• Anthony J Lewis, Du Yuan, Xianghong Zhang, Derek C Angus, Matthew R Rosengart, and Christopher W Seymour.
• 1Department of Surgery, University of Pittsburgh, Pittsburgh, PA. 2Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.
• Crit. Care Med. 2016 Jun 1; 44 (6): e420-31.

ObjectivesMurine models of critical illness are commonly used to test new therapeutic interventions. However, these interventions are often administered at fixed time intervals after the insult, perhaps ignoring the inherent variability in magnitude and temporality of the host response. We propose to use wireless biotelemetry monitoring to define and validate criteria for acute deterioration and generate a physiology-based murine cecal ligation and puncture model that is more similar to the conduct of human trials of sepsis.DesignLaboratory and animal research.SettingUniversity basic science laboratory.SubjectsMale C57BL/6 mice.InterventionsMice underwent cecal ligation and puncture, and an HD-X11 wireless telemetry monitor (Data Sciences International) was implanted that enabled continuous, real-time measurement of heart rate, core temperature, and mobility. We performed a population-based analysis to determine threshold criteria that met face validity for acute physiologic deterioration. We assessed construct validity by temporally matching mice that met these acute physiologic deterioration thresholds with mice that had not yet met deterioration threshold. We analyzed matched blood samples for blood gas, inflammatory cytokine concentration, cystatin C, and alanine aminotransferase.Measurements And Main ResultsWe observed that a 10% reduction in both heart rate and temperature sustained for greater than or equal to 10 minutes defined acute physiologic deterioration. There was significant variability in the time to reach acute deterioration threshold across mice, ranging from 339 to 529 minutes after cecal ligation and puncture. We found adequate construct validity, as mice that met criteria for acute deterioration had significantly worse shock, systemic inflammation (elevated tumor necrosis factor-α, p = 0.003; interleukin-6, p = 0.01; interleukin-10, p = 0.005), and acute kidney injury when compared with mice that had not yet met acute deterioration criteria.ConclusionsWe defined a murine threshold for acute physiologic deterioration after cecal ligation and puncture that has adequate face and construct validity. This model may enable a more physiology-based model for evaluation of novel therapeutics in critical illness.

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