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The metabolic phenotype of rodent sepsis: cause for concern?

ABSTRACT: Rodent 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.We 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).Similar 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.Markedly 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.

SUBMITTER: Zolfaghari PS

PROVIDER: S-EPMC4797805 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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The metabolic phenotype of rodent sepsis: cause for concern?

Zolfaghari Parjam S PS Pinto Bernardo Bollen BB Dyson Alex A Singer Mervyn M

Intensive care medicine experimental 20131029 1

<h4>Purpose</h4>Rodent 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.<h4>Met ...[more]

PMID: 26266794

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Project description:Increasing cannabis use and legalisation highlights the paucity of data we have on the safety of cannabis smoking for respiratory health. Unfortunately, concurrent use of tobacco among marijuana smokers makes it difficult to untangle individual effect of marijuana smoking. Chronic cannabis only smoking has been shown in large cohort studies to reduce forced expiratory volume in 1?s/forced vital capacity via increasing forced vital capacity in chronic use contrary to the picture seen in tobacco smoking. The cause of this is unclear and there are various proposed mechanisms including respiratory muscle training secondary to method of inhalation and acute anti-inflammatory effect and bronchodilation of cannabis on the airways. While cannabis smoke has been shown to increase symptoms of chronic bronchitis, it has not been definitively shown to be associated with shortness of breath or irreversible airway changes. The evidence surrounding the development of lung cancer is less clear; however, preliminary evidence does not suggest association. Bullous lung disease associated with marijuana use has long been observed in clinical practice but published evidence is limited to a total of 57 published cases and only one cross-sectional study looking at radiological changes among chronic users which did not report any increase in macroscopic emphysema. More studies are required to elucidate these missing points to further guide risk stratification, clinical diagnosis and management.Cannabis smoking has increased and is likely to increase further with relaxation of legalisation and medicinal use of cannabinoids.Chronic marijuana smoking often produces symptoms similar to those of chronic tobacco smoking such as cough, sputum production, shortness of breath and wheeze.Cessation of marijuana smoking is associated with a reduction in respiratory symptoms and no increased risk of chronic bronchitis.Spirometry changes seen in chronic marijuana smokers appear to differ from those in chronic tobacco smokers. In chronic marijuana smokers there is an increase in FVC as opposed to a definite decrease in FEV1.Multiple case series have demonstrated peripheral bullae in marijuana smokers, but no observational studies have elucidated the risk.There is currently no clear association between cannabis smoking and lung cancer, although the research is currently limited.To update readers on legalisation of recreational and medicinal cannabis.To summarise the evidence base surrounding the respiratory effects of inhaled marijuana use.To provide clinicians with an understanding of the main differences between cannabis and tobacco to be able to apply this to patient education.To highlight common respiratory problems among cannabis users and the need for recreational drug history taking.

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The metabolic phenotype of rodent sepsis: cause for concern?

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The metabolic phenotype of rodent sepsis: cause for concern?

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