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Part I

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

Zingarelli, Basilia*; Coopersmith, Craig M.; Drechsler, Susanne; Efron, Philip§; Marshall, John C.; Moldawer, Lyle§; Wiersinga, W. Joost||; Xiao, Xianzhong**; Osuchowski, Marcin F.; Thiemermann, Christoph††

doi: 10.1097/SHK.0000000000001243
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ABSTRACT Preclinical 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 preclinical 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 preclinical 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 comorbidities should be included in the study design and sepsis modeling should be extended to mammalian species other than rodents. In addition, 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.

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

Emory University School of Medicine, Atlanta, Georgia

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

§Sepsis and Critical Illness Research Center, University of Florida College of Medicine, Gainesville, Florida

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

||Division of Infectious Diseases, 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

††The William Harvey Research Institute, Barts and London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom

Address reprint requests to Basilia Zingarelli, MD, PhD, Department of Pediatrics, Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. E-mail: Basilia.Zingarelli@cchmc.org; Co-correspondence: Christoph Thiemermann, MD, PhD, The William Harvey Research Institute, Barts and London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom. E-mail: c.thiemermann@qmul.ac.uk

Received 20 April, 2018

Revised 16 May, 2018

Accepted 26 July, 2018

The Austrian Science Fund T707-B13 (SD, MFO); The William Harvey Research Foundation (CT); NWO VIDI (no.: 91716475) and Horizon 2020: MC-ITN “European Sepsis Academy” (WJW); National Institutes of Health R01 GM067202 and GM115973 (BZ); The National Institute of General Medical Sciences GM072808, GM104323, GM109779, and GM113228 (CMC).

The authors report no conflicts of interest.

© 2019 by the Shock Society