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
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