Experimental models of sepsis and septic shock: an overview

Sepsis remains a major cause of morbidity and mortality in surgical patients and trauma victims, mainly due to sepsis-induced multiple organ dysfunction. In contrast to preclinical studies, most clinical trials of promising new treatment strategies for sepsis have fails to demonstrate efficacy. Although many reasons could account for this discrepancy, the misinterpretation of preclinical data obtained from experimental studies, and especially the use of animal models that do not adequately mimic human sepsis may have been contributing factors. In this review, the benefits and limitations of various animal models of sepsis are discussed to clarify the extend to which findings are relevant to human sepsis, particularly with respect to the subsequent design and execution of clinical trials. Such models include intravascular infusion of endotoxin or live bacteria, bacterial peritonitis, cecal ligation and perforation, soft tissue infection, pneumonia or meningitis models, using different animal species including rats, mice, rabbits, dogs, pigs, sheep and nonhuman primates. Despite several limitations, animal models remain essential in the development of all new therapies for sepsis and septic shock, because they provide fundamental information about the pharmacokinetics, toxicity, and mechanism of drug action that cannot be duplicated by other methods. New therapeutic agents should be studies in infection models, even after the initiation of the septic process. Furthermore, debility conditions need to be reproduced to avoid the exclusive use of healthy animals, which often do not represent the human septic patient. A sepse persiste como causa capital de mortalidade e morbidade em pacientes operados e nas vítimas de trauma, principalmente pela disfunção de múltiplos órgãos induzida pela sepse. Em contraste com estudos experimentais, a maioria dos estudos clínicos avaliando potenciais novos tratamentos para a sepse falham em demonstrar eficácia. Apesar de haver diversas possíveis explicações para esta discrepância, a interpretação equivocada dos dados pré-clínicos e. principalmente, o uso de modelos animais que não mimetizam adequadamente a sepse humana podem ter sido fatores contribuintes. Nesta revisão, os benefícios e limitações dos diversos modelos experimentais de sepse são discutidos quanto a relevância com a sepse humana e em relação a futuros ensaios clínicos. Entre os modelos discutidos incluímos a injeção intravascular de endotoxina ou bactérias vivas,