Minimum quality threshold in pre-clinical sepsis studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis

Abstract

BackgroundPre-clinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking.ObjectiveTo address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May 2017. The goal of the conference was to identify limitations of pre-clinical sepsis models and to propose a set of guidelines, defined as the “Minimum Quality Threshold in Pre-Clinical Sepsis Studies” (MQTiPSS), to enhance translational value of these models.MethodsA total of 31 experts from 13 countries participated and were divided into 6 thematic working groups (WG): (1) study design, (2) humane modeling, (3) infection types, (4) organ failure/dysfunction, (5) fluid resuscitation, and (6) antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002–2013).ResultsOverall, the participants reached consensus on 29 points; 20 at “recommendation” (R) and 9 at “consideration” (C) strength. This executive summary provides a synopsis of the MQTiPSS consensus (Tables 1, 2, and 3). Detailed commentaries to all Rs and Cs are simultaneously published in three separate full-length papers.ConclusionsWe believe that these recommendations and considerations will serve to bring a level of standardization to pre-clinical models of sepsis and ultimately improve translation of pre-clinical findings. These guideline points are proposed as “best practices” for animal models of sepsis that should be implemented. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental.

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

“…Whilst efforts are being made to reach consensus on what constitutes experimental sepsis (in mammals) in order to standardise the scientific literature [19], it is not the purpose of the present paper to critique different 'sepsis syndrome' modelling approaches. Furthermore, recommendations have already been published on how to optimise animal welfare within such models [19,20] and will not be discussed in detail. However, in the present paper we will consider how we might rethink our use of animal systems in sepsis research to reduce the translation gap and by extension impact positively on the application of the reduction, refinement and replacement (3Rs) principles.…”

Effects of intestinal alkaline phosphatase on intestinal barrier function in a cecal ligation and puncture (CLP)‐induced mouse model for sepsis

“…Buprenorphine (0.05 mg/kg, Merck Sharp & Dohme) and a glucose solution, at a combined volume of 1 mL, were administered subcutaneously twice a day for analgesia and fluid resuscitation, as recently recommended to do in animal sepsis models. 39 An additional experiment was conducted to determine the influence of the CLP model and of the treatment with IAP on food intake, water intake, urine output, and stool production. In this experiment, 20 male OF1 mice (n = 5/group), were housed in metabolic cages, otherwise undergoing an identical experimental protocol as described above.…”

Animal models for research in human infectious diseases. CMI editorial policy

“…With their short generation time they provide large numbers of animals quickly at relatively low cost [10]. Besides the thigh model for the study of PK/PD, the mouse is also the predominant animal model for the preclinical study of urinary tract infections [11], different types of pneumonia [12] and sepsis [13]. Differences between animal and human immune systems have on the one hand led to more immunological research in human ex vivo cell systems replacing animals; on the other hand due to immunological differences between humans and mice, swine models have been developed due to their similarities with humans in terms of anatomy, genetics, immunology and physiology, their manageable behaviour and size, and the general public acceptance of using pigs for experimental purposes [8].…”