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KEY POINTS Acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure, characterized by acute, diffuse, inflammatory lung injury,[1][1] that results in increased alveolar capillary permeability and the development of nonhydrostatic pulmonary edema. Clinically, ARDS

BACKGROUND: Learning bronchoscopy is challenging for novices, as it requires navigation in a 3-dimensional space under 2-dimensional viewing conditions and execution of complex motor skills with an unfamiliar instrument. Mental practice exercises are based on repeated visualization of motor actions without physically performing them, thereby promoting the learning of skills. We aimed to evaluate whether a teaching intervention including mental practice exercise modules for the acquisition of bronchoscopy skills improves fiberoptic intubation performance of novice learners. METHODS: In this prospective cohort study, 24 pediatric intensive care trainees and respiratory therapists participating in a bronchoscopy learning curriculum in 2016–2017 attended a theoretical lecture followed by self-guided learning. Subsequently, the learners were randomly assigned to either participating in a teaching intervention including mental practice exercises or not (control group). The primary outcome was time to complete their first bronchoscopic intubation using a virtual reality simulator. Secondary outcomes were the occurrence of “red outs” (ie, the anatomy could no longer be visualized) or collisions with the airway wall. Bayesian Poisson Mixture models were used to estimate the effect of the intervention on outcomes. Furthermore, participation in the teaching intervention was examined in short interviews and with descriptive thematic analysis. RESULTS: Subjects in the intervention group completed the bronchoscopy on average 1.2 times faster (rate ratio 1.2 [95% credible intervals 1.1–1.3]). The posterior probability that the teaching intervention reduced the occurrence of “red outs” by more than half was 86%. No differences were found regarding the odds of colliding with the airway wall. Everyone except 1 trainee in the mental practice group engaged with and found the mental practice modules helpful. CONCLUSIONS: A teaching intervention including mental practice exercises represents a valuable additional learning strategy promoting the performance and complex skill acquisition of novice learners in the initial stages of learning bronchoscopy procedures.

Background Treatment with immune checkpoint and BRAF/MEK inhibitors has significantly improved the survival of patients with advanced cutaneous melanoma and other metastatic malignancies. Therapy-related uveitis is a rare ocular adverse event, which may potentially lead to legal blindness. The epidemiology of treatment-related uveitis is currently insufficiently known. Patients and methods In this cohort study, we asked whether exposure to either immune checkpoint or BRAF/MEK inhibitors was associated with a higher risk of developing uveitis compared with the general population. Based on a Bayesian framework, we estimated the probability of developing uveitis with a right-censored, exponential survival model using data from the Zurich Melanoma Registry. The registry included all adult patients treated for advanced cutaneous melanoma between January 2008 and December 2018 at the University Hospital of Zurich, Switzerland. Results In total, 304 patients (64%) were treated with immune checkpoint and 186 patients (38%) with BRAF/MEK inhibitors. Median follow-up time was 74 days (interquartile range: 57–233 days). Eleven patients developed uveitis and 30 patients died. We estimated the probability of developing uveitis per year in the general population as 0.05% (95% credibility interval [CrI]: 0.02%–0.1%). Corresponding posterior probabilities of treatment-related uveitis were 3.48% (95% CrI: 0.93%–7.49%) and 5.04% (95% CrI: 2.07%–9.19%) for immune checkpoint or BRAF/MEK inhibitors (posterior probability for difference: 76%). Conclusions Immune checkpoint and particularly BRAF/MEK inhibitor therapies are associated with an increase in the risk of developing uveitis. Treatment-related uveitis is not associated with systemic adverse events of immune checkpoint or BRAF/MEK inhibitors.

POINTS CLES Le syndrome de detresse respiratoire aigue (SDRA) est une forme gravissime d’insuffisance respiratoire, caracterisee par une atteinte pulmonaire inflammatoire diffuse aigue[1][1] qui entraine une augmentation de la permeabilite des capillaires alveolaires et un œdeme

Diaphragmatic respiratory effort during mechanical ventilation is an important determinant of patient outcome, but direct measurement of diaphragmatic contractility requires specialized instrumentation and technical expertise. We sought to determine whether routinely collected clinical variables can predict diaphragmatic contractility and stratify the risk of diaphragm atrophy.We conducted a secondary analysis of a prospective cohort study on diaphragm ultrasound in mechanically ventilated subjects. Clinical variables, such as breathing frequency, ventilator settings, and blood gases, were recorded longitudinally. Machine learning techniques were used to identify variables predicting diaphragm contractility and stratifying the risk of diaphragm atrophy (10% decrease in thickness from baseline). Performance of the variables was evaluated in mixed-effects logistic regression and random-effects tree models using the area under the receiver operating characteristic curve.Measurements were available for 761 study days in 191 subjects, of whom 73 (38%) developed diaphragm atrophy. No routinely collected clinical variable, alone or in combination, could accurately predict either diaphragm contractility or the development of diaphragm atrophy (model area under the receiver operating characteristic curve 0.63-0.75). The risk of diaphragm atrophy was not significantly different according to the presence or absence of patient-triggered breaths (38.3% vs 38.6%; odds ratio 1.01, 95% CI 0.05-2.03). Diaphragm thickening fraction15% during either of the first 2 d of the study was associated with a higher risk of atrophy (44.6% vs 26.1%; odds ratio 2.28, 95% CI 1.05-4.95).Diaphragmatic contractility and the risk of diaphragm atrophy could not be reliably determined from routinely collected clinical variables and ventilator settings. A single measurement of diaphragm thickening fraction measured within 48 h of initiating mechanical ventilation can be used to stratify the risk of diaphragm atrophy during mechanical ventilation.

Summary Background Mortality in acute respiratory failure remains high despite the use of lung-protective ventilation. Recent studies have shown an association between baseline ventilation parameters (driving pressure or mechanical power) and outcomes for patients with acute respiratory distress syndrome. Strategies focused on limiting these parameters have been proposed to further improve outcomes. However, it remains unknown whether driving pressure and mechanical power should be limited over the entire duration of mechanical ventilation and in all patients with acute respiratory failure. We aimed to estimate the association between exposure to different intensities of mechanical ventilation over time and intensive care unit (ICU) mortality in patients with acute respiratory failure. Methods In this registry-based, prospective cohort study, we obtained data from the Toronto Intensive Care Observational Registry, which includes all patients receiving mechanical ventilation for 4 h or more in nine ICUs that are affiliated with the University of Toronto (Toronto, ON, Canada). We included all adult (≥18 years) patients who received invasive mechanical ventilation between April 11, 2014, and June 5, 2019. Patients were excluded if they received treatment with extracorporeal life support. The primary outcome was ICU mortality. Bayesian joint models were used to estimate the strength of associations, accounting for informative censoring due to death during follow-up. Findings Of 13 939 patients recorded in the registry, 13 408 (96·2%) were eligible for descriptive analysis. The primary analysis comprised 7876 (58·7%) patients with complete baseline characteristics, and a secondary analysis included all 13 408 patients after multiple imputation in the joint model analysis. 2409 (18·0%) of 13 408 patients died in the ICU. After adjustment for baseline characteristics, including age and severity of illness, a significant increase in the hazard of death was found to be associated with each daily increment in driving pressure (hazard ratio 1·064, 95% credible interval 1·057–1·071) or mechanical power (hazard ratio 1·060, 95% credible interval 1·053–1·066). These associations persisted over the duration of mechanical ventilation. Interpretation Cumulative exposure to higher intensities of mechanical ventilation was harmful, even for short durations. Limiting exposure to driving pressure or mechanical power should be evaluated in further studies as promising ventilation strategies to reduce mortality in patients with acute respiratory failure. Funding Canadian Institutes of Health Research.

Background Excessive respiratory muscle effort during mechanical ventilation may cause patient self-inflicted lung injury and load-induced diaphragm myotrauma, but there are no non-invasive methods to reliably detect elevated transpulmonary driving pressure and elevated respiratory muscle effort during assisted ventilation. We hypothesized that the swing in airway pressure generated by respiratory muscle effort under assisted ventilation when the airway is briefly occluded (ΔPocc) could be used as a highly feasible non-invasive technique to screen for these conditions. Methods Respiratory muscle pressure (Pmus), dynamic transpulmonary driving pressure (ΔPL,dyn, the difference between peak and end-expiratory transpulmonary pressure), and ΔPocc were measured daily in mechanically ventilated patients in two ICUs in Toronto, Canada. A conversion factor to predict ΔPL,dyn and Pmus from ΔPocc was derived and validated using cross-validation. External validity was assessed in an independent cohort (Nanjing, China). Results Fifty-two daily recordings were collected in 16 patients. In this sample, Pmus and ΔPL were frequently excessively high: Pmus exceeded 10 cm H2O on 84% of study days and ΔPL,dyn exceeded 15 cm H2O on 53% of study days. ΔPocc measurements accurately detected Pmus > 10 cm H2O (AUROC 0.92, 95% CI 0.83–0.97) and ΔPL,dyn > 15 cm H2O (AUROC 0.93, 95% CI 0.86–0.99). In the external validation cohort (n = 12), estimating Pmus and ΔPL,dyn from ΔPocc measurements detected excessively high Pmus and ΔPL,dyn with similar accuracy (AUROC ≥ 0.94). Conclusions Measuring ΔPocc enables accurate non-invasive detection of elevated respiratory muscle pressure and transpulmonary driving pressure. Excessive respiratory effort and transpulmonary driving pressure may be frequent in spontaneously breathing ventilated patients.

Public health interventions implemented during the coronavirus disease 2019 (COVID-19) pandemic are based on experience gained from past pandemics. The 1918 influenza pandemic is the most extensively researched historical influenza outbreak. All 9335 reports available in the State Archives on 121 152 cases of influenza-like illness from the canton of Bern from 473 of 497 municipalities (95.2%) were collected; the cases were registered between 30 June 1918 and 30 June 1919. The overall incidence rates of newly registered cases per week for the 9 greater regions of Bern for both the first and second waves of the pandemic were calculated. Relative incidence rate ratios (RIRRs) were calculated to estimate the change in the slope of incidence curves associated with public health interventions. During the first wave, school closures (RIRR, 0.16 [95% CI, 0.15 to 0.17]) and restrictions of mass gatherings (RIRR, 0.57 [CI, 0.54 to 0.61]) were associated with a deceleration of epidemic growth. During the second wave, in autumn 1918, cantonal authorities initially reacted hesitantly and delegated the responsibility to enact interventions to municipal authorities, which was associated with a lack of containment of the second wave. A premature relaxation of restrictions on mass gatherings was associated with a resurgence of the epidemic (RIRR, 1.18 [CI, 1.12 to 1.25]). Strikingly similar patterns were found in the management of the COVID-19 outbreak in Switzerland, with a considerably higher amplitude and prolonged duration of the second wave and much higher associated rates of hospitalization and mortality.

The paradigm of supportive care of patients who are critically ill has changed significantly over the past 20 years. Patients on mechanical ventilation are no longer heavily sedated; the goal is a comfortable patient who can interact with health-care professionals and with their family members. Systematic, regular assessment of the patient for pain, anxiety, and sleep deprivation allows early recognition of these distressing symptoms. Appropriate treatment of patients' symptoms should be based on a multi-modal pharmacologic and non-pharmacologic approach. Early mobilization and avoidance of physical restraint are additional patient-centered goals. The presence of family members during daily rounds and at the bedside can reduce the distress of the patient and enhance communication with the health-care team. All of these changes have created new challenges and opportunities for the multidisciplinary health-care team. This review aimed to describe the main components of evidence-based supportive care of patients on mechanical ventilation, beyond the specific settings of the ventilator.

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.

ObjectiveTo describe the size and variability of non-inferiority margins used in non-inferiority trials of medications with primary outcomes involving mortality, and to examine the association between trial characteristics and non-inferiority margin size.DesignSystematic review.Data sourcesMedline, Medline In Process, Medline Epub Ahead of Print and Embase Classic+Embase databases from January 1989 to December 2019.Eligibility criteriaProspective non-inferiority randomised controlled trials comparing pharmacological therapies, with primary analyses for non-inferiority and primary outcomes involving mortality alone or as part of a composite outcome. Trials had to prespecify non-inferiority margins as absolute risk differences or relative to risks of outcome and provide a baseline risk of primary outcome in the control intervention.Results3992 records were screened, 195 articles were selected for full text review and 111 articles were included for analyses. 82% of trials were conducted in thrombosis, infectious diseases or oncology. Mortality was the sole primary outcome in 23 (21%) trials, and part of a composite primary outcome in 88 (79%) trials. The overall median non-inferiority margin was an absolute risk difference of 9% (IQR 4.2%–10%). When non-inferiority margins were expressed relative to the baseline risk of primary outcome in control groups, the median relative non-inferiority margin was 1.5 (IQR 1.3–1.7). In multivariable regression analyses examining the association between trial characteristics (medical specialty, inclusion of paediatric patients, mortality as a sole or part of a composite primary outcome, presence of industry funding) and non-inferiority margin size, only medical specialty was significantly associated with non-inferiority margin size.ConclusionAbsolute and relative non-inferiority margins used in published trials comparing medications are large, allowing conclusions of non-inferiority in the context of large differences in mortality. Accepting the potential for large increases in outcomes involving mortality while declaring non-inferiority is a challenging methodological issue in the conduct of non-inferiority trials.

BACKGROUND Transfusion practice might significantly influence patient morbidity and mortality. Between European countries, transfusion practice of red blood cells (RBC) greatly differs. Only sparse data are available on transfusion practice of general internal medicine physicians in Switzerland. METHODS In this cross-sectional survey, physicians working in general medicine teaching hospitals in Switzerland were investigated regarding their self-reported transfusion practice in anemic patients without acute bleeding. The definition of anemia, transfusion triggers, knowledge on RBC transfusion, and implementation of guidelines were assessed. RESULTS 560 physicians of 71 hospitals (64%) responded to the survey. Anemia was defined at very diverging hemoglobin values (by 38% at a hemoglobin

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.

Nephrology Dialysis Transplantation, 26 (9), ISSN:0931-0509, ISSN:1460-2385

Published ahead of print January 5, 2017., BACKGROUND: Pharmacologic pre- and postconditioning with sevoflurane compared with total IV anesthesia in patients undergoing liver surgery reduced complication rates as shown in 2 recent randomized controlled trials. However, the potential health economic consequences of these different anesthesia regimens have not yet been assessed. METHODS: An expostcost analysis of these 2 trials in 129 patients treated between 2006 and 2010 was performed. We analyzed direct medical costs for in-hospital stay and compared pharmacologic pre- and postconditioning with sevoflurane (intervention) with total IV anesthesia (control) from the perspective of a Swiss university hospital. Year 2015 costs, converted to US dollars, were derived from hospital cost accounting data and compared with a multivariable regression analysis adjusting for relevant covariables. Costs with negative prefix indicate savings and costs with positive prefix represent higher spending in our analysis. RESULTS: Treatment-related costs per patient showed a nonsignificant change by −12,697 US dollars (95% confidence interval [CI], 10,956 to −36,352; P = .29) with preconditioning and by −6139 US dollars (95% CI, 6723 to −19,000; P = .35) with postconditioning compared with the control group. Results were robust in our sensitivity analysis. For both procedures (control and intervention) together, major complications led to a significant increase in costs by 86,018 US dollars (95% CI, 13,839-158,198; P = .02) per patient compared with patients with no major complications. CONCLUSIONS: In this cost analysis, reduced in-hospital costs by pharmacologic conditioning with sevoflurane in patients undergoing liver surgery are suggested. This possible difference in costs compared with total IV anesthesia is the result of reduced complication rates with pharmacologic conditioning, because major complications have significant cost implications.

OBJECTIVE: High FiO(2)s may augment lung damage to exacerbate lung injury in patients with ARDS. Participants enrolled in ARDS Network Trials had a goal PaO(2) range of 55–80 mmHg, yet the effect of oxygen exposure above this arterial oxygen tension range on clinical outcomes is unknown. We sought to determine if oxygen exposure that resulted in a PaO(2)s above goal (>80 mmHg) was associated with worse outcomes in patients with ARDS. DESIGN: Longitudinal analysis of data collected in these trials. SETTING: Ten clinical trials conducted at ARDS Network hospitals between 1996 and 2013. SUBJECTS: Critically ill patients with ARDS. MEASUREMENTS AND MAIN RESULTS: Each day, if the PaO(2) >80 mmHg and FiO(2) > 0.5, we determined above goal oxygen exposure, defined as the difference between the administered FiO(2) and 0.5, and summed these values over the first five days. We determined the effect of a cumulative five-day above goal oxygen exposure on mortality prior to discharge home at 90 days. Among 2994 participants (mean age 51.3 years, 54% male) with a study-entry PaO(2)/FiO(2) that met ARDS criteria, average cumulative above goal oxygen exposure was 0.24 FiO(2)-days (interquartile range 0 to 0.38). Participants with above goal oxygen exposure were more likely to die (adjusted interquartile-range OR=1.20, 95% CI 1.11 to 1.31), and have lower ventilator-free days (adjusted interquartile-range mean difference of −0.83, −1.18 to −0.48) and lower hospital-free days (adjusted interquartile-range mean difference of −1.38, −2.09 to −0.68). We observed a dose-response relationship between the cumulative above goal oxygen exposure and worsened clinical outcomes for participants with mild, moderate, or severe ARDS, suggesting that the observed relationship is not primarily influenced by severity of illness. CONCLUSIONS: Oxygen exposure resulting in arterial oxygen tensions above the protocol goal occurred frequently and was associated with worse clinical outcomes at all levels of ARDS severity.

Background Mitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition. Patients and methods In this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy. They underwent regular ophthalmological examinations including determination of visual function, biomicroscopy, dilated fundoscopy and optical coherence tomography (OCT) for a period of up to 2 years. Retinopathy was diagnosed on defined OCT criteria. Results Sixty-two patients were investigated between 1st October 2011 and 31st July 2015: 13 were treated with the MEK inhibitor binimetinib alone, 10 with a selective BRAF inhibitor, and 39 with combination therapy. In 92% of patients on monotherapy and 100% of those on combination treatment, binimetinib caused dose-related lesions with serous neuroretinal detachments and oedema, strongly dependent on the time after medication. With continued treatment, retinal volume and thickness decreased to levels below baseline, without any apparent functional deficits or changes in structural integrity. Conclusions Binimetinib induces a specific retinopathy with daily fluctuations depending on the time interval after medication. The retinopathy partially recovers, but can still be detected many months later. Retinal thinning, possible first signs of retinal atrophy have been observed after long-term treatment, but, so far, without functional relevance.

Background Although one-lung ventilation (OLV) has become an established procedure during thoracic surgery, sparse data exist about inflammatory alterations in the deflated, reventilated lung. The aim of this study was to prospectively investigate the effect of OLV on the pulmonary inflammatory response and to assess possible immunomodulatory effects of the anesthetics propofol and sevoflurane. Methods Fifty-four adults undergoing thoracic surgery with OLV were randomly assigned to receive either anesthesia with intravenously applied propofol or the volatile anesthetic sevoflurane. A bronchoalveolar lavage was performed before and after OLV on the lung side undergoing surgery. Inflammatory mediators (tumor necrosis factor alpha, interleukin 1beta, interleukin 6, interleukin 8, monocyte chemoattractant protein 1) and cells were analyzed in lavage fluid as the primary endpoint. The clinical outcome determined by postoperative adverse events was assessed as the secondary endpoint. Results The increase of inflammatory mediators on OLV was significantly less pronounced in the sevoflurane group. No difference in neutrophil recruitment was found between the groups. A positive correlation between neutrophils and mediators was demonstrated in the propofol group, whereas this correlation was missing in the sevoflurane group. The number of composite adverse events was significantly lower in the sevoflurane group. Conclusions This prospective, randomized clinical study suggests an immunomodulatory role for the volatile anesthetic sevoflurane in patients undergoing OLV for thoracic surgery with significant reduction of inflammatory mediators and a significantly better clinical outcome (defined by postoperative adverse events) during sevoflurane anesthesia.

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 Melanoma is one of the most aggressive skin cancers. Recently, selective MEK inhibitors have shown efficacy in patients with advanced BRAF- and NRAS-mutant melanoma. Soon after the initiation of clinical oncology trials with MEK inhibitors, it was observed that some participants developed an eye condition resembling central serous chorioretinopathy. The present article addresses the clinical features and management of these MEK inhibitor-associated retinal syndromes. Patients and methods Thirty-two patients with advanced cutaneous melanoma were treated with the selective MEK inhibitor binimetinib (MEK162) in three different Phase 1b or 2 clinical trials. Twenty patients on binimetinib monotherapy and 12 on binimetinib plus RAF inhibitor [pan-kinase RAF inhibitor RAF265 (n = 7) or selective BRAF inhibitor encorafenib (LGX818) (n = 5)] combination therapy underwent ophthalmological examinations at regular intervals, including determination of best corrected visual acuity, perimetry, colour vision testing, dilated fundus examination, and multimodal imaging. Results Grade 1–2 bilateral retinopathies with multiple lesions were observed in 13 of 20 patients on binimetinib monotherapy, 4 of 7 patients on binimetinib plus RAF265 combination therapy, and 2 of 5 patients on binimetinib plus encorafenib combination therapy. In this study population, the rate ranged from 40% to 65%. Retinopathy events appeared during the first 4 weeks, and in some cases, during the first few days of treatment. Patients reported mild and only short-lived visual symptoms. Optical coherence tomography revealed neuroretinal elevations. Central retinal thickness and volume showed dose-dependent increases after the start of treatment, followed by a marked decrease despite continued treatment, which was associated with symptom resolution. No vascular abnormalities were found with fluorescein and indocyanine green angiography. Conclusions Treatment with the selective MEK inhibitor binimetinib as a single agent or in combination with RAF inhibitors induced transient retinopathy with multiple bilateral lesions in some patients. Binimetinib-induced retinopathy was usually mild, self-limiting, and tolerable as visual function was not seriously impaired.

Sepsis and septic shock remain the leading causes of death in intensive care units worldwide.1 Complex pathophysiology together with heterogeneous disease patterns are key features making the treatment of sepsis extremely challenging.2–5 Numerous approaches have been undertaken to attenuate the harmful host response to infection, with a mostly unsuccessful translation into clinical outcome. Despite new pathophysiological insights and major efforts in developing goal-directed therapies, mortality in septic patients remains considerably high, and the treatment of late stage diagnosed patients is generally associated with bad outcome.6 Volatile anesthetics such as desflurane, isoflurane, and sevoflurane have been identified as effective modifiers of the inflammatory response in various states of tissue injury, exerting beneficial effects on organ function and overall outcome in both animals7–12 and patients.13–16 Potential benefits of the application of volatile anesthetics in in vivo models of experimental sepsis have not been systematically explored, and their effect on survival remains unclear. Previous studies elucidating the protective potential of volatile anesthetics have traditionally focused on ischemia–reperfusion injury and not on sepsis. In addition, biomarkers of organ injury were determined, but outcome parameters were not.17 In this study, we investigated in a model of severe murine sepsis with intraabdominal focus (peritonitis) whether the volatile anesthetics desflurane, isoflurane, and sevoflurane impact on overall survival of septic animals. The cecal ligation and puncture (CLP) model is considered the “gold standard” in sepsis research with a disease profile similar to that in human sepsis in that it encompasses more of the clinical features and drug responses of human sepsis, than, for example, the lipopolysaccharide model,18,19 despite the absence of some key features (e.g., kidney and lung injury). In this study, mice were exposed to desflurane, isoflurane, or sevoflurane during induction of sepsis (conditioning). To investigate the effect in a postconditioning setting, desflurane and sevoflurane were applied 24 h after the CLP procedure, when the mice showed pronounced symptoms of inflammation. Survival as well as markers of renal and hepatic organ function was compared with the CLP group without intervention. Being aware of the limitations of animal models of sepsis, the current study illustrates the beneficial effects of the volatile anesthetics desflurane and sevoflurane in states of severe inflammation leading to a remarkably improved 7-day survival and reduced end-organ damage.

Sepsis with multiple organ failure remains a leading cause of hospital morbidity and mortality on ICUs imparting tremendous financial costs. Recently, the primary metabolite of sevoflurane, hexafluoro-2-propanol (HFIP), has been found to exert immunomodulatory properties attenuating inflammatory response to lipopolysaccharides (LPS) in vitro [1]. We investigated whether HFIP attenuates plasma and tissue inflammatory mediator expression in a rat model of endotoxic shock.

Background Transfusing blood products may induce inflammatory reactions within the vascular compartment potentially leading to a systemic inflammatory response. Experiments were designed to assess the inflammatory potential of different blood products in an endothelial cell-based in vitro model and to compare baseline levels of potentially activating substances in transfusion products. Methods The inflammatory response from pre-activated (endotoxin-stimulated) and non-activated endothelial cells as well as neutrophil endothelial transmigration in response to packed red blood cells (PRBC), platelet concentrates (PC) and fresh frozen plasma (FFP) was determined. Baseline inflammatory mediator and lipid concentrations in blood products were evaluated. Results Following incubation with all blood products, an increased inflammatory mediator release from endothelial cells was observed. Platelet concentrates, and to a lesser extent also FFP, caused the most pronounced response, which was accentuated in already pre-stimulated endothelial cells. Inflammatory response of endothelial cells as well as blood product-induced migration of neutrophils through the endothelium was in good agreement with the lipid content of the according blood product. Conclusion Within the group of different blood transfusion products both PC and FFP have a high inflammatory potential with regard to activation of endothelial cells. Inflammation upon blood product exposure is strongly accentuated when endothelial cells are pre-injured. High lipid contents in the respective blood products goes along with an accentuated inflammatory reaction from endothelial cells., PLoS ONE, 7 (3), ISSN:1932-6203

Volatile anaesthetics are known as immunomodulatory substances in inflammatory as well as in ischemia/reperfusion processes [1,2]. We investigated in a model of acute pulmonary inflammation whether these immunomodulatory effects arise from the ether basic structure or from characteristics in their halogenation.

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.

Volatile anesthetics are known to have immunomodulatory effects in conditions of organ injury. A recent study in an experimental sepsis model has shown remarkably improved survival when mice were exposed to volatile anesthetics. In the present study, we show that hexafluoroisopropanol – a water-soluble primary sevoflurane metabolite – has beneficial effects on the overall survival in a murine model of cecal ligation and puncture. Seven-day survival as well as tissue damage markers including transaminases and high mobility group box protein-1 were assessed as measures of end organ damage. In animals undergoing cecal ligation and puncture procedure hexafluoroisopropanol conditioning - but not late postconditioning 24 hours after sepsis induction - significantly increased survival rate (17% vs. 77%, p = 0.037) and attenuated secretion of organ damage markers. This study shows survival benefits by administration of the metabolite of a volatile anesthetic. If successfully translated, hexafluoroisopropanol might offer interesting therapeutic opportunities in the future treatment of abdominal sepsis.

Sepsis with multiple organ failure remains a leading cause of death in ICUs. Acute renal failure is a common complication of severe sepsis and septic shock. The effect of hydroxyethyl starch (HES) on the kidney as well as on liver tissue remains controversial and has never been tested in detail. We investigated in a model of fecal peritonitis the influence of fluid resuscitation with HES 6% in unbalanced versus balanced solutions on inflammatory mediator expression in renal and hepatic tissue.

Direct and rapid removal of pathogens or noxious metabolites from a patient is the most straightforward cure imaginable. Dialysis and plasma filtration/exchange are the current broadly applicable methods to perform a direct removal of disease-causing factors from a patient. We describe the use of stable nanomagnets to rapidly and selectively remove heavy metal ions, overdosed steroid drugs and proteins from human blood. This nanomagnet-based purification method avoids fouling of filter membranes and benefits from a high external surface area, and a correspondingly fast diffusion.