Man is the new mouse: Elective surgery as a key translational model for multi-organ dysfunction and sepsis

Abstract

Translational research in critically ill human patients presents many methodological challenges. Diagnostic uncertainty, coupled with poorly defined comorbidities, make the identification of a suitable control population for case-control investigations an arguably insurmountable challenge. Healthy volunteer experiments using endotoxin infusion as an inflammatory model are methodologically robust, but fail to replicate the onset of, and diverse therapeutic interventions associated with, sepsis/trauma. Animal models are also limited by many of these issues. Major elective surgery addresses many of these shortfalls and offers a key model for exploring the human biology underlying the sepsis syndrome. Surgery triggers highly conserved features of the human inflammatory response that are common to both tissue damage and infection. Surgical patients sustain a predictable and relatively high incidence of sepsis, particularly within the 'higher risk' group. The collection of preoperative samples enables each patient to act as their own control. Thus, the surgical model offers unique and elegant experimental design features that provide an important translational bridge between the basic biological understanding afforded by animal laboratory models and the de novo presentation of human sepsis.

Sepsis Patients with First and Second-Hit Infections Show Different Outcomes Depending on the Causative Organism

“…Firstly, there may be logistical and procedural reasons as to why these patients have an excessive mortality. The increasing levels of multidrug-resistant Gram-negative organisms (Dellinger et al, 2013 ; Cain et al, 2015 ) may render patients with these causative organisms more likely to receive ineffective initial therapy (Micek et al, 2012 ; Zilberberg et al, 2014 ). However, recent data from the World Healthcare-Associated Infections Forum indicates that multidrug-resistant Gram-negative organisms only play a very small role in the UK with incidences below 5%, making this explanation less plausible (Leligdowicz et al, 2014 ).…”

“…Therefore, we defined surrogate first-hit infection subgroups including post-operative elective surgery and trauma patients. There is a large volume of research supporting the use of these groups of patients as a model for investigating first-hit infection (Cain et al, 2015 ). With the advent of new nation-wide systems of sepsis outcomes such as the recording through the work of the UK Sepsis Trust and the National Institute for Health and Care Excellence (NICE), causative organism data may be possible to analyse in the future.…”

“…These sub-groups were patients categorized as having trauma, emergency neurosurgery, elective surgery, and cardiogenic shock as their primary reason for intensive care admission. It has been shown that these patients can provide a plausible and accessible model of the development of severe sepsis (Cain et al, 2015 ).…”

Perioperative medicine and UK plc

“…25 Identifying and/or developing tractable models of pathophysiology where man is the new mouse remains a critical challenge for translational biological understanding. 26 For example, the frequency of sepsis and subclinical organ injury that can now be revealed by many of the new technologies listed above affords a unique, highly individualised approach to understanding early disease processes. Critical to this approach is challenging the endotype in question, often using readily available physiological tests.…”

When Enough Is Enough: Decision Criteria for Moving a Known Drug into Clinical Testing for a New Indication in the Absence of Preclinical Efficacy Data

“…1,2 The literature is replete with examples of contradictions and discordance between animal and human effects, including many cases in which promising animal results have failed to translate to clinically significant efficacy in humans. This is particularly true in some therapeutic areas such as neurodegenerative, psychiatric, and central nervous system diseases, [3][4][5] as well as sepsis 6 and inflammatory diseases. 7 These complexities inherent in translational research present an important opportunity for exploring novel approaches that successfully and efficiently yield outcomes as proximal as possible to eventual human benefit.…”