Trial of Early, Goal-Directed Resuscitation for Septic Shock

Jane Oh, Mercer University College of Pharmacy 2015

Early, goal-directed therapy (EGDT) is a recommendation by the Surviving Sepsis Campaign (SSC) 2012 to resuscitate patients in early septic shock. In the event of persistent arterial hypotension despite volume resuscitation or blood lactate levels > 4 mmol/L, SSC recommends to maintain adequate central venous pressure.1

Two goals during these first six hours of EGDT are to maintain adequate central venous pressure (CVP) to carry out other hemodynamic adjustments, and to maximize mixed or central venous oxygen saturation (ScvO2). During the first six hours of resuscitation, the following goals are recommended by SCC as Grade 1C (“1”= strong evidence for care, “C”= well-done observational or cohort studies with controls): CVP 8-12 mmHg, Mean Arterial Pressure > 65 mmHg, urine output > 0.5mLŸkg-1Ÿhr-1, and central venous (superior vena cava) 70% or mixed venous oxygen saturation >65%.2 The SCC states that this recommendation was influenced largely from a randomized controlled study from Rivers, et al. which showed reduced hospital mortality and hospital stay.1

Title: Trial of Early, Goal-Directed Resuscitation for Septic Shock3
Design Parallel-group, intent-to-treat, randomized controlled trial, 56 hospitals in England; N= 1260
Objective

(Primary)

To test the hypothesis that the six-hour EGDT resuscitation protocol is superior, in terms of clinical and cost-effectiveness measures, to usual care in patients presenting with early septic shock to emergency departments
Study Groups EGDT (six hour resuscitation protocol, n= 630) or usual care (n= 630)
Methods After a 1:1 ratio of 24-hour telephone randomization, study patients initiated antibiotics before randomization. The usual-care group continued to receive monitoring, investigations, and treatment as determined by the treating clinicians. The EGDT group started the resuscitation protocol.
Duration February 16, 2011 to July 24, 2014
Primary outcome measure All-cause mortality at 90 days
Baseline Characteristics EGDT: age 66.4+ 14.6, male 57.0%, refractory hypotension 54.1%, hyperlactatemia 65.4%, blood lactate level 7.0+ 3.5, intravenous fluids administered before hospitalization until randomization 97.9%, supplemental oxygen 73.7%, site of infection: lungs 36.5%, abdomen 6.4%, blood 15.5%, central nervous system 1.9%, soft tissue 6.2%, urinary tract 17.3%, other 3.4%, no sepsis 0.6%, unknown 12.2%

Usual Care: age 64.3+ 15.5, male 58.6%, refractory hypotension 55.6%, hyperlactatemia 63.7%, blood lactate level 6.8+ 3.2, intravenous fluids administered before hospitalization until randomization 97.0%, supplemental oxygen 75.1%, site of infection: lungs 33.1%, abdomen 8.1%, blood 13.7%, central nervous system 1.4%, soft tissue 6.2%, urinary tract 18.7%, other 5.9%, no sepsis 0.5%, unknown 12.3%

Results Death at 90 days: 29.5% EGDT group versus 29.2% usual care group; relative risk in EGDT group, 1.01; 95% confidence interval (CI), 0.85 to 1.20; P= 0.90, for an absolute risk reduction in the EGDT group of -0.3%; 95% CI, -5.4 to 4.7
Adverse Events Common Adverse Effects: Not reported
Serious Adverse Events: EGDT 4.8%, usual-care group 4.2%, P= 0.58
Percentage that Discontinued due to Adverse Events: Not reported
Study Author Conclusions In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome.

This study challenges the EGDT protocol recommendation by SSC based on previous studies showing reduced hospital mortality and hospital stay. Not only did this study conclude that adhering to the strict EGDT protocol did not show a difference in all-cause mortality at 90 days, but also suggests that EDGT increased costs. The study reports a cost-effective probability as below 20% as part of their secondary outcomes.3

References:

  1. Dellinger RP, Levy MM, Rhodes A, et al. International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Surviving Sepsis Campaign. Critical Care Medicine. http://www.sccm.org/Documents/SSC-Guidelines.pdf. Accessed April 6, 2015.
  2. 6-hour bundle. Surviving Sepsis Campaign. http://www.survivingsepsis.org/SiteCollectionDocuments/Bundle-6Hour-Step2a-CVP.pdf. Accessed April 7, 2015.
  3. Mouncey PR, Osborn TM, Power GS, et al. Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med. 2015; 372(14): 1301-11. doi: 10.1056/NEJMoa1500896.
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