Guest Skeptics: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. CHF, COPD, gout, HTN, DM-II, 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 Care
Recognize sepsis early
Broad spectrum antibiotics
Transfer to appropriate care
Article 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).
EXCLUDED if <18yo, contraindications to central venous catheter/blood products, imminent/inevitable death, underlying disease with <90d life expectancy, inpt transfer from another facility, confirmed/suspected pregnancy, unable to randomize or start EGDT within 6hrs 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.
Primary = all-cause death at 90days.
Secondary/Tertiary = 90d 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).
Author’s 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:
The study population included or focused on those in the ED. Yes All patients were recruited from the ED Yes all patients were recruited from the emergency department.
The patients were adequately randomized. Yes
The randomization process was concealed. Yes
The patients were analyzed in the groups to which they were randomized. Yes
The study patients were recruited consecutively (i.e. no selection bias). Yes
The patients in both groups were similar with respect to prognostic factors. Yes
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. NO
All groups were treated equally except for the intervention. Yes
Follow-up was complete (i.e. at least 80% for both groups). Yes
All patient-important outcomes were considered. Yes
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).
More ICU admissions in EGDT group (87%) vs usual care (76.9%),
More fluid given in first 6hrs 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).
PRIMARY OUTCOME = NO SIGNIFICANT DIFFERENCE
90d all-cause mortality (EGDT 18.6% vs usual 18.8%), nor survival time
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).
Dr. Suneel Upadhye
Commentary: 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 Author’s: 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.
The 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.
Clinical Application: Early recognition, liberal IV crystalloid resuscitation, empiric antibiotics (at least cover lung and GU tract) are key interventions for ED sepsis care. This is ready for immediate use in the emergency department.
What do I tell 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.