Continuity with caveats in anesthesia: state and response entropy of the EEG.

The growing use of neuromonitoring in general anesthesia provides detailed insights into the effects of anesthetics on the brain. Our study focuses on the processed EEG indices State Entropy (SE), Response Entropy (RE), and Burst Suppression Ratio (BSR) of the GE EntropyTM Module, which serve as surrogate measures for estimating the level of anesthesia. While retrospectively analyzing SE and RE index values from patient records, we encountered a technical anomaly with a conspicuous distribution of index values. In this single-center, retrospective study, we analyzed processed intraoperative electroencephalographic (EEG) data from 15,608 patients who underwent general anesthesia. We employed various data visualization techniques, including histograms and heat maps, and fitted custom non-Gaussian curves. Individual patients' anesthetic periods were evaluated in detail. To compare distributions, we utilized the Kolmogorov-Smirnov test and Kullback-Leibler divergence. The analysis also included the influence of the BSR on the distribution of SE and RE values. We identified distinct pillar indices for both SE and RE, i.e., index values with a higher probability of occurrence than others. These pillar index values were not age-dependent and followed a non-equidistant distribution pattern. This phenomenon occurs independently of the BSR distribution. SE and RE index values do not adhere to a continuous distribution, instead displaying prominent pillar indices with a consistent pattern of occurrence across all age groups. The specific features of the underlying algorithm responsible for this pattern remain elusive.

Electroencephalographic guided propofol-remifentanil TCI anesthesia with and without dexmedetomidine in a geriatric population: electroencephalographic signatures and clinical evaluation.

Elderly and multimorbid patients are at high risk for developing unfavorable postoperative neurocognitive outcomes; however, well-adjusted and EEG-guided anesthesia may help titrate anesthesia and improve postoperative outcomes. Over the last decade, dexmedetomidine has been increasingly used as an adjunct in the perioperative setting. Its synergistic effect with propofol decreases the dose of propofol needed to induce and maintain general anesthesia. In this pilot study, we evaluate two highly standardized anesthetic regimens for their potential to prevent burst suppression and postoperative neurocognitive dysfunction in a high-risk population. Prospective, randomized clinical trial with non-blinded intervention. Operating room and post anesthesia care unit at Hospital Base San José, Osorno/Universidad Austral, Valdivia, Chile. 23 patients with scheduled non-neurologic, non-cardiac surgeries with age > 69 years and a planned intervention time > 60 min. Patients were randomly assigned to receive either a propofol-remifentanil based anesthesia or an anesthetic regimen with dexmedetomidine-propofol-remifentanil. All patients underwent a slow titrated induction, followed by a target controlled infusion (TCI) of propofol and remifentanil (n = 10) or propofol, remifentanil and continuous dexmedetomidine infusion (n = 13). We compared the perioperative EEG signatures, drug-induced changes, and neurocognitive outcomes between two anesthetic regimens in geriatric patients. We conducted a pre- and postoperative Montreal Cognitive Assessment (MoCa) test and measured the level of alertness postoperatively using a sedation agitation scale to assess neurocognitive status. During slow induction, maintenance, and emergence, burst suppression was not observed in either group; however, EEG signatures differed significantly between the two groups. In general, EEG activity in the propofol group was dominated by faster rhythms than in the dexmedetomidine group. Time to responsiveness was not significantly different between the two groups (p = 0.352). Finally, no significant differences were found in postoperative cognitive outcomes evaluated by the MoCa test nor sedation agitation scale up to one hour after extubation. This pilot study demonstrates that the two proposed anesthetic regimens can be safely used to slowly induce anesthesia and avoid EEG burst suppression patterns. Despite the patients being elderly and at high risk, we did not observe postoperative neurocognitive deficits. The reduced alpha power in the dexmedetomidine-treated group was not associated with adverse neurocognitive outcomes.

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.

The Influence of Electromyographic on Electroencephalogram-Based Monitoring: Putting the Forearm on the Forehead.

BACKGROUND: Monitoring the electroencephalogram (EEG) during general anesthesia can help to safely navigate the patient through the procedure by avoiding too deep or light anesthetic levels. In daily clinical practice, the EEG is recorded from the forehead and available neuromonitoring systems translate the EEG information into an index inversely correlating with the anesthetic level. Electrode placement on the forehead can lead to an influence of electromyographic (EMG) activity on the recorded signal in patients without neuromuscular blockade (NMB). A separation of EEG and EMG in the clinical setting is difficult because both signals share an overlapping frequency range. Previous research showed that indices decreased when EMG was absent in awake volunteers with NMB. Here, we investigated to what extent the indices changed, when EEG recorded during surgery with NMB agents was superimposed with EMG. METHODS: We recorded EMG from the flexor muscles of the forearm of 18 healthy volunteers with a CONOX monitor during different activity settings, that is, during contraction using a grip strengthener and during active diversion (relaxed arm). Both the forehead and forearm muscles are striated muscles. The recorded EMG was normalized by z-scoring and added to the EEG in different amplification steps. The EEG was recorded during anesthesia with NMB. We replayed these combined EEG and EMG signals to different neuromonitoring systems, that is, bispectral index (BIS), CONOX with qCON and qNOX, and entropy module with state entropy (SE) and response entropy (RE). We used the Friedman test and a Tukey-Kramer post hoc correction for statistical analysis. RESULTS: The indices of all neuromonitoring systems significantly increased when the EEG was superimposed with the contraction EMG and with high EMG amplitudes, the monitors returned invalid values, representative of artifact contamination. When replaying the EEG being superimposed with "relaxed" EMG, the qCON and BIS showed significant increases, but not SE and RE. For SE and RE, we observed an increased number of invalid values. CONCLUSIONS: With our approach, we could show that EMG activity during contraction and resting state can influence the neuromonitoring systems. This knowledge may help to improve EEG-based patient monitoring in the future and help the anesthesiologist to use the neuromonitoring systems with more knowledge regarding their function.

Predictors of Low Risk for Delirium during Anesthesia Emergence.

BACKGROUND: Processed electroencephalography (EEG) is used to monitor the level of anesthesia, and it has shown the potential to predict the occurrence of delirium. While emergence trajectories of relative EEG band power identified post hoc show promising results in predicting a risk for a delirium, they are not easily transferable into an online predictive application. This article describes a low-resource and easily applicable method to differentiate between patients at high risk and low risk for delirium, with patients at low risk expected to show decreasing EEG power during emergence. METHODS: This study includes data from 169 patients (median age, 61 yr [49, 73]) who underwent surgery with general anesthesia maintained with propofol, sevoflurane, or desflurane. The data were derived from a previously published study. The investigators chose a single frontal channel, calculated the total and spectral band power from the EEG and calculated a linear regression model to observe the parameters' change during anesthesia emergence, described as slope. The slope of total power and single band power was correlated with the occurrence of delirium. RESULTS: Of 169 patients, 32 (19%) showed delirium. Patients whose total EEG power diminished the most during emergence were less likely to screen positive for delirium in the postanesthesia care unit. A positive slope in total power and band power evaluated by using a regression model was associated with a higher risk ratio (total, 2.83 [95% CI, 1.46 to 5.51]; alpha/beta band, 7.79 [95% CI, 2.24 to 27.09]) for delirium. Furthermore, a negative slope in multiple bands during emergence was specific for patients without delirium and allowed definition of a test for patients at low risk. CONCLUSIONS: This study developed an easily applicable exploratory method to analyze a single frontal EEG channel and to identify patterns specific for patients at low risk for delirium.

Permutation entropy is not an age-independent parameter for EEG-based anesthesia monitoring.

Background: An optimized anesthesia monitoring using electroencephalographic (EEG) information in the elderly could help to reduce the incidence of postoperative complications. Processed EEG information that is available to the anesthesiologist is affected by the age-induced changes of the raw EEG. While most of these methods indicate a "more awake" patient with age, the permutation entropy (PeEn) has been proposed as an age-independent measure. In this article, we show that PeEn is also influenced by age, independent of parameter settings. Methods: We retrospectively analyzed the EEG of more than 300 patients, recorded during steady state anesthesia without stimulation, and calculated the PeEn for different embedding dimensions m that was applied to the EEG filtered to a wide variety of frequency ranges. We constructed linear models to evaluate the relationship between age and PeEn. To compare our results to published studies, we also performed a stepwise dichotomization and used non-parametric tests and effect sizes for pairwise comparisons. Results: We found a significant influence of age on PeEn for all settings except for narrow band EEG activity. The analysis of the dichotomized data also revealed significant differences between old and young patients for the PeEn settings used in published studies. Conclusion: Based on our findings, we could show the influence of age on PeEn. This result was independent of parameter, sample rate, and filter settings. Hence, age should be taken into consideration when using PeEn to monitor patient EEG.

Performance of the SEDLine Monitor: Age Dependency and Time Delay.

BACKGROUND: Devices monitoring the hypnotic component of general anesthesia can help to guide anesthetic management. The main purposes of these devices are the titration of anesthesia dose. While anesthesia at low doses can result in awareness with intraoperative memory formation, excessive administration of anesthetics may be associated with an increased risk of postoperative neurocognitive disorder. We have previously shown for various indices that they are significantly influenced by the patient's age and that the monitors have a significant time delay. Here, we evaluated the influence of patient's age and time delay on the patient state index (PSI) of the SEDLine monitor. METHODS: To analyze the influence of the patient's age, we replayed 2 minutes of electroencephalography (EEG) of 141 patients (19-88 years, ASA I-IV) undergoing general anesthesia maintained with desflurane, sevoflurane, or propofol to the SEDLine monitor. We extracted the PSI as well as the spectral edge frequency (SEF) and performed a linear regression analysis. For evaluation of the time delay, we replayed 5 minutes of EEG of stable episodes of adequate anesthesia (PSI between 25 and 50) or light sedation/wake (PSI >70) in different orders to the SEDLine to simulate sudden changes between the states. Time delays were defined as the required time span of the monitor to reach the stable target index. RESULTS: PSI and SEF increased significantly with the patient's age. These findings did not depend on the administered anesthetic. The evaluation of the correlation between SEF and PSI showed a strong correlation with Spearman's correlation coefficient of ρ = 0.86 (0.82; 0.89). The time delays depended on the type of transition. We found a median time delay of 54 (Min: 46; Max: 61) seconds for the important transition between adequate anesthesia and awake and 55 (Min: 50; Max: 67) seconds in the other direction. CONCLUSIONS: With our analyses, we show that the indices presented on the SEDLine display, the PSI and the SEF, increase with age for patients under general anesthesia. Additionally, a delay of the PSI to react to sudden neurophysiologic changes due to dose of the maintenance anesthetic is of a time course that is clinically significant. These factors should be considered when navigating anesthesia relying on only the proprietary index for the SEDLine monitor.

Unwanted spontaneous responsiveness and burst suppression in patients undergoing entropy-guided total intravenous anesthesia with target-controlled infusion: An observational prospective trial.

STUDY OBJECTIVE: To estimate the incidence of unwanted spontaneous responsiveness and burst suppression (BSupp) in patients undergoing state entropy (SE) and surgical pleth index (SPI)-guided total intravenous anesthesia (TIVA) with target-controlled infusion (TCI). DESIGN: Observational, prospective, single-center study. SETTINGS: Operating room. PATIENTS: 107 adult (<65 years) and elderly (≥65 years) women undergoing breast surgery. INTERVENTIONS: Propofol-remifentanil TIVA-TCI-guided by SE for depth of anesthesia monitoring (target value 40-60) and SPI for antinociception monitoring (target value 20-50) without neuromuscular blockade. MEASUREMENTS: Age; body mass index; American Society of Anesthesiologists physical status classification; concentration at the effect site of propofol (CeP) and remifentanil (CeR) at loss of responsiveness (LoR), median during anesthesia maintenance (MdM), and at return of responsiveness (RoR); propofol infusion duration; incidence of postoperative delirium (POD) with Confusing Assessment Method for the Intensive Care Unit. MAIN RESULTS: During SE-SPI-guided TIVA-TCI, 13.1% of patients showed unwanted spontaneous responsiveness, whereas 45.8% showed BSupp. Unwanted spontaneous responsiveness was observed mainly in adults (p < 0.05), and higher CeP RoR (p < 0.05) was registered. BSupp was observed mainly in patients showing a lower CeP MdM (p < 0.01) and CeP RoR (p < 0.05). Unwanted spontaneous responsiveness and BSupp were not associated with significant differences in CeRs. An age-related hysteresis effect was observed, resulting in higher CeP LoR than CeP RoR (p < 0.001). 12.2% of patients showed POD. Only preoperative serum albumin was associated with increased likelihood of POD (p = 0.046). CONCLUSIONS: The SE-SPI-guided TIVA-TCI did not prevent unwanted spontaneous responsiveness and BSupp. CeP RoR may be used as a proxy for anesthetic sensitivity.

The absence of dominant alpha-oscillatory EEG activity during emergence from delta-dominant anesthesia predicts neurocognitive impairment- results from a prospective observational trial.

STUDY OBJECTIVE: Postoperative neurocognitive disorders (PND) are common complications after surgery under general anesthesia. In our aging society the incidence of PND will increase. Hence, interdisciplinary efforts should be taken to minimize the occurrence of PND. Electroencephalographic (EEG) monitoring of brain activity during anesthesia or emergence from anesthesia is a promising tool to identify patients at risk. We therefore investigated whether we could identify specific EEG signatures during emergence of anesthesia that are associated with the occurrence of PND. DESIGN AND PATIENTS: We performed a prospective observational investigation on 116 patients to evaluate the EEG features during emergence from general anesthesia dominated by slow delta waves in patients with and without delirium in the postoperative care unit (PACU-D) as assessed by the CAM-ICU and the RASS. MAIN RESULTS: During emergence both the frontal and global EEG of patients with PACU-D were significantly different from patients without PACU-D. PACU-D patients had lower relative alpha power and reduced fronto-parietal alpha coherence. CONCLUSIONS: With our analysis we show differences in EEG features associated with anesthesia emergence in patients with and without PACU-D. Frontal and global EEG alpha-band features could help to identify patients with PACU-D. CLINICAL TRIAL NUMBER: NCT03287401.

Changes in medical students´ and anesthesia technician trainees´ attitudes towards interprofessionality - experience from an interprofessional simulation-based course.

BACKGROUND: Interprofessional simulation based education (IPSBE) programs positively impact participants' attitudes towards interprofessional collaboration and learning. However, the extent to which students in different health professions benefit and the underlying reasons for this are subject of ongoing debate. METHODS: We developed a 14-h IPSBE course with scenarios of critical incidents or emergency cases. Participants were final year medical students (FYMS) and final year anesthesia technician trainees (FYATT). To assess attitudes towards interprofessionalism, the University of the West of England Interprofessional Questionnaire was administrated before and after the course. Using focus group illustration maps, qualitative data were obtained from a subcohort of the participants (n = 15). RESULTS: After the course, self-assessment of communication and teamwork skills, attitudes towards interprofessional interactions and relationships showed comparative improvement in both professions. Attitudes towards interprofessional learning improved only in FYMS. Qualitative data revealed teamwork, communication, hierarchy and the perception of one's own and other health profession as main topics that might underlie the changes in participants' attitudes. An important factor was that participants got to know each other during the course and understood each other's tasks. CONCLUSIONS: Since adequate communication and teamwork skills and positive attitudes towards interprofessionality account to effective interprofessional collaboration, our data support intensifying IPSBE in undergraduate health care education.

Sedative Properties of Dexmedetomidine Are Mediated Independently from Native Thalamic Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function at Clinically Relevant Concentrations.

Dexmedetomidine is a selective α2-adrenoceptor agonist and appears to disinhibit endogenous sleep-promoting pathways, as well as to attenuate noradrenergic excitation. Recent evidence suggests that dexmedetomidine might also directly inhibit hyperpolarization-activated cyclic-nucleotide gated (HCN) channels. We analyzed the effects of dexmedetomidine on native HCN channel function in thalamocortical relay neurons of the ventrobasal complex of the thalamus from mice, performing whole-cell patch-clamp recordings. Over a clinically relevant range of concentrations (1-10 µM), the effects of dexmedetomidine were modest. At a concentration of 10 µM, dexmedetomidine significantly reduced maximal Ih amplitude (relative reduction: 0.86 [0.78-0.91], n = 10, and p = 0.021), yet changes to the half-maximal activation potential V1/2 occurred exclusively in the presence of the very high concentration of 100 µM (-4,7 [-7.5--4.0] mV, n = 10, and p = 0.009). Coincidentally, only the very high concentration of 100 µM induced a significant deceleration of the fast component of the HCN activation time course (τfast: +135.1 [+64.7-+151.3] ms, n = 10, and p = 0.002). With the exception of significantly increasing the membrane input resistance (starting at 10 µM), dexmedetomidine did not affect biophysical membrane properties and HCN channel-mediated parameters of neuronal excitability. Hence, the sedative qualities of dexmedetomidine and its effect on the thalamocortical network are not decisively shaped by direct inhibition of HCN channel function.

s-ketamine enhances thalamocortical and corticocortical synaptic transmission in acute murine brain slices via increased AMPA-receptor-mediated pathways.

Despite ongoing research efforts and routine clinical use, the neuronal mechanisms underlying the anesthesia-induced loss of consciousness are still under debate. Unlike most anesthetics, ketamine increases thalamic and cortical activity. Ketamine is considered to act via a NMDA-receptor antagonism-mediated reduction of inhibition, i.e., disinhibition. Intact interactions between the thalamus and cortex constitute a prerequisite for the maintenance of consciousness and are thus a promising target for anesthetics to induce loss of consciousness. In this study, we aim to characterize the influence of s-ketamine on the thalamocortical network using acute brain-slice preparation. We performed whole-cell patch-clamp recordings from pyramidal neurons in cortical lamina IV and thalamocortical relay neurons in acute brain slices from CB57BL/6N mice. Excitatory postsynaptic potentials (EPSPs) were obtained via electrical stimulation of the cortex with a bipolar electrode that was positioned to lamina II/III (electrically induced EPSPs, eEPSPs) or via optogenetic activation of thalamocortical relay neurons (optogenetically induced EPSPs, oEPSPs). Intrinsic neuronal properties (like resting membrane potential, membrane threshold for action potential generation, input resistance, and tonic action potential frequency), as well as NMDA-receptor-dependent and independent spontaneous GABAA-receptor-mediated inhibitory postsynaptic currents (sIPSCs) were evaluated. Wilcoxon signed-rank test (level of significance < 0.05) served as a statistical test and Cohen's U3_1 was used to determine the actual effect size. Within 20 min, s-ketamine (5 µM) significantly increased both intracortical eEPSPs as well as thalamocortical oEPSPs. NMDA-receptor-mediated intracortical eEPSPs were significantly reduced. Intrinsic neuronal properties of cortical pyramidal neurons from lamina IV and thalamocortical relay neurons in the ventrobasal thalamic complex were not substantially affected. Neither a significant effect on NMDA-receptor-dependent GABAA sIPSCs (thought to underly a disinhibitory effect) nor a reduction of NMDA-receptor independent GABAA sIPSCs was observed. Both thalamocortical and intracortical AMPA-receptor-mediated EPSPs were significantly increased.In conclusion, our findings show no evidence for a NMDA-receptor antagonism-based disinhibition, but rather suggest an enhanced thalamocortical and intracortical synaptic transmission, which appears to be driven via increased AMPA-receptor-mediated transmission.

The Strength of Alpha Oscillations in the Electroencephalogram Differently Affects Algorithms Used for Anesthesia Monitoring.

BACKGROUND: Intraoperative patient monitoring using the electroencephalogram (EEG) can help to adequately adjust the anesthetic level. Therefore, the processed EEG (pEEG) provides the anesthesiologist with the estimated anesthesia level. The commonly used approaches track the changes from a fast- and a low-amplitude EEG during wakefulness to a slow- and a high-amplitude EEG under general anesthesia. However, besides these changes, another EEG feature, a strong oscillatory activity in the alpha band (8-12 Hz), develops in the frontal EEG. Strong alpha-band activity during general anesthesia seems to reflect an appropriate anesthetic level for certain anesthetics, but the way the common pEEG approaches react to changes in the alpha-band activity is not well explained. Hence, we investigated the impact of an artificial alpha-band modulation on pEEG approaches used in anesthesia research. METHODS: We performed our analyses based on 30 seconds of simulated sedation (n = 25) EEG, simulated anesthesia (n = 25) EEG, and EEG episodes from 20 patients extracted from a steady state that showed a clearly identifiable alpha peak in the density spectral array (DSA) and a state entropy (GE Healthcare) around 50, indicative of adequate anesthesia. From these traces, we isolated the alpha activity by band-pass filtering (8-12 Hz) and added this alpha activity to or subtracted it from the signals in a stepwise manner. For each of the original and modified signals, the following pEEG values were calculated: (1) spectral edge frequency (SEF95), (2) beta ratio, (3) spectral entropy (SpEntr), (4) approximate entropy (ApEn), and (5) permutation entropy (PeEn). RESULTS: The pEEG approaches showed different reactions to the alpha-band modification that depended on the data set and the amplification step. The beta ratio and PeEn decreased with increasing alpha activity for all data sets, indicating a deepening of anesthesia. The other pEEG approaches behaved nonuniformly. SEF95, SpEntr, and ApEn decreased with increasing alpha for the simulated anesthesia data (arousal) but decreased for simulated sedation. For the patient EEG, ApEn indicated an arousal, and SEF95 and SpEntr showed a nonuniform change. CONCLUSIONS: Changes in the alpha-band activity lead to different reactions for different pEEG approaches. Hence, the presence of strong oscillatory alpha activity that reflects an adequate level of anesthesia may be interpreted differently, by an either increasing (arousal) or decreasing (deepening) pEEG value. This could complicate anesthesia navigation and prevent the adjustment to an adequate, alpha-dominant anesthesia level, when titrating by the pEEG values.

The influence of age on EEG-based anaesthesia indices.

STUDY OBJECTIVE: In the upcoming years there will be a growing number of elderly patients requiring general anaesthesia. As age is an independent risk factor for postoperative delirium (POD) the incidence of POD will increase concordantly. One approach to reduce the risk of POD would be to avoid excessively high doses of anaesthetics by using neuromonitoring to guide anaesthesia titration. Therefore, we evaluated the influence of patient's age on various electroencephalogram (EEG)-based anaesthesia indices. DESIGN AND PATIENTS: We conducted an analysis of previously published data by replaying single electrode EEG episodes of maintenance of general anaesthesia from 180 patients (18-90 years; ASA I-IV) into the five different commercially available monitoring systems and evaluated their indices. We included the State/Response Entropy, Narcotrend, qCON/qNOX, bispectral index (BIS), and Treaton MGA-06. For a non-commercial comparison, we extracted the spectral edge frequency (SEF) from the BIS. To evaluate the influence of the age we generated linear regression models. We also assessed the correlation between the various indices. MAIN RESULTS: During anaesthetic maintenance the values of the SEF, State/Response Entropy, qCON/qNOX and BIS all significantly increased (0.05 Hz/0.19-0.26 index points per year) with the patient's age (p < 0.001); whereas the Narcotrend did not change significantly with age (0.06 index points per year; p = 0.28). The index values of the Treaton device significantly decreased with age (-0.09 index points per year; p < 0.001). These findings were independent of the administered dose of anaesthetics. CONCLUSIONS: Almost all current neuromonitoring devices are influenced by age, with the potential to result in inappropriately high dosage of anaesthetics. Therefore, anaesthesiologists should be aware of this phenomenon, and the next generation of monitors should correct for these changes.

Age-Related EEG Features of Bursting Activity During Anesthetic-Induced Burst Suppression.

Electroencephalographic (EEG) Burst Suppression (BSUPP) is a discontinuous pattern characterized by episodes of low voltage disrupted by bursts of cortical synaptic activity. It can occur while delivering high-dose anesthesia. Current research suggests an association between BSUPP and the occurrence of postoperative delirium in the post-anesthesia care unit (PACU) and beyond. We investigated burst micro-architecture to further understand how age influences the neurophysiology of this pharmacologically-induced state. We analyzed a subset of EEG recordings (n = 102) taken from a larger data set previously published. We selected the initial burst that followed a visually identified "silent second," i.e., at least 1 s of iso-electricity of the EEG during propofol induction. We derived the (normalized) power spectral density [(n)PSD], the alpha band power, the maximum amplitude, the maximum slope of the EEG as well as the permutation entropy (PeEn) for the first 1.5 s of the initial burst of each patient. In the old patients >65 years, we observed significantly lower (p < 0.001) EEG power in the 1-15 Hz range. In general, their EEG contained a significantly higher amount of faster oscillations (>15 Hz). Alpha band power (p < 0.001), EEG amplitude (p = 0.001), and maximum EEG slope (p = 0.045) all significantly decreased with age, whereas PeEn increased (p = 0.008). Hence, we can describe an age-related change in features during EEG burst suppression. Sub-group analysis revealed no change in results based on pre-medication. These EEG changes add knowledge to the impact of age on cortical synaptic activity. In addition to a reduction in EEG amplitude, age-associated burst features can complicate the identification of excessive anesthetic administration in patients under general anesthesia. Knowledge of these neurophysiologic changes may not only improve anesthesia care through improved detection of burst suppression but might also provide insight into changes in neuronal network organization in patients at risk for age-related neurocognitive problems.

Attenuation of Native Hyperpolarization-Activated, Cyclic Nucleotide-Gated Channel Function by the Volatile Anesthetic Sevoflurane in Mouse Thalamocortical Relay Neurons.

As thalamocortical relay neurons are ascribed a crucial role in signal propagation and information processing, they have attracted considerable attention as potential targets for anesthetic modulation. In this study, we analyzed the effects of different concentrations of sevoflurane on the excitability of thalamocortical relay neurons and hyperpolarization-activated, cyclic-nucleotide gated (HCN) channels, which play a decisive role in regulating membrane properties and rhythmic oscillatory activity. The effects of sevoflurane on single-cell excitability and native HCN channels were investigated in acutely prepared brain slices from adult wild-type mice with the whole-cell patch-clamp technique, using voltage-clamp and current-clamp protocols. Sevoflurane dose-dependently depressed membrane biophysics and HCN-mediated parameters of neuronal excitability. Respective half-maximal inhibitory and effective concentrations ranged between 0.30 (95% CI, 0.18-0.50) mM and 0.88 (95% CI, 0.40-2.20) mM. We witnessed a pronounced reduction of HCN dependent Ih current amplitude starting at a concentration of 0.45 mM [relative change at -133 mV; 0.45 mM sevoflurane: 0.85 (interquartile range, 0.79-0.92), n = 12, p = 0.011; 1.47 mM sevoflurane: 0.37 (interquartile range, 0.34-0.62), n = 5, p < 0.001] with a half-maximal inhibitory concentration of 0.88 (95% CI, 0.40-2.20) mM. In contrast, effects on voltage-dependent channel gating were modest with significant changes only occurring at 1.47 mM [absolute change of half-maximal activation potential; 1.47 mM: -7.2 (interquartile range, -10.3 to -5.8) mV, n = 5, p = 0.020]. In this study, we demonstrate that sevoflurane inhibits the excitability of thalamocortical relay neurons in a concentration-dependent manner within a clinically relevant range. Especially concerning its effects on native HCN channel function, our findings indicate substance-specific differences in comparison to other anesthetic agents. Considering the importance of HCN channels, the observed effects might mechanistically contribute to the hypnotic properties of sevoflurane.

The anaesthetic xenon partially restores an amyloid beta-induced impairment in murine hippocampal synaptic plasticity.

BACKGROUND: It is controversially discussed whether general anaesthesia increases the risk of Alzheimer's disease (AD) or accelerates its progression. One important factor in AD pathogenesis is the accumulation of soluble amyloid beta (Aß) oligomers which affect N-methyl-d-aspartate (NMDA) receptor function and abolish hippocampal long-term potentiation (LTP). NMDA receptor antagonists, at concentrations allowing physiological activation, can prevent Aß-induced deficits in LTP. The anaesthetics xenon and S-ketamine both act as NMDA receptor antagonists and have been reported to be neuroprotective. In this study, we investigated the effects of subanaesthetic concentrations of these drugs on LTP deficits induced by different Aß oligomers and compared them to the effects of radiprodil, a NMDA subunit 2B (GluN2B)-selective antagonist. METHODS: We applied different Aß oligomers to murine brain slices and recorded excitatory postsynaptic field potentials before and after high-frequency stimulation in the CA1 region of hippocampus. Radiprodil, xenon and S-ketamine were added and recordings evoked from a second input were measured. RESULTS: Xenon and radiprodil, applied at low concentrations, partially restored the LTP deficit induced by pre-incubated Aß1-42. S-ketamine showed no effect. None of the drugs tested were able to ameliorate Aß1-40-induced LTP-deficits. CONCLUSIONS: Xenon administered at subanaesthetic concentrations partially restored Aß1-42-induced impairment of LTP, presumably via its weak NMDA receptor antagonism. The effects were in a similar range than those obtained with the NMDA-GluN2B antagonist radiprodil. Our results point to protective properties of xenon in the context of pathological distorted synaptic physiology which might be a meaningful alternative for anaesthesia in AD patients.

Modulation of frontal EEG alpha oscillations during maintenance and emergence phases of general anaesthesia to improve early neurocognitive recovery in older patients: protocol for a randomised controlled trial.

BACKGROUND: Postoperative delirium may manifest in the immediate post-anaesthesia care period. Such episodes appear to be predictive of further episodes of inpatient delirium and associated adverse outcomes. Frontal electroencephalogram (EEG) findings of suppression patterns and low proprietary index values have been associated with postoperative delirium and poor outcomes. However, the efficacy of titrating anaesthesia to proprietary index targets for preventing delirium remains contentious. We aim to assess the efficacy of two strategies which we hypothesise could prevent post-anaesthesia care unit (PACU) delirium by maximising the alpha oscillation observed in frontal EEG channels during the maintenance and emergence phases of anaesthesia. METHODS: This is a 2 × 2 factorial, double-blind, stratified, randomised control trial of 600 patients. Eligible patients are those aged 60 years or over who are undergoing non-cardiac, non-intracranial, volatile-based anaesthesia of expected duration of more than 2 h. Patients will be stratified by pre-operative cognitive status, surgery type and site. For the maintenance phase of anaesthesia, patients will be randomised (1:1) to an alpha power-maximisation anaesthesia titration strategy versus standard care avoiding suppression patterns in the EEG. For the emergence phase of anaesthesia, patients will be randomised (1:1) to early cessation of volatile anaesthesia and emergence from an intravenous infusion of propofol versus standard emergence from volatile anaesthesia only. The primary study outcomes are the power of the frontal alpha oscillation during the maintenance and emergence phases of anaesthesia. Our main clinical outcome of interest is PACU delirium. DISCUSSION: This is a largely exploratory study; the extent to which EEG signatures can be modified by titration of pharmacological agents is not known. The underlying concept is maximisation of anaesthetic efficacy by individualised drug titration to a clearly defined EEG feature. The interventions are already clinically used strategies in anaesthetic practice, but have not been formally evaluated. The addition of propofol during the emergence phase of volatile-based general anaesthesia is known to reduce emergence delirium in children; however, the efficacy of this strategy in older patients is not known. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry, ID: 12617001354370 . Registered on 27/09/2017.

Substance-Specific Differences in Human Electroencephalographic Burst Suppression Patterns.

Different anesthetic agents induce burst suppression in the electroencephalogram (EEG) at very deep levels of general anesthesia. EEG burst suppression has been identified to be a risk factor for postoperative delirium (POD). EEG based automated detection algorithms are used to detect burst suppression patterns during general anesthesia and a burst suppression ratio (BSR) is calculated. Unfortunately, applied algorithms do not give information as precisely as suggested, often resulting in an underestimation of the patients' burst suppression level. Additional knowledge of substance-specific burst suppression patterns could be of great importance to improve the ability of EEG based monitors to detect burst suppression. In a re-analysis of EEG recordings obtained from a previous study, we analyzed EEG data of 45 patients undergoing elective surgery under general anesthesia. The patients were anesthetized with sevoflurane, isoflurane or propofol (n = 15, for each group). After skin incision, the used agent was titrated to a level when burst suppression occurred. In a visual analysis of the EEG, blinded to the used anesthetic agent, we included the first distinct burst in our analysis. To avoid bias through changing EEG dynamics throughout the burst, we only focused on the first 2 s of the burst. These episodes were analyzed using the power spectral density (PSD) and normalized PSD, the absolute burst amplitude and absolute burst slope, as well as permutation entropy (PeEn). Our results show significant substance-specific differences in the architecture of the burst. Volatile-induced bursts showed higher burst amplitudes and higher burst power. Propofol-induced bursts had significantly higher relative power in the EEG alpha-range. Further, isoflurane-induced bursts had the steepest burst slopes. We can present the first systematic comparison of substance-specific burst characteristics during anesthesia. Previous observations, mostly derived from animal studies, pointing out the substance-specific differences in bursting behavior, concur with our findings. Our findings of substance-specific EEG characteristics can provide information to help improve automated burst suppression detection in monitoring devices. More specific detection of burst suppression may be helpful to reduce excessive EEG effects of anesthesia and therefore the incidence of adverse outcomes such as POD.

Tranexamic acid impairs hippocampal synaptic transmission mediated by gamma aminobutyric acid receptor type A.

High-dose application of tranexamic acid (TXA), a widely used antifibrinolytic drug, can cause seizures in patients undergoing surgery. Mechanistically, seizures are considered to arise from an imbalance between inhibitory and excitatory synaptic transmission, whose main transmitters are gamma-aminobutyric acid (GABA) and glutamate. In the present study, we investigated the effects of TXA on neuronal excitability and synaptic transmission in the hippocampus, a structure that plays a pivotal role in human epilepsy. In acute slices of the murine hippocampus, fast depolarization-mediated imaging signals (FDSs) and postsynaptic currents (PSCs) were recorded using voltage-sensitive dye imaging and whole-cell patch clamp technique, respectively. FDSs and PSCs were evoked upon stimulation of the dentate gyrus and Schaffer collateral/associational commissural pathway, respectively. GABAA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and N-methyl-d-aspartate (NMDA) receptor-mediated postsynaptic currents were isolated pharmacologically. Application of TXA enhanced FDS propagation in the hippocampus. Neither the resting membrane potential of the investigated neurones nor synaptic transmission mediated by AMPA or NMDA receptors was changed by the application of 1mM TXA. In contrast, TXA dose-dependently reduced GABAA receptor-mediated synaptic transmission. TXA induced the inhibition of GABAA receptor-mediated synaptic transmission in the hippocampus with a potency similar to that of its antagonistic properties against GABAA receptors in the basolateral amygdala (Kratzer et al., 2014). Since impairment of GABAergic transmission is a major cause of epileptic seizures, the observed effect might contribute to the proconvulsive properties of TXA.