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Background The effect of anesthetic drugs on cancer outcomes remains unclear. This trial aimed to assess postoperative circulating tumor cell counts—an independent prognostic factor for breast cancer—to determine how anesthesia may indirectly affect prognosis. It was hypothesized that patients receiving sevoflurane would have higher postoperative tumor cell counts. Methods The parallel, randomized controlled trial was conducted in two centers in Switzerland. Patients aged 18 to 85 yr without metastases and scheduled for primary breast cancer surgery were eligible. The patients were randomly assigned to either sevoflurane or propofol anesthesia. The patients and outcome assessors were blinded. The primary outcome was circulating tumor cell counts over time, assessed at three time points postoperatively (0, 48, and 72 h) by the CellSearch assay. Secondary outcomes included maximal circulating tumor cells value, positivity (cutoff: at least 1 and at least 5 tumor cells/7.5 ml blood), and the association between natural killer cell activity and tumor cell counts. This trial was registered with ClinicalTrials.gov (NCT02005770). Results Between March 2014 and April 2018, 210 participants were enrolled, assigned to sevoflurane (n = 107) or propofol (n = 103) anesthesia, and eventually included in the analysis. Anesthesia type did not affect circulating tumor cell counts over time (median circulating tumor cell count [interquartile range]; for propofol: 1 [0 to 4] at 0 h, 1 [0 to 2] at 48 h, and 0 [0 to 1] at 72 h; and for sevoflurane: 1 [0 to 4] at 0 h, 0 [0 to 2] at 48 h, and 1 [0 to 2] at 72 h; rate ratio, 1.27 [95% CI, 0.95 to 1.71]; P = 0.103) or positivity. In one secondary analysis, administrating sevoflurane led to a significant increase in maximal tumor cell counts postoperatively. There was no association between natural killer cell activity and circulating tumor cell counts. Conclusions In this randomized controlled trial investigating the effect of anesthesia on an independent prognostic factor for breast cancer, there was no difference between sevoflurane and propofol with respect to circulating tumor cell counts over time. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

BACKGROUND Postoperative complications in surgery are a significant burden, not only for the patients but also economically. While several predicting factors have already been identified, it is still not well known if increased levels of inflammatory markers in the immediate perioperative phase correlate with a higher incidence of postoperative complications. This study aimed to evaluate which patient characteristics and intraoperative parameters correlate with increased plasma values of monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 (IL-6) of thoracic surgery patients. A second goal was to explore whether MCP-1 and IL-6 are associated with the incidence of postoperative complications. We hypothesized that there is a positive association between inflammatory markers and the occurrence of complications within 6 months after surgery. METHODS This is a substudy of a recent randomized controlled trial, which defined the effect of desflurane versus propofol anesthesia on morbidity and mortality in patients undergoing thoracic surgery. MCP-1 and IL-6 were determined in plasma obtained before and 30 minutes after 1-lung ventilation, 6 hours after surgery, and on postoperative days 1 and 2. Complications were recorded for 6 months. Mixed linear models were used to examine factors associated with MCP-1 and IL-6 levels. Logistic regression models and receiver operating characteristic curves were used to determine the association between MCP-1 and IL-6 and postoperative complications. RESULTS In the original study, 460 patients were included, MCP-1 and IL-6 levels were determined in 428 patients. MCP-1 was positively associated with the duration of surgery (P = .016), whereas IL-6 levels increased with both the length (P < .001) and invasiveness of lung surgery (thoracoscopic wedge resection or lobectomy versus open lobectomy, P = .005; thoracoscopic wedge resection or lobectomy versus pneumonectomy, P = .021). In an exploratory approach, elevated IL-6 plasma peaks were associated with the occurrence of severe complications defined as Clavien-Dindo score grade ≥IVa during the postoperative phase up to 6 months after thoracic surgery (P = .006). CONCLUSIONS In summary, this substudy reveals factors, which correlate with high MCP-1 and IL-6 values. Moreover, higher IL-6 seems to be associated with postoperative severe complications. Perioperative IL-6 monitoring might be helpful for risk estimation in the perioperative setting of patients after lung surgery.

Background Conservative obesity treatment often leads to limited results. Bariatric surgery is highly efficient, but the candidates are at risk of developing perioperative complications. Bariatric outcomes have been well described in the past, but there are only few reports of perioperative outcomes. The aim of this study was to evaluate the incidence of anaesthetic and surgical complications of Roux-en-Y bypass. Methods Data of all adult patients, who underwent primary Roux-en-Y gastric bypass surgery between 1/2006 and 12/2013 at the University Hospital Zurich were analysed. Using our clinical database, anaesthetic and surgical complications during the first 30 days after surgery were analysed and risk factors determined by multivariate analysis. Results Seven hundred eleven patients (72% female, median age 40 years) were analysed. Overall, surgical complications occurred in 34% patient, while complications attributable to anaesthesia occurred in 37%. Post-operative nausea and vomiting (PONV) were observed in 34%, intubation-related complications in 4%, and delayed extubation in 2% of our patients. Within the first 30 days after surgery, 22% of the patients presented with an infection. Gastrointestinal complications were found in 8%, and bleeding complications in 3%. Anaesthesia complications were less common in older patients and in patients anaesthetized with a volatile anaesthetic. Severe complications were more common in patients with a lower body mass index (BMI) and with longer surgery. The risk to develop a postoperative infection was higher in diabetic patients. Conclusion Roux-en-Y bariatric surgery has few anaesthetic complications, the most common is PONV. PONV is more common in younger patients and not more common with volatile anaesthetics. Major complications are overall rare and occur in patients with lower BMI and longer surgery, likely reflecting more difficult procedures. Electronic supplementary material The online version of this article (10.1186/s12871-018-0654-x) contains supplementary material, which is available to authorized users.

Sepsis and septic shock remain the leading cause of death in intensive care units. Despite significant improvements in sepsis management, mortality still ranges between 20 and 30%. Novel treatment approaches in order to reduce sepsis-related multiorgan failure and death are urgently needed. Robust animal models allow for one or multiple treatment approaches as well as for testing their effect on physiological and molecular parameters. In this article, a simple animal model is presented. First, general anesthesia is induced in animals either with the use of volatile or by intraperitoneal anesthesia. After placement of an intravenous catheter (tail vein), tracheostomy, and insertion of an intraarterial catheter (tail artery), mechanical ventilation is started. Baseline values of mean arterial blood pressure, arterial blood oxygen saturation, and heart rate are recorded. The injection of lipopolysaccharides (1 milligram/kilogram body weight) dissolved in phosphate-buffered saline induces a strong and reproducible inflammatory response via the toll-like receptor 4. Fluid corrections as well as the application of norepinephrine are performed based on well-established protocols. The animal model presented in this article is easy to learn and strongly oriented towards clinical sepsis treatment in an intensive care unit with sedation, mechanical ventilation, continuous blood pressure monitoring, and repetitive blood sampling. Also, the model is reliable, allowing for reproducible data with a limited number of animals in accordance with the 3R (reduce, replace, refine) principles of animal research. While animal experiments in sepsis research cannot easily replaced, repetitive measurements allow for a reduction of animals and keeping septic animals anesthetized diminishes suffering.

Portal vein ligation (PVL) induces liver growth prior to resection. Associating liver partition and portal vein ligation (PVL plus transection=ALPPS) or the addition of the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG) to PVL both accelerate growth via stabilization of HIF-α subunits. This study aims at clarifying the crosstalk of hepatocytes (HC), hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC) in accelerated liver growth. In vivo, liver volume, HC proliferation, vascular density and HSC activation were assessed in PVL, ALPPS, PVL+DMOG and DMOG alone. Proliferation of HC, HSC and LSEC was determined under DMOG in vitro. Conditioned media experiments of DMOG-exposed cells were performed. ALPPS and PVL+DMOG accelerated liver growth and HC proliferation in comparison to PVL. DMOG alone did not induce HC proliferation, but led to increased vascular density, which was also observed in ALPPS and PVL+DMOG. Activated HSC were detected in ALPPS, PVL+DMOG and DMOG, again not in PVL. In vitro, DMOG had no proliferative effect on HC, but conditioned supernatant of DMOG-treated HSC induced VEGF-dependent proliferation of LSEC. Transcriptome analysis confirmed activation of proangiogenic factors in hypoxic HSC. Hypoxia signaling in HSC induces VEGF-dependent angiogenesis. HSC play a crucial role in the cellular crosstalk of rapid liver regeneration.

Background Severe neurological impairment is a problem after subarachnoid haemorrhage (SAH). Although volatile anaesthetics, such as sevoflurane, have demonstrated protective properties in many organs, their use in cerebral injury is controversial. Cerebral vasodilation may lead to increased intracranial pressure (ICP), but at the same time volatile anaesthetics are known to stabilise the SAH-injured endothelial barrier. Objective To test the effect of sevoflurane on ICP and blood-brain barrier function. Design Randomised study. Participants One hundred male Wistar rats included, 96 analysed. Interventions SAH was induced by the endoluminal filament method under ketamine/xylazine anaesthesia. Fifteen minutes after sham surgery or induction of SAH, adult male Wistar rats were randomised to 4 h sedation with either propofol or sevoflurane. Main outcome measures Mean arterial pressure (MAP), ICP, extravasation of water (small), Evan's blue (intermediate) and IgG (large molecule) were measured. Zonula occludens-1 (ZO-1) and beta-catenin (β-catenin), as important representatives of tight and adherens junction proteins, were determined by western blot. Results Propofol and sevoflurane sedation did not affect MAP or ICP in SAH animals. Extravasation of small molecules was higher in SAH-propofol compared with SAH-sevoflurane animals (79.1 ± 0.9 vs. 78.0 ± 0.7%, P = 0.04). For intermediate and large molecules, no difference was detected (P = 0.6 and P = 0.2). Both membrane and cytosolic fractions of ZO-1 as well as membrane β-catenin remained unaffected by the injury and type of sedation. Decreased cytosolic fraction of β-catenin in propofol-SAH animals (59 ± 15%) was found to reach values of sham animals (100%) in the presence of sevoflurane in SAH animals (89 ± 21%; P = 0.04). Conclusion This experiment demonstrates that low-dose short-term sevoflurane sedation after SAH in vivo did not affect ICP and MAP and at the same time may attenuate early brain oedema formation, potentially by preserving adherens junctions. Trial registration No 115/2014 Veterinaramt Zurich.

BACKGROUND Randomized controlled trials (RCTs) data demonstrate that sevoflurane postconditioning improves clinical outcomes of liver resection with inflow occlusion, presumably due to hepatocyte protection from ischemic injury. However, mechanisms remain unclear. This study examines liver biopsy samples obtained in an RCT of sevoflurane postconditioning to test the hypothesis that sevoflurane attenuates hepatocyte apoptosis. METHODS Messenger ribonucleic acid (mRNA) of pro- and antiapoptotic regulators Bax and B-cell lymphoma 2 (Bcl2) was examined in hepatic biopsies obtained during the RCT. Hepatic stellate cells (HSCs) and hepatocytes were exposed to hypoxia/reoxygenation (H/R) in vitro to evaluate the effect of sevoflurane postconditioning on apoptosis. The role of HSC as a potential apoptosis trigger in hepatocytes through the production of reactive oxygen species induced by H/R was explored by transferring supernatants from H/R-exposed HSC to hepatocytes as target cells. RESULTS In patients of the RCT, the Bax/Bcl2 mRNA ratio in liver tissue was markedly decreased in the sevoflurane arm (25% ± 21% reduction; P = .001). In vitro, H/R increased reactive oxygen species production in HSC by 33% ± 16% (P = .025), while it was abolished in the presence of sevoflurane (P < .001). In hepatocytes, caspase was minimally activated by H/R. However, incubation of hepatocytes with supernatants of HSC, previously exposed to H/R, increased caspase activity by 28% ± 13% (P < .001). When exposed to supernatants from HSC undergoing sevoflurane postconditioning, caspase activation in hepatocytes was reduced by 20% ± 9% (P < .001), similarly to the sevoflurane effect on the BAX/Bcl2 mRNA ratio in the liver samples. CONCLUSIONS The study shows that sevoflurane postconditioning affects apoptosis of hepatocytes after ischemia-reperfusion injury in patients. It also demonstrates that HSC may be the effector cells of sevoflurane protection.

Septic encephalopathy is believed to be a result of neuro-inflammation possibly triggered by endotoxins, such as lipopolysaccharides (LPS). Modulation of the immune system is a property of volatile anaesthetics.We aimed to investigate the systemic and cerebral inflammatory response in a LPS-induced sepsis model in rats. We compared two different sedation strategies, intravenous propofol and the volatile anaesthetic sevoflurane, with the hypothesis that the latter may attenuate neuro-inflammatory processes.Laboratory rat study.Basic research laboratories at the University Hospital Zurich and University Zurich Irchel between August 2014 and June 2016.A total of 32 adult male Wistar rats.After tracheotomy and mechanical ventilation, the anaesthetised rats were monitored before sepsis was induced by using intravenous LPS or phosphate-buffered saline as control. Rats were sedated with propofol (10 mg kg h) or sevoflurane (2 vol%) continuously for 12 h.Systemic inflammatory markers such as cytokine-induced neutrophil chemo-attractant protein 1, monocyte chemo-tactic protein-1 and IL-6 were determined. The same cytokines were measured in brain tissue. Cellular response in the brain was assessed by defining neutrophil accumulation with myeloperoxidase and also activation of microglia with ionised calcium-binding adaptor molecule-1 and astrocytes with glial fibrillary acidic protein. Finally, brain injury was determined.Animals were haemodynamically stable in both sedation groups treated with LPS. Blood cytokine peak values were lower in the sevoflurane-LPS compared with propofol-LPS animals. In brain tissue of LPS animals, chemoattractant protein-1 was the only significantly increased cytokine (P = 0.003), however with no significance between propofol and sevoflurane. After LPS challenge, cerebral accumulation of neutrophils was observed. Microglia activation was pronounced in the hippocampus of animals treated with LPS (P = 0.006). LPS induced prominent astrogliosis (P 0.001). There was no significant difference in microglia or astrocyte activation or apoptosis in the brain between sevoflurane and propofol.We have shown that systemic attenuation of inflammation by the volatile anaesthetic sevoflurane did not translate into attenuated neuro-inflammation in this LPS-induced inflammation model.Animal approval No. 134/2014, Veterinäramt Zürich.

Background After portal vein ligation of 1 side of the liver, the other side regenerates at a slow rate. This slow growth may be accelerated to rapid growth by adding a transection between the 2 sides, i.e., performing portal vein ligation and parenchymal transection. We found that in patients undergoing portal vein ligation and parenchymal transection, portal vein hyperflow in the regenerating liver causes a significant reduction of arterial flow due to the hepatic arterial buffer response. We postulated that the reduction of arterial flow induces hypoxia in the regenerating liver and used a rat model to assess hypoxia and its impact on kinetic growth. Methods A rat model of rapid (portal vein ligation and parenchymal transection) and slow regeneration (portal vein ligation) was established. Portal vein flow and pressure data were collected. Liver regeneration was assessed in rats using computed tomography, proliferation with Ki-67, and hypoxia with pimonidazole and HIF-1α staining. Results The rat model confirmed acceleration of regeneration in portal vein ligation and parenchymal transection as well as the portal vein hyperflow seen in patients. Additionally, tissue hypoxia was observed after portal vein ligation and parenchymal transection, while little hypoxia staining was detected after portal vein ligation. To determine if hypoxia is a consequence or an inciting stimulus of rapid liver regeneration, we used a prolyl-hydroxylase blocker to activate hypoxia signaling pathways in the slow model. This clearly accelerated slow to rapid liver regeneration. Inversely, abrogation of hypoxia led to a blunting of rapid growth to slow growth. The topical application of prolyl-hydroxylase inhibitors on livers in rats induced spontaneous areas of regeneration. Conclusion This study shows that pharmacologically induced hypoxic signaling accelerates liver regeneration similar to portal vein ligation and parenchymal transection. Hypoxia is likely an accelerator of liver regeneration. Also, prolyl-hydroxylase inhibitors may be used to enhance liver regeneration pharmaceutically.

International audience; BACKGROUND:Liver hypertrophy induced by partial portal vein occlusion (PVL) is accelerated by adding simultaneous parenchymal transection ("ALPPS procedure"). This preclinical experimental study in pigs tests the hypothesis that simultaneous ligation of portal and hepatic veins of the liver also accelerates regeneration by abrogation of porto-portal collaterals without need for operative transection.METHODS:A pig model of portal vein occlusion was compared with the novel model of simultaneous portal and hepatic vein occlusion, where major hepatic veins draining the portal vein-deprived lobe were identified with intraoperative ultrasonography and ligated using pledgeted transparenchymal sutures. Kinetic growth was compared, and the portal vein system was then studied after 7 days using epoxy casts of the portal circulation. Portal vein flow and portal pressure were measured, and Ki-67 staining was used to evaluate the proliferative response.RESULTS:Pigs were randomly assigned to portal vein occlusion (n = 8) or simultaneous portal and hepatic vein occlusion (n = 6). Simultaneous portal and hepatic vein occlusion was well tolerated and led to mild cytolysis, with no necrosis in the outflow vein-deprived liver sectors. The portal vein-supplied sector increased by 90 ± 22% (mean ± standard deviation) after simultaneous portal and hepatic vein occlusion compared with 29 ± 18% after PVL (P < .001). Collaterals to the deportalized liver developed after 7 days in both procedures but were markedly reduced in simultaneous portal and hepatic vein occlusion. Ki-67 staining at 7 days was comparable.CONCLUSION:This study in pigs found that simultaneous portal and hepatic vein occlusion led to rapid hypertrophy without necrosis of the deportalized liver. The findings suggest that the use of simultaneous portal and hepatic vein occlusion accelerates liver hypertrophy for extended liver resections and should be evaluated further.

Background Matrix-metalloproteinases (MMP) and cancer cell invasion are crucial for solid tumour metastasis. Important signalling events triggered by inflammatory cytokines, such as tumour necrosis factor α (TNFα), include Src-kinase-dependent activation of Akt and focal adhesion kinase (FAK) and phosphorylation of caveolin-1. Based on previous studies where we demonstrated amide-type local anaesthetics block TNFα-induced Src activation in malignant cells, we hypothesized that local anaesthetics might also inhibit the activation and/or phosphorylation of Akt, FAK and caveolin-1, thus attenuating MMP release and invasion of malignant cells. Methods NCI-H838 lung adenocarcinoma cells were incubated with ropivacaine or lidocaine (1 nM-100 µM) in absence/presence of TNFα (20 ng ml−1) for 20 min or 4 h, respectively. Activation/phosphorylation of Akt, FAK and caveolin-1 were evaluated by Western blot, and MMP-9 secretion was determined by enzyme-linked immunosorbent assay. Tumour cell migration (electrical wound-healing assay) and invasion were also assessed. Results Ropivacaine (1 nM–100 μM) and lidocaine (1–100 µM) significantly reduced TNFα-induced activation/phosphorylation of Akt, FAK and caveolin-1 in NCI-H838 cells. MMP-9 secretion triggered by TNFα was significantly attenuated by both lidocaine and ropivacaine (half-maximal inhibitory concentration [IC50]=3.29×10−6 M for lidocaine; IC50=1.52×10−10 M for ropivacaine). The TNFα-induced increase in invasion was completely blocked by both lidocaine (10 µM) and ropivacaine (1 µM). Conclusions At clinically relevant concentrations both ropivacaine and lidocaine blocked tumour cell invasion and MMP-9 secretion by attenuating Src-dependent inflammatory signalling events. Although determined entirely in vitro, these findings provide significant insight into the potential mechanism by which local anaesthetics might diminish metastasis.

Is Oxygen Deficiency Always Harmful? Abstract. The role of the cardiovascular circulation is to supply tissue with oxygen and nutrients. Oxygen deficiency (hypoxia) is considered life-threatening, since cells die, either through apoptotic or necrotic processes. Tissue tries to counteract this by means of evolutionary signalling pathways, such as the nuclear hypoxia-inducible factor, which protects the tissue by promoting cell survival strategies and simultaneously intervening in angiogenesis, haematogenesis and metabolic processes. Recent findings indicate that these conserved signalling pathways can also function as therapeutic approaches in wound healing of bones and skin, as well as in the regeneration of tissues, e.g. in the liver, and in the hematopoietic system.Zusammenfassung. Die Aufgabe des Kreislaufs ist die Versorgung von Gewebe mit Sauerstoff und Nährstoffen. Zustände des Sauerstoffmangels (Hypoxie) werden als bedrohlich erachtet, da abhängig vom Ausprägungsgrad Zellen absterben, sei es durch apoptotische oder nekrotische Vorgänge. Dem versucht das Gewebe durch evolutionär erhaltene Signalwege entgegenzuwirken, z.B. über den nukleären Hypoxie-induzierbaren Faktor, der das Gewebe schützen soll, indem er das Überleben der Zellen fördert und gleichzeitig in Angiogenese, Hämatogenese und Stoffwechselprozesse eingreift. Neuere Erkenntnisse weisen darauf hin, dass gerade diese konservierten Signalwege auch therapeutische Ansätze in der Wundheilung von Knochen und Haut sowie in der Regeneration von Geweben, z.B. der Leber, und dem hämatopoetischen System, bedeuten können.

Zusammenfassung. Die Aufgabe des Kreislaufs ist die Versorgung von Gewebe mit Sauerstoff und Nährstoffen. Zustände des Sauerstoffmangels (Hypoxie) werden als bedrohlich erachtet, da abhängig vom Ausprägungsgrad Zellen absterben, sei es durch apoptotische oder nekrotische Vorgänge. Dem versucht das Gewebe durch evolutionär erhaltene Signalwege entgegenzuwirken, z.B. über den nukleären Hypoxie-induzierbaren Faktor, der das Gewebe schützen soll, indem er das Überleben der Zellen fördert und gleichzeitig in Angiogenese, Hämatogenese und Stoffwechselprozesse eingreift. Neuere Erkenntnisse weisen darauf hin, dass gerade diese konservierten Signalwege auch therapeutische Ansätze in der Wundheilung von Knochen und Haut sowie in der Regeneration von Geweben, z.B. der Leber, und dem hämatopoetischen System, bedeuten können.

Objective Various drugs are available for general anaesthesia, and the anaesthesiologist in charge may choose the one that is considered as the most appropriate for each specific case. When selecting an anaesthetic drug, its specific pharmacokinetic and pharmacodynamics as well as certain non-pharmacological properties have to be considered. This may lead to decisions that may be justified or unjustified according to scientific evidence and local standards. Methods In a prospective, single-centre, non-randomised and non-interventional study, 30 attending anaesthetists were interviewed about their drug prescription for general anaesthesia cases scheduled for the next day. The stated reasons for their choices from available alternatives were recorded and analysed for being justified or unjustified. Results We found 69% of all decisions as justified, while 31% were incorrect, unjustified or random. Female anaesthetists made 83%±15% justified decisions, whereas males achieved a lower performance with 69%±17% justified decisions (p=0.046). Conclusion To a large proportion, convenience, habit and personal preferences influence the decision-making in choosing the anaesthetic medication. A change of paradigm in the postgraduate education and training seems to be necessary.

Objective: Some anaesthetists are convinced that a long interval since the last relaxant dose may be sufficient to recover from anaesthesia without a pharmacological reversal. We intended to demonstrate that the dosing pattern of rocuronium could not predict the necessity of reversal. Methods: In a cohort analysis, we retrospectively analysed 180 anaesthesia records of adult patients who underwent elective surgical interventions in general anaesthesia and tracheal intubation with rocuronium-induced neuromuscular blockade. The extracted records were divided to 3 post hoc groups of 60 each, according to the reversal method employed at the end of anaesthesia: group N with neostigmine, group S with sugammadex and group Z without pharmacological reversal. All cases were terminated after achieving a train of four ratio of 0.9. Dosing patterns of rocuronium were compared by applying a novel pharmacometric calculation method, residual drug activity coefficient (RDAC), which employs both the administered individual drug doses in mg kg-1 and the timing of each drug administration in relation to the time of extubation. The rocuronium dosing pattern was correlated with the employed method of neuromuscular blockade reversal. Results: The dosing for rocuronium in patients without pharmacological reversal was lower than that in both reversal agent groups (n=0.58±0.21, S=0.58±0.17 and Z=0.47±0.17), but there was still a large overlap in the RDAC. Conclusion: The dosage profile of rocuronium alone cannot predict the possibility to refrain from pharmacological reversal.

Summary Volatile anaesthetics such as sevoflurane attenuate inflammatory processes, thereby impacting patient outcome significantly. Their inhalative administration is, however, strictly limited to controlled environments such as operating theatres, and thus an intravenously injectable immunomodulatory drug would offer distinct advantages. As protective effects of volatile anaesthetics have been associated with the presence of trifluorinated carbon groups in their basic structure, in this study we investigated the water-soluble sevoflurane metabolite hexafluoro-2-propanol (HFIP) as a potential immunomodulatory drug in a rat model of endotoxic shock. Male Wistar rats were subjected to intravenous lipopolysaccharide (LPS) and thereafter were treated with HFIP. Plasma and tissue inflammatory mediators, neutrophil invasion, tissue damage and haemodynamic stability were the dedicated end-points. In an endotoxin-induced endothelial cell injury model, underlying mechanisms were elucidated using gene expression and gene reporter analyses. HFIP reduced the systemic inflammatory response significantly and decreased endotoxin-induced tissue damage. Additionally, the LPS-provoked drop in blood pressure of animals was resolved by HFIP treatment. Pathway analysis revealed that the observed attenuation of the inflammatory process was associated with reduced nuclear factor kappa B (NF-κΒ) activation and suppression of its dependent transcripts. Taken together, intravenous administration of HFIP exerts promising immunomodulatory effects in endotoxaemic rats. The possibility of intravenous administration would overcome limitations of volatile anaesthetics, and thus HFIP might therefore represent an interesting future drug candidate for states of severe inflammation.

Background Growing evidence suggests a protective effect of volatile anaesthetics in ischaemia-reperfusion (I/R)-injury, and the accumulation of neutrophils is a crucial event. Pro-inflammatory cytokines carrying the C-X-C-motif including interleukin-8 (IL-8) and CXC-ligand 1 (CXCL1) activate CXC receptor-1 (CXCR1; stimulated by IL-8), CXC receptor-2 (CXCR2; stimulated by IL-8 and CXCL1), or both to induce CD11b-dependent neutrophil transmigration. Inhibition of CXCR1, CXCR2, or both reduces I/R-injury by preventing neutrophil accumulation. We hypothesized that interference with CXCR1/CXCR2 signalling contributes to the well-established beneficial effect of volatile anaesthetics in I/R-injury. Methods Isolated human neutrophils were stimulated with IL-8 or CXCL1 and exposed to volatile anaesthetics (sevoflurane/desflurane). Neutrophil migration was assessed using an adapted Boyden chamber. Expression of CD11b, CXCR1, and CXCR2 was measured by flow cytometry. Blocking antibodies against CXCR1/CXCR2/CD11b and phorbol myristate acetate were used to investigate specific pathways. Results Volatile anaesthetics reduced CD11b-dependent neutrophil transmigration induced by IL-8 by >30% and CD11b expression by 18 and 27% with sevoflurane/desflurane, respectively. This effect was independent of CXCR1/CXCR2 expression and CXCR1/CXCR2 endocytosis. Inhibition of CXCR1 signalling did not affect downregulation of CD11b with volatile anaesthetics. Blocking of CXCR2-signalling neutralized effects by volatile anaesthetics on CD11b expression. Specific stimulation of CXCR2 with CXCL1 was sufficient to induce upregulation of CD11b, which was impaired with volatile anaesthetics. No effect of volatile anaesthetics was observed with direct stimulation of protein kinase C located downstream of CXCR1/CXCR2. Conclusion Volatile anaesthetics attenuate neutrophil inflammatory responses elicited by CXC cytokines through interference with CXCR2 signalling. This might contribute to the beneficial effect of volatile anaesthetics in I/R-injury.

Recent clinical data support an aggressive surgical approach to both primary and metastatic liver tumors. For some indications, like colorectal liver metastases, the amount of liver tissue left behind after liver resection has become the main limiting factor of resectability of large or multiple liver tumors. A minimal amount of functional tissue is required to avoid the severe complication of post-hepatectomy liver failure, which has high morbidity and mortality. Inducing liver growth of the prospective remnant prior to resection has become more established in liver surgery, either in the form of portal vein embolization by interventional radiologists or in the form of portal vein ligation several weeks prior to resection. Recently, it was shown that liver regeneration is more extensive and rapid, when the parenchymal transection is added to portal vein ligation in a first stage and then, after only one week of waiting, resection performed in a second stage (Associating Liver Partition and Portal vein ligation for Staged hepatectomy = ALPPS). ALPPS has rapidly become popular across the world, but has been criticized for its high perioperative mortality. The mechanism of accelerated and extensive growth induced by this procedure has not been well understood. Animal models have been developed to explore both the physiological and molecular mechanisms of accelerated liver regeneration in ALPPS. This protocol presents a rat model that allows mechanistic exploration of accelerated regeneration.

BACKGROUND Patients experiencing acute lung injury (ALI) often need mechanical ventilation for which sedation may be required. In such patients, usually the first choice an intravenously administered drug. However, growing evidence suggests that volatile anesthetics such as sevoflurane are a valuable alternative. In this study, we evaluate pulmonary and systemic effects of long-term (24-hour) sedation with sevoflurane compared with propofol in an in vivo animal model of ALI. METHODS Adult male Wistar rats were subjected to ALI by intratracheal lipopolysaccharide (LPS) application, mechanically ventilated and sedated for varying intervals up to 24 hours with either sevoflurane or propofol. Vital parameters were monitored, and arterial blood gases were analyzed. Inflammation was assessed by the analysis of bronchoalveolar lavage fluid (BALF), cytokines (monocyte chemoattractant protein-1 [MCP-1], cytokine-induced neutrophil chemoattractant protein-1 [CINC-1], interleukin [IL-6], IL-12/12a, transforming growth factor-β, and IL-10) in blood and lung tissue and inflammatory cells. The alveolocapillary barrier was indirectly assessed by wet-to-dry ratio, albumin, and total protein content in BALF. Results are presented as mean ± standard deviation. RESULTS After 9 hours of ventilation and sedation, oxygenation index was higher in the LPS/sevoflurane (LPS-S) than in the LPS/propofol group (LPS-P) and reached 400 ± 67 versus 262 ± 57 mm Hg after 24 hours (P < .001). Cell count in BALF in sevoflurane-treated animals was lower after 18 hours (P = .001) and 24 hours (P < .001) than in propofol controls. Peak values of CINC-1 and IL-6 in BALF were lower in LPS-S versus LPS-P animals (CINC-1: 2.7 ± 0.7 vs 4.0 ± 0.9 ng/mL; IL-6: 9.2 ± 2.3 vs 18.9 ± 7.1 pg/mL, both P < .001), whereas IL-10 and MCP-1 did not differ. Also messenger RNAs of CINC-1, IL-6, IL-12a, and IL-10 were significantly higher in LPS-P compared with LPS-S. MCP-1 and transforming growth factor-β showed no differences. Wet-to-dry ratio was lower in LPS-S (5.4 ± 0.2 vs 5.7 ± 0.2, P = .016). Total protein in BALF did not differ between P-LPS and S-LPS groups. CONCLUSIONS Long-term sedation with sevoflurane compared with propofol improves oxygenation and attenuates the inflammatory response in LPS-induced ALI. Our findings suggest that sevoflurane may improve lung function when used for sedation in patients with ALI.

Background After cerebral injury blood-brain barrier disruption significantly impairs brain homeostasis. Volatile anesthetics have been shown to be protective in ischemia-reperfusion injury scenarios. Their impact on brain endothelial cells after hypoxia-reoxygenation (H/R) has not yet been studied in detail. Methods Rat brain endothelial cells (RBE4) were exposed to severe hypoxia and reoxygenated in air in the presence or absence of sevoflurane. Changes in dextran permeability and architecture of the cellular junctional proteins ZO-1 and β-catenin were measured. To determine necrosis and apoptosis rate DNA content, LDH release and caspase activity were quantified. The role of vascular endothelial growth factor (VEGF) as an inflammatory mediator increasing vascular permeability was assessed. At the same time, it was evaluated if sevoflurane effects are mediated through VEGF. Results were analyzed by unpaired t-tests or one way-analysis of variance followed by Bonferroni’s correction. Results H/R led to a 172% increase in permeability (p

Background Tissue hypoperfusion and inflammation in sepsis can lead to organ failure including kidney and liver. In sepsis, mortality of acute kidney injury increases by more than 50%. Which type of volume replacement should be used is still an ongoing debate. We investigated the effect of different volume strategies on inflammatory mediators in kidney and liver in an early sepsis model. Material and Methods Adult male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP) and assigned to three fluid replenishment groups. Animals received 30mL/kg of Ringer’s lactate (RL) for 2h, thereafter RL (75mL/kg), hydroxyethyl starch (HES) balanced (25mL/kg), containing malate and acetate, or HES saline (25mL/kg) for another 2h. Kidney and liver tissue was assessed for inflammation. In vitro rat endothelial cells were exposed to RL, HES balanced or HES saline for 2h, followed by stimulation with tumor necrosis factor-α (TNF-α) for another 4h. Alternatively, cells were exposed to malate, acetate or a mixture of malate and acetate, reflecting the according concentration of these substances in HES balanced. Pro-inflammatory cytokines were determined in cell supernatants. Results Cytokine mRNA in kidney and liver was increased in CLP animals treated with HES balanced compared to RL, but not after application of HES saline. MCP-1 was 3.5fold (95% CI: 1.3, 5.6) (p

Background Postreperfusion syndrome and haemodynamic instability are predictors for poor outcome after liver transplantation. Cytokine release has been claimed to be responsible for postreperfusion syndrome. However, the underlying pathophysiologic mechanism is not clarified. The aim of this prospective observational study was to correlate cardiac performance (measured by transoesophageal echocardiography (TEE), Doppler and Tissue Doppler Imaging (TDI)) to plasmatic cytokines: IL-6, IL-8, CXCL1, TGF-β and CD40L at 5 different time points during liver transplantation. Methods Seventeen consecutive patients scheduled for orthotopic liver transplantation, age 18 to 75 years without contraindication for transoesophageal echocardiography were included. Patients were monitored with TEE and TDI. Systolic and diastolic cardiac function, MAP, MPAP, CVP, PCWP, CO and blood samples for cytokine assays were recorded or collected after induction, 15 min after vena cava inferior clamping, 2 to 5 min after reperfusion, 60 min after reperfusion and at the end of surgery. Results Mean arterial pressure and catecholamine requirements remained unchanged, MPAP, CVP and CO increased, SVR decreased after unclamping. Postreperfusion syndrome did not develop. The haemodynamic parameters and the variations of TEE parameters were consistent with the volume load changes during clamping and declamping and did not reveal systolic or diastolic cardiac dysfunction. All cytokines, except TGF-β, increased. Conclusion These findings suggest, that significant cytokine release during liver transplantation is not necessarily coincident with haemodynamic instability and impaired cardiac function. Trial registration ClinicalTrials.gov: NCT00547924

Habitat destruction and degradation are the major causes for the decline of the endangered grass-feeding flightless beetle Dorcadion fuliginator in Central Europe. We examined habitat characteristics at 19 localities which still support abundant D. fuliginator populations in the southern part of the Upper Rhine valley (border region of Switzerland, Germany and France) to obtain basic information for the management of deteriorating habitats with declining beetle populations. Populations of D. fuliginator were found in different types of grassland on south, south-west and south-east facing slopes and flat ground. Correspondence analysis showed that plant communities of D. fuliginator localities overlap widely with fertilized, dry hay meadows (phyto-sociologically defined as dry type of the Arrhenatheretum community) and to a minor extent with traditionally extensively cultivated dry grasslands (Xerobrometum and Teucrio-Mesobrometum communities). Average indicator scores of the plant communities characterize the habitat of D. fuliginator as fairly light-exposed and warm, but with relatively large ranges in humidity and nutrient content. The results of a 16-year study on the timing of emergence of the first beetles in a population provided further evidence for the high temperature requirements of D. fuliginator. Proposed conservation measures include traditional cultivation of the present secondary, man-made D. fuliginator habitats, introduction of beetles to suitable motorway embankments as well as large-scale measures allowing natural dynamics in the flood plain along the river Rhine, the presumably primordial habitat of this highly endangered beetle.

PURPOSE OF REVIEW Organ protection remains a primary objective in the anesthetic management of patients undergoing transplantation. An ongoing effort has been made to develop strategies to improve graft outcome and reduce postoperative morbidity and mortality, but trials have reported conflicting results. The aim of this review was to provide a comprehensive summary of the anesthetic management in transplant recipients and to identify current strategies for organ protection. RECENT FINDINGS Decreasing blood products requirements, intraoperative blood glucose control and adequate postoperative pain therapy may improve patient outcome. Vasopressors have been reported to reduce perioperative bleeding but might be associated with postoperative acute renal failure in liver transplantation. Early extubation may increase survival rates in recipients. These perioperative challenges, along with other protective strategies, have been addressed in 20 recently published studies: 10 randomized controlled trials, nine retrospective studies and one prospective study. SUMMARY This review identified several promising strategies ensuring organ protection and improving patient outcome after solid organ transplantation. However, as outcomes were difficult to compare, further evidence will be needed before drawing firm conclusions.

Summary Pulmonary oedema is a hallmark of acute lung injury (ALI), consisting of various degrees of water and proteins. Physiologically, sodium enters through apical sodium channels (ENaC) and is extruded basolaterally by a sodium–potassium–adenosine–triphosphatase pump (Na+/K+-ATPase). Water follows to maintain iso-osmolar conditions and to keep alveoli dry. We postulated that the volatile anaesthetic sevoflurane would impact oedema resolution positively in an in-vitro and in-vivo model of ALI. Alveolar epithelial type II cells (AECII) and mixed alveolar epithelial cells (mAEC) were stimulated with 20 µg/ml lipopolysaccharide (LPS) and co-exposed to sevoflurane for 8 h. In-vitro active sodium transport via ENaC and Na+/K+-ATPase was determined, assessing 22sodium and 86rubidium influx, respectively. Intratracheally applied LPS (150 µg) was used for the ALI in rats under sevoflurane or propofol anaesthesia (8 h). Oxygenation index (PaO2/FiO2) was calculated and lung oedema assessed determining lung wet/dry ratio. In AECII LPS decreased activity of ENaC and Na+/K+-ATPase by 17·4% ± 13·3% standard deviation and 16·2% ± 13·1%, respectively. These effects were reversible in the presence of sevoflurane. Significant better oxygenation was observed with an increase of PaO2/FiO2 from 189 ± 142 mmHg to 454 ± 25 mmHg after 8 h in the sevoflurane/LPS compared to the propofol/LPS group. The wet/dry ratio in sevoflurane/LPS was reduced by 21·6% ± 2·3% in comparison to propofol/LPS-treated animals. Sevoflurane has a stimulating effect on ENaC and Na+/K+-ATPase in vitro in LPS-injured AECII. In-vivo experiments, however, give strong evidence that sevoflurane does not affect water reabsorption and oedema resolution, but possibly oedema formation.

Background Current guidelines for a check-up recommend routine screening not triggered by specific symptoms for some known risk factors and diseases in the general population. Patients' perceptions and expectations regarding a check-up exam may differ from these principles. However, quantitative and qualitative data about the discrepancy between patient- and provider expectations for this type of clinic consultation is lacking. Methods For a year, we prospectively enrolled 66 patients who explicitly requested a "check-up" at our medical outpatient division. All patients actively denied upon prompting having any symptoms or specific health concerns at the time they made their appointment. All consultations were videotaped and analysed for information about spontaneously mentioned symptoms and reasons for the clinic consultation ("open agendas") and for cues to hidden patient agendas using the Roter interaction analysis system (RIAS). Results All patients initially declared to be asymptomatic but this was ultimately the case in only 7 out of 66 patients. The remaining 59 patients spontaneously mentioned a mean of 4.2 ± 3.3 symptoms during their first consultation. In 23 patients a total of 31 hidden agendas were revealed. The primary categories for hidden agendas were health concerns, psychosocial concerns and the patient's concept of disease. Conclusions The majority of patients requesting a general check-up tend to be motivated by specific symptoms and health concerns and are not "asymptomatic" patients who primarily come for preventive issues. Furthermore, physicians must be alert for possible hidden agendas, as one in three patients have one or more hidden reasons for requesting a check-up.

Background: Acute renal failure is a frequent complication of sepsis. Hydroxyethyl starch (HES) is widely used in the treatment of such patients. However, the effect of HES on renal function during sepsis remains controversial. We established an in vitro model of tumor necrosis factor-alpha (TNF-alpha)-stimulated human proximal tubular epithelial (HK-2) cells to assess the possible effects of HES 130/0.42 and HES 200/0.5 on these activated cells. Methods: HK-2 cells were stimulated with TNF-alpha in the presence or absence of HES 130/0.42 or 200/0.5. After 4, 10, and 18 h of incubation, monocyte chemoattractant protein-1 (MCP-1), a key chemoattractant for neutrophils and macrophages, was measured. In addition, viability and cytotoxicity assays were performed. Results: MCP-1 expression was doubled upon TNF-alpha exposure. In the presence of 2% and 4% HES 200/0.5 in 98% (96%) medium over a stimulation time period of 10 h and 18 h, the MCP-1 concentration was decreased between 26% and 56% (P < 0.05). TNF-alpha stimulation resulted in a significant decrease of viability by 53%-63%, whereas viability decreased by only 32%-40% in coincubation with HES 130/0.42 (P < 0.005) and remained even less affected by TNF-alpha in the presence of HES 200/0.5 (P < 0.001). The TNF-alpha-induced cell death rate was attenuated in the presence of HES 200/0.5 (P < 0.05). Conclusions: This in vitro study shows that both HES products modulate cell injury upon inflammatory stimulation. The effect was more pronounced in the HES 200/0.5 group than for HES 130/0.42, suggesting a possible biological difference between the HES types.

Background Acute lung injury is a common complication in critically ill patients. Several studies suggest that volatile anesthetics have immunomodulating effects. The aim of the current study was to assess possible postconditioning with sevoflurane in an in vivo model of endotoxin-induced lung injury. Methods Rats were anesthetized, tracheotomized, and mechanically ventilated. Lipopolysaccharide (saline as control) was administered intratracheally. Upon injury after 2 h of propofol anesthesia, general anesthesia was continued with either sevoflurane or propofol for 4 h. Arterial blood gases were measured every 2 h. After 6 h of injury, bronchoalveolar lavage was performed and lungs were collected. Total cell count, albumin content, concentrations of the cytokines cytokine-induced neutrophil chemoattractant-1 and monocyte chemoattractant protein-1, and phospholipids were analyzed in bronchoalveolar lavage fluid. Expression of messenger RNA for the two cytokines and for surfactant protein B was determined in lung tissue. Histopathologic examination of the lung was performed. Results Significant improvement of the ratio of oxygen tension to inspired oxygen fraction was shown with sevoflurane (mean + or - SD: 243 + or - 94 mmHg [32.4 kPa]) compared with propofol (88 + or - 19 mmHg [11.7 kPa]). Total cell count representing effector cell recruitment as well as albumin content as a measure of lung permeability were significantly decreased in the sevoflurane-lipopolysaccharide group compared with the propofol-lipopolysaccharide group in bronchoalveolar lavage fluid. Expression of the cytokines protein in bronchoalveolar lavage fluid as well as messenger RNA in lung tissue was significantly lower in the sevoflurane-lipopolysaccharide group compared with the propofol-lipopolysaccharide group. Conclusions Postconditioning with sevoflurane attenuates lung damage and preserves lung function in an in vivo model of acute lung injury.