Genotype- and sex-specific changes in vital parameters during isoflurane anesthesia in a mouse model of Alzheimer's disease.

Background: The prevalence of neurodegenerative diseases is increasing as is life expectancy with Alzheimer's disease accounting for two-thirds of dementia cases globally. Whether general anesthesia and surgery worsen cognitive decline is still a matter of debate and most likely depending on the interplay of various influencing factors. In order to account for this complexity, Alzheimer's disease animal models have been developed. The Tg2576 model of Alzheimer's disease is a well-established mouse model exhibiting amyloidopathy and age-dependent sex-specific differences in Alzheimer's disease symptomology. Yet, data on anesthesia in this mouse model is scarce and a systematic comparison of vital parameters during anesthesia with wild-type animals is missing. In order to investigate the safety of general anesthesia and changes in vital parameters during general anesthesia in Tg2576 mice, we did a secondary analysis of vital parameters collected during general anesthesia in aged Tg2576 mice. Methods: After governmental approval (General Administration of the Free State of Bavaria, file number: 55.2-1-54-2532-149-11) 60 mice at 10-12 months of age were exposed to isoflurane (1.6 Vol%) for 120 min, data of 58 mice was analyzed. During general anesthesia, heart rate, respiratory rate, temperature, isoflurane concentration and fraction of inspired oxygen were monitored and collected. Data were analyzed using univariate and multivariate linear mixed regression models. Results: During general anesthesia, heart rate decreased in a sex-specific manner. Respiratory rate decreased and body temperature increased dependent on genotype. However, the changes were limited and all vital parameters stayed within physiological limits. Conclusion: Isoflurane anesthesia in the Tg2576 mouse model is safe and does not seem to influence experimental results by interacting with vital parameters. The present study provides information on appropriate anesthesia in order to advance research on anesthesia and AD and could contribute to improving laboratory animal welfare.

[Position paper on working in the intensive care unit during pregnancy : DIVI recommendations for improving the situation of pregnant employees in the ICU]. / Positionspapier zum Arbeiten in der Schwangerschaft auf der Intensivstation : DIVI-Empfehlungen zur Verbesserung der Lage von schwangeren Mitarbeiterinnen auf einer Intensivstation.

The Maternity Protection Act is intended to protect the mother and the child from hazards, excessive demands and damage to health in the workplace, and from financial disadvantages and loss of employment. However, the objectives defined by the Maternity Protection Act-the safety and health of the pregnant employee on the one hand and the prevention of disadvantages in working life on the other-are not yet adequately achieved in the intensive care unit (ICU). Implementation of the Maternity Protection Act to the benefit of all involved parties should also be promoted in the specialist areas represented by the DIVI, in particular the work of pregnant physicians and nursing staff and other working specialists (respiratory therapists, physiotherapists, speech therapists, psychotherapists, and social workers) in the ICU. The aim of this paper is to raise awareness of the need to consider each pregnant and breastfeeding staff member individually and to work together to find a personal solution for continuing to work in the ICU. Possible ways and solutions to achieve this goal are outlined and practical examples are given for implementation in everyday clinical routine. These are also based on comprehensive presentation of activities according to a traffic light color-code system for all occupational groups. Arguments against pregnant employees working in the ICU are discussed and possible solutions are presented.

[Position paper on working in the intensive care unit during pregnancy : DIVI recommendations for improving the situation of pregnant employees in the ICU]. / Positionspapier zum Arbeiten in der Schwangerschaft auf der Intensivstation : DIVI-Empfehlungen zur Verbesserung der Lage von schwangeren Mitarbeiterinnen auf einer Intensivstation.

The Maternity Protection Act is intended to protect the mother and the child from hazards, excessive demands and damage to health in the workplace, and from financial disadvantages and loss of employment. However, the objectives defined by the Maternity Protection Act-the safety and health of the pregnant employee on the one hand and the prevention of disadvantages in working life on the other-are not yet adequately achieved in the intensive care unit (ICU). Implementation of the Maternity Protection Act to the benefit of all involved parties should also be promoted in the specialist areas represented by the DIVI, in particular the work of pregnant physicians and nursing staff and other working specialists (respiratory therapists, physiotherapists, speech therapists, psychotherapists, and social workers) in the ICU. The aim of this paper is to raise awareness of the need to consider each pregnant and breastfeeding staff member individually and to work together to find a personal solution for continuing to work in the ICU. Possible ways and solutions to achieve this goal are outlined and practical examples are given for implementation in everyday clinical routine. These are also based on comprehensive presentation of activities according to a traffic light color-code system for all occupational groups. Arguments against pregnant employees working in the ICU are discussed and possible solutions are presented.

Successful treatment of out-of-hospital cardiac arrest is still based on quick activation of the chain of survival.

Background and goal of study: Cardiopulmonary resuscitation (CPR) in prehospital care is a major reason for emergency medical service (EMS) dispatches. CPR outcome depends on various factors, such as bystander CPR and initial heart rhythm. Our aim was to investigate whether short-term outcomes such as the return of spontaneous circulation (ROSC) and hospital admission with spontaneous circulation differ depending on the location of the out-of-hospital cardiac arrest (OHCA). In addition, we assessed further aspects of CPR performance. Materials and methods: In this monocentric retrospective study, protocols of a prehospital physician-staffed EMS located in Munich, Germany, were evaluated using the Mann-Whitney U-test, chi-square test, and a multifactor logistic regression model. Results and discussion: Of the 12,073 cases between 1 January 2014 and 31 December 2017, 723 EMS responses with OHCA were analyzed. In 393 of these cases, CPR was performed. The incidence of ROSC did not differ between public and non-public spaces (p = 0.4), but patients with OHCA in public spaces were more often admitted to the hospital with spontaneous circulation (p = 0.011). Shockable initial rhythm was not different between locations (p = 0.2), but defibrillation was performed significantly more often in public places (p < 0.001). Multivariate analyses showed that hospital admission with spontaneous circulation was more likely in patients with shockable initial heart rhythm (p < 0.001) and if CPR was started by an emergency physician (p = 0.006). Conclusion: The location of OHCA did not seem to affect the incidence of ROSC, although patients in public spaces had a higher chance to be admitted to the hospital with spontaneous circulation. Shockable initial heart rhythm, defibrillation, and the start of resuscitative efforts by an emergency physician were associated with higher chances of hospital admission with spontaneous circulation. Bystander CPR and bystander use of automated external defibrillators were low overall, emphasizing the importance of bystander education and training in order to enhance the chain of survival.

Isoflurane has no effect on cognitive or behavioral performance in a mouse model of early-stage Alzheimer's disease.

Background: Patients with Alzheimer's disease show a sex-dependent decline of cognitive and behavioral performance. It is controversially discussed whether general anesthesia itself can aggravate or even cause this neurocognitive decline. Therefore, we investigated the effect of general anesthesia on neurocognitive and behavioral function and amyloidopathy in a mouse model of early-stage Alzheimer's disease with respect to sex. Methods: After governmental approval 10 months old Tg2576 mice and wild type (total 85 mice) either underwent general anesthesia with 1.0 minimal alveolar concentration of isoflurane for 2 h or were not exposed to isoflurane (controls). Following cognitive and behavioral testing using the modified hole board test (mHBT), brains were investigated regarding amyloidopathy, inflammation, and apoptosis. Data were analyzed using repeated measure analysis of variance (ANOVA) and univariate analysis of variance (UNIANOVA). Results: Tg2576 mice showed a decline in memory function (p < 0.001), less anxiety (p = 0.022 and p = 0.024), increased locomotor activity (p = 0.025), and impaired fine motor skills (p < 0.001). Amyloid precursor protein (p < 0.001), soluble amyloid-beta (p < 0.001) and insoluble amyloid deposits (p < 0.001) were increased in Tg2576 animals. Neither sex nor exposure to isoflurane had an effect on cognitive or behavioral testing or expression of amyloid-related biomarkers. Discussion and conclusion: We found that 10 months old Tg2576 showed typical signs of early-stage Alzheimer's disease and corresponding histopathological alterations. Relevant sex-specific differences or an effect of isoflurane anesthesia could not be detected at this early stage of the disease.

Inhalational Anesthetics Do Not Deteriorate Amyloid-ß-Derived Pathophysiology in Alzheimer's Disease: Investigations on the Molecular, Neuronal, and Behavioral Level.

BACKGROUND: Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer's disease (AD) neuropathogenesis, e.g., increased amyloid-ß (Aß) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. OBJECTIVE: In the present study, we want to detail the interactions of inhalational anesthetics with Aß-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aß oligomerization and Aß-mediated neurotoxicity on processes related to cognition. METHODS: Oligomerization of Aß1-42 in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due to anesthetics and Aß1-42, Aß1-40, pyroglutamate-modified amyloid-(AßpE3), and nitrated Aß (3NTyrAß), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and Aß plaque burden in transgenic AD mice (ArcAß) after anesthesia. RESULTS: Whereas isoflurane and sevoflurane did not affect Aß1-42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AßpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aß1-42-induced spine density attenuation. In the presence of Aß1-40 and AßpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aß1-42 or 3NTyrAß, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAß mice. CONCLUSION: None of the anesthetics aggravated Aß-derived AD pathology in vivo. However, Aß and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aß1-42 aggregation, LTP, and spine density.

Neurotoxicity of different amyloid beta subspecies in mice and their interaction with isoflurane anaesthesia.

BACKGROUND: The aim of this study was to assess different amyloid beta subspecies' effects on behaviour and cognition in mice and their interaction with isoflurane anaesthesia. METHODS: After governmental approval, cannulas were implanted in the lateral cerebral ventricle. After 14 days the mice were randomly intracerebroventricularly injected with Aß 1-40 (Aß40), Aß 1-42 (Aß42), 3NTyr10-Aß (Aß nitro), AßpE3-42 (Aß pyro), or phosphate buffered saline. Four days after the injection, 30 mice (6 animals per subgroup) underwent general anaesthesia with isoflurane. A "sham" anaesthetic procedure was performed in another 30 mice (6 animals per subgroup, 10 subgroups in total). During the next eight consecutive days a blinded assessor evaluated behavioural and cognitive performance using the modified hole-board test. Following the testing we investigated 2 brains per subgroup for insoluble amyloid deposits using methoxy staining. We used western blotting in 4 brains per subgroup for analysis of tumour-necrosis factor alpha, caspase 3, glutamate receptors NR2B, and mGlu5. Data were analysed using general linear modelling and analysis of variance. RESULTS: Aß pyro improved overall cognitive performance (p = 0.038). This cognitive improvement was reversed by isoflurane anaesthesia (p = 0.007), presumably mediated by decreased exploratory behaviour (p = 0.022 and p = 0.037). Injection of Aß42 was associated with increased anxiety (p = 0.079). Explorative analysis on a limited number of brains did not reveal insoluble amyloid deposits or differences in the expression of tumour-necrosis factor alpha, NR2B, mGlu5, or caspase 3. CONCLUSIONS: Testing cognitive performance after intracerebroventricular injection of different amyloid beta subspecies revealed that Aß pyro might be less harmful, which was reversed by isoflurane anaesthesia. There is minor evidence for Aß42-mediated neurotoxicity. Preliminary molecular analysis of biomarkers did not clarify pathophysiological mechanisms.