Hormonal basis of sex differences in anesthetic sensitivity.

General anesthesia-a pharmacologically induced reversible state of unconsciousness-enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females.

Understanding the Neural Mechanisms of General Anesthesia from Interaction with Sleep-Wake State: A Decade of Discovery.

The development of cutting-edge techniques to study specific brain regions and neural circuits that regulate sleep-wake brain states and general anesthesia (GA), has increased our understanding of these states that exhibit similar neurophysiologic traits. This review summarizes current knowledge focusing on cell subtypes and neural circuits that control wakefulness, rapid eye movement (REM) sleep, non-REM sleep, and GA. We also review novel insights into their interactions and raise unresolved questions and challenges in this field. Comparisons of the overlapping neural substrates of sleep-wake and GA regulation will help us to understand sleep-wake transitions and how anesthetics cause reversible loss of consciousness. SIGNIFICANCE STATEMENT: General anesthesia (GA), sharing numerous neurophysiologic traits with the process of natural sleep, is administered to millions of surgical patients annually. In the past decade, studies exploring the neural mechanisms underlying sleep-wake and GA have advanced our understanding of their interactions and how anesthetics cause reversible loss of consciousness. Pharmacotherapies targeting the neural substrates associated with sleep-wake and GA regulations have significance for clinical practice in GA and sleep medicine.

Different Doses of Dexmedetomidine Reduce Postoperative Sleep Disturbance Incidence in Patients under General Anesthesia by Elevating Serum Neurotransmitter Levels.

Postoperative sleep disturbance is a common issue that affects recovery in patients undergoing general anesthesia. Dexmedetomidine (Dex) has a potential role in improving postoperative sleep quality. We evaluated the effects of different doses of Dex on postoperative sleep disturbance and serum neurotransmitters in patients undergoing radical gastrectomy under general anesthesia. Patients were assigned to the control, NS, and Dex (Dex-L/M/H) groups based on different treatment doses [0.2, 0.4, and 0.6 µg/(kg · h)]. The Athens Insomnia Scale (AIS) and ELISA kits were used to assess sleep disturbance and serum neurotransmitter (GABA, 5-HT, NE) levels before surgery and on postoperative days one, four, and seven. The effects of different doses on postoperative sleep disturbance incidence and serum neurotransmitter levels were analyzed by the Fisher exact test and one-way and repeated-measures ANOVA. Patients had no differences in gender, age, body mass index, operation time, and bleeding volume. Different Dex doses reduced the postoperative AIS score of patients under general anesthesia, improved their sleep, and increased serum levels of 5-HT, NE, and GABA. Furthermore, the effects were dose-dependent within the range of safe clinical use. Specifically, Dex at doses of 0.2, 0.4, and 0.6 µg/(kg · h) reduced postoperative AIS score, elevated serum neurotransmitter levels, and reduced postoperative sleep disturbance incidence. Collectively, Dex has a potential preventive effect on postoperative sleep disturbance in patients undergoing general anesthesia for radical gastrectomy. The optimal dose of Dex is between 0.2 and 0.6 µg/(kg · h), which significantly reduces the incidence of postoperative sleep disturbance and increases serum neurotransmitter levels.

Neural Ensemble Fragmentation in the Anesthetized Drosophila Brain.

General anesthetics cause a profound loss of behavioral responsiveness in all animals. In mammals, general anesthesia is induced in part by the potentiation of endogenous sleep-promoting circuits, although "deep" anesthesia is understood to be more similar to coma (Brown et al., 2011). Surgically relevant concentrations of anesthetics, such as isoflurane and propofol, have been shown to impair neural connectivity across the mammalian brain (Mashour and Hudetz, 2017; Yang et al., 2021), which presents one explanation why animals become largely unresponsive when exposed to these drugs. It remains unclear whether general anesthetics affect brain dynamics similarly in all animal brains, or whether simpler animals, such as insects, even display levels of neural connectivity that could be disrupted by these drugs. Here, we used whole-brain calcium imaging in behaving female Drosophila flies to investigate whether isoflurane anesthesia induction activates sleep-promoting neurons, and then inquired how all other neurons across the fly brain behave under sustained anesthesia. We were able to track the activity of hundreds of neurons simultaneously during waking and anesthetized states, for spontaneous conditions as well as in response to visual and mechanical stimuli. We compared whole-brain dynamics and connectivity under isoflurane exposure to optogenetically induced sleep. Neurons in the Drosophila brain remain active during general anesthesia as well as induced sleep, although flies become behaviorally inert under both treatments. We identified surprisingly dynamic neural correlation patterns in the waking fly brain, suggesting ensemble-like behavior. These become more fragmented and less diverse under anesthesia but remain wake-like during induced sleep.SIGNIFICANCE STATEMENT When humans are rendered immobile and unresponsive by sleep or general anesthetics, their brains do not shut off - they just change how they operate. We tracked the activity of hundreds of neurons simultaneously in the brains of fruit flies that were anesthetized by isoflurane or genetically put to sleep, to investigate whether these behaviorally inert states shared similar brain dynamics. We uncovered dynamic patterns of neural activity in the waking fly brain, with stimulus-responsive neurons constantly changing through time. Wake-like neural dynamics persisted during induced sleep but became more fragmented under isoflurane anesthesia. This suggests that, like larger brains, the fly brain might also display ensemble-like behavior, which becomes degraded rather than silenced under general anesthesia.

Facilitation of Behavioral and Cortical Emergence from Isoflurane Anesthesia by GABAergic Neurons in Basal Forebrain.

General anesthesia shares many similarities with natural sleep in behavior and electroencephalogram (EEG) patterns. The latest evidence suggests that general anesthesia and sleep-wake behavior may share overlapping neural substrates. The GABAergic neurons in the basal forebrain (BF) have recently been demonstrated to play a key role in controlling wakefulness. It was hypothesized that BF GABAergic neurons may participate in the regulation of general anesthesia. Here, using in vivo fiber photometry, we found that the activity of BF GABAergic neurons was generally inhibited during isoflurane anesthesia, having obviously decreased during the induction of anesthesia and being gradually restored during the emergence from anesthesia, in Vgat-Cre mice of both sexes. Activation of BF GABAergic neurons with chemogenetic and optogenetic approaches decreased sensitivity to isoflurane, delayed induction, and accelerated emergence from isoflurane anesthesia. Optogenetic activation of BF GABAergic neurons decreased EEG δ power and the burst suppression ratio (BSR) during 0.8% and 1.4% isoflurane anesthesia, respectively. Similar to the effects of activating BF GABAergic cell bodies, photostimulation of BF GABAergic terminals in the thalamic reticular nucleus (TRN) also strongly promoted cortical activation and behavioral emergence from isoflurane anesthesia. Collectively, these results showed that the GABAergic BF is a key neural substrate for general anesthesia regulation that facilitates behavioral and cortical emergence from general anesthesia via the GABAergic BF-TRN pathway. Our findings may provide a new target for attenuating the depth of anesthesia and accelerating emergence from general anesthesia.SIGNIFICANCE STATEMENT The basal forebrain (BF) is a key brain region controlling sleep-wake behavior. Activation of GABAergic neurons in the BF potently promotes behavioral arousal and cortical activity. Recently, many sleep-wake-related brain structures have been reported to participate in the regulation of general anesthesia. However, it is still unclear what role BF GABAergic neurons play in general anesthesia. In this study, we aim to reveal the role of BF GABAergic neurons in behavioral and cortical emergence from isoflurane anesthesia and elucidate the underlying neural pathways. Understanding the specific role of BF GABAergic neurons in isoflurane anesthesia would improve our understanding of the mechanisms of general anesthesia and may provide a new strategy for accelerating emergence from general anesthesia.

Propofol-mediated Unconsciousness Disrupts Progression of Sensory Signals through the Cortical Hierarchy.

A critical component of anesthesia is the loss of sensory perception. Propofol is the most widely used drug for general anesthesia, but the neural mechanisms of how and when it disrupts sensory processing are not fully understood. We analyzed local field potential and spiking recorded from Utah arrays in auditory cortex, associative cortex, and cognitive cortex of nonhuman primates before and during propofol-mediated unconsciousness. Sensory stimuli elicited robust and decodable stimulus responses and triggered periods of stimulus-related synchronization between brain areas in the local field potential of Awake animals. By contrast, propofol-mediated unconsciousness eliminated stimulus-related synchrony and drastically weakened stimulus responses and information in all brain areas except for auditory cortex, where responses and information persisted. However, we found stimuli occurring during spiking Up states triggered weaker spiking responses than in Awake animals in auditory cortex, and little or no spiking responses in higher order areas. These results suggest that propofol's effect on sensory processing is not just because of asynchronous Down states. Rather, both Down states and Up states reflect disrupted dynamics.

Mapping general anesthesia states based on electro-encephalogram transition phases.

Cortical electro-encephalography (EEG) served as the clinical reference for monitoring unconsciousness during general anesthesia. The existing EEG-based monitors classified general anesthesia states as underdosed, adequate, or overdosed, lacking predictive power due to the absence of transition phases among these states. In response to this limitation, we undertook an analysis of the EEG signal during isoflurane-induced general anesthesia in mice. Adopting a data-driven approach, we applied signal processing techniques to track θ- and δ-band dynamics, along with iso-electric suppressions. Combining this approach with machine learning, we successfully developed an automated algorithm. The findings of our study revealed that the dampening of the δ-band occurred several minutes before the onset of significant iso-electric suppression episodes. Furthermore, a distinct γ-frequency oscillation was observed, persisting for several minutes during the recovery phase subsequent to isoflurane-induced overdose. As a result of our research, we generated a map summarizing multiple brain states and their transitions, offering a tool for predicting and preventing overdose during general anesthesia. The transition phases identified, along with the developed algorithm, have the potential to be generalized, enabling clinicians to prevent inadequate anesthesia and, consequently, tailor anesthetic regimens to individual patients.

Concomitant use of pre-emptive analgesia with local and general anesthesia in rat uterine pain surgical model.

Preemptive analgesia is used for postoperative pain management, providing pain relief with few adverse effects. In this study, the effect of a preemptive regime on rat behavior and c-fos expression in the spinal cord of the uterine surgical pain model was evaluated. It was a lab-based experimental study in which 60 female Sprague-Dawley rats; eight to 10 weeks old, weighing 150-300 gm were used. The rats were divided into two main groups: (i) superficial pain group (SG) (with skin incision only), (ii) deep pain group (with skin and uterine incisions). Each group was further divided into three subgroups based on the type of preemptive analgesia administered i.e., "tramadol, buprenorphine, and saline subgroups." Pain behavior was evaluated using the "Rat Grimace Scale" (RGS) at 2, 4, 6, 9 and 24 h post-surgery. Additionally, c-fos immunohistochemistry was performed on sections from spinal dorsal horn (T12-L2), and its expression was evaluated using optical density and mean cell count 2 hours postoperatively. Significant reduction in the RGS was noted in both the superficial and deep pain groups within the tramadol and buprenorphine subgroups when compared to the saline subgroup (p ≤ .05). There was a significant decrease in c-fos expression both in terms of number of c-fos positive cells and the optical density across the superficial laminae and lamina X of the spinal dorsal horn in both SD and DG (p ≤ .05). In contrast, the saline group exhibited c-fos expression primarily in laminae I-II and III-IV for both superficial and deep pain groups and lamina X in the deep pain group only (p ≤ .05). Hence, a preemptive regimen results in significant suppression of both superficial and deep components of pain transmission. These findings provide compelling evidence of the analgesic efficacy of preemptive treatment in alleviating pain response associated with uterine surgery.

Spinal Anesthesia or General Anesthesia for Hip Surgery in Older Adults.

BACKGROUND: The effects of spinal anesthesia as compared with general anesthesia on the ability to walk in older adults undergoing surgery for hip fracture have not been well studied. METHODS: We conducted a pragmatic, randomized superiority trial to evaluate spinal anesthesia as compared with general anesthesia in previously ambulatory patients 50 years of age or older who were undergoing surgery for hip fracture at 46 U.S. and Canadian hospitals. Patients were randomly assigned in a 1:1 ratio to receive spinal or general anesthesia. The primary outcome was a composite of death or an inability to walk approximately 10 ft (3 m) independently or with a walker or cane at 60 days after randomization. Secondary outcomes included death within 60 days, delirium, time to discharge, and ambulation at 60 days. RESULTS: A total of 1600 patients were enrolled; 795 were assigned to receive spinal anesthesia and 805 to receive general anesthesia. The mean age was 78 years, and 67.0% of the patients were women. A total of 666 patients (83.8%) assigned to spinal anesthesia and 769 patients (95.5%) assigned to general anesthesia received their assigned anesthesia. Among patients in the modified intention-to-treat population for whom data were available, the composite primary outcome occurred in 132 of 712 patients (18.5%) in the spinal anesthesia group and 132 of 733 (18.0%) in the general anesthesia group (relative risk, 1.03; 95% confidence interval [CI], 0.84 to 1.27; P = 0.83). An inability to walk independently at 60 days was reported in 104 of 684 patients (15.2%) and 101 of 702 patients (14.4%), respectively (relative risk, 1.06; 95% CI, 0.82 to 1.36), and death within 60 days occurred in 30 of 768 (3.9%) and 32 of 784 (4.1%), respectively (relative risk, 0.97; 95% CI, 0.59 to 1.57). Delirium occurred in 130 of 633 patients (20.5%) in the spinal anesthesia group and in 124 of 629 (19.7%) in the general anesthesia group (relative risk, 1.04; 95% CI, 0.84 to 1.30). CONCLUSIONS: Spinal anesthesia for hip-fracture surgery in older adults was not superior to general anesthesia with respect to survival and recovery of ambulation at 60 days. The incidence of postoperative delirium was similar with the two types of anesthesia. (Funded by the Patient-Centered Outcomes Research Institute; REGAIN ClinicalTrials.gov number, NCT02507505.).

Dexamethasone and Surgical-Site Infection.

BACKGROUND: The glucocorticoid dexamethasone prevents nausea and vomiting after surgery, but there is concern that it may increase the risk of surgical-site infection. METHODS: In this pragmatic, international, noninferiority trial, we randomly assigned 8880 adult patients who were undergoing nonurgent, noncardiac surgery of at least 2 hours' duration, with a skin incision length longer than 5 cm and a postoperative overnight hospital stay, to receive 8 mg of intravenous dexamethasone or matching placebo while under anesthesia. Randomization was stratified according to diabetes status and trial center. The primary outcome was surgical-site infection within 30 days after surgery. The prespecified noninferiority margin was 2.0 percentage points. RESULTS: A total of 8725 participants were included in the modified intention-to-treat population (4372 in the dexamethasone group and 4353 in the placebo group), of whom 13.2% (576 in the dexamethasone group and 572 in the placebo group) had diabetes mellitus. Of the 8678 patients included in the primary analysis, surgical-site infection occurred in 8.1% (354 of 4350 patients) assigned to dexamethasone and in 9.1% (394 of 4328) assigned to placebo (risk difference adjusted for diabetes status, -0.9 percentage points; 95.6% confidence interval [CI], -2.1 to 0.3; P<0.001 for noninferiority). The results for superficial, deep, and organ-space surgical-site infections and in patients with diabetes were similar to those of the primary analysis. Postoperative nausea and vomiting in the first 24 hours after surgery occurred in 42.2% of patients in the dexamethasone group and in 53.9% in the placebo group (risk ratio, 0.78; 95% CI, 0.75 to 0.82). Hyperglycemic events in patients without diabetes occurred in 22 of 3787 (0.6%) in the dexamethasone group and in 6 of 3776 (0.2%) in the placebo group. CONCLUSIONS: Dexamethasone was noninferior to placebo with respect to the incidence of surgical-site infection within 30 days after nonurgent, noncardiac surgery. (Funded by the Australian National Health and Medical Research Council and others; PADDI Australian New Zealand Clinical Trials Registry number, ACTRN12614001226695.).

Glutamatergic neurons in the paraventricular hypothalamic nucleus regulate isoflurane anesthesia in mice.

The glutamatergic-mediated excitatory system in the brain is vital for the regulation of sleep-wake and general anesthesia. Specifically, the paraventricular hypothalamic nucleus (PVH), which contains mainly glutamatergic neurons, has been shown to play a critical role in sleep-wake. Here, we sought to explore whether the PVH glutamatergic neurons have an important effect on the process of general anesthesia. We used c-fos staining and in vivo calcium signal recording to observe the activity changes of the PVH glutamatergic neurons during isoflurane anesthesia and found that both c-fos expression in the PVH and the calcium activity of PVH glutamatergic neurons decreased in isoflurane anesthesia and significantly increased during the recovery process. Chemogenetic activation of PVH glutamatergic neurons prolonged induction time and shortened emergence time from anesthesia by decreasing the depth of anesthesia. Using chemogenetic inhibition of PVH glutamatergic neurons under isoflurane anesthesia, we found that inhibition of PVH glutamatergic neurons facilitated the induction process and delayed the emergence accompanied by deepening the depth of anesthesia. Together, these results identify a crucial role for PVH glutamatergic neurons in modulating isoflurane anesthesia.

Consciousness and General Anesthesia: Challenges for Measuring the Depth of Anesthesia.

The optimal consciousness level required for general anesthesia with surgery is unclear, but in existing practice, anesthetic oblivion, may be incomplete. This article discusses the concept of consciousness, how it is altered by anesthetics, the challenges for assessing consciousness, currently used technologies for assessing anesthesia levels, and future research directions. Wakefulness is marked by a subjective experience of existence (consciousness), perception of input from the body or the environment (connectedness), the ability for volitional responsiveness, and a sense of continuity in time. Anesthetic drugs may selectively impair some of these components without complete extinction of the subjective experience of existence. In agreement with Sanders et al. (2012), the authors propose that a state of disconnected consciousness is the optimal level of anesthesia, as it likely avoids both awareness and the possible dangers of oversedation. However, at present, there are no reliably tested indices that can discriminate between connected consciousness, disconnected consciousness, and complete unconsciousness.

Time to Wake Up! The Ongoing Search for General Anesthetic Reversal Agents.

How general anesthetics work remains a topic of ongoing study. A parallel field of research has sought to identify methods to reverse general anesthesia. Reversal agents could shorten patients' recovery time and potentially reduce the risk of postoperative complications. An incomplete understanding of the mechanisms of general anesthesia has hampered the pursuit for reversal agents. Nevertheless, the search for reversal agents has furthered understanding of the mechanisms underlying general anesthesia. The study of potential reversal agents has highlighted the importance of rigorous criteria to assess recovery from general anesthesia in animal models, and has helped identify key arousal systems (e.g., cholinergic, dopaminergic, and orexinergic systems) relevant to emergence from general anesthesia. Furthermore, the effects of reversal agents have been found to be inconsistent across different general anesthetics, revealing differences in mechanisms among these drugs. The presynapse and glia probably also contribute to general anesthesia recovery alongside postsynaptic receptors. The next stage in the search for reversal agents will have to consider alternate mechanisms encompassing the tripartite synapse.

Topographical Features of Pediatric Electroencephalography during High Initial Concentration Sevoflurane for Inhalational Induction of Anesthesia.

BACKGROUND: High-density electroencephalographic (EEG) monitoring remains underutilized in clinical anesthesia, despite its obvious utility in unraveling the profound physiologic impact of these agents on central nervous system functioning. In school-aged children, the routine practice of rapid induction with high concentrations of inspiratory sevoflurane is commonplace, given its favorable efficacy and tolerance profile. However, few studies investigate topographic EEG during the critical timepoint coinciding with loss of responsiveness-a key moment for anesthesiologists in their everyday practice. The authors hypothesized that high initial sevoflurane inhalation would better precipitate changes in brain regions due to inhomogeneities in maturation across three different age groups compared with gradual stepwise paradigms utilized by other investigators. Knowledge of these changes may inform strategies for agent titration in everyday clinical settings. METHODS: A total of 37 healthy children aged 5 to 10 yr underwent induction with 4% or greater sevoflurane in high-flow oxygen. Perturbations in anesthetic state were investigated in 23 of these children using 64-channel EEG with the Hjorth Laplacian referencing scheme. Topographical maps illustrated absolute, relative, and total band power across three age groups: 5 to 6 yr (n = 7), 7 to 8 yr (n = 8), and 9 to 10 yr (n = 8). RESULTS: Spectral analysis revealed a large shift in total power driven by increased delta oscillations. Well-described topographic patterns of anesthesia, e.g., frontal predominance, paradoxical beta excitation, and increased slow activity, were evident in the topographic maps. However, there were no statistically significant age-related changes in spectral power observed in a midline electrode subset between the groups when responsiveness was lost compared to the resting state. CONCLUSIONS: High initial concentration sevoflurane induction causes large-scale topographic effects on the pediatric EEG. Within the minute after unresponsiveness, this dosage may perturb EEG activity in children to an extent where age-related differences are not discernible.

Development of Postanesthesia Care Unit Delirium Is Associated with Differences in Aperiodic and Periodic Alpha Parameters of the Electroencephalogram during Emergence from General Anesthesia: Results from a Prospective Observational Cohort Study.

BACKGROUND: Intraoperative alpha-band power in frontal electrodes may provide helpful information about the balance of hypnosis and analgesia and has been associated with reduced occurrence of delirium in the postanesthesia care unit. Recent studies suggest that narrow-band power computations from neural power spectra can benefit from separating periodic and aperiodic components of the electroencephalogram. This study investigates whether such techniques are more useful in separating patients with and without delirium in the postanesthesia care unit at the group level as opposed to conventional power spectra. METHODS: Intraoperative electroencephalography recordings of 32 patients who developed perioperative neurocognitive disorders and 137 patients who did not were considered in this post hoc secondary analysis. The power spectra were calculated using conventional methods and the "fitting oscillations and one over f" algorithm was applied to separate aperiodic and periodic components to see whether the electroencephalography signature is different between groups. RESULTS: At the group level, patients who did not develop perioperative neurocognitive disorders presented with significantly higher alpha-band power and a broadband increase in power, allowing a "fair" separation based on conventional power spectra. Within the first third of emergence, the difference in median absolute alpha-band power amounted to 8.53 decibels (area under the receiver operator characteristics curve, 0.74 [0.65; 0.82]), reaching its highest value. In relative terms, the best separation was achieved in the second third of emergence, with a difference in medians of 7.71% (area under the receiver operator characteristics curve, 0.70 [0.61; 0.79]). The area under the receiver operator characteristics curve values were generally lower toward the end of emergence with increasing arousal. CONCLUSIONS: Increased alpha-band power during emergence in patients who did not develop perioperative neurocognitive disorders can be traced back to an increase in oscillatory alpha activity and an overall increase in aperiodic broadband power. Although the differences between patients with and without perioperative neurocognitive disorders can be detected relying on traditional methods, the separation of the signal allows a more detailed analysis. This may enable clinicians to detect patients at risk for developing perioperative neurocognitive disorders in the postanesthesia care unit early in the emergence phase.

Medial Septal Glutamatergic Neurons Modulate States of Consciousness during Sevoflurane Anesthesia in Mice.

BACKGROUND: Multiple neural structures involved in maintaining wakefulness have been found to promote arousal from general anesthesia. The medial septum is a critical region that modulates arousal behavior. This study hypothesized that glutamatergic neurons in the medial septum play a crucial role in regulating states of consciousness during sevoflurane general anesthesia. METHODS: Adult male mice were used in this study. The effects of sevoflurane anesthesia on neuronal activity were determined by fiber photometry. Lesions and chemogenetic manipulations were used to study the effects of the altered activity of medial septal glutamatergic neurons on anesthesia induction, emergence, and sensitivity to sevoflurane. Optogenetic stimulation was used to observe the role of acute activation of medial septal glutamatergic neurons on cortical activity and behavioral changes during sevoflurane-induced continuous steady state of general anesthesia and burst suppression state. RESULTS: The authors found that medial septal glutamatergic neuronal activity decreased during sevoflurane anesthesia induction and recovered in the early period of emergence. Chemogenetic activation of medial septal glutamatergic neurons prolonged the induction time (mean ± SD, hM3Dq-clozapine N-oxide vs. hM3Dq-saline, 297.5 ± 60.1 s vs. 229.4 ± 29.9 s, P < 0.001, n = 11) and decreased the emergence time (53.2 ± 11.8 s vs. 77.5 ± 33.5 s, P = 0.025, n = 11). Lesions or chemogenetic inhibition of these neurons produced the opposite effects. During steady state of general anesthesia and deep anesthesia-induced burst suppression state, acute optogenetic activation of medial septal glutamatergic neurons induced cortical activation and behavioral emergence. CONCLUSIONS: The study findings reveal that activation of medial septal glutamatergic neurons has arousal-promoting effects during sevoflurane anesthesia in male mice. The activation of these neurons prolongs the induction and accelerates the emergence of anesthesia.

Long-term Survival after Volatile or Propofol General Anesthesia for Bladder Cancer Surgery: A Retrospective National Registry Cohort Study.

BACKGROUND: Prospective interventional trials and retrospective observational analyses provide conflicting evidence regarding the relationship between propofol versus inhaled volatile general anesthesia and long-term survival after cancer surgery. Specifically, bladder cancer surgery lacks prospective clinical trial evidence. METHODS: Data on bladder cancer surgery performed under general anesthesia between 2014 and 2021 from the National Quality Registry for Urinary Tract and Bladder Cancer and the Swedish Perioperative Registry were record-linked. Overall survival was compared between patients receiving propofol or inhaled volatile for anesthesia maintenance. The minimum clinically important difference was defined as a 5-percentage point difference in 5-yr survival. RESULTS: Of 7,571 subjects, 4,519 (59.7%) received an inhaled volatile anesthetic, and 3,052 (40.3%) received propofol for general anesthesia maintenance. The two groups were quite similar in most respects but differed in American Society of Anesthesiologists Physical Status and tumor stage. Propensity score matching was used to address treatment bias. Survival did not differ during follow-up (median, 45 months [interquartile range, 33 to 62 months]) in the full unmatched cohort nor after 1:1 propensity score matching (3,052 matched pairs). The Kaplan-Meier adjusted 5-yr survival rates in the matched cohort were 898 of 3,052, 67.5% (65.6 to 69.3%) for propofol and 852 of 3,052, 68.5% (66.7 to 70.4%) for inhaled volatile general anesthesia, respectively (hazard ratio, 1.05 [95% CI, 0.96 to 1.15]; P = 0.332). A sensitivity analysis restricted to 1,766 propensity score-matched pairs of patients who received only one general anesthetic during the study period did not demonstrate a difference in survival; Kaplan-Meier adjusted 5-yr survival rates were 521 of 1,766, 67.1% (64.7 to 69.7%) and 482 of 1,766, 68.9% (66.5 to 71.4%) for propofol and inhaled volatile general anesthesia, respectively (hazard ratio, 1.09 [95% CI, 0.97 to 1.23]; P = 0.139). CONCLUSIONS: Among patients undergoing bladder cancer surgery under general anesthesia, there was no statistically significant difference in long-term overall survival associated with the choice of propofol or an inhaled volatile maintenance.

Target-controlled Infusion of Remimazolam in Healthy Volunteers Shows Some Acute Tolerance.

BACKGROUND: Remimazolam exhibits sedative properties by binding to γ-aminobutyric acid type A receptors. Remimazolam is administered as a bolus dose or continuous infusion, but has not been studied using target-controlled infusion (TCI). The study quantified the relationship between the remimazolam concentration, Modified Observer's Assessment of Alertness and Sedation (MOAAS) score, and bispectral index (BIS) using TCI. METHODS: The authors performed a three-period, crossover, dose-ranging clinical trial in 24 healthy volunteers using age and sex stratification. Data collected in the first period, where remimazolam was administered alone using a step-up and step-down TCI protocol, were used for this analysis. Remimazolam concentrations, MOAAS scores, and BIS values were collected at each step at steady state. Data were analyzed using nonlinear mixed-effects modeling methodology. RESULTS: The relationship between remimazolam, BIS, and MOAAS differed between step-up and step-down infusions at similar remimazolam target concentrations. Tolerance, driven by remimazolam or CNS7054, significantly improved overall model fit (P < 0.01) for both BIS and MOAAS models. After 30 min of repeated bolus dosing, mimicking the regimen in the label for procedural sedation, the BIS and probability of MOAAS 2/3 were predicted to be 54 (95% prediction interval, 44 to 67) and 2% (95% prediction interval, 0 to 32%) versus 58 (95% prediction interval, 48 to 70) and 8% (95% prediction interval, 0 to 36%) in a model without and with tolerance, respectively. After 60 min of continuous infusion, mimicking the regimen in the label for general anesthesia, the BIS and probability of MOAAS 0 were predicted to be 40 (95% prediction interval, 33 to 50) and 87% (95% prediction interval, 18 to 100%) versus 50 (95% prediction interval, 41 to 60) and 59% (95% prediction interval, 6 to 99%) in a model without and with tolerance, respectively. CONCLUSIONS: In this study, it was shown that remimazolam-induced sedation is prone to tolerance development, which is potentially mediated by the CNS7054 concentration. The clinical consequences are, however, limited in situations where remimazolam is titrated to effect.

Opioid-free Anesthesia Protocol on the Early Quality of Recovery after Major Surgery (SOFA Trial): A Randomized Clinical Trial.

BACKGROUND: Opioid-free anesthesia is increasingly being adopted to reduce opioid consumption, but its impact on early postoperative recovery after major surgery has not been evaluated in comparative trials. The hypothesis was that an opioid-free anesthesia protocol would enhance the early quality of recovery for patients undergoing scheduled major surgery under general anesthesia. METHODS: The SOFA study was a monocentric, randomized, controlled, assessor- and patient-blinded clinical trial conducted from July 10, 2021, to February 12, 2022. The eligible population included male and female patients undergoing scheduled major surgery, excluding bone procedures, that typically require opioids for postoperative pain management. Patients in the intervention group received a combination of at least two drugs among ketamine, lidocaine, clonidine, and magnesium sulfate, without opioids for anesthesia. The standard group received opioids. The primary outcome was early postoperative quality of recovery, assessed by Quality of Recovery-15 score at 24 h after surgery. Secondary outcomes were Quality of Recovery-15 at 48 and 72 h after surgery, incidence of chronic pain, and quality of life at 3 months. RESULTS: Of the 136 randomized patients, 135 were included in the primary analysis (mean age, 45.9 ± 15.7 yr; 116 females [87.2%]; 85 underwent major plastic surgery [63.9%]), with 67 patients in the opioid-free anesthesia group and 68 in the standard group. The mean Quality of Recovery-15 at 24 h was 114.9 ± 15.2 in the opioid-free anesthesia group versus 108.7 ± 18.1 in the standard group (difference, 6.2; 95% CI, 0.4 to 12.0; P = 0.026). Quality of Recovery-15 scores also differed significantly at 48 h (difference, 8.7; 95% CI, 2.9 to 14.5; P = 0.004) and at 72 h (difference, 7.3; 95% CI, 1.6 to 13.0; P = 0.013). There were no differences in other secondary outcomes. No major adverse events were noticed. CONCLUSIONS: The opioid-free anesthesia protocol improved quality of recovery after major elective surgery in a statistically but not clinically significant manner when compared to standard anesthesia.

Long-term Outcomes with Spinal versus General Anesthesia for Hip Fracture Surgery: A Randomized Trial.

BACKGROUND: The effects of spinal versus general anesthesia on long-term outcomes have not been well studied. This study tested the hypothesis that spinal anesthesia is associated with better long-term survival and functional recovery than general anesthesia. METHODS: A prespecified analysis was conducted of long-term outcomes of a completed randomized superiority trial that compared spinal anesthesia versus general anesthesia for hip fracture repair. Participants included previously ambulatory patients 50 yr of age or older at 46 U.S. and Canadian hospitals. Patients were randomized 1:1 to spinal or general anesthesia, stratified by sex, fracture type, and study site. Outcome assessors and investigators involved in the data analysis were masked to the treatment arm. Outcomes included survival at up to 365 days after randomization (primary); recovery of ambulation among 365-day survivors; and composite endpoints for death or new inability to ambulate and death or new nursing home residence at 365 days. Patients were included in the analysis as randomized. RESULTS: A total of 1,600 patients were enrolled between February 12, 2016, and February 18, 2021; 795 were assigned to spinal anesthesia, and 805 were assigned to general anesthesia. Among 1,599 patients who underwent surgery, vital status information at or beyond the final study interview (conducted at approximately 365 days after randomization) was available for 1,427 (89.2%). Survival did not differ by treatment arm; at 365 days after randomization, there were 98 deaths in patients assigned to spinal anesthesia versus 92 deaths in patients assigned to general anesthesia (hazard ratio, 1.08; 95% CI, 0.81 to 1.44, P = 0.59). Recovery of ambulation among patients who survived a year did not differ by type of anesthesia (adjusted odds ratio for spinal vs. general, 0.87; 95% CI, 0.67 to 1.14; P = 0.31). Other outcomes did not differ by treatment arm. CONCLUSIONS: Long-term outcomes were similar with spinal versus general anesthesia.