Xiphoid Surface Temperature Predicts Mortality in a Murine Model of Septic Shock

Abstract

Sepsis continues to be a major challenge for modern medicine. Several preclinical models were developed to study sepsis and each has strengths and weaknesses. The cecal slurry (CS) method is a practical alternative because it does not require surgery, and the infection can be dosed. However, one disadvantage is that the dosage must be determined for each CS preparation using survival studies. Our aim was to refine a survival protocol for the CS model by determining a premonitory humane endpoint that would reduce animal suffering. Mice become hypothermic in sepsis; therefore, we tested whether reductions in surface temperature (Ts), measured by noninvasive infrared thermometry, could predict eventual death. We injected 154 C57BL/6J mice with CS (0.9-1.8 mg/g) and periodically monitored Ts at the xiphoid process over 5 days. We used, as predictors, combinations of temperature thresholds (29°C -31°C) and times, postinjection (18-36 h). A receiver-operator curve, sensitivity, and specificity were determined. A Distress Index value was calculated for the threshold conditions. The optimum detection threshold (highest Youden index) was found at Ts ≤ 30.5°C at 24 h (90% specific, 84% sensitive). This threshold condition reduced animal suffering by 41% while providing an accurate survival rate estimate. Using this threshold, only 13 of 154 mice would have died from sepsis; 67 would have been euthanized at 24 h, and only 7 of 154 would have been euthanized unnecessarily. In conclusion, using a humane endpoint of Ts ≤ 30.5°C at 24 h accurately predicts mortality and can effectively reduce animal suffering during CS survival protocols.

Impact of ambient temperature on inflammation-induced encephalopathy in endotoxemic mice—role of phosphoinositide 3-kinase gamma

“…Furthermore, ignoring the role of ambient temperature on basal physiological responsiveness in small animals frequently used in preclinical sepsis models leads to far-reaching repercussions of profound misinterpretation. Indeed, usage time course of body temperature for prognosis prediction under chronic cold stress for mice restricts statements of numerous pertinent reports [54][55][56][57][58] merely on the subgroup of septic patients endangered for cold challenge leading to accidental hypothermia [59]. The recent findings in mice showed that a reduced ambient temperature exacerbates SIRS-induced cardiac autonomic dysregulation and myocardial dysfunction [60].…”

Impact of Ambient Temperature on Inflammation-induced Encephalopathy in Endotoxemic Mice—Role of Phosphoinositide 3-Kinase Gamma

“…Importantly, recent guidelines for preclinical studies in sepsis research [32,33] and cerebrovascular research [34][35][36], with the emphasis to improve reproducibility and translational impact, neglected the impact of ambient temperature on pathogenesis of inflammatory diseases or did not consider that their recommended lower baseline limit for housing temperatures of small rodents causes chronic 'cold' stress [37,38]. Furthermore, ignoring the role of ambient temperature on basal physiological responsiveness in small animals frequently used in preclinical sepsis models leads to far-reaching repercussions of profound misinterpretation: Time course of body temperature lowering and development of hypothermia is used for prognosis prediction while mice are under chronic cold stress for mice [39][40][41][42][43]. Clearly, statements of these pertinent reports are restricted merely on the subgroup of septic patients endangered for cold challenge leading to accidental hypothermia [44].…”

“…Clearly, statements of these pertinent reports are restricted merely on the subgroup of septic patients endangered for cold challenge leading to accidental hypothermia [44]. Overall recommendations for endpoint decision on development of hypothermia in preclinical inflammatory and infection research while neglecting T a [32,[40][41][42][43] are clearly misleading.…”

B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes to septic hypotension

“…Infrared thermometer assessment of surface temperature. Xiphoid surface temperature was assessed using the Etekcity Lasergrip infrared, as previously described (74). Briefly, hair from the xiphoid surface was removed, and mice were restrained.…”