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.

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.

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.

Determination of Krogh Coefficient for Oxygen Consumption Measurement from Thin Slices of Rodent Cortical Tissue Using a Fick's Law Model of Diffusion.

To investigate the impact of experimental interventions on living biological tissue, ex vivo rodent brain slices are often used as a more controllable alternative to a live animal model. However, for meaningful results, the biological sample must be known to be healthy and viable. One of the gold-standard approaches to identifying tissue viability status is to measure the rate of tissue oxygen consumption under specific controlled conditions. Here, we work with thin (400 µm) slices of mouse cortical brain tissue which are sustained by a steady flow of oxygenated artificial cerebralspinal fluid (aCSF) at room temperature. To quantify tissue oxygen consumption (Q), we measure oxygen partial pressure (pO2) as a function of probe depth. The curvature of the obtained parabolic (or parabola-like) pO2 profiles can be used to extract Q, providing one knows the Krogh coefficient Kt, for the tissue. The oxygen trends are well described by a Fick's law diffusion-consumption model developed by Ivanova and Simeonov, and expressed in terms of ratio (Q/K), being the rate of oxygen consumption in tissue divided by the Krogh coefficient (oxygen diffusivity × oxygen solubility) for tissue. If the fluid immediately adjacent to the tissue can be assumed to be stationary (i.e., nonflowing), one may invoke conservation of oxygen flux K·(∂P/∂x) across the interface to deduce (Kt/Kf), the ratio of Krogh coefficients for tissue and fluid. Using published interpolation formulas for the effect of salt content and temperature on oxygen diffusivity and solubility for pure water, we estimate Kf, the Krogh coefficient for aCSF, and hence deduce the Kt coefficient for tissue. We distinguish experimental uncertainty from natural biological variability by using pairs of repeated profiles at the same tissue location. We report a dimensionless Krogh ratio (Kt/Kf)=0.562±0.088 (mean ± SD), corresponding to a Krogh coefficient Kt=(1.29±0.21)×10-14 mol/(m·s·Pa) for mouse cortical tissue at room temperature, but acknowledge the experimental limitation of being unable to verify that the fluid boundary layer is truly stationary. We compare our results with those reported in the literature, and comment on the challenges and ambiguities caused by the extensive use of 'biologically convenient' non-SI units for tissue Krogh coefficient.

Brain Complexities and Anesthesia: Their Meaning and Measurement.

SUMMARY: A complex system is often associated with emergence of new phenomena from the interactions between the system's components. General anesthesia reduces brain complexity and so inhibits the emergence of consciousness. An understanding of complexity is necessary for the interpretation of brain monitoring algorithms. Complexity indices capture the "difficulty" of understanding brain activity over time and/or space. Complexity-entropy plots reveal the types of complexity indices and their balance of randomness and structure. Lempel-Ziv complexity is a common index of temporal complexity for single-channel electroencephalogram containing both power spectral and nonlinear effects, revealed by phase-randomized surrogate data. Computing spatial complexities involves forming a connectivity matrix and calculating the complexity of connectivity patterns. Spatiotemporal complexity can be estimated in multiple ways including temporal or spatial concatenation, estimation of state switching, or integrated information. This article illustrates the concept and application of various complexities by providing working examples; a website with interactive demonstrations has also been created.

Propofol-induced Unresponsiveness Is Associated with a Brain Network Phase Transition.

BACKGROUND: The wakeful brain can easily access and coordinate a large repertoire of different states-dynamics suggestive of "criticality." Anesthesia causes loss of criticality at the level of electroencephalogram waveforms, but the criticality of brain network connectivity is less well studied. The authors hypothesized that propofol anesthesia is associated with abrupt and divergent changes in brain network connectivity for different frequencies and time scales-characteristic of a phase transition, a signature of loss of criticality. METHODS: As part of a previously reported study, 16 volunteers were given propofol in slowly increasing brain concentrations, and their behavioral responsiveness was assessed. The network dynamics from 31-channel electroencephalogram data were calculated from 1 to 20 Hz using four phase and envelope amplitude-based functional connectivity metrics that covered a wide range of time scales from milliseconds to minutes. The authors calculated network global efficiency, clustering coefficient, and statistical complexity (using the Jensen-Shannon divergence) for each functional connectivity metric and compared their findings with those from an in silico Kuramoto network model. RESULTS: The transition to anesthesia was associated with critical slowing and then abrupt profound decreases in global network efficiency of 2 Hz power envelope metrics (from mean ± SD of 0.64 ± 0.15 to 0.29 ± 0.28 absolute value, P < 0.001, for medium; and from 0.47 ± 0.13 to 0.24 ± 0.21, P < 0.001, for long time scales) but with an increase in global network efficiency for 10 Hz weighted phase lag index (from 0.30 ± 0.20 to 0.72 ± 0.06, P < 0.001). Network complexity decreased for both the 10 Hz hypersynchronous (0.44 ± 0.13 to 0.23 ± 0.08, P < 0.001), and the 2 Hz asynchronous (0.73 ± 0.08 to 0.40 ± 0.13, P < 0.001) network states. These patterns of network coupling were consistent with those of the Kuramoto model of an order-disorder phase transition. CONCLUSIONS: Around loss of behavioral responsiveness, a small increase in propofol concentrations caused a collapse of long time scale power envelope connectivity and an increase in 10 Hz phase-based connectivity-suggestive of a brain network phase transition.

Comment on Mankowska et al. Critical Flicker Fusion Frequency: A Narrative Review. Medicina 2021, 57, 1096.

We have read with great interest the review by Mankowska et al. [...].

An Electroencephalogram Metric of Temporal Complexity Tracks Psychometric Impairment Caused by Low-dose Nitrous Oxide.

BACKGROUND: Nitrous oxide produces non-γ-aminobutyric acid sedation and psychometric impairment and can be used as scientific model for understanding mechanisms of progressive cognitive disturbances. Temporal complexity of the electroencephalogram may be a sensitive indicator of these effects. This study measured psychometric performance and the temporal complexity of the electroencephalogram in participants breathing low-dose nitrous oxide. METHODS: In random order, 20, 30, and 40% end-tidal nitrous oxide was administered to 12 participants while recording 32-channel electroencephalogram and psychometric function. A novel metric quantifying the spatial distribution of temporal electroencephalogram complexity, comprised of (1) absolute cross-correlation calculated between consecutive 0.25-s time samples; 2) binarizing these cross-correlation matrices using the median of all channels as threshold; (3) using quantitative recurrence analysis, the complexity in temporal changes calculated by the Shannon entropy of the probability distribution of the diagonal line lengths; and (4) overall spatial extent and intensity of brain complexity, was quantified by calculating median temporal complexity of channels whose complexities were above 1 at baseline. This region approximately overlay the brain's default mode network, so this summary statistic was termed "default-mode-network complexity." RESULTS: Nitrous oxide concentration correlated with psychometric impairment (r = 0.50, P < 0.001). Baseline regional electroencephalogram complexity at midline was greater than in lateral temporal channels (1.33 ± 0.14 bits vs. 0.81 ± 0.12 bits, P < 0.001). A dose of 40% N2O decreased midline (mean difference [95% CI], 0.20 bits [0.09 to 0.31], P = 0.002) and prefrontal electroencephalogram complexity (mean difference [95% CI], 0.17 bits [0.08 to 0.27], P = 0.002). The lateral temporal region did not change significantly (mean difference [95% CI], 0.14 bits [-0.03 to 0.30], P = 0.100). Default-mode-network complexity correlated with N2O concentration (r = -0.55, P < 0.001). A default-mode-network complexity mixed-effects model correlated with psychometric impairment (r2 = 0.67; receiver operating characteristic area [95% CI], 0.72 [0.59 to 0.85], P < 0.001). CONCLUSIONS: Temporal complexity decreased most markedly in medial cortical regions during low-dose nitrous oxide exposures, and this change tracked psychometric impairment.

Application of a benchtop colorimetric method for quantification of blood propofol levels.

Quantification of plasma propofol (2,6-diisopropylphenol) in the context of clinical anaesthesia is challenging because of the need for offline blood sample processing using specialised laboratory equipment and techniques. In this study we sought to refine a simple procedure using solid phase extraction and colorimetric analysis into a benchtop protocol for accurate blood propofol measurement. The colorimetric method based on the reaction of phenols (e.g. propofol) with Gibbs reagent was first tested in 10% methanol samples (n = 50) containing 0.5-6.0 µg/mL propofol. Subsequently, whole blood samples (n = 15) were spiked to known propofol concentrations and processed using reverse phase solid phase extraction (SPE) and colorimetric analysis. The standard deviation of the difference between known and measured propofol concentrations in the methanol samples was 0.11 µg/mL, with limits of agreement of - 0.21 to 0.22 µg/mL. For the blood-processed samples, the standard deviation of the difference between known and measured propofol concentrations was 0.09 µg/mL, with limits of agreement - 0.18 to 0.17 µg/mL. Quantification of plasma propofol with an error of less than 0.2 µg/mL is achievable with a simple and inexpensive benchtop method.

An Introduction to Causal Diagrams for Anesthesiology Research.

Making good decisions in the era of Big Data requires a sophisticated approach to causality. We are acutely aware that association ≠ causation, yet untangling the two remains one of our greatest challenges. This realization has stimulated a Causal Revolution in epidemiology, and the lessons learned are highly relevant to anesthesia research. This article introduces readers to directed acyclic graphs; a cornerstone of modern causal inference techniques. These diagrams provide a robust framework to address sources of bias and discover causal effects. We use the topical question of whether anesthetic technique (total intravenous anesthesia vs. volatile) affects outcome after cancer surgery as a basis for a series of example directed acyclic graphs, which demonstrate how variables can be chosen to statistically control confounding and other sources of bias. We also illustrate how controlling for the wrong variables can introduce, rather than eliminate, bias; and how directed acyclic graphs can help us diagnose this problem.This is a rapidly evolving field, and we cover only the most basic elements. The true promise of these techniques is that it may become possible to make robust statements about causation from observational studies-without the expense and artificiality of randomized controlled trials.

Granger Causality of the Electroencephalogram Reveals Abrupt Global Loss of Cortical Information Flow during Propofol-induced Loss of Responsiveness.

BACKGROUND: It is a commonly held view that information flow between widely separated regions of the cerebral cortex is a necessary component in the generation of wakefulness (also termed "connected" consciousness). This study therefore hypothesized that loss of wakefulness caused by propofol anesthesia should be associated with loss of information flow, as estimated by the effective connectivity in the scalp electroencephalogram (EEG) signal. METHODS: Effective connectivity during anesthesia was quantified by applying bivariate Granger to multichannel EEG data recorded from 16 adult subjects undergoing a slow induction of, and emergence from, anesthesia with intravenous propofol. During wakefulness they were conducting various auditory and motor tasks. Functional connectivity using EEG coherence was also estimated. RESULTS: There was an abrupt, substantial, and global decrease in effective connectivity around the point of loss of responsiveness. Recovery of behavioral responsiveness was associated with a comparable recovery in information flow pattern (expressed as normalized values). The median (interquartile range) change was greatest in the delta frequency band: decreasing from 0.15 (0.21) 2 min before loss of behavioral response, to 0.06 (0.04) 2 min after loss of behavioral response (P < 0.001). Regional decreases in information flow were maximal in a posteromedial direction from lateral frontal and prefrontal regions (0.82 [0.24] 2 min before loss of responsiveness, decreasing to 0.17 [0.05] 2 min after), and least for information flow from posterior channels. The widespread decrease in bivariate Granger causality reflects loss of cortical coordination. The relationship between functional connectivity (coherence) and effective connectivity (Granger causality) was inconsistent. CONCLUSIONS: Propofol-induced unresponsiveness is marked by a global decrease in information flow, greatest from the lateral frontal and prefrontal brain regions in a posterior and medial direction. Loss of information flow may be a useful measure of connected consciousness.

Information Integration and Mesoscopic Cortical Connectivity during Propofol Anesthesia.

BACKGROUND: The neurophysiologic mechanisms of propofol-induced loss of consciousness have been studied in detail at the macro (scalp electroencephalogram) and micro (spiking or local field potential) scales. However, the changes in information integration and cortical connectivity during propofol anesthesia at the mesoscopic level (the cortical scale) are less clear. METHODS: The authors analyzed electrocorticogram data recorded from surgical patients during propofol-induced unconsciousness (n = 9). A new information measure, genuine permutation cross mutual information, was used to analyze how electrocorticogram cross-electrode coupling changed with electrode-distances in different brain areas (within the frontal, parietal, and temporal regions, as well as between the temporal and parietal regions). The changes in cortical networks during anesthesia-at nodal and global levels-were investigated using clustering coefficient, path length, and nodal efficiency measures. RESULTS: In all cortical regions, and in both wakeful and unconscious states (early and late), the genuine permutation cross mutual information and the percentage of genuine connections decreased with increasing distance, especially up to about 3 cm. The nodal cortical network metrics (the nodal clustering coefficients and nodal efficiency) decreased from wakefulness to unconscious state in the cortical regions we analyzed. In contrast, the global cortical network metrics slightly increased in the early unconscious state (the time span from loss of consciousness to 200 s after loss of consciousness), as compared with wakefulness (normalized average clustering coefficient: 1.05 ± 0.01 vs. 1.06 ± 0.03, P = 0.037; normalized average path length: 1.02 ± 0.01 vs. 1.04 ± 0.01, P = 0.021). CONCLUSIONS: The genuine permutation cross mutual information reflected propofol-induced coupling changes measured at a cortical scale. Loss of consciousness was associated with a redistribution of the pattern of information integration; losing efficient global information transmission capacity but increasing local functional segregation in the cortical network.

Continuing professional development module : An updated introduction to electroencephalogram-based brain monitoring during intended general anesthesia.

The electroencephalogram (EEG) provides a reliable reflection of the brain's electrical state, so it can reassure us that the anesthetic agents are actually reaching the patient's brain, and are having the desired effect. In most patients, the EEG changes somewhat predictably in response to propofol and volatile agents, so a frontal EEG channel can guide avoidance of insufficient and excessive administration of general anesthesia. Persistent alpha-spindles (around 10 Hz) phase-amplitude coupled with slow delta waves (around 1 Hz) are commonly seen during an "appropriate hypnotic state of general anesthesia". Such patterns can be appreciated from the EEG waveform or from the spectrogram (a colour-coded display of how the power in the various EEG frequencies changes with time). Nevertheless, there are exceptions to this. For example, administration of ketamine and nitrous oxide is generally not associated with the aforementioned alpha-spindle coupled with delta wave pattern. Also, some patients, including older adults and those with neurodegenerative disorders, are less predisposed to generate a strong electroencephalographic "alpha-spindle" pattern during general anesthesia. There might also be some rare instances when the frontal EEG shows a pattern suggestive of general anesthesia, while the patient has some awareness and is able to follow simple commands, albeit this is typically without obvious distress or memory formation. Thus, the frontal EEG alone, as currently analyzed, is an imperfect but clinically useful mirror, and more scientific insights will be needed before we can claim to have a reliable readout of brain "function" during general anesthesia.

RéSUMé: L'électroencéphalogramme (EEG) procure une image fiable de l'état électrique du cerveau, de telle sorte qu'il peut nous rassurer que les agents anesthésiques atteignent bien le cerveau du patient et ont l'effet désiré. Chez la plupart des patients, le tracé de l'EEG change de façon relativement prévisible en réponse au propofol et aux agents volatils; ainsi, une analyse d'EEG frontal peut prévenir l'administration insuffisante ou excessive d'anesthésique générale. Pendant « un état hypnotique adéquat de l'anesthésie générale ¼, on remarquera fréquemment une phase-amplitude de fuseaux alpha (alpha-spindles phase amplitude) (d'environ 10 Hz) couplée à des ondes lentes delta (d'environ 1 Hz). De tels tracés peuvent être observés à partir de l'EEG ou sur un spectrogramme (un affichage par code couleur de la façon dont la puissance dans les diverses fréquences d'EEG se modifie au fil du temps). Toutefois, il existe des exceptions. Par exemple, l'administration de kétamine et de protoxyde d'azote n'est généralement pas associée au tracé de fréquence alpha couplé à l'onde delta susmentionné. En outre, certains patients, notamment des personnes plus âgées et les personnes souffrant de maladies neurodégénératives, sont moins prédisposés à générer un fort tracé électroencéphalographique de 'fréquence alpha' pendant une anesthésie générale. Dans de rares cas, le tracé de l'EEG frontal pourrait évoquer une anesthésie générale alors que le patient est encore quelque peu conscient et capable de suivre des ordres simples, mais ces situations surviennent habituellement sans détresse ni rétention de mémoire évidente. Par conséquent, l'EEG frontal seul tel qu'il est analysé à l'heure actuelle est un miroir clinique utile mais imparfait, et des recherches scientifiques seront nécessaires avant de pouvoir affirmer que nous disposons d'une mesure fiable de la « fonction ¼ cérébrale pendant l'anesthésie générale.

A Metabolic Mechanism for Anaesthetic Suppression of Cortical Synaptic Function in Mouse Brain Slices-A Pilot Investigation.

Regulation of synaptically located ionotropic receptors is thought to be the main mechanism by which anaesthetics cause unconsciousness. An alternative explanation, which has received much less attention, is that of primary anaesthetic disruption of brain metabolism via suppression of mitochondrial proteins. In this pilot study in mouse cortical slices, we investigated the effect of disrupting cellular metabolism on tissue oxygen handling and cortical population seizure-like event (SLE) activity, using the mitochondrial complex I inhibitor rotenone, and compared this to the effects of the general anaesthetics sevoflurane, propofol and ketamine. Rotenone caused an increase in tissue oxygen (98 mmHg to 157 mmHg (p < 0.01)) before any measurable change in SLE activity. Thereafter, tissue oxygen continued to increase and was accompanied by a significant and prolonged reduction in SLE root mean square (RMS) activity (baseline RMS of 1.7 to 0.7 µV, p < 0.001) and SLE frequency (baseline 4.2 to 0.4 events/min, p = 0.001). This temporal sequence of effects was replicated by all three anaesthetic drugs. In conclusion, anaesthetics with differing synaptic receptor mechanisms all effect changes in tissue oxygen handling and cortical network activity, consistent with a common inhibitory effect on mitochondrial function. The temporal sequence suggests that the observed synaptic depression-as seen in anaesthesia-may be secondary to a reduction in cellular metabolic capacity.

Genetic Analysis of Patients Who Experienced Awareness with Recall while under General Anesthesia.

BACKGROUND: Intraoperative awareness with recall while under apparently adequate general anesthesia is a rare, unexplained, and often very distressing phenomenon. It is possible that a relatively small number of genetic variants might underlie the failure of general anesthetic drugs to adequately suppress explicit memory formation and recall in the presence of apparently adequate anesthesia concentrations. METHODS: The authors recruited 12 adult patients who had experienced an episode of intraoperative awareness with recall (compared with 12 controls), performed whole exome sequencing, and applied filtering to obtain a set of genetic variants that might be associated with intraoperative awareness with recall. The criteria were that the variant (1) had a minor allele frequency less than 0.1% in population databases, (2) was within exonic or splicing regions, (3) caused a nonsynonymous change, (4) was predicted to be functionally damaging, (5) was expressed in the top 50% of genes expressed in the brain, and (6) was within genes in Kyoto Encyclopedia of Genes and Genomes pathways associated with general anesthesia, drug metabolism, arousal, and memory. RESULTS: The authors identified 29 rare genetic variants in 27 genes that were absent in controls and could plausibly be associated with this disorder. One variant in CACNA1A was identified in two patients and two different variants were identified in both CACNA1A and CACNA1S. Of interest was the relative overrepresentation of variants in genes encoding calcium channels and purinergic receptors. CONCLUSIONS: Within the constraints of the filtering process used, the authors did not find any single gene variant or gene that was strongly associated with intraoperative awareness with recall. The authors report 27 candidate genes and associated pathways identified in this pilot project as targets of interest for future larger biologic and epidemiologic studies.

Transient electroencephalographic alpha power loss during maintenance of general anaesthesia.

BACKGROUND: EEG activity in the extended alpha frequency range (7-17 Hz) during maintenance of general anaesthesia is primarily determined by effect-site concentrations of the hypnotic and analgesic drugs used. Intermittent alpha loss during surgery, unexplained by changes in anaesthetic or opioid concentrations, could represent arousal of the cortex as a result of increased surgical stimulation. METHODS: A generalised linear model was fitted to alpha power recorded from patients undergoing general anaesthesia from induction until waking using three explanatory variables: age-adjusted volatile anaesthetic effect-site concentration, and estimated effect-site propofol and opioid concentrations. Model residuals were decomposed into uncorrelated white noise and a fluctuating auto-correlated trend. Deviations of this local trend were classified as 'unexpected alpha dropout events'. To investigate whether these alpha dropouts might be explained by the effect of noxious stimulation, we related their occurrence to whether a patient was undergoing surgery involving the body cavity or not. RESULTS: Alpha power dropouts occurred in 73 of the 237 patients included in the final analysis (31%, median amplitude of -3.5 dB, duration=103 s). They showed a bimodal or broadly skewed distribution, being more probable soon after initial incision (32%), dropping to around 10% at 1 h, and then again increasing to >30% in operations lasting >3 h. Multivariate analysis showed that alpha dropouts were significantly associated with body cavity surgery (P=0.003) and with longer operations (P<0.001). CONCLUSIONS: A loss of alpha power, unexplained by changes in anaesthetic or opioid concentrations, is suggestive of thalamocortical depolarisation induced by body cavity noxious stimuli, and could provide a measure of nociception during surgery.

Non-sinusoidal waves in the EEG and their simulated effect on anaesthetic quantitative EEG monitors.

The effect of anaesthetic drugs on the cortex are commonly estimated from the electroencephalogram (EEG) by quantitative EEG monitors such as the Bispectral Index (BIS). These monitors use ratios of high to low frequency power which assumes that each neurological process contributes a unique frequency pattern. However, recent research of the effect of deep brain stimulation on EEG beta oscillations suggests that wave shape, a non-sinusoidal feature that is only measurable in the time-domain, can change the frequency 'signature' of a neurological rhythmical process by the inclusion or removal of harmonic frequencies. If wave shape variations are present in the EEG of anaesthetised patients, then quantitative EEG monitors likely overestimate the anaesthetic drug effect. The purpose of this paper is to investigate alpha-wave shape in the EEG of anaesthetised patients and demonstrate the effect of wave shape on the frequency ratios that are commonly utilised in the BIS quantitative EEG monitor. EEG data, demographic information, and surgery details were collected prospectively from 305 patients undergoing a general anaesthetic for elective surgery. Alpha-wave shape was categorised by triangularity of the EEG extrema, a measure of how peaked (towards a sawtooth wave) or flat (towards a square wave) the extremum was. The alpha-wave was then artificially modified to either a sawtooth wave or square wave, and BetaRatio and PowerFastSlow metrics calculated. Age was found to be the only significant predictor of alpha wave triangularity. The artificially modified square-alpha waves increased the power in the frequency spectrum at 26 Hz by 1-5 dB, and increased the BetaRatio by 0.7. The alpha-wave of anaesthetised patients contains non-sinusoidal components which likely impact depth of anaesthesia calculations.