Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis

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

doi:10.1007/s15010-018-1183-8

Abstract

PurposePre-clinical animal studies precede the majority of clinical trials. While the clinical sepsis definitions 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. To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May, 2017. The conference goal 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.Methods31 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).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” that should be implemented for animal sepsis models. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental.

Highlights

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]
Not all experiments must measure all parameters of organ dysfunction but animal models should be fully exploited f

Summary

We recommend that the treatment be randomized and blinded when feasible

5. The development and validation of standardized criteria to monitor the well-being of septic animals is recommended. 6. The development and validation of standardized criteria for euthanasia of septic animals is recommended (exceptions possible). 7. Analgesics recommended for surgical sepsis consistent with ethical considerations d. 8. We recommend that challenge with LPS is not an appropriate model for replicating human sepsis. 9. We recommend that microorganisms used in animal models preferentially replicate those commonly found in human sepsis e. To define objective evidence of the severity of organ/system dysfunction, a scoring system should be developed, validated and used, or use an existing scoring system. Not all experiments must measure all parameters of organ dysfunction but animal models should be fully exploited f.

14. Fluid resuscitation is essential unless part of the study

Findings

Compliance with ethical standards