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Effect of a single dose of tobramycin on systemic inflammatory response-induced acute kidney injury in a 6-hour porcine model
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.
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2009 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 10, 2782-2790 p.Article in journal (Refereed) Published
Abstract [en]


To evaluate whether the addition of tobramycin further compromises renal function in inflammatory response-induced acute kidney injury. Effective antibiotic treatment in septic shock is crucial for the outcome. The combination of aminoglycosides with different beta-lactam antibiotics offers a broad antimicrobial coverage, rapid bacterial killing, synergistic effects, and low antibiotic-induced endotoxin release. However, aminoglycosides have nephrotoxic effects that may aggravate sepsis-induced acute kidney injury.


Prospective, randomized, placebo-controlled experimental study.


University research unit.


Twenty-four healthy pigs.


The animals were anesthetized and randomized to four groups. Groups I (n = 8) and II (n = 8) received endotoxin infusion for 6 hrs, whereas groups III (n = 4) and IV (n = 4) received saline. Groups I and III received 7 mg/kg of tobramycin 20 mins after the initiation of the protocol, whereas groups II and IV received saline.


The renal elimination rate of a bolus dose of cefuroxime was chosen as the primary end point. Renal function was also evaluated by urine output, creatinine clearance, plasma cystatin C, plasma urea, and urine NAG (N-acetyl-beta-D-glucoaminidase). After 3 hrs, there were significantly lower cefuroxime elimination rates in the two endotoxin groups than in the nonendotoxin groups. No difference in cefuroxime elimination rates between groups I and II could be detected at any time point. Similarly, there were changes indicating acute kidney injury in urine output, creatinine clearance, and plasma cystatin C in the endotoxin groups with no differences between groups I and II. Plasma urea and urine NAG did not differ between any of the groups.


The result of this study does not lend any support to the hypothesis that a single dose of tobramycin enhances the risk of acute renal failure in cases with systemic inflammatory response-induced acute kidney injury.

Place, publisher, year, edition, pages
2009. Vol. 37, no 10, 2782-2790 p.
Keyword [en]
animal model, aminoglycosides, kidney failure, sepsis, endotoxic shock, swine
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-114023DOI: 10.1097/CCM.0b013e3181a988f8ISI: 000270234700015PubMedID: 19707126OAI: oai:DiVA.org:uu-114023DiVA: diva2:292630
Available from: 2010-02-08 Created: 2010-02-08 Last updated: 2013-08-02Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 655
Lipopolysaccharide, animal model, pig, tobramycin, endotoxin elimination, immunoparalysis, secondary sepsis
National Category
Infectious Medicine
Research subject
Infectious Diseases
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)
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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