Date:  October 22nd, 2014 

Reference: Goal-Directed Resuscitation for Patients with Early Septic Shock. The ARISE Trial. NEJM Oct 2014

Guest Skeptic: Dr. Suneel Upadhye. Associate Clinical Professor of Emergency Medicine, McMaster University.  Associate Member Department of Clinical Epidemiology and Biostatistics. Chair Canadian Association of Emergency Physicians Standards Committee. Sepsis Researcher.

Case: 62-year-old man sent from a nursing home with a three day history of a productive cough, intermittent fevers and today is a bit confused.  The transfer notes include a history of congestive heart failure, COPD, gout, hypertension, type-2 diabetes, and mild dementia.  His vital signs are as follows: Temp 39.1C, heart rate 103, blood pressure 115/100, respiratory rate 26, Oxygen saturation Sat 92% and a normal blood sugar.

Questions: Does an ED patient with septic shock need aggressive EGDT or “usual” resuscitation?

Background: Suneel’s Five Key Points of Sepsis Carefive+fingers

  1. Recognize sepsis early
  2. Broad spectrum antibiotics
  3. Fluid resuscitation
  4. Lactate levels
  5. Transfer to appropriate care

Reference: Goal-Directed Resuscitation for Patients with Early Septic Shock. The ARISE Trial. NEJM Oct 2014

  • Population: Adults >18yo presenting to emergency department within 6hrs with suspected/confirmed infection, 2+ SIRS criteria, and evidence of refractory hypotension (sBP<90 or MAP<65 after IVF >1000ml within 1st hour) or hypoperfusion (lactate >4).
    • Exclusions: Age <18-years-old, contraindications to central venous catheter/blood products, imminent/inevitable death, underlying disease with <90 day life expectancy, inpt transfer from another facility, confirmed/suspected pregnancy, unable to randomize or start EGDT within 6-hours of ED arrival.
  • Intervention: Full EGDT provided by a trained study team using a standardized EGDT delivery protocol
  • Control:Usual” care as per physician discretion. Use of SCVO2 NOT allowed. All patients mandated for IV antibiotics prior to randomization.
  • Outcome:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary/Tertiary Outcomes: 90 day survival time, ICU mortality, 28d mortality, in-hospital 60d mortality, cause-specific 90d mortality, length of stay in ED/ICU/hospital, use of critical interventions (mech ventilation, vasopressor support, renal dialysis), discharge destination of survivors, adverse events. A priori subgroup analyses for demographics, APACHE scores, mech ventilation, refractory hypotension, lactate level, and IV fluid resuscitation volume (<20cc/kg vs >20cc/kg).

Authors’ Conclusions: “In critically ill patients presenting to the emergency department with early septic shock, EGDT did no reduce all-cause mortality at 90 days.”

Quality Check List for Randomized Control Trials:


  1. The study population included or focused on those in the Emergency Department. Yes All patients were recruited from the ED Yes. All patients were recruited from the emergency department.
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Yes
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results: All groups were well balanced and similar. In this case the demographic and clinical characteristics nearly identical in both cohorts (EGDT n=796, usual care n=804).

  • No Significant Differences:
    • IV fluid volumes given in both arms (avg 2.5L)
    • Randomization times (avg. 2.7hrs after ED arrival),
    • Mean time to antibiotics (avg 70min; lungs & urinary most common sites of origin)
    • Positive blood culture rates (38% both groups).
  • Significant Differences:
    • More ICU admissions in EGDT group (87%) vs. usual care (76.9%),
    • More fluid given in first 6-hours in EGDT arm (diff approx 250cc),
    • Vasopressors 66.6% EGDT vs. usual care (57.8%),
    • Blood transfusion (13.6% EGDT vs. 7.0% usual),
    • Dobutamine (15.4% vs. 2.6%),
    • Higher MAP (76.5 EGDT vs. 75.3 usual).

No significant difference in all cause mortality at 90 days.

  • Primary Outcome: 90 day all-cause mortality
    • EGDT 18.6% vs. usual 18.8%
  • Secondary and Tertiary Outcomes:
    • ED length of stay shorter in EGDT (1.4hrs) vs. usual care (2.0hrs)
    • Vasopressor use EGDT (76.3%) vs. usual (65.8%),
    • No difference mean vasopressor infusion times.
    • No other significant differences in secondary or tertiary outcomes.
    • No difference in adverse event rates (7.1% EGDT vs. 5.3% usual).

Screen Shot 2015-04-25 at 3.11.12 PM

This was a very well done study with very good methods. They had good randomization, multi-center and multi country. They did intention to treat analysis. There was >99% follow for both groups. Planned safety analysis at 50% enrolment. This was reviewed by a independent data and safety monitoring committee.

Only obvious and unavoidable issue was they were unable to blind physicians and patients due to nature of interventions.  However, we feel that this would have favored EGDT and only strengthens the result accepting the null hypothesis of no superiority.

No clinically relevant differences in all primary, secondary or tertiary outcomes (although some are statistically different).

There have been some other great reviews of the ARISE trial:

Our Conclusions Compared to Authors’: This is the second large 2014 sepsis resuscitation trial (ProCESS spring 2014) suggesting that aggressive EGDT protocols are not necessary to increase survival in septic shock patients, compared to “usual” care involving early recognition, IV fluid resuscitation and empiric antibiotics treatment.

This information confirms (as did ProCESS 2014) what many clinicians without EGDT resources/capabilities have hoped for and believed, that invasive resuscitation is not needed beyond liberal IV crystalloid resuscitation (>30cc/kg), broad-spectrum antibiotics, and serial lactate monitoring.

SGEM Bottom Line: Invasive EGDT-based sepsis resuscitation is not required compared to early recognition and liberal IV fluid resuscitation and empiric antibiotics in the septic patients.

Case Resolution: Having recognized the sepsis potential of this patient and confirming a high lactate, you initiate broad spectrum antibiotics for what is most likely a clinical pneumonia. You give aggressive fluid resuscitation with IV normal saline or ringers lactate. Then call your consultant to arrange admission to the intensive care unit.

Dr. Suneel Upadhye

Dr. Suneel Upadhye

Clinical Application: Early recognition, liberal IV crystalloid resuscitation, empiric antibiotics (at least cover lung and GU tract) are key interventions for emergency department sepsis care.  This is ready for immediate use in the emergency department.

What Do I Tell My Patients? We are going to give you lots of IV fluids, broad spectrum antibiotics and admit you to the hospital.

Keener Kontest: Winner last week was Dr. Chris Belcher a PGY1 Emergency Medicine resident from Kentucky. He knew the oldest hospital north of the Mexican boarder is the Hotel Dieu Hospital in Quebec City founded in 1637.

Listen to the podcast to hear this weeks keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

Upcoming conferences: SkiBEEM 2015 is January 26th-28th in Beautiful Sun Peaks, BC.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.