Abstract
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.
Highlights
Despite increasing ethical standards for conducting animal research, death is still often used as an endpoint in mouse sepsis studies
Improvements are necessary to achieve more ethical and humane treatment of animals in research related to critical care medicine [7, 9, 10], and for experimental sepsis research [10], where clear endpoint markers have not been established for the gold standard sepsis model of cecal ligation and puncture (CLP)
Body temperature can assess disease progression and predict death in CLP sepsis To determine whether body temperature could be utilized to monitor disease progression in sepsis, mice were subjected to sham surgery, moderate CLP or severe CLP procedures, and body temperature was monitored through a rectal probe every 4 h
Summary
Despite increasing ethical standards for conducting animal research, death is still often used as an endpoint in mouse sepsis studies. Surrogate markers of death involve using criteria related to pain, suffering, and/or illness, such as clinically relevant scoring systems that semi-quantitatively assess the physical appearance and/or behavior of an animal [4,5,6], in order to gauge the time at which animals should be humanely euthanized [7]. These decisions must be carefully balanced with minimizing premature termination of animal studies, which may lead to incomplete observations and may necessitate use of even more animals [7, 8]. Improvements are necessary to achieve more ethical and humane treatment of animals in research related to critical care medicine [7, 9, 10], and for experimental sepsis research [10], where clear endpoint markers have not been established for the gold standard sepsis model of cecal ligation and puncture (CLP)
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