Thermoneutral Housing Temperature Improves Survival in a Murine Model of Polymicrobial Peritonitis

Carpenter, Kelsey C; Zhou, Yesen; Hakenjos, John M.; Fry, Chris; Nemzek, Jean A.

doi:10.1097/shk.0000000000001551

Cited by 13 publications

(5 citation statements)

References 43 publications

(61 reference statements)

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“…32 Contrasting with this report, Carpenter et al found that higher ambient temperatures (30°C vs 22°C) improved survival of male mice after CLP. 33 The reasons for this are likely complex. Body temperature affects many aspects of the immune response including antigen presentation, leukocyte trafficking and activation.…”

Section: Discussionmentioning

confidence: 99%

Common Variables That Influence Sepsis Mortality in Mice

Garcia¹,

Singh²,

Mireles³

et al. 2023

JIR

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Sepsis is characterized by a dysregulated host immune response to infection, leading to organ dysfunction and a high risk of death. The cecal ligation and puncture (CLP) mouse model is commonly used to study sepsis, but animal mortality rates vary between different studies. Technical factors and animal characteristics may affect this model in unanticipated ways, and if unaccounted for, may lead to serious biases in study findings. We sought to evaluate whether mouse sex, age, weight, surgeon, season of experiments, and timing of antibiotic administration influenced mortality in the CLP model. Methods: We created a comprehensive dataset of C57BL/6J mice that had undergone CLP surgery within our lab during years 2015-2020 from published and unpublished studies. The primary outcome was defined as the time from sepsis induction to death or termination of study (14 days). The Log rank test and Cox regression models were used to analyze the dataset. The study included 119 mice, of which 43% were female, with an average age of 12.6 weeks, an average weight of 25.3 g. 38 (32%) of the animals died. Results: In the unadjusted analyses, experiments performed in the summer and higher weight predicted a higher risk of mortality. In the stratified Cox model by sex, summer season (adjusted hazard ratio [aHR]=5.61, p=0.004) and delayed antibiotic administration (aHR=1.46, p=0.029) were associated with mortality in males, whereas higher weight (aHR=1.52, p=0.005) significantly affected mortality in females. In addition, delayed antibiotic administration (HR=1.42, p=0.025) was associated with mortality in the nonsummer seasons, but not in the summer season. Discussion: In conclusion, some factors specific to sex and season have a significant influence on sepsis mortality in the CLP model. Consideration of these factors along with appropriate group matching or adjusted analysis is critical to minimize variability beyond the experimental conditions within a study.

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Section: Discussionmentioning

confidence: 99%

Common Variables That Influence Sepsis Mortality in Mice

Garcia¹,

Singh²,

Mireles³

et al. 2023

JIR

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“…This interpretation is supported by the finding that mice, whose metabolic rate is 7 times that of humans, housed at 30 ° C had higher survival from sepsis compared to mice housed at 20 ° C. The mice housed in thermoneutral conditions had mean energy expenditures 1.8 times basal whereas in cooler temperatures their mean energy expenditures were 3.1 times basal [35].…”

Section: Glucosementioning

confidence: 85%

<strong></strong>Thiamine and High Dose Insulin Treatment for Sepsis<strong> </strong>

Bradley¹

2023

Preprint

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Sepsis is a major health problem and accounts for 20 per cent of deaths worldwide. It is the most expensive condition treated in United States hospitals at $27 billion per year or about $20,000 per patient. Treatment consisting largely of fluid resuscitation and antibiotics has only marginal impact. Mortality is about 27 per cent for hospitalized patients and about 42 per cent for patients in intensive care.There are two phases of sepsis – a hyper inflammatory phase and a subsequent hypo inflammatory phase.During the hyper inflammatory phase the metabolic rate increases associated with an increase in body temperature and a rapid escalation of immune system functioning including increased numbers of leucocytes and migration of those leucocytes to infected and damaged tissues and an increased supply and consumption of glucose to fuel this immune system.During the subsequent hypo inflammatory phase the metabolic rate declines and this is associated with a decrease in body temperature and a generalized decrease in the physiological activity of many organs including the immune system akin to hibernation. The activated immune system has priority for the available glucose over most other organs and physiological functions during such potentially life threatening circumstances. Thus adenosine triphosphate (ATP) production by mitochondria (the source of energy at the cellular level for the organism as a whole) also has a lower priority for the available glucose relative to the activated immune system. If glucose availability is threatened then mitochondrial production of ATP is partially or substantially suppressed in favor of glycolysis because glycolysis can rapidly produce large quantities of ATP that are necessary for immune cell function in infected, anaerobic, ischemic, or damaged tissues.However, glycolysis is only a temporary fix as it cannot produce the quantities of ATP necessary on an ongoing basis for the normal functioning of the healthy animal. Mitochondrial production of ATP must be recommenced for full recovery.It appears that the partial or substantial suppression of mitochondrial production of ATP by activation of the immune response becomes relatively fixated in some patients leading to a substantial ATP deficit. This is the fundamental issue of sepsis.This paper reviews the metabolism of glucose and insulin during sepsis and concludes that high dose insulin with mild hyper glycaemia in conjunction with the intravenous administration of thiamine, an inhibitor of the pyruvate dehydrogenase kinase enzymes, to re-establish physiological ATP production by mitochondria, administered early in the hypo metabolic (hypo inflammatory) phase of sepsis should significantly improve survival.

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“…Furthermore, modifications to the method for temperature collection (with or without isoflurane anesthesia) had dramatic impacts on core body temperature at site 1 (Figure 1B vs Figure 3B). Past studies have shown that septic mice with higher core body temperatures display increased mortality rate 35,36 , and that temperature is an often-overlooked factor in preclinical sepsis models that impacts reproducibility and variability 37 . Similarly, despite animals at site 1 having lower body temperatures, their survival was actually higher than site 2.…”

Section: Discussionmentioning

confidence: 99%

Development and characterization of a fecal-induced peritonitis model of murine sepsis: results from a multi-laboratory study and iterative modification of experimental conditions

Sharma

Chwastek

Dwivedi

et al. 2023

Preprint

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Background: Preclinical sepsis models have been criticized for their inability to recapitulate human sepsis and suffer from methodological shortcomings that limit external validity and reproducibility. The National Preclinical Sepsis Platform (NPSP) is a consortium of basic science researchers, veterinarians, and stakeholders in Canada undertaking standardized multi-laboratory sepsis research to increase the efficacy and efficiency of bench-to-bedside translation. In this study, we aimed to develop and characterize a 72-hour fecal-induced peritonitis (FIP) model of murine sepsis conducted in two independent laboratories. The experimental protocol was optimized by sequentially modifying dose of fecal slurry and timing of antibiotics in an iterative fashion, and then repeating the experimental series at site 1 and site 2. Results: Escalating doses of fecal slurry (0.5 to 2.5 mg/g) resulted in increased disease severity, as assessed by the modified Murine Sepsis Score (MSS), with either minimal (< 20%) or severe (> 60%) mortality outcomes. However, the MSS was a poor predictor of progression to death during the experiments, and mice were found dead without elevated MSS scores. Administration of antibiotics within 4 hours of inoculation rescued the animals from sepsis, as evidenced by 100% survival and reduced bacterial load in peritoneum and blood, compared with late administration of antibiotics after 12 hours. Site 1 and site 2 had statistically significant differences in mortality (60% vs 88%; p < 0.05) for the same dose of fecal slurry (0.75 mg/g) and marked difference in temperature between groups. Microbiome analysis between two batches of fecal slurry revealed differences in beta-diversity and differential abundance analysis, which correlated with differences in mortality in two separate experimental series. Conclusions: We demonstrate a systematic approach to optimizing a 72-hour FIP model of murine sepsis for use in multi-laboratory studies. Alterations to experimental conditions, such as dose of fecal slurry and timing of antibiotics, have clear impact on outcomes. Differences in mortality between sites despite rigorous standardization warrants further investigations to better understand inter-laboratory variation and methodological design in preclinical studies. The use of surrogate mortality endpoints in preclinical sepsis models may introduce bias in evaluation and analysis of outcomes.

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Thermoneutral Housing Temperature Improves Survival in a Murine Model of Polymicrobial Peritonitis

Cited by 13 publications

References 43 publications

Common Variables That Influence Sepsis Mortality in Mice

Common Variables That Influence Sepsis Mortality in Mice

<strong></strong>Thiamine and High Dose Insulin Treatment for Sepsis<strong> </strong>

Development and characterization of a fecal-induced peritonitis model of murine sepsis: results from a multi-laboratory study and iterative modification of experimental conditions

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