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.

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.

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.

Perioperative risk factors for postoperative pulmonary complications after major oral and maxillofacial surgery with microvascular reconstruction: A retrospective analysis of 648 cases.

BACKGROUND: Postoperative pulmonary complications (PPCs) are common and result in prolonged hospital stays, higher costs and increased mortality. However, data on the incidence and predictors of PPCs after major oral and maxillofacial surgery with microvascular reconstruction are rare. This retrospective analysis identifies perioperative risk factors for postoperative pulmonary complications (PPCs) after major oral and maxillofacial surgery with microvascular reconstruction. METHODS: Perioperative data and patient records of 648 subjects were analyzed in the period of June 2007 to May 2013. PPCs were defined as pneumonia, atelectasis, pleural effusions, pulmonary embolism, pulmonary oedema, pneumothorax or respiratory failure. RESULTS: 18.8% of all patients developed PPCs. Patient-related risk factors for PPCs were male sex, advanced age, smoking, alcohol abuse, a body mass index >30, American Society of Anaesthesiologists grade higher than 2, pre-existent pulmonary diseases and preoperative antihypertensive medication. Among the investigated procedure-related variables, the length of the operation, the amount of fluid administration and blood transfusion and an impaired oxygenation index during surgery were shown to be associated with the development of PPCs. Using a multivariable logistic regression model, we identified a body mass index >30, American Society of Anaesthesiologists grade higher than 2 and alcohol abuse as independent risk factors for PPCs. CONCLUSIONS: Several perioperative factors can be identified that are associated with the development of PPCs. Patients having one or more of these conditions should be subjected to intensified postoperative pulmonary care.

Situation awareness errors in anesthesia and critical care in 200 cases of a critical incident reporting system.

BACKGROUND: A loss of adequate Situation Awareness (SA) may play a major role in the genesis of critical incidents in anesthesia and critical care. This observational study aimed to determine the frequency of SA errors in cases of a critical incident reporting system (CIRS). METHODS: Two experts independently reviewed 200 cases from the German Anesthesia CIRS. For inclusion, reports had to be related to anesthesia or critical care for an individual patient and take place in an in-hospital setting. Based on the SA framework, the frequency of SA errors was determined. Representative cases were analyzed qualitatively to illustrate the role of SA for decision-making. RESULTS: SA errors were identified in 81.5%. Predominantly, errors occurred on the levels of perception (38.0%) and comprehension (31.5%). Errors on the level of projection played a minor role (12.0%). The qualitative analysis of selected cases illustrates the crucial role of SA for decision-making and performance. CONCLUSIONS: SA errors are very frequent in critical incidents reported in a CIRS. The SA taxonomy was suitable to provide mechanistic insights into the central role of SA for decision-making and thus, patient safety.

Impact of Hyperpolarization-activated, Cyclic Nucleotide-gated Cation Channel Type 2 for the Xenon-mediated Anesthetic Effect: Evidence from In Vitro and In Vivo Experiments.

BACKGROUND: The thalamus is thought to be crucially involved in the anesthetic state. Here, we investigated the effect of the inhaled anesthetic xenon on stimulus-evoked thalamocortical network activity and on excitability of thalamocortical neurons. Because hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels are key regulators of neuronal excitability in the thalamus, the effect of xenon on HCN channels was examined. METHODS: The effects of xenon on thalamocortical network activity were investigated in acutely prepared brain slices from adult wild-type and HCN2 knockout mice by means of voltage-sensitive dye imaging. The influence of xenon on single-cell excitability in brain slices was investigated using the whole-cell patch-clamp technique. Effects of xenon on HCN channels were verified in human embryonic kidney cells expressing HCN2 channels. RESULTS: Xenon concentration-dependently diminished thalamocortical signal propagation. In neurons, xenon reduced HCN channel-mediated Ih current amplitude by 33.4 ± 12.2% (at -133 mV; n = 7; P = 0.041) and caused a left-shift in the voltage of half-maximum activation (V1/2) from -98.8 ± 1.6 to -108.0 ± 4.2 mV (n = 8; P = 0.035). Similar effects were seen in human embryonic kidney cells. The impairment of HCN channel function was negligible when intracellular cyclic adenosine monophosphate level was increased. Using HCN2 mice, we could demonstrate that xenon did neither attenuate in vitro thalamocortical signal propagation nor did it show sedating effects in vivo. CONCLUSIONS: Here, we clearly showed that xenon impairs HCN2 channel function, and this impairment is dependent on intracellular cyclic adenosine monophosphate levels. We provide evidence that this effect reduces thalamocortical signal propagation and probably contributes to the hypnotic properties of xenon.

Differences between state entropy and bispectral index during analysis of identical electroencephalogram signals: a comparison with two randomised anaesthetic techniques.

BACKGROUND: It is claimed that bispectral index (BIS) and state entropy reflect an identical clinical spectrum, the hypnotic component of anaesthesia. So far, it is not known to what extent different devices display similar index values while processing identical electroencephalogram (EEG) signals. OBJECTIVE: To compare BIS and state entropy during analysis of identical EEG data. Inspection of raw EEG input to detect potential causes of erroneous index calculation. DESIGN: Offline re-analysis of EEG data from a randomised, single-centre controlled trial using the Entropy Module and an Aspect A-2000 monitor. SETTING: Klinikum rechts der Isar, Technische Universität München, Munich. PATIENTS: Forty adult patients undergoing elective surgery under general anaesthesia. INTERVENTIONS: Blocked randomisation of 20 patients per anaesthetic group (sevoflurane/remifentanil or propofol/remifentanil). Isolated forearm technique for differentiation between consciousness and unconsciousness. MAIN OUTCOME MEASURES: Prediction probability (PK) of state entropy to discriminate consciousness from unconsciousness. Correlation and agreement between state entropy and BIS from deep to light hypnosis. Analysis of raw EEG compared with index values that are in conflict with clinical examination, with frequency measures (frequency bands/Spectral Edge Frequency 95) and visual inspection for physiological EEG patterns (e.g. beta or delta arousal), pathophysiological features such as high-frequency signals (electromyogram/high-frequency EEG or eye fluttering/saccades), different types of electro-oculogram or epileptiform EEG and technical artefacts. RESULTS: PK of state entropy was 0.80 and of BIS 0.84; correlation coefficient of state entropy with BIS 0.78. Nine percent BIS and 14% state entropy values disagreed with clinical examination. Highest incidence of disagreement occurred after state transitions, in particular for state entropy after loss of consciousness during sevoflurane anaesthesia. EEG sequences which led to false 'conscious' index values often showed high-frequency signals and eye blinks. High-frequency EEG/electromyogram signals were pooled because a separation into EEG and fast electro-oculogram, for example eye fluttering or saccades, on the basis of a single EEG channel may not be very reliable. These signals led to higher Spectral Edge Frequency 95 and ratio of relative beta and gamma band power than EEG signals, indicating adequate unconscious classification. The frequency of other artefacts that were assignable, for example technical artefacts, movement artefacts, was negligible and they were excluded from analysis. CONCLUSION: High-frequency signals and eye blinks may account for index values that falsely indicate consciousness. Compared with BIS, state entropy showed more false classifications of the clinical state at transition between consciousness and unconsciousness.

Electromyographic permutation entropy quantifies diaphragmatic denervation and reinnervation.

Spontaneous reinnervation after diaphragmatic paralysis due to trauma, surgery, tumors and spinal cord injuries is frequently observed. A possible explanation could be collateral reinnervation, since the diaphragm is commonly double-innervated by the (accessory) phrenic nerve. Permutation entropy (PeEn), a complexity measure for time series, may reflect a functional state of neuromuscular transmission by quantifying the complexity of interactions across neural and muscular networks. In an established rat model, electromyographic signals of the diaphragm after phrenicotomy were analyzed using PeEn quantifying denervation and reinnervation. Thirty-three anesthetized rats were unilaterally phrenicotomized. After 1, 3, 9, 27 and 81 days, diaphragmatic electromyographic PeEn was analyzed in vivo from sternal, mid-costal and crural areas of both hemidiaphragms. After euthanasia of the animals, both hemidiaphragms were dissected for fiber type evaluation. The electromyographic incidence of an accessory phrenic nerve was 76%. At day 1 after phrenicotomy, PeEn (normalized values) was significantly diminished in the sternal (median: 0.69; interquartile range: 0.66-0.75) and mid-costal area (0.68; 0.66-0.72) compared to the non-denervated side (0.84; 0.78-0.90) at threshold p<0.05. In the crural area, innervated by the accessory phrenic nerve, PeEn remained unchanged (0.79; 0.72-0.86). During reinnervation over 81 days, PeEn normalized in the mid-costal area (0.84; 0.77-0.86), whereas it remained reduced in the sternal area (0.77; 0.70-0.81). Fiber type grouping, a histological sign for reinnervation, was found in the mid-costal area in 20% after 27 days and in 80% after 81 days. Collateral reinnervation can restore diaphragm activity after phrenicotomy. Electromyographic PeEn represents a new, distinctive assessment characterizing intramuscular function following denervation and reinnervation.

Monitoring depth of anesthesia utilizing a combination of electroencephalographic and standard measures.

BACKGROUND: For decades, monitoring depth of anesthesia was mainly based on unspecific effects of anesthetics, for example, blood pressure, heart rate, or drug concentrations. Today, electroencephalogram-based monitors promise a more specific assessment of the brain function. To date, most approaches were focused on a "head-to-head" comparison of either electroencephalogram- or standard parameter-based monitoring. In the current study, a multimodal indicator based on a combination of both electro encephalographic and standard anesthesia monitoring parameters is defined for quantification of "anesthesia depth." METHODS: Two hundred sixty-three adult patients from six European centers undergoing surgery with general anesthesia were assigned to 1 of 10 anesthetic combinations according to standards of the enrolling hospital. The anesthesia multimodal index of consciousness was developed using a data-driven approach, which maps standard monitoring and electroencephalographic parameters into an output indicator that separates different levels of anesthesia from awake to electroencephalographic burst suppression. Obtained results were compared with either a combination of standard monitoring parameters or the electroencephalogram-based bispectral index. RESULTS: The anesthesia multimodal index of consciousness showed prediction probability (P(K)) of 0.96 (95% CI, 0.95 to 0.97) to separate different levels of anesthesia (wakefulness to burst suppression), whereas the bispectral index had significantly lower PK of 0.80 (0.76 to 0.81) at corrected threshold P value of less than 0.05. At the transition between consciousness and unconsciousness, anesthesia multimodal index of consciousness yielded a PK of 0.88 (0.85 to 0.91). CONCLUSION: A multimodal integration of both standard monitoring and electroencephalographic parameters may more precisely reflect the level of anesthesia compared with monitoring based on one of these aspects alone.

Tranexamic acid impairs γ-aminobutyric acid receptor type A-mediated synaptic transmission in the murine amygdala: a potential mechanism for drug-induced seizures?

BACKGROUND: Tranexamic acid (TXA) is commonly used to reduce blood loss in cardiac surgery and in trauma patients. High-dose application of TXA is associated with an increased risk of postoperative seizures. The neuronal mechanisms underlying this proconvulsant action of TXA are not fully understood. In this study, the authors investigated the effects of TXA on neuronal excitability and synaptic transmission in the basolateral amygdala. METHODS: Patch clamp recordings and voltage-sensitive dye imaging were performed in acute murine brain slices. Currents through N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor type A (GABAA) receptors were recorded. GABAA receptor-mediated currents were evoked upon electrical stimulation or upon photolysis of caged GABA. TXA was applied at different concentrations. RESULTS: Voltage-sensitive dye imaging demonstrates that TXA (1 mM) reversibly enhances propagation of neuronal excitation (mean ± SEM, 129 ± 6% of control; n = 5). TXA at concentrations of 0.1, 0.3, 1, 5, or 10 mM led to a dose-dependent reduction of GABAA receptor-mediated currents in patch clamp recordings. There was no difference in the half-maximal inhibitory concentration for electrically (0.76 mM) and photolytically (0.84 mM) evoked currents (n = 5 to 9 for each concentration), and TXA did not affect the paired-pulse ratio of GABAA receptor-mediated currents. TXA did not impact glutamatergic synaptic transmission. CONCLUSIONS: This study clearly demonstrates that TXA enhances neuronal excitation by antagonizing inhibitory GABAergic neurotransmission. The results provide evidence that this effect is mediated via postsynaptic mechanisms. Because GABAA receptor antagonists are known to promote epileptiform activity, this effect might explain the proconvulsant action of TXA.

Brain electrical activity obeys Benford's law.

BACKGROUND: Monitoring and automated online analysis of brain electrical activity are frequently used for verifying brain diseases and for estimating anesthetic depth in subjects undergoing surgery. However, false diagnosis with potentially catastrophic consequences for patients such as intraoperative awareness may result from unnoticed irregularities in the process of signal analysis. Here we ask whether Benford's Law can be applied to detect accidental or intended modulation of neurophysiologic signals. This law states that the first digits of many datasets such as atomic weights or river lengths are distributed logarithmically and not equally. In particular, we tested whether data obtained from electrophysiological recordings of human patients representing global activity and organotypic slice cultures representing pure cortical activity follow the predictions of Benford's Law in the absence and in the presence of an anesthetic drug. METHODS: Electroencephalographic (EEG) recordings from human subjects and local field potential recordings from cultured cortical brain slices were obtained before and after administration of sevoflurane. The first digit distribution of the datasets was compared with the Benford distribution. RESULTS: All datasets showed a Benford-like distribution. Nevertheless, distributions belonging to different anesthetic levels could be distinguished in vitro and in human EEGs. With sevoflurane, the first digit distribution of the in vitro data becomes steeper, while it flattens for EEG data. In the presence of high frequency noise, the Benford distribution falls apart. CONCLUSIONS: In vitro and EEG data show a Benford-like distribution which is altered by sevoflurane or destroyed by noise used to simulate artefacts. These findings suggest that algorithms based on Benford's Law can be successfully used to detect sevoflurane-induced signal modulations in electrophysiological recordings.

Sevoflurane anesthesia improves cognitive performance in mice, but does not influence in vitro long-term potentation in hippocampus CA1 stratum radiatum.

BACKGROUND: Whether the occurrence of postoperative cognitive dysfunction is a result of the effects of surgery or anesthesia is under debate. In this study, we investigated the impact of sevoflurane anesthesia on cognitive performance and cellular mechanisms involved in learning and memory. METHODS: Male C57Bl6/J mice (4-5 months) were exposed to one minimum alveolar concentration sevoflurane for two hours. After 24 h, cognitive performance of mice was assessed using the modified hole board test. Additionally, we evaluated hippocampal long-term potentiation and expression levels of different receptor subunits by recording excitatory postsynaptic field potentials and using the western blot technique, respectively. Non-anesthetized mice served as controls. RESULTS: In anesthetized mice, neither cognitive performance nor long-term potentiation was impaired 24 h after anesthesia. Interestingly, sevoflurane anesthesia induced even an improvement of cognitive performance and an elevation of the expression levels of N-methyl-D-aspartate (NMDA) receptor type 1 and 2B subunits in the hippocampus. CONCLUSIONS: Since NMDA receptor type 1 and 2B subunits play a crucial role in processes related to learning and memory, we hypothesize that sevoflurane-induced changes in NMDA receptor subunit composition might cause hippocampus-dependent cognitive improvement. The data of the present study are in favor of a minor role of anesthesia in mediating postoperative cognitive dysfunction.

Functional outcome in female rats after 45 minutes of deep hypothermic circulatory arrest: gender matters.

BACKGROUND: After adjusting for cofactors, female gender remains an independent risk factor. The aim of our study was to investigate the role of gender on functional outcome 14 days after 45 minutes of deep hypothermic circulatory arrest (DHCA) in rats. METHODS: After institutional animal care committee Institutional Review Board approval, 40 male and 40 female rats were randomly divided into two groups (40 DHCA, 40 controls). The rats were neutered or sham-neutered and 40 of them were subjected to DHCA with 40 controls remaining naïve. Postoperative functional performance was assessed with modified hole-board test. Brain morphology was assessed using hematoxylin and eosin (HE) staining and cerebral inflammation/apoptosis determined immunohistochemically. Data were analyzed using general linear models (post hoc analysis of variance [ANOVA] and Bonferroni t tests) and Kruskal-Wallis (post hoc Mann-Whitney U test) (p < 0.05). RESULTS: Cognition and behavior after 45 minutes of DHCA were comparable to that of four naïve rats in all four DHCA groups. Motor function and morphologic outcome were better in females. Nuclear factor kappa B (NFκB) was upregulated in the female normal group. Activated caspase-3 was higher in females whereas poly(ADP-ribose) polymerase was in males. Of note is the secondary finding of a high drop-out rate during the early postoperative phase in the female groups (16 out of 37). CONCLUSIONS: Postoperative motor skills were better in females, with less neuronal damage, more neuronal NFκB, and activated caspase-3. However, the chance finding of a high mortality rate in females warrants investigation with mortality as the principal aim, focusing on heart, liver, lung, kidney, and intestine with regard to its rate.

Does the cerebral state index separate consciousness from unconsciousness?

BACKGROUND: The Cerebral State Monitor™ (CSM) is an electroencephalogram (EEG)-based monitor that is claimed to measure the depth of hypnosis during general anesthesia. We calculated the prediction probability (P(K)) for its ability to separate consciousness from unconsciousness in surgical patients with different anesthetic regimens. METHODS: Digitized EEG recordings of a previous study of 40 nonpremedicated, adult patients undergoing elective surgery under general anesthesia were replayed using an EEG player and reanalyzed using the CSM. Patients were randomly assigned to receive either sevoflurane-remifentanil or propofol-remifentanil. The study design included a slow induction of anesthesia and an episode of intended wakefulness. CSM values at loss and return of consciousness were compared. P(K) was calculated from values 30 seconds before and 30 seconds after loss and return of consciousness. RESULTS: The P(K) for the differentiation between consciousness and unconsciousness was 0.75 ± 0.03 (mean ± SE). For sevoflurane-remifentanil, P(K) was 0.71 ± 0.04. For propofol-remifentanil, P(K) was 0.81 ± 0.03. CONCLUSIONS: The ability of CSM for separation of consciousness and unconsciousness was comparable to other commercially available EEG-based indices.

Xenon administration immediately after but not before or during cardiopulmonary bypass with cerebral air embolism impairs cerebral outcome in rats.

CONTEXT: The neuroprotective properties of xenon might improve cerebral outcome after cardiac surgery using cardiopulmonary bypass. However, in the presence of cerebral air emboli, xenon impaired cognitive and histological outcome in a rat cardiopulmonary bypass model, a result which is due to the property of xenon to expand air bubbles. OBJECTIVE: The current study was designed to assess whether cerebral outcome in the setting of cardiopulmonary bypass with cerebral air embolism could be altered by administration of xenon restricted to periods when the occurrence of cerebral air embolism is unlikely. DESIGN: With institutional review board approval, 40 rats were allocated randomly to one of four groups (n = 10) which determined the period of xenon inhalation: 'before', 'during' or 'after' cardiopulmonary bypass or 'none'. SETTING: Rats were subjected to 90  min of normothermic cardiopulmonary bypass combined with 10 small cerebral air emboli. Xenon was administered according to group assignment: the 'none' group received no xenon; in the other groups, the lungs were ventilated with 56% xenon before, during or after cardiopulmonary bypass and cerebral air embolism. MAIN OUTCOME MEASURES: Motor and cognitive outcomes were tested using the modified hole-board test. Cerebral infarction volumes were determined on postoperative day 21. RESULTS: Animals that received xenon after cardiopulmonary bypass and cerebral air embolism had impaired motor function scores [after: median 6.6 (range 0.25-8), before: 0.5 (0-3), during: 1.5 (0.25-2.75), none: 1 (0-1.75)] and cognitive performance [after: 9 (6.5-9), before: 0 (0-5.5), during: 1 (0-5.5), none: 1 (0-4)] compared with all other groups (P < 0.05). Administration of xenon after cardiopulmonary bypass and cerebral air embolism also led to larger cerebral infarction volumes [after: 74 µl (54-157), before: 45 µl (20-82), during: 33 µl (23-54), none: 22 µl (17-78)] compared with the groups that received xenon during cardiopulmonary bypass and cerebral air embolism or no xenon at all (P < 0.05). CONCLUSION: Xenon administered immediately after cardiopulmonary bypass and cerebral air embolism impaired motor, cognitive and histological outcome in rats. At no time did inhalation of xenon lead to any beneficial effects on cerebral outcome when compared with inhalation of nitrogen.

Perioperative moxifloxacin treatment in rats subjected to deep hypothermic circulatory arrest: reduction in cerebral inflammation but without improvement in cognitive performance.

OBJECTIVE: Moxifloxacin reduces infectious complications after cerebral damage, such as ischemia and stroke. This study investigated whether moxifloxacin treatment influences cerebral inflammation and improves cognitive outcome after cardiopulmonary bypass with deep hypothermic circulatory arrest in rats. METHODS: Rats were randomly assigned to deep hypothermic circulatory arrest (n = 40), sham operation (n = 40), and untreated control (n = 20) groups. Deep hypothermic circulatory arrest and sham groups were equally subdivided into moxifloxacin and placebo subgroups, receiving 6 × 100 mg/kg moxifloxacin or saline solution every 2 hours intraperitoneally. Hippocampal tumor necrosis factor α, nuclear factor κB, cyclooxygenase 2, and macrophages were assessed immunohistochemically. Histologic outcome was determined with hematoxylin and eosin. Neurologic outcome was assessed preoperatively and postoperatively. Cognitive performance was tested with the modified hole board test for 14 postoperative days. RESULTS: On postoperative day 14, deep hypothermic circulatory arrest moxifloxacin group was lower than deep hypothermic circulatory arrest placebo group in hippocampal neurons positive for tumor necrosis factor α (1.33, 0.73-2.37, vs 4.10, 2.42-18.67), nuclear factor κB (3.03, 1.33-5.20, vs 9.32, 2.53-24.14), and cyclooxygenase 2 (3.16, 0.68-6.04, vs 8.07, 3.27-19.91) and also had fewer macrophages than all other groups (72, 60-90, vs deep hypothermic circulatory arrest placebo 128, 76-203, sham moxifloxacin 89, 48-96, and sham placebo 81, 47-87). On postoperative day 14, both deep hypothermic circulatory arrest groups showed impaired motor, cognitive, and histologic outcomes relative to sham-operated groups, with no difference between deep hypothermic circulatory arrest subgroups. CONCLUSIONS: Moxifloxacin transiently reduces cerebral inflammatory reaction, but without impact on neurologic function, histologic outcome, or long-term cognitive performance.