Experiences of medical students and nursing trainees from unexpected death through simulation training.

BACKGROUND: Dying in simulation training is controversially discussed. On the one hand, the danger of an emotional overload of the learners is pointed out. On the other hand, dying in simulation settings is addressed as an opportunity to prepare future health professionals to deal with patient death. The present study investigates how medical students and nursing trainees experience the sudden death of a simulated patient and how and under which conditions it can be valuable to simulate the patient's death. METHODS: At the TUM School of Medicine in Munich, Germany, we developed an interprofessional, simulation-based course in which participants were unexpectedly confronted with a cardiac arrest scenario within which resuscitation had to be discontinued due to an advanced directive. After the course, focus groups were conducted with nine medical students and six nursing trainees. Data were analysed using Grounded Theory techniques. RESULTS: The participants reported low to high emotional involvement. The active renunciation of life-sustaining measures was felt to be particularly formative and caused a strange feeling and helplessness. Questions of what could have been done differently determined interviewees' thoughts. The participants appreciated the opportunity to experience what it feels like to lose a patient. The course experience encouraged interviewees to reflect on dying and the interviewees explained that they feel better prepared to face death after the course. The unexpected character of the confrontation, presence of the advanced directive and debriefing positively affected the impact of the simulation. CONCLUSIONS: The study recognises simulation training as a promising approach for preparing future health care professionals to encounter a patient's death.

Changes in medical students´ and anesthesia technician trainees´ attitudes towards interprofessionality - experience from an interprofessional simulation-based course.

BACKGROUND: Interprofessional simulation based education (IPSBE) programs positively impact participants' attitudes towards interprofessional collaboration and learning. However, the extent to which students in different health professions benefit and the underlying reasons for this are subject of ongoing debate. METHODS: We developed a 14-h IPSBE course with scenarios of critical incidents or emergency cases. Participants were final year medical students (FYMS) and final year anesthesia technician trainees (FYATT). To assess attitudes towards interprofessionalism, the University of the West of England Interprofessional Questionnaire was administrated before and after the course. Using focus group illustration maps, qualitative data were obtained from a subcohort of the participants (n = 15). RESULTS: After the course, self-assessment of communication and teamwork skills, attitudes towards interprofessional interactions and relationships showed comparative improvement in both professions. Attitudes towards interprofessional learning improved only in FYMS. Qualitative data revealed teamwork, communication, hierarchy and the perception of one's own and other health profession as main topics that might underlie the changes in participants' attitudes. An important factor was that participants got to know each other during the course and understood each other's tasks. CONCLUSIONS: Since adequate communication and teamwork skills and positive attitudes towards interprofessionality account to effective interprofessional collaboration, our data support intensifying IPSBE in undergraduate health care education.

Sedative Properties of Dexmedetomidine Are Mediated Independently from Native Thalamic Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function at Clinically Relevant Concentrations.

Dexmedetomidine is a selective α2-adrenoceptor agonist and appears to disinhibit endogenous sleep-promoting pathways, as well as to attenuate noradrenergic excitation. Recent evidence suggests that dexmedetomidine might also directly inhibit hyperpolarization-activated cyclic-nucleotide gated (HCN) channels. We analyzed the effects of dexmedetomidine on native HCN channel function in thalamocortical relay neurons of the ventrobasal complex of the thalamus from mice, performing whole-cell patch-clamp recordings. Over a clinically relevant range of concentrations (1-10 µM), the effects of dexmedetomidine were modest. At a concentration of 10 µM, dexmedetomidine significantly reduced maximal Ih amplitude (relative reduction: 0.86 [0.78-0.91], n = 10, and p = 0.021), yet changes to the half-maximal activation potential V1/2 occurred exclusively in the presence of the very high concentration of 100 µM (-4,7 [-7.5--4.0] mV, n = 10, and p = 0.009). Coincidentally, only the very high concentration of 100 µM induced a significant deceleration of the fast component of the HCN activation time course (τfast: +135.1 [+64.7-+151.3] ms, n = 10, and p = 0.002). With the exception of significantly increasing the membrane input resistance (starting at 10 µM), dexmedetomidine did not affect biophysical membrane properties and HCN channel-mediated parameters of neuronal excitability. Hence, the sedative qualities of dexmedetomidine and its effect on the thalamocortical network are not decisively shaped by direct inhibition of HCN channel function.

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.

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.

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.

Xenon attenuates hippocampal long-term potentiation by diminishing synaptic and extrasynaptic N-methyl-D-aspartate receptor currents.

BACKGROUND: The memory-blocking properties of general anesthetics are of high clinical relevance and scientific interest. The inhalational anesthetic xenon antagonizes N-methyl-D-aspartate (NMDA) receptors. It is unknown if xenon affects long-term potentiation (LTP), a cellular correlate for memory formation. In hippocampal brain slices, the authors investigated in area CA1 whether xenon affects LTP, NMDA receptor-mediated neurotransmission, and intracellular calcium concentrations. METHODS: In sagittal murine hippocampal brain slices, the authors investigated the effects of xenon on LTP by recording excitatory postsynaptic field potentials. Using fluorometric calcium imaging, the authors tested the influence of xenon on calcium influx during high-frequency stimulation. In addition, using the patch-clamp technique, the xenon effect on synaptic and extrasynaptic NMDA receptors and L-type calcium channels was examined. RESULTS: In the absence of xenon, high-frequency stimulation reliably induced LTP and potentiated field potential slopes to (mean ± SEM) 127.2 ± 5.8% (P < 0.001). In the presence of xenon, high-frequency stimulation induced only a short-term potentiation, and field potentials returned to baseline level after 15-20 min (105.9 ± 2.9%; P = 0.090). NMDA receptor-mediated excitatory postsynaptic currents were reduced reversibly by xenon to 65.9 ± 9.4% (P = 0.007) of control. When extrasynaptic receptors were activated, xenon decreased NMDA currents to 58.2 ± 5.8% (P < 0.001). Xenon reduced the increase in intracellular calcium during high-frequency stimulation without affecting L-type calcium channels. CONCLUSIONS: N-methyl-D-aspartate receptor activation is crucial for the induction of CA1 LTP. Thus, the depression of NMDA receptor-mediated neurotransmission presumably contributes to the blockade of LTP under xenon. Because LTP is assumed to be involved in learning and memory, its blockade might be a key mechanism for xenon's amnestic properties.

s-ketamine enhances thalamocortical and corticocortical synaptic transmission in acute murine brain slices via increased AMPA-receptor-mediated pathways.

Despite ongoing research efforts and routine clinical use, the neuronal mechanisms underlying the anesthesia-induced loss of consciousness are still under debate. Unlike most anesthetics, ketamine increases thalamic and cortical activity. Ketamine is considered to act via a NMDA-receptor antagonism-mediated reduction of inhibition, i.e., disinhibition. Intact interactions between the thalamus and cortex constitute a prerequisite for the maintenance of consciousness and are thus a promising target for anesthetics to induce loss of consciousness. In this study, we aim to characterize the influence of s-ketamine on the thalamocortical network using acute brain-slice preparation. We performed whole-cell patch-clamp recordings from pyramidal neurons in cortical lamina IV and thalamocortical relay neurons in acute brain slices from CB57BL/6N mice. Excitatory postsynaptic potentials (EPSPs) were obtained via electrical stimulation of the cortex with a bipolar electrode that was positioned to lamina II/III (electrically induced EPSPs, eEPSPs) or via optogenetic activation of thalamocortical relay neurons (optogenetically induced EPSPs, oEPSPs). Intrinsic neuronal properties (like resting membrane potential, membrane threshold for action potential generation, input resistance, and tonic action potential frequency), as well as NMDA-receptor-dependent and independent spontaneous GABAA-receptor-mediated inhibitory postsynaptic currents (sIPSCs) were evaluated. Wilcoxon signed-rank test (level of significance < 0.05) served as a statistical test and Cohen's U3_1 was used to determine the actual effect size. Within 20 min, s-ketamine (5 µM) significantly increased both intracortical eEPSPs as well as thalamocortical oEPSPs. NMDA-receptor-mediated intracortical eEPSPs were significantly reduced. Intrinsic neuronal properties of cortical pyramidal neurons from lamina IV and thalamocortical relay neurons in the ventrobasal thalamic complex were not substantially affected. Neither a significant effect on NMDA-receptor-dependent GABAA sIPSCs (thought to underly a disinhibitory effect) nor a reduction of NMDA-receptor independent GABAA sIPSCs was observed. Both thalamocortical and intracortical AMPA-receptor-mediated EPSPs were significantly increased.In conclusion, our findings show no evidence for a NMDA-receptor antagonism-based disinhibition, but rather suggest an enhanced thalamocortical and intracortical synaptic transmission, which appears to be driven via increased AMPA-receptor-mediated transmission.

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

As thalamocortical relay neurons are ascribed a crucial role in signal propagation and information processing, they have attracted considerable attention as potential targets for anesthetic modulation. In this study, we analyzed the effects of different concentrations of sevoflurane on the excitability of thalamocortical relay neurons and hyperpolarization-activated, cyclic-nucleotide gated (HCN) channels, which play a decisive role in regulating membrane properties and rhythmic oscillatory activity. The effects of sevoflurane on single-cell excitability and native HCN channels were investigated in acutely prepared brain slices from adult wild-type mice with the whole-cell patch-clamp technique, using voltage-clamp and current-clamp protocols. Sevoflurane dose-dependently depressed membrane biophysics and HCN-mediated parameters of neuronal excitability. Respective half-maximal inhibitory and effective concentrations ranged between 0.30 (95% CI, 0.18-0.50) mM and 0.88 (95% CI, 0.40-2.20) mM. We witnessed a pronounced reduction of HCN dependent Ih current amplitude starting at a concentration of 0.45 mM [relative change at -133 mV; 0.45 mM sevoflurane: 0.85 (interquartile range, 0.79-0.92), n = 12, p = 0.011; 1.47 mM sevoflurane: 0.37 (interquartile range, 0.34-0.62), n = 5, p < 0.001] with a half-maximal inhibitory concentration of 0.88 (95% CI, 0.40-2.20) mM. In contrast, effects on voltage-dependent channel gating were modest with significant changes only occurring at 1.47 mM [absolute change of half-maximal activation potential; 1.47 mM: -7.2 (interquartile range, -10.3 to -5.8) mV, n = 5, p = 0.020]. In this study, we demonstrate that sevoflurane inhibits the excitability of thalamocortical relay neurons in a concentration-dependent manner within a clinically relevant range. Especially concerning its effects on native HCN channel function, our findings indicate substance-specific differences in comparison to other anesthetic agents. Considering the importance of HCN channels, the observed effects might mechanistically contribute to the hypnotic properties of sevoflurane.

Isoflurane anaesthesia reversibly improves cognitive function and long-term potentiation (LTP) via an up-regulation in NMDA receptor 2B subunit expression.

Postoperative cognitive dysfunction (POCD) is a decline in cognitive performance after a surgery performed under anaesthesia. The exact roles of surgery and/or anaesthesia for facilitating POCD are unclear. This study investigates the effects of isoflurane anaesthesia on cognitive performance and cellular mechanisms involved in learning and memory function. Male C57BL6/J mice (age: 4-5 months) were anaesthetized with isoflurane in oxygen/air (FiO(2)=0.5) for 2h, non-anaesthetized mice served as controls. After 24h, neurocognitive function, in vitro long-term potentiation (LTP), or protein expression were evaluated. In a visuospatial test, anaesthetized mice showed better cognitive performance as they learned faster compared to controls. In hippocampal slices of anaesthetized mice, in vitro LTP was enhanced as reflected in an increased extracellular field potential (fEPSP) slope after 1h to 210.2+/-17% (control: 156.8+/-7.2%; n=14; p<0.05). NR2B subunits of the NMDA receptors were selectively up-regulated in hippocampal neurones after anaesthesia. Blocking these receptors either with the NR2B selective antagonists ifenprodil or RO25-6981 (R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol), prevents the anaesthesia-induced improvement in cognitive function as well as enhancement of in vitro LTP. The anaesthesia-mediated effects on NR2B subunits were fully reversed to control levels seven days after anaesthesia. The present data suggests that isoflurane anaesthesia induces a hippocampus-specific elevation of NR2B subunit composition, enhances LTP in CA1 neurones, and produces hippocampal-dependent cognitive improvement.

Xenon attenuates excitatory synaptic transmission in the rodent prefrontal cortex and spinal cord dorsal horn.

BACKGROUND: The molecular mechanisms of the inhalational anesthetic xenon are not yet fully understood. Recently, the authors showed that xenon reduces both N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic transmission in a brain slice preparation of the amygdala. In the current study, the authors examined the effects of xenon on synaptic transmission in the prefrontal cortex and the spinal cord dorsal horn (substantia gelatinosa). METHODS: In rodent brain or spinal cord slice preparations, the authors used patch clamp technique to investigate the impact of xenon on NMDA and AMPA receptor-mediated excitatory postsynaptic currents, as well as on gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents. The currents were either evoked upon electrical stimulation (NMDA-eEPSCs and AMPA-eEPSCs) or upon photolysis of caged L-glutamate (p-NMDA-Cs and p-AMPA-Cs). In addition, the authors investigated the effects of xenon on AMPA receptor-mediated miniature excitatory postsynaptic currents. RESULTS: In both central nervous system regions, xenon had virtually no effect on inhibitory postsynaptic currents. In the prefrontal cortex (spinal cord), xenon reversibly reduced NMDA-eEPSCs to approximately 58% (72%) and AMPA-eEPSCs to approximately 67% (65%) of control. There was no difference in the xenon-induced reduction of NMDA-eEPSCs and p-NMDA-Cs, or AMPA-eEPSCs and p-AMPA-Cs. Xenon did not affect the frequency of miniature excitatory postsynaptic currents but reduced their amplitude. CONCLUSIONS: In the current study, the authors found that xenon depresses NMDA and AMPA receptor-mediated synaptic transmission in the prefrontal cortex and the substantia gelatinosa without affecting gamma-aminobutyric acid type A receptor-mediated synaptic transmission. These results provide evidence that the effects of xenon are primarily due to postsynaptic mechanisms.

Xenon reduces N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic transmission in the amygdala.

BACKGROUND: The neuronal and molecular targets of the inhalational general anesthetic xenon are a matter of debate. The current knowledge is largely based on studies using neurons in culture or heterologous expression systems. In the current study, the authors evaluated for the first time the effect of xenon on synaptic transmission in the basolateral amygdala in an in vitro brain slice preparation of the mouse. METHODS: A patch clamp technique was used to evaluate the effects of xenon on N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs), as well as on gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents. The currents were either evoked upon electrical stimulation (NMDA-eEPSCs, AMPA-eEPSCs) or upon focal, laser-guided photolysis of caged l-glutamate (p-NMDA-Cs, p-AMPA-Cs). In addition, the authors investigated the effects of xenon on miniature EPSCs. RESULTS: Xenon reversibly reduced basal synaptic transmission but had no effect on gamma-aminobutyric acid type A receptor-mediated inhibitory synaptic transmission. Xenon concentration-dependently diminished NMDA-eEPSCs and p-NMDA-Cs to the same amount. Likewise, xenon-induced reduction of AMPA-eEPSCs and p-AMPA-Cs did not differ. Xenon did not affect the frequency of miniature EPSCs but reduced their amplitude. CONCLUSIONS: In the current study, xenon considerably depressed NMDA and AMPA receptor-mediated synaptic transmission in the basolateral amygdala without affecting inhibitory synaptic transmission. The results provide evidence that the effects of xenon on NMDA- and AMPA-EPSCs are primarily mediated via postsynaptic mechanisms.

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.

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.

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.

GABA(A) receptor activation and open-channel block by volatile anaesthetics: a new principle of receptor modulation?

The rapid application of solutions containing the volatile anaesthetics isoflurane or sevoflurane induced inward currents in human embryonic kidney (HEK293) cells carrying rat recombinant alpha(1)beta(2)gamma(2L) GABA(A) receptor assemblies. The responses evoked by the anaesthetics applied via a fast delivery system were recorded using the patch-clamp technique in the whole-cell mode. The anaesthetics induced a fast inward current which was followed by a prominent tail current upon the rapid withdrawal of the agent. These currents were simulated using a kinetic scheme embodying two agonist-like binding steps required for receptor activation, and one binding step by which the anaesthetic induces an open-channel block. According to this model of a biphasic receptor modulation, the open-channel block delays the ion flux through the ligand-gated receptors and, thus, prolongs the overall duration of the current response. Open-channel blocks might also be operative in other ligand-gated ion channels to modulate synaptic strength.

Cloned human and murine serotonin(3A) receptors expressed in human embryonic kidney 293 cells display different single-channel kinetics.

In the present study, well-resolved single-channel events of cloned human and murine homomeric 5-hydroxytryptamine type 3 (h5-HT(3A) and m5-HT(3A)) receptors, expressed in human embryonic kidney 293 cells, are reported for the first time. 5-HT (1 microM) applied in Ca(2+)- and Mg(2+)-free external solution to excised outside-out membrane patches induced non-rectifying single-channel inward currents. These currents were not observed in untransfected cells or in the presence of the antagonist ondansetron (1 microM). The mean single-channel conductance of the h5-HT(3A) and m5-HT(3A) receptors was 48+/-8 pS and 46+/-7 pS, the mean reversal potential was 10.3+/-1.8 mV and 4.7+/-5.3 mV, respectively. The analysis of single-channel open-times revealed for both h5-HT(3A) and m5-HT(3A) receptors only one type of open state, but different mean open-times (7.1+/-2.9 ms vs. 4.1+/-0.8 ms) indicating species-dependent gating mechanisms of 5-HT(3) receptors.

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.

Isoflurane and sevoflurane dose-dependently impair hippocampal long-term potentiation.

Isoflurane and sevoflurane are commonly used volatile anaesthetics. Although acting via similar cellular mechanisms, the effect of different volatile anaesthetics on synaptic plasticity might differ. In the present study, using acute murine brain slice preparations, we compared the effects of isoflurane and sevoflurane on synaptic transmission and synaptic plasticity (long-term potentiation, LTP) in the CA1 stratum radiatum of the hippocampus. Isoflurane and sevoflurane dose-dependently diminished excitatory postsynaptic field potentials. In the presence of isoflurane (sevoflurane) at concentrations of 0.19, 0.28 and 0.37mM (0.11, 0.21 and 0.42mM), which correspond to 0.7-, 1.0- and 1.4-fold (0.3-, 0.6- and 1.1-fold) minimum alveolar concentration (MAC), high frequency stimulation reliably induced LTP. When isoflurane (sevoflurane) was applied at concentrations of 0.56 and 0.74mM (0.63 and 0.84mM), which equal 2.1- and 2.7-fold (1.7- and 2.2-fold) MAC, LTP was blocked. Our results indicate, that both anaesthetics influence synaptic strength to a similar degree, with only high concentrations blocking hippocampal CA1 stratum radiatum long-term potentiation.