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      Microvascular permeability during experimental human endotoxemia: an open intervention study

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          Abstract

          Introduction

          Septic shock is associated with increased microvascular permeability. As a model for study of the pathophysiology of sepsis, endotoxin administration to humans has facilitated research into inflammation, coagulation and cardiovascular effects. The present study was undertaken to determine whether endotoxin administration to human volunteers can be used as a model to study the sepsis-associated increase in microvascular permeability.

          Methods

          In an open intervention study conducted in a university medical centre, 16 healthy volunteers were evaluated in the research unit of the intensive care unit. Eight were administered endotoxin intravenously (2 ng/kg Escherichia coli O113) and eight served as control individuals. Microvascular permeability was assessed before and 5 hours after the administration of endotoxin ( n = 8) or placebo ( n = 8) by three different methods: transcapillary escape rate of I 125-albumin; venous occlusion strain-gauge plethysmography to determine the filtration capacity; and bioelectrical impedance analysis to determine the extracellular and total body water.

          Results

          Administration of endotoxin resulted in the expected increases in proinflammatory cytokines, temperature, flu-like symptoms and cardiovascular changes. All changes were significantly different from those in the control group. In the endotoxin group all microvascular permeability parameters remained unchanged from baseline: transcapillary escape rate of I 125-albumin changed from 7.2 ± 0.6 to 7.7 ± 0.9%/hour; filtration capacity changed from 5.0 ± 0.3 to 4.2 ± 0.4 ml/min per 100 ml mmHg × 10 -3; and extracellular/total body water changed from 0.42 ± 0.01 to 0.40 ± 0.01 l/l (all differences not significant).

          Conclusion

          Although experimental human endotoxaemia is frequently used as a model to study sepsis-associated pathophysiology, an endotoxin-induced increase in microvascular permeability in vivo could not be detected using three different methods. Endotoxin administration to human volunteers is not suitable as a model in which to study changes in microvascular permeability.

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          Most cited references42

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          Increased vascular permeability: a major cause of hypoalbuminaemia in disease and injury.

          The rate of loss of albumin to the tissue spaces (measured as transcapillary escape rate) rose by more than 300% in patients with septic shock, and the average increase within 7 h of cardiac surgery was 100%. The transcapillary escape rate in cachectic cancer patients was twice that of a group of healthy individuals. The rate of loss of albumin to the tissue spaces is normally 5%/h, which is more than 10 times the rates of synthesis and catabolism, and these large rate increases indicate that increased vascular permeability is an important cause of the lowered concentration of albumin commonly seen in acute and chronic disease.
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            Brief report: shock and multiple-organ dysfunction after self-administration of Salmonella endotoxin.

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              Cytokine signaling--regulation of the immune response in normal and critically ill states.

              Cytokines are produced during the activation of innate and acquired immunity, and are the principal means for intercellular communication of a microbial invasion. Cytokines serve to initiate the inflammatory response and to define the magnitude and the nature of the acquired immune response. The response of critically ill patients to their injury and/or invading pathogens is dependent, in large part, on the pattern of cytokines which are produced. The immunologic response of critically ill patients can vary from a strongly proinflammatory response, characterized by increased production of tumor necrosis factor-alpha, interleukin (IL)-1, interferon (IFN)-gamma, and IL-12 to one predominantly of anergy, characterized by increased production of T(H)2 cytokines, like IL-10 and to IL-4. Therapeutic efforts to modify the host immune response in critical illness will require a more thorough understanding of the cytokine milieu and the factors that determine their production.
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                Author and article information

                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                2005
                21 February 2005
                : 9
                : 2
                : R157-R164
                Affiliations
                [1 ]Departments of Intensive Care Medicine and Pharmacology-Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [2 ]Department of Pharmacology-Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [3 ]Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [4 ]Department of Intensive Care Medicine and Nijmegen UniversityCenter for Infectious Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                Article
                cc3050
                10.1186/cc3050
                1175929
                15774049
                048363df-9dba-4ef0-98ca-dc4d0e0792cf
                Copyright © 2005 van Eijk et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 6 August 2004
                : 9 December 2004
                : 16 December 2004
                : 10 January 2005
                Categories
                Research

                Emergency medicine & Trauma
                Emergency medicine & Trauma

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