ARISE

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ARISE and ANZICS writers. "Goal-directed resuscitation for patients with early septic shock". The New England Journal of Medicine. 2014. 371(16):1496-1506.
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Clinical Question

In patients presenting to an emergency department with severe sepsis or septic shock, does early goal-directed therapy reduce all-cause mortality at 90 days when compared to usual care?

Bottom Line

Among patients with severe sepsis or septic shock presenting to an emergency department, early goal-directed therapy did not reduce all-cause mortality at 90 days when compared to usual care.

Major Points

The single-center Rivers Trial (2001) demonstrated that early goal-directed therapy (EGDT) conferred a mortality benefit among patients with severe sepsis or septic shock. Resuscitation using EGDT involved administration of fluids, vasopressors, and transfusion of RBCs guided by objective measurement of MAP, CVP, ScvO2 and UOP early after identification of the condition. The protocol was subsequently recommended for these conditions by the Surviving Sepsis Campaign.[1] The utility of the protocol was called into question when the 2014 ProCESS trial did not find a mortality difference when EGDT was compared to either clinician-directed "usual care" or an alternative goal-directed resuscitation protocol. As ProCESS enrolled patients at academic medical centers, it was unclear if EGDT would provide benefit for patients enrolled in a more heterogeneous environment.

The 2014 Australasian Resuscitation in Sepsis Evaluation (ARISE) trial randomized 1600 patients with severe sepsis or septic shock at 51 academic and non-academic centers in Australia, New Zealand, Finland, Hong Kong, and Ireland to EGDT or physician-guided usual care in an unblinded fashion. There was no difference in the primary outcome of all-cause mortality at 90 days (18.6% vs. 18.8%). Mortality was similar for both groups at 28 days, in the ICU, and through day 60 of hospitalization. The trial was limited in its unblinded fashion and lower than expected mortality rate, which led to underpowering.

The outcomes of ProCESS and ARISE (and ProMISe[2] published in 2015) support moving away from EGDT as the default therapy for severe sepsis and septic shock. As both trials involved early identification and treatment (including volume resuscitation) of individuals with these conditions, they do not support delayed management. Early, clinically-appropriate administration of antibiotics and supporting organ perfusion with fluid resuscitation and vasopressor therapy are still main components of modern sepsis treatment.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[3]

  • Begin treatment and resuscitation immediately (best practice statement [BPS] are ungraded, strong recommendations)
  • For sepsis-induced hypoperfusion, give ≥30 mL/kg IV crystalloid fluid in the first 3 hours (strong recommendation, low quality evidence)
  • After initial resuscitation, given additional fluids guided by frequent reassessment of status of hemodynamics like HR, BP, PaO2, RR, temp, UOP, noninvasive, and/or invasive monitoring (BPS)
  • Target MAP of 65 mm Hg in patients requiring vasopressors (strong recommendation, moderate quality of evidence
    • Norepinephrine as first line vasopressor (strong recommendation, moderate quality of evidence)
      • Add vasopressin up to 0.03 U/min (weak recommendation, moderate quality of evidence) or epinephrine (weak recommendation, low quality of evidence) to raise MAP to target
      • Can add vasopressin up to 0.03 U/min to decrease norepinephrine dose (weak recommendation, moderate quality of evidence)
  • Suggested guiding resuscitation to normalize lactate in those with lactate elevations (weak recommendation, low quality of evidence)
  • Recommend administration of IV antimicrobials as soon as possible, preferably within 1 hour of recognition (strong recommendation, moderate quality of evidence)

Design

  • Prospective, multicenter, open-label, randomized controlled trial
  • N=1,591
    • EGDT (n=793)
    • Usual care (n=798)
  • Setting: 51 centers, mostly in Australia, New Zealand and then Finland, Hong Kong, Ireland
  • Enrollment: 2008-2014
  • Follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcome: All-cause mortality

Population

Inclusion Criteria

  • Age ≥18 years
  • Infection or suspected infection
  • ≥2 SIRS criteria and one of the following:
    • Refractory hypotension defined by SBP <90 mmHg or MAP <65 mmHg after 1L IV fluids administered within 60 minutes
    • Hypoperfusion defined by serum lactate ≥4.0 mMol/L
  • Meeting criteria for eligibility <6 hours after presenting to the ED
  • Randomization <2 hours after meeting the remaining inclusion criteria

Exclusion Criteria

  • Age <18 years
  • Contraindication to CVC placement
  • Contraindication blood product administration
  • Active bleeding causing hemodynamic instability
  • Underlying disease causing a life expectancy <90 days or death deemed imminent and inevitable
  • Limitation of therapy order preventing implementation of the study protocol or other aggressive care
  • Inpatient transfer from another acute health care facility
  • Confirmed or suspected pregnancy
  • Unable to start EGDT within one hour of randomization or continue EGDT for 6 hours

Baseline Characteristics

From the EGDT group.

  • Demographics: Age 63 years, male 60%, home-dwelling 94%
  • Health data: Charlson comorbidity index score 1
  • Critical care data:
    • APACHE II score: 15
    • Ventilation: Invasive 9%, noninvasive 8%
    • Vasopressors: 22%
    • Fluids: Total volume 2515 mL, 34.6 mL/kg
  • Inclusion criteria:
    • Refractory hypotension: 70%
    • SBP: 79 mmHg
    • Lactate ≥4 mmol/L: 46% (when meeting criteria 7 mmol/L)
  • Time:
    • Until meeting inclusion criteria: 1.4 hours
    • Until randomization: 2.8 hours

Interventions

  • Randomized to in a 1:1 ratio (with stratification by site) to a group:
    • EGDT: A protocol modeling the Rivers trial. Details are in the supplementary appendix,[4] but in general it required placement of an arterial line and CVC for ScvO2 monitoring. Fluids, blood products, and/or dobutamine were administered following a standardized algorithm.
    • Usual care: Specific treatment decisions were made by the treating team and were not bound by a protocol. ScvO2 measurement wasn't allowed in the first 6 hours
  • Antibiotic therapy was left to the discretion of the treating team

Outcomes

Presented as EGDT vs. usual care.

Primary Outcome

All-cause mortality at 90 days
18.6% vs. 18.8% (RR 0.98; 95% CI 0.80-1.21; P=0.90)

Secondary Outcomes

Median duration of stay
ED: 1.4 vs. 2.0 hours (P<0.001)
ICU: 2.8 vs. 2.8 days (P=0.81)
Hospital: 8.2 vs. 8.5 days (P=0.89)
Organ support
Invasive ventilation: 30.0% vs. 31.5% (RR 0.95; 95% CI 0.82-1.11; P=0.52)
Duration: 62.2 vs. 65.5 hours (P=0.28)
Vasopressors: 76.3% vs. 65.8% (RR 1.16; P<0.001)
Duration: 29.4 vs. 34.2 (P=0.24)
RRT: 13.4% vs. 13.5% (RR 0.99; 95% CI 0.77-1.27; P=0.94)
Duration: 57.8 vs. 85.9 hours (P=0.40)

Additional Outcomes

All-cause mortality by day 28
14.8% vs. 15.9% (RR 0.93; 95% CI 0.73-1.17; P=0.53)
All-cause mortality in ICU
10.9% vs. 12.9% (RR 0.85; 95% CI 0.64-1.13; P=0.28)
All-cause mortality by day 60 in hospital
14.5% vs. 15.7% (RR 0.92; 95% CI 0.73-1.17; P=0.53)

Subgroup Analysis

There was no significant difference for the primary outcome by geographic region, age, APACHE II score, invasive ventilation, refractory hypotension, hypoperfusion, or IV fluid before randomization.

Adverse Events

Patients with ≥1 adverse event
7.1% vs. 5.3% (RR 1.34; 95% CI 0.91-1.98; P=0.15)
Arterial catheter-associated thrombus: 0 vs. 1 event
Bleeding or arterial puncture with ScvO2 or central line insertion: 10 vs. 1 events
Pneumothorax with ScvO2 or central line insertion: 3 vs. 0 events
Arrhythmia: 34 vs. 41 events
Acute pulmonary edema: 14 vs. 6 events
MI: 0 vs. 0 events
pRBC transfusion reaction: 1 vs. 0 events
Serious adverse events up to day 90 except deaths
4 vs. 15 events

Criticisms

  • Not blinded
  • Patients were not as ill as other large sepsis trials
  • Underpowered given lower than anticipated mortality
  • Those assigned to the usual-care group may have received some of the same therapies derived from the EGDT protocol

Funding

  • National Health and Medical Research Council of Australia
  • The Alfred Foundation

Further Reading

  1. Survivingsepsis.org. "About the Surviving Sepsis Campaign." Accessed 2014-03-19.
  2. Mouncey PR, et al. "Trial of early, goal-directed resuscitation for septic shock." The New England Journal of Medicine. 2015; Published online 2015-03-17. Accessed 2015-03-18.
  3. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  4. ARISE Supplementary appendix.