Correlation between Bilirubin Elimination with the Cytokine Adsorber CytoSorb® and Mortality in Critically Ill Patients with Hyperbilirubinemia.

INTRODUCTION: Hyperbilirubinemia is often the first evidence for any kind of liver disorder and over one-third of all patients in intensive care units (ICU) show elevated bilirubin concentrations. In critically ill patients, high concentrations of serum bilirubin are correlated with a poor outcome. Therapies to lower bilirubin concentrations are often just symptomatically and their effect on the patients' outcome is hardly evaluated. Therefore, this study investigates whether the extracorporeal elimination of bilirubin with the cytokine adsorber CytoSorb® (CS) reduces mortality in patients with hyperbilirubinemia. METHODS: Patients with bilirubin concentrations >10 mg/dL at the ICU were screened for evaluation from 2018 to 2020. Patients with kidney replacement therapy and older than 18 years were included. Patients with continuously decreasing bilirubin concentrations after liver transplantation or other liver support systems (i.e., Molecular Adsorbents Recirculating System [MARS®], Advanced Organ Support [ADVOS]) were excluded. CS therapy was used in clinical routine and was indicated by the treating physicians. Statistical analysis was performed with IBM SPSS statistics utilizing a multivariate model. Primary outcome measure was the effect of CS on the 30-day mortality. RESULTS: Data from 82 patients (mean Simplified Acute Physiology Score [SAPS] II: 74 points, mean bilirubin: 18 mg/dL, mean lactate: 3.7 mmol/L) were analyzed. There were no significant differences in patients with and without CS treatment. The multivariate model showed no significant effect of CS therapy (p = 0.402) on the 30-day mortality. In addition, a significant effect of bilirubin concentration (p = 0.274) or Model for End-Stage Liver Disease score (p = 0.928) on the 30-day mortality could not be shown. In contrast, lactate concentration (p = 0.001, b = 0.044) and SAPS II (p = 0.025, b = 0.008) had significant impact on 30-day mortality. CONCLUSION: The use of CS in patients with hyperbilirubinemia did not result in a significant reduction in 30-day mortality. Randomized and controlled studies with mortality as primary outcome measure are needed in the future to justify their use.

Pharyngeal electrical stimulation can modulate swallowing in cortical processing and behavior - magnetoencephalographic evidence.

BACKGROUND: The act of swallowing is a complex neuromuscular function that is processed in a distributed network involving cortical, subcortical and brainstem structures. Difficulty in swallowing arises from a variety of neurologic diseases for which therapeutic options are currently limited. Pharyngeal electrical stimulation (PES) is a novel intervention designed to promote plastic changes in the pharyngeal motor cortex to aid dysphagia rehabilitation. In the present study we evaluate the effect of PES on cortical swallowing network activity and associated changes in swallowing performance. METHODS: In a randomized, crossover study design 10min of real (0.2-ms pulses, 5Hz, 280V, stimulation intensity at 75% of maximum tolerated threshold) or sham PES were delivered to 14 healthy volunteers in two separate sessions. Stimulation was delivered via a pair of bipolar ring electrodes mounted on an intraluminal catheter positioned in the pharynx. Before and after each intervention swallowing capacity (ml/s) was tested using a 150ml-water swallowing stress test. Event-related desynchronization (ERD) of cortical oscillatory activity during volitional swallowing was recorded applying whole-head magnetoencephalography before, immediately after and 45min past the intervention. RESULTS: A prominent reduction of ERD in sensorimotor brain areas occurred in the alpha and beta frequency ranges immediately after real PES but not after sham stimulation (p<0.05) and had faded after 45min. Volume per swallow and swallowing capacity significantly increased following real stimulation only. CONCLUSION: Attenuation of ERD following PES reflects stimulation-induced increased swallowing processing efficiency, which is associated with subtle changes in swallowing function in healthy subjects. Our data contribute evidence that swallowing network organization and behavior can effectively be modulated by PES.

Evidence for adaptive cortical changes in swallowing in Parkinson's disease.

Dysphagia is a relevant symptom in Parkinson's disease, whose pathophysiology is poorly understood. It is mainly attributed to degeneration of brainstem nuclei. However, alterations in the cortical contribution to deglutition control in the course of Parkinson's disease have not been investigated. Here, we sought to determine the patterns of cortical swallowing processing in patients with Parkinson's disease with and without dysphagia. Swallowing function in patients was objectively assessed with fiberoptic endoscopic evaluation. Swallow-related cortical activation was measured using whole-head magnetoencephalography in 10 dysphagic and 10 non-dysphagic patients with Parkinson's disease and a healthy control group during self-paced swallowing. Data were analysed applying synthetic aperture magnetometry, and group analyses were done using a permutation test. Compared with healthy subjects, a strong decrease of cortical swallowing activation was found in all patients. It was most prominent in participants with manifest dysphagia. Non-dysphagic patients with Parkinson's disease showed a pronounced shift of peak activation towards lateral parts of the premotor, motor and inferolateral parietal cortex with reduced activation of the supplementary motor area. This pattern was not found in dysphagic patients with Parkinson's disease. We conclude that in Parkinson's disease, not only brainstem and basal ganglia circuits, but also cortical areas modulate swallowing function in a clinically relevant way. Our results point towards adaptive cerebral changes in swallowing to compensate for deficient motor pathways. Recruitment of better preserved parallel motor loops driven by sensory afferent input seems to maintain swallowing function until progressing neurodegeneration exceeds beyond the means of this adaptive strategy, resulting in manifestation of dysphagia.

Magnetoencephalographic evidence for the modulation of cortical swallowing processing by transcranial direct current stimulation.

Swallowing is a complex neuromuscular task that is processed within multiple regions of the human brain. Rehabilitative treatment options for dysphagia due to neurological diseases are limited. Because the potential for adaptive cortical changes in compensation of disturbed swallowing is recognized, neuromodulation techniques like transcranial direct current stimulation (tDCS) are currently considered as a treatment option. Here we evaluate the effect of tDCS on cortical swallowing network activity and behavior. In a double-blind crossover study, anodal tDCS (20 min, 1 mA) or sham stimulation was administered over the left or right swallowing motor cortex in 21 healthy subjects in separate sessions. Cortical activation was measured using magnetoencephalography (MEG) before and after tDCS during cued "simple", "fast" and "challenged" swallow tasks with increasing levels of difficulty. Swallowing response times and accuracy were measured. Significant bilateral enhancement of cortical swallowing network activation was found in the theta frequency range after left tDCS in the fast swallow task (p=0.006) and following right tDCS in the challenged swallow task (p=0.007), but not after sham stimulation. No relevant behavioral effects were observed on swallow response time, but swallow precision improved after left tDCS (p<0.05). Anodal tDCS applied over the swallowing motor cortex of either hemisphere was able to increase bilateral swallow-related cortical network activation in a frequency specific manner. These neuroplastic effects were associated with subtle behavioral gains during complex swallow tasks in healthy individuals suggesting that tDCS deserves further evaluation as a treatment tool for dysphagia.

GazeAlyze: a MATLAB toolbox for the analysis of eye movement data.

This article presents GazeAlyze, a software package, written as a MATLAB (MathWorks Inc., Natick, MA) toolbox developed for the analysis of eye movement data. GazeAlyze was developed for the batch processing of multiple data files and was designed as a framework with extendable modules. GazeAlyze encompasses the main functions of the entire processing queue of eye movement data to static visual stimuli. This includes detecting and filtering artifacts, detecting events, generating regions of interest, generating spread sheets for further statistical analysis, and providing methods for the visualization of results, such as path plots and fixation heat maps. All functions can be controlled through graphical user interfaces. GazeAlyze includes functions for correcting eye movement data for the displacement of the head relative to the camera after calibration in fixed head mounts. The preprocessing and event detection methods in GazeAlyze are based on the software ILAB 3.6.8 Gitelman (Behav Res Methods Instrum Comput 34(4), 605-612, 2002). GazeAlyze is distributed free of charge under the terms of the GNU public license and allows code modifications to be made so that the program's performance can be adjusted according to a user's scientific requirements.

Can the cytokine adsorber CytoSorb® help to mitigate cytokine storm and reduce mortality in critically ill patients? A propensity score matching analysis.

BACKGROUND: A cytokine storm is life threatening for critically ill patients and is mainly caused by sepsis or severe trauma. In combination with supportive therapy, the cytokine adsorber Cytosorb® (CS) is increasingly used for the treatment of cytokine storm. However, it is questionable whether its use is actually beneficial in these patients. METHODS: Patients with an interleukin-6 (IL-6) > 10,000 pg/ml were retrospectively included between October 2014 and May 2020 and were divided into two groups (group 1: CS therapy; group 2: no CS therapy). Inclusion criteria were a regularly measured IL-6 and, for patients allocated to group 1, CS therapy for at least 90 min. A propensity score (PS) matching analysis with significant baseline differences as predictors (Simplified Acute Physiology Score (SAPS) II, extracorporeal membrane oxygenation, renal replacement therapy, IL-6, lactate and norepinephrine demand) was performed to compare both groups (adjustment tolerance: < 0.05; standardization tolerance: < 10%). U-test and Fisher's-test were used for independent variables and the Wilcoxon test was used for dependent variables. RESULTS: In total, 143 patients were included in the initial evaluation (group 1: 38; group 2: 105). Nineteen comparable pairings could be formed (mean initial IL-6: 58,385 vs. 59,812 pg/ml; mean SAPS II: 77 vs. 75). There was a significant reduction in IL-6 in patients with (p < 0.001) and without CS treatment (p = 0.005). However, there was no significant difference (p = 0.708) in the median relative reduction in both groups (89% vs. 80%). Furthermore, there was no significant difference in the relative change in C-reactive protein, lactate, or norepinephrine demand in either group and the in-hospital mortality was similar between groups (73.7%). CONCLUSION: Our study showed no difference in IL-6 reduction, hemodynamic stabilization, or mortality in patients with Cytosorb® treatment compared to a matched patient population.

Altered cortical swallowing processing in patients with functional dysphagia: a preliminary study.

OBJECTIVE: Current neuroimaging research on functional disturbances provides growing evidence for objective neuronal correlates of allegedly psychogenic symptoms, thereby shifting the disease concept from a psychological towards a neurobiological model. Functional dysphagia is such a rare condition, whose pathogenetic mechanism is largely unknown. In the absence of any organic reason for a patient's persistent swallowing complaints, sensorimotor processing abnormalities involving central neural pathways constitute a potential etiology. METHODS: In this pilot study we measured cortical swallow-related activation in 5 patients diagnosed with functional dysphagia and a matched group of healthy subjects applying magnetoencephalography. Source localization of cortical activation was done with synthetic aperture magnetometry. To test for significant differences in cortical swallowing processing between groups, a non-parametric permutation test was afterwards performed on individual source localization maps. RESULTS: Swallowing task performance was comparable between groups. In relation to control subjects, in whom activation was symmetrically distributed in rostro-medial parts of the sensorimotor cortices of both hemispheres, patients showed prominent activation of the right insula, dorsolateral prefrontal cortex and lateral premotor, motor as well as inferolateral parietal cortex. Furthermore, activation was markedly reduced in the left medial primary sensory cortex as well as right medial sensorimotor cortex and adjacent supplementary motor area (p<0.01). CONCLUSIONS: Functional dysphagia--a condition with assumed normal brain function--seems to be associated with distinctive changes of the swallow-related cortical activation pattern. Alterations may reflect exaggerated activation of a widely distributed vigilance, self-monitoring and salience rating network that interferes with down-stream deglutition sensorimotor control.