Use of Biotelemetry to Define Physiology-Based Deterioration Thresholds in a Murine Cecal Ligation and Puncture Model of Sepsis

Abstract

Objective Murine 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 (CLP) model that is more similar to the conduct of human trials of sepsis. Design Laboratory and animal research Setting University basic science laboratory Subjects Male C57BL/6 mice Interventions Mice underwent CLP, and an HD-X11 wireless telemetry monitor (DSI) 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 Results We observed that a 10% reduction in both heart rate and temperature sustained for >=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 CLP. We found adequate construct validity, as mice, which met criteria for acute deterioration had significantly worse shock, systemic inflammation (elevated TNFα, p=0.003; IL-6, p=0.01; IL-10, p=0.005), and acute kidney injury when compared to mice that had not yet met acute deterioration criteria. Conclusion We defined a murine threshold for acute physiologic deterioration after CLP that has adequate face and construct validity. This model may enable a more physiology-based model for evaluation of novel therapeutics in critical illness.

Antagonism of the Neurokinin-1 Receptor Improves Survival in a Mouse Model of Sepsis by Decreasing Inflammation and Increasing Early Cardiovascular Function

“…Whereas the former study adopted the goal directed resuscitation philosophy to improve survival in severe sepsis in the murine model of CLP, we pharmacologically attenuated the NK-1R interaction. A 2016 study defined that physiological deterioration after CLP occurred within 8 hours [35], results nearly identical to our data. This early deterioration also reinforces why delayed treatment with the NK-1R antagonist at 8 hours was not effective.…”

Sepsis-3 on the Block

“…Notably, M-CASS correlated well with the magnitude of organ damage/dysfunction (by AST, ALT, urea and creatinine) and inflammation. Soon after, two similar murine scores were tested in fecal-induced peritonitis (3) and cecal ligation and puncture (CLP) (4) models demonstrating a high predictive capacity for outcome. In the latter, biotelemetry-based measurements (i.e.…”

“…In rodents, monitoring of MODS/MOF is difficult but not impossible. Multiple repeated organ-related readouts can be obtained non-invasively by echocardiography (5,6), telemetry (4), or novel micro-CT/magnetic resonance techniques (7). Repeated low-volume sampling of blood (5,8) and urine (9) is also possible.…”

Application of a Framework to Assess the Usefulness of Alternative Sepsis Criteria

“…12 One such example is the typical hypothermic response to a cecal-ligation and puncture model of sepsis in mice, 13 which contrasts with fever commonly seen in many humans with infection. 14 Sepsis criteria for this purpose may place more value on domains like congruence with specific biologic pathways, offending organisms, or directionality of the immune response, captured within content and construct validity.…”