Delirium is a serious acute neurocognitive condition that is common and debilitating in older people who undergo major surgery or are acutely ill. The nature of delirium, baseline comorbidity of older adults and related contextual factors present unique ethical challenges in delirium prevention and treatment trials; yet there is limited literature on how these challenges should be best addressed. The objective of this rapid review was to examine the reporting of key ethical processes for older adults (approval, recruitment, consent, retention) in delirium intervention trials. A rapid search in December 2023 with restricted key terms (“Delirium,” “Randomized Controlled Trial”), databases (PubMed, CINAHL), older adult participants and English language, and a final publication date range of 2020 to 2023, resulted in 411 articles screened, 153 full-text reviews, and 51 randomized controlled trial (RCTs) reports (with 11 published protocols) included. Data extraction and synthesis aligned with general guidance for ethical approval, processes and reporting of clinical studies, including for people with key vulnerabilities for research participation. Trials were categorized by degree of ethical reporting and statistical tests explored associated trial characteristics. The 51 RCTs were conducted in diverse countries, with the most sizeable proportion in China (51%). Most trials evaluated a delirium prevention (96%) and/or pharmacological intervention (69%) and were individually randomized (88%), phase 3 (84%), and perioperative (75%). No trial fully reported all ethical processes. Most of the 51 trials fully reported who provided consent (88%), the consent approach (88%), and ethical approval details (63%); around half fully reported safety assessments (59%) and how, where and when participants were recruited (49%). However, few trials fully reported who recruited participants (31%), who obtained consent (22%); how trial information was provided (27%), whether capacity was assessed prior to consent (10%), how participants were supported though the trial design or processes (18%) or in-trial communications (8%). Compared to the 19 trials (37%) with little to no reporting of ethical processes, the 16 (31%) trials with fuller reporting more often had a separately published protocol (56% vs 0%, P < .001), were conducted outside of China (87.5% vs 11%, P < .001) and had lower median consent (56% vs 96%, P < .01) and retention rates (89% vs 96%, P < .05). These results will help inform future efforts focused on improving the conduct and reporting of ethical processes in delirium trials.

BACKGROUND:Anaesthesia is crucial in ensuring patient comfort and safety during surgical procedures by inducing a temporary loss of sensation, memory, and consciousness. However, its multifaceted nature presents challenges in defining its aims and expected outcomes. This study aimed to establish a consensus on anaesthesia's definition and core aims using a structured Delphi process. METHODS:We conducted a modified three-round eDelphi method involving 23 international experts. Participants engaged in iterative online surveys to refine a consensus definition and aims. Consensus was predefined as achieving ≥80% agreement. The process included external expert reviews to enhance objectivity and validity. Statistical analyses included median, interquartile range (IQR), and agreement percentages. RESULTS:The Delphi process resulted in consensus on 49 aims and a refined definition of anaesthesia. The final definition emphasises safe, effective, individualised, patient-centred, and empathetic care, ensuring optimal surgical conditions while enhancing patient outcomes. Key aims included preoperative optimisation, stress and pain reduction, organ function preservation, prompt emergence and recovery, interdisciplinary teamwork, continuous outcome assessment, and sustainability in anaesthesia practices. The final agreement rate for the updated definition was 82.6% (median: 10, IQR: 9-10). Additionally, environmental sustainability was recognised as an integral aim. CONCLUSION:The consensus developed in this study provides a structured framework for defining anaesthesia's objectives, improving patient-centred care, guiding clinical practice, and fostering research. By incorporating sustainability and long-term patient outcomes, the consensus supports the evolution of precision anaesthesia. Future research will validate these defined aims in various perioperative settings and refine the consensus based on real-world applications.

ImportanceDelirium is common after cardiac surgery and associated with adverse outcomes. Intraoperative benzodiazepines may increase postoperative delirium but restricting intraoperative benzodiazepines has not yet been evaluated in a randomized trial.ObjectiveTo determine whether an institutional policy of restricted intraoperative benzodiazepine administration reduced the incidence of postoperative delirium.Design, Setting, and ParticipantsThis pragmatic, multiperiod, patient- and assessor-blinded, cluster randomized crossover trial took place at 20 North American cardiac surgical centers. All adults undergoing open cardiac surgery at participating centers during the trial period were included through a waiver of individual patient consent between November 2019 and December 2022.InterventionInstitutional policies of restrictive vs liberal intraoperative benzodiazepine administration were compared. Hospitals (clusters) were randomized to cross between the restricted and liberal benzodiazepine policies 12 to 18 times over 4-week periods.Main Outcomes and MeasuresThe primary outcome was the incidence of delirium within 72 hours of surgery as detected in routine clinical care, using either the Confusion Assessment Method–Intensive Care Unit or the Intensive Care Delirium Screening Checklist. Intraoperative awareness by patient report was assessed as an adverse event.ResultsDuring the trial, 19 768 patients (mean [SD] age, 65 [12] years; 14 528 [73.5%] male) underwent cardiac surgery, 9827 during restricted benzodiazepine periods and 9941 during liberal benzodiazepine periods. During restricted periods, clinicians adhered to assigned policy in 8928 patients (90.9%), compared to 9268 patients (93.2%) during liberal periods. Delirium occurred in 1373 patients (14.0%) during restricted periods and 1485 (14.9%) during liberal periods (adjusted odds ratio [aOR], 0.92; 95% CI, 0.84-1.01; P = .07). No patient spontaneously reported intraoperative awareness.Conclusions and RelevanceIn intention-to-treat analyses, restricting benzodiazepines during cardiac surgery did not reduce delirium incidence but was also not associated with an increase in the incidence of patient-reported intraoperative awareness. Given that smaller effect sizes cannot be ruled out, restriction of benzodiazepines during cardiac surgery may be considered. Research is required to determine whether restricting intraoperative benzodiazepines at the patient level can reduce the incidence of postoperative delirium.Trial RegistrationClinicalTrials.gov Identifier: NCT03928236

INTRODUCTION:In high-income countries, the prevalence of frailty ranges from 10% to 37%. However, data from low- and middle-income countries remain largely unavailable, and no information is currently available on the prevalence of frailty or cognitive impairment in the Georgian population. Preoperative frailty is a known risk factor for postoperative delirium and neurocognitive disorders, which can be life-threatening in the population of older adults. METHODS AND ANALYSIS:This protocol describes a prospective, single-centre observational cohort study investigating preoperative frailty and postoperative neurocognitive disorders in older adults presenting for surgery in Georgia. The study will include 230 participants. Patients will be enroled after their cognitive health is evaluated using the Montreal Cognitive Assessment test. Frailty and neuropsychological tests are conducted at baseline, discharge, 30 days, 3 months and 12 months postoperatively. Additionally, IL-6 levels are measured in blood samples to assess systemic inflammatory levels preoperatively. Participants will be followed up for 1 year. ETHICS AND DISSEMINATION:Our trial has been approved by the Ethics Committee of the LTD 'New Hospitals' clinic (Approval No. 23/01). Patient recruitment began in April 2023 in Tbilisi, Georgia, and will continue until 2026. Dissemination plans include presentations at scientific conferences, publication in peer-reviewed journals, engagement with stakeholders and outreach through popular media. TRIAL REGISTRATION NUMBER:NCT06700291.

Damage to the brain can have disastrous and long-lasting consequences. The European Society of Anaesthesiology and Intensive Care (ESAIC) is aware of the importance of taking good care of the brain, both of patients and of anaesthesia and intensive care unit (ICU) caregivers, and has organised a complete learning track on brain health to bring this concern to the attention of practitioners. This learning track included an online Focus Meeting on Brain Health (November 25, 2023). We here provide readers with a digest of the information that was delivered during that meeting in an opinion paper driven by the authors’ own reading of the literature. It is divided according to the meeting's sessions, including how to improve the health of an injured brain, how to keep a young or old brain healthy, how to keep a healthy adult brain unimpaired, how monitoring can impact brain health in the operating room and in the intensive care unit, and how to keep the anaesthesia and ICU caregivers’ brain healthy. Each part is a brief and focused summary. The main delivered messages are that the management of injured brain patients involves an adequate choice of sedation, adequate brain monitoring, and focused attention to specific points depending on the underlying pathology; that several measures can be undertaken to protect the brain of the very young needing anaesthesia; that it is possible to detect older patients at risk of postoperative neurocognitive disorders, and that dedicated perioperative management by a multidisciplinary expert team may improve their outcomes; that apparently healthy adult brains may suffer during anaesthesia; that the electroencephalogram may track peri-operative brain dysfunction, and that female patients should be given special care in this respect; that multimodal brain monitoring helps to detect pathological processes and to maintain brain homeostasis; and that burnout in anaesthesiologists can be effectively fought using personal, organisational, managerial and legal approaches.

BACKGROUND:Postoperative delirium (POD) following surgery is a prevalent and distressing condition associated with adverse patient outcomes and an increased healthcare burden. OBJECTIVES:To assess the effectiveness of the Safe Brain Initiative care bundle (SBI-CB) in reducing POD in the postanesthesia care unit (PACU). DESIGN:A multicenter, quality-improvement initiative with retrospective analysis of collected data. SETTING:The study was conducted in the operating rooms and postanesthesia care units (PACUs) of four hospitals across Denmark and Turkey. PATIENTS:The convenience sample of patients were aged ≥18 years, scheduled for surgery, and could communicate verbally. Age, sex, preoperative delirium, and the American Society for Anesthesiology physical status classification were used in statistical methods to control for potential confounding influences. INTERVENTION:The SBI-CB, 18 delirium-reducing recommendations aligned with international guidelines. The intervention included patient education, staff training, coordination meetings across centers, and a dashboard for the monitoring of outcomes in the PACU. MAIN OUTCOME MEASURES:The primary outcome was the POD trend in the PACU during implementation months, assessed through Nu-DESC screening at up to three time points in the PACU. We also examined the length of hospital stay. RESULTS:Data were collected from 18,697 adult patients across four hospitals. Initial POD incidence in the PACU after the first three months was 16.36% across all sites (n = 1021). POD in the PACU was observed across all age groups, with peak incidence in younger (18-35 years) and older (>75 years) patients. General anesthesia and longer surgical duration (>1 h) were identified as significant risk factors for POD in the PACU. Matched patients who experienced POD in the PACU had longer stays in hospital, with a mean increase from 35 to 69 h (p < 0.001). Implementation of the SBI-CB was associated with a decreased risk of POD in the PACU for each month of SBI-CB implementation (adjusted odds ratio 0.96, 95% confidence interval: [0.94, 0.97], p < 0.001). CONCLUSIONS:The presented pragmatic implementation of a multidisciplinary care bundle, encompassing pre-, intra-, and postoperative measures alongside outcome monitoring, has the potential to significantly reduce the incidence of POD in the PACU. Improved patient outcomes may be achieved for general surgical departments with patient cohorts not typically considered at risk for developing POD. TRIAL REGISTRATION:Clinicaltrials.gov, identifier NCT05765162.

Damage to the brain can have disastrous and long-lasting consequences. The European Society of Anaesthesiology and Intensive Care (ESAIC) is aware of the importance of taking good care of the brain, both of patients and of anaesthesia and intensive care unit (ICU) caregivers, and has organised a complete learning track on brain health to bring this concern to the attention of practitioners. This learning track included an online Focus Meeting on Brain Health (November 25, 2023). We here provide readers with a digest of the information that was delivered during that meeting in an opinion paper driven by the authors' own reading of the literature. It is divided according to the meeting's sessions, including how to improve the health of an injured brain, how to keep a young or old brain healthy, how to keep a healthy adult brain unimpaired, how monitoring can impact brain health in the operating room and in the intensive care unit, and how to keep the anaesthesia and ICU caregivers' brain healthy. Each part is a brief and focused summary. The main delivered messages are that the management of injured brain patients involves an adequate choice of sedation, adequate brain monitoring, and focused attention to specific points depending on the underlying pathology; that several measures can be undertaken to protect the brain of the very young needing anaesthesia; that it is possible to detect older patients at risk of postoperative neurocognitive disorders, and that dedicated perioperative management by a multidisciplinary expert team may improve their outcomes; that apparently healthy adult brains may suffer during anaesthesia; that the electroencephalogram may track peri-operative brain dysfunction, and that female patients should be given special care in this respect; that multimodal brain monitoring helps to detect pathological processes and to maintain brain homeostasis; and that burnout in anaesthesiologists can be effectively fought using personal, organisational, managerial and legal approaches.

BackgroundChronic post-surgical pain (CPSP) is recognised as one of the most common and debilitating complications of major surgery. Progression from acute to chronic pain after surgery involves sensitisation of central nervous system pathways with the N-methyl-D-aspartate (NMDA) receptor having a central role. Ketamine is a potent, non-selective NMDA antagonist commonly used for management of acute postoperative pain. Inconsistent but largely supportive evidence from small trials of a preventative effect of perioperative ketamine on CPSP risk suggests that a confirmative large trial is needed.MethodsThe ROCKet (Reduction Of Chronic Post-surgical Pain with Ketamine) Trial is a multicentre, double-blind, placebo-controlled, individually randomised superiority trial conducted in 36 hospitals across Australia, New Zealand, and Hong Kong. The trial aims to recruit 4884 patients undergoing abdominal, thoracic, or major orthopaedic surgery. Eligible participants are randomised equally to perioperative intravenous ketamine or placebo for up to 72 h. Incidence of pain in the area of the index surgery is measured by structured telephone interview at 3 months (primary trial endpoint) and 12 months. Pain severity, nature, and associated psychological and quality of life indices are measured using the modified Brief Pain Inventory short form, Neuropathic Pain Questionnaire, Kessler K-10 Psychological Distress Scale, Pain Catastrophising Scale, EQ-5D-3L, and measures of healthcare utilisation and costs. The trial is being conducted by the Department of Critical Care, University of Melbourne, and the Australian and New Zealand College of Anaesthetists Clinical Trials Network. The trial is funded by the Australian National Health and Medical Research Council.DiscussionThe ROCKet trial will clarify the effectiveness of ketamine in primary prevention of CPSP. In addition, it will provide high-quality, prospective data on the epidemiology of CPSP which will better inform further research into prevention and management of CPSP.Trial registrationAustralian New Zealand Clinical Trials Registry (ACTRN12617001619336) on the date of 12/11/2017.

There is a potential differential effect of sevoflurane compared with propofol on postoperative delirium and other perioperative neurocognitive disorders. More generally, there are perhaps differences between volatile and intravenous anaesthetic agents in their possible impact on perioperative neurocognitive disorders. Strengths and limitations of a recent study in this journal and its contribution to our understanding of the impact of anaesthetic technique on perioperative neurocognitive disorders are discussed.

Background As the adverse effects of blood transfusions are better understood, recommendations support single-unit red blood cell (RBC) transfusions (SRBCT). However, an isolated SRBCT across the entire index admission suggests even the single unit may be avoidable. We sought to identify the characteristics of cardiac surgery patients receiving an isolated SRBCT and analyze the impact on outcomes. Methods The Society of Thoracic Surgeons Adult Cardiac Surgery Database was queried for the period between January 1, 2010, and December 31, 2019. Patients aged >18 years undergoing isolated coronary artery bypass grafting or isolated aortic valve replacement were included. A total of 2,151,430 encounters were analyzed. Results Of the 847,442 patients (39.3%) receiving any RBC transfusion during their index admission, 206,555 (24.4%) received only 1 unit. Propensity-matching analysis determined SRBCT patients were significantly older (67.26 vs 64.02 years; odds ratio [OR], 1.02; P < .001), female (39.1% vs 17.8%; OR, 1.57; P < .001), non-White (18.2% vs 13.1%; OR, 0.81; P < .001), and had a smaller body surface area (1.94 vs 2.07 m2; OR, 0.20; P < .001). They also had higher mortality (1.4% vs 1.0%, P < .001), stroke (1.7% vs 1.2%, P < .001), prolonged ventilation (6.4% vs 3.4%, P < .001), renal failure (1.8% vs 0.9%, P < .001), and reoperations (1.3% vs. 0.5%, P < .001) than patients who received 0 RBCs. Conclusions SRBCT is a common occurrence in adult cardiac surgery. This low-volume transfusion is strongly associated with higher morbidity, even after controlling for preoperative risk factors.

A recent systematic review and meta-analysis by Wang and colleagues in the British Journal of Anaesthesia calls into question the concept that perioperative benzodiazepine administration is associated with development of postoperative delirium in older individuals after anaesthesia and surgery. This editorial focuses on potential bias within the systematic review and addresses major concerns surrounding benzodiazepine use in the older perioperative population.

The prevalence of neurocognitive disorders is rapidly increasing in high-income countries as the population ages and the prevention and management of many other life-threatening diseases improves. In Australia, dementia (including Alzheimer's disease) is now the leading cause of death in females and the second leading cause of death in males. Moreover, people older than 65 years comprise 16% of the population but receive more than a third of elective surgeries.1Australian Institute of Health and WelfareDementia in Australia.https://www.aihw.gov.au/reports/dementia/dementia-in-aus/contents/aboutDate accessed: September 1, 2023Google Scholar The convergence of these two issues highlights the importance of understanding how cognitive decline might play a part in outcomes after surgery and anaesthesia. Unfortunately, perioperative studies on the effect of preoperative neurocognitive disorders on postoperative outcomes, other than further cognitive decline, are scarce. One prospective study2Robinson TN Wu DS Pointer LF Dunn CL Moss M Preoperative cognitive dysfunction is related to adverse postoperative outcomes in the elderly.J Am Coll Surg. 2012; 215 (discussion 17–18.): 12-17Crossref PubMed Scopus (178) Google Scholar screened for cognition and showed that impaired preoperative cognition is associated with poor outcomes including higher incidence of delirium, longer hospital stay, discharge institutionalisation, and 6 month mortality. Two retrospective database searches linked preoperative poor cognition to poor outcomes for hip fracture repair3Seitz DP Gill SS Gruneir A et al.Effects of dementia on postoperative outcomes of older adults with hip fractures: a population-based study.J Am Med Dir Assoc. 2014; 15: 334-341Summary Full Text Full Text PDF PubMed Scopus (76) Google Scholar and all major surgeries.4Hu CJ Liao CC Chang CC Wu CH Chen TL Postoperative adverse outcomes in surgical patients with dementia: a retrospective cohort study.World J Surg. 2012; 36: 2051-2058Crossref PubMed Scopus (82) Google Scholar Unfortunately, with the exception of delirium, much of the research into perioperative neurocognitive disorder has focused largely on further deterioration in cognition after surgery rather than generalised poor postoperative outcomes. It would be informative to have information on a link between pre-existing neurocognitive disorder and more generalised complications rather than specifically on further cognitive deterioration. Such knowledge would further underscore the imperative of preoperative screening in individuals older than 65 years as an integral part of preoperative assessment.5Crosby G Culley DJ Hyman BT Preoperative cognitive assessment of the elderly surgical patient: a call for action.Anesthesiology. 2011; 114: 1265-1268Crossref PubMed Scopus (57) Google Scholar This information would ideally be obtained by a prospective observational study in patients who were assessed for cognition preoperatively and categorised into no neurocognitive disorder or mild or major neurocognitive disorders. Subsequent long-term follow-up of outcomes would then provide data enabling an association between cognition and postoperative complications. In the absence of a prospective observational study, lower levels of evidence might provide some insight into any link between preoperative cognition and general long-term outcomes. In The Lancet Healthy Longevity, Alexander Abess and colleagues6Abess AT Deiner SG Briggs A et al.Association of neurocognitive disorders with morbidity and mortality in older adults undergoing major surgery in the USA: a retrospective, population-based, cohort study.Lancet Healthy Longev. 2023; 4: e608-e617Summary Full Text Full Text PDF Scopus (1) Google Scholar used an administrative database (US Medicare) to investigate a link between pre-existing neurocognitive disorder and mortality, discharge destination, complications, and type of surgery. The database was large, comprising more than 5·2 million individuals aged 65 years and older, 767 830 (14·59%) of whom had a pre-existing neurocognitive disorder. Abess and colleagues found that individuals with a neurocognitive disorder had higher rates of mortality at 30 days, 90 days, and 365 days after surgery compared with those without an existing neurocognitive disorder. In analysis of secondary outcomes, Abess and colleagues also found higher discharge rates to a nursing facility, and higher rates of delirium, stroke, wound infection, and urinary tract infection in those with a neurocognitive disorder compared with those without a neurocognitive disorder. These results should be taken in context. The authors acknowledge the limitations of an administrative database. Such databases are derived from information recorded by chart abstraction personnel for the purpose of billing and demographic use and differ markedly from electronic medical records or protocol-driven, prospective research data. Data might be inaccurate because of miscalculations at the administrative level, clinician misclassification, or limitations of the codes.7Boncyk CS Jelly CA Freundlich RE The blessing and the curse of the administrative database.Ann Am Thorac Soc. 2020; 17: 174-175Crossref Scopus (2) Google Scholar The authors state that Medicare claim data fail to identify dementia in about half of clinically diagnosed patients. To compensate for these missed cases, the authors have included altered mental status and unspecified signs and symptoms of cognitive function and awareness in their list of neurocognitive disorders. The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), specifically defines mild neurocognitive disorder as a cognitive concern, modest impairment of cognition, and non-interference with daily activities, and describes major neurocognitive disorder as cognitive concern, substantial impairment of cognitive performance, and interference with daily activities. These definitions have also been applied to the perioperative period.8Evered L Silbert B Knopman DS et al.Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery—2018.Br J Anaesth. 2018; 121: 1005-1012Summary Full Text Full Text PDF PubMed Scopus (388) Google Scholar These descriptions include many individuals who would not be coded using International Classification of Diseases (ICD) codes, especially for mild neurocognitive disorders. This is acknowledged by Abess and colleagues. The authors further acknowledge that they used a list of ICD tenth revision codes, which would tend to emphasise severe neurocognitive disorders and obscure more moderate neurocognitive disorders. This is highlighted by the fact that only 156 154 (2·97%) of the population in this study had a diagnosed neurocognitive disorder according to ICD codes. This contrasts with previous estimates of individuals older than 65 years with clinical symptoms of dementia of 10%.9Manly JJ Jones RN Langa KM et al.Estimating the prevalence of dementia and mild cognitive impairment in the US: the 2016 health and retirement study harmonized cognitive assessment protocol project.JAMA Neurol. 2022; 79: 1242-1249Crossref PubMed Scopus (46) Google Scholar This does not even take into account the further 22% prevalence rate of minor neurocognitive disorder in this population,9Manly JJ Jones RN Langa KM et al.Estimating the prevalence of dementia and mild cognitive impairment in the US: the 2016 health and retirement study harmonized cognitive assessment protocol project.JAMA Neurol. 2022; 79: 1242-1249Crossref PubMed Scopus (46) Google Scholar or the high postoperative incidence of delirium.10Marcantonio ER Delirium in hospitalized older adults.N Engl J Med. 2017; 377: 1456-1466Crossref PubMed Scopus (551) Google Scholar Clearly the ICD classification in the report by Abess and colleagues has deficiencies, as it does not report a large number of individuals with neurocognitive disorder. The authors explicitly state that their use of the term neurocognitive disorder has been used liberally and does not align with the DSM-5 use of the term. It would have been appropriate for the authors to assign a more fitting term to describe their criteria for categorising ICD coding. Despite these limitations, Abess and colleagues6Abess AT Deiner SG Briggs A et al.Association of neurocognitive disorders with morbidity and mortality in older adults undergoing major surgery in the USA: a retrospective, population-based, cohort study.Lancet Healthy Longev. 2023; 4: e608-e617Summary Full Text Full Text PDF Scopus (1) Google Scholar have drawn attention to poor outcomes after anaesthesia and surgery in those with neurocognitive disorders. This is an important step to acknowledging that neurocognitive disorders must be considered as a risk factor for surgery along with other more recognised comorbidities. We declare no competing interests. Association of neurocognitive disorders with morbidity and mortality in older adults undergoing major surgery in the USA: a retrospective, population-based, cohort studyOur findings suggest that the presence of a neurocognitive disorder is independently associated with an increased risk of mortality. Identification of a neurocognitive disorder before surgery can help clinicians to better disclose risks and plan for patient care after hospital discharge. Full-Text PDF Open Access

Introduction:Xenon exhibits significant neuroprotection against a wide range of neurological insults in animal models. However, clinical evidence that xenon improves outcomes in human studies of neurological injury remains elusive. Previous reviews of xenon's method of action have not been performed in a systematic manner. The aim of this review is to provide a comprehensive summary of the evidence underlying the cellular interactions responsible for two phenomena associated with xenon administration: anesthesia and neuroprotection. Methods:A systematic review of the preclinical literature was carried out according to the PRISMA guidelines and a review protocol was registered with PROSPERO. The review included both in vitro models of the central nervous system and mammalian in vivo studies. The search was performed on 27th May 2022 in the following databases: Ovid Medline, Ovid Embase, Ovid Emcare, APA PsycInfo, and Web of Science. A risk of bias assessment was performed utilizing the Office of Health Assessment and Translation tool. Given the heterogeneity of the outcome data, a narrative synthesis was performed. Results:The review identified 69 articles describing 638 individual experiments in which a hypothesis was tested regarding the interaction of xenon with cellular targets including: membrane bound proteins, intracellular signaling cascades and transcription factors. Xenon has both common and subtype specific interactions with ionotropic glutamate receptors. Xenon also influences the release of inhibitory neurotransmitters and influences multiple other ligand gated and non-ligand gated membrane bound proteins. The review identified several intracellular signaling pathways and gene transcription factors that are influenced by xenon administration and might contribute to anesthesia and neuroprotection. Discussion:The nature of xenon NMDA receptor antagonism, and its range of additional cellular targets, distinguishes it from other NMDA antagonists such as ketamine and nitrous oxide. This is reflected in the distinct behavioral and electrophysiological characteristics of xenon. Xenon influences multiple overlapping cellular processes, both at the cell membrane and within the cell, that promote cell survival. It is hoped that identification of the underlying cellular targets of xenon might aid the development of potential therapeutics for neurological injury and improve the clinical utilization of xenon. Systematic review registration:https://www.crd.york.ac.uk/prospero/, identifier: 336871.

Surgery in the older patient is associated with short- and long-term cognitive changes, including delirium, post-operative cognitive dysfunction (POCD) and neurocognitive decline (NCD). The inflammatory response to surgery may be a contributing factor. We investigated the association between inflammatory biomarkers and cognitive change up to 3 months following surgery. We recruited 70 older adults undergoing elective non-cardiac surgery. Baseline and 3 month neurocognitive and functional assessments were performed, and delirium was assessed for 5 days following surgery. A control group of age-similar subjects underwent assessment at similar time points. Blood was collected in 55 patients at baseline and post-surgery at 30 min, 6h, 24h and 48h for inflammatory biomarker analysis (Tumor Necrosis Factor (TNF)-α, Interleukin (IL)-6, IL-10, IL-18). POCD was attributed if there was ≥ 1.96 SD decline in two or more neuropsychological tests compared with time-matched controls. NCD major and mild was attributed according to DSM-V criteria. Patients underwent a range of non-cardiac surgical procedures and were aged 69.5 (SD 6.7)y and 48.6% were female. Mean baseline MMSE was 27.1 (7.5). Delirium was identified post-operatively in 4% of subjects. At 3 months, 18 (32.7%) subjects had some form of cognitive decline: POCD 7%, Mild NCD 16% or Major NCD 15%. IL-6 was significantly elevated following surgery and remained so to 48h. IL-10 was elevated at 6h but declined to baseline by 48h. Both IL-18 and TNF-α were transiently lower than baseline at 30 minutes, but then returned to close to baseline levels. There was no association between inflammatory biomarker levels and delirium or cognitive change at 3 months. We have confirmed the presence of new cognitive decline in a significant number of older patients up to 3 months following non-cardiac surgery. We identified changes in inflammatory biomarkers, especially IL-6 which was elevated for at least 48h, but no association with cognitive change. Ongoing research will address more specific biomarkers of neuronal injury.