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Mitochondrial stress in early experimental sepsis revealed by electron transport chain inhibition
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 Neuroscience, Neurosurgery.
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 Surgical Sciences, Anaesthesiology and Intensive Care.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Increased plasma lactate in sepsis may not be due to insufficient oxygen

delivery, but accelerated glycolysis and mitochondrial dysfunction may also contribute. To

assess critical pathophysiological steps in non-ischemic lactate increase we studied the muscle metabolism with microdialysis in a sepsis model in pigs submitted to continuous E. coli infusion (sepsis group, n=12) for 3 hours (h). A control group (sham group, n=4) underwent the same procedures but did not receive E. coli. Protocolized interventions were applied to normalize oxygen delivery (DO2) and blood pressure. Metabolism was intervened locally via microdialysis catheters with the electron-transport chain inhibitor sodium cyanide and the inhibitor of the major energy consuming enzyme Na+/K+-ATPase ouabain.

Results: All pigs in the sepsis group had positive blood cultures at 1 h. Median (range) Sequential Organ Failure Assessment (SOFA) score at 0 h was 0 (0-1) in both groups. At 3 h, SOFA increased to 6 (3-6) in the sepsis group but remained virtually unchanged in the sham group. Plasma lactate increased in the sepsis group despite that protocolized interventions maintained DO2.

Sepsis accelerated glycolysis with a decrease in glucose, maintained or increased in lactate and pyruvate with a virtually normal lactate-to-pyruvate ratio (LPR) in microdialysate from catheters without intervention. The local cyanide intervention produced a severe energy crisis as evidenced by a dramatically elevated LPR, a lowered pyruvate and an increased lactate in both the sepsis and sham group. During sepsis, when the cyanide effect gradually diminished, this energy crisis normalized in the sham group but partly persisted in the sepsis group.

Conclusions: Our findings suggest a reduction in mitochondrial oxidative capacity induced by sepsis, as revealed by cyanide inhibition. Decreasing energy consumption with a local ouabain intervention did not impact glucose and fat metabolism in sepsis or sham animals.

National Category
Anesthesiology and Intensive Care
Identifiers
URN: urn:nbn:se:uu:diva-327928OAI: oai:DiVA.org:uu-327928DiVA, id: diva2:1131170
Available from: 2017-08-12 Created: 2017-08-12 Last updated: 2017-08-13
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. p. 83
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1352
Keywords
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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Supervisors
Available from: 2017-09-08 Created: 2017-08-13 Last updated: 2017-10-17

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