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      High Spinal Anesthesia Enhances Anti-Inflammatory Responses in Patients Undergoing Coronary Artery Bypass Graft Surgery and Aortic Valve Replacement: Randomized Pilot Study

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          Abstract

          Background

          Cardiac surgery induces many physiologic changes including major inflammatory and sympathetic nervous system responses. Here, we conducted a single-centre pilot study to generate hypotheses on the potential immune impact of adding high spinal anaesthesia to general anaesthesia during cardiac surgery in adults. We hypothesized that this strategy, previously shown to blunt the sympathetic response and improve pain management, could reduce the undesirable systemic inflammatory responses caused by cardiac surgery.

          Methods

          This prospective randomized unblinded pilot study was conducted on 14 patients undergoing cardiac surgery for coronary artery bypass grafting and/or aortic valve replacement secondary to severe aortic stenosis. The primary outcome measures examined longitudinally were serum pro-inflammatory (IL-6, IL-1b, CCL2), anti-inflammatory (IL-10, TNF-RII, IL-1Ra), acute phase protein (CRP, PTX3) and cardiovascular risk (sST2) biomarkers.

          Results

          The kinetics of pro- and anti-inflammatory biomarker was determined following surgery. All pro-inflammatory and acute phase reactant biomarker responses induced by surgical stress were indistinguishable in intensity and duration between control groups and those who also received high spinal anaesthesia. Conversely, IL-10 levels were markedly elevated in both intensity and duration in the group receiving high spinal anesthesia (p = 0.005).

          Conclusions

          This hypothesis generating pilot study suggests that high spinal anesthesia can alter the net inflammatory response that results from cardiac surgery. In appropriately selected populations, this may add incremental benefit by dampening the net systemic inflammatory response during the week following surgery. Larger population studies, powered to assess immune, physiologic and clinical outcomes in both acute and longer term settings, will be required to better assess potential benefits of incorporating high spinal anesthesia.

          Trial Registration

          ClinicalTrials.gov NCT00348920

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          Most cited references32

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          Routine clinical markers of the magnitude of the systemic inflammatory response after elective operation: a systematic review.

          Operative injury to the body from all procedures causes a stereotypical cascade of neuroendocrine, cytokine, myeloid, and acute phase responses. This response has been examined commonly by the use of cortisol, interleukin-6 (IL-6), white cell count, and C-reactive protein (CRP). We aimed to determine which markers of the systemic inflammatory response were useful in determining the magnitude of injury after elective operations.
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            Mechanisms of immune tolerance to allergens: role of IL-10 and Tregs.

            During the past 20 years, major advances have been made in understanding the molecular and cellular mechanisms of allergen tolerance in humans. The demonstration of T cell tolerance, particularly that mediated by the immune-suppressive functions of IL-10, led to a major conceptual change in this area. Currently, the known essential components of allergen tolerance include the induction of allergen-specific regulatory subsets of T and B cells, the immune-suppressive function of secreted factors, such as IL-10 and TGF-β, the production of IgG4 isotype allergen-specific blocking antibodies, and decreased allergic inflammatory responses by mast cells, basophils, and eosinophils in inflamed tissues.
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              Does intraoperative ketamine attenuate inflammatory reactivity following surgery? A systematic review and meta-analysis.

              Reports regarding the ability of the anesthetic drug ketamine to attenuate the inflammatory response to surgery are conflicting. In this systematic review we examined the effect of perioperative ketamine administration on postoperative inflammation as assessed by concentrations of the biomarker interleukin-6 (IL-6). This study was based on a systematic search in PubMed, Scopus, Web of Knowledge, and the Cochrane Library. English written randomized controlled trials conducted in humans were eligible. To be included in the analysis, outcome had to relate to inflammation or immune modulation. Each study was reviewed independently by 2 assessors. Data were analyzed according to the GRADE's approach and reported in compliance with the PRISMA recommendations. Fourteen studies were eligible for evaluation (684 patients). Surgery was performed under general anesthesia, and ketamine was given before or during the surgery in varied doses Eight studies involved cardiopulmonary bypass operations, 4 were for abdominal surgery, 1 thoracic surgery, and 1 cataract surgery. Three studies were deemed of low quality. Nine studies measured IL-6 concentrations within the first 6 hours postoperatively; but in 3 studies, other potent anti-inflammatory drugs were used as premedication or during the operation; thus 6 studies (n = 331) were included in the meta-analysis. Using postoperative IL-6 concentrations as an outcome, ketamine had an anti-inflammatory effect; the meta-analysis showed a mean preoperative-postoperative IL-6 concentration difference (95% confidence interval) of -71 (-101 to -41) pg/mL. It can be concluded that intraoperative administration of ketamine significantly inhibits the early postoperative IL-6 inflammatory response. Future studies should further examine the anti-inflammatory effect of ketamine during major surgery, determine whether ketamine treatment alters functional outcomes, elucidate the mechanisms of its anti-inflammatory effect, and suggest an appropriate dosing regimen.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                1 March 2016
                2016
                : 11
                : 3
                : e0149942
                Affiliations
                [1 ]Department of Anesthesia and Perioperative Medicine, St. Boniface Hospital, University of Manitoba, Winnipeg, Manitoba, Canada
                [2 ]Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
                [3 ]Section of Cardiac Surgery, Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada
                San Raffaele Scientific Institute, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TL SK DM DF KH. Performed the experiments: TL SK DM KF DF. Analyzed the data: TL KF KH. Contributed reagents/materials/analysis tools: KF KH. Wrote the paper: TL KH.

                [¤]

                Current address: Division of Cardiac Surgery, University of Alberta, Edmonton, Canada

                Article
                PONE-D-15-10185
                10.1371/journal.pone.0149942
                4773142
                26930568
                5c8b37d9-2d0b-4582-8802-3d36e7b97fed
                © 2016 Lee et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 March 2015
                : 1 February 2016
                Page count
                Figures: 5, Tables: 2, Pages: 15
                Funding
                Funding provided by Canada Research Chairs ( http://www.chairs-chaires.gc.ca/home-accueil-eng.aspx) to KH, St. Boniface Hospital Research Centre, Grant Number: Internal Funding, Specific Purpose Account of TL to TL, University of Manitoba, Department of Anesthesia Grant number: AOC2008-07 to TL and Health Sciences Centre Foundation, Grant Number: SK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Inflammation
                Medicine and Health Sciences
                Anesthesiology
                Anesthesia
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Anesthesia
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Cardiovascular Procedures
                Coronary Artery Bypass Grafting
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Cardiovascular Procedures
                Cardiac Surgery
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Cardiovascular Procedures
                Cardiopulmonary Bypass
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Anesthetics
                Medicine and Health Sciences
                Pain Management
                Anesthetics
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Uncategorized
                Uncategorized

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