[The quantitative EEG in electroencephalogram-based brain monitoring during general anesthesia]. / Das quantifizierte EEG im elektroenzephalogrammbasierten Monitoring während Allgemeinanästhesie.

The electroencephalogram (EEG) is increasingly being used in the clinical routine of anesthesia in German-speaking countries. In over 90% of patients the frontal EEG changes somewhat predictably in response to administration of the normally used anesthetic agents (propofol and volatile gasses). An adequate depth of anesthesia and appropriate concentrations of anesthetics in the brain generate mostly frontal oscillations between 8 and 12 Hz as well as slow delta waves between 0.5 and 4 Hz. The frontal EEG channel is well-suited for avoidance of insufficient depth of anesthesia and excessive administration of anesthetics. This article explains the clinical interpretation of the most important EEG patterns and the biophysical background. Also discussed are important limitations and pitfalls for the clinical routine, which the anesthetist should know in order to utilize the EEG as an admittedly incomplete but clinically extremely important parameter for the level of consciousness.

Phorbol-12-myristate-13-acetate induces nociceptin in human Mono Mac 6 cells via multiple transduction signalling pathways.

BACKGROUND: Nociceptin in the peripheral circulation has been proposed to have an immunoregulatory role with regards to inflammation and pain. However, the mechanisms involved in its regulation are still not clear. The aim of this study was to investigate signalling pathways contributing to the regulation of the expression of nociceptin under inflammatory conditions. METHODS: Mono Mac 6 cells (MM6) were cultured with or without phorbol-12-myristate-13-acetate (PMA). Prepronociceptin (ppNOC) mRNA was detected by RT-qPCR and extracellular nociceptin by fluorescent-enzyme immunoassay. Intracellular nociceptin and phosphorylated kinases were measured using flow cytometry. To evaluate the contribution of various signalling pathways to the regulation of ppNOC mRNA and nociceptin protein, cells were pre-treated with specific kinase inhibitors before co-culturing with PMA. RESULTS: ppNOC mRNA was expressed in untreated MM6 at low concentrations. Exposure of cells to PMA upregulated ppNOC after nine h compared with controls without PMA (median normalized ratio with IQR: 0.18 (0.15-0.26) vs. 0 (0-0.02), P<0.01). Inhibition of mitogen-activated protein kinases specific for signal transduction reversed the PMA effects (all P<0.001). Induction of nociceptin protein concentrations in PMA stimulated MM6 was prevented predominantly by identity of ERK inhibitor (P<0.05). CONCLUSIONS: Upregulation of nociceptin expression by PMA in MM6 cells involves several pathways. Underlying mechanisms involved in nociceptin expression may lead to new insights in the treatment of pain and inflammatory diseases.

[Processed EEG for personalized dosing of anesthetics during general anesthesia]. / Das prozessierte EEG zur personalisierten Dosierung von Anästhetika während Allgemeinanästhesie.

Electroencephalogram (EEG)-guided anesthesia is indispensable in modern operating rooms and has become established as the standard form of monitoring. Many anesthesiologists rely on processed EEG indices in the hope of averting anesthesia-related complications, such as intraoperative awareness, postoperative delirium and other cognitive complications in their patients. This educational review aims to provide information on the five most prevalent monitors used to guide depth of sedation during general anesthesia. This article elucidates the principles underpinning the application of these monitors where known, which are generally based on power in various EEG frequency bands and on the burst suppression pattern. Convinced that EEG-guided anesthesia has the potential of benefitting many surgical patients, it is felt that many basic principles and shortcomings of processed EEG indices need to be better understood in the clinical practice. After discussing the different monitors and clinically relevant data from the literature, the article gives a short practical guidance on how to critically interpret processed EEG information and troubleshooting of confounded indices in the context of clinical situations.

Expression of the nociceptin precursor and nociceptin receptor is modulated in cancer and septic patients.

BACKGROUND: A role of nociceptin and its receptor (NOP) in pain and immune function has been suggested. The hypothesis was that mRNA expression of NOP and the nociceptin precursor pre-pronociceptin (pN/OFQ) in peripheral blood cells differs in end-stage cancer patients suffering from chronic pain and septic intensive care unit (ICU) patients compared with healthy controls. METHODS: Blood samples were drawn from end-stage cancer patients and septic ICU patients. Additionally, postoperative patients representing individuals with surgical stress and healthy controls were enrolled as comparative groups. NOP and pN/OFQ mRNA expression, quantified by real-time polymerase chain reaction (RT-PCR), was compared between study groups, and associated to opioid medication, pain intensities, and the inflammatory markers procalcitonin (PCT) and interleukin-6. RESULTS: NOP expression was significantly higher in cancer patients [normalized ratio, median (inter-quartile range): 10.2 (7.4/17.8)], postoperative patients [8.0 (5.3/10.2)], and ICU patients [6.6 (4.2/9.5)] compared with healthy controls [4.4 (2.7/7.0); P<0.001]. Expression of pN/OFQ was lower in cancer patients [3.8 (1.9/5.9)] and ICU patients [1.9 (1.0/2.7)] but not in postoperative patients compared with healthy controls [7.2 (6.1/9.4); P<0.001]. Increased plasma PCT was associated with decreased pN/OFQ in all patient groups. In cancer patients, no association was seen with pain scores, opioid medication or duration of analgesia, and NOP or pN/OFQ mRNA. CONCLUSIONS: NOP and pN/OFQ expression in peripheral blood cells was modulated in end-stage cancer and septic patients compared with healthy controls, whereas changes in postoperative patients were minor. The involvement of the NOP-pN/OFQ system in inflammation, impaired immune function, and pain has to be further elucidated.

Psychological burden, stressors and resources of social workers working with women and children who suffered extreme violence by the 'Islamic state': A mixed method study.

OBJECTIVE: This explorative study aimed to determine the extent of psychological burden in social workers working with traumatized refugees. In addition, distressing and helpful factors determining the psychosocial burden were to be identified and described. METHODS: Cross-sectional, mixed method design using quantitative and qualitative methods. The quantitative part included the Perceived Stress Questionnaire (PSQ) and items to assess specific factors of the working-context. The qualitative part is based on 5 focus groupdiscussions and 16 individual interviews. Evaluation was carried out using qualitative content analysis (QCA) including cross-analysis along the subscales of the PSQ to organise the qualitative material. RESULTS: N = 54 social workers completed the questionnaire. High scores were found for all subscales of the PSQ. The distressing factor rated the highest was need of interpreters to communicate (M = 5.1, SD = 1.71), the helpful factor rated the highest was communication skills (M = 6.35, SD = 0.73). In the QCA, aspects of distressing and helpful factors were identified and further detailed. CONCLUSION: According to the here presented study results, the psychological burdens of social workers working with refugees seem to be high. The impact of distressing factors such as working with interpreters and exposure to trauma content or PTSD symptoms might be reduced by offering specific education and supervision. The individual extent of psychological burden should be considered and (re-)evaluated on a regular basis as secondary prevention. Helpful factors like self-care, teamwork, networking and cooperation are evident and should be supported by implementing professional and psychological support.

Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus.

LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(TFH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications.

A single exposure to hyperbaric oxygen increases levels of circulating nucleosomes but does not induce mononuclear cell apoptosis in divers.

Recent reports that hyperbaric oxygenation (HBO2) induced apoptosis in T-cell lines raised concern about a possible immunosuppressive effect of HBO2. Nucleosomes, DNA fragments wrapped around a histone core, have been observed in the circulation in diseases with increased cell death such as sepsis. Our aim was to investigate, whether HBO2 increases circulating nucleosomes as a marker of cell death and induces apoptosis of peripheral blood mononuclear cells in vivo. After informed consent 29 healthy volunteers were exposed to a 30 minute dive at 2.8 atmospheres absolute in a pressure chamber under resting conditions, while breathing 100% oxygen. Samples were obtained before and 24 hours after exposure. Circulating nucleosomes were measured in serum. Caspase-3 activation, Bcl-2 expression and mRNA of Bcl-2, Bcl-xl and Bax were analyzed in mononuclear cell extracts. Nucleosomes were elevated markedly 24h after exposure (p<0.01), while caspase-3 was not activated significantly. mRNA levels of Bcl-2, Bcl-xl and Bax were not altered. In conclusion, while evidence of elevated levels of circulating nucleosomes was found, mononuclear cell apoptosis was not affected by a single exposure to hyperbaric oxygen.

Dipyrone is the preferred nonopioid analgesic for the treatment of acute and chronic pain. A survey of clinical practice in German-speaking countries.

PURPOSE: Nonopioid analgesics are frequently used for the treatment of acute and chronic pain. Dipyrone is an alternative to NSAIDs and paracetamol, however, data on the frequency of its usage by anaesthesiologists in the perioperative and chronic pain setting are lacking and its adverse reactions are a matter of debate. METHODS: The link to a questionnaire on the use of nonopioid analgesics (NSAIDs, COX-2 inhibitors, paracetamol, dipyrone) and the safety of dipyrone in the perioperative and chronic pain setting was mailed to anaesthesiologists and pain physicians. RESULTS: A total of 2237 responses were analysed. About 97.4% of the respondents used nonopioid analgesics for the treatment of acute pain, with 93.8% administering dipyrone, 54.0% NSAIDs, 41.8% COX-2 inhibitors and 49.2% paracetamol. Nonopioid analgesics were administered preoperatively by 22.3%, intraoperatively by 86.1% and postoperatively by 73.0% of the respondents. For chronic pain management, 76.7% of the respondents prescribed oral dipyrone in combination with other nonopioid analgesics; 19.9% used dipyrone as sole nonopioid, whereas 2.9% denied its use. Cases of dipyrone-associated agranulocytosis were observed by 3.5% of the respondents of the acute and 1.5% of the chronic pain questionnaire, respectively. The majority of respondents (acute pain: 73.0%, chronic pain 59.3%) performed no blood cell counts to monitor dipyrone therapy. Patients were rarely informed about possible adverse drug reactions. CONCLUSIONS: Dipyrone is the preferred nonopioid analgesic in the perioperative and chronic pain setting. Although cases of agranulocytosis occur, benefits apparently outweigh the risks according to anaesthesiologists. Measures like patient information may improve safety. SIGNIFICANCE: A survey of anaesthesiologist in German-speaking countries revealed dipyrone as preferred nonopioid analgesic for the treatment of acute and chronic pain. Benefits seem to outweigh the risks, specifically the risk of agranulocytosis. Information of medical staff and patients on adverse drug reactions and symptoms of agranulocytosis should be implemented.

Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes.

The influence of CYP2D6 genotype and CYP2D6 inhibitors on enantiomeric plasma levels of tramadol and O-desmethyltramadol as well as response to tramadol was investigated. One hundred and seventy-four patients received one hundred intravenous tramadol 3 mg/kg for postoperative analgesia. Blood samples drawn 30, 90, and 180 min after administration were analyzed for plasma concentrations of the enantiomers (+)-, (-)tramadol and (+)-, (-)O-desmethyltramadol by liquid chromatography-tandem mass spectrometry. Different CYP2D6 genotypes displaying zero (poor metabolizer (PM)), one (heterozygous individual (HZ)/intermediate metabolizer (IM)), two extensive metabolizer (EM), and three (ultra rapid metabolizer (UM)) active genes were compared. Concentrations of O-desmethyltramadol differed in the four genotype groups. Median (1/3 quartile) area under the concentration-time curves for (+)O-desmethyltramadol were 0 (0/11.4), 38.6 (15.9/75.3), 66.5 (17.1/118.4), and 149.7 (35.4/235.4) ng x h/ml for PMs, HZ/IMs, EMs, and UMs (P<0.001). Comedication with CYP2D6 inhibitors decreased (+) O-desmethyltramadol concentrations (P<0.01). In PMs, non-response rates to tramadol treatment increased fourfold compared with the other genotypes (P<0.001). In conclusion, CYP2D6 genotype determined concentrations of O-desmethyltramadol enantiomers and influenced efficacy of tramadol treatment.

Contraindications to regional anaesthesia in obstetrics: a survey of German practice.

BACKGROUND: We assessed current practice regarding indications and contraindications to regional analgesia and anaesthesia for labour and delivery in Germany. METHODS: Questionnaires were mailed to the directors of 918 German departments of anaesthesiology. RESULTS: A total of 397 completed replies were received representing 41.3% of all deliveries in Germany. More than half of the respondents never perform spinal or epidural anaesthesia when the platelet count falls below 65x10(9)/L. Preeclampsia, which was not graded for severity, was considered an absolute contraindication to regional block by 15% and placenta praevia by 30% of respondents. If a woman had taken aspirin three days before, the numbers of respondents considering epidural anaesthesia contraindicated (40.2%) were nearly double those considering spinal anaesthesia contraindicated (21.7%) (P<0.001). For a platelet count of 79x10(9)/L, epidural anaesthesia was thought to be contraindicated by 37% and spinal anaesthesia by 22.2% (P=0.001). In departments with <500 deliveries/year, reluctance to use regional blockade was more pronounced than in departments with >1000 deliveries/year. CONCLUSION: Clinical practice varies considerably in Germany. Concerns regarding the use of regional blockade were more prevalent in hospitals with small delivery units. Indications and contraindications are not consistent in Germany and some recommendations or guidelines are needed.

Phenol wastewater remediation: advanced oxidation processes coupled to a biological treatment.

Nowadays, there are increasingly stringent regulations requiring more and more treatment of industrial effluents to generate product waters which could be easily reused or disposed of to the environment without any harmful effects. Therefore, different advanced oxidation processes were investigated as suitable precursors for the biological treatment of industrial effluents containing phenol. Wet air oxidation and Fenton process were tested batch wise, while catalytic wet air oxidation and H2O2-promoted catalytic wet air oxidation processes were studied in a trickle bed reactor, the last two using over activated carbon as catalyst. Effluent characterisation was made by means of substrate conversion (using high liquid performance chromatography), chemical oxygen demand and total organic carbon. Biodegradation parameters (i.e. maximum oxygen uptake rate and oxygen consumption) were obtained from respirometric tests using activated sludge from an urban biological wastewater treatment plant (WWTP). The main goal was to find the proper conditions in terms of biodegradability enhancement, so that these phenolic effluents could be successfully treated in an urban biological WWTP. Results show promising research ways for the development of efficient coupled processes for the treatment of wastewater containing toxic or biologically non-degradable compounds.

[Urosepsis. Current therapy and diagnosis]. / Urosepsis Aktuelle Therapie und Diagnostik.

Urosepsis is defined as sepsis caused by urinary tract infection. This occurs in 25% of all sepsis cases. Because of the increasing incidence of sepsis, this entity will be seen more frequently in medical practice and outpatient units. The immediate identification and treatment of the septic focus is crucial. Depending on severity, early reconstitution of adequate oxygen delivery has parallel priority, therefore necessitating intensive care unit treatment within the first hours. Therapy should consist of eliminating the infectious focus, antimicrobial treatment, supportive therapy, and special sepsis therapy.

Effects of opioids on human serotonin transporters.

The serotonin (5-hydroxtryptamine, 5-HT) system plays a role in analgesia and emesis. The aim of this study was to test whether opioids or ketamine inhibit the human 5-HT transporter and whether this increases free plasma 5-HT concentrations. HEK293 cells, stably transfected with the human 5-HT transporter cDNA, were incubated with morphine, hydromorphone, fentanyl, alfentanil, pethidine (meperidine), tramadol, ketamine, and the reference substance citalopram (specific 5-HT transporter inhibitor). The uptake of [(3)H]5-HT was measured by liquid scintillation counting. In a second series of experiments, study drugs were incubated with plasma of ten healthy blood donors and change of 5-HT plasma-concentrations were measured (ELISA). The end point was the inhibition of the 5-HT transporter by different analgesics either in HEK293 cells or in human platelets ex vivo. Tramadol, pethidine, and ketamine suppressed [(3)H]5-HT uptake dose-dependently with an IC50 of 1, 20.9, and 230 µM, respectively. These drugs also prevented 5-HT uptake in platelets with an increase in free plasma 5-HT. Free 5-HT concentrations in human plasma were increased by citalopram 1 µM, tramadol 20 µM, pethidine 30 µM, and ketamine 100 µM to 280 [248/312]%, 269 [188/349]%, and 149 [122/174]%, respectively, compared to controls without any co-incubation (means [95 % CI]; all p < 0.005). No change in both experimental settings was observed for the other opioids. Tramadol and pethidine inhibited the 5-HT transporter in HEK293 cells and platelets. This inhibition may contribute to serotonergic effects when these opioids are given in combination, e.g., with monoamine oxidase inhibitors or selective serotonin reuptake inhibitors.

Gender differences in sepsis: genetically determined?

In the pathogenesis of sepsis, tumor necrosis factor (TNF) release and host reaction may be genetically determined as demonstrated for TNFbeta Ncol polymorphism. Gender differences are considered as another important prognostic variable in patients with sepsis with better survival for women. The effect of sexual dimorphism on the genetic background of sepsis, however, is unknown. In a prospective study at two university hospital surgical intensive care units, (Bonn and Kiel), the role of the genomic marker TNFbeta Ncol polymorphism was evaluated with respect to gender. Two-hundred and one patients (68 women and 133 men) with severe sepsis were evaluated. A fragment of genomic DNA including the polymorphic site of the restriction enzyme Ncol was amplified by means of polymerase chain reaction. The genotype of each patient was determined after Ncol digestion of the amplified product. The genotype distribution of patients homozygous for TNFB1, heterozygous or homozygous for TNFB2 was comparable between men and women with severe sepsis. In women, no difference in survival rate was found between the different genotypes, while mortality rate was significantly increased in men homozygous for TNFB2 compared with the other genotypes (P < 0.05; P < 0.01, chi2 test). Overall, survival rate was higher for women (P < 0.05) but was not significantly different between men and women with respect to genotypes (P = 0.07 for TNFB2/B2). Poor prognosis of surgical sepsis can be determined by male gender and the genomic marker TNFbeta Ncol polymorphism which should be considered for further therapeutic interventions in sepsis.

-308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter.

Tumor necrosis factor (TNF) is recognized as a central mediator of sepsis, septic shock, and multiple organ failure. These host reactions are associated with increased TNF levels in circulation, presumably due to increased TNF production. A previously described nucleotide variation at position -308 in the promoter region of the human TNF gene was shown to be associated with the clinical outcome of malaria. In this study we addressed the relevance of the -308 polymorphism for expression of the human TNF gene in response to bacterial endo- toxin in vivo and in vitro. First, we typed 80 patients suffering from severe sepsis and 153 healthy individuals and found no association of the -308 variation with incidence of the disease. In contrast, the NcoI marker in the closely linked lymphotoxin-alpha (LT-alpha) gene showed association with survivaL This discrepancy can be explained by the linkage of the TNFB2(NcoI) allele to the common TNF1 (-308) allele. Second, we generated reporter gene constructs with the promoter deletions and with both -308 variation in the context of the extended human TNF promoter region. Although such constructs were highly inducible by lipopolysaccharide (LPS) in transient transfections into a macrophage cell line, the -308 variation had no significant effect on transcription, consistent with the promoter deletion study. We conclude that the functional consequence of the -308 polymorphism may be unrelated to transcriptional response of the TNF gene to bacterial endotoxin.

Prothrombin gene G20210A mutation and elevated anticardiolipin antibodies in a patient with combined portal-mesenteric vein thrombosis.

A 29-year-old man was admitted to the ICU after emergency laparotomy for portal-mesenteric vein thrombosis. Under continuous intravenous heparin therapy the portal-mesenteric shunt occluded on the first postoperative day. After thrombectomy the heparin dose was increased, and the patient remained free of symptoms (partial thromboplastin time 53 s). Two days later abdominal distension developed concomitantly with ventilatory distress due to a large retroperitoneal hematoma. The patient was mechanically ventilated and underwent the third consecutive laparotomy for the hematoma removal on the fifth day. During the surgical procedure the abdomen was packed with towels to stop multiple bleeding sites. The heparin dose was reduced, aiming for a partial thromboplastin time of 30-35 s. Initial coagulation tests revealed increased levels of anticardiolipin immunoglobulin G. After removal of the surgical towels the patient was successfully weaned from mechanical ventilation and discharged from the ICU. Two weeks later genomic testing revealed that he also had a G20210A mutation of the prothrombin gene. Both, increased levels of anticardiolipin immunoglobulin G and the G20210A mutation of the prothrombin gene predispose to thrombosis. Increased levels of anticardiolipin immunoglobulin G may also cause bleeding. Long-term anticoagulation therapy was started with a vitamin K antagonist, and 2 months later a follow-up showed that the patient had no further symptoms of portal-mesenteric vein thrombosis or bleeding. This case illustrates that the convergence of multiple risk factors, including genetic defects, must be considered in patients suffering from thrombosis in unusual sites

Protective functions of intracellular heat-shock protein (HSP) 70-expression in patients with severe sepsis.

Intracellular expression of heat-shock-protein 70 (HSP70) arose early in evolutionary development as a tool to protect cellular homeostasis. HSP70 detects proteins that are incorrectly folded or denatured. They form a complex with such proteins which can lead to correct folding, compartmentalization in organelles, or to proteolytic degradation. HSP70 also appears to protect proteins from degeneration. Intracellular HSP70-expression is induced by a wide variety of stimuli including heat, fever, hypoxia, oxygen radicals, endotoxins, cytokines, and heavy metal ions. Pre-emptive induction of HSP70-expression reduces organ dysfunction and mortality in animal models of sepsis.

The Pstl polymorphism of the endotoxin-inducible heat-shock protein 70-2 gene does not affect messenger RNA level in human whole-blood cultures.

OBJECTIVE: To determine whether the human leukocyte antigen linked biallelic heat-shock protein 70-2 (HSP70-2) gene polymorphism is associated with variable HSP70-2 messenger RNA expression. DESIGN: Prospective observational study in consecutive healthy blood donors. SETTING: Department of Anesthesiology, laboratory for molecular biology in a university hospital. PARTICIPANTS: 24 healthy blood donors. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We studied the functional implication of the HSP70-2 (G/A) PstI gene polymorphism in 24 healthy, white blood donors with various HSP70-2 (G/A) genotypes by analyzing the endotoxin-inducible HSP70-2 mRNA expression by means of the reverse transcription-polymerase chain reaction. HSP70 expression was expressed semiquantitatively by calculating the ratio of HSP70-2 mRNA and the constitutively expressed glutaraldehyde 3-phosphate dehydrogenase mRNA. No significant differences in HSP70-2 mRNA expression after lipopolysaccharide (from Salmonella minnesota Re 595) stimulation were detected in individuals homozygous for the allele A (0.68, range 0.38-1, n = 10), in individuals homozygous for the allele G (0.79, range 0.42-1.1, n = 8), and in heterozygotes (HSP70-2 G/A; 0.52, range 0.4-0.67, n = 6; p > 0.05). CONCLUSIONS: The PstI polymorphism of the endotoxin-inducible HSP70-2 gene is not associated with variable HSP70-2 mRNA expression ex vivo. This finding is in accordance with the observation that HSP70-2 genotypes do not affect clinical outcome in human systemic inflammation.