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Effects of Tigecycline and Doxycycline on Inflammation and Hemodynamics in Porcine Endotoxemia: a Prospective, Randomized and Placebo Controlled Trial
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, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
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2015 (English)In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 43, no 6, 604-611 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Antibiotics might, apart from an antimicrobial effect, also exert anti-inflammatory effects. The novel antibiotic tigecycline, potentially useful in septic shock from Gram-negative multi-resistant bacteria, is structurally related to antibiotics with known anti-inflammatory properties. However, its anti-inflammatory effects have previously not been explored in vivo. Using a sterile integrative porcine sepsis model, we investigated the anti-inflammatory and circulatory effects of tigecycline in comparison to doxycycline and placebo.

METHODS: Eighteen pigs were randomized to receive tigecycline 100 mg, doxycycline 200 mg or placebo and subjected to 6 h endotoxin infusion at 0.5 μg x kg x h. Markers of inflammation, nitric oxide (NO) production, vascular permeability, hemodynamics, organ dysfunction, tissue metabolism and acid-base parameters were monitored.

RESULTS: Peak plasma tumor necrosis alpha (TNF-α) was lower in the doxycycline group (P=0.031) but not in the tigecycline group (P=0.86) compared to placebo with geometric mean plasma concentrations of 16, 79 and 63 ng x ml, respectively. Mean arterial pressure was higher 4-6 h in the tigecycline group with values at 6 h of 107± 9 mmHg compared to the placebo and doxycycline groups (85 ± 27 mmHg and 90 ± 32 mmHg, respectively) (P=0.025). The white blood cell and the neutrophil granulocyte counts were less reduced in the doxycycline group, but not in the tigecycline group at 4-6 h (P=0.009 and p=0.019, respectively). Other markers of inflammation, organ dysfunction, tissue metabolism and acid-base parameters were unaffected by tigecycline.

CONCLUSIONS: Consistent with known anti-inflammatory properties, doxycycline yielded decreased TNF-α levels. Tigecycline did not affect cytokine levels but counteracted hypotension and hypoperfusion.

Place, publisher, year, edition, pages
2015. Vol. 43, no 6, 604-611 p.
National Category
Anesthesiology and Intensive Care
Identifiers
URN: urn:nbn:se:uu:diva-244766DOI: 10.1097/SHK.0000000000000351ISI: 000354734300013PubMedID: 25664982OAI: oai:DiVA.org:uu-244766DiVA: diva2:789831
Available from: 2015-02-20 Created: 2015-02-20 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Oxygen delivery and mitochondrial dysfunction as assessed by microdialysis during interventions in experimental sepsis
Open this publication in new window or tab >>Oxygen delivery and mitochondrial dysfunction as assessed by microdialysis during interventions in experimental sepsis
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Early administration of broad-spectrum antibiotics is the first goal in sepsis treatment. Besides from bacteriostatic/bactericidal effects, some antibiotics may also modify the host´s response to infection. The novel antibiotic tigecycline may exert such properties; however, this property has not been evaluated in large-animal trials. We compared tigecycline with doxycycline and placebo in relation to anti-inflammatory, circulatory and organ dysfunction effects in a sterile pig model of sepsis. Doxycycline, but not tigecycline, reduced the inflammatory response as manifested by tumor necrosis factor alpha levels in plasma. Tigecycline, however, had a stabilizing effect on the circulation not exerted by doxycycline or placebo.

To achieve rapid restoration of the circulating blood volume - another major goal in sepsis treatment - fluid bolus administration of is some-times practiced. In addition to crystalloids, albumin-containing solutions are suggested. Yet, some animal-experimental data suggests that rapid bolus administration of albumin reduces albumin’s plasma-expanding effect. We compared a rapid intravenous bolus of radiolabeled albumin with a slow infusion in a sterile pig model of sepsis. Rapid bolus of administration did not reduce plasma levels of albumin following administration and did not increase the amount of albumin that left the circulation.

Inadequate oxygen delivery (DO2) by the circulation to the tissues may cause increased plasma lactate, which is the most striking effect of sepsis on the metabolism. However, experimental data and clinical trials refute this link, instead, suggesting other mechanisms, including impaired oxygen extraction, mitochondrial dysfunction and accelerated aerobic glycolysis. We investigated the impact of DO2, oxygen consumption (VO2), hemodynamic parameters and inflammatory response on plasma lactate and organ dysfunction in two experimental sepsis models. In the most severe cases of shock, with DO2, there was an increase in plasma lactate, but without a decrease in VO2, invalidating the assumption that the increase in lactate is due to anaerobic metabolism.

To identify critical steps in the sepsis-induced increase in lactate, we inhibited the major energy-producing step in the electron transport chain (ETC). The combination of sepsis and ETC inhibition led to a cellular energy crisis. This finding suggests that early sepsis induces a partial mitochondrial dysfunction.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 83 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1352
Keyword
sepsis, animal models, microdialysis, endotoxin, Escherichia coli, tigecycline, doxycycline, albumins, capillary leak syndrome, lactic acid, oxygen delivery, multiple organ failure, mitochondria, tumor necrosis factor alpha, interleukin-6, cyanides, ouabain
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-326788 (URN)978-91-513-0028-3 (ISBN)
Public defence
2017-09-29, Hedstrandsalen, Ing 70, Akademiska sjukhuset, Sjukhusvägen, Uppsala, 13:00 (English)
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Available from: 2017-09-08 Created: 2017-08-13 Last updated: 2017-10-17

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von Seth, MagnusSjölin, JanLarsson, AndersEriksson, MatsHillered, LarsLipcsey, Miklós

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