"Sepsis bundles": No good evidence of benefit
A randomized trial testing SEP-1 against usual care is long overdue
SEP-1, the Centers for Medicare & Medicaid Services (CMS)’s much-maligned sepsis “quality” measure, was the brainchild of a small group of insiders conceived in the early- to mid-2000s.
Given how SEP-1 has aged, it should be no surprise it was an ugly baby.
Its genesis was led by Dr. Emmanuel Rivers, who back then was a superstar in critical care after publication in the New England Journal of Medicine of the randomized trial he led claiming that “early goal-directed therapy” saved lives in sepsis.
But there were some alleged …. problems with that trial, and also with the process at the National Quality Forum that eventually resulted in SEP-1:
As the WSJ reported, Dr. Rivers’s methodology, findings, and conflicts of interest came under scrutiny after a researcher with access to the data asserted it was incomplete—alleging that had all patients’ data been appropriately analyzed, the trial would have been negative.
Dr. Rivers and his center, Henry Ford Hospital, had financial relationships with Edwards Lifesciences, makers of the invasive catheter used in Rivers’s trial to measure continuous central venous oxygenation saturation.
Early versions of SEP-1 included a requirement for the use of invasive ScvO2 monitoring.
The co-chair of the NQF committee was the senior vice president of a medical device manufacturers’ trade organization, whose past chairman was the CEO of Edwards Lifesciences.
SEP-1 was pushed through without waiting for the outcomes of three ongoing multicenter trials testing goal-directed therapy for sepsis. The three trials refuted Rivers’s original findings, showing no benefit of an “early goal-directed protocol” over usual sepsis care.
The NQF persisted in endorsing SEP-1 anyway, prompting an unusual public rebuke from Drs. Peter Eichacker, Dharmvir Jaswal, and Charles Natanson of the National Institutes of Health, who together wrote in BMJ in 2018:
“SEP-1 is a performance measure for managing patients with sepsis that was endorsed by the National Quality Forum and adopted by the Centers for Medicare and Medicaid Services while controversial interventions [invasive monitoring of central venous oxygenation—Ed.] were still undergoing clinical testing. Even after this testing showed lack of efficacy, the interventions were not removed. Furthermore, a trade organisation with direct ties to a manufacturer standing to benefit from SEP-1 took part in the endorsement.”
The requirement for invasive monitoring was eventually removed, but what does all this say about the integrity of the rest of SEP-1’s development process?
10 Years Later, There’s Still No Good Evidence For SEP-1
A 2025 systematic review of studies examining the relationship between mortality and compliance with SEP-1 does not help its cause.
The primary finding of the review was that the quality of evidence overall was low to very low.
Five observational studies showed a statistically significant association between bundle compliance and mortality, while seven did not.
Among the five studies that found an association between bundle compliance and mortality, two were small single-center studies.
The studies were all observational and thus prone to bias.
There were 17 studies included in the review, but they were too heterogeneous to perform a meta-analysis. Five did not report on the association between bundle compliance and mortality.
Because SEP-1 was enacted by CMS’s administrative fiat, no randomized trials have been performed before or since to gauge its effectiveness.
CMS Payment Policy, Not Evidence, Controls Sepsis Care
CMS implemented SEP-1 in 2015 initially as a pay-for-reporting measure. To avoid financial penalties, hospitals have had to report their compliance with the bundle elements of I.V. fluid administration, blood culture and lactate collection, and antibiotics, delivered in the first 3 hours.
Hospitals haven’t been penalized thus far for not complying with the bundle, only for not reporting their compliance rates.
That’s about to change, raising the stakes. Starting in 2026, according to CMS’s “final rule,” hospitals will be financially penalized if they do not comply with the bundle elements above a certain threshold.
Professional Societies Disagree on SEP-1
SEP-1 has set up an interesting divergence of advocacy among professional societies.
The major U.S. critical care society and the major “chest physicians” society have both voiced support for the measure.
The major U.S. “thoracic” society has not taken a formal position that we are aware of.
The Infectious Diseases Society of America (IDSA) has consistently opposed SEP-1 since at least 2016. Around 2022, IDSA joined the American College of Emergency Physicians (ACEP), the Pediatric Infectious Diseases Society (PIDS), the Society for Healthcare Epidemiology of America (SHEA), the Society of Hospital Medicine (SHM), and the Society of Infectious Diseases Pharmacists (SIDP) to formally object to the renewal of the measure, arguing that it was unsupported by evidence.
A Hint of Heresy, A Glimmer of Hope?
Tamás Szakmány, MD, PhD, a moderator at the critical care society’s 2025 annual meeting, suggested publicly that a randomized trial ought to be performed testing SEP-1 against usual care, media outlets reported.
This was remarkable as it seemed to diverge from the society’s previous official position, and Dr. Szakmány is the editor-in-chief of Critical Care Explorations, the “official open-access, peer-reviewed journal of the Society of Critical Care Medicine,” according to their website.
Dr Szakmány mused on the possibility of a multinational trial, since randomization to “usual care” (without SEP-1) would be administratively prohibited in the U.S.
But not completely prohibited: CMS has the authority to grant exceptions to SEP-1 reporting for the purposes of research. It appears the agency did so in 2020 for the PCORI-funded CLOVERS randomized trial comparing fluid strategies in septic shock, in which patients were routinely exempted from receiving crystalloid resuscitation if they were improving. This conflicted with SEP-1’s resuscitation volume requirements, and of course, the hosting health systems would not have allowed this if they were to be “dinged” on their reporting by CMS.
If the major critical care societies endorsed a proper cluster-randomized trial testing SEP-1 against usual care, it would help open the door.
The chest society’s 2022 letter to CMS in support of SEP-1 made the case that this would be unethical or unsafe. But the equipoise of data (and its general absence) does not support these concerns.
If such a study were conducted at major academic medical centers, high-quality care would be expected with or without the bundle requirement. The most likely finding would be a lack of benefit from SEP-1 compliance.
Some would argue the measure should continue anyway, to guarantee minimal standards of care. But a negative randomized trial would at least provide a roadmap toward granting more flexibility at high-performing centers, where SEP-1 represents a burden to care teams without benefit to patients.
References
“New Recommendations to Improve Sepsis Outcomes”, IDSA communication, October 2023.
“SEP-1 protocol to manage severe sepsis and septic shock”, Chest/ACCP website, 2022.
The keys to sepsis care are simple: (1) high index of suspicion; (2) early, broad-spectrum antibiotics; and (3) aggressive volume resuscitation in those who are volume depleted/responsive, vasopressors for those who need them. That’s it. The SEP-1 bundle makes proscribes specific things that clearly don’t improve outcomes, and now, it will penalize us if we don’t comply. It’s ridiculous.
And, just so you know, my hospital has a greater than 89% bundle compliance and fantastic sepsis outcomes. I’m on the sepsis committee. So I’m not complaining because we suck at sepsis.
Simply put..enforced reliance on protocol based medical decision trees is lousy medicine and has greatly diminished physician led healthcare.
There are so many unforeseen ramifications. None of which are good for patient care.