Chronic psychological stress has been implicated as a risk factor for Alzheimer’s disease (AD), potentially through cortisol-mediated acceleration of disease progression. However, the molecular pathways underlying this relationship remain poorly understood. Epigenetic regulation of the glucocorticoid and mineralocorticoid receptor genes (NR3C1 and NR3C2), which encode receptors for cortisol, may play an important role, but has not been examined in relation to AD progression. Therefore, this study investigated associations between DNA methylation of NR3C1/NR3C2 and AD-related phenotypes, including cognition, brain amyloid-β (Aβ) burden, and regional brain volumes. These associations were examined in two independent cohorts of cognitively unimpaired individuals with accumulating brain Aβ (n = 89–298 across outcomes) using linear regression and meta-analyses. The study also explored whether DNA methylation within NR3C1 and NR3C2 interacted with depression symptoms to influence relationships with AD-related phenotypes. While only nominal associations were observed in direct analyses, stronger associations emerged in interaction with depressive symptoms. Interaction analyses showed that relationships between DNA methylation and AD-related phenotypes (cognition, hippocampal volume and ventricular expansion) differed depending on the presence of depression symptoms. Consistent patterns across cohorts were observed, with associations primarily evident among individuals with clinically relevant depressive symptoms. One site (NR3C1 cg24052866) was associated with cognitive decline, one (NR3C1 cg08845721) with cross-sectional hippocampal volume, and eight (NR3C1 cg21979215, cg16594263; NR3C2 cg27460943, cg17253842, cg04867484, cg10993059, cg25672354, cg27234800) with ventricular expansion. These exploratory findings suggest epigenetic variation within cortisol receptor genes may influence AD-related neurodegeneration in a depression-dependent manner.

BACKGROUND:Older adults undergoing surgery frequently experience postoperative delirium and postoperative neurocognitive disorders (NCD), but the neuropathophysiology of these conditions remains obscure. A postoperative inflammatory cascade with subsequent neuronal injury is one theory that requires further investigation. We report the incidence of delirium and postoperative NCD using updated nomenclature and investigate changes in inflammatory and neuronal injury biomarkers associated with these conditions. METHODS:We performed a prospective, longitudinal, cohort study with older adults aged 60 years or more undergoing major elective noncardiac surgery. Patients completed cognitive assessments preoperatively and at 3 and 28 months postoperatively, alongside twice-daily delirium assessments during hospital admission. Plasma was obtained before surgical incision and at 30 minutes, 6, 24, and 48 hours postoperatively and assayed for cytokines (interleukin [IL]-6, IL-10, IL-18, tumor necrosis factor [TNF]α) and neuronal injury markers (neurofilament light [NfL], total Tau, and pTau181). RESULTS:We enrolled 79 patients (mean age: 69 [standard deviation {SD}: 6.5]; female: 45.6%). Thirteen patients (15.2%) experienced postoperative delirium. At 3 months, 18 of 63 (28.6%) had postoperative NCD, and at long-term follow-up, 17 of 46 (37.0%) had NCD. IL-6, IL-10, total Tau, p-Tau181, and NfL levels were 10.3, 1.9, 1.3, 1.2, and 1.6 times higher at 48 hours postsurgery compared to baseline (all P <.05). IL-18 levels were 1.1 times lower. TNFα remained unchanged. Linear mixed-effects models revealed that greater elevations in IL-6 levels were associated with increased delirium risk (β = 22.23, standard error {SE} = 9.48, P =.02) and long-term NCD (β = 12.46, SE = 6.02, P =.04). CONCLUSIONS:Using updated nomenclature, postoperative delirium and postoperative NCD affect a third of surgical patients and inflammatory and neuronal injury markers are elevated after surgical intervention. Increases in IL-6 and pTau181 at the time of surgery are associated with postoperative delirium; increases in IL-6 are also associated with long-term NCD. Specific biomarkers follow unique time courses after anesthesia and surgery.

INTRODUCTION:Peri-operative neurocognitive disorders are common among older adults presenting for surgery and anaesthesia. Cognitive screening is recommended to identify patients at risk for adverse neurocognitive outcomes, though the most appropriate peri-operative tool remains debated. Remote assessment methods may be advantageous, but they need robust validation. We aimed to examine the feasibility and validity of the Modified Telephone Interview for Cognitive Status (TICS-M) among older adults and provide recommended TICS-M scores to identify those most at risk of poor postoperative cognitive outcomes. METHODS:As part of a prospective longitudinal study with 215 older adults living in the community or scheduled for elective surgery, we conducted the modified, 22-item, 50-point version of the TICS remotely, followed by in-person assessments using two common cognitive screening tools: the Mini-Mental State Examination (MMSE); Alzheimer's Disease Assessment Scale Cognition Subscale (ADAS-Cog); and a comprehensive neuropsychological and functional assessment. RESULTS:The TICS-M was feasible and acceptable, with a completion rate of 86%. TICS-M scores correlated with scores on the MMSE (r = 0.61, p < 0.001) and ADAS-Cog (r = -0.55, p < 0.001) at baseline, and associations remained consistent at 12- and 24-month follow-up. After controlling for age, sex and education, baseline performance on the TICS-M was independently associated with subsequent cognitive impairment at 12 months (OR 0.84, 95% CI 0.77-0.92, p < 0.001) and 24 months (OR 0.84, 95% CI 0.76-0.94, p = 0.001). A TICS-M score of 32.5 was the optimal threshold to identify people with cognitive impairment (0.76, 95% CI 0.70-0.82, p < 0.001). DISCUSSION:The TICS-M is a feasible, valid and reliable remotely administered tool that shows utility in the peri-operative environment. We recommend its implementation into routine clinical practice for remote pre-operative assessment in patients aged ≥ 65 y scheduled for surgery and anaesthesia.

BACKGROUND:Peri-operative neurocognitive disorders are one of the most common complications affecting older adults after anaesthesia and surgery. It is not clear how exposure to surgery and anaesthesia contributes to the prevalence of long-term neurocognitive disorders. This study aimed to report the prevalence of neurocognitive disorders, and explore pre-operative factors associated with neurocognitive disorders 5 years after elective orthopaedic surgery. METHODS:A prospective, 5-year longitudinal, cohort study was performed recruiting patients (aged ≥ 60 y) undergoing elective orthopaedic surgery and a contemporaneous non-surgical control group. Neurocognitive disorder was evaluated and classified at baseline and 5-year review incorporating: self- and informant-reported cognition; functional participation; and performance on neuropsychological tests. RESULTS:Recruitment at 5-year follow-up included 195 patients and 21 control participants. In the patient cohort the prevalence of neurocognitive disorder was 38.1% (n = 75), with 61 (30.1%) meeting the criteria for mild neurocognitive disorder and 14 (7.1%) for major neurocognitive disorder. At 5-year follow-up, 121 (61.4%) patients were classified with a neurocognitive disorder, with 88 (44.7%) characterised with mild neurocognitive disorder and 33 (16.8%) with major neurocognitive disorder. Age (odds ratio (95%CI) 1.07 (1.02-1.13); p = 0.01) and baseline cognitive impairment (odds ratio (95%CI) 2.1 (1.06-4.15); p = 0.03) were significant predictors of neurocognitive disorder 5 years after surgery. CONCLUSION:More than half of older adult patients had some form of neurocognitive disorder 5 years after elective orthopaedic surgery. Surgery and anaesthesia may be associated with the trajectory of cognitive decline in at-risk older adults, including those with pre-operative cognitive impairment. Cognitive screening should be factored into pre-operative assessments of older adults to inform subsequent care.

Preoperative biofluid biomarkers reflecting pathophysiological, neuronal injury, and inflammation as well as those for Alzheimer's disease (AD) may be valuable tools for the risk stratification of perioperative neurocognitive disorders (PNDs) in older adults. We summarized current evidence relating these preoperative biomarkers to PND beyond 7 days, in older surgical participants aged ≥60 years. Studies that evaluated the association of preoperative biomarkers with cognitive decline as an outcome, beyond 7 days, were identified through searches of 6 databases and 3 trial registries to 17 January 2024. Preclinical studies, intracranial surgical, or studies with participants aged <60 years were excluded. Studies varied widely in the assessment of PND, so a wide range of cognitive outcomes was accepted, including those using the term postoperative cognitive dysfunction (POCD) to define cognitive decline. The pooled incidence of POCD utilizing a binary cognitive outcome was summarized. Fifteen studies involving 2103 participants were included. Marked heterogeneity was evident in the cognitive outcome metrics, assessment timeframes, limiting a quantitative synthesis. Of the 9 studies using binarized cognitive outcomes, the incidence of POCD was 23.4% (95% confidence interval [CI], 6.6-46.2) at <3 months, 11.4% (95% CI, 8.1-15.0) at 3 to <12 months, and 6.9% (95% CI, 1.9-14.5) at ≥12 months postoperatively. Of the 15 studies, 9 described blood-based biomarkers, 4 described cerebrospinal fluid (CSF) biomarkers, and 2 measured both blood and CSF markers. The biomarkers evaluated reflected the pathogenic indicators neuronal injury (9 studies), inflammation (5 studies) and of amyloid (5 studies), and Tau (1 study). The studies included were of medium to high quality. Evidence was the most promising for amyloid biomarkers, with 4 of 5 included studies demonstrating associations of lower preoperative biofluid amyloid biomarker levels with increased risk of POCD. In conclusion, preoperative biofluid amyloid biomarkers may hold potential utility for the prediction of POCD, although current evidence remains limited. Other potential preoperative biomarkers for POCD included p-Tau181 and Neurofilament Light, however small sample sizes, study heterogeneity, and conflicting results limited conclusions drawn. Standardized cognitive outcome metrics and common assessment timeframes are additionally required in future studies to ascertain the prognostic utility of these biomarkers for POCD.

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.

Quality perioperative care not only involves careful preoperative assessment but also identifying the appropriate level of postoperative care. For some patients this involves planned admission to ICU or High Dependency Unit (HDU) postoperatively. With the limited resources and existent bed pressures it is important this postoperative destination is identified in advance. In this study we aimed to assess whether attendance in specialist preadmission clinic, involving an assessment by either an anaesthetic consultant or perioperative medicine physician, was related to unplanned ICU/HDU admissions postoperatively. All patient surgeries conducted at St Vincent's Hospital Melbourne between July-December 2019 were retrospectively collected. Patients were excluded if they were emergency cases, hospital transfers or cardiac cases. Patients were grouped as either being seen in preadmission clinic by an anaesthetist/perioperative medicine physician or not and whether they were later admitted to ICU. Patients were counted as planned ICU admissions if there was a preoperative bed request or a noted plan for ICU ahead of surgery. Of 7712 surgeries conducted, 160 were admitted to ICU (2.07%). Of the ICU admissions, 73 were unplanned (0.9% of all surgeries) and 87 were planned (1.1%). Of the unplanned admissions, 19 were seen in preadmission clinic and 54 were not. This suggests that a preoperative review by a specialist anaesthetic consultant or perioperative medicine physician was associated with a reduction in unplanned ICU/HDU admission at our hospital.

BACKGROUND Chronic post-surgical pain (CPSP) represents a significant issue for many patients following surgery; however, the long-term incidence and impact have not been well described following cardiac surgery. Our aim was to characterize CPSP at least 5 years following coronary artery bypass grafting (CABG) surgery. METHODS This prospective observational study investigated a cohort of patients from a larger trial investigating cognitive outcomes following CABG surgery, with 89 of 148 eligible patients (60.1%) assessed for CPSP at a mean (standard deviation [SD]) of 6.8 [1.2] years. Questionnaires interrogated pain presence, intensity, location, neuropathic characteristics, Geriatric Depression Scale scores (GDS) and instrumental activities of daily living (IADL). RESULTS CPSP was described in 21/89 (23.6%), with 10 rating it as moderate to severe. Six of the CPSP patients (29%) met criteria for neuropathic pain (6.7% overall). The highest rate of CPSP was associated with the leg surgical site (chest 12/89 [13.5%], arm 8/68 [11.8%] and leg (saphenous vein graft-SVG) 11/37 [29.7%]; χ2  = 6.523, p = 0.038). IADL scores were significantly lower for patients with CPSP (mean [SD]: 36.7 [1.6] vs. no CPSP 40.6 [0.6]; p = 0.006). Patients had GDS scores consistent with moderate depression (GDS >8) in 3/21 (14.3%) with CPSP, versus 3/68 (4.4%) non-CPSP patients (χ2  = 3.20, p = 0.073). CONCLUSIONS This study identified a CPSP incidence of 23.6% at a mean of 6.8 years after CABG surgery, with the highest pain proportion at SVG harvest sites. CPSP was associated with neuropathic pain symptoms and had a significant impact on IADLs. This emphasizes the need for long-term follow-up of CABG patients. SIGNIFICANCE This study highlights the impact of CPSP 7 years following cardiac surgery and highlights the effect of surgical site, neuropathic pain and the importance of including pain assessment and management in the long-term follow-up of cardiac surgical patients. Strategies to address and prevent chronic pain following cardiac surgery should be further explored.

Objectives:An increasing number of people are undergoing lumbar puncture (LP) for the purposes of research. Performing LP for research purposes introduces considerations that differ from LP performed for clinical, diagnostic or therapeutic reasons. The demand for research LP will greatly increase as biomarkers are used to both diagnose and monitor disease progression in clinical trials. Minimising adverse events is paramount because research participants receive no clinical benefit and often need repeat procedures. We describe the experience of performing LP for research by anaesthetists.Methods:We reviewed the clinical protocol and incidence of adverse events in 326 research LP in an anaesthesia department.Results:There was a lower incidence of adverse events compared with previous reports when LP was undertaken for clinical reasons. The incidence of severe post-LP headache was 1.3% when an atraumatic spinal needle with a 27 gauge tip and a 22 gauge shaft was used.Conclusions:We describe the practice to sample cerebrospinal fluid (CSF) by LP for research purposes. Specific practices include the sitting position of the participant, aspiration rather than passive CSF withdrawal, attention to the sterility of the procedure, monitoring of vital signs and importantly the use of 22/27 gauge microtip spinal needle.Trial registration numbers:ACTRN12612000493842, NCT04623242.

Older adults who undergo elective surgery may be at risk of an altered cognitive trajectory leading to long-term decline. We investigated the incidence of cognitive decline in the elderly following elective non-cardiac surgery five years post-operatively and examined whether differences in classification criteria for cognitive outcomes resulted in different incidence rates. We prospectively studied older adults following orthopaedic surgery, alongside non-surgical control participants. All participants completed a battery of neuropsychological tests before surgery and again five years postoperatively. We classified Postoperative Cognitive Dysfunction (POCD), (a change-based construct historically used in anesthesiology and surgery) as a decline of two standard deviations (SD) on two or more cognitive tests compared to controls. We also assessed Neurocognitive Disorders (NCD) relative to change in controls, a term recently introduced to align cognitive disorders with community medicine. Major NCD was defined by a decline of two SD on any test, accompanied by a subjective memory complaint and observed decline in instrumental activities of daily living. Mild NCD was classified as a memory complaint and a decline of one SD on at least one test. From an initial 300 participants enrolled, 227 participants (surgical = 199, non-surgical control = 34) completed the five year follow-up. Average (SD) follow-up age was 74.8 (6. 6) years and 154 (67.8%) were female. We identified POCD at five years in 28 (14.2%), and major NCD in 38 (19.3%) participants. Mild NCD was more common, occurring in 81 (41.1%) participants. Cognitive decline five years postoperatively was associated with increasing age, whereas education history and anesthetic technique (spinal or GA) were not significantly associated. Further analyses will determine the role of cardiovascular risk factors. We found both overlap and differences in the incidence rate of cognitive decline according to the criteria used for classification. Regardless of classification criteria and nomenclature, we found higher rates of cognitive decline amongst non-cardiac surgical patients compared to rates reported in the general population. Our findings provide support that even elective, non-cardiac surgical procedures under anesthesia are associated with a faster rate of cognitive decline amongst older adults. Possible pathophysiological mechanisms, including cardiovascular factors, will be discussed.

BACKGROUND: The perioperative inflammatory response may be implicated in adverse outcomes including neurocognitive dysfunction and cancer recurrence after oncological surgery. The immunomodulatory role of anesthetic agents has been demonstrated in vitro; however, its clinical relevance is unclear. The purpose of this meta-analysis was to compare propofol and sevoflurane with respect to biomarkers of perioperative inflammation. The secondary aim was to correlate markers of inflammation with clinical measures of perioperative cognition. METHODS: Databases were searched for randomized controlled trials examining perioperative inflammation after general anesthesia using propofol compared to sevoflurane. Inflammatory biomarkers investigated were interleukin (IL)-6, IL-10, tissue necrosis factor alpha (TNF-α), and C-reactive protein (CRP). The secondary outcome was incidence of perioperative neurocognitive disorders. Meta-analysis with metaregression was performed to determine the difference between propofol and sevoflurane. RESULTS: Twenty-three studies were included with 1611 participants. Studies varied by surgery type, duration, and participant age. There was an increase in the mean inflammatory biomarker levels following surgery, with meta-analysis revealing no difference in effect between propofol and sevoflurane. Heterogeneity between studies was high, with surgery type, duration, and patient age contributing to the variance across studies. Only 5 studies examined postoperative cognitive outcomes; thus, a meta-analysis could not be performed. Nonetheless, of these 5 studies, 4 reported a reduced incidence of cognitive decline associated with propofol use. CONCLUSIONS: Surgery induces an inflammatory response; however, the inflammatory response did not differ as a function of anesthetic technique. This absence of an effect suggests that patient and surgical variables may have a far more significant impact on the postoperative inflammatory responses than anesthetic technique. The majority of studies assessing perioperative cognition in older patients reported a benefit associated with the use of propofol; however, larger trials using homogenous outcomes are needed to demonstrate such an effect.

Introduction Hyperammonemia is a rare complication post solid organ transplant, with a high mortality. We report a case of hyperammonemic encephalopathy in separate cardiac and lung transplant recipients, likely related to donor derived infection acquired from the same donor. Case Report A 63-year-old male with sarcoid cardiomyopathy on LVAD support and no known hepatic disease received cardiac transplantation. He was extubated on day (D) 4 with normal allograft function and mentation. He received basiliximab induction, steroids, mycophenolate (MMF) and tacrolimus (TAC) on D6. He developed hallucinations on D8 followed by paranoia and reduced GCS on D9, with no focal neurological deficit. Cranial CT/MRI and CSF were unremarkable. Initial blood results showed raised CRP, WCC with mildly elevated urea, creatinine, bilirubin & transaminase. Serum ammonia (NH3) was 549µmol/L. He was intubated and diagnosed with hyperammonemic encephalopathy. Hyperammonemic encephalopathy had also been diagnosed in the lung transplant recipient, a 65-year-old male with COPD, from the same donor. He received basiliximab induction, steroids, MMF and Cyclosporine A (CSA) on D1. He developed right sided hypertonia and reduced consciousness on D6, with elevated NH3 (177µmol/L). Both received Mycoplasma / Ureaplasma combination antibiotics - moxifloxacin and azithromycin (lung), moxifloxacin and minocycline (cardiac); metronidazole, rifaximin, lactulose, ammonia scavengers and dialysis. NH3 normalised by D12 (lung) and D15 (cardiac) with improvement in mental state. At D30, both remain dependent on dialysis with ongoing antibiotics, steroids, and moderate immunosuppression. Both patients required tracheostomy for critical illness myopathy. The aetiology of hyperammonemia is putative, however both recipients had Mycoplasma hominis identified on blood cultures. M. hominis and Ureaplasma spp. were present in bronchial washings in the lung recipient, and sputum, pleural and pericardial fluid from cardiac recipient. The donor had culture negative urethritis at donation with Mycoplasma and Ureaplasma spp. confirmed on retrospective bronchial washing PCR. Summary Hyperammonemia should be suspected in transplant recipients with altered mental state. Transplant units need increased awareness of the potential impact of infection by urease-producing organisms.

General anesthesia and surgery are associated with an increase in neural injury biomarkers. Elevations of these neural injury biomarkers in the perioperative period are associated with postoperative delirium. Xenon has been shown to be protective against a range of neurological insults in animal models. It remains to be seen if xenon anesthesia is neuroprotective in the perioperative setting in humans. Twenty-four participants scheduled for lithotripsy were randomized to receive either xenon or sevoflurane general anesthesia. There was no statistically significant difference in the concentrations of postoperative neural injury biomarkers between the xenon and sevoflurane group. Following the procedure there was a significant increase in the concentration from baseline of all three biomarkers at 1 hour post-induction with a return to baseline at 5 hours. General anesthesia for lithotripsy was associated with a significant increase at 1 hour post-induction in the neural injury biomarkers total tau, neurofilament light and tau phosphorylated at threonine 181, a marker of tau phosphorylation. The protocol was approved by the St. Vincent's Hospital Melbourne Ethics Committee (approval No. HREC/18/SVHM/221) on July 20, 2018 and was registered with the Australia New Zealand Clinical Trials Registry (registration No. ACTRN12618000916246) on May 31, 2018.

Perioperative neurocognitive disorders (PND), including postoperative delirium (POD), are the most common complications of anesthesia and surgery in those 65y or more, especially following cardiac surgery. PND are associated with increased risk of poor recovery and long-term outcomes including increased risk of morbidity, dementia and mortality. With no therapeutic targets currently available, prevention is the key to reducing PND. Whilst the pathophysiology of POD and PND remains to be elucidated, current hypotheses highlight the impact of inflammation on these outcomes. This study aimed to identify the trajectory of biomarkers throughout the perioperative period and associations with POD and PND to identify targets for therapeutic interventions to prevent POD and other PND. The RECOGNISED trial was a prospective trial investigating PND and inflammatory biomarkers across the perioperative period in patients undergoing cardiac surgery. Neuropsychological testing occurred at baseline, and 3 and 12 months postoperatively. Blood samples for inflammatory biomarkers were collected at baseline and 30 minutes, 6, 24 and 48 hours after commencement of surgery. Patients were aged 70y (6) and 24% were male. IL-6 levels increased at every postoperative time point compared with baseline, with a maximum increase at 6h (1.6 (4.4) vs 113.8 (154.2), p<0.001). IL-10 levels also increased at every postoperative timepoint, with maximum increase at 6h (0.32 (0.23) vs 10.5 (17.5), p < 0.001). IL-18 levels were significantly increased at 24 and 48h, with peak increase at 24h (111.9 (51.6) vs 133.8 (54.7), p < 0.001). TNF-α levels were significantly increased at 30 minutes and 6h postoperatively, with maximal increase at 6h (6.1 (1.7) vs 12.8 (7.9), p < 0.001). Patients with POD experienced a significantly greater increase in IL-6 at 6h compared to patients without POD. There was no association between peak IL-10, IL-18 or TNF- α levels and POD. Associations between these biomarkers and other PND will be discussed. These results demonstrate significant increases in both pro-inflammatory and anti-inflammatory biomarkers during the perioperative period. IL-6 levels at 6h were predictive of POD, confirming the role of inflammation in the development of POD. IL-6 may be a useful target for therapeutic interventions to prevent POD.

BACKGROUND:Postoperative delirium (POD) is an acute syndrome including inattention and impaired cognition that affects approximately 42% of older cardiac surgical patients. POD is linked to adverse outcomes including morbidity, mortality, and further cognitive decline. Less is known about the subjective psychological experience of POD and its ongoing impact on well-being. METHODS:We performed a qualitative analysis of the long-term psychological sequelae of older adults who experience POD after cardiac surgery. We sampled 30 patients aged 60 years and older who experienced at least 2 episodes of POD during a prior hospital admission. We administered semistructured interviews with participants via telephone 3 to 5 years postoperatively. Interviews were transcribed and thematically analyzed. Data were interpreted in accordance with the naturalist paradigm. RESULTS:Three overarching themes emerged in our qualitative analysis. The first reflected the multifaceted presentation of POD, including distortion of time and reality; feelings of isolation; and a loss of self, identity, and control. The second theme reflected the psychological challenges associated with functional decline after surgery. Common examples of functional decline included cognitive difficulties, excessive fatigue, and a perceived loss of independence. The final theme captured the emotional sequelae of acute illness, which included low mood, reduced motivation, and social comparisons. CONCLUSIONS:Our findings emphasize the multidimensional experience of POD and long-term effects on psychological wellbeing. Our research highlights the beneficial role multidisciplinary clinicians play in managing POD including strategies that may be embedded into clinical practice and helps anesthesiologists understand why patients who have experienced POD in the past may present with specific concerns should they require subsequent surgery.