Abstract
BackgroundClinical 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.MethodsWe 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.ResultsLatent 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).ConclusionsWe 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.
Highlights
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
Clinical data for murine phenotypes in cohorts 1 and 2 We previously developed and validated criteria that define acute physiologic deterioration after cecal ligation and puncture (CLP): (1) 10% decline of heart rate from its peak value and (2) a scaled 10% drop in core temperature calculated as 10% × [16]
The benefit of immediate antibiotics was similar in both groups. In this biotelemetry-enhanced murine model of polymicrobial sepsis, we demonstrate the feasibility of deriving clinical sepsis phenotypes prior to overt physiologic
Summary
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. As studies of novel sepsis therapeutics continue to be neutral, future gains may come from clinical trials that enrich for groups of sepsis patients that share clinical or biologic characteristics, termed phenotypes, and explore for differences in treatment effects by phenotype [5, 6]. To support this agenda in precision treatment, recent adult and pediatric human cohort studies propose biologic and clinical phenotypes of sepsis that are both prognostic of outcome and predictive of treatment response [7,8,9,10,11]. Sepsis severity scoring systems have been developed, but these are subjective and the validity as platforms for the testing of new agents remains to be determined [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
