Permutation Entropy Does Not Track the Electroencephalogram-Related Manifestations of Paradoxical Excitation During Propofol-Induced Loss of Responsiveness: Results From a Prospective Observational Cohort Study.

BACKGROUND: During the anesthetic-induced loss of responsiveness (LOR), a "paradoxical excitation" with activation of ß-frequencies in the electroencephalogram (EEG) can be observed. Thus, spectral parameters-as widely used in commercial anesthesia monitoring devices-may mistakenly indicate that patients are awake when they are actually losing responsiveness. Nonlinear time-domain parameters such as permutation entropy (PeEn) may analyze additional EEG information and appropriately reflect the change in cognitive state during the transition. Determining which parameters correctly track the level of anesthesia is essential for designing monitoring algorithms but may also give valuable insight regarding the signal characteristics during state transitions. METHODS: EEG data from 60 patients who underwent general anesthesia were extracted and analyzed around LOR. We derived the following information from the power spectrum: (i) spectral band power, (ii) the spectral edge frequency as well as 2 parameters known to be incorporated in monitoring systems, (iii) beta ratio, and (iv) spectral entropy. We also calculated (v) PeEn as a time-domain parameter. We used Friedman's test and Bonferroni correction to track how the parameters change over time and the area under the receiver operating curve to separate the power spectra between time points. RESULTS: Within our patient collective, we observed a "paradoxical excitation" around the time of LOR as indicated by increasing beta-band power. Spectral edge frequency and spectral entropy values increased from 19.78 [10.25-34.18] Hz to 25.39 [22.46-30.27] Hz (P = .0122) and from 0.61 [0.54-0.75] to 0.77 [0.64-0.81] (P < .0001), respectively, before LOR, indicating a (paradoxically) higher level of high-frequency activity. PeEn and beta ratio values decrease from 0.78 [0.77-0.82] to 0.76 [0.73-0.81] (P < .0001) and from -0.74 [-1.14 to -0.09] to -2.58 [-2.83 to -1.77] (P < .0001), respectively, better reflecting the state transition into anesthesia. CONCLUSIONS: PeEn and beta ratio seem suitable parameters to monitor the state transition during anesthesia induction. The decreasing PeEn values suggest a reduction of signal complexity and information content, which may very well describe the clinical situation at LOR. The beta ratio mainly focuses on the loss of power in the gamma-band. PeEn, in particular, may present a single parameter capable of tracking the LOR transition without being affected by paradoxical excitation.

Separation of responsive and unresponsive patients under clinical conditions: comparison of symbolic transfer entropy and permutation entropy.

Electroencephalogram (EEG)-based monitoring during general anesthesia may help prevent harmful effects of high or low doses of general anesthetics. There is currently no convincing evidence in this regard for the proprietary algorithms of commercially available monitors. The purpose of this study was to investigate whether a more mechanism-based parameter of EEG analysis (symbolic transfer entropy, STE) can separate responsive from unresponsive patients better than a strictly probabilistic parameter (permutation entropy, PE) under clinical conditions. In this prospective single-center study, the EEG of 60 surgical ASA I-III patients was recorded perioperatively. During induction of and emergence from anesthesia, patients were asked to squeeze the investigators' hand every 15s. Time of loss of responsiveness (LoR) during induction and return of responsiveness (RoR) during emergence from anesthesia were registered. PE and STE were calculated at -15s and +30s of LoR and RoR and their ability to separate responsive from unresponsive patients was evaluated using accuracy statistics. 56 patients were included in the final analysis. STE and PE values decreased during anesthesia induction and increased during emergence. Intra-individual consistency was higher during induction than during emergence. Accuracy values during LoR and RoR were 0.71 (0.62-0.79) and 0.60 (0.51-0.69), respectively for STE and 0.74 (0.66-0.82) and 0.62 (0.53-0.71), respectively for PE. For the combination of LoR and RoR, values were 0.65 (0.59-0.71) for STE and 0.68 (0.62-0.74) for PE. The ability to differentiate between the clinical status of (un)responsiveness did not significantly differ between STE and PE at any time. Mechanism-based EEG analysis did not improve differentiation of responsive from unresponsive patients compared to the probabilistic PE.Trial registration: German Clinical Trials Register ID: DRKS00030562, November 4, 2022, retrospectively registered.

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

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.

Time delay of monitors of the hypnotic component of anesthesia: analysis of state entropy and index of consciousness.

Monitors evaluating the hypnotic component of anesthesia by analyzing the electroencephalogram (EEG) may help to decrease the incidence of intraoperative awareness with recall. To calculate an index representing the anesthetic level, these monitors have different time delays until the correct index is displayed. In previous studies, intraoperatively recorded real and simulated EEG signals were used to determine time delays of cerebral state and Narcotrend and Bispectral indices. In the present study, we determined time delays of state entropy and index of consciousness. For this purpose, recorded real and simulated EEG sequences representing different anesthetic levels were played back to the tested monitors. Simulated and real perioperatively recorded EEG signals indicating stable states "awake," "general anesthesia," and "cortical suppression" were used to evaluate the time delays. Time delays were measured when switching from one state to another and were defined as the required time span of the monitor to reach the stable target index. Comparable results were obtained using simulated and real EEG sequences. Time delays were not constant and ranged from 18 to 152 seconds. They were also different for increasing and decreasing values. Time delays were dependent on starting and target index values. Time delays of index calculation may limit the investigated monitor's ability to prevent interoperative awareness with recall. Different time delays for increasing and decreasing transitions could be a problem if the monitors are used for pharmacodynamic studies.

Assessment of Regional Perfusion and Organ Function: Less and Non-invasive Techniques.

Sufficient organ perfusion essentially depends on preserved macro- and micro-circulation. The last two decades brought substantial progress in the development of less and non-invasive monitoring of macro-hemodynamics. However, several recent studies suggest a frequent incoherence of macro- and micro-circulation. Therefore, this review reports on interactions of macro- and micro-circulation as well as on specific regional and micro-circulation. Regarding global micro-circulation the last two decades brought advances in a more systematic approach of clinical examination including capillary refill time, a graded assessment of mottling of the skin and accurate measurement of body surface temperatures. As a kind of link between macro- and microcirculation, a number of biochemical markers can easily be obtained. Among those are central-venous oxygen saturation (ScvO2), plasma lactate and the difference between central-venous and arterial CO2 (cv-a-pCO2-gap). These inexpensive markers have become part of clinical routine and guideline recommendations. While their potential to replace parameters of macro-circulation such as cardiac output (CO) is limited, they facilitate the interpretation of the adequacy of CO and other macro-circulatory markers. Furthermore, they give additional hints on micro-circulatory impairment. In addition, a number of more sophisticated technical approaches to quantify and visualize micro-circulation including video-microscopy, laser flowmetry, near-infrared spectroscopy (NIRS), and partial oxygen pressure measurement have been introduced within the last 20 years. These technologies have been extensively used for scientific purposes. Moreover, they have been successfully used for educational purposes and to visualize micro-circulatory disturbances during sepsis and other causes of shock. Despite several studies demonstrating the association of these techniques and parameters with outcome, their practical application still is limited. However, future improvements in automated and "online" diagnosis will help to make these technologies more applicable in clinical routine. This approach is promising with regard to several studies which demonstrated the potential to guide therapy in different types of shock. Finally several organs have specific patterns of circulation related to their special anatomy (liver) or their auto-regulatory capacities (brain, kidney). Therefore, this review also discusses specific issues of monitoring liver, brain, and kidney circulation and function.

Secondary Lingular Sleeve Resection to Avoid Pneumonectomy Following Bronchial Anastomotic Dehiscence after Left Lower Lobe Sleeve Resection for Destroyed Lung Syndrome.

Bronchial sleeve resections are technically demanding procedures compared with lobectomies. In case of bronchial anastomotic dehiscence, secondary pneumonectomy is the treatment of choice. However, a secondary pneumonectomy is usually associated with high morbidity and mortality. Here, we first report, to the best of our knowledge, a secondary lingular sleeve resection following bronchial anastomotic dehiscence after left lower lobe sleeve resection in a patient with a destroyed lobe syndrome due to a pseudotumor. This approach enabled the avoidance of secondary pneumonectomy, hence reducing the possible pneumonectomy-associated complications.

Evaluation of M-AID, a first aid application for mobile phones.

BACKGROUND: When performed effectively, cardiopulmonary resuscitation (CPR) by bystanders reduces mortality due to sudden cardiac arrest. Telemedicine applications offer a means by which bystanders can get specific instructions for handling the emergency situation. M-AID, a first aid application for mobile phones, uses an intelligent algorithm of 'yes' or 'no' questions to judge the ongoing situation and give the user detailed instructions. The aim of this study was to evaluate the benefit of this mobile phone application in a scenario of sudden cardiac arrest. METHODS: One hundred and nineteen volunteers were assigned at random either to the test or the control group. All participants were confronted with the same scenario of acute coronary syndrome leading to cardiac arrest. The participants were either equipped with a mobile phone running the software (test group) or had to handle the situation without support (control group). The participants received a certain amount of credits for each action taken according to a pre-defined protocol and these credits were added to a score and compared between the groups. Participants were divided into subgroups according to their medical and technical experience. RESULTS: The test group generally achieved a slightly higher average score that was not statistically significant (21.11 versus 19.97; p=0.302). In contrast, the performance of the individuals in the control group was significantly faster (2.41 min versus 4.24 min; p<0.001). Use of the mobile phone software did not enhance the chance of survival. Subgroup analysis showed that experienced mobile phone users performed significantly better than non-experienced individuals, but not as well as participants with advanced first aid knowledge. CONCLUSIONS: Experience in the use of mobile phones is a prerequisite for the efficient use of the tested M-AID version. This application cannot replace skills acquisition by practical training. In a subgroup with experience in mobile phone use and basic knowledge in CPR, the device improved performance of CPR.

Circle of life of secretory vesicles in gastric enterochromaffin-like cells.

Enterochromaffin-like (ECL) cells are neuroendocrine cells in the gastric epithelium characterized by numerous electron-empty, histamine-containing secretory vesicles. The antral hormone gastrin is the key stimulus of histamine secretion from this cell type, thereby controling acid secretion. Following receptor binding, gastrin activates a biphasic calcium signal in ECL cells that involves activation of inositol triphosphate receptors and calcium entry across the plasma membrane. Dihydropyridines block gastrin-induced histamine secretion. However, no depolarization was observed following stimulation with gastrin. Elevation of intracellular calcium by gastrin is an important prerequisite for exocytosis. In permeabilized ECL cells, addition of calcium results in histamine release, which can be inhibited by tetanus toxin and botulinum neurotoxin A, underlining the functional importance of the synaptosome-associated protein of 25 kDa (SNAP-25) and synaptobrevin. Immunocytochemistry also confirmed the presence of these SNAP receptor (SNARE) proteins, as well as synaptophysin, synaptotagmin, and syntaxin. Following 3-6 h of incubation in isolated cells, several transcription factors are induced by gastrin, such as ERK1/2, Sp1, and CRE. Gastrin thereby directly stimulates transcription of the vesicular monoamine transporter subtype 2 (VMAT-2) and chromogranins. Gene expression of histidine decarboxylase (HDC) appears to be stimulated by a putative "gastrin-responsive" element adjacent to the HDC exon 1 gene. ECL cells thereby share several similarities with adrenal chromaffin cells and neurons, but have their own functional properties. Gastrin coordinates secretion, synthesis, and storage by activating diverging signal transducers, leading to a functional synergy in this cell type.

Time delay of index calculation: analysis of cerebral state, bispectral, and narcotrend indices.

BACKGROUND: On the basis of electroencephalographic analysis, several parameters have been proposed as a measure of the hypnotic component of anesthesia. All currently available indices have different time lags to react to a change in the level of anesthesia. The aim of this study was to determine the latency of three frequently used indices: the Cerebral State Index (Danmeter, Odense, Denmark), the Bispectral Index (Aspect Medical Systems Inc., Newton, MA), and the Narcotrend Index (MonitorTechnik, Bad Bramstedt, Germany). METHODS: Artificially generated signals were used to produce up to 14 constant index values per monitor that indicate "awake state," "general anesthesia," and "deep anesthesia" and smaller steps in between. The authors simulated loss of and return to consciousness by changing between the artificial electroencephalographic signals in a full-step and two stepwise approaches and measured the time necessary to adapt the indices to the particular input signal. RESULTS: Time delays between 14 and 155 s were found for all indices. These delays were not constant. Results were different for decreasing and increasing values and between the full-step and the stepwise approaches. Calculation time depended on the particular starting and target index value. CONCLUSIONS: The time delays of the tested indices may limit their value in prevention of recall of intraoperative events. Furthermore, different latencies for decreasing and increasing values may indicate a limitation of these monitors for pharmacodynamic studies.

Expression of the endocytic proteins dynamin and amphiphysin in rat gastric enterochromaffin-like cells.

Dynamin and amphiphysin play crucial roles in a variety of endocytic processes. Previous investigations of expression and functions of these proteins were performed mostly on neurons. The aim of this study was to investigate the presence and interaction of dyn and amph in gastric enterochromaffin-like cells. These endocrine cells of the gastric mucosa play a pivotal role in the regulation of acid secretion. Exocytosis of histamine-containing secretory vesicles has been described in detail. However, the mechanisms of endocytosis are unknown in this neuroendocrine cell type. Using RT-PCR and western blotting, we detected dynamin-1, -2 and -3 in highly enriched isolated enterochromaffin-like cells. Dynamin-1 and -2 were expressed at similar high levels, whereas dynamin-3 was of low abundance. Immunofluorescence microscopy located dynamin-1 and -2 to the cytoplasm and cell surface, whereas dynamin-3 was distributed differently in the perinuclear area. The presence of amphiphysin-1 and -2 RNAs was revealed by RT-PCR and a new splice variant of amphiphysin-2 was detected. Amphiphysin-1 and -2 were also detected in enterochromaffin-like cells by immunohistochemistry in the same locations as dynamin-1 and -2. Amphiphysin-1 and dynamin-1 co-immunoprecipitated with amphiphysin-2. In addition, dynamin-1 and amphiphysin-2 partially colocalized at the plasma membrane. Our results confirm the interaction of dynamin and amphiphysin and imply a role in endocytosis in enterochromaffin-like cells. To our knowledge, this is the first demonstration of the co-expression of all three dynamin isoforms in a non-tumor cell.

Physiology of gastric enterochromaffin-like cells.

Enterochromaffin-like (ECL) cells are neuroendocrine cells in the gastric mucosa that control acid secretion by releasing histamine as a paracrine stimulant. The antral hormone gastrin and the neural messenger pituitary adenylyl cyclase-activating peptide (PACAP) potently stimulate histamine synthesis, storage, and secretion by ECL cells. Histamine is stored in secretory vesicles via V-type ATPases and vesicular monoamine transporters of subtype 2 (VMAT-2). Plasmalemmal calcium entry occurs via L-type calcium channels upon stimulation with secretagogues. K(+) and Cl(-) channels maintain the membrane potential. Calcium-triggered exocytosis of histamine is mediated by interacting SNARE proteins, especially by synaptobrevin and SNAP-25. Dynamins and amphiphysins appear to play a key role in endocytosis. ECL cells are under transcriptional control of various hormones. Gastrin stimulates transcriptional activity of the histidine decarboxylase (HDC), VMAT-2, and chromogranin A promoter by activation of Sp1 elements and CREB. During chronic Helicobacter pylori infection, pro-inflammatory cytokines are released that can also affect ECL cells, thus impairing their secretory function and viability, which can predispose to hypochlorhydria and gastric carcinogenesis.

Intracellular signal transduction during gastrin-induced histamine secretion in rat gastric ECL cells.

Activation of G(q) protein-coupled receptors usually causes a biphasic increase in intracellular calcium concentration ([Ca(2+)](i)) that is crucial for secretion in nonexcitable cells. In gastric enterochromaffin-like (ECL) cells, stimulation with gastrin leads to a prompt biphasic calcium response followed by histamine secretion. This study investigates the underlying signaling events in this neuroendocrine cell type. In ECL cells, RT-PCR suggested the presence of inositol 1,4,5-trisphosphate receptor (IP(3)R) subtypes 1-3. The IP(3)R antagonist 2-aminoethoxydiphenyl borate abolished both gastrin-induced elevation of [Ca(2+)](i) and histamine release. Thapsigargin increased [Ca(2+)](i), however, without inducing histamine secretion. In thapsigargin-pretreated cells, gastrin increased [Ca(2+)](i) through calcium influx across the plasma membrane. Both nimodipine and SKF-96365 inhibited gastrin-induced histamine release. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate induced histamine secretion, an effect that was prevented by nimodipine. In summary, gastrin-stimulated histamine release depends on IP(3)R activation and plasmalemmal calcium entry. Gastrin-induced calcium influx was mediated by dihydropyridine-sensitive calcium channels that appear to be L-type channels activated through a pathway involving activation of PKC.

Expression of histidine decarboxylase and synthesis of histamine by human small cell lung carcinoma.

We recently found that human small cell lung carcinomas (SCLCs) express, in addition to other neuroendocrine markers, vesicular monoamine transporters. Our present results indicate that SCLCs are histaminergic. We detected the biosynthetic enzyme histidine decarboxylase by immunohistochemistry in paraffin sections of 12 biopsies of SCLC tumors. This finding was supported by immunoblotting and reverse transcription-polymerase chain reaction experiments using established SCLC cell lines, frozen and paraffin-embedded SCLC tumors. Moreover, we found histamine to be synthesized, stored, and released by cultured SCLC cells. Our novel observations may be useful for developing new diagnostic tools for this frequent and highly malignant tumor.

Tumor necrosis factor-alpha effects on rat gastric enterochromaffin-like cells.

Gastric enterochromaffin-like (ECL) cells are histamine-producing cells in the gastric epithelium which are responsible for the peripheral regulation of acid secretion. The gastric mucosa is frequently infected with Helicobacter pylori, leading to increased levels of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). The aim of our current study was to identify the effect of TNF-alpha on programmed cell death. ECL cells were isolated from the rat corpus mucosa to a purity >90%. TNF receptor and adapter protein presence were determined using RT-PCR, Western blot and immunocytochemistry. Apoptosis was measured by Tdt-mediated dUTP nick end labeling reaction and by DNA fragmentation based ELISA. Isolated ECL cells were found to express the TNF receptor p55 and IFN-gamma receptor, but not the TNF receptor p75 or CD95. TNF-alpha (25 ng/ml) increased apoptosis in ECL cells approximately 4-fold, IFN-gamma had no effect. Western blot analysis revealed that TNF-alpha caused degradation of I kappa B alpha within 10 min. EMSA demonstrated that TNF-alpha led to increased DNA-binding activity of NF kappa B and that proteasome inhibitors counteracted NF kappa B activation. Proteasome inhibitors, specific antisense oligodeoxynucleotides against the p65 subunit of the NF kappa B complex and the NO synthase inhibitor N(G)-monomethyl-L-arginine completely prevented TNF-alpha-induced apoptosis. Our data suggest that TNF-alpha induces apoptosis of isolated gastric ECL cells via activation of NF kappa B and the generation of NO.