Inadvertent catastrophes are often hidden just beneath good intentions. Such is the case with the most recent iteration of the Surviving Sepsis Campaign’s treatment bundle.
Published in Intensive Care Medicine by Levy et al, this special editorial includes the Surviving Sepsis Campaign’s most recent recommendations for the early and aggressive treatment of sepsis (1). Most notably these recommendations have dissolved the 3 and 6-hour bundles in favor of a solitary 1-hour bundle. Items to be successfully completed within this brief time window include
-Measurement of a serum lactate (and remeasurement if the initial value is above 2 mmol/L)
-Obtainment of blood cultures prior to antibiotics
-The initiation of 30 ml/kg fluid bolus in patients with hypotension and/or a lactate > 4 mmol/L
-The addition of vasopressors if patient is hypotensive during or after fluid resuscitation in order -to maintain a MAP >65
On face value such expectations seem reasonable. In fact, from a financial standpoint the Emergency Department may actual prefer these guidelines to the current Sep-1 criteria, as it is easier to translate a single 1-hour treatment bundle into an EHR order set than the more logistically complex 3 and 6-hour bundles. And while no one would argue against an aggressive and timely resuscitation in the face of a patient presenting with septic shock, this is not the mandate that such a guideline will promote. Rather by condensing the 3 and 6-hours bundles into a single 1-hour treatment directive, the authors have created a logistical nightmare. Achieving the 3-hour treatment bundle is challenging enough for most Emergency Departments (2). Most EDs increase sepsis-bundle compliance not by improving the quality of care, but by entering anyone presenting to the ED with even the smallest sign of potential infection into the sepsis pathway. (3). Compressing the time required to complete these quality measures will only heighten these “beat the clock strategies”.
The use of this resource heavy protocolized care is based off an overreaching interpretation of evidence, which when reviewed in totality suggests the futility of such bluntly applied endeavors.
First the authors assume that protocolized care is superior to individualized treatment guided by the bedside clinician. This hypothesis has its roots in early goal directed therapy, which was pushed to the forefront of sepsis care following the blockbuster trial in the NEJM by Rivers et al, citing its overwhelming superiority compared to standard care (4). But this small, single center study has since been disproven, and in fact 3 large high quality multicenter RCTs were unable to find any benefit to protocolized care when compared to the unstructured judgment of the treating physician (5,6,7).
The second assumption is that earlier treatment is better, which can be attributed to a number of datasets reporting a temporal benefit associated with earlier completion of the sepsis bundle (8,9,10,11,12). A number presenting a statistically significant increase in mortality for every hour delay. But of course what these authors do not take into account is that this data is incomplete. These are all observational cohorts that separate patients by the time to intervention. Such analyses have extensive methodological limitations. None were randomized to receive treatment at a certain time threshold, and as such causative statements cannot be made. Further, though the authors present impressively small p-values, the true effect size are for the most part minimal. The analysis by Seymour et al published in the NEJM reports a 1.04 (95% CI, 1.03 to 1.06) increase in the odds of death for every hour delay to completion of the 3-hour sepsis bundle (10). Simply put, for every 148 patients in whom the completion of the sepsis bundle occurs, one additional person will die. Furthermore, these temporal benefits for early treatment were only present in the sickest subset of patients with septic shock. When this cohort of patients was excluded from the analysis, the authors were unable to demonstrate benefit to earlier completion of the sepsis bundle.
The third assumption is that all components of the bundle are equally efficacious and should be applied with uniform zeal. Again this assertion is not supported by the evidence. When Seymour et al examined the individual components of the sepsis bundle, they noted that while time-to-antibiotic administration showed similar temporal benefits to completion of the entire sepsis bundle, time to administration of the fluid bolus did not (10). Andrews et al, report the findings from an RCT demonstrating the patients presenting to the Emergency Department in Zambia who were randomized to receive fluid boluses guided by a protocol, did significantly worse than patients who received no fluid bolus at all (13). In fact, all of these patients presented with sepsis and hypotension, and the rates of resolution of shock were equal between groups. This calls into question the hemodynamic utility of a fluid bolus and whether timely source control is enough.
Finally, all these studies view this question from a very limited perspective. By examining only the patients retrospectively determined to have sepsis, the authors conveniently excluded patients without sepsis who are exposed to all the risks associated with broad spectrum antibiotics and large volume fluid resuscitation without any potential for benefit. As such the harm they are exposed to from overtreatment is also purged from the subsequent analysis. It is these unintended, and unmeasured consequences that are most concerning. Each of us has been witness to the victims of overzealous sepsis care. The patient presenting with suspected pneumonia that only after the CMS mandated 30 cc/kg fluid challenge does it become apparent their symptoms were not infectious but due to underlying cardiac infirmity. How many patients receive broad-spectrum antibiotics and large volume fluid resuscitations needlessly? How many patients do we screen in order to identify the few that may benefit from aggressive care?
Though well-intentioned, the current sepsis bundles, and the financial penalties associated with their noncompliance, have laid a heavy weight on already overstressed Emergency Departments. The proposed abbreviated bundle only serves to heighten that burden by further restricting the time allotted for the identification and treatment of patients with suspected sepsis. All without any evidence of benefit, nor knowledge of the logistical consequences such recommendations will cost.
Please do not mistake this as an argument in favor of returning to the former nihilism of past centuries. Rather an appeal for a more thoughtful approach regarding the application of our current sepsis protocols. Consider the consequences of blindly adhering to these broad reaching, resource-laden protocols, not only for the few patients with sepsis, but for those without, needlessly exposed to these aggressive treatment bundles. Consider the consequences for the Emergency Departments charged with the task of differentiating the sick from the well. And finally consider the consequences for the healthcare system as a whole both on a local and national level. If we fail to do so, there may come a time in the not so distant future when we look back upon our marginal gains in sepsis care, only to discover we have drowned an entire populace in our endeavors.
- Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med. 2018;
- Deis AS, Whiles BB, Brown AR, Satterwhite CL, Simpson SQ. Three-Hour Bundle Compliance and Outcomes in Patients With Undiagnosed Severe Sepsis. Chest. 2018;153(1):39-45.
- Venkatesh, Arjun K. et al. Preliminary Performance on the New CMS Sepsis-1 National Quality Measure: Early Insights From the Emergency Quality Network (E-QUAL). Annals of Emergency Medicine , Volume 71 , Issue 1 , 10 – 15.e1
- Liu B, Ding X, Yang J. Effect of early goal directed therapy in the treatment of severe sepsis and/or septic shock. Curr Med Res Opin. 2016;32(11):1773-1782.
- Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015;372:1301-1311
- The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370:1683-1693
- The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496-1506
- Damiani E, Donati A, Serafni G et al (2015) Efect of performance improvement programs on compliance with sepsis bundles and mortality: a systematic review and meta-analysis of observational studies. PLoS One 10:e0125827
- Rhodes A, Phillips G, Beale R et al (2015) The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study). Intensive Care Med 41:1620–1628
- Seymour CW, Gesten F, Prescott H et al (2017) Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 376:2235–2244
- Liu VX, Morehouse JW, Marelich GP et al (2016) Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. Am J Respir Crit Care Med 193(11):1264–1270
- Leisman DE, Doerfer ME, Ward MF et al (2017) Survival benfit and cost savings from compliance with a simplified 3-hour sepsis bundle in a series of prospective, multisite. Observational cohorts. Crit Care Med 45:395–406
- Andrews B, Semler MW, Muchemwa L, et al. Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial. JAMA. 2017;318(13):1233-1240.