Beverley A. Orser

Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia

Cardiac arrest victims may experience transient brain hypoperfusion leading to delayed death of hippocampal CA1 neurons and cognitive impairment. We prevented this in adult rats by inhibiting the expression of transient receptor potential melastatin 7 (TRPM7), a transient receptor potential channel that is essential for embryonic development, is necessary for cell survival and trace ion homeostasis in vitro, and whose global deletion in mice is lethal. TRPM7 was suppressed in CA1 neurons by intrahippocampal injections of viral vectors bearing shRNA specific for TRPM7. This had no ill effect on animal survival, neuronal and dendritic morphology, neuronal excitability, or synaptic plasticity, as exemplified by robust long-term potentiation (LTP). However, TRPM7 suppression made neurons resistant to ischemic death after brain ischemia and preserved neuronal morphology and function. Also, it prevented ischemia-induced deficits in LTP and preserved performance in fear-associated and spatial-navigational memory tasks. Thus, regional suppression of TRPM7 is feasible, well tolerated and inhibits delayed neuronal death in vivo.

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.

Silence, Power and Communication in the Operating Room

Title. Silence, power and communication in the operating room Aim This paper is a report of a study conducted to explore whether a 1- to 3-minute preoperative interprofessional team briefing with a structured checklist was an effective way to support communication in the operating room. Background Previous research suggests that nurses often feel constrained in their ability to communicate with physicians. Previous research on silence and power suggests that silence is not only a reflection of powerlessness or passivity, and that silence and speech are not opposites, but closely interrelated. Methods We conducted a retrospective study of silences observed in communication between nurses and surgeons in a multi-site observational study of interprofessional communication in the operating room. Over 700 surgical procedures were observed from 2005–2007. Instances of communication characterized by unresolved or unarticulated issues were identified in field notes and analysed from a critical ethnography perspective. Findings We identified three forms of recurring ‘silences’: absence of communication; not responding to queries or requests; and speaking quietly. These silences may be defensive or strategic, and they may be influenced by larger institutional and structural power dynamics as well as by the immediate situational context. Conclusions There is no single answer to the question of why ‘nobody said anything’. Exploring silences in relation to power suggests that there are multiple and complex ways that constrained communication is produced in the operating room, which are essential to understand in order to improve interprofessional communication and collaboration.

An anaesthetic drug error : minimizing the risk

A medication error caused a near fatal cardiac arrest in a previously healthy patient undergoing elective surgery. Inadvertent epinephrine injection induced ventricular dysrhythmias, hypertension, hypotension and pulmonary oedema. The case was investigated using critical-incident technique and was reviewed by the Risk Management Team of the Department of Anaesthesia. The purpose of this report is to present the recommendations resulting from the investigation. These include: improved resident training in intravenous drug management, the use of anaesthetic drug ampoules with distinct labels, and the development of a standardized colour code system for labels on anaesthetic drug ampoules. Furthermore, it is recommended that all anaesthetic drug errors be reported to the Canadian agencies responsible for drug packaging in order to identify patterns in anaesthetic drug errors, and to facilitate the implementation of effective drug identification systems.RésuméPendant une opération non urgente, une erreur de médicament provoque un arrêt cardiaque chez un patient non taré. De l’épinéphrine injectée par mégarde provoque des dysrythmies ventriculaires, de l’hypertension, de l’hypotension, et de l’oedème pulmonaire. Cet accident fait l’objet d’une investigation par la technique de l’incident critique et est révisé par l’équipe de gestion du risque de département d’anesthésie. Ce rapport expose les recommandations qui découlent de cette investigation. Ils comprennent l’amélioration de la formation des résidents au regard de la manipulation des préparations intraveineuses, l’utilisation d’ampoules étiquetées distinctivement et l’élaboration d’un code de couleur standard pour les étiquettes de préparation anesthésiques. On recommande aussi que toutes les erreurs de drogues anesthésiques soient rapportée aux organismes canadiens responsables de l’emballage des drogues de façon à identifier la tendance des erreurs médicamenteuses en anesthésie et faciliter l’implantation de systèmes d’identification réellement efficaces.

Magnesium deficiency increases ketamine sensitivity in rats

PurposeInhibition of the NMDA receptor likely contnbutes to ketamine’s neurodepressive properties. Magnesium also inhibits the NMDA receptor by binding to a site associated with the ketamine-bindmg domain. Electrophysiological studies suggest that magnesium prevents ketamine from binding to the NMDA receptor and thereby prevents ketamine inhibition. We undertook anin vivo study to determine if magnesium deficiency was associated with an increased sensitivity to ketamine.MethodsWeanling rats were maintained on a Mg2+ -deficient or control diet for 14 days. In Study I, rats were anaesthetized then sacrificed and the Mg2+ concentrations in the brain and plasma were measured. In a second prospective study, experimental animals were rendered hypomagnesaemic and the potency of 125 mg·kg−ip ketamine was evaluated. Animals were then were fed a Mg2+ -containing diet and ketamine sensitivity was re-examined 14 days later.ResultsThe Mg2+ -deficient diets rendered the rats hypomagnesaemic as indicated by the brain and plasma concentration of Mg2+. In Study 2. the time to loss of righting reflex was shorter: 1.9 ± 0.3 mm (n = 12) and 2.6 ± 0.2 min (n = 16, P < 0.05), whereas the latency to toe pinch was prolonged: 25 0 ± 5.8 min (n= 12)vs 3.1 ± 2.1 min (n = 16, P < 0.05) in the Mg2+ -deficient compared with age-matched control animals, respectively. The hypomagnesaemic animals had a higher death rate following ketamine injection. The increased sensitivity to ketamine was no longer apparent when the animals were re-tested following replenishment of Mg2+.ConclusionHypomagnesaemia is associated with an increased sensitivity to ketamine.RésuméObjectifL’inhibition du récepteur NMDA contnbue vraisemblablement aux propriétés neurodépressives de la kétamme. Le magnésium inhibe aussi le récepteur NMDA en se liant avec un site spécifique à la kétamine. Des études électrophysiologiques suggèrent que le magnésium empêche la kétamine de se lier au récepteur NMDA et prévient ainsi l’inhibition de la kétamme. Cette étudein vivo visart à établir si la déficience en magnésium augmentait la sensibilité à la kétamme.MéthodesDes rats Weanling ont été maintenus sur une diète déficiente en Mg2+ ou sur une diète de contrôle pendant 14 jours. Au cours de la première expénence, les rats ont été anesthésiés puis sacrifiés. Les concentrations plasmatiques et cérébrales de Mg2+ ont alors été mesurées. Dans la deuxième étude prospective, chez les animaux de laboratoire rendus hypomagnésémiques, on évaluait la puissance de 125 mg·kg−1 de kétammeip. Les animaux recevaient alors une diète contenant du Mg2+ et la sensibilité à la kétamine était réévaluée 14 pours plus tard.RésultatsLes diètes déficientes en Mg produisaient de l’hypomagnésémie comme le révélaient les concentrations plasmatiques et cérébrales de Mg2+. Les rats de la deuxième étude avaient un réflexe de redressement plus court: 1.9 ± 0,3 min (n= 12)vs 2.6 ± 0.2 min (n= 16. P < 0,05). alors que la latence du retrait après compression de l’orteil était prolongée: 25,0 ± 5,8 min (n= 12) vs 3,1 ± 2.1 min (n= 16. P < 0.05) chez les rats hypomagnésémiques comparativement aux animaux de contrôle appanés pour l’âge. Les animaux hypomagnésémiques avaient un taux de mortalité plus élevé après l’injection de kétamine. Laugmentation de la sensibilité à la kétamine disparaissait quand les animaux étaient de nouveau examinés après réapprovisionnement en Mg2+ConclusionL’hypomagnésémie augmente la sensibilité à la kétamme.

TEMPORARY REMOVAL: Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery—2018

Abstract 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 regulates atypical type-A γ-aminobutyric acid receptors in alveolar type II epithelial cells.

Background:Volatile anesthetics act primarily through upregulating the activity of &ggr;-aminobutyric acid type A (GABAA) receptors. They also exhibit antiinflammatory actions in the lung. Rodent alveolar type II (ATII) epithelial cells express GABAA receptors and the inflammatory factor cyclooxygenase-2 (COX-2). The goal of this study was to determine whether human ATII cells also express GABAA receptors and whether volatile anesthetics upregulate GABAA receptor activity, thereby reducing the expression of COX-2 in ATII cells. Methods:The expression of GABAA receptor subunits and COX-2 in ATII cells of human lung tissue and in the human ATII cell line A549 was studied with immunostaining and immunoblot analyses. Patch clamp recordings were used to study the functional and pharmacological properties of GABAA receptors in cultured A549 cells. Results:ATII cells in human lungs and cultured A549 cells expressed GABAA receptor subunits and COX-2. GABA induced currents in A549 cells, with half-maximal effective concentration of 2.5 µM. Isoflurane (0.1–250 µM) enhanced the GABA currents, which were partially inhibited by bicuculline. Treating A549 cells with muscimol or with isoflurane (250 µM) reduced the expression of COX-2, an effect that was attenuated by cotreatment with bicuculline. Conclusions:GABAA receptors expressed by human ATII cells differ pharmacologically from those in neurons, exhibiting a higher affinity for GABA and lower sensitivity to bicuculline. Clinically relevant concentrations of isoflurane increased the activity of GABAA receptors and reduced the expression of COX-2 in ATII cells. These findings reveal a novel mechanism that could contribute to the antiinflammatory effect of isoflurane in the human lung.

Symposium on ergonomics in drug delivery

T HE Canadian Standards Association (CSA) Symposium on Ergononics in Drug Delivery was held on January 21, 1997, at The Michener Institute for Applied Health Sciences in Toronto, Canada. Ergonomics is the engineering discipline that reconciles the design of products and systems with human capabilities and linfitations. Inattention to human factors can lead to a misfit between the task, the physical environment, and the people. The impact of human factors is only beginning to be appreciated in the design of medical systems. Therefore, it is not surprising that human error is a major contributing factor to many mishaps in medicine. Human factors contribute to errors during anaesthesia, particularly those associated with the administration of drugs. Drug error is increasingly being recognized as a major cause of morbidity and mortality in patients undergoing anaesthesia and misidentification of ampoules or syringes is often a contributing factor. In the last year, the CSA has received numerous requests from concerned individuals to address several pressing issues in drug delivery. Most importantly, it was suggested that the CSA develop national standards for the labeling of drug ampoules and vials. In addition, the need for a national standard for Metered Dose Inhaler Spacer Devices was identified. In order to develop an effective standard, it is important that all affected groups be given an opportunity to provide their perspective. Therefore, the purpose of the symposium was not only to educate those who attended, but to determine if new standards are required. The symposium was attended by individuals representing academia, consumer groups, pharmaceutical and device manufacturers, health care practitioners, and hospital and retail pharmacists. In addition, representatives from both the provincial and federal regulatory authorities attended. The sessions were moderated by Dr. Wayne Taylor, an Associate Professor of Business, Public and Health Policy at McMaster University. The morning discussion was devoted to ergonomic issues in drug delivery, drug safety in critical care environments, and the design of a blueprint for error-proofing pharmaceutical trademarks and labels. Perspectives were provided by the Canadian Anaesthetists Society, the Canadian Drug Manufacturers Association, the Canadian Nurses Association, Health Canada Drugs Directorate, and other interested organizations. The discussion generated four specific recommendations.