Title: “The 52 in 52 Review: Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock”
Article Citation: Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. Emanuel Rivers, M.D., M.P.H., Bryant Nguyen, M.D., Suzanne Havstad, M.A., Julie Ressler, B.S., Alexandria Muzzin, B.S., Bernhard Knoblich, M.D., Edward Peterson, Ph.D., and Michael Tomlanovich, M.D., for the Early Goal-Directed Therapy Collaborative Group*
N Engl J Med 2001; 345:1368-1377. November 8, 2001. DOI: 10.1056/NEJMoa010307
What we already know about the topic: This is certainly taking a look back, but at the time, the incidence of sepsis had been increasing over several decades (likely secondary to better understanding of the disease process and diagnostic techniques) while outcomes were unchanged. Mortality from sepsis was still high despite a variety of interventions. There was also no uniform treatment protocol for sepsis. There was a general understanding, however, that global tissue hypoxia preceded multiorgan failure and death, and that the timing of administration of care seemed to play a role in mortality.
Why this study is important: This was the first major sepsis study that demonstrated substantial benefits to Early Goal Directed Therapy, and was essentially a paradigm shift in how ED physicians practiced when treating sepsis. Rivers demonstrated, fairly definitively, that the immediate administration of protocolized treatment that included aggressive fluids, pressors, blood transfusion, and antibiotics could be given during the “critical golden hours” where a septic patient would rapidly start to deteriorate and tissue hypoxia progressed to multiorgan failure.
Brief overview of the study: Rivers and colleagues performed a randomized controlled trial, which was performed at a single academic tertiary hospital in Detroit over the period of 3 years. 268 patients were randomized, with 236 eventually completing the study. Inclusion criteria were patients with severe sepsis or septic shock, ≥ 2 SIRS features, and either systolic BP of less than or equal to 90 after a 20-30 cc/kg infusion of crystalloid, or lactate greater or equal to 4mmol/L.
River’s protocol included crystalloid given every 30 minutes to maintain a CVP of 8-12 mm Hg, pressors to achieve a MAP above 65, blood transfusion to a hematocrit of 30% if the central venous O2 sat was less than 70%, as well as the infusion of Dobutamine if the central venous O2 sat was still below 70% after transfusion. Equally importantly, the patients’ “temperature, heart rate, urine output, blood pressure, and central venous pressure were measured continuously for the first 6 hours of treatment and assessed every 12 hours for 72 hours.” These markers, as we know, are incredibly important in our understanding of the clinical direction the patient is going, and how tailoring treatment to these markers is now standard of care.
The control group allowed physicians to choose their own treatment plan, as long as certain goals were set, which included a CVP between 8-12 mm Hg, MAP greater than or equal to 65%, and urine output greater than 0.5 ml/kg/hr. Consultation with an intensivist and transfer of care to the ICU as soon as possible was also a goal.
The results of the study are likely well known to readers. The primary outcome of the study, which was in-hospital mortality, was significantly decreased in the EGDT group compared to the control group (30.5% vs. 46.5%, P = 0.009), and equally importantly, the secondary outcome subgroups all favored EGDT, including the severity of sepsis as well as 28-day and 60-day mortality.
Limitations: While an incredible and landmark study, there were several limitations. First, this was a single center study, which always causes issues in knowing how reproducible this study is. Secondly, Dr. Rivers’ interventions were bundled, so it was, at the time, difficult to know if it was a specific component(s) of the bundle that improved mortality, the bundle in its entirety, or some combination of the bundle had synergistic properties to improve mortality. Finally, it is worth noting that the Rivers’ control group had a noticeably higher mortality rate than the national average mortality to septic patients, again causing concern about reproducibility and the fact that the study was performed in a single center.
The bottom line: This study re-shaped the landscape of sepsis and emergency medicine, standardized aspects of EM care across the entire country, and furthered our understanding of the pathophyisology and clinical course of this devastating disease process. Rivers is undoubtedly responsible for countless lives saved since this study emerged. While we may gripe about sepsis bundles from time to time, we should know that with early recognition, we have the power to change the course the patient takes during his or her hospital stay, and should strive to do so from the minute they hit the door.
