By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH

SYNOPSIS: A longitudinal study from a single healthcare system found that adherence to the Medicare Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) resulted in some changes in process measures, but did not lead to improvements in clinical outcomes.

SOURCE: Barbash IJ, Davis BS, Yabes JG, et al. Treatment patterns and clinical outcomes after the introduction of the Medicare Sepsis Performance Measure (SEP-1). Ann Intern Med 2021;174:927-935.

Even though evidence-based guidelines for the management of sepsis have been developed and disseminated, morbidity and mortality for sepsis remain unacceptably high. In 2015, the Centers for Medicare and Medicaid Services (CMS) implemented the Severe Sepsis and Septic Shock Early Management Bundle (SEP-1), which requires hospitals to collect and report data on their adherence to a multi-component treatment bundle. Since then, substantial debate has occurred regarding the usefulness of SEP-1, particularly regarding whether it leads to improvement in patient survival. Therefore, Barbash and colleagues sought to determine whether adherence to SEP-1 leads to improved outcomes in hospitalized patients with community-onset sepsis.

The investigators conducted a longitudinal study using data from 11 academic and community hospitals that are part of a large healthcare system (University of Pittsburgh Medical Center Health System [UPMC]). Patients included in the study were 18 years of age or older and had community-onset sepsis and organ failure within six hours of arrival to the emergency department. SEP-1-adherent therapy was defined as intravenous (IV) antibiotics, lactate measurement, and crystalloid IV fluid administration within three hours of suspected infection, and repeated lactate measurement and administration of a vasopressor within six hours of suspected infection. Time zero was defined as the time a fluid culture (e.g., blood, urine, respiratory, or other) was ordered. Patients were stratified into two groups for comparison: before SEP-1 (January 2013-September 2015) and after SEP-1 (January 2016-December 2017). Exclusion criteria included transfers to other institutions outside the UPMC system, hospital stays < 24 hours or > 30 days, early comfort care, and repeated encounters. The primary outcomes of interest were admission to the intensive care unit (ICU), in-hospital mortality, and discharge to home among survivors.

There were 29,051 patients in the before-SEP-1 group and 22,759 in the after-SEP-1 group. Not surprisingly, adherence in the after-SEP-1 group was much greater for three-hour lactate measurement (P < 0.001), antibiotic administration within three hours (P = 0.001), and adherence to administration of 30 mL/kg of IV fluids within three hours (P < 0.001). There was no meaningful difference in the rate of vasopressor administration within six hours (P = 0.61). A time series analysis determined that SEP-1 was associated with a 50% increase in checking lactate levels, a 10% increase in broad-spectrum antibiotic use, and a 30% increase in IV fluid administration within three hours of culture orders if the expected rate of trends that occurred before SEP-1 had continued.

Adherence to SEP-1 was not associated with statistically significant or clinically important outcomes, including admission to the ICU (P = 0.055), in-hospital mortality (P = 0.87), or discharge home (P = 0.145). Subgroup analysis showed a similar null effect in patients with septic shock. No statistically significant differences in the primary outcomes were found in patients requiring vasopressors before or after SEP-1. Finally, there was some evidence of ascertainment bias as a result of increased culture ordering in the after-SEP-1 group.


Adherence to an authoritative and widely implemented sepsis bundle based on solid clinical evidence failed to improve outcomes in patients with community-onset sepsis and septic shock. Indeed, this is an unexpected and disappointing finding. But credit should be given to Barbash and colleagues for conducting this study and reminding us that even the most rational and plausible dogma should not be above reproach.

So why did following the SEP-1 bundle not improve outcomes? There are several possible explanations. One is that we still do not have a deep enough understanding of the pathophysiology of sepsis to know how and when to intervene. Another is the inherent weakness of measuring serum lactate, which can be elevated in numerous other conditions besides sepsis and infections. This can lead to the over-administration of IV fluids that can be harmful in certain patients with comorbid illnesses, such as congestive heart failure or those on hemodialysis.

A third explanation is the possibility that many patients with sepsis were misdiagnosed. There is no gold standard definition of sepsis useful at the bedside that accurately takes into account the many nuances of how infections manifest in the human body. It also is important to remember that many infections, especially pneumonia, are caused by viruses, and large volume fluid resuscitation and broad-spectrum antibiotics are not indicated in such cases.

The study had a few limitations that should not be overlooked. First, it might have been more pragmatic to define time zero as when a fluid culture actually was collected, rather than ordered. Whether this had any impact on the findings is not clear. Second, the overall mortality was relatively low, raising the possibility that many patients were not sick enough for small increases in quality of care to make a substantial difference. Third, there was no control group to compare with the after-SEP-1 group, although this would have been difficult to construct since SEP-1 was instituted as a national policy. Finally, the study was conducted at a healthcare system well known for its high quality in emergency and critical care medicine, thus limiting the generalizability to other healthcare settings and institutions.

Should CMS require that hospitals continue to comply with SEP-1? The study by Barbash raises serious questions about the appropriateness of that policy. Further studies are warranted, especially from smaller hospitals and other geographic areas.