Murine sepsis phenotypes and differential treatment effects in a randomized trial of prompt antibiotics and fluids.

Autor: Seymour CW; Departments of Critical Care Medicine Emergency Medicine, University of Pittsburgh School of Medicine, 3550 Terrace St, Scaife Hall, #639, Pittsburgh, PA, 15261, USA. seymourcw@upmc.edu.; Clinical Research, Investigation, and Systems Modeling of Acute Illness Center (CRISMA), University of Pittsburgh School of Medicine, Pittsburgh, USA. seymourcw@upmc.edu.; Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, USA. seymourcw@upmc.edu., Kerti SJ; Departments of Critical Care Medicine Emergency Medicine, University of Pittsburgh School of Medicine, 3550 Terrace St, Scaife Hall, #639, Pittsburgh, PA, 15261, USA.; Clinical Research, Investigation, and Systems Modeling of Acute Illness Center (CRISMA), University of Pittsburgh School of Medicine, Pittsburgh, USA., Lewis AJ; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, USA., Kennedy J; Departments of Critical Care Medicine Emergency Medicine, University of Pittsburgh School of Medicine, 3550 Terrace St, Scaife Hall, #639, Pittsburgh, PA, 15261, USA.; Clinical Research, Investigation, and Systems Modeling of Acute Illness Center (CRISMA), University of Pittsburgh School of Medicine, Pittsburgh, USA., Brant E; Departments of Critical Care Medicine Emergency Medicine, University of Pittsburgh School of Medicine, 3550 Terrace St, Scaife Hall, #639, Pittsburgh, PA, 15261, USA.; Clinical Research, Investigation, and Systems Modeling of Acute Illness Center (CRISMA), University of Pittsburgh School of Medicine, Pittsburgh, USA., Griepentrog JE; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, USA., Zhang X; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, USA., Angus DC; Departments of Critical Care Medicine Emergency Medicine, University of Pittsburgh School of Medicine, 3550 Terrace St, Scaife Hall, #639, Pittsburgh, PA, 15261, USA.; Clinical Research, Investigation, and Systems Modeling of Acute Illness Center (CRISMA), University of Pittsburgh School of Medicine, Pittsburgh, USA., Chang CH; Departments of Critical Care Medicine Emergency Medicine, University of Pittsburgh School of Medicine, 3550 Terrace St, Scaife Hall, #639, Pittsburgh, PA, 15261, USA.; Clinical Research, Investigation, and Systems Modeling of Acute Illness Center (CRISMA), University of Pittsburgh School of Medicine, Pittsburgh, USA.; Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, USA., Rosengart MR; Departments of Critical Care Medicine Emergency Medicine, University of Pittsburgh School of Medicine, 3550 Terrace St, Scaife Hall, #639, Pittsburgh, PA, 15261, USA.; Clinical Research, Investigation, and Systems Modeling of Acute Illness Center (CRISMA), University of Pittsburgh School of Medicine, Pittsburgh, USA.; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, USA.
Jazyk: angličtina
Zdroj: Critical care (London, England) [Crit Care] 2019 Nov 28; Vol. 23 (1), pp. 384. Date of Electronic Publication: 2019 Nov 28.
DOI: 10.1186/s13054-019-2655-7
Abstrakt: Background: Clinical and biologic phenotypes of sepsis are proposed in human studies, yet it is unknown whether prognostic or drug response phenotypes are present in animal models of sepsis. Using a biotelemetry-enhanced, murine cecal ligation and puncture (CLP) model, we determined phenotypes of polymicrobial sepsis prior to physiologic deterioration, and the association between phenotypes and outcome in a randomized trial of prompt or delayed antibiotics and fluids.
Methods: We performed a secondary analysis of male C57BL/6J mice in two observational cohorts and two randomized, laboratory animal experimental trials. In cohort 1, mice (n = 118) underwent biotelemetry-enhanced CLP, and we applied latent class mixed models to determine optimal number of phenotypes using clinical data collected between injury and physiologic deterioration. In cohort 2 (N = 73 mice), inflammatory cytokines measured at 24 h after deterioration were explored by phenotype. In a subset of 46 mice enrolled in two trials from cohort 1, we tested the association of phenotypes with the response to immediate (0 h) vs. delayed (2 to 4 h) antibiotics or fluids initiated after physiologic deterioration.
Results: Latent class mixture modeling derived a two-class model in cohort 1. Class 2 (N = 97) demonstrated a shorter time to deterioration (mean SD 7.3 (0.9) vs. 9.7 (3.2) h, p < 0.001) and lower heart rate at 7 h after injury (mean (SD) 564 (55) vs. 626 (35) beats per minute, p < 0.001). Overall mortality was similar between phenotypes (p = 0.75). In cohort 2 used for biomarker measurement, class 2 mice had greater plasma concentrations of IL6 and IL10 at 24 h after CLP (p = 0.05). In pilot randomized trials, the effects of sepsis treatment (immediate vs. delayed antibiotics) differed by phenotype (p = 0.03), with immediate treatment associated with greater survival in class 2 mice only. Similar differential treatment effect by class was observed in the trial of immediate vs. delayed fluids (p = 0.02).
Conclusions: We identified two sepsis phenotypes in a murine cecal ligation and puncture model, one of which is characterized by faster deterioration and more severe inflammation. Response to treatment in a randomized trial of immediate versus delayed antibiotics and fluids differed on the basis of phenotype.
Databáze: MEDLINE
Externí odkaz: