Enabling personalized perioperative risk prediction by using a machine-learning model based on preoperative data.

Preoperative risk assessment is essential for shared decision-making and adequate perioperative care. Common scores provide limited predictive quality and lack personalized information. The aim of this study was to create an interpretable machine-learning-based model to assess the patient's individual risk of postoperative mortality based on preoperative data to allow analysis of personal risk factors. After ethical approval, a model for prediction of postoperative in-hospital mortality based on preoperative data of 66,846 patients undergoing elective non-cardiac surgery between June 2014 and March 2020 was created with extreme gradient boosting. Model performance and the most relevant parameters were shown using receiver operating characteristic (ROC-) and precision-recall (PR-) curves and importance plots. Individual risks of index patients were presented in waterfall diagrams. The model included 201 features and showed good predictive abilities with an area under receiver operating characteristic (AUROC) curve of 0.95 and an area under precision-recall curve (AUPRC) of 0.109. The feature with the highest information gain was the preoperative order for red packed cell concentrates followed by age and c-reactive protein. Individual risk factors could be identified on patient level. We created a highly accurate and interpretable machine learning model to preoperatively predict the risk of postoperative in-hospital mortality. The algorithm can be used to identify factors susceptible to preoperative optimization measures and to identify risk factors influencing individual patient risk.

Association of immature platelets with perioperative complications in neurosurgery.

Immature platelets are newly formed platelets with an increased prothrombotic potential. This study evaluates whether immature platelets are associated with relevant complications in neurosurgical patients. Data were obtained in the frame of a prospectively conducted observational study exploring the association between immature platelets and major cardiovascular events after surgery. Immature platelet fraction (IPF) and H-IPF (highly fluorescent immature platelet fraction) were measured preoperatively and postoperatively at the neurosurgical ward (24-72 hours after surgery). Therapy-relevant complications after surgery were stratified using the Clavien-Dindo Grade (CDG >2) as primary outcome. Data were analyzed in 391 neurosurgical patients. While preoperatively there were no differences in IPF or H-IPF, patients with higher therapy-complication grades had higher values post-op compared to patients with lower grade complications (≤2 CDG). Cut-off values identified by receiver operating characteristic curve analysis revealed that there were significantly more patients with H-IPF ≥0.95% in the group with serious complications (CDG >2) [odds ratio OR (95% confidence interval CI) = 2.06 (1.09-3.9), p = .025], whereas this association was not present for the IPF cutoff value. In a multivariate model, H-IPF≥0.95% was independently associated with serious complications after surgery [OR (95% CI) = 1.97 (1.03-3.78), p = .041]. These findings suggest that H-IPF is associated with surgical complications and may improve risk stratification of neurosurgical patients (clinicaltrials.gov: NCT02097602, registration date: 27/03/2014).

What is the context?Immature platelets are newly formed platelets with a higher thrombotic potential and play an important role in atherothrombotic events.Higher levels of immature platelets were observed in patients with acute coronary syndrome or stroke.Lately, the focus in immature platelet research shifted from observation to outcomes. Immature platelets were identified as independent predictors of major cardiovascular events in cardiologic patients with coronary artery disease. Besides, an association between immature platelets and major cardiovascular events was described in surgical patients after non-cardiac surgery.What is new?This study builds on these findings and extends the focus to perioperative complications after neurosurgery.The data were obtained prospectively in the frame of an observational clinical trial exploring the association of immature platelets and major cardiovascular events in general. Data measured in the neurosurgical cohort of that study (391 neurosurgical patients) were analyzed in the present work.Within the limitations of our study, our analyses suggest that the postoperative IPF (immature platelet fraction) and H-IPF (highly fluorescent immature platelet fraction) values, which were measured at the neurosurgical ward after surgery are both associated with higher therapy-relevant complication grades (>2 according to Clavien-Dindo Grade), whereas preoperatively obtained values were not.What is the impact?This is the first study showing a relationship between immature platelets and therapy-relevant perioperative complications in neurosurgical patients. It could be a pilot trial for varied scientific questions including risk stratification of neurosurgical patients.

Ready for a "breakthrough" with ketamine? A look at recent pharmacological insights!

PURPOSE OF REVIEW: To update pharmacological insights on ketamine integrating information from different disciplines for developing steps to "breakthrough" approaches in clinical challenges. RECENT FINDINGS: Pharmacokinetic/pharmacodynamic (PK/PD) models have incorporated recirculation, ketamine metabolites, drug-drug interaction, and covariates such as age. Ketamine-induced relief from treatment-resistant depression has been explained by "disinhibition" of gamma-aminobutyric acid-ergic interneurons and synaptogenic mechanisms requiring neurotrophic signals. Neuroimaging/electroencephalographic investigations have shown an increase in gamma spectral power in healthy volunteers and patients with depression, but also opposite changes in functional network connectivity after subanesthetic ketamine. Volunteer data may not be transferable to clinical conditions. Altered states of consciousness induced by subanesthetic ketamine have been described by disruption of resisting-state functional networks and frontoparietal connectivity with preservation of multisensory and sensor-motor networks. This has been interpreted as a "disconnected consciousness". SUMMARY: More precise PK/PD models may improve the ketamine use regimen. The findings from research on depression are an important discovery because ketamine's impact on neuronal plasticity and synaptogenesis in human brain disease has directly been documented. Psychic adverse effects with subanesthetic ketamine are related to a "disconnected consciousness". Overall, progress has been made, but the "breakthrough" still has to come.

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.

Machine learning for a combined electroencephalographic anesthesia index to detect awareness under anesthesia.

Spontaneous electroencephalogram (EEG) and auditory evoked potentials (AEP) have been suggested to monitor the level of consciousness during anesthesia. As both signals reflect different neuronal pathways, a combination of parameters from both signals may provide broader information about the brain status during anesthesia. Appropriate parameter selection and combination to a single index is crucial to take advantage of this potential. The field of machine learning offers algorithms for both parameter selection and combination. In this study, several established machine learning approaches including a method for the selection of suitable signal parameters and classification algorithms are applied to construct an index which predicts responsiveness in anesthetized patients. The present analysis considers several classification algorithms, among those support vector machines, artificial neural networks and Bayesian learning algorithms. On the basis of data from the transition between consciousness and unconsciousness, a combination of EEG and AEP signal parameters developed with automated methods provides a maximum prediction probability of 0.935, which is higher than 0.916 (for EEG parameters) and 0.880 (for AEP parameters) using a cross-validation approach. This suggests that machine learning techniques can successfully be applied to develop an improved combined EEG and AEP parameter to separate consciousness from unconsciousness.

Improved Survival in Liver Transplant Patients Receiving Prolonged-release Tacrolimus-based Immunosuppression in the European Liver Transplant Registry (ELTR): An Extension Study.

BACKGROUND: We compared, through the European Liver Transplant Registry, long-term liver transplantation outcomes with prolonged-release tacrolimus (PR-T) versus immediate-release tacrolimus (IR-T)-based immunosuppression. This retrospective analysis comprises up to 8-year data collected between 2008 and 2016, in an extension of our previously published study. METHODS: Patients with <1 month follow-up were excluded; patients were propensity score matched for baseline characteristics. Efficacy measures included: univariate/multivariate analyses of risk factors influencing graft/patient survival up to 8 years posttransplantation, and graft/patient survival up to 4 years with PR-T versus IR-T. Overall, 13 088 patients were included from 44 European centers; propensity score-matched analyses comprised 3006 patients (PR-T: n = 1002; IR-T: n = 2004). RESULTS: In multivariate analyses, IR-T-based immunosuppression was associated with reduced graft survival (risk ratio, 1.49; P = 0.0038) and patient survival (risk ratio, 1.40; P = 0.0215). There was improvement with PR-T versus IR-T in graft survival (83% versus 77% at 4 y, respectively; P = 0.005) and patient survival (85% versus 80%; P = 0.017). Patients converted from IR-T to PR-T after 1 month had a higher graft survival rate than patients receiving IR-T at last follow-up (P < 0.001), or started and maintained on PR-T (P = 0.019). One graft loss in 4 years was avoided for every 14.3 patients treated with PR-T versus IR-T. CONCLUSIONS: PR-T-based immunosuppression might improve long-term outcomes in liver transplant recipients than IR-T-based immunosuppression.

Impact of instructor professional background and interim retesting on knowledge and self-confidence of schoolchildren after basic life support training: a cluster randomised longitudinal study.

INTRODUCTION: To increase the rate of bystander resuscitation, basic life support (BLS) training for schoolchildren is now recommended on a broad level. However, debate continues about the optimal teaching methods. In this study, we investigated the effects of a 90 min BLS training on female pupils' BLS knowledge and self-confidence and whether learning outcomes were influenced by the instructors' professional backgrounds or test-enhanced learning. METHODS: We conducted a cluster randomised, longitudinal trial in a girls' grammar school in Germany from 2013 to 2014. Pupils aged 10-17 years were randomised to receive BLS training conducted by either emergency physicians or medical students. Using a multiple-choice questionnaire and a Likert-type scale, BLS knowledge and self-confidence were investigated before training (t0), 1 week (t1) and 9 months after training (t2). To investigate whether test-enhanced learning influenced learning outcomes, the questionnaire was administered 6 months after the training in half of the classrooms. The data were analysed using linear mixed-effects models. RESULTS: The study included 460 schoolchildren. BLS knowledge (mean number of correct answers) increased from 5.86 at t0 to 9.24 at t1 (p<0.001) and self-confidence (mean score on the Likert-type scale) increased from 8.70 at t0 to 11.29 at t1 (p<0.001). After 9 months, knowledge retention was good (8.94 at t2; p=0.080 vs t1), but self-confidence significantly declined from t1 to 9.73 at t2 (p<0.001). Pupils trained by medical students showed a slight but statistically significant greater increase in the knowledge at both t1 and t2, whereas instructors' background did not influence gain or retention of self-confidence. Retesting resulted in a marginally, non-significantly better retention of knowledge. CONCLUSIONS: BLS training led to short-term gains in knowledge and self-confidence. Although knowledge was retained at 9 months after the training session, self-confidence significantly decreased. Interim testing did not appear to impact retention of knowledge or self-confidence. Medical students should be considered as instructors for these courses given their favourable learning outcomes and greater availability.

2018 Annual Report of the European Liver Transplant Registry (ELTR) - 50-year evolution of liver transplantation.

The purpose of this registry study was to provide an overview of trends and results of liver transplantation (LT) in Europe from 1968 to 2016. These data on LT were collected prospectively from 169 centers from 32 countries, in the European Liver Transplant Registry (ELTR) beginning in 1968. This overview provides epidemiological data, as well as information on evolution of techniques, and outcomes in LT in Europe over more than five decades; something that cannot be obtained from only a single center experience.

Self-confidence and knowledge of German ICU physicians in palliative care - a multicentre prospective study.

BACKGROUND: Little is known about ICU physicians' self-confidence and knowledge related to palliative care. Our objective was to investigate self-confidence and knowledge of German ICU physicians related to palliative care, and to assess the impact of work experience, gender, specialty and additional certifications in pain or palliative medicine. METHODS: In a multicentre prospective observational study ICU physicians of ten hospitals were asked to rate their self-confidence and to complete a multiple choice questionnaire for the assessment of knowledge. Beyond descriptive statistics and non-parametric tests for group comparisons, linear regression analysis was used to assess the impact of independent variable on self-confidence and knowledge. Spearman's rank test was calculated. RESULTS: 55% of answers in the knowledge test were correct and more than half of the participants rated themselves as "rather confident" or "confident". Linear regression analysis revealed that an additional certificate in either pain or palliative medicine significantly increased both knowledge and self-confidence, but only 15 out of 137 participants had at least one of those certificates. Relation between self-confidence and the results of the knowledge test was weak (r = 0.270 in female) and very weak (r = -0.007 in male). CONCLUSIONS: Although the questionnaire needs improvement according to the item analysis, it appears that, with respect to palliative care, ICU Physicians' self-confidence is not related to their knowledge. An additional certificate in either pain or palliative medicine was positively correlated to both self-confidence and knowledge. However, only a minority of the participants were qualified through such a certificate.

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

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

Immature platelets as a novel biomarker for adverse cardiovascular events in patients after non-cardiac surgery.

This study evaluates whether immature platelets (IPF) determined in the post anesthesia care unit (PACU) can predict major adverse cardiovascular events (MACE) or other thromboembolic events after intermediate and high-risk surgery. IPF are increased in patients with acute coronary syndrome and recently gained interest as novel biomarker for risk stratification. In this prospective observational trial 732 patients undergoing intermediate or high-risk non-cardiac surgery were enrolled (NCT02097602). IPF was measured preoperatively and postoperatively in the PACU. Primary outcome was a composite endpoint defined as MACE, deep vein thrombosis or pulmonary embolism during hospital stay (modMACE). A cut off for IPF identifying a threshold between a low and high risk for modMACE was calculated by log-rank optimization. A multivariate Cox regression was calculated in a forward stepwise manner to assess the relation between this IPF cut off and modMACE as well as other established risk factors (inclusion if p<0.05). Preoperatively, there were no differences in IPF between patients with and without modMACE (3.1 % [2.2 % - 4.7 %](median [interquartile range]) vs. 2.8 % [1.9 % - 4.3 %]. Patients with modMACE (28 of 730 patients; 3.8 %) had higher IPF values in the PACU compared to patients without modMACE (3.6 % [2.6-6 %] vs. 2.9 % [2-4.4 %]; p=0.011). The optimal cut off of IPF > 5.4 % was associated with an increased risk for modMACE after adjustment for covariates (hazard ratio: 2.528; 95 % confidence interval: 1.156 to 5.528, p=0.02). In conclusion, IPF is an independent predictor of modMACE after surgery and might improve risk stratification of surgical patients.

Coherence of BOLD signal and electrical activity in the human brain during deep sevoflurane anesthesia.

INTRODUCTION: Changes in neural activity induce changes in functional magnetic resonance (fMRI) blood oxygenation level dependent (BOLD) signal. Commonly, increases in BOLD signal are ascribed to cellular excitation. OBJECTIVE: The relationship between electrical activity and BOLD signal in the human brain was probed on the basis of burst suppression EEG. This condition includes two distinct states of high and low electrical activity. METHODS: Resting-state simultaneous EEG and BOLD measurements were acquired during deep sevoflurane anesthesia with burst suppression EEG in nineteen healthy volunteers. Afterwards, fMRI volumes were assigned to one of the two states (burst or suppression) as defined by the EEG. RESULTS: In the frontal, parietal and temporal lobes as well as in the basal ganglia, BOLD signal increased after burst onset in the EEG and decreased after onset of EEG suppression. In contrast, BOLD signal in the occipital lobe was anticorrelated to electrical activity. This finding was obtained consistently in a general linear model and in raw data. CONCLUSIONS: In human brains exhibiting burst suppression EEG induced by sevoflurane, the positive correlation between BOLD signal and electrical brain activity could be confirmed in most gray matter. The exceptional behavior of the occipital lobe with an anticorrelation of BOLD signal and electrical activity might be due to specific neurovascular coupling mechanisms that are pronounced in the deeply anesthetized brain.

Safe Brain Tumor Resection Does not Depend on Surgery Alone - Role of Hemodynamics.

Aim of this study was to determine if perioperative hemodynamics have an impact on perioperative infarct volume and patients' prognosis. 201 cases with surgery for a newly diagnosed or recurrent glioblastoma were retrospectively analyzed. Clinical data and perioperative hemodynamic parameters, blood tests and time of surgery were recorded. Postoperative infarct volume was quantitatively assessed by semiautomatic segmentation. Mean diastolic blood pressure (dBP) during surgery (rho -0.239, 95% CI -0.11 - -0.367, p = 0.017), liquid balance (rho 0.236, 95% CI 0.1-0.373, p = 0.017) and mean arterial pressure (MAP) during surgery (rho -0.206, 95% CI -0.07 - -0.34, p = 0.041) showed significant correlation to infarct volume. A rank regression model including also age and recurrent surgery as possible confounders revealed mean intraoperative dBP, liquid balance and length of surgery as independent factors for infarct volume. Univariate survival analysis showed mean intraoperative dBP and MAP as significant prognostic factors, length of surgery also remained as significant prognostic factor in a multivariate model. Perioperative close anesthesiologic monitoring of blood pressure and liquid balance is of high significance during brain tumor surgery and should be performed to prevent or minimize perioperative infarctions and to prolong survival.

Utility of basophil activation testing to assess perioperative anaphylactic reactions in real-world practice.

INTRODUCTION: Perioperative anaphylactic reactions due to drugs and substances associated with general anesthesia can potentially be life-threatening. The objective of this study was to investigate the significance of the basophil activation test (BAT) for allergy diagnosis work up. METHODS: A total of 14 patients (5 men, 9 women; mean age: 57.8 years) with clinical records of anaphylactic reactions under general anesthesia were studied by means of anesthesia records, skin and serological tests. Eleven healthy subjects without any history of allergic sensitization to anaesthetic drugs served as controls. BATs based on stimulation of whole blood cells measuring CD63 activation of basophils and using CCR3 as basophil marker by flow cytometry (Flow CAST®, BÜHLMANN Laboratories AG, Schönenbuch, Switzerland) were performed with the following substances (in dependence on the history and the skin tests of the patient): analgesics (acetylsalicylic acid, celecoxib, diclofenac, ibuprofen, indometacin, metamizole, paracetamol, propyphenazone, tramadol), antibiotics (PPL (benzylpenicilloyl polylysine), MDM (minor determinant mixture), amoxicillin, cefuroxime, ciprofloxacin, doxycycline, erythromycin, roxithromycin, sulfamethoxazole, trimethoprim), local anesthetics (articaine, bupivacaine, lidocaine, prilocaine, procaine, methyl-4-hydroxybenzoate), narcotics and NMBA (atracurium, cisatracurium, etomidate, neostigmine, midazolam, mivacurium, pancuronium, propofol, pyridostigmine, succinylcholine, sufentanil, thiopental, vecuronium), and other individual substances. RESULTS: Three patients showed positive results in the BAT: One to metamizole, one to PPL, and one to pancuronium. BATs with these substances were negative in controls. CONCLUSIONS: The BAT should be used complementary to skin tests, especially if IgE-mediated mechanisms are presumed and skin tests are inconclusive. A positive reaction in BAT identifies the culprit agent with high probability.

[HERA-QUEST: HTA evaluation of generic pharmaceutical products to improve quality, economic efficiency, patient safety and transparency in drug product changes in hospitals]. / HERA-QUEST: HTA-Evaluation generischer Arzneimittel zur Verbesserung von Qualität, Oekonomie, Patientensicherheit und Transparenz bei Produktumstellungen in Kliniken.

In view of the rising cost pressure and an increasing number of drug shortages, switches between generic drug preparations have become a daily routine in hospitals. To ensure consistently high treatment quality and best possible patient safety, the equivalence of the new and the previous drug preparation must be ensured before any change in the purchase of pharmaceutical products takes place. So far, no easily usable, transparent and standardized instrument for this kind of comparison between generic drug products has been available. A group of pharmaceutical experts has developed the drug HTA (health technology assessment) model "HERA" (HTA Evaluation of geneRic phArmaceutical products) through a multi-step process. The instrument is designed to perform both a qualitative and economic comparison of equivalent drug preparations ("aut idem" substitution) before switching products. The economic evaluation does not only consider unit prices and consumption quantity, but also the processing costs associated with a product change process. The qualitative comparison is based on the evaluation of 34 quality criteria belonging to six evaluation fields (e.g., approval status, practical handling, packaging design). The objective evaluation of the quality criteria is complemented by an assessment of special features of the individual hospital for complex drug switches, including the feedback of the physicians utilizing the drug preparation. Thus potentially problematic switches of pharmaceutical products can be avoided at the best possible rate, contributing to the improvement of patient safety. The novel drug HTA model HERA is a tool used in clinical practice that can add to an increase in quality, therapeutic safety and transparency of drug use while simultaneously contributing to the economic optimization of drug procurement in hospitals. Combining these two is essential for hospitals facing the tension between rising cost pressure and at the same time increasing demands on quality and transparency, triggered by, amongst others, current legislation (Hospital Structures Act, anti-corruption legislation).

Drug-induced sleep endoscopy with target-controlled infusion using propofol and monitored depth of sedation to determine treatment strategies in obstructive sleep apnea.

BACKGROUND: Drug-induced sleep endoscopy (DISE) has become an important diagnostic examination tool in the treatment decision process for surgical therapies in the treatment of obstructive sleep apnea (OSA). Currently, there is a variety of regimes for the performance of DISE, which renders comparison and assessment across results difficult. It remains unclear how the different regimes influence the findings of the examination and the resulting conclusions and treatment recommendations. This study aimed to investigate the correlation between increasing levels of sedation (i.e., light, medium, and deep) induced by propofol using a target-controlled infusion (TCI) pump, with the obstruction patterns at the levels of the velum, oropharynx, tongue base, and epiglottis (i.e., VOTE classification). A second goal was the establishment of a sufficient sedation level to enable a reliable decision regarding treatment recommendations. MATERIAL AND METHODS: Forty-three patients with OSA underwent a DISE procedure using propofol TCI. Three levels of sedation were defined, depending on entropy levels and assessment of sedation: light sedation, medium sedation, and deep sedation. The evaluation of the upper airway at each level, with increasing sedation, was documented using the VOTE classification. The elapsed time at which each assessment was performed was recorded. RESULTS: Upper airway changes occurred and were measured throughout the DISE procedure. Clinically useful determinations of airway closure occurred at medium sedation; this level of sedation was most probably achieved with a blood propofol concentration of 3.2 µg/ml. In all 43 patients, definite treatment decisions could be made at medium sedation level. Increasing sedation did not result in changes in the treatment decision. CONCLUSIONS: Changes in upper airway collapse during DISE with propofol TCI occur at levels of medium sedation. Decisions regarding surgical treatment could be made at this level of sedation. CLINICAL TRIAL NAME: Upper Airway Collapse in Patients with Obstructive Sleep Apnea Syndrome by Drug Induced Sleep Endoscopy (URL: https://clinicaltrials.gov/ct2/results?term=NCT02588300&Search=Search ) REGISTRATION NUMBER: NCT02588300.

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

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 in vitro. 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.

A period of immobility after remifentanil administration protects from nausea: an experimental randomized cross-over study.

BACKGROUND: The opioid remifentanil induces a decrease of vestibulo-ocular reflex function, which has been associated with nausea and vomiting when the subjects are moved. The study investigates in healthy female volunteers if immobility after remifentanil administration protects from nausea and vomiting. METHODS: In volunteers, a standardized movement intervention (a manually applied head-trunk movement forward, backward and sideward) was started 5 min (session A), 35 min (session B) or 60 min (session C) after cessation of a remifentanil infusion (0.15 µg · kg-1 · min-1). In a cross-over design, 16 participants were randomized to the early (sessions A and B) or the late intervention group (sessions A and C). Nausea was assessed using a 11-point numerical rating scale before and after each movement intervention. Differences within and between groups were assessed with non-parametric tests for paired and unpaired data. RESULTS: Comparing sessions A, B and C, intensity of nausea was time-dependent after cessation of remifentanil administration (p = 0.015). In the early intervention group, nausea decreased from median 5.0 [IQR 1.5;6.0] in session A to 2.0 [1.0;3.0] in session B (p = 0.094); in the late intervention group nausea decreased from 3.5 [2.0;5.0] in session A to 0.5 [0.0;2.0] in session C (p = 0.031). CONCLUSIONS: In summary, in young healthy women, immobility after remifentanil administration protects from nausea and vomiting in a time-dependent manner. In analogy to motion sickness, opioid-induced nausea and vomiting in female volunteers can be triggered by movement. TRIAL REGISTRATION: German Clinical Trials Register DRKS00010667 . The trial was registered retrospectively on June, 20th 2016.

Neural Correlates of Sevoflurane-induced Unconsciousness Identified by Simultaneous Functional Magnetic Resonance Imaging and Electroencephalography.

BACKGROUND: The neural correlates of anesthetic-induced unconsciousness have yet to be fully elucidated. Sedative and anesthetic states induced by propofol have been studied extensively, consistently revealing a decrease of frontoparietal and thalamocortical connectivity. There is, however, less understanding of the effects of halogenated ethers on functional brain networks. METHODS: The authors recorded simultaneous resting-state functional magnetic resonance imaging and electroencephalography in 16 artificially ventilated volunteers during sevoflurane anesthesia at burst suppression and 3 and 2 vol% steady-state concentrations for 700 s each to assess functional connectivity changes compared to wakefulness. Electroencephalographic data were analyzed using symbolic transfer entropy (surrogate of information transfer) and permutation entropy (surrogate of cortical information processing). Functional magnetic resonance imaging data were analyzed by an independent component analysis and a region-of-interest-based analysis. RESULTS: Electroencephalographic analysis showed a significant reduction of anterior-to-posterior symbolic transfer entropy and global permutation entropy. At 2 vol% sevoflurane concentrations, frontal and thalamic networks identified by independent component analysis showed significantly reduced within-network connectivity. Primary sensory networks did not show a significant change. At burst suppression, all cortical networks showed significantly reduced functional connectivity. Region-of-interest-based thalamic connectivity at 2 vol% was significantly reduced to frontoparietal and posterior cingulate cortices but not to sensory areas. CONCLUSIONS: Sevoflurane decreased frontal and thalamocortical connectivity. The changes in blood oxygenation level dependent connectivity were consistent with reduced anterior-to-posterior directed connectivity and reduced cortical information processing. These data advance the understanding of sevoflurane-induced unconsciousness and contribute to a neural basis of electroencephalographic measures that hold promise for intraoperative anesthesia monitoring.