• Dominique J Pepper, Junfeng Sun, Xizhong Cui, Judith Welsh, Charles Natanson, and Peter Q Eichacker.
• Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD.
• Crit. Care Med. 2019 Oct 1; 47 (10): 129013001290-1300.

ObjectiveTo address three controversial components in the Centers for Medicare and Medicaid Service's sepsis bundle for performance measure (SEP-1): antibiotics within 3 hours, a 30 mL/kg fluid infusion for all hypotensive patients, and repeat lactate measurements within 6 hours if initially elevated. We hypothesized that antibiotic- and fluid-focused bundles like SEP-1 would probably show benefit, but evidence supporting specific antibiotic timing, fluid dosing, or serial lactate requirements would not be concordant. Therefore, we performed a meta-analysis of studies of sepsis bundles like SEP-1.Data SourcesPubMed, Embase, ClinicalTrials.gov through March 15, 2018.Study SelectionStudies comparing survival in septic adults receiving versus not receiving antibiotic- and fluid-focused bundles.Data ExtractionTwo investigators (D.J.P., P.Q.E.).Data SynthesisSeventeen observational studies (11,303 controls and 4,977 bundle subjects) met inclusion criteria. Bundles were associated with increased odds ratios of survival (odds ratio [95% CI]) in 15 studies with substantial heterogeneity (I = 61%; p < 0.01). Survival benefits were consistent in the five largest (1,697-12,486 patients per study) (1.20 [1.11-1.30]; I = 0%) and six medium-sized studies (167-1,029) (2.03 [1.52-2.71]; I = 8%) but not the six smallest (64-137) (1.25 [0.42-3.66]; I = 57%). Bundles were associated with similarly increased survival benefits whether requiring antibiotics within 1 hour (n = 7 studies) versus 3 hours (n = 8) versus no specified time (n = 2); or 30 mL/kg fluid (n = 7) versus another volume (≥ 2 L, n = 1; ≥ 20 mL/kg, n = 2; 1.5-2 L or 500 mL, n = 1 each; none specified, n = 4) (p = 0.19 for each comparison). In the only study employing serial lactate measurements, survival was not increased versus others. No study had a low risk of bias or assessed potential adverse bundle effects.ConclusionsAvailable studies support the notion that antibiotic- and fluid-focused sepsis bundles like SEP-1 improve survival but do not demonstrate the superiority of any specific antibiotic time or fluid volume or of serial lactate measurements. Until strong reproducible evidence demonstrates the safety and benefit of any fixed requirement for these interventions, the present findings support the revision of SEP-1 to allow flexibility in treatment according to physician judgment.

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