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Modulating Organ Dysfunction in Experimental Septic Shock: Effects of Aminoglycosides, Antiendotoxin Measures and Endotoxin Tolerance
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
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 [en]
Lipopolysaccharide, animal model, pig, tobramycin, endotoxin elimination, immunoparalysis, secondary sepsis
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
URN: urn:nbn:se:uu:diva-149274ISBN: 978-91-554-8031-8OAI: oai:DiVA.org:uu-149274DiVA: diva2:404381
Public defence
2011-04-29, Grönvallsalen, ing. 70, Akademiska sjukhuset, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
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
List of papers
1. Effect of a single dose of tobramycin on systemic inflammatory response-induced acute kidney injury in a 6-hour porcine model
Open this publication in new window or tab >>Effect of a single dose of tobramycin on systemic inflammatory response-induced acute kidney injury in a 6-hour porcine model
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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]

OBJECTIVE:

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.

DESIGN:

Prospective, randomized, placebo-controlled experimental study.

SETTING:

University research unit.

SUBJECTS:

Twenty-four healthy pigs.

INTERVENTIONS:

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.

MEASUREMENTS AND MAIN RESULTS:

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.

CONCLUSIONS:

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.

Keyword
animal model, aminoglycosides, kidney failure, sepsis, endotoxic shock, swine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-114023 (URN)10.1097/CCM.0b013e3181a988f8 (DOI)000270234700015 ()19707126 (PubMedID)
Available from: 2010-02-08 Created: 2010-02-08 Last updated: 2013-08-02Bibliographically approved
2. Inflammatory and circulatory effects of the reduction of endotoxin concentration in established porcine endotoxemic shock: a model of endotoxin elimination
Open this publication in new window or tab >>Inflammatory and circulatory effects of the reduction of endotoxin concentration in established porcine endotoxemic shock: a model of endotoxin elimination
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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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-114020 (URN)10.1097/CCM.0b013e31819b5683 (DOI)000263779300033 ()19237914 (PubMedID)
Available from: 2010-02-08 Created: 2010-02-08 Last updated: 2013-08-02Bibliographically approved
3. Differences in Organ Dysfunction in Endotoxin Tolerant Pigs Under Intensive Care Exposed to a Second Hit of Endotoxin
Open this publication in new window or tab >>Differences in Organ Dysfunction in Endotoxin Tolerant Pigs Under Intensive Care Exposed to a Second Hit of Endotoxin
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2012 (English)In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 37, no 5, 501-510 p.Article in journal (Refereed) Published
Abstract [en]

Endotoxin tolerance is a well-studied phenomenon associated with a reduced inflammatory response. In the switch from an inflammatory to an anti-inflammatory response in clinical sepsis the concept of endotoxin tolerance is of obvious interest. However, only limited data exist regarding the effect of endotoxin tolerance on organ dysfunction and, therefore, this was investigated in a porcine intensive care sepsis model. Twenty-seven healthy pigs, including nine control animals, were included in the study. Twelve pigs pre-exposed to 24 h of intravenous endotoxin infusion and intensive care and six unexposed pigs were given either a high- or low-dose endotoxin challenge for 6 h. Inflammatory, circulatory, hypoperfusion and organ dysfunction parameters were followed. The inflammatory responses as well as parameters representing circulation, hypoperfusion, cardiac and renal function were all markedly attenuated in animals pre-exposed to endotoxin and intensive care as compared with animals not pre-exposed. In animals pre-exposed to endotoxin and given the high-dose of endotoxin challenge, deterioration in pulmonary function was equal to or even worse than in animals not pre-exposed.In contrast to the overall protective effect of endotoxin tolerance observed in other organ systems, the lungs of endotoxin tolerant animals demonstrated an increased responsiveness to high-dose endotoxin challenge.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-168692 (URN)10.1097/SHK.0b013e318249bb0d (DOI)000303010000009 ()22266970 (PubMedID)
Note

Previous title as submitted: "Compartmentalization of organ endotoxin tolerance in a porcine model of secondary sepsis"

Available from: 2012-02-15 Created: 2012-02-15 Last updated: 2016-09-24Bibliographically approved
4. Endotoxin tolerance variation over 24 h during porcine endotoxemia: association to changes in circulation and organ dysfunction
Open this publication in new window or tab >>Endotoxin tolerance variation over 24 h during porcine endotoxemia: association to changes in circulation and organ dysfunction
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2013 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 1, e53221- p.Article in journal (Refereed) Published
Abstract [en]

Endotoxin tolerance (ET), defined as reduced inflammatory responsiveness to endotoxin challenge following a first encounter with endotoxin, is an extensively studied phenomenon. Although reduced mortality and morbidity in the presence of ET has been demonstrated in animal studies, little is known about the temporal development of ET. Further, in acute respiratory distress syndrome ET correlates to the severity of the disease, suggesting a complicated relation between ET and organ dysfunction. Eighteen pigs were subjected to intensive care and a continuous endotoxin infusion for 24 h with the aim to study the time course of early ET and to relate ET to outcome in organ dysfunction. Three animals served as non-endotoxemic controls. Blood samples for cytokine analyses were taken and physiological variables registered every third hour. Production of TNF-α, IL-6, and IL-10 before and after endotoxin stimulation ex vivo was measured. The difference between cytokine values after and before ex vivo LPS stimulation (Δ-values) was calculated for all time points. ΔTNF-α was employed as the principal marker of ET and lower ΔTNF-α values were interpreted as higher levels of ET. During endotoxin infusion, there was suppression of ex vivo productions of TNF-α and IL-6 but not of IL-10 in comparison with that at 0 h. The ex vivo TNF-α values followed another time concentration curve than those in vivo. ΔTNF-α was at the lowest already at 6 h, followed by an increase during the ensuing hours. ΔTNF-α at 6 h correlated positively to blood pressure and systemic vascular resistance and negatively to cardiac index at 24 h. In this study a temporal variation of ET was demonstrated that did not follow changes in plasma TNF-α concentrations. Maximal ET occurred early in the course and the higher the ET, the more hyperdynamic the circulation 18 h later.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-149277 (URN)10.1371/journal.pone.0053221 (DOI)000313552400016 ()
Available from: 2011-03-16 Created: 2011-03-16 Last updated: 2013-02-25Bibliographically approved

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