Prompt Administration of Antibiotics and Fluids in the Treatment of Sepsis: A Murine Trial*

Lewis, Anthony; Griepentrog, John E.; Zhang, Xianghong; Angus, Derek C.; Seymour, Christopher W.; Rosengart, Matthew R.

doi:10.1097/ccm.0000000000003004

Cited by 27 publications

(29 citation statements)

References 44 publications

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“…Due to the semi-quantitative and subjective nature of all three scoring systems, we monitored body temperature as an objective vital sign: our data show that temperature decreases over time in a sepsis severity-dependent manner and that reduced body temperature is a robust predictor of death in the CLP mouse model of sepsis—a novel and important finding. Recent studies by Lewis et al have shown that body temperature tracking with an implanted wireless biotelemetry device is useful for monitoring the physiologic response to antibiotic treatment and fluid resuscitation in murine sepsis [ 25 ], which is consistent with our findings that body temperature can be used to monitor disease severity in CLP sepsis.…”

Section: Discussionsupporting

confidence: 90%

Body temperature and mouse scoring systems as surrogate markers of death in cecal ligation and puncture sepsis

Safiah

Sharma

Kwong

et al. 2018

ICMx

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BackgroundDespite increasing ethical standards for conducting animal research, death is still often used as an endpoint in mouse sepsis studies. Recently, the Murine Sepsis Score (MSS), Mouse Clinical Assessment Score for Sepsis (M-CASS), and Mouse Grimace Scale (MGS) were developed as surrogate endpoint scoring systems for assessing pain and disease severity in mice. The objective of our study was to compare the effectiveness of these scoring systems and monitoring of body temperature for predicting disease progression and death in the cecal ligation and puncture (CLP) sepsis model, in order to better inform selection of surrogate endpoints for death in experimental sepsis.MethodsC57Bl/6J mice were subjected to control sham surgery, or moderate or severe CLP sepsis. All mice were monitored every 4 h for surrogate markers of death using modified versions of the MSS, M-CASS, and MGS scoring systems until 24 h post-operatively, or until endpoint (inability to ambulate) and consequent euthanasia.ResultsThirty percent of mice subjected to moderate severity CLP reached endpoint by 24 h post-CLP, whereas 100% undergoing severe CLP reached endpoint within 20 h. Modified MSS, M-CASS, and MGS scores all increased, while body temperature decreased, in a time-dependent and sepsis severity-dependent manner, although modified M-CASS scores showed substantial variability. Receiver operating characteristic curves demonstrate that the last recorded body temperature (AUC = 0.88; 95% CI 0.77–0.99), change in body temperature (AUC = 0.89; 95% CI 0.78–0.99), modified M-CASS (AUC = 0.93; 95% CI 0.85–1.00), and modified MSS (AUC = 0.95; 95% CI 0.88–1.01) scores are all robust for predicting death in CLP sepsis, whereas modified MGS (AUC = 0.78; 95% CI 0.63–0.92) is less robust.ConclusionsThe modified MSS and body temperature are effective markers for assessing disease severity and predicting death in the CLP model, and should thus be considered as valid surrogate markers to replace death as an endpoint in mouse CLP sepsis studies.

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Section: Discussionsupporting

confidence: 90%

Body temperature and mouse scoring systems as surrogate markers of death in cecal ligation and puncture sepsis

Safiah

Sharma

Kwong

et al. 2018

ICMx

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“…A 1-cm ligation, 21-gauge double puncture model of cecal ligation and puncture (CLP) under anesthesia was performed as previously described [16]. At the time of CLP, an HD-X11 wireless biotelemetry device (Data Sciences International, St. Paul, MN) capable of continuously measuring heart rate, core temperature, and activity was implanted into the peritoneal cavity in accordance with manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

“…Latent class-based methods are applied in patients with acute respiratory distress syndrome (ARDS) to identify subphenotypes that are predictive of response to fluid management strategies [15]. We sought to capitalize on a recent murine randomized trial of prompt vs. delayed antibiotics and fluids enhanced by biotelemetry monitoring [16, 17] and use latent class methods to (i) identify murine sepsis phenotypes prior to overt, physiologic deterioration, (ii) explore their biologic profiles, and (iii) test their association with response to treatment. We hypothesized these data would provide “proof-of-concept” that drug-response phenotypes exist in a commonly used preclinical model of sepsis.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

Self Cite

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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.

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“…heart rate, body temperature, mobility) in mice (105–107). Recently, Lewis et al (108) demonstrated a large-scale utility of biotelemetry monitoring for fluid resuscitation and antimicrobial treatment in CLP mice. In vivo wireless monitoring of cardiovascular endpoints has been successfully tested in pigs (109), dogs and non-human primates (110).…”

Section: Chapter 2: Humane Modelingmentioning

confidence: 99%

Part I: Minimum Quality Threshold in Preclinical Sepsis Studies (MQTiPSS) for Study Design and Humane Modeling Endpoints

Zingarelli

Coopersmith

Drechsler

et al. 2019

Shock

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Pre-clinical animal studies are mandatory before new treatments can be tested in clinical trials. However, their use in developing new therapies for sepsis has been controversial because of limitations of the models and inconsistencies with the clinical conditions. In consideration of the revised definition for clinical sepsis and septic shock (Sepsis-3), a Wiggers-Bernard Conference was held in Vienna in May 2017 to propose standardized guidelines on pre-clinical sepsis modeling. The participants conducted a literature review of 260 most highly cited scientific articles on sepsis models published between 2003 and 2012. The review showed, for example, that mice were used in 79% and euthanasia criteria were defined in 9% of the studies. Part I of this report details the recommendations for study design and humane modeling endpoints that should be addressed in sepsis models. The first recommendation is that survival follow-up should reflect the clinical time course of the infectious agent used in the sepsis model. Furthermore, it is recommended that therapeutic interventions should be initiated after the septic insult replicating clinical care. To define an unbiased and reproducible association between a new treatment and outcome, a randomization and blinding of treatments as well as inclusion of all methodological details in scientific publications is essential. In all pre-clinical sepsis studies, the high standards of animal welfare must be implemented. Therefore, development and validation of specific criteria for monitoring pain and distress, and euthanasia of septic animals, as well as the use of analgesics are recommended. A set of four considerations is also proposed to enhance translation potential of sepsis models. Relevant biological variables and co-morbidities should be included in the study design and sepsis modeling should be extended to mammalian species other than rodents. Additionally, the need for source control (in case of a defined infection focus) should be considered. These recommendations and considerations are proposed as "best practices" for animal models of sepsis that should be implemented.

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Prompt Administration of Antibiotics and Fluids in the Treatment of Sepsis: A Murine Trial*

Abstract: We conclude that antibiotic therapy is highly time sensitive, and efforts should be made to deliver this critical therapy as early as possible in sepsis, perhaps extending into the first point of medical contact outside the hospital.

Cited by 27 publications

References 44 publications

Body temperature and mouse scoring systems as surrogate markers of death in cecal ligation and puncture sepsis

Body temperature and mouse scoring systems as surrogate markers of death in cecal ligation and puncture sepsis

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

Part I: Minimum Quality Threshold in Preclinical Sepsis Studies (MQTiPSS) for Study Design and Humane Modeling Endpoints

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