Sepsis Management: I Still Haven’t Found What I’m Looking For


sepsis1The word “sepsis” comes from ancient Greek and means decay, no doubt describing the rotting flesh of those afflicted with this condition. Descriptions of septic manifestations have been described as early as Hippocratic times. In our time it remains an epidemiologically important condition, affecting approximately 300,000 people annually in the U.S. In spite of advances in diagnosis and management in the last decade, its mortality rate is still as high as 30%.

Anecdotally, sepsis management used to involve putting a patient in septic shock on dopamine drip, leave him in a corner of a busy emergency room and essentially forget about him and leave him to his own devices. Recognition of a septic patient was not prompt and even when diagnosis was made; treatment plans were inadequate at best. Then in 2001, a game-changer came in the form of the Manny Rivers’ Early Goal Directed Therapy (EGDT) in Severe Sepsis and Septic Shock Trial, commonly known as the Rivers’ trial.

In the EGDT trial, Dr. Rivers protocolized an aggressive recognition and treatment algorithm to resuscitate those found to be in severe sepsis or septic shock. In the randomized control trial, the treatment arm (those who were treated following the EGDT protocol) achieved an astounding level of mortality benefit that to this day has not been reproduced. Despite the lack of reproducibility, the EGDT protocol became the cornerstone of sepsis resuscitation and is the backbone of the Surviving Sepsis Campaign 6-hour bundle. Early screening for sepsis, source control, early antibiotic usage and aggressive fluid infusion became widely implemented.


Dr. Emanuel Rivers who proposed Early Goal Directed Therapy (EGDT) in Severe Sepsis and Septic Shock Trial.

In spite of the popularity of the EGDT protocol, EGDT is not without its critics. One prominent voice of dissent comes from Dr. Paul Marik, who published paper after paper criticizing EGDT’s various components, most notably, the external validity of this single center study with a unique population, the use of invasive monitoring to guide resuscitation and aggressive fluid resuscitation. As Manny Rivers’ EGDT protocol became widely standardized in institutions worldwide, it became apparent that compliance to place invasive monitoring for every septic patient in the EDis difficult due to the high patient volume and lack of providers. Likewise, evidence against various components of EGDT such as usage of central venous oxygen saturation, central venous pressure to gauge fluid status started to become overwhelming.

Though the core of EGDT, which are early recognition and aggressive treatment, stands the test of time, other components are starting to erode in the face of mounting newer evidence. The Emergency Medicine Shock Research Network (EMShockNet) Investigators trial on lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy demonstrated that lactate clearance as a resuscitation goal is non-inferior to that of central venous oxygen saturation.At the same time, Marik and Cavallazzi’s2011 meta-analysis debunked the myth of central venous pressure measuring fluid responsiveness.Both studies brought doubt in the necessity of invasive monitoring. What once seemed like the gold standard for sepsis management is no longer the unquestionable truth.

Three large multi-centers randomized controlled trials, ProCESS, ARISE and PROMISE set out to answer the question whether EGDT really is better than traditional care, where resuscitation is guided by provider’s judgment. When ProCESS trial findings was published earlier this year, the naysayers of EGDT rejoiced in unison since the EGDT group did no better than the standard care group who didn’t receive any fancy monitoring or get a ton of fluids. Surviving Sepsis Campaign stood firm against calls for change to current recommendations, citing the need for more evidence.

Less than a year after the publishing of ProCESS trial, ARISE study findings was published, further supporting that standard care group without invasive monitoring such as central venous catheter or arterial catheter did not have higher mortality than the EGDT group. Both ProCESS and ARISE were methodologically superior to Rivers’ original EGDT trial and this time, Surviving Sepsis Campaign released a statement acknowledging that current best evidence does not support the routine usage of central venous oxygen saturation or central venous pressure, thus negating the necessity of mandatory usage of invasive monitoring.

sepsis2Current recommendation will be reviewed by Surviving Sepsis Campaign and I strongly believe that PROMISE trial will confirm the findings from the ProCESS and ARISE trials and that eventually, Surviving Sepsis Campaign will no longer recommend the routine use of central venous lines for resuscitation endpoint monitoring. Is this the end of EGDT? This is very hard to say since at the core of EGDT lays the need for early recognition of sepsis and I think in the end, this is what saves lives. The STOP sepsis collaborative (, early results seem to support this concept. It is noteworthy to consider that the ProCESS trial and ARISE trials do not answer to the lingering question regarding the best amount of intravenous fluid or what type of fluid to give. These debates will continue in the future and I look forward to read the results. Ultimately, the Rivers trial’s greatest legacy may be to remove sepsis from our peripheries and place it front and center.

As medical professionals, it’s important to recognize that evidence is fluid and ever changing. One has to be vigilant in obtaining the latest evidence in order to provide optimal care to the patient. It has been estimated that it takes 17 years for research evidence to be translated into practice and this is a disservice to patients. We can shorten the research translation gap through journal clubs and research councils. An innovative approach is to take advantage of social media. Emergency medicine and critical care medicine community are on the forefront of this movement. On the “twitter-verse”, #FOAMed stands for “Free Open Access Medicine education” and it’s a forum for experienced practitioners to share latest evidence and invite instant peer-review. All these innovations in my opinion will likely lead to improved sepsis care.


The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-Directed Resuscitation for Patients with Early Septic Shock. N Engl J Med. 2014 Oct 1. [Epub ahead of print]

Balas E, Boren S. Managing clinical knowledge for health care improvement. In: Bemmel J, McCray AT (eds). Section 1: health and clinical management. In Yearbook of Medical Informatics: Patient Centered Systems. Stuttgart, Germany: SchattauerVerlagsgesellschaft; 2000:65-70.

Carlbom DJ, Rubenfeld GD. Barriers to implementing protocol-based sepsis resuscitation in the emergency department–results of a national survey. Crit Care Med. 2007 Nov;35(11):2525-32.

De Backer D, Aldecoa C, Njimi H, Vincent JL. Dopamine versus norepinephrine in the  treatment of septic shock: a meta-analysis*.Crit Care Med. 2012 Mar;40(3):725-30

Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb 24;303(8):739-46. PubMed PMID: 20179283; PubMed Central PMCID: PMC2918907.

Jones AE, Puskarich MA. The Surviving Sepsis Campaign guidelines 2012: update for emergency physicians. Ann Emerg Med. 2014 Jan;63(1):35-47. doi: 10.1016/j.annemergmed.2013.08.004. Epub 2013 Sep 23.

Kumar A, Roberts D, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006 Jun;34(6):1589-96.

Marik PE1, Cavallazzi R. Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense. Crit Care Med. 2013 Jul;41(7):1774-81. doi: 10.1097/CCM.0b013e31828a25fd.

Marik PE. Early management of severe sepsis: concepts and controversies. Chest. 2014 Jun;145(6):1407-18. doi: 10.1378/chest.13-2104.

MarikPE.Surviving sepsis: going beyond the guidelines. Ann Intensive Care. 2011 Jun 7;1(1):17. doi: 10.1186/2110-5820-1-17.

ProCESS Investigators, A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18.

Rivers, E, Nguyen, B, et al. (for the 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; 345(19):1368-77


 Leon Chen, MSc, AGACNP-BC, CCRN, CPENLeon Chen

Leon Chen is Critical Care Medicine Nurse Practitioner of the Department of Anesthesiology and Critical Care Medicine at Memorial Sloan Kettering Cancer Center. He also serves as Adjunct Clinical Faculty for NYU College of Nursing and is a graduate of NYUCN’s bachelors and masters programs.

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