Discovering the Intriguing Properties of Extrasynaptic γ-Aminobutyric Acid Type A Receptors.

Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors. By Caraiscos VB, Elliott EM, You-Ten KE, Cheng VY, Belelli D, Newell JG, Jackson MF, Lambert JJ, Rosahl TW, Wafford KA, MacDonald JF, Orser BA. Proc Natl Acad Sci U S A 2004; 101:3662-7. Reprinted with permission. In this Classic Paper Revisited, the author recounts the scientific journey leading to a report published in the Proceedings of the National Academy of Sciences (PNAS) and shares several personal stories from her formative years and "research truths" that she has learned along the way. Briefly, the principal inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), was conventionally thought to regulate cognitive processes by activating synaptic GABA type A (GABAA) receptors and generating transient inhibitory synaptic currents. However, the author's laboratory team discovered a novel nonsynaptic form of tonic inhibition in hippocampal pyramidal neurons, mediated by extrasynaptic GABAA receptors that are pharmacologically distinct from synaptic GABAA receptors. This tonic current is highly sensitive to most general anesthetics, including sevoflurane and propofol, and likely contributes to the memory-blocking properties of these drugs. Before the publication in PNAS, the subunit composition of GABAA receptors that generate the tonic current was unknown. The team's research showed that GABAA receptors containing the α5 subunit (α5GABAARs) generated the tonic inhibitory current in hippocampal neurons. α5GABAARs are highly sensitive to GABA, desensitize slowly, and are thus well suited for detecting low, persistent, ambient concentrations of GABA in the extracellular space. Interest in α5GABAARs has surged since the PNAS report, driven by their pivotal roles in cognitive processes and their potential as therapeutic targets for treating various neurologic disorders.

Self-harm presentations to hospital trauma centre emergency departments during the first year of the COVID-19 pandemic.

The COVID-19 pandemic raised concerns regarding increased suicide-related behaviours. We compared characteristics and counts of Emergency Department (ED) presentations for self-harm, an important suicide-related outcome, during versus prior to the pandemic's first year. We included patients presenting with self-harm to the ED of two trauma centres in Toronto, Canada. Time series models compared intra-pandemic (March 2020-February 2021) presentation counts to predictions from pre-pandemic data. The self-harm proportion of ED presentations was compared between the intra-pandemic period and preceding three years. A retrospective chart review of eligible patients seen from March 2019-February 2021 compared pre- vs. intra-pandemic patient and injury characteristics. While monthly intra-pandemic self-harm counts were largely within expected ranges, the self-harm proportion of total presentations increased. Being widowed (OR=9.46; 95 %CI=1.10-81.08), employment/financial stressors (OR=1.65, 95 %CI=1.06-2.58), job loss (OR=3.83; 95 %CI=1.36-10.76), and chest-stabbing self-harm (OR=2.50; 95 %CI=1.16-5.39) were associated with intra-pandemic presentations. Intra-pandemic self-harm was also associated with Intensive Care Unit (ICU) admission (OR=2.18, 95 %CI=1.41-3.38). In summary, while the number of self-harm presentations to these trauma centres did not increase during the early pandemic, their proportion was increased. The association of intra-pandemic self-harm with variables indicating medically severe injury, economic stressors, and being widowed may inform future suicide and self-harm prevention strategies.

Crosstalk between GABAA receptors in astrocytes and neurons triggered by general anesthetic drugs.

General anesthetic drugs cause cognitive deficits that persist after the drugs have been eliminated. Astrocytes may contribute to such cognition-impairing effects through the release of one or more paracrine factors that increase a tonic inhibitory conductance generated by extrasynaptic γ-aminobutyric acid type A (GABAA) receptors in hippocampal neurons. The mechanisms underlying this astrocyte-to-neuron crosstalk remain unknown. Interestingly, astrocytes express anesthetic-sensitive GABAA receptors. Here, we tested the hypothesis that anesthetic drugs activate astrocytic GABAA receptors to initiate crosstalk leading to a persistent increase in extrasynaptic GABAA receptor function in neurons. We also investigated the signaling pathways in neurons and aimed to identify the paracrine factors released from astrocytes. Astrocytes and neurons from mice were grown in primary cell cultures and studied using in vitro electrophysiological and biochemical assays. We discovered that the commonly used anesthetics etomidate (injectable) and sevoflurane (inhaled) stimulated astrocytic GABAA receptors, which in turn promoted the release paracrine factors, that increased the tonic current in neurons via a p38 MAPK-dependent signaling pathway. The increase in tonic current was mimicked by exogenous IL-1ß and abolished by blocking IL-1 receptors; however, unexpectedly, IL-1ß and other cytokines were not detected in astrocyte-conditioned media. In summary, we have identified a novel form of crosstalk between GABAA receptors in astrocytes and neurons that engages a p38 MAPK-dependent pathway. Brief commentary BACKGROUND: Many older patients experience cognitive deficits after surgery. Anesthetic drugs may be a contributing factor as they cause a sustained increase in the function of "memory blocking" extrasynaptic GABAA receptors in neurons. Interestingly, astrocytes are required for this increase; however, the mechanisms underlying the astrocyte-to-neuron crosstalk remain unknown. TRANSLATIONAL SIGNIFICANCE: We discovered that commonly used general anesthetic drugs stimulate GABAA receptors in astrocytes, which in turn release paracrine factors that trigger a persistent increase in extrasynaptic GABAA receptor function in neurons via p38 MAPK. This novel form of crosstalk may contribute to persistent cognitive deficits after general anesthesia and surgery.

The Physician Anesthesia Workforce in Canada From 1996 to 2018: A Longitudinal Analysis of Health Administrative Data.

BACKGROUND: A robust anesthesia workforce is essential to the provision of safe surgical, obstetrical, and critical care but information describing the physician anesthesia workforce and volume of clinical services delivered in Canada is limited. This study examines the Canadian physician anesthesia workforce, exploring trends in physician characteristics and activity levels over time. Practice patterns of specialist anesthesiologists and family physician anesthetists (FPAs) working in urban and rural communities were of particular interest. METHODS: Physicians who provided anesthesia care between 1996 and 2018 were identified using health administrative data from the Canadian Institute of Health Information (CIHI). In addition, data from the Canadian Post-MD Education Registry (CAPER) were used to characterize physicians pursuing postgraduate anesthesia training (1996-2019). Descriptive analyses of physician demographics, training, location, specialty designations, and volume of clinical services were undertaken. RESULTS: Between 1996 and 2018, the anesthesia workforce grew 1.8-fold to 3681 physicians, including 536 FPAs. Over the same time, nerve block services increased 7-fold, and payments for other anesthesia services increased 5-fold. The average age of the anesthesiology workforce increased by 2.3 years and the annual retirement rate was 3%. The workforce has become more gender balanced but remains predominantly male (73% in 2018). The proportion of physicians who were trained internationally (about 30%; 38% in rural areas) remained stable (and higher than that in the overall physician workforce). FPAs provided most anesthesia care in rural Canada and their attrition rate was generally 2- to 3-fold higher than specialists. Physicians in the rural anesthesia workforce provided anesthesia services more intensively over time. Relatively few FPAs who left the anesthesia workforce entered full retirement and they instead contributed other medical services to their communities. CONCLUSIONS: This study provides foundational information regarding anesthesia workforce capacity over a 22-year period, including insights into demographics, locations of practice, and clinical volumes. The results do not quantify the gap between service capacity and need; however, they support the need for a national workforce strategy to achieve equitable access to sustainable anesthesia services in Canada, particularly for rural communities.

Reduced excitatory neurotransmission in the hippocampus after inflammation and sevoflurane anaesthesia.

Background: Inflammation and general anaesthesia likely contribute to perioperative neurocognitive disorders, possibly by causing a neuronal imbalance of excitation and inhibition. We showed previously that treatment with lipopolysaccharide (LPS) and sevoflurane causes a sustained increase in a tonic inhibitory conductance in the hippocampus; however, whether excitatory neurotransmission is also altered remains unknown. The goal of this study was to examine excitatory synaptic currents in the hippocampus after treatment with LPS and sevoflurane. Synaptic plasticity in the hippocampus, a cellular correlate of learning and memory, was also studied. Methods: Mice were injected with vehicle or LPS (1 mg kg-1 i.p.), and after 24 h they were then exposed to vehicle or sevoflurane (2.3%; 2 h). Hippocampal slices were prepared 48 h later. Excitatory synaptic currents were recorded from pyramidal neurones. Long-term potentiation (LTP) and long-term depression (LTD) were studied in the Schaffer collateral-cornu ammonis 1 pathway. Results: The amplitude of miniature excitatory postsynaptic currents (EPSCs) was reduced after LPS+sevoflurane (P<0.001), whereas that of spontaneous EPSCs was unaltered, as evidenced by cumulative distribution plots. The frequency, area, and kinetics of both miniature and spontaneous EPSCs were unchanged, as were LTP and LTD. Conclusions: The reduced amplitude of miniature EPSCs, coupled with the previously reported increase in tonic inhibition, indicates that the combination of LPS and sevoflurane markedly disrupts the balance of excitation and inhibition. Restoring this balance by pharmacologically enhancing excitatory neurotransmission and inhibiting the tonic current may represent an effective therapeutic option for perioperative neurocognitive disorders.

Effect of inhaled anaesthetics on cognitive and psychiatric outcomes in critically ill adults: a systematic review and meta-analysis.

BACKGROUND: Sedation of critically ill patients with inhaled anaesthetics may reduce lung inflammation, time to extubation, and ICU length of stay compared with intravenous (i.v.) sedatives. However, the impact of inhaled anaesthetics on cognitive and psychiatric outcomes in this population is unclear. In this systematic review, we aimed to summarise the effect of inhaled anaesthetics on cognitive and psychiatric outcomes in critically ill adults. METHODS: We searched MEDLINE, EMBASE, and PsycINFO for case series, retrospective, and prospective studies in critically ill adults sedated with inhaled anaesthetics. Outcomes included delirium, psychomotor and neurological recovery, long-term cognitive dysfunction, ICU memories, anxiety, depression, post-traumatic stress disorder (PTSD), and instruments used for assessment. RESULTS: Thirteen studies were included in distinct populations of post-cardiac arrest survivors (n=4), postoperative noncardiac patients (n=3), postoperative cardiac patients (n=2), and mixed medical-surgical patients (n=4). Eight studies reported delirium incidence, two neurological recovery, and two ICU memories. One study reported on psychomotor recovery, long-term cognitive dysfunction, anxiety, depression, and PTSD. A meta-analysis of five trials found no difference in delirium incidence between inhaled and i.v. sedatives (relative risk 0.95 [95% confidence interval: 0.59-1.54]). Compared with i.v. sedatives, inhaled anaesthetics were associated with fewer hallucinations and faster psychomotor recovery but no differences in other outcomes. There was heterogeneity in the instruments used and timing of these assessments. CONCLUSIONS: Based on the limited evidence available, there is no difference in cognitive and psychiatric outcomes between adults exposed to volatile sedation or intravenous sedation in the ICU. Future studies should incorporate outcome assessment with validated tools during and after hospital stay. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42021236455.

The anesthesia workforce in Canada: a methodology to identify physician anesthesia providers using health administrative data.

BACKGROUND: Safe and timely anesthesia services are an integral component of modern health care systems. There are, however, increasing concerns about the availability of anesthesia services in Canada. Thus, a comprehensive approach to assess the capacity of the anesthesia workforce to provide service is a critical need. Data regarding the anesthesia services provided by specialists and family physicians are available through the Canadian Institute for Health Information (CIHI) but collating the data across delivery jurisdictions has proven challenging. As a result, information related to the activity of physician anesthesia providers is routinely excluded from annual physician workforce reports. Our goal was to develop a novel approach to identifying and characterizing the anesthesia workforce on a pan-Canadian scale. METHODS: The study was approved by the University of Ottawa Office of Research Ethics and Integrity. We developed a methodology to identify physicians who provided anesthesia services in Canada between 1996 and 2018 using data elements from the CIHI National Physician Database. We iteratively consulted with expert advisors and compared the results with Scott's Medical Database, the Canadian Medical Association (CMA) Masterfile, and the College of Family Physicians of Canada membership database. RESULTS: The methodology identified providers of anesthesia services using data elements from the CIHI National Physician Database, including categories of the National Grouping System, specialty designations, activity levels and participation thresholds. Physicians who provided anesthesia services only sporadically and medical residents-in-training were excluded. This methodology produced estimates of anesthesia providers that aligned with other sources. The process we followed was sequential, transparent, and intuitive, and was strengthened by collaboration and iterative consultation with experts and stakeholders. CONCLUSIONS: Using physician activity patterns, this novel methodology allows stakeholders to identify which physician provide anesthesia services in Canada. It is an essential step in developing a pan-Canadian anesthesia workforce strategy that can be used to examine patterns and trends related to the workforce and support evidence-informed workforce decision-making. It also establishes a foundation for assessing the effectiveness of a variety of interventions aimed at optimizing physician anesthesia services in Canada.

Cognitive deficits after general anaesthesia in animal models: a scoping review.

BACKGROUND: It remains controversial whether general anaesthetic drugs contribute to perioperative neurocognitive disorders in adult patients. Preclinical studies have generated conflicting results, likely because of differing animal models, study protocols, and measured outcomes. This scoping review of preclinical studies addressed the question: 'Do general anaesthetic drugs cause cognitive deficits in adult animals that persist after the drugs have been eliminated from the brain?' METHODS: Reports of preclinical studies in the MEDLINE database published from 1953 to 2021 were examined. A structured review process was used to assess original studies of cognitive behaviours, which were measured after treatment (≥24 h) with commonly used general anaesthetic drugs in adult animals. RESULTS: The initial search yielded 380 articles, of which 106 were fully analysed. The most frequently studied animal model was male (81%; n=86/106) rodents (n=106/106) between 2-3 months or 18-20 months of age. Volatile anaesthetic drugs were more frequently studied than injected drugs, and common outcomes were memory behaviours assessed using the Morris water maze and fear conditioning assays. Cognitive deficits were detected in 77% of studies (n=82/106) and were more frequent in studies of older animals (89%), after inhaled anaesthetics, and longer drug treatments. Limitations of the studies included a lack of physiological monitoring, mortality data, and risk of bias attributable to the absence of randomisation and blinding. CONCLUSIONS: Most studies reported cognitive deficits after general anaesthesia, with age, use of volatile anaesthetic drugs, and duration of anaesthesia as risk factors. Recommendations to improve study design and guide future research are presented.

Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.

BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.

The Impact of Inflammation and General Anesthesia on Memory and Executive Function in Mice.

BACKGROUND: Perioperative neurocognitive disorders (PNDs) are complex, multifactorial conditions that are associated with poor long-term outcomes. Inflammation and exposure to general anesthetic drugs are likely contributing factors; however, the relative impact of each factor alone versus the combination of these factors remains poorly understood. The goal of this study was to compare the relative impact of inflammation, general anesthesia, and the combination of both factors on memory and executive function. METHODS: To induce neuroinflammation at the time of exposure to an anesthetic drug, adult male mice were treated with lipopolysaccharide (LPS) or vehicle. One day later, they were anesthetized with etomidate (or vehicle). Levels of proinflammatory cytokines were measured in the hippocampus and cortex 24 hours after LPS treatment. Recognition memory and executive function were assessed starting 24 hours after anesthesia using the novel object recognition assay and the puzzle box, respectively. Data are expressed as mean (or median) differences (95% confidence interval). RESULTS: LPS induced neuroinflammation, as indicated by elevated levels of proinflammatory cytokines, including interleukin-1ß (LPS versus control, hippocampus: 3.49 pg/mg [2.06-4.92], P < .001; cortex: 2.60 pg/mg [0.83-4.40], P = .010) and tumor necrosis factor-α (hippocampus: 3.50 pg/mg [0.83-11.82], P = .002; cortex: 2.38 pg/mg [0.44-4.31], P = .021). Recognition memory was impaired in mice treated with LPS, as evinced by a lack of preference for the novel object (novel versus familiar: 1.03 seconds [-1.25 to 3.30], P = .689), but not in mice treated with etomidate alone (novel versus familiar: 2.38 seconds [0.15-4.60], P = .031). Mice cotreated with both LPS and etomidate also exhibited memory deficits (novel versus familiar: 1.40 seconds [-0.83 to 3.62], P = .383). In the puzzle box, mice treated with either LPS or etomidate alone showed no deficits. However, the combination of LPS and etomidate caused deficits in problem-solving tasks (door open task: -0.21 seconds [-0.40 to -0.01], P = .037; plug task: -0.30 seconds [-0.50 to -0.10], P < .001; log values versus control), indicating impaired executive function. CONCLUSIONS: Impairments in recognition memory were driven by inflammation. Deficits in executive function were only observed in mice cotreated with LPS and etomidate. Thus, an interplay between inflammation and etomidate anesthesia led to cognitive deficits that were not observed with either factor alone. These findings suggest that inflammation and anesthetic drugs may interact synergistically, or their combination may unmask covert or latent deficits induced by each factor alone, leading to PNDs.

Perioperative Neurocognitive Screening Tools for At-Risk Surgical Patients.

Purpose of Review: Perioperative neurocognitive disorders are common after surgery and have serious socioeconomic impacts. Despite this, these disorders remain under-recognized and underdiagnosed. To facilitate detection and direct patients toward appropriate preventative interventions, assessment of cognition during the perioperative period is of critical importance. However, there are considerable barriers to the widespread clinical implementation of cognitive assessments, including a lack of consensus regarding the optimal tool for use in specific clinical scenarios. Recent Findings: We provide an overview of the most widely used and validated cognitive assessment tools, including those that permit telemedicine-enabled patient encounters. Summary: No single tool is optimal for all contexts. This narrative review can help clinicians to identify the appropriate cognitive screening tool for their needs by describing the advantages and disadvantages of several available tools, thereby enabling the identification of patients at risk of cognitive decline and facilitating optimization of patient-focused perioperative care.

Consensus statement on networks for high-quality rural anesthesia, surgery, and obstetric care in Canada.

OBJECTIVE: To describe the essential components of well-resourced and high-functioning multidisciplinary networks that support high-quality anesthesia, surgery, and maternity care for rural Canadians, delivered as close to home as possible. COMPOSITION OF THE COMMITTEE: A volunteer Writers' Group was drawn from the Society of Obstetricians and Gynaecologists of Canada, the Society of Rural Physicians of Canada, the Royal College of Physicians and Surgeons of Canada, the Canadian Association of General Surgeons, the College of Family Physicians of Canada, and the Association of Canadian University Departments of Anesthesia. METHODS: A collaborative effort over the past several years among the professional stakeholders has culminated in this consensus statement on networked care designed to integrate and support a specialist and non-specialist, urban and rural, anesthesia, surgery, and maternity work force into high-functioning networks based on the best available evidence. REPORT: Surgical and maternity triage needs to be embedded within networks to address the tensions between sustainable regional programs and local access to care. Safety and quality must be demonstrated to be equivalent across similar patients and procedures, regardless of network site. Triage of patients across multiple sites is a quality outcome metric requiring continuous iterative scrutiny. Clinical coaching between rural and regional centres can be helpful in building and sustaining high-functioning networks. Maintenance of quality and the provision of continuing professional development in low-volume settings represent a mutual value proposition. CONCLUSION: The trusting relationships that are foundational to successful networks are built through clinical coaching, continuing professional development, and quality improvement. Currently, a collaborative effort in British Columbia is delivering a provincial program-Rural Surgical Obstetrical Networks-built on the principles and supporting evidence described in this consensus statement.