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.

Effect of Propofol on Heart Rate and Its Coupling to Cortical Slow Waves in Humans.

BACKGROUND: Propofol causes significant cardiovascular depression and a slowing of neurophysiological activity. However, literature on its effect on the heart rate remains mixed, and it is not known whether cortical slow waves are related to cardiac activity in propofol anesthesia. METHODS: The authors performed a secondary analysis of electrocardiographic and electroencephalographic data collected as part of a previously published study where n = 16 healthy volunteers underwent a slow infusion of propofol up to an estimated effect-site concentration of 4 µg/ml. Heart rate, heart rate variability, and individual slow electroencephalographic waves were extracted for each subject. Timing between slow-wave start and the preceding R-wave was tested against a uniform random surrogate. Heart rate data were further examined as a post hoc analysis in n = 96 members of an American Society of Anesthesiologists Physical Status II/III older clinical population collected as part of the AlphaMax trial. RESULTS: The slow propofol infusion increased the heart rate in a dose-dependent manner (mean ± SD, increase of +4.2 ± 1.5 beats/min/[µg ml-1]; P < 0.001). The effect was smaller but still significant in the older clinical population. In healthy volunteers, propofol decreased the electrocardiogram R-wave amplitude (median [25th to 75th percentile], decrease of -83 [-245 to -28] µV; P < 0.001). Heart rate variability showed a loss of high-frequency parasympathetic activity. Individual cortical slow waves were coupled to the heartbeat. Heartbeat incidence peaked about 450 ms before slow-wave onset, and mean slow-wave frequency correlated with mean heart rate. CONCLUSIONS: The authors observed a robust increase in heart rate with increasing propofol concentrations in healthy volunteers and patients. This was likely due to decreased parasympathetic cardioinhibition. Similar to non-rapid eye movement sleep, cortical slow waves are coupled to the cardiac rhythm, perhaps due to a common brainstem generator.

Changes in Intra- and Cross-Hemispheric Directed Functional Connectivity in the Electroencephalographic Signals during Propofol-Induced Loss of Consciousness.

BACKGROUND: Numerous, sometimes conflicting, changes in brain functional connectivity have been associated with the transition from wakefulness to unresponsiveness at induction of general anesthesia. However, relatively few studies have looked at: the detailed time evolution of the transition; for different EEG frequency bands; and in the clinical scenario of surgical patients undergoing general anesthesia. METHODS: We investigated the changes in the frontal and fronto-parietal directed and undirected functional connectivity to multichannel EEG data recorded from 29 adult male surgical patients undergoing propofol-induced loss of consciousness during induction of anesthesia. Directed functional connectivity was estimated using bivariate frequency domain Granger causality, and undirected connectivity was assessed using EEG coherence. RESULTS: Around the point of loss of consciousness: local frontal, interhemispheric frontal, and frontoparietal feedback and feedforward Granger causality all decreased between 31% and 51.5% in the delta-band (median [interquartile range] for local frontal: 0.14 [0.08, 0.27] to 0.08 [0.06, 0.12] (p=0.02)). After a lag of a few minutes, Granger Causality markedly increased in the gamma and beta bands for local frontal (0.03 [0.02, 0.07] to 0.09 [0.07, 0.11](p<0.001)) and long-distance cross-hemispheric frontoparietal feedback (0.02 [0.01, 0.04] to 0.07 [0.04, 0.09], p<0.001) and feedforward (0.02 [0.01, 0.04] to 0.03 [0.03, 0.04], p=0.01) coupling; but not for within-hemispheric frontoparietal feedback and feedforward. Frontal interhemispheric EEG coherence significantly decreased in the lower frequencies (f<12Hz) at loss of consciousness, while no significant increase for the beta and gamma bands was observed. CONCLUSIONS: Propofol-induced loss of consciousness in surgical patients is associated with a global breakdown in low-frequency directed functional connectivity, coupled with a high-frequency increase between closely located brain regions. At loss of consciousness, Granger causality shows more pronounced changes than coherence.

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.

Electroencephalographic signatures of consciousness: uncovering the fake news.

Amongst electroencephalographic markers of anaesthetic-induced unresponsiveness, those that estimate loss of frontoparietal functional connectivity detect loss of sensory perceptual connection with the outside world, rather than full phenomenological unconsciousness. This transition to unconsciousness is manifest as further incremental changes in indices of electroencephalographic complexity.

Support-vector classification of low-dose nitrous oxide administration with multi-channel EEG power spectra.

Support-vector machines (SVMs) can potentially improve patient monitoring during nitrous oxide anaesthesia. By elucidating the effects of low-dose nitrous oxide on the power spectra of multi-channel EEG recordings, we quantified the degree to which these effects generalise across participants. In this single-blind, cross-over study, 32-channel EEG was recorded from 12 healthy participants exposed to 0, 20, 30 and 40% end-tidal nitrous oxide. Features of the delta-, theta-, alpha- and beta-band power were used within a 12-fold, participant-wise cross-validation framework to train and test two SVMs: (1) binary SVM classifying EEG during 0 or 40% exposure (chance = 50%); (2) multi-class SVM classifying EEG during 0, 20, 30 or 40% exposure (chance = 25%). Both the binary (accuracy 92%) and the multi-class (accuracy 52%) SVMs classified EEG recordings at rates significantly better than chance (p < 0.001 and p = 0.01, respectively). To determine the relative importance of frequency band features for classification accuracy, we systematically removed features before re-training and re-testing the SVMs. This showed the relative importance of decreased delta power and the frontal region. SVM classification identified that the most important effects of nitrous oxide were found in the delta band in the frontal electrodes that was consistent between participants. Furthermore, support-vector classification of nitrous oxide dosage is a promising method that might be used to improve patient monitoring during nitrous oxide anaesthesia.

Encapsulation Dynamics of Neuromuscular Blocking Drugs by Sugammadex.

BACKGROUND: The clinical actions of sugammadex have been well studied, but the detailed molecular mechanism of the drug encapsulation process has not been systematically documented. The hypothesis was that sugammadex would attract rocuronium and vecuronium via interaction with the sugammadex side-chain "tentacles," as previously suggested. METHODS: Computational molecular dynamics simulations were done to investigate docking of sugammadex with rocuronium and vecuronium. To validate these methods, strength of binding was assessed between sugammadex and a heterogeneous group of nine other drugs, the binding affinities of which have been experimentally determined. These observations hinted that high concentrations of unbound sugammadex could bind to propofol, potentially altering its pharmacokinetic profile. This was tested experimentally in in vitro cortical slices. RESULTS: Sugammadex encapsulation of rocuronium involved a sequential progression down a series of metastable states. After initially binding beside the sugammadex molecule (mean ± SD center-of-mass distance = 1.17 ± 0.13 nm), rocuronium then moved to the opposite side to that hypothesized, where it optimally aligned with the 16 hydroxyl groups (distance, 0.82 ± 0.04 nm) before entering the sugammadex cavity to achieve energetically stable encapsulation by approximately 120 ns (distance, 0.35 ± 0.12 nm). Vecuronium formed fewer hydrogen bonds with sugammadex than did rocuronium; hence, it was less avidly bound. For the other molecules, the computational results showed good agreement with the available experimental data, showing a clear bilogarithmic relation between the relative binding free energy and the association constant (R2 = 0.98). Weaker binding was manifest by periodic unbinding. The brain slice results confirmed the presence of a weak propofol-sugammadex interaction. CONCLUSIONS: Computational simulations demonstrate the dynamics of neuromuscular blocking drug encapsulation by sugammadex occurring from the opposite direction to that hypothesized and also how high concentrations of unbound sugammadex can potentially weakly bind to other drugs given during general anesthesia.

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.

The art of chasing numbers in titration of anaesthetic dose.

There is no difference in between-patient variability of concentrations when comparing propofol and sevoflurane titrated to a bispectral index of 40-60. There is about a 300% variation in hypnotic concentration between the bottom 5% and top 5% of the population. Anaesthesia titration cannot be based solely on measured or estimated drug concentrations.

Five commercial 'depth of anaesthesia' monitors provide discordant clinical recommendations in response to identical emergence-like EEG signals.

BACKGROUND: 'Depth of anaesthesia' monitors claim to measure hypnotic depth during general anaesthesia from the EEG, and clinicians could reasonably expect agreement between monitors if presented with the same EEG signal. We took 52 EEG signals showing intraoperative patterns of diminished anaesthesia, similar to those that occur during emergence (after surgery) and subjected them to analysis by five commercially available monitors. METHODS: We compared five monitors (BIS, Entropy-SE, Narcotrend, qCON, and Sedline) to see if index values remained within, or moved out of, each monitors' recommended index range for general anaesthesia for at least 2 min during a period of supposed lighter anaesthesia, as observed by changes in the EEG spectrogram obtained in a previous study. RESULTS: Of the 52 cases, 27 (52%) had at least one monitor warning of potentially inadequate hypnosis (index above range) and 16 of the 52 cases (31%) had at least one monitor signifying excessive hypnotic depth (index below clinical range). Of the 52 cases, only 16 (31%) showed concordance between all five monitors. Nineteen cases (36%) had one monitor discordant compared with the remaining four, and 17 cases (33%) had two monitors in disagreement with the remaining three. CONCLUSIONS: Many clinical providers still rely on index values and manufacturer's recommended ranges for titration decision making. That two-thirds of cases showed discordant recommendations given identical EEG data, and that one-third signified excessive hypnotic depth where the EEG would suggest a lighter hypnotic state, emphasizes the importance of personalised EEG interpretation as an essential clinical skill.