Transitions into conscious states are partially mediated by inactivation of sleep networks and activation of arousal networks. Pharmacologic hastening of emergence from general anesthesia has largely ...focused on activating subcortical monoaminergic networks, with little attention on antagonizing the γ-aminobutyric acid type A receptor (GABAAR). As the GABAAR mediates the clinical effects of many common general anesthetics, the authors hypothesized that negative GABAAR modulators would hasten emergence, possibly via cortical networks involved in sleep.
The authors investigated the capacity of the benzodiazepine rescue agent, flumazenil, which had been recently shown to promote wakefulness in hypersomnia patients, to alter emergence. Using an in vivo rodent model and an in vitro GABAAR heterologous expression system, they measured flumazenil's effects on behavioral, neurophysiologic, and electrophysiologic correlates of emergence from isoflurane anesthesia.
Animals administered intravenous flumazenil (0.4 mg/kg, n = 8) exhibited hastened emergence compared to saline-treated animals (n = 8) at cessation of isoflurane anesthesia. Wake-like electroencephalographic patterns occurred sooner and exhibited more high-frequency electroencephalography power after flumazenil administration (median latency ± median absolute deviation: 290 ± 34 s) compared to saline administration (473 ± 186 s; P = 0.042). Moreover, in flumazenil-treated animals, there was a decreased impact on postanesthesia sleep. In vitro experiments in human embryonic kidney-293T cells demonstrated that flumazenil inhibited isoflurane-mediated GABA current enhancement (n = 34 cells, 88.7 ± 2.42% potentiation at 3 μM). Moreover, flumazenil exhibited weak agonist activity on the GABAAR (n = 10 cells, 10.3 ± 3.96% peak GABA EC20 current at 1 μM).
Flumazenil can modulate emergence from isoflurane anesthesia. The authors highlight the complex role GABAARs play in mediating consciousness and provide mechanistic links between emergence from anesthesia and arousal.
The active zone (AZ) is a thickening of the presynaptic membrane where exocytosis takes place. Chemical synapses contain neurotransmitter-loaded synaptic vesicles (SVs) that at rest are tethered away ...from the synaptic release site, but after the presynaptic inflow of Ca+2 elicited by an action potential translocate to the AZ to release their neurotransmitter load. We report that tissue-type plasminogen activator (tPA) is stored outside the AZ of cerebral cortical neurons, either intermixed with small clear-core vesicles or in direct contact with the presynaptic membrane. We found that cerebral ischemia-induced release of neuronal tPA, or treatment with recombinant tPA, recruits the cytoskeletal protein βII-spectrin to the AZ and promotes the binding of SVs to βII-spectrin, enlarging the population of SVs in proximity to the synaptic release site. This effect does not require the generation of plasmin and is followed by the recruitment of voltage gated calcium channels (VGCC) to the presynaptic terminal that leads to Ca+2-dependent synapsin I phosphorylation, freeing SVs to translocate to the AZ to deliver their neurotransmitter load. Our studies indicate that tPA activates the SV cycle and induces the structural and functional changes in the synapse that are required for successful neurotransmission.
The retrospective analysis of electroencephalogram (EEG) signals acquired from patients under general anesthesia is crucial in understanding the patient's unconscious brain's state. However, the ...creation of such database is often tedious and cumbersome and involves human labor. Hence, we developed a Raspberry Pi-based system for archiving EEG signals recorded from patients under anesthesia in operating rooms (ORs) with minimal human involvement.
Using this system, we archived patient EEG signals from over 500 unique surgeries at the Emory University Orthopaedics and Spine Hospital, Atlanta, for about 18 months. For this, we developed a software package that runs on a Raspberry Pi and archives patient EEG signals from a SedLine Root EEG Monitor (Masimo) to a secure Health Insurance Portability and Accountability Act (HIPAA) compliant cloud storage. The OR number corresponding to each surgery was archived along with the EEG signal to facilitate retrospective EEG analysis. We retrospectively processed the archived EEG signals and performed signal quality checks. We also proposed a formula to compute the proportion of true EEG signal and calculated the corresponding statistics. Further, we curated and interleaved patient medical record information with the corresponding EEG signals.
We retrospectively processed the EEG signals to demonstrate a statistically significant negative correlation between the relative alpha power (8-12 Hz) of the EEG signal captured under anesthesia and the patient's age.
Our system is a standalone EEG archiver developed using low cost and readily available hardware. We demonstrated that one could create a large-scale EEG database with minimal human involvement. Moreover, we showed that the captured EEG signal is of good quality for retrospective analysis and combined the EEG signal with the patient medical records. This project's software has been released under an open-source license to enable others to use and contribute.
Although aging itself is not a disease, there are many comorbidities that become more common with aging. Heart disease, cancer, and other chronic illnesses are either more common or more severe in ...aging patients. Approximately 5.5 million people in the United States have Alzheimer's disease (AD), with the principal risk factor being age. It is estimated that the incidence of AD diagnosis doubles every 5 years after the age of 65 1. Therefore, as the population ages, the impact of AD on the healthcare landscape will increase. Understanding how to manage patients with AD is critical as we begin to care for more elderly patients in the perioperative period 2. In addition to their other health considerations, aging surgical patients are increasingly more likely to have pre-existing AD or be at risk for developing AD. There is growing interest to determine how anesthesia affects the development or progression of AD. Similarly, a best practice for the anesthetic management of patients with AD is not yet defined. Finally, the relationship between AD and susceptibility to or exacerbation of postoperative cognitive dysfunction (POCD) is not well understood. In this review, we will discuss both the clinical and the preclinical data related to anesthesia and AD, describe the overlapping pathophysiology of neurodegeneration and provide some insight into the anesthetic care of patients with AD.
Advanced age, American Society of Anesthesiologists physical status (ASA) classification and the presence of cognitive impairment are associated with an elevated risk of postoperative morbidity and ...mortality. The visual paired comparison (VPC) task, which relies on recognition of novel images, examines declarative memory. VPC scores have demonstrated the ability to detect mild cognitive impairment and track progression of neurodegenerative disease. Quantitative pupillometry may have similar value. We evaluate for associations between these variables of interest and the feasibility of performing these tests in the preoperative clinic. Prospective data from 199 patients seen in the preoperative clinic at a tertiary academic center were analyzed. A 5 min VPC task (Neurotrack Technologies, Inc, Redwood City, CA) was administered during their scheduled preoperative clinic visit. Pupillary light reflexes were measured at the same visit (PLR-3000™, Neuroptics Corp, Irvine, California).Thirty-four percent of patients were categorized as ASA 2 and 58% as ASA 3. Median age was 57 (IQR: 44–69). Associations were demonstrated between age and ASA physical status (Mann–Whitney U Test, p < 0.0001), maximum pupil size (Spearman Rank Correlation, r = − 0.40, p < 0.0001), and maximum constriction velocity (Spearman Rank Correlation, r = − 0.39, p < 0.0001). Our data also revealed an association between VPC score and age (Spearman Rank Correlation, p = 0.0016, r = − 0.21) but not ASA score (Kruskal–Wallis Test, p = 0.14). When compared to a nonsurgical cohort with no history of memory impairment, our population scored worse on the VPC task (Mann–Whitney U Test, p = 0.0002). A preoperative 5 min VPC task and pupillometry are feasible tests in the preoperative setting and may provide a valuable window into an individual’s cognition prior to elective surgery.
The importance of obstructive sleep apnea in patients undergoing surgery with general anesthesia is well-defined, but the surgical and anesthetic implications of other sleep disorders are less clear. ...We sought to evaluate response to surgery with general anesthesia in patients with central disorders of hypersomnolence or restless legs syndrome.
We surveyed patients on their most recent surgical procedure with general anesthesia, querying about procedure, recovery, and any changes in sleep disorder symptomatology following the procedure.
Forty-five patients with restless legs syndrome and 57 patients with central disorders of hypersomnolence (15 narcolepsy type 2, 1 narcolepsy type 1, 30 idiopathic hypersomnia, 1 Kleine-Levin syndrome, and 10 subjective sleepiness) completed the survey, with response rates of 45.5 and 53.8%, respectively. While patients in both groups were equally likely to report surgical complications and difficulty awakening from anesthesia, hypersomnolent patients were more likely to report worsened sleepiness (40% of the hypersomnolent group vs. 11% of the RLS group,
= 0.001) and worsening of their sleep disorder symptoms (40% of the hypersomnolent group vs. 9% of the RLS group,
= 0.0001).
Patients with sleep disorders other than sleep apnea frequently report surgical or anesthetic complications. Patients with hypersomnolence disorders commonly perceive that their sleep disorder worsened following a procedure; whether this might be related to long term effects of general anesthesia in a particularly vulnerable clinical population requires further study.
Objective
The transition from psoriasis to psoriatic arthritis (PsA) occurs in 20–30% of patients; however, the mechanisms underlying the emergence of musculoskeletal disease are not well understood. ...Metabolic disease is prevalent in psoriasis patients, but whether metabolic factors, other than obesity, increase arthritis risk in psoriasis patients is not known. This study was undertaken to investigate the link between metabolic changes and disease progression in psoriasis patients.
Methods
To characterize the metabolic alterations during the progression of arthritis in psoriasis patients, we analyzed cross‐sectional healthy controls and PsA samples and longitudinal psoriasis serum samples, before and after PsA onset. Nontargeted metabolomic profiling was performed using liquid chromatography mass spectrometry.
Results
We identified several serum metabolites that differed between PsA patients, psoriasis patients, and healthy controls. Differentially abundant bile acids, purines, pyrimidines, glutathione, lipids, and amino acid metabolites were noted in these 3 groups. We also noted differences between psoriasis patients who progressed and those who did not progress to PsA. Bile acid and butyrate levels were depressed in those who progressed to PsA compared to those who did not, and the level of inflammatory lipid mediators increased following PsA diagnosis. In particular, the combination of leukotriene B4 and glycoursodeoxycholic acid sulfate were sensitive and specific predictors of PsA progression.
Conclusion
We observed notable differences in bile acid, purine, lipid, and amino acid–derived metabolites, among the healthy controls, psoriasis patients, and PsA patients and identified changes during the transition from psoriasis to PsA. The decreased bile acid and butyrate levels and elevated guanine levels in psoriasis patients at risk for PsA were particularly striking and may reflect gut microbial dysbiosis and dysregulated hepatic metabolism, leading to altered proliferation of immune cells and enhanced cytokine expression.
•Anesthetic emergence and recovery are dissociable postoperative events.•Prehabilitative exercise may modulate emergence and/or recovery from anesthesia.•Exercise hastened recovery from isoflurane ...anesthesia in rats with and without diabetes.•Ten days of moderate exercise was associated with increased expression of PSD-95.
Diabetes has been demonstrated to be one of the strongest predictors of risk for postoperative delirium and functional decline in older patients undergoing surgery. Exercise is often prescribed as a treatment for diabetic patients and regular physical activity is hypothesized to decrease the risk of postoperative cognitive impairments. Prior studies suggest that anesthetic emergence trajectories and recovery are predictive of risk for later postoperative cognitive impairments. Therapeutic strategies aimed at improving emergence and recovery from anesthesia may therefore be beneficial for diabetic patients. Wistar (n = 32) and Goto-Kakizaki (GK) type 2 diabetic (n = 32) rats between 3–4 months old underwent treadmill exercise for 30 min/day for ten days or remained inactive. Pre-anesthesia spontaneous alternation behavior was recorded with a Y-maze. Rats then received a 2-h exposure to 1.5–2 % isoflurane or oxygen only. The time to reach anesthetic emergence and post-anesthesia recovery behaviors was recorded for each rat. Postsynaptic density protein-95 (PSD-95), an important scaffolding protein required for synaptic plasticity, protein levels were quantified from hippocampus using western blot. Spontaneous alternation behavior (p = 0.044) and arm entries (p < 0.001) were decreased in GK rats. There was no difference between groups in emergence times from isoflurane, but exercise hastened the recovery time (p = 0.008) for both Wistar and GK rats. Following 10 days of exercise, both Wistar and GK rats show increased levels of PSD-95 in the hippocampus. Prehabilitation with moderate intensity exercise, even on a short timescale, is beneficial for recovery from isoflurane in rats, regardless of metabolic disease status.
Bacterial cellulose is a strong and ultrapure form of cellulose produced naturally by several species of the Acetobacteraceae. Its high strength, purity, and biocompatibility make it of great ...interest to materials science; however, precise control of its biosynthesis has remained a challenge for biotechnology. Here we isolate a strain of Komagataeibacter rhaeticus (K. rhaeticus iGEM) that can produce cellulose at high yields, grow in low-nitrogen conditions, and is highly resistant to toxic chemicals. We achieved external control over its bacterial cellulose production through development of a modular genetic toolkit that enables rational reprogramming of the cell. To further its use as an organism for biotechnology, we sequenced its genome and demonstrate genetic circuits that enable functionalization and patterning of heterologous gene expression within the cellulose matrix. This work lays the foundations for using genetic engineering to produce cellulose-based materials, with numerous applications in basic science, materials engineering, and biotechnology.
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