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Minimum Quality Threshold in Pre-Clinical Sepsis Studies (Mqtipss): An International Expert Consensus Initiative for Improvement of Animal Modeling in Sepsis

Osuchowski, Marcin F.*; Ayala, Alfred; Bahrami, Soheyl*; Bauer, Michael; Boros, Mihaly§; Cavaillon, Jean-Marc||; Chaudry, Irshad H.; Coopersmith, Craig M.**; Deutschman, Clifford S.††; Drechsler, Susanne*; Efron, Philip‡‡; Frostell, Claes§§; Fritsch, Gerhard||||,¶¶; Gozdzik, Waldemar***; Hellman, Judith†††; Huber-Lang, Markus‡‡‡; Inoue, Shigeaki§§§; Knapp, Sylvia||||||; Kozlov, Andrey V.*; Libert, Claude¶¶¶,****; Marshall, John C.††††; Moldawer, Lyle L.‡‡; Radermacher, Peter‡‡‡‡; Redl, Heinz*; Remick, Daniel G.§§§§; Singer, Mervyn||||||||; Thiemermann, Christoph¶¶¶¶; Wang, Ping*****; Wiersinga, W. Joost†††††; Xiao, Xianzhong‡‡‡‡‡; Zingarelli, Basilia§§§§§

doi: 10.1097/SHK.0000000000001212
International Expert Consensus for Pre-Clinical Sepsis Studies
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ABSTRACT Preclinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of preclinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on preclinical sepsis modeling was held in Vienna in May, 2017. The goal of the conference was to identify limitations of preclinical sepsis models and to propose a set of guidelines, defined as the “Minimum Quality Threshold in Preclinical Sepsis Studies” (MQTiPSS), to enhance translational value of these models. A total of 31 experts from 13 countries participated and were divided into six thematic Working Groups: Study Design, Humane modeling, Infection types, Organ failure/dysfunction, Fluid resuscitation, and 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). Overall, the participants reached consensus on 29 points; 20 at “recommendation” and nine at “consideration” strength. This Executive Summary provides a synopsis of the MQTiPSS consensus. We believe that these recommendations and considerations will serve to bring a level of standardization to preclinical models of sepsis and ultimately improve translation of preclinical findings. These guideline points are proposed as “best practices” for animal models of sepsis that should be implemented. To encourage its wide dissemination, this article is freely accessible on the Intensive Care Medicine Experimental and Infection journal websites. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection, and Intensive Care Medicine Experimental.

*Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria

Rhode Island Hospital and Alpert School of Medicine at Brown University, Providence, Rhode Island

Jena University Hospital, Jena, Germany

§Institute of Surgical Research, University of Szeged, Szeged, Hungary

||Institut Pasteur, Paris, France

University of Alabama at Birmingham School of Medicine, Birmingham, Alabama

**Emory University School of Medicine, Atlanta, Georgia

††Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York

‡‡University of Florida College of Medicine, Gainesville, Florida

§§Division of Anaesthesia and Intensive Care, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden

||||AUVA Trauma Center, Vienna, Austria

¶¶Paracelsus Medical University, Salzburg, Austria

***Wroclaw Medical University, Wroclaw, Poland

†††University of California School of Medicine, San Francisco, California

‡‡‡Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany

§§§Kobe University Graduate School of Medicine, Kobe, Japan

||||||Medical University Vienna, Department of Medicine 1, Vienna, Austria

¶¶¶Center for Inflammation Research, VIB, Ghent, Belgium

****University Ghent, Ghent, Belgium

††††Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Canada

‡‡‡‡Institute of Anaesthesiological Pathophysiology and Process Development, University Hospital of Ulm, Ulm, Germany

§§§§Boston University School of Medicine, Boston, Massachusetts

||||||||Bloomsbury Institute of Intensive Care Medicine, University College London, UK

¶¶¶¶The William Harvey Research Institute, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London, UK

*****Feinstein Institute for Medical Research, Manhasset, New York

†††††Division of Infectious Diseases, and Center for Experimental and Molecular Medicine, the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

‡‡‡‡‡Xiangya School of Medicine, Central South University, Chagnsha, Hunan, China

§§§§§Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio

Address reprint requests to Dr Marcin F. Osuchowski, DVM, PhD, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Donaueschingenstrasse 13, A-1200 Vienna, Austria. E-mail:

Received 19 April, 2018

Revised 22 June, 2018

Accepted 22 June, 2018

CF controls the Claes Frostell Research & Consulting AB company that participated in supporting several clinical and experimental studies.

All other authors report no conflicts of interest.

Executive Summary

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This modeling thing, it's pretty easy, but actually it's also really tough.” Cara Delevingne

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With the ultimate goal to reduce mortality/morbidity in patients, animal modeling of diseases has been limited by poor translation (1, 2). This is often fueled by the low fidelity of available model systems (3, 4), their inappropriate study designs (2) and selective use of animal data (5, 6). When compared with other inflammatory states (e.g., arthritis, atherosclerosis), the complexity of sepsis has hampered the development of high-fidelity models. However, this challenge can be aptly embraced by building on recent advances in the understanding of sepsis pathophysiology and avoiding past errors. Any promising sepsis model must be specifically tailored to the posited hypothesis, “reverse translated” to its clinical counterpart (7, 8), and adjusted as new pathophysiological evidence emerges. This is echoed by the US Food and Drug Administration (FDA) in their 2010 Guidance for Industry and FDA Staff: “FDA believes that the animal…(model)…should provide a test system that offers a best attempt at simulating the clinical setting.” (General Considerations for Animal Studies for Cardiovascular Devices;

Unfortunately, while the clinical definition of sepsis is currently in its third iteration (9) and the Surviving Sepsis Campaign Guidelines for patient management have been updated three times (10), preclinical sepsis research has not been subjected to any organized attempt at introducing best practices, management guidelines, and standardization (11). This creates a large quality gap and confusion with conflicting data reflecting huge variations in, for example, insult severity, fluid resuscitation, and study duration. Effective animal modeling and reporting guidelines have recently been proposed for other specific diseases such as pulmonary fibrosis (12), stroke (13, 14), heart failure (15), and malaria (16) making the void in the field of preclinical sepsis even more apparent. It is essential that animal models of sepsis continue to evolve. Lack of sufficient standardization of preclinical models will continue to limit the utility of sepsis animal research as a useful platform for advancing clinical outcomes and care in sepsis (17, 18) and will reduce the opportunities to identify and test new therapies.

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To address this perceived deficit, the Ludwig Boltzmann Institute of Experimental and Clinical Traumatology in the AUVA Research Center organized in May 2017 in Vienna a Wiggers-Bernard Conference on “Pre-clinical Modeling in Sepsis: Exchanging Opinions and Forming Recommendations.” The key goal was to create publishable material that characterizes elements that should be included in preclinical sepsis studies and defined by the so called “Minimum Quality Threshold in Pre-Clinical Sepsis Studies” (MQTiPSS) descriptor. The Wiggers-Bernard Conference participants identified and addressed several broad, critically-important concepts in animal sepsis modeling. A total of 31 experts from 13 countries participated in the initiative (including five members of the Sepsis-3 definitions task force) and were divided into six thematic Working Groups: study design, humane endpoints, infection types, organ failure/dysfunction, critical fluid resuscitation, and antimicrobial therapy.

The initiative consisted of three phases: preparatory (prior to the meeting; approximately 3 months), during which participants performed a systematic review of the 260 top cited (over 29,000 citations in aggregate) 2003 to 2012 preclinical publications (using ISI Web of Knowledge database; query: “sepsis model”; 374 individual experiments analyzed) and identified the key modeling topics to be discussed, discussion during which the participants spent two days at the Wiggers-Bernard Conference examining preclinical sepsis models and ultimately voted to reach consensus on the proposed points (either at the “recommendation” or “consideration” strength), and post-meeting refinement of the accepted points and finalization of the arguments to be included in the final publications (using a modified Delphi method; approximately three months). Following the format used by the Sepsis-3 task force (8), at least 2/3 (over 65%) of the votes were required for approval of a proposed point.

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First, a definition for an animal model of sepsis was formulated and (unanimously) approved: “An experimental animal (mammal) model of sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to an infection.” Second, Wiggers-Bernard Conference participants reached consensus on 29 points; 20 at “recommendation” strength and nine at “consideration” strength (listed in Tables 1–3). All consensus points were reached either unanimously or with no more than two abstentions per point (point 8). The “recommendation” strength indicates virtually unanimous agreement among the 31 participants, regarding both the content and the need for rapid implementation. Issues that require additional discussion before final recommendations could be made were classified as considerations.

Table 1

Table 1

Table 2

Table 2

Table 3

Table 3

The current executive summary briefly describes the Wiggers-Bernard Conference initiative and presents the compiled consensus points. The details of the recommendations/considerations are published in three separate papers (19–21) subsequently appearing in the 2019 January issue of Shock. Tables 1–3 summarize the main MQTiPSS consensus points published in those articles: Part I—Table 1 content (19), Part II—Table 2 (20), and Part III—Table 3 (21). Each publication is built on two (related) Working Group themes and includes a narrative clarifying caveats and intricacies related to the accepted consensus points.

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The presented consensus has not received formal endorsement from professional bodies. Writing an initial consensus was a strategic decision given that an expert opinion report has a shorter publication turnaround and our intention was to rapidly introduce the MQTiPSS concept. The Wiggers-Bernard Conference was conceived not as a one-time event but rather as an initial “call-to-arms”; an invitation to interested parties to provide further refinement and expansion of the proposed points. The on-going expansion initiatives include formation of a Task Force (under the auspices of the Shock Society; June 2017) for creation of robust, defined parameters to score sepsis models for clinical relevance. Another iteration of the Wiggers-Bernard Conference on animal sepsis models is planned for October 2019 at the joint conference of the European Shock Society and International Federation of Shock Societies in Crete, Greece.

In summary, we believe that the proposed guidelines represent the first concrete steps toward creation of a realistic framework for standardization of animal models of sepsis (i.e., MQTiPSS). Such a framework, once widely employed, will improve the quality of preclinical investigation and arm clinicians with better tools for combating sepsis in patients.

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Antimicrobial therapy; experiment; fluid resuscitation; guidelines; humane modeling; infection types; organ dysfunction; study design

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