New England Journal of Medicine October 16, 2014

Goal-Directed Resuscitation for Patients with Early Septic Shock (The ARISE Trial)

The ARISE Investigators and the ANZICS Clinical Trials Group (Sandra L. Peake et al.)

Bottom Line

In adult patients presenting to the emergency department with early septic shock, early goal-directed therapy (EGDT) did not reduce 90-day all-cause mortality compared to standard, non-protocolized resuscitation care.

Key Findings

1. At 90 days, all-cause mortality showed no significant difference between the EGDT group (18.6%, 147 of 792 patients) and the usual-care group (18.8%, 150 of 798 patients) (RR 0.98; 95% CI 0.80 to 1.21; P=0.90) [1.1.3].

2. Patients managed with EGDT received a significantly larger mean volume of intravenous fluids during the first 6 hours post-randomization compared to the usual-care group (1,964 mL vs. 1,713 mL; P<0.001).

3. During the initial 6-hour resuscitation period, the EGDT group had significantly higher rates of administration for vasopressors (66.6% vs. 57.8%), dobutamine (15.4% vs. 2.6%), and red-cell transfusions (13.6% vs. 7.0%) (P<0.001 for all comparisons).

4. There were no significant differences in secondary morbidity outcomes, including duration of mechanical ventilation, use of renal replacement therapy, or median hospital length of stay between the two groups.

Study Design

Design

Multicenter, Randomized Controlled Trial

Open-Label

Sample

1,600

Patients

Duration

90 days

Median

Setting

Multicenter, predominantly Australasia

Population Adult patients presenting to the emergency department with suspected infection, meeting two or more systemic inflammatory response syndrome (SIRS) criteria, and evidencing early septic shock (defined as hypoperfusion with a lactate ≥ 4.0 mmol/L or refractory hypotension despite a fluid challenge).

Intervention Early goal-directed therapy (EGDT) for 6 hours, utilizing continuous central venous oxygen saturation (ScvO2) monitoring to achieve predefined sequential targets: central venous pressure (CVP) of 8-12 mmHg, mean arterial pressure (MAP) ≥ 65 mmHg, and ScvO2 ≥ 70%, by systematically titrating intravenous fluids, vasopressors, packed red blood cells, and inotropic agents.

Comparator Usual resuscitation care, where all hemodynamic monitoring, fluid therapy, and medication administration were determined entirely at the discretion of the treating clinicians, explicitly excluding continuous ScvO2 measurement during the initial 6-hour period.

Outcome All-cause mortality within 90 days after randomization.

Study Limitations

• The trial was open-label because blinding of the complex, device-dependent EGDT protocol was unfeasible, which could theoretically introduce performance bias, although objective mortality endpoints mitigate this.

• The overall baseline 90-day mortality was remarkably low (around 18.6-18.8%) compared to earlier historical cohorts (e.g., 46.5% in the 2001 Rivers trial), indicating that the enrolled population may have been less severely ill or that temporal improvements in general sepsis care inherently maximized survival.

• Patients in the 'usual care' group received prompt antibiotics and aggressive fluid resuscitation—fundamental concepts heavily derived from earlier EGDT studies—meaning the trial effectively tested the utility of the strict hemodynamic monitoring devices/targets rather than the concept of early aggressive resuscitation itself.

Clinical Significance

The ARISE trial conclusively demonstrated that the strict, algorithmic, and invasive monitoring parameters of Early Goal-Directed Therapy (EGDT), such as central venous pressure targets and continuous ScvO2 monitoring, are unnecessary for patients with early septic shock. Instead, contemporary 'usual care' focusing on rapid clinical identification, prompt antibiotic administration, and adequate initial fluid resuscitation achieves equivalent survival outcomes without the resource utilization and potential risks of invasive central lines and mandated transfusions.

Historical Context

In 2001, Dr. Emanuel Rivers published a landmark, single-center trial demonstrating a massive absolute mortality reduction (16%) in severe sepsis and septic shock patients using Early Goal-Directed Therapy (EGDT), which subsequently became a cornerstone of the global Surviving Sepsis Campaign guidelines. However, over the ensuing decade, critical care evolved heavily; early antibiotics and fluids became standard practice. The medical community began to question if the rigid, invasive components of EGDT (like continuous ScvO2 measurement, mandated red blood cell transfusions, and rigid CVP targets) were still beneficial. ARISE (Australasia), ProCESS (USA), and ProMISe (UK) were three harmonized, large-scale multicenter RCTs launched to rigorously test EGDT against modern usual care. All three definitively showed no additional survival benefit, initiating a paradigm shift away from prescriptive hemodynamic algorithms to early, individualized basic resuscitation.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the physiological parameters targeted in Early Goal-Directed Therapy (EGDT) as evaluated in the ARISE trial, and what is the underlying pathophysiological rationale for targeting them?

Key Response

EGDT traditionally targets central venous pressure (CVP), mean arterial pressure (MAP), and central venous oxygen saturation (ScvO2). The rationale was to optimize cardiac preload, afterload, and contractility to balance systemic oxygen delivery with consumption, thereby reversing global tissue hypoxia (indicated by low ScvO2) early in the shock state to prevent irreversible multi-organ failure.

Resident

Given the ARISE trial results, how does modern standard care for early septic shock in the emergency department differ from the original Rivers EGDT protocol, and which specific interventions are now considered unnecessary?

Key Response

Modern standard care emphasizes early recognition, rapid administration of broad-spectrum antibiotics, and adequate fluid resuscitation based on clinical judgment and dynamic measures. The ARISE trial demonstrated that routine insertion of central venous catheters for continuous ScvO2 monitoring, mandated blood transfusions to a specific hematocrit target, and routine use of inotropes based purely on ScvO2 numbers do not improve mortality and are unnecessary.

Fellow

The ARISE trial was published contemporaneously with the ProCESS and ProMISe trials. How do the baseline characteristics and mortality rates of the control groups in these three trials compare to the original 2001 Rivers study, and what does this imply about the evolution of sepsis care?

Key Response

The control group mortality in the 2001 Rivers trial was approximately 46%, whereas in ARISE, ProCESS, and ProMISe, it was roughly 18-20%. This drastic reduction implies that baseline standard sepsis care evolved significantly over that decade with earlier antibiotics and more aggressive initial fluid resuscitation (partly due to the Surviving Sepsis Campaign), rendering the strict, invasive EGDT protocol redundant in modern practice.

Attending

How should the findings of the ARISE trial influence departmental policies regarding resource allocation, specifically concerning the necessity of early central line placements and ICU admissions for patients presenting with early septic shock?

Key Response

The ARISE trial empowers attendings to adopt a less invasive approach, demonstrating that standard, non-protocolized care is safe and effective. Departmental policies can shift away from mandatory early central line placements for CVP/ScvO2 monitoring, thereby reducing iatrogenic complications, decreasing costs, and potentially allowing for the safe initial management of hemodynamically stabilizing patients in lower-acuity settings rather than mandating immediate ICU transfer.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ARISE trial utilized a pragmatic, unblinded design for the intervention while standardizing the primary outcome. What are the potential methodological risks of using 'standard care' as a control arm in an unblinded resuscitation trial, and how did the investigators attempt to mitigate contamination bias?

Key Response

In unblinded pragmatic trials, 'standard care' can drift toward the intervention (contamination bias) because clinicians are aware of the trial and the principles of EGDT. Investigators mitigated this by blinding the clinical teams managing the control group to ScvO2 values (even if a central line was placed for other reasons) and by utilizing 90-day all-cause mortality as the primary outcome, which is an objective, hard endpoint immune to subjective ascertainment bias.

Journal Editor

As a peer reviewer assessing the generalizability of the ARISE trial, how might the requirement for rapid screening and enrollment in highly developed healthcare systems (like those in Australia and New Zealand) limit the external validity of the findings to resource-limited settings?

Key Response

A critical reviewer would note that the baseline 'standard care' in Australian and New Zealand EDs is of exceptionally high quality, characterized by rapid triage, swift antibiotic delivery, and robust nurse-to-patient ratios. In resource-limited settings where standard care is less structured and early recognition is delayed, the protocolized approach of EGDT might still offer a survival benefit by enforcing a minimum standard of care, limiting the external validity of ARISE in those environments.

Guideline Committee

Based on the combined high-quality evidence from ARISE, ProCESS, and ProMISe, how should the Surviving Sepsis Campaign guidelines be updated regarding hemodynamic monitoring, and what level of evidence supports moving away from static CVP and ScvO2 targets?

Key Response

The guidelines should be updated to strongly recommend against the routine use of invasive EGDT protocols targeting specific static CVP and ScvO2 goals for all septic shock patients. The combined data from these three large, multicenter RCTs provides Level 1 (high-quality) evidence that such targets do not improve survival over standard care. Guidelines should instead pivot toward recommending dynamic measures of fluid responsiveness, such as passive leg raises or stroke volume variation, guided by clinical markers of perfusion like capillary refill or lactate clearance.

Clinical Landscape

Noteworthy Related Trials

2001

Rivers Trial

n = 263 · NEJM

Tested

Early goal-directed therapy (EGDT) targeting CVP, MAP, and ScvO2

Population

Patients with severe sepsis or septic shock

Comparator

Standard therapy

Endpoint

In-hospital mortality

Key result: EGDT significantly reduced in-hospital mortality compared to standard therapy (30.5% vs 46.5%).

2014

ProCESS Trial

n = 1341 · NEJM

Tested

Protocol-based EGDT or protocol-based standard therapy

Population

Patients with early septic shock

Comparator

Usual care

Endpoint

60-day in-hospital mortality

Key result: There was no significant difference in mortality between protocol-based EGDT, protocol-based standard care, and usual care.

2015

ProMISe Trial

n = 1260 · NEJM

Tested

Early goal-directed therapy (EGDT)

Population

Patients with early septic shock in the UK

Comparator

Usual resuscitation

Endpoint

90-day all-cause mortality

Key result: EGDT did not reduce 90-day mortality compared to usual care and led to higher use of intensive care resources.

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