Search

Background and Purpose: Endocannabinoids are lipid mediators, which elicit complex biological effects that extend beyond the central nervous system. Tissue concentrations of endocannabinoids increase in atherosclerosis, and for the endocannabinoid N-arachidonoyl-ethanolamine (anandamide, AEA), this has been linked to an anti-inflammatory function. In this study, we set out to determine the anti-inflammatory mechanism of action of AEA, specifically focusing on vascular smooth muscle cells., Experimental Approach: RNA-sequencing, RT-qPCR, LC-MS/MS, NanoBit, ChIP, microscale thermophoresis, NMR structural footprinting, Gal4 reporter gene assays and loss of function approaches in cell and ex vivo organ culture were used., Key Results: AEA pretreatment attenuated the cytokine-mediated induction of inflammatory gene expression such as CCL2. This effect was also observed in preparations obtained from cannabinoid receptor knockout mice and after pertussis toxin treatment. The anti-inflammatory effect of AEA required preincubation, suggesting an effect through gene induction. AEA increased the expression of the nuclear receptors NR4A1 and NR4A2. Knockdown and knockout of these receptors blocked the AEA-mediated anti-inflammatory effect in cell culture and aortic organ culture, respectively. Conversely, NR4A agonists (CsnB, C-DIM12) attenuated inflammatory gene expression. AEA binds to NR4A, and mutations in NR4A attenuated this effect. The interaction of AEA with NR4A caused recruitment of the nuclear corepressor NCoR1 to the CCL2 promoter, resulting in gene suppression., Conclusion and Implications: By binding to NR4A, AEA elicits an anti-inflammatory response in vascular smooth muscle cells. NR4A-binding by AEA analogues may represent novel anti-inflammatory agents., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Since 2021, international guidelines for cardiopulmonary resuscitation recommend the implementation of so-called "life-saving systems". These systems include smartphone alerting systems (SAS), which enable dispatch centres to alert first responders via smartphone applications, who are in proximity of a suspected out-of-hospital cardiac arrest (OHCA). However, the effect of SAS on survival remains unknown., Aim: The aim is to assess the rate of survival to hospital discharge in adult patients with OHCA not witnessed by emergency medical services (EMS): before and after SAS implementation., Design: Multicentre, prospective, observational, intention-to-treat, pre-post design clinical trial., Population: Adults (aged ≥ 18 years), OHCA not witnessed by EMS, no traumatic cause for cardiac arrest, cardiopulmonary resuscitation initiated or continued by EMS., Setting: Dispatch-centre-based., Outcomes: Primary: survival to hospital discharge. Secondary: time to first compression, rate of basic life support measures before EMS arrival, rate of patients with shockable rhythm at EMS arrival, Cerebral Performance Category at hospital discharge, and duration of hospital stay., Sample Size: Assuming an absolute difference in survival rates to hospital discharge of 4% in the two groups (11% before implementation of the SAS versus 15% after) and 80% power, and a type 1 error rate of 0.05, the required sample size is N  = 1,109 patients per group (at least N  = 2,218 evaluated patients in total)., Conclusions: The HEROES trial will investigate the effects of a SAS on the survival rate after OHCA., Trial Registration: German Clinical Trials Register (DRKS, ID: DRKS00032920)., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘MPM is chair of Region der Lebensretter e.V. (non-profit organisation), member of the executive committee of the German Resuscitation Council (GRC), shareholder of SmartResQ ApS, Denmark, and received speaker honoraria by Stryker. JG is board member of Region der Lebensretter e.V. HJB is vice chair of Region der Lebensretter e.V. GT is board member of Region der Lebensretter e.V., secretary of the GRC, and shareholder of Resuscitec GmbH, Freiburg, Germany. JSP is member of Region der Lebensretter e.V. and member of the executive committee of the GRC. All other authors have no conflicts of interest to declare’., (© 2024 The Author(s).)

Background: Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients., Methods: 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival., Results: Most patients were between 50 and 70 years of age. PaO 2 /FiO 2 ratio prior to ECMO was 72 mmHg (IQR: 58-99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41-0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28-1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events., Conclusions: Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival., Trial Registration: Registered in the German Clinical Trials Register (study ID: DRKS00022964, retrospectively registered, September 7th 2020, https://www.drks.de/drks&#95;web/navigate.do?navigationId=trial.HTML&TRIAL&#95;ID=DRKS00022964 ., (© 2022. The Author(s).)

Background: Hypotension and bradycardia are known side effects of general anesthesia, while little is known about further macro- and microhemodynamic changes during induction. Intriguing is furthermore, why some patients require no vasopressor medication to uphold mean arterial pressure, while others need vasopressor support., Objective: Determination of macro- and microhemodynamic changes during induction of general anesthesia., Methods: We enrolled 150 female adults scheduled for gynaecological surgery into this prospective observational, single-blinded trial. Besides routinely measuring heart rate (HR) and mean arterial blood pressure (MAP), the non-invasive technique of thoracic electrical bioimpedance was applied to measure cardiac output (CO), cardiac index (CI), stroke volume (SV), stroke volume variability (SVV) and index of myocardial contractility (ICON) before induction of anesthesia, 7 times during induction, and, finally, after surgery in the recovery room. Changes in microcirculation were assessed using sidestream dark field imaging to establish the perfused boundary region (PBR), a validated gauge of glycocalyx health. Comparisons were made with Friedman's or Wilcoxon test for paired data, and with Mann-Whitney-U test for unpaired data, with post-hoc corrections for multiple measurements by the Holm-Bonferroni method., Results: 83 patients did not need vasopressor support, whereas 67 patients required therapy (norepinephrine, atropine or cafedrine/theodrenaline) to elevate MAP values to ≥70mmHg during induction, 54 of these receiving norepinephrine (NE) alone. Pre-interventional (basal) values of CO, CI, ICON, SV and SVV were all significantly lower in the group of patients later requiring NE (p < 0.04), whereas HR and MAP were identical for both groups. HR, MAP and CO decreased from baseline to 12 min after induction of general anesthesia in both the patients without and those with NE support. Heart rate decreased significantly by about 25% in both groups (-19 to -21 bpm). The median individual decrease of MAP amounted to -26.7% (19.7/33.3, p < 0.001) and -26.1% (11.6/33.2, p < 0.001), respectively, whereas for CO it was -40.7% (34.1/50.1, p < 0.001) and -43.5% (34.8/48.7). While these relative changes did not differ between the two groups, in absolute values there were significantly greater decreases in CO, CI, SV and ICON in the group requiring NE. Noteably, NE did not restore ICON or the other cardiac parameters to levels approaching those of the group without NE. PBR was measured in a total of 84 patients compiled from both groups, there being no intergroup differences. It increased 6.4% (p < 0.001) from pre-induction to the end of the operation, indicative of damage to microvascular glycocalyx., Conclusion: Non-invasive determination of CO provides additional hemodynamic information during anesthesia, showing that induction results in a significant decrease not only of MAP but also of CO and other cardiac factors at all timepoints compared to baseline values. The decrease of CO was greater than that of MAP and, in contrast to MAP, did not respond to NE. There was also no sign of a positive inotropic effect of NE in this situation. Support of MAP by NE must consequently result from an increase in peripheral arterial resistance, posing a risk for oxygen supply to tissue. In addition, general anesthesia and the operative stimulus lead to an impairment of the microcirculation.

Background: Early recognition of high-risk-patients with acute respiratory distress syndrome (ARDS) might improve their outcome by less protracted allocation to intensified therapy including extracorporeal membrane oxygenation (ECMO). Among numerous predictors and classifications, the American European Consensus Conferenece (AECC)- and Berlin-definitions as well as the oxygenation index (OI) and the Murray-/Lung Injury Score are the most common. Most studies compared the prediction of mortality by these parameters on the day of intubation and/or diagnosis of ARDS. However, only few studies investigated prediction over time, in particular for more than three days., Objective: Therefore, our study aimed at characterization of the best predictor and the best day(s) to predict 28-days-mortality within four days after intubation of patients with ARDS., Methods: In 100 consecutive patients with ARDS severity according to OI (mean airway pressure*FiO2/paO2), modified Murray-score without radiological points (Murray&#95;mod), AECC- and Berlin-definition, were daily documented for four days after intubation. In the subgroup of 49 patients with transpulmonary thermodilution (TPTD) monitoring (PiCCO), extravascular lung water index (EVLWI) was measured daily., Primary Endpoint: Prediction of 28-days-mortality (Area under the receiver-operating-characteristic curve (ROC-AUC)); IBM SPSS 26., Results: In the totality of patients the best prediction of 28-days-mortality was found on day-1 and day-2 (mean ROC-AUCs for all predictors/scores: 0.632 and 0.620). OI was the best predictor among the ARDS-scores (AUC=0.689 on day-1; 4-day-mean AUC = 0.625). AECC and Murray&#95;mod had 4-day-means AUCs below 0.6. Among the 49 patients with TPTD, EVLWI (4-day-mean AUC=0.696) and OI (4-day-mean AUC=0.695) were the best predictors. AUCs were 0.789 for OI on day-1, and 0.786 for EVLWI on day-2. In binary regression analysis of patients with TPTD, EVLWI (B=-0.105; Wald=7.294; p=0.007) and OI (B=0.124; Wald=7.435; p=0.006) were independently associated with 28-days-mortality. Combining of EVLWI and OI provided ROC-AUCs of 0.801 (day-1) and 0.824 (day-2). Among the totality of patients, the use of TPTD-monitoring "per se" and a lower SOFA-score were independently associated with a lower 28-days-mortality., Conclusions: Prognosis of ARDS-patients can be estblished within two days after intubation. The best predictors were EVLWI and OI and their combination. TPTD-monitoring "per se" was independently associated with reduced mortality., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Wolfgang Huber is member of the Medical Advisory Board of Pulsion Medical Systems SE, Feldkirchen, Germany. All other authors have no conflict of interest. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Induction of hypoxia-inducible-factor-1α (HIF-1α) pathway and HIF-target genes allow adaptation to hypoxia and are associated with reduced incidence of acute mountain sickness (AMS). Little is known about HIF-pathways in conjunction with inflammation or exercise stimuli under acute hypobaric hypoxia in non-acclimatized individuals. We therefore tested the hypotheses that 1) both hypoxic and inflammatory stimuli induce hypoxic-inflammatory signaling pathways in vitro, 2) similar results are seen in vivo under hypobaric hypoxia, and 3) induction of HIF-dependent genes is associated with AMS in 11 volunteers. In vitro, peripheral blood mononuclear cells (PBMCs) were incubated under hypoxic (10%/5% O 2 ) or inflammatory (CD3/CD28) conditions. In vivo, Interleukin 1β (IL-1β), C-X-C Chemokine receptor type 4 (CXCR-4), and C-C Chemokine receptor type 2 (CCR-2) mRNA expression, cytokines and receptors were analyzed under normoxia (520 m above sea level (a.s.l.)), hypobaric hypoxia (3883 m a.s.l.) before/after exercise, and after 24 h under hypobaric hypoxia. In vitro, isolated hypoxic ( p = 0.004) or inflammatory ( p = 0.006) stimuli induced IL-1β mRNA expression. CCR-2 mRNA expression increased under hypoxia ( p = 0.005); CXCR-4 mRNA expression remained unchanged. In vivo, cytokines, receptors, and IL-1β, CCR-2 and CXCR-4 mRNA expression increased under hypobaric hypoxia after 24 h (all p ≤ 0.05). Of note, proinflammatory IL-1β and CXCR-4 mRNA expression changes were associated with symptoms of AMS. Thus, hypoxic-inflammatory pathways are differentially regulated, as combined hypoxic and exercise stimulus was stronger in vivo than isolated hypoxic or inflammatory stimulation in vitro., Competing Interests: The authors have no conflicts of interest to declare.

Background: Plasma-based resuscitation showed protective effects on the endothelial glycocalyx compared with crystalloid resuscitation. There is paucity of data regarding the effect of coagulation factor concentrates (CFC) on the glycocalyx in hemorrhagic shock (HS). We hypothesized that colloid-based resuscitation supplemented with CFCs offers a therapeutic value to treat endothelial damage following HS., Methods: Eighty-four rats were subjected to pressure-controlled (mean arterial pressure (MAP) 30-35 mm Hg) and lab-guided (targeted cutoff: lactate >2.2. mmol/L and base deficit > 5.5 mmol/L) HS. Animals were resuscitated with fresh frozen plasma (FFP), human albumin (HA) or Ringer's lactate (RL) and RL or HA supplemented with fibrinogen concentrate (FC) or prothrombin complex concentrate (PCC). Serum epinephrine and the following markers of endothelial damage were assessed at baseline and at the end-of-observation (120 min after shock was terminated): syndecan-1, heparan sulfate, and soluble vascular endothelial growth factor receptor 1 (sVEGFR 1)., Results: Resuscitation with FFP had no effect on sVEGFR1 compared with crystalloid-based resuscitation (FFP: 19.3 ng/mL vs. RL: 15.9 ng/mL; RL+FC: 19.7 ng/mL; RL+PCC: 18.9 ng/mL; n.s.). At the end-of-observation, syndecan-1 was similar among all groups. Interestingly, HA+FC treated animals displayed the highest syndecan-1 concentration (12.07 ng/mL). Resuscitation with FFP restored heparan sulfate back to baseline (baseline: 36 ng/mL vs. end-of-observation: 36 ng/mL)., Conclusion: The current study revealed that plasma-based resuscitation normalized circulating heparan sulfate but not syndecan-1. Co-administration of CFC had no further effect on glycocalyx shedding suggesting a lack of its therapeutic potential., Level of Evidence: VExperimental in vivo study.

Background: Patients undergoing cardiac surgery commonly develop systemic inflammation associated with tissue edema, which impairs outcome. One main pathomechanism leading to the edema is the deterioration of the endothelial glycocalyx, a key component of the vascular barrier. In animal models hydrocortisone has proved to be protective for the glycocalyx., Objective: This trial evaluates the effect of hydrocortisone on glycocalyx integrity in patients undergoing cardiac surgery with cardiopulmonary bypass., Methods: In a prospective, randomized interventional pilot trial, 30 patients received either hydrocortisone (100 mg over 10 min) or placebo (saline control) before surgery. Plasma concentrations of glycocalyx constituents (syndecan-1, heparan sulfate) and various clinical parameters (respiratory and renal function, inflammatory markers, use of vasopressors, length of stay at the intensive care unit) were measured. Primary endpoint was a significant difference of glycocalyx constituents in plasma. Comparisons were made with Friedman's and Wilcoxon tests (paired data), or the Kruskal-Wallis and Mann-Whitney U tests (unpaired data). Holm-Bonferroni method was used for post-hoc corrections., Results: Heparan sulfate and syndecan-1 increased significantly during and after cardiac surgery with cardiopulmonary bypass in both groups. Whereas the maximum increase of heparan sulfate was 12.3-fold in the control vs. 3.8-fold in the pretreated group (p < 0.05), syndecan-1 values showed no significant difference between the groups (maximal increase 3-fold). The inflammatory markers C-reactive protein and interleukin-6 were also higher in the control than in the hydrocortisone group, but there was no difference in patient mortality (zero), or in any clinical parameters., Conclusions: Pretreatment with hydrocortisone ameliorated shedding of heparan sulfate, a major constituent of the endothelial glycocalyx, in patients undergoing cardiac surgery with cardiopulmonary bypass, but had no relevant influence on various clinical parameters or patient mortality. The relatively small number of patients in this pilot study probably precluded detection of positive outcome differences.

Objective: Normobaric (NH) and hypobaric hypoxia (HH) are associated with acute mountain sickness (AMS) and cognitive dysfunction. Only few variables, like heart-rate-variability, are correlated with AMS. However, prediction of AMS remains difficult. We therefore designed an expedition-study with healthy volunteers in NH/HH to investigate additional non-invasive hemodynamic variables associated with AMS., Methods: Eleven healthy subjects were examined in NH (FiO 2 13.1%; equivalent of 3.883 m a.s.l; duration 4 h) and HH (3.883 m a.s.l.; duration 24 h) before and after an exercise of 120 min. Changes in parameters of electrical cardiometry (cardiac index (CI), left-ventricular ejection time (LVET), stroke volume (SV), index of contractility (ICON)), near-infrared spectroscopy (cerebral oxygenation, rScO 2 ), Lake-Louise-Score (LLS) and cognitive function tests were assessed. One-Way-ANOVA, Wilcoxon matched-pairs test, Spearman's-correlation-analysis and Student's t-test were performed., Results: HH increased heart rate (HR), mean arterial pressure (MAP) and CI and decreased LVET, SV and ICON, whereas NH increased HR and decreased LVET. In both NH and HH cerebral oxygenation decreased and LLS increased significantly. After 24 h in HH, 6 of 11 subjects (54.6%) developed AMS. LLS remained increased until 24 h in HH, whereas cognitive function remained unaltered. In HH, HR and LLS were inversely correlated ( r  = - 0.692; p  < 0.05). More importantly, the rScO2-decrease after exercise in NH significantly correlated with LLS after 24 h in HH ( r  = - 0.971; p  < 0.01) and rScO2 correlated significantly with HR ( r  = 0.802; p  < 0.01), CI ( r  = 0.682; p  < 0.05) and SV ( r  = 0.709; p  < 0.05) after exercise in HH., Conclusions: Both acute NH and HH altered hemodynamic and cerebral oxygenation and induced AMS. Subjects, who adapted their CI had higher rScO2 and lower LLS. Furthermore, rScO2 after exercise under normobaric conditions was associated with AMS at high altitudes., Competing Interests: All authors have given their consent for publication in this journal. Written informed consent was obtained from the participants for publication of their individual details and accompanying figures in this manuscript. The consent form is held by the authors and is available for review by the Editor-in-Chief.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Problem: The endothelial glycocalyx (EGX) plays an important role in vascular integrity. Recently, increased levels of EGX components were detected in the circulating blood of healthy pregnant women and were related to the increased tendency to edema formation during gestation. However, the EGX has not yet been systematically studied in non-pregnant women during ovulatory cycles., Method of Study: Serum levels of EGX components syndecan-1, heparan sulfate, and hyaluronan in healthy women (n = 16) at 3 phases of the ovulatory cycle (early follicular phase, at ovulation, and mid-luteal phase) were compared with a control group of healthy men (n = 10). Using immunofluorescence microscopy in cultured human umbilical vein endothelial cells, the effects of progesterone and estrogen on the EGX were measured., Results: Syndecan-1 increased from 11.1 ± 2.4 ng/mL at ovulation to 12.6 ± 2.3 ng/mL in mid-luteal phase (P = .031) and of heparan sulfate from 663 ± 35 ng/mL to 782 ± 55 ng/mL (P = .011). In contrast to estrogen, there was a detrimental effect of progesterone on the EGX in HUVECs., Conclusion: The relationship between the natural menstrual cycle and the EGX as an indicator of vascular permeability may provide a new explanation for premenstrual edema in healthy women. This may be an attendant phenomenon of a regular physiological process, the hormonal downregulation of the vascular barrier during pregnancy., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The endothelial glycocalyx plays a decisive role in maintaining vascular homeostasis. Previous animal models have mainly focused on in-vitro experiments or the isolated beating guinea pig heart. To further evaluate underlying mechanisms of up- and down regulation, knock-out animals seem to be a promising option., Objective: Aim of the present study was to evaluate if an isolated mouse-heart model is suitable for glycocalyx research., Methods: Isolated beating mouse hearts (C57/Bl6J) underwent warm, no-flow ischemia and successive reperfusion. Coronary effluent was analyzed by ELISA and Western blot for the glycocalyx core protein: syndecan-1. Hearts were prepared for either immunofluorescence or electron microscopy and lysed for Western blot analysis., Results: An endothelial glycocalyx covering the total capillary circumference and syndecan-1 were detected by electron and immunofluorescence microscopy. Ischemia/reperfusion seriously deteriorated both findings. Confoundingly, syndecan-1 was not detectable either in the coronary effluent or in the lysates of blood-free hearts by ELISA or Western blot technique., Conclusions: Blood vessels of mouse hearts contain an endothelial glycocalyx comparable to that of other animals also with respect to its core protein syndecan-1. But, for studies including quantification of intravascular soluble glycocalyx constituents, the amount of syndecan-1 in mouse hearts seems to be too low.

Background: The use of artificial colloids has declined in critical care, whereas they are still used in perioperative medicine. Little is known about the nephrotoxic potential in noncritically ill patients during routine surgery. The objective of this trial was to evaluate the influences of albumin 5% and balanced hydroxyethyl starch 6% (130/0.4) on renal function and kidney injury., Methods: One hundred urologic patients undergoing elective cystectomy were randomly assigned for this prospective, single-blinded, controlled study with two parallel groups to receive either albumin 5% or balanced hydroxyethyl starch 6% (130/0.4) as the only perioperative colloid. The primary endpoint was the ratio of serum cystatin C between the last visit at day 90 and the first preoperative visit. Secondary endpoints were estimated glomerular filtration rate and serum neutrophil gelatinase-associated lipocalin until the third postoperative day and risk, injury, failure, loss, and end-stage renal disease criteria at postoperative days 3 and 90., Results: The median cystatin C ratio was 1.11 (interquartile range, 1.01 to 1.23) in the albumin and 1.08 (interquartile range, 1.00 to 1.20) in the hydroxyethyl starch group (median difference = 0.03; 95% CI, -0.09 to 0.08; P = 0.165). Also, there were no significant differences concerning serum cystatin C concentrations; estimated glomerular filtration rate; risk, injury, failure, loss, and end-stage renal disease criteria; and neutrophil gelatinase-associated lipocalin. Infusion requirements, transfusion rates, and perioperative hemodynamics were similar in both groups., Conclusions: With respect to renal function and kidney injury, this study indicates that albumin 5% and balanced hydroxyethyl starch 6% have comparable safety profiles in noncritically ill patients undergoing major surgery.

Background: Near-fatal asthma attacks are life threatening events that often require mechanical ventilation. Extracorporeal carbon dioxide removal (ECCO 2 R) is, beside extracorporeal membrane oxygenation (ECMO), a well-established rescue option whenever ventilation gets to its limits. But there seems to be very rare experience with those techniques in avoiding mechanical ventilation in severe asthma attacks., Case Presentation: A 67-year-old man with a near-fatal asthma attack deteriorated under non-invasive ventilation conditions. Beside pharmacological treatment, the intensivists decided to use an extracorporeal carbon dioxide removal system (ECCO 2 R) to avoid sedation and intubation. Within only a few hours, there was a breakthrough and the patient's status improved continuously. One and a half days later, weaning from ECCO 2 R was already completed., Conclusions: The discussion deals with several advantages of extracorporeal lung support in acute asthma, the potential of avoiding intubation and sedation, as well as the benefits of a conscious and spontaneously breathing patient. Extracorporeal membrane oxygenation (ECMO) in general and ECCO 2 R in particular is a highly effective method for the treatment of an acute near-fatal asthma attack. Pathophysiological aspects favor the "awake" approach, without sedation, intubation, and mechanical ventilation. Therefore, experienced clinicians might consider "awake" ECCO 2 R in similar cases.

The purpose of this manuscript is to review the role of endothelial glycocalyx (EG) in the field of critical and perioperative medicine and to discuss possible future directions for investigations in this area. Under physiological conditions, EG has several well-defined functions aimed to prevent the disruption of vessel wall integrity. Under pathological conditions, the EG represent one of the earliest sites of injury during inflammation. EG structure and function distortion contribute to organ dysfunction related to sepsis, trauma, or global ischemia of any origin. Discovering new therapeutic approaches (either pharmacological or non-pharmacological) aimed to protect the EG against injury represents a promising direction in clinical medicine. Further, the currently-used common interventions in the acutely ill - fluids, blood products, nutritional support, organ-supporting techniques (e.g. continuous renal replacement therapy, extracorporeal circulation), temperature modulation and many others - should be re-evaluated during acute illness in terms of their EG "friendliness". To assess new therapies that protect the EG, or to evaluate the effect of currently-used interventions on EG integrity, a relevant marker or method to determine EG damage is needed. Such marker or method should be available to clinicians within hours, preferably in the form of a point-of-care test at the bedside. Collaborative research between clinical disciplines and laboratory medicine is warranted, and targeting the EG represents major challenges for both.

Background: Newly approved immunotherapeutic agents, like CTLA-4 inhibitors and antibodies against PD-1, are a promising therapeutic option in cancer therapy., Case Presentation: A 74-year-old man, with a history of advanced stage melanoma and treatment with ipilimumab, pembrolizumab and nivolumab, was admitted to the hospital due to respiratory failure with hypoxemia and dyspnoea. He rapidly developed severe acute respiratory distress syndrome (ARDS), which required treatment in the intensive care unit which included mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Computed tomographic imaging (CT) showed signs of a pneumonitis, with an ARDS pattern related to the use of PD-1 antibodies. Treating the patient with high-dose immunosuppressive steroids led to an overall improvement. He was transferred to a rehabilitation hospital and subsequently to his home., Discussion and Conclusion: This is a unique case report of a patient suffering a grade 4 adverse event under nivolumab who survived having been treated with ECMO. It highlights the possibility of associated adverse reactions as well as the use of ECMO in palliative care patients. ECMO can be of great success even in patients with malignancies, but careful decision making should be done on a case by case basis., Competing Interests: Conflict of interest: All authors declare that there are no conflicts of interest.

Purpose of Review: Ventilator-induced lung injury is a major contributor to perioperative lung injury. The end-expiratory lung volume, regional lung overdistension, and tidal recruitment are known to be the main factors causing subsequent alveolar damage and inflammation. The alveolar-capillary membrane including the endothelial glycocalyx as an integral part of the vascular endothelium seems to play a major role in different kinds of lung injury., Recent Findings: Recent studies underline the pivotal importance of the endothelial glycocalyx in lung injury. The glycocalyx regulates and modulates plasma endothelial cell interactions. Several triggers are known to deteriorate the gylcocalyx such as fluid overload, ischemia, and TRALI. The clinical manifestation is inflammation, capillary leak, and edema formation. Breakdown of the endothelial gylcocalyx is of gaining importance in the context of one-lung ventilation, known to be a major risk factor for postoperative lung injury. Studies suggest that volatile anesthetics may have a protective influence on the endothelial glycocalyx of pulmonary capillaries and reduce ischemia-reperfusion injury. This might be of clinical relevance for postoperative outcome., Summary: This review focuses on the involvement of the pulmonary endothelial glycocalyx in the context of perioperative lung injury. The pathophysiological mechanisms and trigger factors of glycocalyx deterioration are discussed, and prevention strategies are taken into consideration.

Background: Cardiac surgery often causes ischemia and development of a systemic inflammatory response syndrome, which impairs vascular barrier function, normally maintained by the endothelial cell line and the endothelial glycocalyx (EG). The EG normally covers and protects healthy endothelial cells throughout the vasculature. The aim of the present study was to assess the disruption of the cellular part of the microvascular barrier by determining parameters of endothelial cell activation known to influence and reflect cell-cell junctional integrity. Particular attention was placed on angiopoietins and their important effects on endothelial gap junctions. Furthermore, comparative measurements were undertaken in patients undergoing on- and off-pump cardiac surgery, the latter group presumably experiencing less ischemic stress., Methods: 30 patients undergoing elective coronary artery bypass surgery were assigned to the conventional coronary artery bypass (CCAB) group (n = 15) or the off-pump coronary artery bypass grafting (OPCAB) group (n = 15). Blood samples were obtained for measuring angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial (VE)-cadherin, and endocan at various time points., Results: There were significant increases in all measured parameters in both study groups versus the respective basal values. Maximal increases were as follows: Ang-1: CCAB +220%, OPCAB +166%, p < 0.05 each; Ang-2: CCAB +150%, OPCAB +20%, p < 0.05 each; VE-cadherin: CCAB +87%, OPCAB +66%, p < 0.05 each; endocan: CCAB +323%, OPCAB +72%, p < 0.05 each., Conclusion: The present study demonstrates the activation of endothelial cells, shedding of cell-cell contacts and a potential intrinsic counterregulation by Ang-1 and endocan in patients undergoing major cardiac surgery. Quantitatively greater deviations of parameters in the CCAB than in the OPCAB group suggest a relation between the occurrence of ischemia/reperfusion and the extent of endothelial activation., (© 2017 S. Karger AG, Basel.)

Introduction: The aim of the study was to evaluate the feasibility and safety of avoiding invasive mechanical ventilation (IMV) by using extracorporeal CO2 removal (ECCO2R) in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) and acute hypercapnic respiratory failure refractory to noninvasive ventilation (NIV)., Methods: Case-control study. Patients with acute hypercapnic respiratory failure refractory to NIV being treated with a pump-driven veno-venous ECCO2R system (iLA-Activve(®); Novalung, Heilbronn, Germany) were prospectively observed in five European intensive care units (ICU). Inclusion criteria were respiratory acidosis (pH ≤ 7.35, PaCO2 > 45 mmHg) with predefined criteria for endotracheal intubation (ClinicalTrials.gov NCT01784367). The historical controls were patients with acute hypercapnic respiratory failure refractory to NIV who were treated with IMV. The matching criteria were main diagnosis, age, SAPS-II score and pH., Results: Twenty-five cases (48.0 % male, mean age 67.3 years) were matched with 25 controls. Intubation was avoided in 14 patients (56.0 %) in the ECCO2R group with a mean extracorporeal blood flow of 1.3 L/min. Seven patients were intubated because of progressive hypoxaemia and four owing to ventilatory failure despite ECCO2R and NIV. Relevant ECCO2R-associated adverse events were observed in 11 patients (44.0 %), of whom 9 (36.0 %) suffered major bleeding complications. The mean time on IMV, ICU stay and hospital stay in the case and control groups were 8.3 vs. 13.7, 28.9 vs. 24.0 and 36.9 vs. 37.0 days, respectively, and the 90-day mortality rates were 28.0 vs. 28.0 %., Conclusions: The use of veno-venous ECCO2R to avoid invasive mechanical ventilation was successful in just over half of the cases. However, relevant ECCO2R-associated complications occurred in over one-third of cases. Despite the shorter period of IMV in the ECCO2R group there were no significant differences in length of stay or in 28- and 90-day mortality rates between the two groups. Larger, randomised studies are warranted for further assessment of the effectiveness of ECCO2R.

Background: Postoperative nausea and vomiting (PONV) is one of the most common and distressing complications after general anesthesia and surgery, with young non-smoking females receiving postoperative opioids being high-risk patients. This register-based study aims to evaluate the effect of low-dose haloperidol (0.5 mg intravenously) directly after induction of general anesthesia to reduce the incidence of PONV in the postoperative anesthesiological care unit (PACU)., Methods: Multivariable regression models were used to investigate the association between low-dose haloperidol and the occurrence of PONV using a patient registry containing 2,617 surgical procedures carried out at an university hospital., Results: Haloperidol 0.5 mg is associated with a reduced risk of PONV in the total collective (adjusted odds ratio = 0.75, 95% confidence interval: [0.56, 0.99], p = 0.05). The results indicate that there is a reduced risk in male patients (adjusted odds ratio = 0.45, 95% confidence interval: [0.28, 0.73], p = 0.001) if a dose of 0.5 mg haloperidol was administered while there seems to be no effect in females (adjusted odds ratio = 1.02, 95% confidence interval: [0.71, 1.46], p = 0.93). Currently known risk factors for PONV such as female gender, duration of anesthesia and the use of opioids were confirmed in our analysis., Conclusion: This study suggests that low-dose haloperidol has an antiemetic effect in male patients but has no effect in female patients. A confirmation of the gender-specific effects we have observed in this register-based cohort study might have major implications on clinical daily routine.

Objective: Perturbation of the endothelial glycocalyx is discussed in the pathogenesis of complications related to cardiopulmonary bypass. We evaluated the effects of cardiopulmonary bypass on the microcirculation and the microvascular endothelial glycocalyx of infants undergoing surgery for congenital cardiac defects., Methods: The microcirculation was visualized at the ear conch using Sidestream dark field imaging before surgery (T0), after admission to the intensive care unit (T1), 24 hours postsurgery (T2), and 7 days postsurgery (T3). Glycocalyx thickness was assessed by measurement of the perfused boundary region. Microcirculatory parameters included total and perfused vessel density, vessel diameters, and microcirculatory flow index., Results: A total of 40 infants undergoing cardiac surgery (36 with cardiopulmonary bypass, 4 without cardiopulmonary bypass) were examined. As controls, measurements before and after cardiac catheterization (n = 6) and before and after surgery for cleft palate (n = 9) were performed. After surgery with cardiopulmonary bypass, the perfused boundary region was significantly increased, indicating reduced glycocalyx thickness at T1 compared with preoperative values with a stepwise return to baseline by T3. In the control groups, no significant perfused boundary region changes were noted. Furthermore, after cardiopulmonary bypass, a transient, significant reduction of the microcirculatory flow index and the perfused vessel density was seen at T1. Similar changes were observed after cardiac surgery without cardiopulmonary bypass, but not in the other controls., Conclusions: Our study reveals for the first time local perturbations of the endothelial glycocalyx and microvascular perfusion in infants after surgery with cardiopulmonary bypass. Microcirculatory monitoring might be a useful tool to evaluate interventions aiming at reduction of bypass-related complications., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

We are presenting the case of a 76-year-old female scheduled for major abdominal surgery. Her past medical history was remarkable for a three-vessel coronary artery disease, with a severely impaired left ventricular function. She had already undergone complex coronary artery bypass surgery. Currently, she presented with the rare constellation of a hemodynamic relevant and interventionally intractable stenosis of the left subclavian artery proximal to a crucial coronary bypass from left internal mammary artery to the left anterior descending. To protect this patient from perioperative myocardial infarction, an intra-aortic balloon pump was successfully used.

Background: There is no doubt today about the existence of the endothelial glycocalyx (EG) and its decisive role in maintaining vascular homeostasis in adult humans. Shedding of the EG has been demonstrated in adults with sepsis or trauma, in patients undergoing major operations, and after ischemia/reperfusion. The aim of the present study was to demonstrate whether shedding of the EG also occurs in infants undergoing heart operations., Methods: Two major constituents of the EG (syndecan-1 and hyaluronan) were measured in the arterial serum of 42 infants during cardiac operations in a prospective observational study. The groups were defined according to the ischemic impact: cardiac operations with cardiopulmonary bypass under beating heart conditions (CPB group, regional ischemia of lungs, n = 10), operations with cardiopulmonary bypass and aortic clamping (CPB+AC group, regional ischemia of heart and lungs, n = 24), and cardiac operations with deep hypothermic circulatory arrest (CPB+AC+DHCA group, whole-body ischemia, n = 8)., Results: Syndecan-1 and hyaluronan were detected in all infants, providing an indication for the presence of a glycocalyx. During the operations, no significant difference in syndecan-1 concentration was observed in the CPB group, but levels increased significantly in both other groups (maximum increases: CPB+AC 3.0-fold, CPB+AC+DHCA 3.7-fold, p < 0.05). Hyaluronan increased significantly in the course of the operation in all groups (maximum increases: CPB 1.2-fold, CPB+AC 1.4-fold, CPB+AC+DHCA 1.7-fold, p < 0.05)., Conclusions: The present data provides the first evidence for basal turnover of vascular EG in infants. Similarly to the process in adults, the shedding of this structure increases with ischemia/reperfusion, the extent being dependent on the degree of ischemic challenge., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Acute normovolemic hemodilution (ANH) and volume loading (VL) are standard blood-sparing procedures. However, VL is associated with hypervolemia, which may cause tissue edema, cardiopulmonary complications and a prolonged hospital stay. The body reacts to hypervolemia with release of atrial natriuretic peptide (ANP) from the heart. ANP has been shown to deteriorate the endothelial glycocalyx, a vital part of the vascular permeability barrier. The aim of the present study was to evaluate and compare ANP release and damage to the glycocalyx during ANH and VL., Methods: ANH or VL with 6% hydroxyethyl starch 130/0.4 was administered prior to elective surgery in patients of good cardiopulmonary health (n =9 in each group). We measured concentrations of ANP in plasma and of three main constituent parts of the glycocalyx (hyaluronan, heparan sulfate and syndecan 1) in serum before and after ANH or VL. Heparan sulfate and syndecan 1 levels in urine were also determined., Results: In contrast to ANH, VL (20 ml/kg) induced a significant release of ANP (approximately +100%, P <0.05) and increased the serum concentration of two glycocalyx constituents, hyaluronan and syndecan 1 (both by about 80%, P <0.05). Elevation of syndecan 1 was also detected in the urine of patients undergoing VL, but no increase was found in patients undergoing ANH. Heparan sulfate levels were not influenced by either procedure., Conclusion: These data suggest that hypervolemia increases the release of ANP and causes enhanced shedding of the endothelial glycocalyx. This perturbation must be expected to impair the vascular barrier, implying that VL may not be as safe as generally assumed and that it should be critically evaluated.

Background: Strategies targeting the protection of the vascular barrier, in particular the endothelial glycocalyx, are subjects of current research. Antithrombin III and hydrocortisone have been shown to reduce shedding of the glycocalyx following ischaemia/reperfusion. Platelet adhesion to endothelial cells is one consequence of ischaemia/reperfusion., Objective: Our goal was to evaluate the effect of pharmacological protection of the glycocalyx on platelet adhesion., Design: An experimental interventional animal study., Setting: The study was carried out in a basic science laboratory at the University of Munich., Animals: Eighty male guinea pigs (250 to 300 g) were used for the experiment., Main Outcome Measures: The effect of preischaemic treatment with hydrocortisone 10 μg ml(-1) or antithrombin 1 IU ml on adherence of platelets was evaluated in isolated, beating guinea pig hearts (Langendorff model). Hearts were subjected to warm ischaemia (20 min at 37 °C) and consecutive reperfusion. Platelets were injected at the beginning of reperfusion via the aortic cannula and platelet concentration was measured in the effluent (after passing through the coronary vascular system)., Results: Ischaemia and reperfusion led to significant shedding of the endothelial glycocalyx. Coronary venous release of syndecan-1 increased nine-fold, and heparan sulphate showed a 20.3-fold increase after ischaemia/reperfusion (both P < 0.01). Pretreatment with hydrocortisone or antithrombin III reduced endothelial glycocalyx shedding significantly (P < 0.05). Adherence of platelets to the coronary vascular bed increased more than 2.5-fold when they were injected during reperfusion. About 40% of this increase was blocked by pretreatment of hearts with hydrocortisone or antithrombin., Conclusion: Pretreatment with hydrocortisone or antithrombin III can reduce platelet adhesion during reperfusion after warm ischaemia by protection of the endothelial glycocalyx.

USCOM is an ultrasound-based method which has been accepted for noninvasive hemodynamic monitoring in various clinical conditions (USCOM, Ultrasonic cardiac output monitoring). The present study aimed at comparing the accuracy of the USCOM device with that of the thermodilution technique in patients with septicemia. We conducted a prospective observational study in a medical but noncardiological ICU of a university hospital. Septic adult patients (median age 55 years, median SAPS-II-Score 43 points) on mechanical ventilation and catecholamine support were monitored with USCOM and PiCCO (n = 70). Seventy paired left-sided CO measurements (transaortic access = CO(US-A)) were obtained. The mean CO(US-A) were 6.55 l/min (±2.19) versus CO(PiCCO) 6.5 l/min (±2.18). The correlation coefficient was r = 0.89. Comparison by Bland-Altman analysis revealed a bias of -0.36 l/min (±0.99 l/min) leading to a mean percentage error of 29%. USCOM is a feasible and rapid method to evaluate CO in septic patients. USCOM does reliably represent CO values as compared to the reference technique based on thermodilution (PiCCO). It seems to be appropriate in situations where CO measurements are most pertinent to patient management.

We are reporting the case of a female patient who had to undergo splenectomy after she suffered splenic rupture as a result from "kinetic therapy" during the treatment for pulmonary failure secondary to sepsis. Four years later the patient was again admitted with a clinical picture consistent with sepsis. Two blood cultures were positive for pneumococci confirming the diagnosis of pneumococcal sepsis. This paper discusses the potential risks of kinetic therapy in patients with ARDS. After splenectomy there is increased risk of infection with certain bacteria, funghi, viruses and protozoa. The most common bacterial pathogen is pneumococcus. A polyvalent vaccine is available for prophylaxis. Although penicillin G is still commonly used as an antibiotic therapy for pneumococcal infection, increased resistance of pathogens to penicillin must be anticipated. Alternative antibiotic regimens are demonstrated.