Years after its debut, studies continue to question the efficacy of EGDT
Two years ago I called into question the use of the sepsis bundle of therapies defined by the “Surviving Sepsis” campaign (EPM, March 2010) Although aggressively managing sepsis is a good thing, and the mere focus on the rapid identification and application of appropriate management strategies for sepsis is essential to good patient outcomes, it appears that EGDT and the research it was based on may have promised more than it could deliver.
As it is with many modalities that are rapidly and widely accepted based on a few sentinel studies, years later we often find that our early adoption was premature and ill advised. With all due respect to the authors of the study, I respectfully submit that the sepsis bundle described in EGDT fits squarely into that category.
Several years following its publication, even the non-clinical press was questioning whether undisclosed conflicts of interest, regarding the ownership of the central venous oxygen saturation catheter and financial transactions to providers from the company that produced it, raised fatal issues of bias with the baseline study (Wall Street Journal Digital Digest, August 14, 2008)
Irrespective of the potential bias, the study appears to have 25 “mystery patients.” The study reported results on 263 patients who were randomized to standard (133) treatment or EGDT (130). However, 288 patients were originally randomized. Twenty five of these patients were later excluded from the analysis. The rationale for removing them was that they were later determined not be in severe septic shock. Here is the problem. When statistical analysis is run on all 288 patients, the reported mortality rate reduction of 16% is reduced to something not statistically significant. However, it appears that a relatively high proportion of the 25 patients were patients either in the standard therapy group that survived or in the EGDT arm that died, thus distorting the results. So, if you add them back in, the mortality benefit reported by the original study is nullified.
Subsequent studies have questioned the efficacy of EGDT altogether. With respect to a modified early goal directed therapy protocol, Crowe concluded, “Although we found a trend toward decreased mortality in patients with septic shock treated with EGDT, with an absolute difference of 8.7%, this difference was not statistically significant. Compliance with individual elements of the protocol was variable.” (Am J Emerg Med. 2010 Jul;28(6):689-93.) Further, Paul Marik stated that “Current sepsis bundles may force physicians to provide unproven or even harmful care. As administered and studied to date, only antibiotics meet the stated criteria of proof for bundle inclusion.” (Ann Intensive Care. 2011; 1: 17.)
EGDT and the Surviving Sepsis campaign has undoubtedly raised awareness of sepsis, resulting in earlier detection and more effective management. However, what is the best approach to sepsis? It is my opinion that the sepsis bundle is a mixed bag of tricks that lacks focus and could subject patients to unnecessary risk. First, is every element of the bundle necessary? Maybe not. If you added two of your favorite foods to the bundle – say, ice cream and blueberries – the mortality benefit from EGDT would be the same. Does that mean that ice cream and blue berries are effective, much less necessary for the management of sepsis? In the same way, it may be appropriate to question some of the components of the EGDT bundle that may not contribute to any consistent patient benefit. Further research is needed to determine which therapies are necessary, which ones are not and which may pose unnecessary risk to the patient.
Second, and more specifically, does every patient with sepsis or systemic inflammatory response (SIRS) need a central line, central venous oxygen saturation determination, and/or blood transfusion? Maybe. Maybe not.
Time, cost and safety are all issues when it comes to starting central lines. For sepsis, does the evidence support the increased time it takes, the additional cost and the associated risk to the patient? For the sake of sepsis alone, when peripheral access is available, I don’t think their use is justified. Certainly, if there is poor or no peripheral access, the benefits likely outweigh the downsides. However, the two main reasons given in EGDT to gain central access in septic patients are to guide fluid management by measuring the central venous pressure and for the measurement of central venous oxygen saturations. Each sounds reasonable. However, so did sodium bicarb for metabolic acidosis, hyperventilation in head injured patients and the use of MAST trousers. In each of these cases, intuition, and even early research, proved incorrect.
Regarding the benefit from central access, Marik called into question physiologic assumptions which are the foundation of EGDT. (Marik, P.E., et al. Early Goal Directed Therapy: On Terminal Life Support? Am J Emerg Med 28(2):243, February 2010). In his article, Marik made several profound statements:
- Central venous pressures may not correlate well with intravascular volume
- Central venous oxygen saturations in sepsis are frequently normal or increased, not low
- There is no evidence that PRBCs actually increase central venous oxygen saturation
- There is no definitive evidence that dobutamine increases central venous oxygen saturation
Boyd questioned the relationship between CVP, fluid balance, and their association with 28 day mortality, concluding that CVP only correlated with actual fluid balance at 12 hours, but not at days 1 through 4. (Crit Care Med. 2011 Feb;39(2):259-65.) These researchers conclude that inserting a central line indiscriminately in all septic patients to guide fluid therapy by CVP measurement should at least be questioned, if not discontinued altogether.
What about central venous oxygen saturations? Although not definitive, Puskarich’s research raises some interesting questions about their importance, value and accuracy in predicting outcomes. (Acad Emerg Med. 2012 Mar;19(3):252-258.) He investigated 203 ED patients in septic shock, comparing ScVO2 > 70 and lactate clearance. The overall mortality rate in this group was 19.7%. Interestingly, if only the ScVO2 > 70 goal was met, the mortality rate was 41%. However, if only the lactate clearance goals were achieved, the mortality rate was 8%. But there was no correlation between achieving the ScVO2 goal and lactate clearance. If central venous oxygen saturation is a true marker for cellular oxygenation and if we are to believe that achieving 70 or greater is a marker for improvement, then why does it not correlate with lactate clearance?
If you are an EGDT skeptic like me, certain components of the bundle seem more likely than others to provide the majority of any benefit claimed by EGDT, and including those components in daily practice seems sound and just. Early sepsis recognition, aggressive fluid resuscitation, early broad spectrum antimicrobials, and perhaps, lactate clearance seem to make sense. These will likely, in my opinion, be the modified bundle of the future.
Although this article may not definitively answer the questions at hand and may raise more questions than provide solutions, the questions raised should be sufficient for us to stop the runaway train of EGDT and begin unbundling the bundle. More research is clearly needed. It is not necessary, in my opinion, to withdraw support from EGDT. Rather, we should be looking to examine the therapy, keep what is appropriate and discard the rest.
Kevin Klauer, DO, EJD Editor-in-chief of Emergency Physicians Monthly, CMO of Emergency Medicine Physicians, Vice Speaker of the ACEP Council.