Bertram Scheller

Ketamine Dysregulates the Amplitude and Connectivity of High-Frequency Oscillations in Cortical–Subcortical Networks in Humans: Evidence From Resting-State Magnetoencephalography-Recordings

Hypofunctioning of the N-methyl-D-aspartate receptor (NMDA-R) has been prominently implicated in the pathophysiology of schizophrenia (ScZ). The current study tested the effects of ketamine, a dissociative anesthetic and NMDA-R antagonist, on resting-state activity recorded with magnetoencephalography (MEG) in healthy volunteers. In a single-blind cross-over design, each participant (n = 12) received, on 2 different sessions, a subanesthetic dose of S-ketamine (0.006 mg/Kg) and saline injection. MEG-data were analyzed at sensor- and source-level in the beta (13-30 Hz) and gamma (30-90 Hz) frequency ranges. In addition, connectivity analysis at source-level was performed using transfer entropy (TE). Ketamine increased gamma-power while beta-band activity was decreased. Specifically, elevated 30-90 Hz activity was pronounced in subcortical (thalamus and hippocampus) and cortical (frontal and temporal cortex) regions, whilst reductions in beta-band power were localized to the precuneus, cerebellum, anterior cingulate, temporal and visual cortex. TE analysis demonstrated increased information transfer in a thalamo-cortical network after ketamine administration. The findings are consistent with the pronounced dysregulation of high-frequency oscillations following the inhibition of NMDA-R in animal models of ScZ as well as with evidence from electroencephalogram-data in ScZ-patients and increased functional connectivity during early illness stages. Moreover, our data highlight the potential contribution of thalamo-cortical connectivity patterns towards ketamine-induced neuronal dysregulation, which may be relevant for the understanding of ScZ as a disorder of disinhibition of neural circuits.

Interleukin-22 detected in patients with abdominal sepsis.

Interleukin 22 (IL-22) is a TH17-like cytokine known to specifically activate epithelial cells, thereby strengthening immune defense at host/environment interfaces. Animal studies suggest that IL-22 may play a crucial role in clinical sepsis. However, little is known about IL-22 in sepsis patients. In a single-center university hospital setting, serum IL-22 levels were assessed in 16 patients with the diagnosis of abdominal sepsis, 16 patients who have undergone elective major abdominal surgery without the diagnosis of sepsis, and 21 healthy volunteers. In accordance with current knowledge, we observed enhanced levels of IL-6 and IL-10 in serum specimens of sepsis patients compared with surgical control patients. Here, we report, for the first time, a modest but significant elevation of serum IL-22 detectable in abdominal sepsis patients (P < 0.001). Median serum concentrations of IL-22 were 111.8 pg/mL, 3.4 or 2.0 pg/mL, and 9.3 pg/mL for abdominal sepsis patients, surgical control patients (presurgery or postsurgery), and healthy volunteers, respectively. Interleukin 22 produced in the course of abdominal sepsis may contribute to host defense and stabilization of mucosal barrier functions under conditions of systemic infection.

High-frequency Components of Auditory Evoked Potentials Are Detected in Responsive but Not in Unconscious Patients

Background: The dose-dependent suppression of midlatency auditory evoked potentials by general anesthetics has been proposed to measure depth of anesthesia. In this study, perioperatively recorded midlatency auditory evoked potentials were analyzed in a time-frequency space to identify significant changes induced by general anesthesia. Methods: Perioperatively recorded auditory evoked potentials of 19 patients, recorded at varying levels of anesthesia, were submitted to a multiscale analysis using the wavelet analysis. Energy contents of the signal were calculated in frequency bands 0-57.1 Hz, 57.1-114.3 Hz, 114.3-228.6 Hz, and 228.6-457.1 Hz. A Friedman test and a Dunn multiple comparisons test were performed to identify significant differences. Results: Statistical evaluation showed a highly significant decrease of the wavelet energies for the frequency bands 57.1-114.3 Hz (P < 0.0001), 114.3-228.6 Hz (P < 0.0001), and 228.6-457.1 Hz (P < 0.0001) for the measuring points representing deep general anesthesia. This decrease is accompanied by a decrease in the wavelet energy of the frequency band 0-57.1 Hz of no statistical significance (P = 0.021) (level of significance set to P = 0.01). The changes are most prominent in the poststimulus interval between 10 and 30 ms. Conclusions: This study describes the presence of high-frequency components of the auditory evoked potential. The amount of these components is higher during responsiveness when compared to unconsciousness. Temporal localization of the high-frequency components within the auditory evoked potential shows that they represent a response to the auditory stimulus. Further studies are required to identify the source of these high-frequency components.

The early activation of toll-like receptor (TLR)-3 initiates kidney injury after ischemia and reperfusion

Acute kidney injury (AKI) is one of the most important complications in hospitalized patients and its pathomechanisms are not completely elucidated. We hypothesize that signaling via toll-like receptor (TLR)-3, a receptor that is activated upon binding of double-stranded nucleotides, might play a crucial role in the pathogenesis of AKI following ischemia and reperfusion (IR). Male adult C57Bl6 wild-type (wt) mice and TLR-3 knock-out (-/-) mice were subjected to 30 minutes bilateral selective clamping of the renal artery followed by reperfusion for 30 min 2.5h and 23.5 hours or subjected to sham procedures. TLR-3 down-stream signaling was activated already within 3 h of ischemia and reperfusion in post-ischemic kidneys of wt mice lead to impaired blood perfusion followed by a strong pro-inflammatory response with significant neutrophil invasion. In contrast, this effect was absent in TLR-3-/- mice. Moreover, the quick TLR-3 activation resulted in kidney damage that was histomorphologically associated with significantly increased apoptosis and necrosis rates in renal tubules of wt mice. This finding was confirmed by increased kidney injury marker NGAL in wt mice and a better preserved renal perfusion after IR in TLR-3-/- mice than wt mice. Overall, the absence of TLR-3 is associated with lower cumulative kidney damage and maintained renal blood perfusion within the first 24 hours of reperfusion. Thus, we conclude that TLR-3 seems to participate in the pathogenesis of early acute kidney injury.

Prednisolone as preservation additive prevents from ischemia reperfusion injury in a rat model of orthotopic lung transplantation.

The lung is, more than other solid organs, susceptible for ischemia reperfusion injury after orthotopic transplantation. Corticosteroids are known to potently suppress pro-inflammatory processes when given in the post-operative setting or during rejection episodes. Whereas their use has been approved for these clinical indications, there is no study investigating its potential as a preservation additive in preventing vascular damage already in the phase of ischemia. To investigate these effects we performed orthotopic lung transplantations (LTX) in the rat. Prednisolone was either added to the perfusion solution for lung preservation or omitted and rats were followed for 48 hours after LTX. Prednisolone preconditioning significantly increased survival and diminished reperfusion edema. Hypoxia induced vasoactive cytokines such as VEGF were reduced. Markers of leukocyte invasiveness like matrix metalloprotease (MMP)-2, or common pro-inflammatory molecules like the CXCR4 receptor or the chemokine (C-C motif) ligand (CCL)-2 were downregulated by prednisolone. Neutrophil recruitment to the grafts was only increased in Perfadex treated lungs. Together with this, prednisolone treated animals displayed significantly reduced lung protein levels of neutrophil chemoattractants like CINC-1, CINC-2α/β and LIX and upregulated tissue inhibitor of matrix metalloproteinase (TIMP)-1. Interestingly, lung macrophage invasion was increased in both, Perfadex and prednisolone treated grafts, as measured by MMP-12 or RM4. Markers of anti-inflammatory macrophage transdifferentiation like MRC-1, IL-13, IL-4 and CD163, significantly correlated with prednisolone treatment. These observations lead to the conclusion that prednisolone as an additive to the perfusion solution protects from hypoxia triggered danger signals already in the phase of ischemia and thus reduces graft edema in the phase of reperfusion. Additionally, prednisolone preconditioning might also lead to macrophage polarization as a beneficial long-term effect.

Deguelin Attenuates Reperfusion Injury and Improves Outcome after Orthotopic Lung Transplantation in the Rat

The main goal of adequate organ preservation is to avoid further cellular metabolism during the phase of ischemia. However, modern preservation solutions do rarely achieve this target. In donor organs hypoxia and ischemia induce a broad spectrum of pathologic molecular mechanisms favoring primary graft dysfunction (PGD) after transplantation. Increased hypoxia-induced transcriptional activity leads to increased vascular permeability which in turn is the soil of a reperfusion edema and the enhancement of a pro-inflammatory response in the graft after reperfusion. We hypothesize that inhibition of the respiration chain in mitochondria and thus inhibition of the hypoxia induced mechanisms might reduce reperfusion edema and consecutively improve survival in vivo. In this study we demonstrate that the rotenoid Deguelin reduces the expression of hypoxia induced target genes, and especially VEGF-A, dose-dependently in hypoxic human lung derived cells. Furthermore, Deguelin significantly suppresses the mRNA expression of the HIF target genes VEGF-A, the pro-inflammatory CXCR4 and ICAM-1 in ischemic lungs vs. control lungs. After lung transplantation, the VEGF-A induced reperfusion-edema is significantly lower in Deguelin-treated animals than in controls. Deguelin-treated rats exhibit a significantly increased survival-rate after transplantation. Additionally, a downregulation of the pro-inflammatory molecules ICAM-1 and CXCR4 and an increase in the recruitment of immunomodulatory monocytes (CD163+ and CD68+) to the transplanted organ involving the IL4 pathway was observed. Therefore, we conclude that ischemic periods preceding reperfusion are mainly responsible for the increased vascular permeability via upregulation of VEGF. Together with this, the resulting endothelial dysfunction also enhances inflammation and consequently lung dysfunction. Deguelin significantly decreases a VEGF-A induced reperfusion edema, induces the recruitment of immunomodulatory monocytes and thus improves organ function and survival after lung transplantation by interfering with hypoxia induced signaling.

Disposable laryngeal tube suction: Standard insertion technique versus two modified insertion techniques for patients with a simulated difficult airway

OBJECTIVE The disposable laryngeal tube suction (LTS-D) is a supraglottic airway device that can be used as an alternative to tracheal tube to provide ventilation. We tested the hypothesis that, with a frontal jaw thrust insertion technique (FIT/JT), the rate of correct placement attempts in patients with a simulated difficult airway by means of a rigid cervical immobilization collar could be significantly increased compared to the standard insertion technique (SIT) recommended by the manufacturer. METHODS 70 adult patients undergoing trauma surgery under general anaesthesia had an LTS-D inserted, randomly assigned to the SIT or FIT/JT. In the FIT/JT, the operator was standing in front of the patients head, and forced chin lift to create sufficient retropharyngeal space was performed. The rate of successful tube placements within 180s and with a maximum of two attempts was the main outcome variable. To distinguish between the effects of the frontal approach and the jaw thrust manoeuvre, a third group was studied after completion of the SIT and FIT/JT groups. The standard insertion technique, but with a jaw thrust manoeuvre (SIT/JT), was employed in another 35 consecutive patients. RESULTS Overall placement success was 49% (SIT, 17/35 patients, P<0.001), 91% (SIT/JT, 32/35 patients) and 100% (FIT/JT). The time required for successful insertion was shortest in the FIT/JT group (23±6s), and significantly longer in the SIT/JT (42±29s, P<0.001) and SIT groups (51±29s, P<0.0001). CONCLUSION In anaesthetised patients with a simulated difficult airway created with a rigid cervical collar, the overall LTS-D placement success was significantly higher when a jaw thrust manoeuvre was performed, regardless of the particular technique used to introduce the LTS-D. Therefore, an intense jaw thrust manoeuvre should be performed whenever an LTS-D is being inserted.

The discriminant power of simultaneous monitoring of spontaneous electroencephalogram and evoked potentials as a predictor of different clinical states of general anesthesia

Spontaneous or evoked electrical brain activity is increasingly used to monitor general anesthesia. Previous studies investigated the variables from spontaneous electroencephalogram (EEG), acoustic (AEP), or somatosensory evoked potentials (SSEP). But, by monitoring them separately, the available information from simultaneous gathering could be missed. We investigated whether the combination of simultaneous information from EEG, AEP, and SSEP shows a more discriminant power to differentiate between anesthesia states than from information derived from each measurement alone. Therefore, we assessed changes of 30 EEG, 21 SSEP, and 29 AEP variables recorded from 59 patients during four clinical states of general anesthesia: “awake,” “light anesthesia,” “surgical anesthesia,” and “deep surgical anesthesia.” The single and combined discriminant powers of EEG, AEP, and SSEP variables as predictors of these states were investigated by discriminant analysis. EEG variables showed a higher discriminant power than AEP or SSEP variables: 85%, 46%, and 32% correctly classified cases, respectively. The frequency of correctly classified cases increased to 90% and 91% with information from EEG + AEP and EEG + AEP + SSEP, respectively. Thus, future anesthesia monitoring should consider combined information simultaneously distributed on different electrophysiological measurements, rather than single variables or their combination from EEG or AEP or SSEP.

Time-dependent effects of hyperoxia on the BOLD fMRI signal in primate visual cortex and LGN

Hyperoxia is present in many anaesthesia protocols used in animal blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. However, little data exist on the influence of hyperoxia on the magnitude of stimulus-induced relative changes in BOLD fMRI signal (DeltaBOLD%). No study to date has investigated these effects in a time-resolved manner, although cerebral vasoregulation offers sites for a time-dependent interaction of hyperoxia and DeltaBOLD%. Here we investigated time-dependent effects of an inspiratory oxygen fraction of 90%. We tightly clamped end tidal CO(2) and body temperature and recorded physiological parameters relevant to rCBF in (fentanyl/isoflurane) anaesthetized monkeys while using visual stimulation to elicit DeltaBOLD%. To clarify whether changes in DeltaBOLD% arose from changes in baseline blood oxygenation or rather altered neuronal or vascular reactivity, we directly measured changes in rCBV using monocrystalline ion oxide nanoparticles (MION) as contrast agent. In visual cortex we found a biphasic modulation of stimulus-induced DeltaBOLD% under hyperoxia: We observed first a significant decrease in DeltaBOLD% by -24% for data averaged over the time interval of 0-180 min post onset of hyperoxia followed by a subsequent recovery to baseline. rCBV response amplitudes were decreased by 21% in the same time interval (0-180 min). In the LGN, we neither found a significant modulation of DeltaBOLD% nor of MION response amplitude. The cerebrovascular effects of hyperoxia may, therefore, be regionally specific and cannot be explained by a deoxyhemoglobin dilution model accounting for plasma oxygenation without assuming altered neuronal activity or altered neurovascular coupling.

Individual organ failure and concomitant risk of mortality differs according to the type of admission to ICU : a retrospective study of SOFA score of 23,795 patients

Introduction Organ dysfunction or failure after the first days of ICU treatment and subsequent mortality with respect to the type of intensive care unit (ICU) admission is poorly elucidated. Therefore we analyzed the association of ICU mortality and admission for medical (M), scheduled surgery (ScS) or unscheduled surgery (US) patients mirrored by the occurrence of organ dysfunction/failure (OD/OF) after the first 72h of ICU stay. Methods For this retrospective cohort study (23,795 patients; DIVI registry; German Interdisciplinary Association for Intensive Care Medicine (DIVI)) organ dysfunction or failure were derived from the Sequential Organ Failure Assessment (SOFA) score (excluding the Glasgow Coma Scale). SOFA scores were collected on admission to ICU and 72h later. For patients with a length of stay of at least five days, a multivariate analysis was performed for individual OD/OF on day three. Results M patients had the lowest prevalence of cardiovascular failure (M 31%; ScS 35%; US 38%), and the highest prevalence of respiratory (M 24%; ScS 13%; US 17%) and renal failure (M 10%; ScS 6%; US 7%). Risk of death was highest for M- and ScS-patients in those with respiratory failure (OR; M 2.4; ScS 2.4; US 1.4) and for surgical patients with renal failure (OR; M 1.7; ScS 2.7; US 2.4). Conclusion The dynamic evolution of OD/OF within 72h after ICU admission and mortality differed between patients depending on their types of admission. This has to be considered to exclude a systematic bias during multi-center trials.