Time to treatment and mortality for clinical sepsis subtypes

Abstract

Background: Sepsis is common, deadly, and heterogenous. Prior analyses of patients with sepsis and septic shock in New York State showed a risk-adjusted association between more rapid antibiotic administration and bundled care completion, but not an intravenous fluid bolus, with reduced in-hospital mortality. However, it is unknown if clinically identifiable sepsis subtypes modify these associations.

Methods: Secondary analysis of patients with sepsis and septic shock enrolled in the New York State Department of Health cohort from January 1, 2015 to December 31, 2016. Patients were classified as clinical sepsis subtypes (α, β, γ, δ-types) using the Sepsis ENdotyping in Emergency CAre (SENECA) approach. Exposure variables included time to 3-h sepsis bundle completion, antibiotic administration, and intravenous fluid bolus completion. Then logistic regression models evaluated the interaction between exposures, clinical sepsis subtypes, and in-hospital mortality.

Results: 55,169 hospitalizations from 155 hospitals were included (34% α, 30% β, 19% γ, 17% δ). The α-subtype had the lowest (N = 1,905, 10%) and δ-subtype had the highest (N = 3,776, 41%) in-hospital mortality. Each hour to completion of the 3-h bundle (aOR, 1.04 [95%CI, 1.02-1.05]) and antibiotic initiation (aOR, 1.03 [95%CI, 1.02-1.04]) was associated with increased risk-adjusted in-hospital mortality. The association differed across subtypes (p-interactions < 0.05). For example, the outcome association for the time to completion of the 3-h bundle was greater in the δ-subtype (aOR, 1.07 [95%CI, 1.05-1.10]) compared to α-subtype (aOR, 1.02 [95%CI, 0.99-1.04]). Time to intravenous fluid bolus completion was not associated with risk-adjusted in-hospital mortality (aOR, 0.99 [95%CI, 0.97-1.01]) and did not differ among subtypes (p-interaction = 0.41).

Conclusion: Timely completion of a 3-h sepsis bundle and antibiotic initiation was associated with reduced risk-adjusted in-hospital mortality, an association modified by clinically identifiable sepsis subtype.

Keywords: Antibiotics; Precision medicine; Sepsis; Subtypes.

Fig. 1

Cohort accrual

Fig. 2

Cumulative proportions of bundle and bundle item completion, stratified by clinical sepsis subtype. Shown are the proportions of cohort completing the 3-h bundle of sepsis care over the first 12-h after protocol initiation (Panel A), the administration of broad-spectrum antibiotics over the first 12-h after protocol initiation (Panel B), and initial intravenous fluid bolus completion over the first 6-h after protocol initiation (Panel C), stratified by clinical sepsis subtype

Fig. 3

Adjusted odds ratios of in-hospital mortality, stratified by clinical sepsis subtype. Shown are odd ratios with 95% confidence intervals for in-hospital mortality, per hour, to completion of the 3-h bundle, initiation of antibiotics, and completion of the initial intravenous fluid bolus completion, by clinical sepsis subtype. ^aOmnibus P values for interaction between sepsis protocol items as well as the sepsis subtypes

Fig. 4

Crude in-hospital mortality and predicted risks of in-hospital death by clinical sepsis subtype. Shown are the crude in-hospital mortality and model-estimated risks of in-hospital mortality for each clinical sepsis subtype, across a range of times from initiation of protocol to completion of the 3-h bundle (Panel A) and initiation of antibiotics (Panel B). Bars associated with model-estimated risks represent 95% confidence