continuous ScvO2 monitoring may not be necessary in modern sepsis management, given improved usual care.
• They highlight that time to antibiotics and aggressive fluid resuscitation remain critical, but universal central venous oximetry–guided therapy may not translate into better outcomes.
• Future research should clarify which hemodynamic targets and monitoring strategies confer benefit.

Literature Review

A. Previous Studies and Meta-Analyses

• Rivers et al. (2001) – The landmark single-center RCT that first demonstrated a survival benefit with protocolized EGDT in severe sepsis.
• ProCESS (2014) – A U.S. multicenter study that showed no mortality difference between protocolized resuscitation (including an EGDT-like arm) and usual care in septic shock, similar to ARISE.
• ProMISe (Trial) – A UK-based sister study to ARISE and ProCESS, also concluding no difference in outcomes with EGDT vs. standard care.

B. Contrasting Methodological Quality

• ARISE was a pragmatic, multicenter RCT with an adequately powered sample (1600 patients), in contrast to the original single-center Rivers trial, which had fewer patients and was subject to potential selection biases.

C. Comparisons with Guidelines

• Earlier surviving sepsis guidelines recommended EGDT. Subsequent guidelines have relaxed mandatory ScvO2 targets, focusing on standardized screening, early antibiotics, fluid challenges, and clinically guided vasopressor use.

D. This Trial’s Contribution

• Confirms the findings of ProCESS and ProMISe: strict EGDT does not confer additional mortality benefit over modern usual care, which already incorporates many sepsis bundle elements.

Critical Analysis

A. Strengths

• Large, multicenter international RCT with broad generalizability.
• Rigorous trial design with central randomization, minimal loss to follow-up, and clear primary outcome.

B. Limitations

• Open-label design with potential observer bias, though balanced by objective primary outcomes (mortality).
• Conducted primarily in well-resourced centers; applicability to resource-limited settings may be limited.

Clinical Application

The ARISE findings suggest that strict protocol-based EGDT with continuous ScvO2 monitoring does not further reduce mortality compared with timely antibiotics, fluid resuscitation, and hemodynamic support guided by clinical judgment.

How To Use This Info In Practice

Practitioners should continue prioritizing rapid antibiotic administration, fluid resuscitation, and goal-directed hemodynamic monitoring tailored to each patient’s clinical trajectory rather than mandating universal EGDT protocols.