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Inflammatory and circulatory effects of the reduction of endotoxin concentration in established porcine endotoxemic shock: a model of endotoxin elimination
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
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2009 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 3, 1031-e4 p.Article in journal (Refereed) Published
Abstract [en]

Objective:

To study whether a reduction of the endotoxin load, once a generalized inflammatory state has been established, reduces the inflammatory response and endotoxin-induced effects on circulation, hypoperfusion, and organ dysfunction.

Design:

Prospective parallel-grouped placebo-controlled randomized interventional experimental study.

Setting:

University research unit.

Subjects:

Healthy pigs.

Interventions:

The animals were subjected to a continuous endotoxin infusion rate of either 4.0 or 0.063 µg endotoxin × kg-1 × h-1 for 1, 2, or 6 hours. The 1- and 2-hour infusion groups represented the applied therapy by a reduction of the endotoxin load of 5/6 and 2/3, respectively.

Measurements and Main Results:

During a 6-hour experiment, laboratory and physiologic parameters were recorded hourly in 26 anesthetized and mechanically ventilated pigs. Primary end point was to detect differences in tumor necrosis factor-[alpha] (TNF-[alpha]) concentration during the last 3 hours of the experiment. Despite the early reduction of the endotoxin load, no effect on TNF-[alpha] concentration was observed. Similarly, in circulatory parameters, such as mean arterial pressure and oxygen delivery, and in platelet count and renal function, no effects were noted. However, there was some improvement in pulmonary compliance and function as determined by Pao2, Paco2, and pH. These changes were associated with slight improvements in leukocyte response and capillary leakage.

Conclusions:

Termination of the endotoxin infusion represents an incontestable model of endotoxin concentration reduction. Endotoxin elimination strategies applied at the TNF-[alpha] peak or later will have very little or no effect on TNF-[alpha]–mediated toxicity. Nevertheless, there was an effect on the leukocyte response that was associated with an improvement in respiratory function and microcirculation, making it impossible to rule out fully the beneficial effect of this strategy. However, the effects were limited in relation to the magnitude of the endotoxin concentration reduction and the very early application of the antiendotoxin measure.

Place, publisher, year, edition, pages
2009. Vol. 37, no 3, 1031-e4 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-114020DOI: 10.1097/CCM.0b013e31819b5683ISI: 000263779300033PubMedID: 19237914OAI: oai:DiVA.org:uu-114020DiVA: diva2:292629
Available from: 2010-02-08 Created: 2010-02-08 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Modulating Organ Dysfunction in Experimental Septic Shock: Effects of Aminoglycosides, Antiendotoxin Measures and Endotoxin Tolerance
Open this publication in new window or tab >>Modulating Organ Dysfunction in Experimental Septic Shock: Effects of Aminoglycosides, Antiendotoxin Measures and Endotoxin Tolerance
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Sepsis is a common diagnose in the intensive care population, burdened with a high mortality. The systemic inflammatory reaction underlying the development of septic organ dysfunction can be modeled using Gram-negative bacterial lipopolysaccharide, endotoxin. This thesis used a porcine endotoxemic experimental sepsis model to address clinical questions difficult to answer in clinical trials; furthermore a model of secondary sepsis was developed.

No additional effect on the development of renal dysfunction by tobramycin was found, indicating that a single dose of tobramycin does not further compromise renal function in inflammatory-induced acute kidney injury.

Antiendotoxin treatment had no measurable effect on TNF-α-mediated toxicity once the inflammatory cascade was activated. There was an effect on the leukocyte response that was associated with improvements in respiratory function and microcirculation, making it impossible to rule out fully the beneficial effect of this strategy. However, the effects were limited in relation to the magnitude of the endotoxin concentration reduction and the very early application of the antiendotoxin measure.

The lungs stood out compared to the other organ systems as having a threshold endotoxin dose for the protective effect of endotoxin tolerance. As to the development of circulatory and renal dysfunction, tolerance to endotoxin was evident regardless of the endotoxin pre-exposure and challenge dose.

There was a temporal variation of endotoxin tolerance that did not follow changes in plasma TNF-α concentrations and maximal tolerance was seen very early in the course. More pronounced endotoxin tolerance at the time of maximum tolerance was associated with a more marked hyperdynamic circulation, reduced oxygen consumption and thrombocytopenia eighteen hours later.

It might be of interest to use the experimental model of long-term endotoxemia followed by a second hit, which has been designed to resemble an intensive care setting, for the study of treatment effects of immunomodulating therapies in secondary sepsis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 81 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 655
Keyword
Lipopolysaccharide, animal model, pig, tobramycin, endotoxin elimination, immunoparalysis, secondary sepsis
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:uu:diva-149274 (URN)978-91-554-8031-8 (ISBN)
Public defence
2011-04-29, Grönvallsalen, ing. 70, Akademiska sjukhuset, Uppsala, 13:15 (Swedish)
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Note
Paper 3, previous title as submitted: "Compartmentalization of organ endotoxin tolerance in a porcine model of secondary sepsis"Available from: 2011-04-07 Created: 2011-03-16 Last updated: 2012-03-02Bibliographically approved

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Lipcsey, MiklósLarsson, AndersTano, EvaRubertsson, StenEriksson, MatsSjölin, Jan

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