1. Incorporate into practice the critical components of early goal directed treatment for sepsis.
2. Identify the areas of controversy surrounding EGDT and rationally apply the principles to clinical practice.
3. Improve awareness, regarding the recognition and aggressive management of sepsis to improve patient outcomes
Ten years after the study was completed, Early Goal Directed Therapy (EGDT) for the treatment of severe sepsis and septic shock continues to generate much controversy and debate. In spite of multiple publications supporting its findings, questions continue about its therapeutic endpoints, general applicability in “real world’ scenarios, and whether continued research comparing EGDT to a control group is unethical, among others.
Sepsis is common, lethal, and expensive. It is responsible for over 225,000 deaths per year and is the most expensive disease requiring hospitalization since 1997, accounting for over $50 billion per year in health care costs. This disease is highly relevant to emergency medicine as over 50% of these patients are admitted through the emergency department (ED). To answer the question of “Does EGDT work?” one needs to only look at the data to find socioeconomic benefits.
The original EGDT trial found a mortality reduction from 46.5% in the control group to 30.0% in the EGDT group. In 2006, analysis of available randomized and observational data from 12 other academic and community centers, totaling 1,298 patients, yielded similar results. Mortality was reduced from 44.8% in the control group to 24.5% in the EGDT group. Put another way, for every 5 patients treated with EGDT, one life was saved! This is a better number than aspirin + streptokinase for acute myocardial infarction 5-week mortality (NNT=19) or tPA for acute ischemic stroke within 4.5 hours (NNT=15). To date, there are at least 24 peer reviewed publications, totaling over 2,000 patients citing outcome benefit with EGDT, with mortality reductions ranging from 9% to 40%. Furthermore, there are at least 28 published abstracts, increasing the total to over 10,000 patients, with similar results.
Not only does EGDT provide mortality benefit it also decreases health care resource consumption. Examples include decrease in vasopressor use, hospital and intensive care unit length of stay, and mechanical ventilation days. In summary, data from over 10,000 patients shows that an early, upstream intervention (EGDT) provided in the ED has significant positive downstream benefits. With an average ED wait time of over 5 hours for an ICU bed, there are few options other than making this an ED intervention. This benefit has been shown not only in the academic setting, but in the community as well. In fact, this data includes over 1,100 patients in the community setting and it shows an average absolute mortality reduction of 20.9%.
In an era of increasing scrutiny with respect to health care dollars, a program such as EGDT should demonstrate fiscal justification. It has been shown in academic centers that EGDT provides a 23.4% reduction in hospital costs, a cost per life saved of $32,336, and a median reduction in hospital facility charges of 39.2%. Implementation of a sepsis protocol has been shown to decrease total costs ($16,103 vs. $21,985), showing that implementation of a sepsis protocol can save lives and “result in substantial savings in an otherwise very expensive condition”. In a before and after implementation study, EGDT decreased cost on average by $9,346.60 per patient, resulting in an average cost savings of $4 million every six months. Whether EGDT is provided by an ED based, mobile intensive care unit team, or ICU based approach, all have similar cost effectiveness ratios.
The concept of EGDT was provided in 1976 in the first emergency medicine journal. Building on these concepts, the original EGDT trial proved benefit of an aggressive and early goal-oriented approach to shock reversal. Unfortunately, EGDT remains controversial. Despite the data, current detractors to EGDT continue to question which parts of the protocol drive benefit. Why should we really care? In the early stages of shock, whether you resuscitate your patient to a preset oxygen delivery, central venous pressure, or central venous mixed oxygen saturation, it may not matter. It is likely that EGDT is greater as a whole than the sum of its parts and searching for the most effective component is missing the point: EGDT has been shown for almost a decade and in thousands of patients that it is beneficial. Detractors also state that the benefit of EGDT is that we are simply monitoring our patients better when instituting the protocol. No monitoring device in the history of medicine, unless linked with a therapy that improves outcome, has ever been shown to improve outcome. That is true for pulse oximetry all the way to pulmonary artery catheterization. Understanding these historical precedents, one can understand that it is not the monitoring, but EGDT, that is improving outcome.
The overwhelming majority of the data shows that EGDT works and shows how important a specialty response is to saving lives. Despite this, we may be losing the vision of responding to challenge as well as change. We follow stroke protocols, acute coronary syndrome protocols and trauma protocols routinely. And yet, a study originating from our own specialty with robust supportive evidence continues to be questioned. These questions are not supported by evidence. So if you want to save lives, save your institution money, and improve your department’s standing in the house of medicine, employing EGDT in the treatment of severe sepsis and septic shock will accomplish all of your goals!
Brian Fuller, MD, is an assistant professor of anesthesiology and emergency medicine at Washington University School of Medicine in St. Louis.
Emanuel Rivers, MD, MPH, IOM, is the vice chairman and research director at Henry Ford Hospital, and is a clinical professor at Wayne State University.
I am actually a fan of early goal-directed therapy for sepsis. For that matter, I think stroke centers do great work and do positively impact stroke management. However, tPA, given in 1% of all stroke victims, 13% of those eligible, has little to no impact on these improvements. When we focus on management of a disease process you know what happens? The care gets better. The same is true for early goal-directed therapy (EGDT) for sepsis.
When it comes down to EGDT, there are so many treatments included in the sepsis bundle, you can’t tell what’s really working. I really doubt that every component of EGDT is a value-added step. Hey, let’s add coconut cream pie or chocolate covered cherries to the bundle. The point is, by adding coconut cream pie or anything else to EGDT, the data would look just as good. The only difference is that the patients would get a tasty treat along with all of the other components of the bundle.
Coconut cream pie cannot positively our negatively influence outcomes in sepsis. My question is, “How many pieces of coconut cream pie are already being served in this expensive sepsis cocktail?”
My initial concern is that the inclusion criteria are way too broad. In order to classify someone as septic, they must have systemic inflammatory response syndrome (SIRS) and a source of infection. To diagnose SIRS, you need 2 or more of the following:
-A temperature over 38.3C or less than 36.0C
-A heart rate over 90
-A respiratory rate over 20
-A WBC count less than 4,000 or over 12,000
-Acutely alerted mental status
-Hyperglycemia in non-diabetic patients
How many SIRS patients really don’t deserve a central line and an ICU admission? Do we really intend for those with a fever, strep tonsillitis and dehydration, who have a heart rate over 90 and a temperature of 38.5 to get the kitchen sink thrown at them? This makes no sense.
Just like many seemingly good ideas in medicine, once the train leaves the station, it takes years to slow it down, validating efficacy. This is a classic example. One study and 263 patients later (Rivers, NEJM 2001) and we have doubts surfacing nearly ten years later.
Perhaps the most compelling article raising questions about the sepsis bundle is from a consensus panel of 55 international experts revisited the components of the sepsis bundle and reviewed the recommendations, assigning a grade of strong or weak and an associated level of evidence; A = High quality, B = Moderate quality, C = Low quality and D = Very low quality. Fifteen strong recommendations were assigned only a C or D. Several items, including recombinant activated protein C (Xigris) administration, at a cost of $14,000 for a 100kg patient, and stress dose steroid therapy were classified as weak, assigned B and C, respectively. Three items with a strong recommendation and a moderate quality of evidence were the administration of crystalloid fluid resuscitation, administration of broad-spectrum antimicrobials within one hour of diagnosis of septic shock and maintaining a target hemoglobin of 7 to 9g/dL in the context of sepsis. Despite the momentum behind EGDT within 6 hours, the level of evidence supporting this recommendation was “Low quality,” a level C.
So, what does the evidence actually say regarding tight glycemic control and steroids? Physiologic stress results in hyperglycemia and suppressed adrenal function with poor responses to corticotropin or ACTH stimulation testing. Are these markers for bad disease or opportunities for intervention? The data suggests they are only markers.
With respect to intensive insulin therapy, otherwise known as “tight glycemic control,” the preponderance of evidence shows two things: No difference in mortality, and a substantially higher rate of hypoglycemic events. Treggiari reported no difference in mortality for 10,456 ICU patients treated with tight control versus no protocol at all. They also noted 3 to 4 times more likelihood for moderate to severe hypoglycemia.
Consensus is that high dose steroids are harmful. Although there is some controversy regarding low-dose, physiologic corticosteroids, strong data reflects that they do not influence mortality rates in sepsis.
Finally, there is much focus on which vasopressor is best. Following aggressive volume resuscitation, vasopressors seem like a reasonable consideration. However, there is no definitive data proving this assumption. A recent Cochrane database review reported no conclusive evidence to support one vasopressor over another or that vasopressors impact mortality at all.
Early recognition of sepsis, aggressive volume resuscitation to maintain perfusion and early broad-spectrum antibiotics are clearly interventions that positively influence mortality. The remaining components may only be stealing the credit for their success without contributing any additional positive benefit themselves.
Kevin Klauer, DO, is the Editor-in-Chief of Emergency Physicians Monthly and the Chief Medical Officer at Emergency Medicine Physicians.
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1. Maryn McKenna, Controversy Swirls Around Early Goal-Directed Therapy in Sepsis: Pioneer Defends Ground-Breaking Approach to Deadly Disease. Annals of Emergency Medicine - December 2008 (Vol. 52, Issue 6, Pages 651-654
3. Treggiari, M.M., et al., Intensive insulin therapy and mortality in critically ill patients: Crit Care 12(1):R29, February 29, 2008.
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