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

Research output: Contribution to journalReview article

Manasi Nandi, Simon K Jackson, Duncan Macrae, Manu Shankar-Hari, Jordi L Tremoleda, Elliot Lilley

Original languageEnglish
Pages (from-to)1715-1734
Number of pages20
JournalClinical Science
Issue number13
Accepted/In press25 Jun 2020
Published17 Jul 2020

Bibliographical note

© 2020 The Author(s).

King's Authors


Sepsis is a major worldwide healthcare issue with unmet clinical need. Despite extensive
animal research in this area, successful clinical translation has been largely unsuccessful.
We propose one reason for this is that, sometimes, the experimental question is misdirected
or unrealistic expectations are being made of the animal model.
As sepsis models can lead to a rapid and substantial suffering – it is essential that we continually review experimental approaches and undertake a full harm:benefit impact assessment
for each study. In some instances, this may require refinement of existing sepsis models. In
other cases, it may be replacement to a different experimental system altogether, answering a mechanistic question whilst aligning with the principles of reduction, refinement and
replacement (3Rs).
We discuss making better use of patient data to identify potentially useful therapeutic targets
which can subsequently be validated in preclinical systems. This may be achieved through
greater use of construct validity models, from which mechanistic conclusions are drawn. We
argue that such models could provide equally useful scientific data as face validity models,
but with an improved 3Rs impact. Indeed, construct validity models may not require sepsis
to be modelled, per se. We propose that approaches that could support and refine clinical translation of research findings, whilst reducing the overall welfare burden on research

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