Publications by authors named "Matthias Kreuzer"

49 Publications

The influence of age on EEG-based anaesthesia indices.

J Clin Anesth 2021 May 8;73:110325. Epub 2021 May 8.

Department of Anesthesiology and Intensive Care Medicine, Technical University of Munich, School of Medicine, Munich, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jclinane.2021.110325DOI Listing
May 2021

Altered sleep behavior in a genetic mouse model of impaired fear extinction.

Sci Rep 2021 Apr 26;11(1):8978. Epub 2021 Apr 26.

Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, University of Innsbruck, Innsbruck, Austria.

Sleep disturbances are a common complaint of anxiety patients and constitute a hallmark feature of post-traumatic stress disorder (PTSD). Emerging evidence suggests that poor sleep is not only a secondary symptom of anxiety- and trauma-related disorders but represents a risk factor in their development, for example by interfering with emotional memory processing. Fear extinction is a critical mechanism for the attenuation of fearful and traumatic memories and multiple studies suggest that healthy sleep is crucial for the formation of extinction memories. However, fear extinction is often impaired in anxiety- and trauma-related disorders-an endophenotype that is perfectly modelled in the 129S1/SvImJ inbred mouse strain. To investigate whether these mice exhibit altered sleep at baseline that could predispose them towards maladaptive fear processing, we compared their circadian sleep/wake patterns to those of typically extinction-competent C57BL/6 mice. We found significant differences regarding diurnal distribution of sleep and wakefulness, but also sleep architecture, spectral features and sleep spindle events. With regard to sleep disturbances reported by anxiety- and PTSD patients, our findings strengthen the 129S1/SvImJ mouse models' face validity and highlight it as a platform to investigate novel, sleep-focused diagnostic and therapeutic strategies. Whether the identified alterations causally contribute to its pathological anxiety/PTSD-like phenotype will, however, have to be addressed in future studies.
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http://dx.doi.org/10.1038/s41598-021-88475-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076259PMC
April 2021

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

Front Cell Neurosci 2020 21;14:606687. Epub 2021 Jan 21.

Department of Anesthesiology and Intensive Care Medicine, Technical University of Munich School of Medicine, Munich, Germany.

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 I 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), = 12, = 0.011; 1.47 mM sevoflurane: 0.37 (interquartile range, 0.34-0.62), = 5, < 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, = 5, = 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.
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http://dx.doi.org/10.3389/fncel.2020.606687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858256PMC
January 2021

Effects of noxious stimulation on the electroencephalogram during general anaesthesia: a narrative review and approach to analgesic titration.

Br J Anaesth 2021 02;126(2):445-457

Department of Anaesthesiology, Waikato Clinical School, University of Auckland, Hamilton, New Zealand.

Electroencephalographic (EEG) activity is used to monitor the neurophysiology of the brain, which is a target organ of general anaesthesia. Besides its use in evaluating hypnotic states, neurophysiologic reactions to noxious stimulation can also be observed in the EEG. Recognising and understanding these responses could help optimise intraoperative analgesic management. This review describes three types of changes in the EEG induced by noxious stimulation when the patient is under general anaesthesia: (1) beta arousal, (2) (paradoxical) delta arousal, and (3) alpha dropout. Beta arousal is an increase in EEG power in the beta-frequency band (12-25 Hz) in response to noxious stimulation, especially at lower doses of anaesthesia drugs in the absence of opioids. It is usually indicative of a cortical depolarisation and increased cortical activity. At higher concentrations of anaesthetic drug, and with insufficient opioids, delta arousal (increased power in the delta band [0.5-4 Hz]) and alpha dropout (decreased alpha power [8-12 Hz]) are associated with noxious stimuli. The mechanisms of delta arousal are not well understood, but the midbrain reticular formation seems to play a role. Alpha dropout may indicate a return of thalamocortical communication, from an idling mode to an operational mode. Each of these EEG changes reflect an incomplete modulation of pain signals and can be mitigated by administration of opioid or the use of regional anaesthesia techniques. Future studies should evaluate whether titrating analgesic drugs in response to these EEG signals reduces postoperative pain and influences other postoperative outcomes, including the potential development of chronic pain.
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http://dx.doi.org/10.1016/j.bja.2020.10.036DOI Listing
February 2021

Age influences on Propofol estimated brain concentration and entropy during maintenance and at return of consciousness during total intravenous anesthesia with target-controlled infusion in unparalyzed patients: An observational prospective trial.

PLoS One 2020 22;15(12):e0244145. Epub 2020 Dec 22.

Department of Medicine-DIMED, Section of Anesthesiology and Intensive Care, University of Padova, Padova, Italy.

Purpose: Aging affects pharmacodynamics/pharmacokinetics of anesthetics, but age effects on Entropy-guided total intravenous anesthesia with target-controlled infusions (TIVA-TCI) are not fully characterized. We compared aging effects on effective estimated brain concentration of Propofol (CeP) during TIVA-TCI Entropy-guided anesthesia, without neuromuscular blockade (NMB).

Methods: We performed an observational, prospective, single-center study enrolling 75 adult women undergoing Entropy-guided Propofol-Remifentanil TIVA-TCI for breast surgery. Primary endpoint was the relationship between age and CeP at maintenance of anesthesia (MA) during Entropy-guided anesthesia. Secondary endpoints were relationships between age and CeP at arousal reaction (AR), return of consciousness (ROC) and explicit recall evenience. We calculated a linear model to evaluate the age's impact on observational variable and performed pairwise tests to compare old (≥65 years, n = 50) and young (<65 years, n = 25) patients or patients with and without an AR.

Results: We did not observe age-related differences in CeP during MA, but CeP significantly (p = 0,01) decreased with age at ROC. Entropy values during MA increased with age and were significantly higher in the elderly (RE: median 56[IQR49.3-61] vs 47.5[42-52.5],p = 0.001; SE: 51.6[45-55.5] vs 44[IQR40-50],p = 0.005). 18 patients had an AR, having higher maximum RE (92.5[78-96.3] vs 65[56.5-80.5],p<0.001), SE (79[64.8-84] vs 61[52.5-69],p = 0.03, RE-SE (12.5[9.5-16.5] vs 6 [3-9],p<0.001.

Conclusion: Older age was associated with lower CeP at ROC, but not during MA in unparalysed patients undergoing breast surgery. Although RE and SE during MA, at comparable CeP, were higher in the elderly, Entropy, and in particular an increasing RE-SE, is a reliable index to detect an AR.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244145PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755218PMC
March 2021

Application of Referencing Techniques in EEG-Based Recordings of Contact Heat Evoked Potentials (CHEPS).

Front Hum Neurosci 2020 2;14:559969. Epub 2020 Dec 2.

Institute of Clinical Pharmacology, Goethe University, Frankfurt am Main, Germany.

Evoked potentials in the amplitude-time spectrum of the electroencephalogram are commonly used to assess the extent of brain responses to stimulation with noxious contact heat. The magnitude of the - and -waves are used as a semi-objective measure of the response to the painful stimulus: the higher the magnitude, the more painful the stimulus has been perceived. The strength of the --wave response is also largely dependent on the chosen reference electrode site. The goal of this study was to examine which reference technique excels both in practical and theoretical terms when analyzing noxious contact heat evoked potentials (CHEPS) in the amplitude-time spectrum. We recruited 21 subjects (10 male, 11 female, mean age of 55.79 years). We applied seven noxious contact heat stimuli using two temperatures, 51°C, and 54°C, to each subject. During EEG analysis, we aimed to identify the referencing technique which produces the highest -wave and -wave amplitudes with as little artifactual influence as possible. For this purpose, we applied the following six referencing techniques: mathematically linked A1/A2 (earlobes), average reference, REST, AFz, Pz, and mathematically linked PO7/PO8. We evaluated how these techniques impact the - amplitudes of CHEPS based on our data from healthy subjects. Considering all factors, we found that mathematically linked earlobes to be the ideal referencing site to use when displaying and evaluating CHEPS in the amplitude-time spectrum.
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http://dx.doi.org/10.3389/fnhum.2020.559969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738344PMC
December 2020

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

Front Syst Neurosci 2020 3;14:599962. Epub 2020 Dec 3.

Department of Anesthesiology and Intensive Care Medicine, School of Medicine, Technical University Munich, Munich, Germany.

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 ( = 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 ( < 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 ( < 0.001), EEG amplitude ( = 0.001), and maximum EEG slope ( = 0.045) all significantly decreased with age, whereas PeEn increased ( = 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.
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http://dx.doi.org/10.3389/fnsys.2020.599962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744408PMC
December 2020

Sleep/Wake Behavior and EEG Signatures of the TgF344-AD Rat Model at the Prodromal Stage.

Int J Mol Sci 2020 Dec 5;21(23). Epub 2020 Dec 5.

Department of Anesthesiology, Emory University, Atlanta, GA 30322, USA.

Transgenic modification of the two most common genes (APPsw, PS1ΔE9) related to familial Alzheimer's disease (AD) in rats has produced a rodent model that develops pathognomonic signs of AD without genetic tau-protein modification. We used 17-month-old AD rats ( = 8) and age-matched controls (AC, = 7) to evaluate differences in sleep behavior and EEG features during wakefulness (WAKE), non-rapid eye movement sleep (NREM), and rapid eye movement sleep (REM) over 24-h EEG recording (12:12h dark-light cycle). We discovered that AD rats had more sleep-wake transitions and an increased probability of shorter REM and NREM bouts. AD rats also expressed a more uniform distribution of the relative spectral power. Through analysis of information content in the EEG using entropy of difference, AD animals demonstrated less EEG information during WAKE, but more information during NREM. This seems to indicate a limited range of changes in EEG activity that could be caused by an AD-induced change in inhibitory network function as reflected by increased GABAAR-β2 expression but no increase in GAD-67 in AD animals. In conclusion, this transgenic rat model of Alzheimer's disease demonstrates less obvious EEG features of WAKE during wakefulness and less canonical features of sleep during sleep.
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http://dx.doi.org/10.3390/ijms21239290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730237PMC
December 2020

State entropy and burst suppression ratio can show contradictory information: A retrospective study.

Eur J Anaesthesiol 2020 Dec;37(12):1084-1092

From the Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Anaesthesiology and Intensive Care, Munich, Germany (M-G, S-P, G-S, M-K).

Background: Burst suppression is a characteristic electroencephalographic (EEG) pattern that reflects very deep levels of general anaesthesia and may correlate with increased risk of adverse outcomes such as postoperative delirium. EEG-based monitors such as the Entropy Module estimate the level of anaesthesia (state entropy) and provide another index reflecting the occurrence of burst suppression, that is the ratio of burst and suppression (BSR). In the Entropy Module, state entropy and BSR are not interconnected, as they are in the bispectral index (BIS). Hence, state entropy and BSR may provide contradicting information regarding the level of anaesthesia.

Objectives: We aimed to describe the frequency and characteristics of contradicting state entropy and BSR and to present possible strategies of how to act in these situations.

Methods: We based our analyses on state entropy and BSR trend recordings from 2551 patients older than 59 years that showed BSR was > 0 throughout their intervention under general anaesthesia. We determined the maximum state entropy when BSR was > 0, the minimum state entropy with BSR = 0 and the duration of high state entropy with BSR > 0. Further, we selected four exemplar patients to present details of how state entropy and BSR can contradict each other during anaesthesia.

Results: We observed a wide range of state entropy values with BSR > 0. The median [IQR] of the maximum state entropy with BSR > 0 was 53 [45 to 61] and the median of the minimum state entropy without BSR was 21 [15 to 26]. Contradictory BSR and state entropy could persist over several minutes. The presented cases highlight these contradictory BSR and state entropy situations.

Conclusions: Our results illustrate contradictory state entropy and BSR indices that may be relevant for anaesthesia navigation. Longer-lasting episodes may lead to incorrect titration of the depth of the hypnotic component of anaesthesia. Hence, our results demonstrate the necessity to monitor and check the raw EEG or EEG parameters that are less processed than the commercially available indices to safely navigate anaesthesia.
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http://dx.doi.org/10.1097/EJA.0000000000001312DOI Listing
December 2020

Propofol Affects Cortico-Hippocampal Interactions via β3 Subunit-Containing GABA Receptors.

Int J Mol Sci 2020 Aug 14;21(16). Epub 2020 Aug 14.

Department of Anaesthesiology, Experimental Anaesthesiology Section, Eberhard-Karls-University, Waldhörnlestrasse 22, 72072 Tübingen, Germany.

Background: General anesthetics depress neuronal activity. The depression and uncoupling of cortico-hippocampal activity may contribute to anesthetic-induced amnesia. However, the molecular targets involved in this process are not fully characterized. GABA receptors, especially the type with β3 subunits, represent a main molecular target of propofol. We therefore hypothesized that GABA receptors with β3 subunits mediate the propofol-induced disturbance of cortico-hippocampal interactions.

Methods: We used local field potential (LFP) recordings from chronically implanted cortical and hippocampal electrodes in wild-type and β3(N265M) knock-in mice. In the β3(N265M) mice, the action of propofol via β3subunit containing GABA receptors is strongly attenuated. The analytical approach contained spectral power, phase locking, and mutual information analyses in the 2-16 Hz range to investigate propofol-induced effects on cortico-hippocampal interactions.

Results: Propofol caused a significant increase in spectral power between 14 and 16 Hz in the cortex and hippocampus of wild-type mice. This increase was absent in the β3(N265M) mutant. Propofol strongly decreased phase locking of 6-12 Hz oscillations in wild-type mice. This decrease was attenuated in the β3(N265M) mutant. Finally, propofol reduced the mutual information between 6-16 Hz in wild-type mice, but only between 6 and 8 Hz in the β3(N265M) mutant.

Conclusions: GABA receptors containing β3 subunits contribute to frequency-specific perturbation of cortico-hippocampal interactions. This likely explains some of the amnestic actions of propofol.
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http://dx.doi.org/10.3390/ijms21165844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461501PMC
August 2020

Technical considerations when using the EEG export of the SEDLine Root device.

J Clin Monit Comput 2020 Aug 19. Epub 2020 Aug 19.

Department of Anesthesiology and Intensive Care, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

Electroencephalographic (EEG) patient monitoring during general anesthesia can help to assess the real-time neurophysiology of unconscious states. Some monitoring systems like the SEDLine Root allow export of the EEG to be used for retrospective analysis. We show that changes made to the SEDLine display during recording affected the recorded EEG. These changes can strongly impact retrospective analysis of EEG signals. Real-time changes of the feed speed in the SEDLine Root device display modifies the sampling rate of the exported EEG. We used a patient as well as a simulated EEG recording to highlight the effects of the display settings on the extracted EEG. Therefore, we changed EEG feed and amplitude resolution on the display in a systematic manner. To visualize the effects of these changes, we present raw EEG segments and the density spectral array of the recording. Changing the display's amplitude resolution affects the amplitudes. If the amplitude resolution is too fine, the exported EEG contains clipped amplitudes. If the resolution is too coarse, the EEG resolution becomes too low leading to a low-quality signal making frequency analysis impossible. The proportion of clipped or zero-line data caused by the amplitude setting was > 60% in our sedated patient. Changing the display settings results in undocumented changes in EEG amplitude, sampling rate, and signal quality. The occult nature of these changes could make the analysis of data sets difficult if not invalid. We strongly suggest researchers adequately define and keep the EEG display settings to export good quality EEG and to ensure comparability among patients.
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http://dx.doi.org/10.1007/s10877-020-00578-9DOI Listing
August 2020

Clinical implications of using non-invasive haemoglobin monitoring for red blood cell transfusion decision in hip arthroplasty.

Transfus Apher Sci 2020 Aug 26;59(4):102770. Epub 2020 Apr 26.

Department of Anesthesia, Unidade Local de Saúde de Matosinhos - Hospital Pedro Hispano, Matosinhos, Portugal. Electronic address:

Introduction: The decision to transfuse red blood cells requires accurate haemoglobin concentration values. In this study, we evaluated if continuous non-invasive haemoglobin (SpHb) measurement could substitute laboratory determined haemoglobin (LabHb) in patients undergoing elective hip replacement. As secondary objective, we analyzed the trend of the difference between techniques.

Materials/methods: LabHb measurements were done using an automated analyser and SpHb measurements were acquired using Radical-7®. In randomly selected patients undergoing hip replacement, whenever blood was collected for LabHb, concomitant SpHb was recorded. Correlation, bias and accuracy of SpHb were calculated in comparison with LabHb.

Results: 108 paired measurements were obtained from 43 patients. The Pearson R of the correlation between SpHb and LabHb was 0.7 (p < 0.001). Bland-Altman test revealed a bias of 1 ± 1.4 g dL, meaning Lab Hb was recurrently higher than SpHb. Limits of agreement were [-1.7; 3.8]. Considering RBC transfusion threshold of 8 g dL, we found that in two situations transfusion decision would differ based on the measurement considered. Trending ability of SpHb study showed a significant difference between preoperative and postoperative LabHb-SpHb.

Discussion: There was a good correlation between SpHb and LabHb, while bias and limits of agreement were higher than those in literature. There was a limited trending ability of SpHb during the perioperative period. Despite this, using SpHb instead of LabHb for decision making regarding transfusion would only change the decision in 1.9 % of our cases. Our findings suggest that this device could be used as a reference but cannot replace venous puncture as gold standard.
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http://dx.doi.org/10.1016/j.transci.2020.102770DOI Listing
August 2020

Intraoperative electroencephalographic burst suppression may help to identify patients at risk for long-term adverse outcome: Findings from a case of homozygous twins.

Anaesth Crit Care Pain Med 2020 10 4;39(5):629-630. Epub 2020 Apr 4.

Department of Medicine, Anaesthesiology and Intensive Care, University of Padova, Via V. Gallucci, 13, 35121, Padova, Italy.

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http://dx.doi.org/10.1016/j.accpm.2019.12.012DOI Listing
October 2020

Of Parachutes, Speedometers, and EEG: What Evidence Do We Need to Use Devices and Monitors?

Anesth Analg 2020 05;130(5):1274-1277

Department of Anesthesiology and Intensive Care, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

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http://dx.doi.org/10.1213/ANE.0000000000004653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735682PMC
May 2020

Spectral and Entropic Features Are Altered by Age in the Electroencephalogram in Patients under Sevoflurane Anesthesia.

Anesthesiology 2020 05;132(5):1003-1016

From the Department of Anaesthesiology and Intensive Care, Klinikum rechts der Isar, Technical University Munich, Munich, Germany (M.K., S.B., G.S.) the Department of Anesthesiology (M.K., M.A.S., P.S.G.) the Medical Scientist Training Program (M.A.S.), Emory University School of Medicine, Atlanta, Georgia the Anesthesiology and Research Divisions, Atlanta Veterans Affairs Medical Center, (M.K., M.A.S., P.S.G.) Atlanta, Georgia the Department of Anaesthesia, Waikato Clinical School, University of Auckland, Hamilton, New Zealand (D.H., J.W.S.) the Waikato District Health Board, Hamilton, New Zealand (D.H., J.W.S.) the Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.H.) the Department of Anesthesiology, Columbia University Irving Medical Center, New York, New York (P.S.G.).

Background: Preexisting factors such as age and cognitive performance can influence the electroencephalogram (EEG) during general anesthesia. Specifically, spectral EEG power is lower in elderly, compared to younger, subjects. Here, the authors investigate age-related changes in EEG architecture in patients undergoing general anesthesia through a detailed examination of spectral and entropic measures.

Methods: The authors retrospectively studied 180 frontal EEG recordings from patients undergoing general anesthesia, induced with propofol/fentanyl and maintained by sevoflurane at the Waikato Hospital in Hamilton, New Zealand. The authors calculated power spectral density and normalized power spectral density, the entropic measures approximate and permutation entropy, as well as the beta ratio and spectral entropy as exemplary parameters used in current monitoring systems from segments of EEG obtained before the onset of surgery (i.e., with no noxious stimulation).

Results: The oldest quartile of patients had significantly lower 1/f characteristics (P < 0.001; area under the receiver operating characteristics curve, 0.84 [0.76 0.92]), indicative of a more uniform distribution of spectral power. Analysis of the normalized power spectral density revealed no significant impact of age on relative alpha (P = 0.693; area under the receiver operating characteristics curve, 0.52 [0.41 0.63]) and a significant but weak effect on relative beta power (P = 0.041; area under the receiver operating characteristics curve, 0.62 [0.52 0.73]). Using entropic parameters, the authors found a significant age-related change toward a more irregular and unpredictable EEG (permutation entropy: P < 0.001, area under the receiver operating characteristics curve, 0.81 [0.71 0.90]; approximate entropy: P < 0.001; area under the receiver operating characteristics curve, 0.76 [0.66 0.85]). With approximate entropy, the authors could also detect an age-induced change in alpha-band activity (P = 0.002; area under the receiver operating characteristics curve, 0.69 [0.60 78]).

Conclusions: Like the sleep literature, spectral and entropic EEG features under general anesthesia change with age revealing a shift toward a faster, more irregular, oscillatory composition of the EEG in older patients. Age-related changes in neurophysiological activity may underlie these findings however the contribution of age-related changes in filtering properties or the signal to noise ratio must also be considered. Regardless, most current EEG technology used to guide anesthetic management focus on spectral features, and improvements to these devices might involve integration of entropic features of the raw EEG.
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http://dx.doi.org/10.1097/ALN.0000000000003182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159998PMC
May 2020

Time delay of the qCON monitor and its performance during state transitions.

J Clin Monit Comput 2021 Apr 10;35(2):379-386. Epub 2020 Feb 10.

Department of Anesthesiology and Intensive Care, Technical University of Munich School of Medicine, Ismaninger Str. 22, 81675, Munich, Germany.

We investigated the performance of the qCON index regarding its time delay for sudden changes in the anesthetic level as well as to separate responsiveness from unresponsiveness during loss and return of responsiveness (LOR and ROR). For evaluation of the time delay, we replayed relevant EEG episodes to the qCON to simulate sudden changes between the states (i) awake/sedation, (ii) adequate anesthesia, or (iii) suppression. We also replayed EEG from 40 patients during LOR and ROR to evaluate the qCON's ability to separate responsiveness from unresponsiveness. The time delays depended on the type of transition. The delays for the important transition between awake/sedation and adequate anesthesia were 21(5) s from awake/sedation to adequate anesthesia and 26(5) s in the other direction. The performance of the qCON to separate responsiveness from unresponsiveness depended on signal quality, the investigation window, i.e. ± 30 s or ± 60 s around LOR/ROR, and the specific transition being tested. AUC was 0.63-0.90 for LOR and 0.61-0.79 for ROR. Time delay and performance during state transitions of the qCON were similar to other monitoring systems such as bispectral index. The better performance of qCON during LOR than ROR probably reflects the sudden change in EEG activity during LOR and the more heterogeneous EEG during ROR.
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http://dx.doi.org/10.1007/s10877-020-00480-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943427PMC
April 2021

Diazepam and ethanol differently modulate neuronal activity in organotypic cortical cultures.

BMC Neurosci 2019 12 10;20(1):58. Epub 2019 Dec 10.

Dept. of Anesthesiology and Intensive Care, Experimental Anesthesiology Section, University Hospital Tübingen, Tübingen, Germany.

Background: The pharmacodynamic results of diazepam and ethanol administration are similar, in that each can mediate amnestic and sedative-hypnotic effects. Although each of these molecules effectively reduce the activity of central neurons, diazepam does so through modulation of a more specific set of receptor targets (GABA receptors containing a γ-subunit), while alcohol is less selective in its receptor bioactivity. Our investigation focuses on divergent actions of diazepam and ethanol on the firing patterns of cultured cortical neurons.

Method: We used electrophysiological recordings from organotypic slice cultures derived from Sprague-Dawley rat neocortex. We exposed these cultures to either diazepam (15 and 30 µM, n = 7) or ethanol (30 and 60 mM, n = 11) and recorded the electrical activity at baseline and experimental conditions. For analysis, we extracted the episodes of spontaneous activity, i.e., cortical up-states. After separation of action potential and local field potential (LFP) activity, we looked at differences in the number of action potentials, in the spectral power of the LFP, as well as in the coupling between action potential and LFP phase.

Results: While both substances seem to decrease neocortical action potential firing in a not significantly different (p = 0.659, Mann-Whitney U) fashion, diazepam increases the spectral power of the up-state without significantly impacting the spectral composition, whereas ethanol does not significantly change the spectral power but the oscillatory architecture of the up-state as revealed by the Friedman test with Bonferroni correction (p < 0.05). Further, the action potential to LFP-phase coupling reveals a synchronizing effect of diazepam for a wide frequency range and a narrow-band de-synchronizing effect for ethanol (p < 0.05, Kolmogorov-Smirnov test).

Conclusion: Diazepam and ethanol, induce specific patterns of network depressant actions. Diazepam induces cortical network inhibition and increased synchronicity via gamma subunit containing GABA receptors. Ethanol also induces cortical network inhibition, but without an increase in synchronicity via a wider span of molecular targets.
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http://dx.doi.org/10.1186/s12868-019-0540-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902402PMC
December 2019

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

Neuropharmacology 2019 06 30;151:21-32. Epub 2019 Mar 30.

Department of Anaesthesiology and Intensive Care Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.

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 (Aβ) 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 Aβ-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 Aβ oligomers and compared them to the effects of radiprodil, a NMDA subunit 2B (GluN2B)-selective antagonist.

Methods: We applied different Aβ 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 Aβ. S-ketamine showed no effect. None of the drugs tested were able to ameliorate Aβ-induced LTP-deficits.

Conclusions: Xenon administered at subanaesthetic concentrations partially restored Aβ-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.
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http://dx.doi.org/10.1016/j.neuropharm.2019.03.031DOI Listing
June 2019

Transient electroencephalographic alpha power loss during maintenance of general anaesthesia.

Br J Anaesth 2019 May 30;122(5):635-642. Epub 2019 Jan 30.

Department of Anaesthesia, Waikato Clinical School, University of Auckland, Hamilton, New Zealand; Waikato District Health Board, Hamilton, New Zealand. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bja.2018.11.029DOI Listing
May 2019

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.

Trials 2019 Feb 22;20(1):146. Epub 2019 Feb 22.

Department of Anaesthesiology, Waikato Clinical Campus, University of Auckland, Hamilton, New Zealand.

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.
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http://dx.doi.org/10.1186/s13063-019-3178-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387545PMC
February 2019

Faster emergence behavior from ketamine/xylazine anesthesia with atipamezole versus yohimbine.

PLoS One 2018 29;13(10):e0199087. Epub 2018 Oct 29.

Atlanta VA Center for Visual and Neurocognitive Rehabilitation, Decatur, Georgia, United States of America.

Recent interest in reversal of the hypnotic effects of anesthesia has mainly focused on overcoming a surge in GABA-mediated inhibitory signaling through activation of subcortical arousal circuits or antagonizing GABA receptors. Here we examine the reversal of anesthesia produced from non-GABA agents ketamine/xylazine and the effects of antagonists of adrenoreceptors. These antagonists vary in selectivity and produce temporally unique waking behavior post-anesthesia. We compared two antagonists with differential selectivity for α1- vs. α2-receptors, yohimbine (YOH, 1:40 selectivity) and atipamezole (ATI, 1:8500). Adult mice received intraperitoneal injections of either YOH (4.3 mg/kg), ATI (0.4 mg/kg), or saline after achieving sustained loss of righting following injection of ketamine/xylazine (ketamine: 65.0 mg/kg; xylazine: 9.9 mg/kg). Behaviors indicative of the post-anesthesia, re-animation sequence were carefully monitored and the timing of each behavior relative to anesthesia induction was compared. Both YOH and ATI hastened behaviors indicative of emergence, but ATI was faster than YOH to produce certain behaviors, including whisker movement (YOH: 21.9±1.5 min, ATI: 17.5±0.5 min, p = 0.004) and return of righting reflex (RORR) (YOH: 40.6±8.8 min, ATI: 26.0±1.2 min, p<0.001). Interestingly, although YOH administration hastened early behavioral markers of emergence relative to saline (whisking), the completion of the emergence sequence (time from first marker to appearance of RORR) was delayed with YOH. We attribute this effect to antagonism of α1 receptors by yohimbine. Also notable was the failure of either antagonist to hasten the re-establishment of coordinated motor behavior (e.g., attempts to remove adhesive tape on the forepaw placed during anesthesia) relative to the end of emergence (RORR). In total, our work suggests that in addition to pharmacokinetic effects, re-establishment of normal waking behaviors after anesthesia involves neuronal circuits dependent on time and/or activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199087PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205597PMC
March 2019

Substance-Specific Differences in Human Electroencephalographic Burst Suppression Patterns.

Front Hum Neurosci 2018 21;12:368. Epub 2018 Sep 21.

Department of Anesthesiology and Intensive Care, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.

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 ( = 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.
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http://dx.doi.org/10.3389/fnhum.2018.00368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160564PMC
September 2018

Propofol and Sevoflurane Differentially Modulate Cortical Depolarization following Electric Stimulation of the Ventrobasal Thalamus.

Front Comput Neurosci 2017 11;11:109. Epub 2017 Dec 11.

Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

The neuronal mechanisms how anesthetics lead to loss of consciousness are unclear. Thalamocortical interactions are crucially involved in conscious perception; hence the thalamocortical network might be a promising target for anesthetic modulation of neuronal information pertaining to arousal and waking behavior. General anesthetics affect the neurophysiology of the thalamus and the cortex but the exact mechanisms of how anesthetics interfere with processing thalamocortical information remain to be elucidated. Here we investigated the effect of the anesthetic agents sevoflurane and propofol on thalamocortical network activity . We used voltage-sensitive dye imaging techniques to analyze the cortical depolarization in response to stimulation of the thalamic ventrobasal nucleus in brain slices from mice. Exposure to sevoflurane globally decreased cortical depolarization in a dose-dependent manner. Sevoflurane reduced the intensity and extent of cortical depolarization and delayed thalamocortical signal propagation. In contrast, propofol neither affected area nor amplitude of cortical depolarization. However, propofol exposure resulted in regional changes in spatial distribution of maximum fluorescence intensity in deep regions of the cortex. In summary, our experiments revealed substance-specific effects on the thalamocortical network. Functional changes of the neuronal network are known to be pivotally involved in the anesthetic-induced loss of consciousness. Our findings provide further evidence that the mechanisms of anesthetic-mediated loss of consciousness are drug- and pathway-specific.
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http://dx.doi.org/10.3389/fncom.2017.00109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732174PMC
December 2017

EEG Based Monitoring of General Anesthesia: Taking the Next Steps.

Authors:
Matthias Kreuzer

Front Comput Neurosci 2017 22;11:56. Epub 2017 Jun 22.

Department of Anesthesiology, Emory University School of MedicineAtlanta, GA, United States.

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http://dx.doi.org/10.3389/fncom.2017.00056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479908PMC
June 2017

The Input Is Reflected in the Output: Evaluating Neurophysiologic Monitors With Simulated Data.

Anesth Analg 2017 05;124(5):1734-1735

Department of Anesthesiology, Emory University, Atlanta, Georgia, Research Service, Atlanta VA Medical Center, Atlanta, Georgia Department of Anaesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Department of Anesthesiology, Emory University, Atlanta, Georgia, Research Service, Atlanta VA Medical Center, Atlanta, Georgia.

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http://dx.doi.org/10.1213/ANE.0000000000001958DOI Listing
May 2017

Infrared pupillometry helps to detect and predict delirium in the post-anesthesia care unit.

J Clin Monit Comput 2018 Apr 8;32(2):359-368. Epub 2017 Mar 8.

Department of Anesthesiology, Emory University, Atlanta, GA, USA.

This study evaluates the capability of pupillary parameters to detect and predict delirium in the post-anesthesia care unit (PACU-D) following general anesthesia. PACU-D may complicate and prolong the patient's postoperative course, consequently increasing hospital costs. After institutional approval, 47 patients undergoing surgical interventions with general anesthesia were included in the study. We measured the pupillary reflexes at signing of informed consent, during surgery 20 min after intubation and when the primary inhaled anesthetic was turned off, and 15 and 45 min after PACU admittance and upon discharge from the PACU. We evaluated patients for delirium using the confusion assessment method for the intensive care unit (CAM-ICU) score after 15 and 60 min in the PACU. We chose receiver operating curve (ROC) and area under the curve (AUC) to compare the performance of non-pupillary parameters to pupillary parameters, such as pupil diameter, percent constriction, and dilation velocity, to detect and predict PACU-D. Percent constriction (AUC = 0.93, optimal threshold = 18.5%) and dilation velocity (AUC = 0.93, optimal threshold = 0.35 mm/s) showed excellent ability to detect and predict delirium persisting throughout the PACU stay. These pupillary measures showed superior performance compared to other pupillary measures and features commonly associated with delirium, e.g., age (AUC = 0.73), total opioids (AUC = 0.56), or length of surgery (AUC = 0.40). Our results suggest that pupillometry and the parameters derived from the recording may identify delirious patients in the PACU. This information can help to efficiently structure their care in a timely manner, and potentially avoid adverse complications for the patient and financial consequences for the hospital.
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http://dx.doi.org/10.1007/s10877-017-0009-zDOI Listing
April 2018

Anesthetic Management of a Patient With Multiple Previous Episodes of Postanesthesia Care Unit Delirium: A Case Report.

A A Case Rep 2017 Jun;8(12):311-315

From the *Department of Anesthesiology, Emory University, Atlanta, Georgia; †Department of Anesthesiology & Perioperative Care, University of California, Irvine, California; and ‡Department of Anesthesiology, Atlanta VA Medical Center, Decatur, Georgia.

We report the case of a 37-year-old female patient who required 22 surgeries following a pedestrian versus car accident. She was enrolled in a clinical study investigating emergence from anesthesia. In 10 of her 22 surgeries, we assessed her cognitive status in the postanesthesia care unit (PACU) using the Confusion Assessment Method. We observed PACU delirium in all 4 cases in which the patient received sevoflurane, but only in 1 of 6 cases in which she received propofol. The patient showed EEG α-band activity similar to that of an elderly patient who may reflect a greater risk of PACU delirium.
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http://dx.doi.org/10.1213/XAA.0000000000000497DOI Listing
June 2017

Monitoring depth of sedation: evaluating the agreement between the Bispectral Index, qCON and the Entropy Module's State Entropy during flexible bronchoscopy.

Minerva Anestesiol 2017 Jun 8;83(6):563-573. Epub 2017 Feb 8.

Medical Clinic and Policlinic, Rechts der Isar Hospital, Technical University of Munich, Munich, Germany -

Background: We investigated the correlation and agreement of three depth of anesthesia indices, Bispectral Index (BIS), qCON and state entropy (SE) during propofol sedation, because there is extensive literature that deals with the comparability of these indices during general anesthesia, but not during sedation.

Methods: We recorded electroencephalogram (EEG) and SE trend data, using the Entropy Module from 21 patients who underwent elective bronchoscopy with target-controlled infusion of propofol. EEG data were replayed to BIS and qCON with an EEG player. We calculated the Spearman correlation to evaluate similarities in index trend behavior and estimated the general index agreement of displaying the same anesthetic level, i.e., wakefulness, sedation and anesthesia. We used coughing episodes and the bronchoscope placement to investigate the index for possible arousal reactions.

Results: We found a high to very high correlation of the indices' trend during the procedure. Furthermore, qCON was significantly lower than BIS and SE. All indices increased significantly after bronchoscope placement and coughing. The agreement of BIS/SE was 68% and around 50% for BIS/qCON and qCON/SE. The median duration of disagreement by >10 points was 39 s for BIS/SE and around 75 s for qCON with BIS and SE.

Conclusions: The results indicate a high probability of similar index performance between SE, BIS and qCON with the caveat of a different index scaling for qCON. These results can help the user of these monitoring devices to translate findings from one index to the other.
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http://dx.doi.org/10.23736/S0375-9393.17.11262-9DOI Listing
June 2017

Involvement of GluN2B subunit containing N-methyl-d-aspartate (NMDA) receptors in mediating the acute and chronic synaptotoxic effects of oligomeric amyloid-beta (Aβ) in murine models of Alzheimer's disease (AD).

Neuropharmacology 2017 Sep 4;123:100-115. Epub 2017 Feb 4.

Non-Clinical Science, Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany.

To elucidate whether a permanent reduction of the GluN2B subunit affects the pathology of Alzheimer's disease (AD), we cross-bred mice heterozygous for GluN2B receptors in the forebrain (hetGluN2B) with a mouse model for AD carrying a mutated amyloid precursor protein with the Swedish and Arctic mutation (mAPP) resulting in a hetGluN2B/mAPP transgenic. By means of voltage-sensitive dye imaging (VSDI) in the di-synaptic hippocampal pathway and the recording of field excitatory postsynaptic potentials (fEPSPs), hippocampal slices of all genotypes (WT, hetGluN2B, mAPP and hetGluN2B/mAPP, age 9-18 months) were tested for spatiotemporal activity propagation and long-term potentiation (LTP) induction. CA1-LTP induced by high frequency stimulation (HFS; 100 Hz/1s) was not different in all genotypes. Aβ (50 nM)-application reduced potentiation of fEPSP in WT and hetGluN2B/mAPP mice, LTP in mAPP and hetGluN2B mice was not affected. For VSDI a fast depolarization signal was evoked in the granule cell layer and propagation was analysed in hippocampal CA3 and CA1 region before and after theta stimulation (100pulses/5 Hz). LTP was not significantly different between all genotypes. In mAPP mice θ-stim produced an epileptiform activity reflected in a pronounced prolongation of the FDS compared to the other genotypes. In slices of hetGluN2B/mAPP and GluN2B mice, however, these parameters were similar to WT mice indicating a reversal effect of the attenuated GluN2B expression. The induction of a hetGluN2B mutation in the mAPP reversed some pathophysiological changes on hippocampal LTP and provide further evidence for the involvement of the glutamatergic system in AD and emphasize the GluN2B subunit as a potential target for AD treatment.
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http://dx.doi.org/10.1016/j.neuropharm.2017.02.003DOI Listing
September 2017

Distinct Parameters in the EEG of the PLP α-SYN Mouse Model for Multiple System Atrophy Reinforce Face Validity.

Front Behav Neurosci 2016 10;10:252. Epub 2017 Jan 10.

Department of Pharmacology and Toxicology, Institute for Pharmacy, Leopold-Franzens University of Innsbruck Innsbruck, Austria.

Multiple system atrophy (MSA) is a neurodegenerative movement disorder characterized by parkinsonian symptoms and cerebellar symptoms. Sleep disturbances also play a crucial role in MSA. One of the most convincing animal models in MSA research is the PLP α-SYN model, but to date no studies on sleep disturbances in this mouse model, frequently found in MSA patients are available. We identified spectral shifts within the EEG of the model, strikingly resembling results of clinical studies. We also characterized muscle activity during REM sleep, which is one of the key symptoms in REM sleep behavioral disorder. Spectral shifts and REM sleep-linked muscle activity were age dependent, supporting Face Validity of the PLP α-SYN model. We also strongly suggest our findings to be critically evaluated for Predictive Validity in future studies. Currently, research on MSA lacks potential compounds attenuating or curing MSA. Future drugs must prove its potential in animal models, for this our study provides potential biomarkers.
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http://dx.doi.org/10.3389/fnbeh.2016.00252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222844PMC
January 2017