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      Neuroprotection against stroke and encephalopathy after cardiac surgery

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          Abstract

          Cerebral ischemia in the perioperative period is a major risk factor for stroke, encephalopathy, and cognitive decline after cardiothoracic surgery. After coronary artery bypass grafting, both stroke and encephalopathy can result in poor patient outcomes and increased mortality. Neuroprotection aims to lessen the severity and occurrence of further injury mediated by stroke and encephalopathy and to aid the recovery of conditions already present. Several pharmacological and non-pharmacological methods of neuroprotection have been investigated in experimental studies and in animal models, and, although some have shown effectiveness in protection of the central nervous system, for most, clinical research is lacking or did not show the expected results. This review summarizes the value and need for neuroprotection in the context of cardiothoracic surgery and examines the use and effectiveness of several agents and methods with an emphasis on clinical trials and clinically relevant neuroprotectants.

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          Most cited references104

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          Intraoperative ketamine does not affect postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial

          Background Delirium and pain are common and serious postoperative complications. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia and to spare postoperative opioids. Some evidence also suggests that ketamine prevents delirium. The primary purpose of this trial was to evaluate the effectiveness of ketamine in preventing postoperative delirium in older adults after major surgery. Secondary outcomes, viewed as strongly related to delirium, were postoperative pain and opioid consumption. Methods This was a multicentre, international, randomised trial that enrolled adults older than 60 undergoing major cardiac and noncardiac surgery under general anaesthesia. Participants were enrolled prior to surgery and gave written informed consent. We used a computer-generated randomisation sequence. Patients at study sites were randomised to one of three study groups in blocks of 15 to receive intraoperative administration of (i) placebo (intravenous normal saline), (ii) low dose ketamine (0.5 mg/kg) or (iii) high dose ketamine (1 mg/kg). Study drug was administered following induction of anaesthesia, prior to surgical incision. Participants, clinicians, and investigators were all masked to group assignment. Delirium and pain were assessed twice daily in the first three postoperative days using the Confusion Assessment Method and Visual Analog Scale, respectively. Postoperative opioid use was recorded, and hallucinations and nightmares were assessed. Analyses were performed by intention-to-treat and adverse events were evaluated. The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] trial is registered in clinicaltrials.gov; NCT01690988 Findings Between February 6, 2014 and June 26, 2016, 1360 patients assessed and 672 were randomised, with 222 in the placebo group, 227 in the low dose ketamine group, and 223 in the high dose ketamine group. There was no difference in postoperative delirium incidence between those in the combined ketamine groups and those who received placebo (19.45% vs. 19.82%, respectively; absolute difference, 0.36%; 95% CI, −6.07% to 7.38%; p=0.92). There were no significant differences among the three groups in maximum pain scores (p=0.88) or median opioid consumption (p=0.47) over time. There were more postoperative hallucinations (p=0.01) and nightmares (p=0.03) with escalating doses of ketamine. Adverse events (cardiovascular, renal, infectious, gastrointestinal, bleeding), whether viewed individually (P value for each >0.40) or collectively (82/222 [36.9%] in placebo group, 90/227 [39.6%] in low dose ketamine group, 91/223 in high dose ketamine group [40.8%]; P=0.69), did not differ significantly across the three groups. Interpretation The administration of a single subanaesthetic dose of ketamine to older adults during major surgery did not show evidence of reducing postoperative delirium, pain, or opioid consumption, and might cause harm by inducing negative experiences. Given current evidence and guidelines related to ketamine and postoperative analgesia, the unexpected secondary findings regarding pain and opioid consumption warrant replication or refutation in subsequent research. Funding The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The principal investigators (MSA and GAM) had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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            Stress, Glucocorticoids, and Damage to the Nervous System: The Current State of Confusion.

            An extensive literature demonstrates that glucocorticoids (GCs), the adrenal steroids secreted during stress, can have a broad range of deleterious effects in the brain. The actions occur predominately, but not exclusively, in the hippocampus, a structure rich in corticosteroid receptors and particularly sensitive to GCs. The first half of this review considers three types of GC effects: a) GC-induced atrophy, in which a few weeks' exposure to high GC concentrations or to stress causes reversible atrophy of dendritic processes in the hippocampus; b) GC neurotoxicity where, over the course of months, GC exposure kills hippocampal neurons; c) GC neuroendangerment, in which elevated GC concentrations at the time of a neurological insult such as a stroke or seizure impairs the ability of neurons to survive the insult. The second half considers the rather confusing literature as to the possible mechanisms underlying these deleterious GC actions. Five broad themes are discerned: a) that GCs induce a metabolic vulnerability in neurons due to inhibition of glucose uptake; b) that GCs exacerbate various steps in a damaging cascade of glutamate excess, calcium mobilization and oxygen radical generation. In a review a number of years ago, I concluded that these two components accounted for the deleterious GC effects. Specifically, the energetic vulnerability induced by GCs left neurons metabolically compromised, and less able to carry out the costly task of containing glutamate, calcium and oxygen radicals. More recent work has shown this conclusion to be simplistic, and GC actions are shown to probably involve at least three additional components: c) that GCs impair a variety of neuronal defenses against neurologic insults; d) that GCs disrupt the mobilization of neurotrophins; e) that GCs have a variety of electrophysiological effects which can damage neurons. The relevance of each of those mechanisms to GC-induced atrophy, neurotoxicity and neuroendangerment is considered, as are the likely interactions among them.
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              Perioperative Rosuvastatin in Cardiac Surgery.

              Complications after cardiac surgery are common and lead to substantial increases in morbidity and mortality. Meta-analyses of small randomized trials have suggested that perioperative statin therapy can prevent some of these complications.
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                Author and article information

                Journal
                Interv Med Appl Sci
                Interv Med Appl Sci
                imas
                IMAS
                Interventional Medicine & Applied Science
                Akadémiai Kiadó (Budapest )
                2061-1617
                2061-5094
                28 February 2019
                March 2019
                : 11
                : 1
                : 27-37
                Affiliations
                [1 ]Cardiothoracic Research, Department of Surgery, Hunter Holmes McGuire Veterans Affairs Medical Center , Richmond, VA, USA
                Author notes
                [* ]Corresponding author: Benita Dharmaraj, MD, MHSA; Cardiothoracic Research, Department of Surgery, Hunter Holmes McGuire Veterans Affairs Medical Center, 1201 Broad Rock Boulevard, Surgical Service (112), Richmond, VA 23249, USA; Fax: +1 80 46 75 54 00; E-mail: benita.dharmaraj@ 123456va.gov
                Article
                10.1556/1646.11.2019.01
                7044570
                0812a178-45de-47b6-87e0-70bf5c3a357c
                © 2019 The Author(s)

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium for non-commercial purposes, provided the original author and source are credited, a link to the CC License is provided, and changes – if any – are indicated.

                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 101, Pages: 11
                Product
                Funding
                Funding sources: No financial support was received for this study.
                Categories
                Review

                neuroprotection,cardiothoracic surgery,cardiac surgery,stroke,encephalopathy,pharmacological agents,anesthesia,sedation

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