Title: “The 52 in 52 Review: Early goal-directed therapy in the treatment of severe sepsis and septic shock”

Article Citation: Rivers E, Nguyen B, Havstad S, Ressler J, et al; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. PMID: 11794169.

What we already know about the topic: In patients with sepsis or septic shock, inflammatory changes causes circulatory abnormalities such as intravascular volume depletion, peripheral vasodilatation, myocardial depression, and increased metabolism which can then lead to an imbalance between systemic oxygen delivery and oxygen demand, resulting in global tissue hypoxia. Goal-directed therapy,  involving targeted adjustments of preload, afterload, and contractility to balance oxygen delivery with oxygen demand has been used for severe sepsis and septic shock in the ICU setting.

Why this study is important: In this study, the authors evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit, as defined by intensive monitoring of specific circulatory parameters with the aggressive management of 5 key parameters to specified targets to optimize oxygen delivery to tissues. This was one of the first studies to look at the effects of starting aggressive protocolized care early on in the ED treatment of septic patients.

Brief overview of the study: The Rivers trial randomized 263 patients with severe sepsis or septic shock at a single urban Detroit ED to a protocol of early goal-directed therapy (EGDT) vs. standard therapy. In the EGDT arm, patients received an arterial line and a central line with continuous central venous oxygen saturation (ScvO2) monitoring. The EGDT group consisted of several sequential goals in the ER prior to ICU admission: CVP 8-12mmHg, achieved with fluid boluses, MAP >65mmHg, achieved with vasopressors if necessary, ScvO2 >70%, achieved with packed RBC transfusions and dobutamine if necessary, and UOP >0.5mL/kg/hr. The study found thatthe EGDT arm had a 16% absolute risk reduction in mortality.

Limitations: There are several limitations in the Rivers trial, which subsequent studies such as ProCESS tried to address. First, ED staff taking care of patients could not be blinded due to the nature of the intervention. Secondly, the study has been criticized for a “Rivers effect” — that is, having a dedicated critical care trained doctor taking care of patients in the intervention arm. Based on the trial, it’s also difficult to determine what decreased mortality in patients and whether it was the entire EGDT protocol or a component. Finally, patients who received EGDT all received additional fluid (4.9 L vs. 3.5 L (P<0.001)) and additional blood product (0-6 hours: 64.1% vs. 18.5% (P<0.001)) compared to those in the standard treatment arm, which in the critically ill could be harmful due to fluid overload.

Take home points: While the Rivers trial was groundbreaking in that it demonstrated adopting early goal directed care prior to the ICU decreased mortality in septic patients, the study had several limitations. Subsequent multi-center trials such as ProCESS, ProMISe and ARISE demonstrated that in patients who are recognized early on as having sepsis and treated with intravenous fluids and antibiotics, there was no significant benefit in EGDT.