Copyright @ 200 by the Shock Society. Unauthorized reproduction of this article is prohibited. 8 EXPERIMENTAL MODELS OF SEPSIS AND THEIR CLINICAL RELEVANCE Luiz F. Poli-de-Figueiredo,* † Alejandra G. Garrido,* Naomi Nakagawa,* and Paulina Sannomiya* *Heart Institute, and † Department of Surgery, University of Sa ˜ o Paulo School of Medicine, Sa ˜ o Paulo, Brazil Received 17 Dec 2007; first review completed 18 Feb 2008; accepted in final form 11 Mar 2008 ABSTRACT—Sepsis remains a major cause of morbidity and mortality mainly because of sepsis-induced multiple organ dysfunction. In contrast to preclinical studies, most clinical trials of promising new treatment strategies for sepsis have failed 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 potentials and limitations of various animal models of sepsis are discussed to clarify to which extent these findings are relevant to human sepsis. 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 replaced by other methods. New therapeutic agents should be studied 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. KEYWORDS—Animal models, bacteremia, endotoxin, shock, sepsis INTRODUCTION Sepsis remains a major cause of morbidity and mortality worldwide despite developments in monitoring devices, diag- nostic tools, and new therapeutic options (1, 2). It is a clinical syndrome resulting from a complex interaction between host and infectious agents, characterized by a systemic activation of multiple inflammatory pathways, including cytokine net- work and coagulation (3). The main cause of death is multiple organ failure, which is the final pathway for sepsis-induced systemic and regional hemodynamic changes, widespread microcirculatory disturbances, and cellular alterations, lead- ing to an uncoupling between blood flow and metabolic requirements (4, 5). Extensive clinical and animal research, with substantial ex- penses, have been undertaken to address the pathophysiology and treatment of severe sepsis and septic shock (6, 7). In contrast to many preclinical studies, most clinical trials of promising new treatment strategies for sepsis have failed to demonstrate efficacy (8, 9). Although many reasons could account for this discrepancy, the misinterpretation of preclin- ical data obtained from experimental studies and especially the use of animal models that do not adequately mimic human sepsis may have been contributing factors. We reviewed the experimental models of sepsis, addressing their limitations and benefits, to clarify the extent to which their findings are relevant to human sepsis. LIMITATIONS The animal model most frequently used at the beginning of preclinical studies is rodents (6). However, they are quite re- sistant to endotoxin, have distinct hemodynamic profiles, and limited blood volume in comparison with humans (10). En- dotoxemia and bacteremia represent models without an in- fectious focus. They may reproduce many characteristics of sepsis and are highly controlled and standardized. However, they reflect a primarily systemic challenge without an in- fectious focus and the sepsis-induced immune reaction that characterizes human sepsis. Therefore, experimental models with an infectious focus are more clinically relevant (11). In human sepsis, gram-positive organisms and fungi have exceeded gram-negative organisms as a cause of sepsis, but they are very uncommon in animal studies (8), in contrary to gram-negative bacteria. This does not reflect the diversity of infectious agents, sites of infection, and progress of the in- fection encountered clinically. There is an increasing concern about possible important differences in host inflammatory responses to sepsis caused by gram-positive versus gram- negative bacteria (8, 12). Experimental evidences suggest that the efficacy of mediator-specific anti-inflammatory agents in sepsis may be altered by the bacteria type of underlying infection with significant differences between gram-negative and gram-positive strains (8). I.v. bacteria infusion, caused by the relatively large inocula that are required, probably constitutes a model of endotoxin intoxication rather than evolving infection. Intraperitoneal challenges typically require 100- to 1,000-fold fewer bacteria (13). Thus, the models used most extensively do not precisely replicate many important clinical parameters and do not du- plicate the dynamic interactions among investigational drugs, microbial pathogens, and host defenses that occur in patients with sepsis. Although promising agents are studied later in larger animals, including primates, and attempts are made to mimic various aspects of human septic shock, the experimental conditions encountered in human sepsis trials are more 53 SHOCK, Vol. 30, Supplement 1, pp. 53Y59, 2008 Address reprint requests to Luiz F. Poli-de-Figueiredo, Av Dr. Arnaldo, 455-4th floor Suite 4215, Sao PauloYSPYBrazil, ZIP 01246-903. E-mail: lpoli@uol.com.br. DOI: 10.1097/SHK.0b013e318181a343 Copyright Ó 2008 by the Shock Society