Abstract
PurposeRodent models of sepsis are frequently used to investigate pathophysiological mechanisms and to evaluate putative therapeutic strategies. However, preclinical efficacy in these models has failed to translate to the clinical setting. We thus questioned the representativeness of such models and herein report a detailed comparison of the metabolic and cardiovascular phenotypes of long-term faecal peritonitis in fluid-resuscitated rats and mice with similar mortality profiles.MethodsWe conducted prospective laboratory-controlled studies in adult male Wistar rats and C57 black mice. Animals were made septic by intraperitoneal injection of faecal slurry. Rats received continuous intravenous fluid resuscitation, whereas mice received intermittent fluid boluses subcutaneously. Sham-treated animals served as controls. Survival was assessed over 72 h. In separate studies, whole body metabolism (O2 consumption, CO2 production) was measured over 24 h with echocardiography performed at early (6 h) and established (24 h) phases of sepsis. Blood gas analysis was performed at 6 h (rats) and 24 h (rats, mice).ResultsSimilar survival curves were seen in both rodent models with approximately 75% mortality at 72 h. In mice, sepsis caused severity-dependent falls in core temperature and global metabolism. Oxygen consumption in severely septic mice fell by 38% within 2 h, and 80% at 22 h compared with baseline values. This was only partially restored by external warming. By contrast, septic rats maintained core temperature; only severely affected animals showed a pre-mortem decline in oxygen consumption. Significant myocardial dysfunction was seen in mice during early and established sepsis, whereas peak velocity and other hemodynamic variables in rats were similar at 6 h and significantly worse by 24 h in severely septic animals only.ConclusionsMarkedly differing metabolic and cardiovascular profiles were seen in long-term fluid-resuscitated rat and mouse models of bacterial sepsis despite similar mortality. The mouse model, in particular, does not represent the human condition. We urge caution in applying findings in murine models to septic patients, both with regard to our understanding of pathophysiology and the failure to translate preclinical efficacy into successful clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1186/2197-425X-1-6) contains supplementary material, which is available to authorized users.
Highlights
Severe sepsis is the exaggerated host inflammatory response to an infectious insult leading to multiple organ failure (MOF) and, in many cases, death [1]
Similar survival curves were observed in both rodent models; most of the deaths had occurred by 48 h with an approximately 75% mortality at 72 h (Figure 1A,B)
While core temperature fell by 1.5°C in mildly septic mice, severely septic animals became profoundly hypothermic, reaching approximately 29°C by 6 h
Summary
Severe sepsis is the exaggerated host inflammatory response to an infectious insult leading to multiple organ failure (MOF) and, in many cases, death [1]. Rodent models are routinely used to investigate both pathophysiological mechanisms and novel therapeutic strategies. This is facilitated by rapid breeding, ease of care, relatively low costs and powerful genetic technology [2]. Numerous positive therapeutic intervention studies in such laboratory models have failed to translate into clinical benefit in subsequent human trials. This has resulted in much closer scrutiny of these models and their relevance to patients [3,4]. The physiological, immunological and biochemical phenotype of these models, and temporal changes thereof, are largely unknown
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