脓毒症集束化治疗方案（SEP-1）依从性与实施对死亡率的影响

原文图文 · 图 30 张

REBEL Rundown

Key Points

Evidence is lacking: Evidence specific to compliance with and implementation of the CMS SEP-1 bundle is overall low quality

Parts do not make a whole: While the bundle itself has not demonstrated a mortality benefit, individual components like early antibiotics and targeted fluid resuscitation have value

Money matters: SEP-1 remains a CMS core measure tied to reimbursement

Possible harm: Concerns remain about potential harm from antibiotic overtreatment

Patients aren’t checklists: individualized, physiologically appropriate resuscitation should continue to take precedence over administrative bundles

Introduction

Sepsis is a leading cause of death carrying an age adjusted mortality rate of ~76 per 100,000 when discounting spikes of ~30% during the COVID-19 pandemic 1. For years, early goal directed therapy (EGDT) has been at the center of sepsis treatment. EGDT encompasses targeting early medical resuscitative efforts to objective measures, though studies have disagreed on the ideal target measure. A landmark study of EGDT, Rivers et al. showed a 16% reduction in in-hospital mortality by utilizing a rigorous protocol targeting central venous pressures of 8-12 with fluid boluses, mean arterial pressure >65 with vasopressors, and mixed venous oxygen saturations of >70% with red blood cell transfusions then dobutamine during the first 6 hours of therapy 2. More recent multicenter trials, including ProCESS, ARISE, and ProMISe3, however, demonstrated that rigid protocolization of EGDT offers no mortality benefit compared with usual care.

The SEP-1 bundle issued by the Centers for Medicaid and Medicare Services (CMS), outlined below, similarly protocolizes the early treatment of sepsis4. The bundle was initially implemented as a pay-for-reporting measure and is now part of the hospital Value Based Purchasing (VBP) program which seeks to reward quality care over volume of care based on adherence to core measures.

According to the Infectious Disease Society of America (IDSA), studies have shown that implementation of SEP-1 has increased broad spectrum antibiotic use and aggressive fluid resuscitation without reducing mortality rates5. Furthermore, IDSA recommends the retirement of the bundle rather than inclusion in the value based paying program as it may increase treatment of non-infectious sepsis mimics and SIRS.

In 2023, CMS incorporated the SEP-1 bundle as a pay-for-performance measure as part of their hospital value based purchasing program. This change required compliance with the SEP-1 bundle in totality. Ford et. al. note that such “rigidity as an all or nothing mandate may disempower clinicians from providing personalized care based on an individual patient’s clinical picture and physiology”6. As such, Ford et al. sought to evaluate whether implementation or compliance with the SEP-1 bundle in totality has mortality benefit.

Paper

Ford JS et al. The Effect of Severe Sepsis and Septic Shock Management Bundle (SEP-1) Compliance and Implementation on Mortality Among Patients With Sepsis: A Systematic Review.  Ann Intern Med. 2025. PMID 39961104

Previously Covered On REBEL

The Protocolized Management in Sepsis (ProMISe) Trial

Early Sepsis Screening in the Emergency Department

Time to Antibiotics in Sepsis: A Metric Not Supported by High-Quality Evidence

Petition to Retire the Surviving Sepsis Campaign Guidelines

Are Antibiotics for Sepsis in One Hour Feasible in the ED?

Fluid Administration in End-Stage Renal Disease for Severe Sepsis and Septic Shock

Congestive Heart Failure and Sepsis: A Closer Look at Fluid Management

REBEL Cast Ep116: The CLOVERS Trial

What They Did

CLINICAL QUESTION

Is there any moderate or high-level evidence that SEP-1 compliance and/or implementation is associated with improvement in sepsis mortality?

STUDY DESIGN

Systematic Review using PRISMA guidelines

Search of 5 databases (PubMed, Web of Science, EMBASE, CINAHL Complete, and the Cochrane Library) from inception to 26 November 2024 without language restriction

Articles were independently screened by two authors for inclusion, disagreements were resolved by consensus for title/abstract screening and by a third author for full text screening.

Three authors independently extracted data using a standardized tool to include study design, study population demographics, raw proportions of primary outcomes, and unadjusted and adjusted measures of association for primary outcomes.

Newcastle-Ottowa scale (NOS) was used as a measure of study quality to assess risk for selection bias, comparability between groups, and ascertainment of exposure or outcome. NOS criteria was modeled on previously conducted systemic reviews evaluating sepsis bundles.

Due to heterogeneity a meta analysis was omitted to prevent misleading pooled data. because the studies were too heterogeneous for a meta-analysis, the authors performed a qualitative synthesis (no forest plot)

Two authors independently reviewed for confounders and bias with disagreements resolved by consensus.

POPULATION

Inclusion Criteria:

Articles focused on adults aged ≥18 years with sepsis, severe sepsis, or septic shock. 1 study included patients aged 16 years or older but had a median age of 45 years.

Studies assessing both 3-hour and 6-hour sepsis bundles even if the bundle was not explicitly named “SEP-1.” 4 studies assessed only 3 hour bundles

Studies that compared mortality between patients who received each bundle and those who did not (effect of compliance).

Studies that compared sepsis mortality between a pre–SEP-1 implementation period and a post–SEP-1 implementation period (effect of implementation).

Exclusion Criteria:

Studies focused on bundles not sufficiently similar to Sep-1Studies including data from the NYS Sepsis Care Improvement Initiative due to fluid bolus completion within 6 hours compared to 3 hours with SEP-1

Studies from Surviving Sepsis Campaign 2008 which contained 1-hour, 6-hour, and 24-hour components

Surviving Sepsis Campaign 2018 which contained 1-hour components)

Articles assessing the effects of individual sepsis bundle components on mortality

INTERVENTION & COMPARATOR

Intervention Group:

Compliance with the SEP-1 bundle (3-hour or 6-hour metrics)

Comparator Group:

Compliance with the SEP-1 bundle (3-hour or 6-hour metrics)

OUTCOMES

Primary Outcome:

Sepsis mortality (commonly reported as in-hospital or 28-day mortality)

(Some) Secondary Outcomes:

Hospital and ICU length of stay (LOS),

30-day/60-day hospital readmissions

Vasopressor days

Bundle component adherence.

Safety Outcomes

Severe bradycardia (Heart rate <50 beats/min)

Cardiac arrhythmia

Cardiac arrest

Results:

(Note: Because this is a systematic review without a meta-analysis, pooled patient demographics like overall median age or sex were not available.)

6,922 articles met initial inclusion criteria

4,403 studies remained after removing duplicates

46 studies remained after title and abstract screening

After full text assessment, 17 studies remained11 concurrent cohort studies evaluating SEP-1 compliance

1 case control study evaluating SEP-1 compliance

5 before-after cohort studies evaluating SEP-1 implementation

Newcastle-Ottowa Scale identified none of the included studies as low risk for bias and GRADE assessment identified all as low level evidence.

Critical Results

(Note: A meta-analysis was not performed due to high methodological heterogeneity among the included studies, so a single pooled odds ratio/relative risk cannot be reported. Furthermore, the overall level of evidence supporting SEP-1 was graded as “Low”.)

Strengths

Followed PRISMA guidelines

Performed a thorough search of the literature across 5 databases

Use of standardized tools for bias assessment and evidence grading.

Use of standardized data extraction tool

Authors attempted to limit confounders via demographic and seasonality adjustments for mortality

Highly relevant clinical question as cost of policy may dictate ED workflow

Dual clinical questions evaluating both compliance and implementation of the bundle show effects of the mandate on patient and system levels

Limitations

All evidence was identified as not at low risk of bias and low-level evidence.Heavy confounding exists in observational trials with classic sepsis being more likely to receive the bundle.

Studies included all iterations of SEP-1 bundles without adjustment for whether mortality impact varied between older or newer versions of the bundle limiting applicability to the current SEP-1 bundle.

There was methodologic heterogeneity limiting comparability of included studies and resulting in inability to perform meta-analysisSample sizes varied widely (158–252,599).

The number of study centers ranged from 1 to 3,241.

Outcomes assessed included either 28-day or in-hospital mortality, reported by odds ratio (OR) or absolute risk reduction (ARR).

Evaluations were conducted via record linkage or blindly.

Discussion

Article Analysis

Ford et al. performed a thorough, systematic, and structured evaluation of data surrounding the SEP-1 bundle.

Studies showing mortality benefit vs. no benefit were nearly evenly divided:5 studies showed benefit when evaluating compliance on the patient level.1 did not adjust for confounders,

1 found benefit only in severe sepsis,

1 found benefit only in septic shock

1 included only Medicare beneficiaries

1 study showed benefit when evaluating hospital level implementationThis study failed to adjust for pre-existing mortality trends

7 studies showed no benefit when evaluating compliance on the patient level

4 showed no benefit when evaluating compliance on the hospital implementation level

Heterogeneity of studies, low level of evidence, and lack of specificity to SEP-1 detract from the review’s validity.

Authors did not comment on the statistical significance of their findings.

There are identified harms associated with protocolization and EGDT

Studies show SEP-1 implementation has led to increased broad-spectrum antibiotic use and aggressive fluid resuscitation without reducing mortality5 . This may lead to increased antibiotic resistance.

Protocolization risks over treatment of non-infectious sepsis mimics such as pancreatitis or stimulant intoxication.

Protocolization does not take individual factors into account- for instance large volume fluid boluses may not be appropriate in patients with significant cardiopulmonary disease.

Arguments against sepsis treatment protocolization

The Rivers study was a single center trial published in 2001 and is specific to the emergency department without applicability to ICU’s which are also subject to the CMS VBP program.

Large multicenter trials and meta-analyses (ProCESS, ARISE, and ProMISe) have since found no differences between usual care and EGDT. This may be in part due to improvement in usual care over the course of 20 years7.

Focus in the medical community has shifted away from using rigid protocolization, focusing instead on individual patient needs regarding fluid responsiveness and vasopressors3.

Arguments for sepsis treatment protocolization

Population level protocolization is operationally efficient

Protocolization may increase the level of patient monitoring with increased adherence to testing, vital signs monitoring, and re-evaluation

Improves sepsis care delivery, such as timely antibiotic use, even if there is no shown mortality benefit with protocolization.

CMS updates

CMS is developing a sepsis 30-day mortality electronic clinical quality measure aimed at a more patient outcome–focused approach.

However, this new measure does not differentiate between SIRS, sepsis, and septic shock.

It will require external validity studies to assess its effectiveness.

CMS Manual V5.14 (2023) allows clinicians to provide less than 30/ml/kg if specific hemodynamic assessments (CO, SV etc.) are measured.

Author's Conclusion

“This review found no moderate- or high-level evidence to support that compliance with or implementation of SEP-1 was associated with sepsis mortality. CMS should reconsider the addition of SEP-1 to the Hospital VBP Program.”

Our Conclusion

While Ford et al’s review was carried out with rigorous structural integrity, the heterogeneity and low level of evidence highlights that further high level evidence evaluating the SEP-1 bundle is needed to understand the impact on mortality. When considered alone, the review is insufficient to change current practice. When considered in congruence with additional evidence, such as the ProCESS, ARISE, and ProMISe trials and IDSA guidelines, this review adds to the argument that protocolization of sepsis care discounts patients’ differing physiologies and presentations that lead to varying responses to intervention. As such, in our practice we continue to rely on strong clinical judgement and close evaluation of patient conditions to guide resuscitation and treatment.

Clinical Bottom Line

Despite CMS linking SEP-1 compliance to hospital reimbursement, this comprehensive systematic review reveals there is no moderate- or high-quality evidence that the bundle actually reduces sepsis mortality; emergency clinicians should continue prioritizing individualized, physiologically-appropriate resuscitation over blind adherence to administrative checklists.

References

Morrissey, R. et al.

Demographic and regional trends of sepsis mortality in the United States, 1999–2022. BMC Infectious Diseases.

PMID: 40211200

Rivers, E. et al.

Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 1368–1377.

PMID: 11794169

Nguyen HB et al.

Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE. Crit Care. Jul 2016

PMID: 27364620

Centers for Medicare and Medicaid Services. (2020, August)

Severe Sepsis and Septic Shock: Management Bundle Measure.

Link is Here

Rhee C, et al.

Improving sepsis outcomes in the era of pay-for-performance and electronic quality measures: A joint IDSA/ACEP/Pids/Shea/SHM/SIDP position paper. Clinical Infectious Diseases, 2023.

PMID: 37831591

Ford JS, et al.

The Effect of Severe Sepsis and Septic Shock Management Bundle (SEP-1) Compliance and Implementation on Mortality Among Patients With Sepsis: A Systematic Review. Ann Intern Med. February 2025.

PMID: 39961104

The PRISM Investigators; et al.

Early, goal-directed therapy for septic shock — a patient-level meta-analysis. New England Journal of Medicine, 2017

PMID: 28320242

Evans L, et al.

Surviving sepsis campaign: international guidelines for management of sepsis and septic shock. Intensive Care Med. Nov 2021.

PMID: 34599691

Vincent, J.-L., et al.

Early management of sepsis. Clinical and Experimental Emergency Medicine,

PMID: 27752546

Gaieski DF, et al.

Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the Emergency Department. Critical Care Medicine, 2010.

PMID: 20048677

Post Peer Reviewed By: Marco Propersi DO, (X/IG: @Marco_Propersi), Mark Ramzy, DO (X/IG: @MRamzyDO) and Dorian Alexander, MD

Meet the Authors

Maren Leibowitz, MD

Clinical Instructor

Northwestern University, Chicago, IL

Melissa Smith, MD, RN

PGY-3 Emergency Medicine Resident

Northwestern University, Chicago, IL

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