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Effect of the Administration Rate on the Biological Responses To A Fixed Dose of Endotoxin in the Anesthetized Pig
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.
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.
2008 (English)In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 29, no 2, 173-180 p.Article in journal (Refereed) Published
Abstract [en]

There have been difficulties to demonstrate a relationship between endotoxin concentration and clinical response. One hypothesis for this difficulty might be that a fast increase in endotoxin concentration elicits a stronger biological response than a more gradual one of the same dose. The aim of the present study was to investigate the existence of such a response. Eighteen randomized pigs were given the same amount of endotoxin either with an initial infusion rate of 4 μg kg-1 h-1, which after 1 h was tapered to 0.5 μg kg-1 h-1, and after 2 h to 0.063 μg kg-1 h-1 (group I), or with a reverse escalating order with the lowest infusion rate given first (group II). After 3 h, the endotoxin infusion was stopped, and the pigs were observed for another 3 h. The responses in TNF-α, core temperature, leukocytes, platelets, MAP, left ventricular stroke work index, mixed venous saturation, base excess, pH, and pulmonary compliance were greater in group I than in group II, whereas the IL-6 response did not differ between groups. The biological responses of inflammation, hypotension, hypoperfusion, and organ dysfunction are increased if the organism is exposed to a fixed amount of endotoxin more quickly.

Abbreviations - BE-Base excess; CI-Cardiac index; DO2-Oxygen delivery; Fio2-fraction of oxygen; Hb-Hemoglobin; LVSWI-Left ventricular stroke work index; MPAP-Mean pulmonary arterial pressure; Paco2-Arterial partial pressure of carbon dioxide; Pao2-Arterial partial pressure of oxygen; pH-Potentia Hydrogenii; SEM-Standard error of the mean; Svo2-Venous oxygen saturation

Place, publisher, year, edition, pages
2008. Vol. 29, no 2, 173-180 p.
Keyword [en]
Animal model, cytokines, sepsis, endotoxic shock, pig
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-12977DOI: 10.1097/shk.0b013e318067dfbcISI: 000252733500005PubMedID: 17667361OAI: oai:DiVA.org:uu-12977DiVA: diva2:40747
Available from: 2008-02-20 Created: 2008-02-20 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Pathophysiological, Inflammatory and Haemostatic Responses to Various Endotoxaemic Patterns: An Experimental Study in the Pig
Open this publication in new window or tab >>Pathophysiological, Inflammatory and Haemostatic Responses to Various Endotoxaemic Patterns: An Experimental Study in the Pig
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Septic shock is frequently seen in intensive care units and is associated with significant mortality. Endotoxin – a major mediator of the pathophysiologic responses – is released during lysis of Gram-negative bacteria. These responses can be mimicked in the endotoxaemic pig.

This thesis focuses on the following topics: the inflammatory and pathophysiological responses to various endotoxin doses and infusion patterns; covariations between endotoxin induced inflammatory and pathophysiological responses; whether the biological effects of endotoxin can be modulated by clopidogrel and whether tobramycin or ceftazidime reduce plasma cytokine levels.

Endotoxin induced linear log-log cytokine and F2-isoprostane responses. Leukocyte and platelet responses, pulmonary compliance, circulatory variables as well as indicators of plasma leakage and hypoperfusion exhibited log-linear responses to the endotoxin dose. Biological responses to endotoxaemia such as inflammation, hypotension, hypoperfusion and organ dysfunction were more expressed when the organism was exposed to endotoxin at a higher rate. These results may facilitate the possibility to choose relevant endotoxin administration, when experiments are set up in order to evaluate certain responses to endotoxaemia.

Correlation studies between cytokines, leukocytes, platelets and the endotoxin dose were in agreement with the well-known ability of endotoxin to induce cytokine expression and to activate both primary haemostasis and leukocytes. Free radical mediated lipid peroxidation and COX-mediated inflammation correlated to cytokine expression and organ dysfunction in endotoxaemic shock.

Endotoxaemic pigs pretreated with clopidogrel, exhibited a trend towards less expressed deterioration of renal function, although blocking of ADP-induced primary haemostasis is not a key mediator of endotoxin induced deterioration of renal function.

Tobramycin did not neutralise the biological effects of endotoxin or the plasma levels of endotoxin, suggesting that these antibiotics do not bind to endotoxin.

Reduction in IL-6 was greater in pigs treated with ceftazidime and tobramycin as compared with those given saline, indicating a possible anti-inflammatory effect of both antibiotics.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 69 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 197
Keyword
Anaesthesiology and intensive care, sepsis, animal model, cytokines, isoprostanes, endotoxic shock, pig, Anestesiologi och intensivvård
Identifiers
urn:nbn:se:uu:diva-7237 (URN)91-554-6709-1 (ISBN)
Public defence
2006-12-01, Hedstrandsalen, Ing 70, Akademiska sjukhuset, 751 85, UPPSALA, 13:15
Opponent
Supervisors
Available from: 2006-11-09 Created: 2006-11-09 Last updated: 2011-04-12Bibliographically approved

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Lipcsey, MiklósLarsson, AndersEriksson, MatsSjölin, Jan

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