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      Effects of methylprednisolone on blood-brain barrier and cerebral inflammation in cardiac surgery—a randomized trial

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          Abstract

          Background

          Cognitive dysfunction is a frequent complication to open-heart surgery. Cerebral inflammation caused by blood-brain barrier (BBB) dysfunction due to a systemic inflammatory response is considered a possible etiology. The effects of the glucocorticoid, methylprednisolone, on cerebrospinal fluid (CSF) markers of BBB function, neuroinflammation, and brain injury in patients undergoing cardiac surgery with cardiopulmonary bypass were studied.

          Methods

          In this prospective, randomized, blinded study, 30 patients scheduled for elective surgical aortic valve replacement were randomized to methylprednisolone 15 mg/kg ( n = 15) or placebo ( n = 15) as a bolus dose administered after induction of anesthesia. CSF and blood samples were obtained the day before and 24 h after surgery for assessment of systemic and brain inflammation (interleukin-6, interleukin-8, tumor necrosis factor-alpha), axonal injury (total-tau, neurofilament light chain protein), neuronal injury (neuron-specific enolase), astroglial injury (S-100B, glial fibrillary acidic protein), and the BBB integrity (CSF/serum albumin ratio).

          Results

          In the control group, there was a 54-fold and 17-fold increase in serum interleukin-6 and interleukin-8, respectively. This systemic activation of the inflammatory cytokines was clearly attenuated by methylprednisolone ( p < 0.001). The increase of the CSF levels of the astroglial markers was not affected. A postoperative BBB dysfunction was seen in both groups as the CSF/serum albumin ratio increased from 6.4 ± 8.0 to 8.0 in the placebo group ( p < 0.01) and from 5.6 ± 2.3 to 7.2 in the methylprednisolone group ( p < 0.01) with no difference between groups ( p = 0.98). In the CSF, methylprednisolone attenuated the interleukin-6 release ( p < 0.001), which could be explained by the fall in systemic interleukin-6, and the serum to CSF gradient of IL-6 seen both at baseline and after surgery. In the CSF, methylprednisolone enhanced the interleukin-8 release ( p < 0.001) but did not affect postoperative changes in CSF levels of tumor necrosis factor alpha. Serum levels of S-100B and neuron-specific enolase increased in both groups with no difference between groups. CSF levels of total tau, neurofilament light chain protein, and neuron-specific enolase were not affected in any of the groups.

          Conclusions

          Preventive treatment with high-dose methylprednisolone attenuated the systemic inflammatory response to open-heart surgery with cardiopulmonary bypass, but did not prevent or attenuate the increase in BBB permeability or the neuroinflammatory response.

          Trial registration

          Clinical Trials, Identifier: NCT01755338, registered 24 December 2012

          Electronic supplementary material

          The online version of this article (10.1186/s12974-018-1318-y) contains supplementary material, which is available to authorized users.

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          Most cited references24

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          Essential involvement of interleukin-8 (IL-8) in acute inflammation.

          Neutrophil infiltration into inflammatory sites is one of the hallmarks of acute inflammation. Locally produced chemotactic factors are presumed to mediate the sequence of events leading to the infiltration at inflammatory sites. Interleukin-8 (IL-8), a novel leukocyte chemotactic activating cytokine (chemokine), is produced by various types of cells upon stimulation with inflammatory stimuli and exerts a variety of functions on leukocytes, particularly, neutrophils in vitro. However, no definitive evidence has been presented on its role in recruiting and activating neutrophils in the lesions of various types of inflammatory reactions. We administered a highly specific neutralizing antibody against IL-8 in several types of acute inflammatory reactions, including lipopolysaccharide (LPS)-induced dermatitis, LPS/IL-1-induced arthritis, lung reperfusion injury, and acute immune complex-type glomerulonephritis. Anti-IL-8 treatment prevented neutrophil-dependent tissue damage as well as neutrophil infiltration in these conditions. These results suggest that IL-8 plays a causative role in acute inflammation by recruiting and activating neutrophils.
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            Resolving postoperative neuroinflammation and cognitive decline.

            Cognitive decline accompanies acute illness and surgery, especially in the elderly. Surgery engages the innate immune system that launches a systemic inflammatory response that, if unchecked, can cause multiple organ dysfunction. We sought to understand the mechanisms whereby the brain is targeted by the inflammatory response and how this can be resolved. C57BL/6J, Ccr2(RFP/+)Cx3cr1(GFP/+), Ikk(F/F) mice and LysM-Cre/Ikk(F/F) mice underwent stabilized tibial fracture operation under analgesia and general anesthesia. Separate cohorts of mice were tested for systemic and hippocampal inflammation, integrity of the blood-brain barrier (BBB), and cognition. The putative resolving effects of the cholinergic pathway on these postoperative responses were also studied. Peripheral surgery disrupts the BBB via release of tumor necrosis factor-alpha (TNFα), which facilitates the migration of macrophages into the hippocampus. Macrophage-specific deletion of Ikappa B kinase (IKK)β, a central coordinator of TNFα signaling through activation of nuclear factor (NF) κB, prevents BBB disruption and macrophage infiltration in the hippocampus following surgery. Activation of the α7 subtype of nicotinic acetylcholine receptors, an endogenous inflammation-resolving pathway, prevents TNFα-induced NF-κB activation, macrophage migration into the hippocampus, and cognitive decline following surgery. These data reveal the mechanisms for bidirectional communication between the brain and immune system following aseptic trauma. Pivotal molecular mechanisms can be targeted to prevent and/or resolve postoperative neuroinflammation and cognitive decline. Copyright © 2011 American Neurological Association.
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              Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators.

              Acute changes in cerebral function after elective coronary bypass surgery is a difficult clinical problem. We carried out a multicenter study to determine the incidence and predictors of -- and the use of resources associated with -- perioperative adverse neurologic events, including cerebral injury. In a prospective study, we evaluated 2108 patients from 24 U.S. institutions for two general categories of neurologic outcome: type I (focal injury, or stupor or coma at discharge) and type II (deterioration in intellectual function, memory deficit, or seizures). Adverse cerebral outcomes occurred in 129 patients (6.1 percent). A total of 3.1 percent had type I neurologic outcomes (8 died of cerebral injury, 55 had nonfatal strokes, 2 had transient ischemic attacks, and 1 had stupor), and 3.0 percent had type II outcomes (55 had deterioration of intellectual function and 8 had seizures). Patients with adverse cerebral outcomes had higher in-hospital mortality (21 percent of patients with type I outcomes died, vs. 10 percent of those with type II and 2 percent of those with no adverse cerebral outcome; P<0.001 for all comparisons), longer hospitalization (25 days with type I outcomes, 21 days with type II, and 10 days with no adverse outcome; P<0.001), and a higher rate of discharge to facilities for intermediate- or long-term care (69 percent, 39 percent, and 10 percent ; P<0.001). Predictors of type I outcomes were proximal aortic atherosclerosis, a history of neurologic disease, and older age; predictors of type II outcomes were older age, systolic hypertension on admission, pulmonary disease, and excessive consumption of alcohol. Adverse cerebral outcomes after coronary bypass surgery are relatively common and serious; they are associated with substantial increases in mortality, length of hospitalization, and use of intermediate- or long-term care facilities. New diagnostic and therapeutic strategies must be developed to lessen such injury.
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                Author and article information

                Contributors
                mattias.danielsson@vgregion.se
                bjorn.reinsfelt@vgregion.se
                anne.westerlind@vgregion.se
                henrik.zetterberg@clinchem.gu.se
                kaj.blennow@neuro.gu.se
                + 46 31 3427433 , sven-erik.ricksten@aniv.gu.se
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                27 September 2018
                27 September 2018
                2018
                : 15
                : 283
                Affiliations
                [1 ]Department of Anesthesiology and Intensive Care Medicine, Sahlgrenska University Hospital, University of Gothenburg, SE-413 45 Gothenburg, Sweden
                [2 ]Deparment of Anesthesiology and Intensive Care Medicine, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden
                Author information
                http://orcid.org/0000-0002-1445-7525
                Article
                1318
                10.1186/s12974-018-1318-y
                6158839
                30261896
                1c620668-4ba7-4c73-9da6-ef53414935c6
                © The Author(s). 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 June 2018
                : 18 September 2018
                Funding
                Funded by: Swedish State Support for Clinical Research
                Award ID: ALFGBG-721141
                Award ID: ALFGBG-144341
                Award ID: ALFGBG-139671
                Award Recipient :
                Funded by: Swedish Research Council
                Award ID: K2010-61X-14002, K2010-63P-21562-01-4 and K2011-61X-20401-05-6
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Neurosciences
                aortic valve replacement,cardiopulmonary bypass,cerebrospinal fluid,neuroinflammatory response,methylprednisolone

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