Animal models of sepsis: why does preclinical efficacy fail to translate to the clinical setting?
OBJECTIVE
To postulate reasons as to why the benefits seen with novel therapies in animal models of sepsis fail to translate to the clinical setting.


METHODS
MEDLINE searches and relevant book chapters.


METHODS
Thousands of preclinical trials performed over more than five decades have failed to find more than a handful of drugs and techniques that significantly improve outcomes in clinical sepsis. We review current concepts surrounding the variety of animal models used today, ranging from simple models of acute toxemia to more complex models of abdominal sepsis. Differences between animal and human populations are also examined including species, age, comorbidity, and the use of supportive therapies. Finally, we examine differences between preclinical and clinical trial design, and the potential for experimental and publication bias.


CONCLUSIONS
Animal models of sepsis are still too heterogeneous with regard to type of insult, duration, and supportive therapy to be regarded as representative of the human condition. Using standardized animal models may eliminate some of the differences between animal and human studies, allowing a greater degree of translation.
Dyson
Alex
A
Bloomsbury Institute of Intensive Care Medicine, Department of Medicine, University College London, London, United Kingdom.
Singer
Mervyn
M
D000367:Age Factors; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001419:Bacteria; D002491:Central Nervous System Agents / Q000494:pharmacology; D002986:Clinical Trials as Topic / Q000379:methods; D015897:Comorbidity; D004195:Disease Models, Animal; D004731:Endotoxins / Q000008:administration & dosage / Q000097:blood; D005440:Fluid Therapy; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D017594:Publication Bias; D018805:Sepsis / Q000276:immunology* / Q000628:therapy*; D012720:Severity of Illness Index; D012737:Sex Factors; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000900:Anti-Bacterial Agents; D002491:Central Nervous System Agents; D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide