Sepsis: EGDT Continues to Deliver

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altLast month, Dr. Kevin Klauer suggested that emergency physicians “unbundle the sepsis bundle.”
This month, Dr. Emanuel Rivers offers his rebuttal, explaining why EGDT greatly improves sepsis outcomes.

Last month, Dr. Kevin Klauer suggested that emergency physicians “unbundle the sepsis bundle.”

This month, Dr. Emanuel Rivers offers his rebuttal, explaining why EGDT greatly improves sepsis outcomes.

The concept and components of early goal directed therapy (EGDT) for sepsis management has been part of the emergency medicine (EM) literature for over 40 years.1-3 Eleven years after the original publication of EGDT, the literature reflects the opposite position to that of Dr. Klauer, as put forth in last month’s Op/Ed. EGDT has been validated and proven effective in over 54 publications comprising over 23,000 patients (shown in the table at right).4 Because of these robust finding, the emergency department (ED) has had the most influential impact on sepsis outcomes in the last decade.5 EGDT remains one of the most important components of the Surviving Sepsis Campaign (SSC) recommendations.6 EGDT has not “failed to deliver,” as Dr. Klauer suggests.

In addition, large health care organizations such as Kaiser Health Care, Catholic Health Care West, Catholic Health Partners, HCA Healthcare have adopted EGDT. It has received the Joint Commission on Accreditation of Healthcare Organizations national quality award two years in a row and the results are not only improved outcomes but decreased hospital costs.7,8 This does not represent “premature” and “ill advised” treatment, as described by Dr. Klauer.

The conduction and results of the EGDT study are impeccable. After a decade of multiple confirmatory studies (single and multi-center), regurgitating inaccuracies to cast doubt on the EGDT study using a newspaper (which is under international investigation) is inappropriate. Furthermore, unilaterally relying on a source which did not publish a reply from the leadership of Henry Ford Health Systems is unacceptable. The EGDT study received no financial support from industry or extra-mural sources. This reply has been publically available on the Henry Ford Hospital Web site since 2008;
The sepsis bundle is not a “mixed bag of tricks that lacks focus,” as described by Dr. Klauer. Each of the EGDT components have been validated and the concept remains a strong level 1 recommendation from the SSC (68 international experts representing 29 international organizations).


In addition to hemodynamic monitoring, the CVP catheter provides an avenue for vasopressor administration which is contraindicated through peripheral veins. The study Dr. Klauer referenced was a retrospective ICU based study examining the outcome benefit of vasopressin in patients in shock for over 12 hours duration and after volume resuscitation.10,11,12 This was not an early resuscitation study which prospectively evaluated the merits of CVP.

CVP is a pressure and must be interpreted in the context of other surrogate measures of flow such as ScvO2. CVP measurement is indicative of fluid responsiveness in the lower ranges.13,14 In higher ranges, CVP is taken in the context of ScvO2, a high value with a low ScvO2 indicates myocardial suppression, necessitating inotropic therapy. CVP as part of EGDT has been shown to have a significant association with 30-day mortality.15 Early, aggressive fluid therapy which is associated with improved outcomes must be distinguished from late aggressive fluid therapy.16 The administered volume in the EGDT group within the first 6 hours was significantly greater compared to standard therapy group, but over 72 hours there were no differences in the amount of fluid between the two groups. Paradoxically, this is associated with decreased mechanical ventilation, vasopressor and corticosteroid therapy.3,17-20 Thus, CVP is not the problem; it is the clinician’s interpretation as with any hemodynamic variable.

Multiple studies, including a meta-analysis, show that an ScvO2 >70% is independently and significantly associated with mortality reduction in the first 6 hours.21-25 ScvO2 significantly predicts outcome 47 hours after the onset of acute lung injury and up to 48 hours in the ICU phase of sepsis.15,26 One of the reasons why a high ScvO2 is seen is because emergency intubation and mechanical ventilation has a strong effect on ScvO2. In a prospective multicenter observational study, ScvO2 increased from 61.8 +/- 12.6% to 68.9 +/- 12.2%. ScvO2 increases significantly in response to emergency intubation in the majority of septic patients.27

Vallet et al. found that mortality is optimized when an ScvO2 of 69.5% is used as a trigger for red blood cell (RBC) transfusion.28 RBC transfusion does not negatively alter the sublingual microcirculation in patients with altered capillary perfusion at baseline.29 Furthermore, there are no clinically significant adverse effects on global indexes of tissue oxygenation30, mortality rates in sepsis31 and acute lung injury.32

Recognition of myocardial dysfunction (low cardiac index) requiring inotropic (dobutamine) occurs in 12-15% of patients.33 A low ScvO2 is highly predictive of a low cardiac index26 and is independently associated with decreased risk of mortality.34 Patients with systolic dysfunction have a mortality rate of 36.3% without and 16.67% with EGDT.35 Patients who benefit from receiving RBC or dobutamine are patients with elevated lactate concentrations.36

Nguyen et al. found that the clearance of lactate over the first 6 hours after presentation was associated with significant decreases in sepsis biomarkers, organ function and mortality.37,38,42,43 Taking a page from these findings, Jones et al. declared that lactate clearance of at least 10% is equivalent to ScvO2 using the EGDT algorithm in a noninferiority study.39 This was concluded in spite of the low number of interventions (only 10% of the patient population), lower illness severity and lack of cardiopulmonary events compared to the original study. Using the same data set by Boyd quoted above, normal lactate levels were present in patients with high mortality, questioning the value of lactate clearance advocated by Dr. Klauer.40 Twenty to 50% of septic shock patients will never elevate lactate levels at presentation or during the clinical course, frequently develop multi-system organ failure and death.24,40-43 Thus lactate clearance, while helpful, is of limited clinical utility when used alone. ScvO2 and lactate are complimentary endpoints and not mutually exclusive.

Dr. Klauer asks: “For sepsis, does the evidence support the increased time it takes, the additional cost and the associated risk to the patient?” The mortality risk for a patient that qualifies for EGDT is from 30 to 47%.5 The urgency comes from understanding the illness severity, short-long term consequences of inaction and accountability (i.e. acute myocardial infarction (AMI), trauma, stroke or cardiac arrest). The components of EGDT are supported by evidence and it is not a menu. Do you pick and choose which parts of the recommended therapy for AMI, trauma, stroke or cardiac arrest?

After the EGDT publication, a 10-12% drop in mortality has been seen nationally over the last decade.44 Sepsis is the most expensive diagnosis being treated in hospitals in the U.S., consuming over $54 billion per year. Compliance to EGDT results in a 20% reduction in hospital-related
costs and decreases hospital length of stay by 4-5 days.45,46 As the most expensive and lethal cause of hospitalization in the last 10 years, severe sepsis and septic shock is an EM disease. Our specialty is one that responds to crisis as well as change. Our patients expect and deserve nothing less.

Emanuel P. Rivers, MD, MPH, is the vice chairman and research director, department of emergency medicine at Henry Ford Hospital. Dr. Rivers is also a clinical professor at Wayne State University         


1.    Weil MH, Shubin H. Treatment of shock caused by bacterial infections. Calif Med 1973;119:7-13.
2.    Wilson RF, Wilson JA, Gibson D, Sibbald WJ. Shock in the emergency department. Jacep 1976;5:678-90.
3.    Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Task Force of the American College of Critical Care Medicine, Society of Critical Care Medicine. Crit Care Med 1999;27:639-60.
4.    Rivers EP, Katranji M, Jaehne KA, et al. Early Interventions in Severe Sepsis and Septic Shock: A Review of the Evidence One Decade Later. Minerva Anestesiol 2012.
5.    Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Critical Care Medicine 2010;38:367-74.
6.    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;345:1368-77.
7.    Zubrow MT, Sweeney TA, Fulda GJ, et al. Improving care of the sepsis patient. Jt Comm J Qual Patient Saf 2008;34:187-91.
8.    Focht A, Jones AE, Lowe TJ. Early goal-directed therapy: improving mortality and morbidity of sepsis in the emergency department. Jt Comm J Qual Patient Saf 2009;35:186-91.
9.    Marik PE, Varon J. Goal-directed therapy for severe sepsis. N Engl J Med 2002;346:1025-6; author reply -6.
10.    Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354:2564-75.
11.    Ferrer R, Artigas A, Suarez D, et al. Effectiveness of Treatments for Severe Sepsis: A Prospective Multicenter Observational Study. Am J Respir Crit Care Med 2009.
12.    Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 2011;39:259-65.
13.    Magder S, Bafaqeeh F. The clinical role of central venous pressure measurements. J Intensive Care Med 2007;22:44-51.
14.    Magder S. Invasive intravascular hemodynamic monitoring: technical issues. Crit Care Clin 2007;23:401-14.
15.    Varpula M, Tallgren M, Saukkonen K, Voipio-Pulkki LM, Pettila V. Hemodynamic variables related to outcome in septic shock. Intensive Care Med 2005;31:1066-71.
16.    Murphy CV, Schramm GE, Doherty JA, et al. The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock. Chest 2009.
17.    Kampmeier TG, Rehberg S, Westphal M, Lange M. Vasopressin in sepsis and septic shock. Minerva Anestesiol 2010;76:844-50.
18.    Levy MM, Macias WL, Vincent JL, et al. Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med 2005;33:2194-201.
19.    Cohen R. Use of corticosteroids in septic shock. Minerva Anestesiol 2011;77:190-5.
20.    Micek ST, Roubinian N, Heuring T, et al. Before-after study of a standardized hospital order set for the management of septic shock. Crit Care Med 2006;34:2707-13.
21.    Pope JV, Jones AE, Gaieski DF, Arnold RC, Trzeciak S, Shapiro NI. Multicenter study of central venous oxygen saturation (ScvO(2)) as a predictor of mortality in patients with sepsis. Ann Emerg Med 2010;55:40-6 e1.
22.    Castellanos-Ortega A, Suberviola B, Garcia-Astudillo LA, et al. Impact of the surviving sepsis campaign protocols on hospital length of stay and mortality in septic shock patients: Results of a 3-year follow-up quasi-experimental study. Crit Care Med 2010.
23.    Jeong SJ, Song YG, Kim CO, et al. Measurement of Plasma sTREM-1 in Patients with Severe Sepsis Receiving Early Goal-Directed Therapy and Evaluation of Its Usefulness. Shock 2012.
24.    Cannon CM, for the Multicenter Severe S, Septic Shock Collaborative G. The GENESIS Project (GENeralization of Early Sepsis InterventionS): A Multicenter Quality Improvement Collaborative. Acad Emerg Med 2010;17:1258.
25.    Chamberlain DJ, Willis EM, Bersten AB. The severe sepsis bundles as processes of care: A meta-analysis. Aust Crit Care 2011.
26.    Grissom CK, Morris AH, Lanken PN, et al. Association of physical examination with pulmonary artery catheter parameters in acute lung injury. Crit Care Med 2009;37:2720-6.
27.    Hernandez G, Pena H, Cornejo R, et al. Impact of emergency intubation on central venous oxygen saturation in critically ill patients: a multicenter observational study. Crit Care 2009;13:R63.
28.    Vallet B, Robin E, Lebuffe G. Venous oxygen saturation as a physiologic transfusion trigger. Crit Care 2010;14:213.
29.    Sakr Y, Chierego M, Piagnerelli M, et al. Microvascular response to red blood cell transfusion in patients with severe sepsis*. Crit Care Med 2007.
30.    Walsh TS, McArdle F, McLellan SA, et al. Does the storage time of transfused red blood cells influence regional or global indexes of tissue oxygenation in anemic critically ill patients? Crit Care Med 2004;32:364-71.
31.    Vincent JL, Sakr Y, Sprung C, Harboe S, Damas P. Are blood transfusions associated with greater mortality rates? Results of the Sepsis Occurrence in Acutely Ill Patients study. Anesthesiology 2008;108:31-9.
32.    Engoren M. The Effect of Red Blood Cell Transfusion on 90-day Mortality in Patients With Acute Lung Injury. J Intensive Care Med 2012;27:112-8.
33.    Parrillo JE. Cardiovascular dysfunction in septic shock: new insights into a deadly disease. Int J Cardiol 1985;7:314-21.
34.    Afessa B. Elements of the sepsis resuscitation bundle not equally associated with reduced mortality. 2011.
35.    Shah S, Ouellette DR. Early goal-directed therapy for sepsis in patients with preexisting left ventricular dysfunction: a retrospective comparison of outcomes based upon protocol adherence. Chest 2010;138:897A.
36.    Gilbert EM, Haupt MT, Mandanas RY, Huaringa AJ, Carlson RW. The effect of fluid loading, blood transfusion, and catecholamine infusion on oxygen delivery and consumption in patients with sepsis. Am Rev Respir Dis 1986;134:873-8.
37.    Falk JL, Rackow EC, Leavy J, Astiz ME, Weil MH. Delayed lactate clearance in patients surviving circulatory shock. Acute care 1985;11:212-5.
38.    Nguyen HB, Kuan WS, Batech M, et al. Outcome effectiveness of the severe sepsis resuscitation bundle with addition of lactate clearance as a bundle item: a multi-national evaluation. Crit Care 2011;15:R229.
39.    Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. Jama 2010;303:739-46.
40.    Wacharasint P, Nakada TA, Boyd JH, Russell JA, Walley KR. Normal-Range Blood Lactate Concentration in Septic Shock is Prognostic and Predictive. Shock 2012.
41.    Dugas D, Mackenhauer J, Joyce N, Donnino M. Prevalence and characteristics of non-lactate and lactate expressors in septic shock. Crit Care Med 2009;37:A227.
42.    Na S, Joshi M, Li C-h, et al. Implementation of a 6-hour severe sepsis bundle in multiple asian countries is associated with decrease mortality. Chest 2009;136:20S-e-.
43.    Levraut J, Ciebiera JP, Chave S, et al. Mild hyperlactatemia in stable septic patients is due to impaired lactate clearance rather than overproducti
on. Am J Respir Crit Care Med 1998;157:1021-6.
44.    Kumar G, Kumar N, Taneja A, et al. Nationwide trends of severe sepsis in the 21st century (2000-2007). Chest 2011;140:1223-31.
45.    Shorr AF, Micek ST, Jackson WL, Jr., Kollef MH. Economic implications of an evidence-based sepsis protocol: can we improve outcomes and lower costs? Crit Care Med 2007;35:1257-62.
46.    Talmor D, Greenberg D, Howell MD, Lisbon A, Novack V, Shapiro N. The costs and cost-effectiveness of an integrated sepsis treatment protocol. Crit Care Med 2008;36:1168-74.


1 Comment

  1. Thank you to Dr. Rivers for an enlightening and well referenced response to Dr. Klauer’s essay questioning the evidentiary basis for EGDT. Also, thank you to EP Monthly for publishing both sides of this debate. Acute time-dependent threats to health and well-being like sepsis, stroke, myocardial infarction, and trauma are the reason that emergency medicine exists, in my opinion. All of these acute emergencies require prompt and accurate diagnostics and in today’s increasingly crowded, EMR-documentation driven ED fishbowl, finding the needle in the haystack (well appearing, but sick patient) can be a tremendous challenge. See this story in today’s NY Times:

    I would like to see a diagnostic systematic review to understand the body of evidence for accuracy of history, physical exam, and bedside tests to diagnose sepsis. A contribution to the Academic Emergency Medicine Evidence Based Diagnostics series would be the ideal destination for this manuscript. Personally, I believe that EGDT works, but we need to focus EGDT resources towards the appropriate denominator which means understanding how well we (EM) can or cannot diagnose sepsis at the bedside.

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