Part I: Minimum Quality Threshold in Preclinical Sepsis Studies (MQTiPSS) for Study Design and Humane Modeling Endpoints

Abstract

Pre-clinical animal studies are mandatory before new treatments can be tested in clinical trials. However, their use in developing new therapies for sepsis has been controversial because of limitations of the models and inconsistencies with the clinical conditions. In consideration of the revised definition for clinical sepsis and septic shock (Sepsis-3), a Wiggers-Bernard Conference was held in Vienna in May 2017 to propose standardized guidelines on pre-clinical sepsis modeling. The participants conducted a literature review of 260 most highly cited scientific articles on sepsis models published between 2003 and 2012. The review showed, for example, that mice were used in 79% and euthanasia criteria were defined in 9% of the studies. Part I of this report details the recommendations for study design and humane modeling endpoints that should be addressed in sepsis models. The first recommendation is that survival follow-up should reflect the clinical time course of the infectious agent used in the sepsis model. Furthermore, it is recommended that therapeutic interventions should be initiated after the septic insult replicating clinical care. To define an unbiased and reproducible association between a new treatment and outcome, a randomization and blinding of treatments as well as inclusion of all methodological details in scientific publications is essential. In all pre-clinical sepsis studies, the high standards of animal welfare must be implemented. Therefore, development and validation of specific criteria for monitoring pain and distress, and euthanasia of septic animals, as well as the use of analgesics are recommended. A set of four considerations is also proposed to enhance translation potential of sepsis models. Relevant biological variables and co-morbidities should be included in the study design and sepsis modeling should be extended to mammalian species other than rodents. Additionally, the need for source control (in case of a defined infection focus) should be considered. These recommendations and considerations are proposed as "best practices" for animal models of sepsis that should be implemented.

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

“…We studied LPS-induced SIRS at a T a of 30 °C (within thermoneutral zone for mice [ 46 ]) and at the upper edge of the recommended standard housing temperatures for laboratory mice, e.g., at 26 °C [ 30 , 47 ]. Importantly, recent guidelines for preclinical studies in sepsis research [ 48 ] and cerebrovascular research [ 49 – 51 ], 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 [ 52 , 53 ]. 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.…”

Phenylmethimazole is a candidate drug for the treatment of severe forms of coronavirus disease 2019 (COVID-19) as well as other virus-induced “cytokines storm”

“…An important point to be stressed is that although LPS-treated mice are no longer considered an appropriate model of human sepsis, most of the data regarding the inflammatory process have not been refuted [16] , [17] . Furthermore, the mouse model is considered valid if the data are replicated in another animal model (mammal) [18] and indeed the efficacy of C10 has been observed also in a preliminary study performed in horses [5] . In this study the pretreatment with C10 has prevented clinical manifestations and mortality in LPS- and peritonitis-induced endotoxic shock.…”

Rethinking animal models of sepsis – working towards improved clinical translation whilst integrating the 3Rs

“…Criticism of sepsis models per se, have focussed on questionable experimental time courses, including the duration of the 'sepsis syndrome' , choice of endpoints or the length of follow up in survivors -which do not necessarily correspond to the clinical situation. It has been argued that the duration of follow-up is often too short and may not capture the more persistent changes in the inflammatory response that ensue in patients [26,27]. However, performing longer term sepsis studies in animals has the potential to increase the welfare burden and this requires careful consideration of harm vs. benefit.…”