Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018.

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Recommendations for the Nomenclature of Cognitive Change Associated with Anaesthesia and Surgery-20181.

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018.

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Recommendations for the Nomenclature of Cognitive Change Associated With Anaesthesia and Surgery-2018.

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Recommendations for the Nomenclature of Cognitive Change Associated with Anaesthesia and Surgery-2018.

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines (Diagnostic and Statistical Manual for Mental Disorders, fifth edition [DSM-5] and National Institute for Aging and the Alzheimer Association [NIA-AA]) are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Isoflurane affects the cytoskeleton but not survival, proliferation, or synaptogenic properties of rat astrocytes in vitro.

BACKGROUND: More than half of the cells in the brain are glia and yet the impact of general anaesthetics on these cells is largely unexamined. We hypothesized that astroglia, which are strongly implicated in neuronal well-being and synapse formation and function, are vulnerable to adverse effects of isoflurane. METHODS: Cultured rat astrocytes were treated with 1.4% isoflurane in air or air alone for 4 h. Viability, proliferation, and cytoskeleton were assessed by colorimetric assay, immunocytochemistry, or a migration assay at the end of treatment or 2 days later. Also, primary rat cortical neurones were treated for 4 days with conditioned medium from control [astrocyte-conditioned media (ACM)], or isoflurane-exposed astrocytes (Iso-ACM) and synaptic puncta were assessed by synapsin 1 and PSD-95 immunostaining. RESULTS: By several measures, isoflurane did not kill astrocytes. Nor, based on incorporation of a thymidine analogue, did it inhibit proliferation. Isoflurane had no effect on F-actin but reduced expression of α-tubulin and glial fibrillary acidic protein both during exposure (P<0.05 and P<0.001, respectively) and 2 days later (P<0.01), but did not impair astrocyte motility. ACM increased formation of PSD-95 but not synapsin 1 positive puncta in neuronal cultures, and Iso-ACM was equally effective. CONCLUSIONS: Isoflurane decreased expression of microtubule and intermediate filament proteins in astrocytes in vitro, but did not affect their viability, proliferation, motility, and ability to support synapses.

Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar.

Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches.

Measurement of post-operative cognitive dysfunction after cardiac surgery: a systematic review.

Post-operative cognitive dysfunction (POCD) is a decline in cognitive function from pre-operative levels, which has been frequently described after cardiac surgery. The purpose of this study was to examine the variability in the measurement and definitions for POCD using the framework of a 1995 Consensus Statement on measurement of POCD. Electronic medical literature databases were searched for the intersection of the search terms 'thoracic surgery' and 'cognition, dementia, and neuropsychological test.' Abstracts were reviewed independently by two reviewers. English articles with >50 participants published since 1995 that performed pre-operative and post-operative psychometric testing in patients undergoing cardiac surgery were reviewed. Data relevant to the measurement and definition of POCD were abstracted and compared with the recommendations of the Consensus Statement. Sixty-two studies of POCD in patients undergoing cardiac surgery were identified. Of these studies, the recommended neuropsychological tests were carried out in less than half of the studies. The cognitive domains measured most frequently were attention (n=56; 93%) and memory (n=57; 95%); motor skills were measured less frequently (n=36; 60%). Additionally, less than half of the studies examined anxiety and depression, performed neurological exam, or accounted for learning. Four definitions of POCD emerged: per cent decline (n=15), standard deviation decline (n=14), factor analysis (n=13), and analysis of performance on individual tests (n=12). There is marked variability in the measurement and definition of POCD. This heterogeneity may impede progress by reducing the ability to compare studies on the causes and treatment of POCD.

Delirium is associated with early postoperative cognitive dysfunction.

The purpose of this analysis was to determine if postoperative delirium was associated with early postoperative cognitive dysfunction (at 7 days) and long-term postoperative cognitive dysfunction (at 3 months). The International Study of Postoperative Cognitive Dysfunction recruited 1218 subjects >or= 60 years old undergoing elective, non-cardiac surgery. Postoperatively, subjects were evaluated for delirium using the criteria of the Diagnostic and Statistical Manual. Subjects underwent neuropsychological testing pre-operatively and postoperatively at 7 days (n = 1018) and 3 months (n = 946). Postoperative cognitive dysfunction was defined as a composite Z-score > 2 across tests or at least two individual test Z-scores > 2. Subjects with delirium were significantly less likely to participate in postoperative testing. Delirium was associated with an increased incidence of early postoperative cognitive dysfunction (adjusted risk ratio 1.6, 95% CI 1.1-2.1), but not long-term postoperative cognitive dysfunction (adjusted risk ratio 1.3, 95% CI 0.6-2.4). Delirium was associated with early postoperative cognitive dysfunction, but the relationship of delirium to long-term postoperative cognitive dysfunction remains unclear.

SCH 57790, a selective muscarinic M(2) receptor antagonist, releases acetylcholine and produces cognitive enhancement in laboratory animals.

The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.

Metabolic stabilization of benzylidene ketal M(2) muscarinic receptor antagonists via halonaphthoic acid substitution.

The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.

Gene expression following acute morphine administration.

The long-term response to neurotropic drugs depends on drug-induced neuroplasticity and underlying changes in gene expression. However, alterations in neuronal gene expression can be observed even following single injection. To investigate the extent of these changes, gene expression in the medial striatum and lumbar part of the spinal cord was monitored by cDNA microarray following single injection of morphine. Using robust and resistant linear regression (MM-estimator) with simultaneous prediction confidence intervals, we detected differentially expressed genes. By combining the results with cluster analysis, we have found that a single morphine injection alters expression of two major groups of genes, for proteins involved in mitochondrial respiration and for cytoskeleton-related proteins. RNAs for these proteins were mostly downregulated both in the medial striatum and in lumbar part of the spinal cord. These transitory changes were prevented by coadministration of the opioid antagonist naloxone. Data indicate that microarray analysis by itself is useful in describing the effect of well-known substances on the nervous system and provides sufficient information to propose a potentially novel pathway mediating its activity.

Facilitation of acetylcholine release and improvement in cognition by a selective M2 muscarinic antagonist, SCH 72788.

Current treatment of Alzheimer's Disease (AD) requires acetylcholinesterase inhibition to increase acetylcholine (ACh) concentrations in the synaptic cleft. Another mechanism by which ACh levels can be increased is blockade of presynaptic M2 muscarinic autoreceptors that regulate ACh release. An antagonist designed for this purpose must be highly selective for M2 receptors to avoid blocking postsynaptic M1 receptors, which mediate the cognitive effects of ACh. Structure-activity studies of substituted methylpiperadines led to the synthesis of 4-[4-[1(S)-[4-[(1,3-benzodioxol-5-yl)sulfonyl]phenyl]ethyl]-3(R)-methyl-1-piperazinyl]-4-methyl-1-(propylsulfonyl)piperidine. This compound, SCH 72788, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 0.5 nM, and its affinity at M1 receptors is 84-fold lower. SCH 72788 is a functional M2 antagonist that competitively inhibits the ability of the agonist oxotremorine-M to inhibit adenylyl cyclase activity. In an in vivo microdialysis paradigm, SCH 72788 increases ACh release from the striatum of conscious rats. The compound is also active in a rodent model of cognition, the young rat passive avoidance response paradigm. The effects of SCH 72788 suggest that M2 receptor antagonists may be useful for treating the cognitive decline observed in AD and other dementias.

Alcohol use, drug use and alcohol-related problems among men who have sex with men: the Urban Men's Health Study.

AIMS: To measure the prevalence and independent associations of heavy and problematic use of alcohol and recreational drugs among a household-based sample of urban MSM (men who have sex with men). DESIGN: Cross-sectional survey. PARTICIPANTS: Men who identified as being gay or bisexual or who reported sex with another man in the prior 5 years were included in this analysis (n = 2172). SETTING: A probability telephone sample of MSM was taken within Zip Codes of four large American cities (Chicago, Los Angeles, New York and San Francisco) estimated to have total concentrations of at least 4% of all households with one resident MSM. MEASUREMENTS: Standard measures of alcohol use, problems associated with alcohol use, and recreational drug use were administered by trained telephone interviewers. FINDINGS: Both recreational drug (52%) and alcohol use (85%) were highly prevalent among urban MSM, while current levels of multiple drug use (18%), three or more alcohol-related problems (12%), frequent drug use (19%) and heavy-frequent alcohol use (8%) were not uncommon. The associations of heavy and/or problematic substance use are complex, with independent multivariate associations found at the levels of demographics, adverse early life circumstances, current mental health status, social and sexual practices and connection to gay male culture. CONCLUSIONS: The complex pattern of associations with heavy and/or problematic substance use among urban MSM suggests that heavy and/or problematic substance use is grounded in multiple levels: the individual, the interpersonal and the socio-cultural.

Design and synthesis of piperidinyl piperidine analogues as potent and selective M2 muscarinic receptor antagonists.

Identification of a number of highly potent M2 receptor antagonists with >100-fold selectivity against the M1 and M3 receptor subtypes is described. In the rat microdialysis assay, this series of compounds showed pronounced enhancement of brain acetylcholine release after oral administration.

Diphenyl sulfoxides as selective antagonists of the muscarinic M2 receptor.

Structure activity studies on [4-(phenylsulfonyl)phenyl]methylpiperazine led to the discovery of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl(S)-sufinyl]phenyl]-1-pi perazineacetonitrile, 1, an M2 selective muscarinic antagonist. Affinity at the cloned human M2 receptor was 2.7 nM; the M1/M2 selectivity is 40-fold.

Diphenylsulfone muscarinic antagonists: piperidine derivatives with high M2 selectivity and improved potency.

Piperidine analogues of our previously described piperazine muscarinic antagonists are described. Piperidine analogues show a distinct structure-activity relationship (SAR) that differs from comparable piperazines. Compounds with high selectivity and improved potency for the M2 receptor have been identified. The lead compound, 12b, increases acetylcholine release in vivo. Compounds of this class may be useful for the treatment of cognitive disorders such as Alzheimer's disease (AD).

Substance use and HIV risk profile of gay/bisexual males who drop out of substance abuse treatment.

This analysis was undertaken to identify (a) the level of HIV sexual risk behaviors of men who drop out of treatment and (b) baseline variables associated with later treatment dropout. A cross-sectional sample of 340 gay/bisexual men were recruited from an outpatient substance abuse treatment facility in San Francisco. We compared participants who completed less than 15 visits with participants who graduated from the program. Men who dropped out were more likely than treatment graduates to report injection drug use, social problems related to substance use, self-blaming coping strategies, and more recent substance use prior to entering treatment and less likely to have a college degree, report using sex for tension relief, and have previously attended Alcoholics Anonymous or Narcotics Anonymous. Given the strong link between the substance abuse and HIV epidemics, substance abuse treatment agencies have been forced into addressing the issues of HIV sexual risk taking with their clients. Strategies toward reducing substance use relapse and HIV risk reduction are offered.

Benzylidene ketal derivatives as M2 muscarinic receptor antagonists.

Benzylidene ketal derivatives were investigated as selective M2 receptor antagonists for the treatment of Alzheimer's disease. Compound 10 was discovered to have subnanomolar M2 receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, 10 demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition.

An outcome evaluation to measure changes in sexual risk-taking among gay men undergoing substance use disorder treatment.

OBJECTIVE: To evaluate the effects of safe sex intervention at a substance use disorder treatment agency designed to serve gay men. METHOD: Of all eligible men, 456 (78%) were recruited as they entered treatment for a substance use disorder. This cohort was followed for five waves of data collection, each wave measuring the previous 90 days. Assigned to the experimental condition (treatment for substance use disorder plus a safe sex intervention) were 82 men; 65 were assigned to the regular substance use disorder treatment. RESULTS: Although levels of risk within each wave were never significantly different between the two treatment groups, reductions in unprotected anal intercourse (UAI) with a nonmonogamous partner for both groups from the baseline Wave-1 levels were uniformly significant (all p's < .05). Such high-risk sex in the year-long follow-up period was correlated with UAI reported at intake, enjoyment of UAI, relative youth, heavier concurrent use of alcohol or amphetamines and greater numbers of sexual partners. CONCLUSIONS: We conclude that: (1) substantial HIV risk reductions can occur after initiation of treatment for substance use disorder among gay men; (2) risk reductions begin soon after treatment begins; (3) lapses to unsafe sex are common during treatment; (4) continued UAI is most likely among those men who are riskier at intake, who continue to be more sexually active and who are more likely to combine substance use and sexual behavior; (5) AIDS prevention activities conducted at treatment agencies cannot reach all high-risk substance-using gay men.