Antibiotic- and Fluid-Focused Bundles Potentially Improve Sepsis Management, but High-Quality Evidence Is Lacking for the Specificity Required in the Centers for Medicare and Medicaid Service's Sepsis Bundle (SEP-1)

Abstract

Objective: To 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 sources: PubMed, Embase, ClinicalTrials.gov through March 15, 2018.

Study selection: Studies comparing survival in septic adults receiving versus not receiving antibiotic- and fluid-focused bundles.

Data extraction: Two investigators (D.J.P., P.Q.E.).

Data synthesis: Seventeen 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.

Conclusions: Available 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.

Figure 1.

Effect of treatment with a sepsis bundle on the odds ratio (OR) of survival (95% CI) in the 17 individual studies analyzed (inverted open triangles). Studies are shown stratified by terciles into the five studies with the largest-sized number of patients enrolled (1,697–12,486 patients, 29,385 total), the six studies with medium-sized number of patients (167–1,029, 2,326 total), and the five studies with the smallest number of patients enrolled (64–137, 652 total). The overall ORs (95% CI) and I² are shown for each of these three groups (inverted closed triangles).

Figure 2.

Effect of treatment with a sepsis bundle on the odds ratio (OR) of survival (95% CI) in studies grouped based on whether the bundles studied required antibiotics be administered (inverted open triangles). in less than or equal to 1 hr or less than or equal to 3 hr or the bundle did not state when antibiotics should be administered. The overall ORs (95% CI) and I² are shown for each of these three groups. The overall effects of bundles did not differ significantly (p = 0.19) comparing the three groups (inverted closed triangles).

Figure 3.

Effect of treatment with a sepsis bundle on the odds ratio (OR) of survival (95% CI) in studies grouped based on whether the bundles studied specified that 30 mL/kg fluid be administered, that a volume other than 30 mL/kg be given as shown in the figure, or that did not specify what volume be administered (i.e., an individualized volume) (inverted open triangles). The overall ORs (95% CI) and I2 are shown for each of these three groups (inverted closed triangles). The overall effects of bundles did not differ significantly (p = 0.19) comparing studies requiring 30 mL/kg to all other studies not requiring this volume. This difference was also not significant (p = 0.27) when the one study requiring a fluid volume greater than or equal to 2 L was combined with those requiring 30 mL/kg and compared with all other studies. NS = not significant.

Figure 4.

This figure shows whether bundle treatment increased the proportion of patients receiving timely antibiotics or fluids or decreased the mean time to antibiotics or fluids compared to no bundle treatment in studies providing data. A and C, The effect of treatment with a sepsis bundle on the odds ratio (OR [95% CI]) of patients receiving timely (i.e., within a prespecified time period) antibiotics or fluids is shown. B and D, The effect of treatment with a sepsis bundle on the time to (calculated as the mean difference in time [95% CI]) antibiotics or fluids is shown. Both individual and overall ORs are shown as inverted solid triangles.