Early Goal Directed Therapy for Sepsis: No Longer?

In 2001, the Rivers trial showed that Early Goal Directed Therapy for septic shock resulted in a 16% absolute mortality risk reduction1. In the treatment arm of this trial, septic patients with a lactate above 4 mmol/L or systolic blood pressure less than 90 mmHg received a central line and protocolized management of central venous pressure and mixed venous oxygen saturation.  Two recent studies have challenged the necessity of central venous catheterization and advanced hemodynamic monitoring in septic shock.  In 2010, Jones et al. published a study in JAMA that showed no significant mortality difference in patients resuscitated with serial lactates and those resuscitated with mixed venous oxygen saturation2. The ProCESS trial, published last month in NEJM, showed no significant mortality difference in patients resuscitated using protocol based EGDT, protocol based standard care that did not require placement of a central venous catheter, and usual care3.  In the ProCESS trial, 56% of patients treated with protocol based standard care and 57% of patients treated with usual care received central line placement compared to 100% of patients in the protocol based EGDT arm.  Taken together, these two studies call into question the necessity of EGDT and placement of a central line for fluid refractory septic shock.


The results of these two trials are certainly noteworthy but should be interpreted narrowly.  In both studies, septic patients were rapidly identified using standard screening protocols.  Also, in both studies, there was strong adherence to the three-hour sepsis resuscitation bundle outlined by the Surviving Sepsis Campaign.  Rapid identification and treatment of septic patients with antibiotics and fluids when indicated is not being called into question.


Further, critics of the JAMA study point out that the number of patients randomized was significantly less than the number of patients studied and that a lactate clearance of less than 10% was used as the threshold to initiate therapy to improve oxygen delivery.  This means that if the initial lactate decreased from 10 mmol/L to 9 mmol/l additional resuscitative measures were not initiated.  Most clinicians would not be satisfied with this level of lactate clearance.


One of the most significant findings in the ProCESS study was that mortality in the usual care arm was 18%, significantly lower than septic shock mortality in 2001 when the Rivers study was conducted.  More than 70% of patients in the ProCESS study were involved in some type of sepsis protocol, a credit to the work of the Surviving Sepsis Campaign.  Also, while evidence for use of central venous catheters for hemodynamic monitoring is not as strong as it was 12 years ago, the sickest patients will still require central catheters for the infusion of high dose vasopressors to maintain MAP>65 which was supported in a companion paper to ProCESS.


Given the methodological challenges to the JAMA study and the exceedingly low mortality and high use of protocolized care in the proCESS study, more information is needed.  The ARISE and ProMISe trials are currently underway and will provide more insight into the utility of protocolized sepsis management.  Until then, the Surviving Sepsis Campaign recommends ongoing adherence to the three AND six hour resuscitation bundles with a reminder that protocolized care of severe sepsis and septic shock confers an absolute mortality reduction of 16-18%.


  1. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-137. Link.


  1. Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010: 303:739-746. Link.


  1. Yearly DM, Kellum JA, Juang DT, et al: A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014; DOI: 10.1056/NEJMoa1401602. Link.

Central Venous Catheter , Sepsis , Septic Shock , central line , Procedure blog of the week , HPC updates , central line placement

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Tags: Central Line; Central Venous Catheter; Septic Shock; Sepsis; Early Goal Directed Therapy; ProCESS, HPC updates

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