Age-Related Quality of Life in Cardiac Surgical Patients with Extracorporeal Life Support.

BACKGROUND: The rationale of the study was to analyze the impact of age on quality of life (QoL) in patients who had undergone cardiac surgery with consecutive extracorporeal life support (ECLS) treatment. METHODS: The study population consisted of 200 patients, operated upon between August 2006 and December 2018. The patient cohort was divided into two groups following an arbitrary cutoff age of 70 years. Comparative outcome analysis was calculated utilizing the European Quality of Life-5-Dimensions-5-Level Version (EQ-5D-5L). RESULTS: A total of 113 patients were 70 years or less old (group young), whereas 87 patients were older than 70 years (group old). In 45.7% of cases, the ECLS system was established during cardiogenic shock and external cardiac massage. The overall survival-to-discharge was 31.5% (n = 63), with a significantly better survival in the younger patient group (young = 38.9%; old = 21.8%, p = 0.01). Forty-two patients (66%) responded to the QoL survey after a median follow-up of 4.3 years. Older patients reported more problems with mobility (y = 52%; o = 88%, p = 0.02) and self-care (y = 24%; o = 76%, p = 0.01). However, the patients' self-rated health status utilizing the Visual Analogue Scale revealed no differences (y = 70% [50-80%]; o = 70% [60-80%], p = 0.38). Likewise, the comparison with an age-adjusted German reference population revealed similar QoL indices. There were no statistically significant differences in the EQ-5D-5L index values related to sex, number of comorbidities, and emergency procedures. CONCLUSION: Despite the limited sample size due to the high mortality rate especially in elderly, the present study suggests that QoL of elderly patients surviving ECLS treatment is almost comparable to younger patients.

Evaluation of comprehensiveness and reliability of electronic health records concerning resuscitation efforts within academic intensive care units: a retrospective chart analysis.

BACKGROUND: According to the literature, the validity and reliability of medical documentation concerning episodes of cardiopulmonary resuscitation (CPR) is suboptimal. However, little is known about documentation quality of CPR efforts during intensive care unit (ICU) stays in electronic patient data management systems (PDMS). This study analyses the reliability of CPR-related medical documentation within the ICU PDMS. METHODS: In a retrospective chart analysis, PDMS records of three ICUs of a single university hospital were searched over 5 y for CPR check marks. Respective datasets were analyzed concerning data completeness and data consistency by comparing the content of three documentation forms (physicians' log, nurses' log, and CPR incident form), as well as physiological and therapeutic information of individual cases, for missing data and plausibility of CPR starting time and duration. To compare data reliability and completeness, a quantitative measure, the Consentaneity Index (CI), is proposed. RESULTS: One hundred sixty-five datasets were included into the study. In 9% (n = 15) of cases, there was neither information on the time points of CPR initiation nor on CPR duration available in any data source. Data on CPR starting time and duration were available from at least two data sources in individual cases in 54% (n = 90) and 45% (n = 74), respectively. In these cases, the specifications of CPR starting time did differ by a median ± interquartile range of 10.0 ± 18.5 min, CPR duration by 5.0 ± 17.3 min. The CI as a marker of data reliability revealed a low consistency of CPR documentation in most cases, with more favorable results, if the time interval between the CPR episode and the time of documentation was short. CONCLUSIONS: This study reveals relevant proportions of missing and inconsistent data in electronic CPR documentation in the ICU setting. The CI is suggested as a tool for documentation quality analysis and monitoring of improvements.

[Work and Training of Young Doctors in Germany - a Comprehensive Analysis of Survey Results from Six Disciplines]. / Die Arbeits- und Weiterbildungssituation junger Ärztinnen und Ärzte in Deutschland ­ eine zusammenfassende Analyse von Befragungsergebnissen aus sechs Fachrichtungen.

OBJECTIVE: The working and training conditions of young physicians in Germany have changed over the last few years, as a result of far-reaching changes in the healthcare system. Therefore, Germany-wide surveys among young physicians of several disciplines were evaluated in a pooled analysis, in order to obtain a current interdisciplinary impression of conflicts in their daily work. MATERIAL AND METHODS: Data from web-based surveys from residents training in six disciplines were analyzed together retrospectively. One focus was a gratification crises model for the assessment of psychosocial workload. RESULTS: Data on 4041 participants were evaluated. In day-to-day work, young physicians were burdened with a high proportion of tasks that were not directly medical. Instruments of good subspecialty training, such as training contracts, curricula and regular feedback were associated with a lower psychosocial workload, which was generally significant among the participants. An economic influence on medical-professional decisions was subjectively clearly present among the participants. CONCLUSION: Many young doctors find the current work and training conditions in the medical work environment unsatisfactory. This might have consequences not only for the doctors themselves, but also for the patients they care for. A healthy work environment with health professionals in good health is therefore crucial and should be in everyone's interest.

[Working conditions and health status of young physicians and nurses in German hospitals]. / Arbeitsbedingungen und Gesundheitszustand junger Ärzte und professionell Pflegender in deutschen Krankenhäusern.

BACKGROUND: Profound transformations in the German healthcare system lead to intense working conditions for young employees in inpatient care. Published data suggest associated health risks. OBJECTIVES: This investigation aims to assess current stress factors, their consequences, and subjective measures for improvement. METHODS: During September 2017, a cross-sectional survey was conducted among physicians and nurses ≤35 years of age and with work experience in inpatient care not exceeding six years. Field access was gained via seven scientific and professional societies. The electronic questionnaire consisted of mainly validated instruments. Regression models included confounders into the final data analysis. RESULTS: Included in the final data analysis were 1060 complete cases. The overall response rate was 13%. Different stress factors (e.g. time-related or psychosocial) were found at high levels. These stress factors were connected to reduced health and higher risk of burnout. Furthermore, they were associated with inferior perceived quality of care. Young physicians claimed less documentation requirements and less intense working conditions. Young nurses demanded fair salary and an appropriate nurse-patient allocation. CONCLUSION: Today's working conditions in inpatient care are a threat to the health status of young employees. General conditions, which ensure a sustainable healthy and effective working environment, need to be ensured.

In Vivo Effects of Neostigmine and Physostigmine on Neutrophil Functions and Evaluation of Acetylcholinesterase and Butyrylcholinesterase as Inflammatory Markers during Experimental Sepsis in Rats.

INTRODUCTION: Recent studies have shown that acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) may serve as important diagnostic and therapeutic targets in sepsis. Since polymorphonuclear neutrophils (PMNs) play a pivotal role in the early phase of sepsis, we evaluated the potential therapeutic effects of cholinesterase inhibitors on PMN functions during cecal ligation and puncture- (CLP-) induced sepsis and investigated the roles of AChE and BChE as inflammatory markers under standardized experimental conditions. METHODS: Sham surgery or CLP was performed in male Wistar rats (n = 60). Animals were randomized into four groups: physostigmine, 100 µg/kg; neostigmine, 75 µg/kg; 0.9% saline (control group); and sham group, each applied four times over 24 h. The levels of reactive oxygen species (ROS) production and CD11b/CD62l expression were quantified by flow cytometry at t = 0, 6, 15, 20, and 24 h. Blood gas analysis as well as AChE and BChE activity levels was measured by validated point-of-care measurements. Clinical scores and survival times were determined. RESULTS: CLP induced a significant increase in ROS production and CD11b upregulation by rat PMNs. Treatment with physostigmine or neostigmine significantly reduced ROS production and CD11b upregulation by PMNs 20 h after CLP induction. In physostigmine-treated animals, survival times were significantly improved compared to the control animals, but not in neostigmine-treated animals. While AChE activity significantly decreased in the control animals at t > 6 h, AChE activity did not change in the sham group. BChE activity decreased at t > 20 h in the control animals. CONCLUSION: While AChE activity may serve as an acute inflammatory marker, BChE activity shows a delayed decrease. Administration of centrally acting physostigmine in CLP-induced sepsis in rats has protective effects on PMN functions and improves survival times, which may be of interest in clinical practice.

Relevance of peripheral cholinesterase activity on postoperative delirium in adult surgical patients (CESARO): A prospective observational cohort study.

BACKGROUND: The cholinergic system is considered to play a key role in the development of postoperative delirium (POD), which is a common complication after surgery. OBJECTIVES: To determine whether peri-operative acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities are associated with the development of POD in in-hospital surgical patients, and raise hypotheses on cholinergic regulatory mechanisms in POD. DESIGN: A prospective multicentre observational study by the Peripheral Cholinesterase-activity on Neurocognitive Dysfunctions in Surgical Patients (CESARO) study group. SETTING: Nine German hospitals. PATIENTS: Patients of at least 18 years of age scheduled for inpatient elective surgery for a variety of surgical procedures. A total of 650 patients (mean age 61.5 years, 52.8% male) were included. METHODS: Clinical variables, and peripheral AChE and BuChE activities, were assessed throughout the peri-operative period using bedside point-of-care measurements (one pre-operative and two postoperative measurements). POD screening was conducted postoperatively for at least 24 h and up to the third postoperative day using a validated screening tool (nursing delirium screening scale). RESULTS: In all, 179 patients (27.5%) developed POD within the early postoperative phase. There was a lower BuChE activity in patients with delirium compared with patients without delirium pre-operatively (Cohen's r = 0.07, P = 0.091), on postoperative day 1 (Cohen's r = 0.12, P = 0.003) and on postoperative day 2 (Cohen's r = 0.12, P = 0.002). In contrast, there was a significantly higher AChE activity in patients with delirium compared with patients without delirium pre-operatively (Cohen's r = 0.10, P = 0.012), on postoperative day 1 (Cohen's r = 0.11, P = 0.004) and on postoperative day 2 (Cohen's r = 0.13, P = 0.002). After adjusting for covariates in multiple logistic regression, a significant association between both BuChE and AChE activities and POD was not found. However, in the multivariable analysis using the Generalized Estimating Equation, cholinesterase activities showed that a decrease of BuChE activity by 100 U L increased the risk of a delirium by approximately 2.1% (95% CI 1.6 to 2.8%) and for each 1 U g of haemoglobin increase in AChE activity, there was a 1.4% (95% CI 0.6 to 2.2%) increased risk of POD. CONCLUSION: Peri-operative peripheral cholinesterase activities may be related to the development of POD, but the clinical implications remain unclear. Further studies, in homogeneous patient groups with a strict protocol for measurement time points, are needed to investigate the relationship between cholinesterase activities and POD. TRIAL REGISTRATION: www.clinicaltrials.gov. Identifier NCT01964274.

Adenosine A2A and A2B Receptor Substantially Attenuate Ischemia/Reperfusion Injury in Septic rat Hearts.

INTRODUCTION: Mechanical and morphological ischemia and reperfusion (I/R) injury is reduced in septic hearts. The mechanism behind this "cardioprotection" is less well understood. As adenosine receptors play a major role for cardioprotection in non-septic hearts, we investigated the influence of adenosine receptors in a model of I/R in septic hearts. METHODS: SHAM operation or cecal ligation and puncture (CLP) was performed in adult male Wistar rats (n = 60). After 24 h of incubation, hearts were isolated and randomly assigned to a group with or without adenosine receptor (Ador) antagonists (SCH 58261 and MRS 1706) administered before reperfusion. Ischemia and reperfusion lasted for 40 min each. Cardiac function of the heart was determined by measuring left ventricular pressure (LVP). RESULTS: Before I/R, CLP hearts showed a significant mechanical left ventricular impairment (CLP: 63 ± 5 mmHg vs. SHAM: 104 ± 6 mmHg. After I/R, left ventricular function was significantly reduced in SHAM (24 ± 32 mmHg), but not in CLP hearts (65 ± 13 mmHg). mRNA expression for the AdorA2a and AdorA2b was significantly increased in CLP, but not in SHAM hearts. LVP of CLP hearts deteriorated when AdorA2a and AdorA2b were blocked. CONCLUSIONS: The morphological and functional I/R injury in septic animals is less pronounced compared to non-septic animals. By a combined blockade of AdorA2a and AdorA2b this "cardioprotective" effect is nearly abolished in septic hearts. This is the first study showing, that AdorA2a and AdorA2b may play an important role for a reduced functional I/R injury in the septic heart.

The impact of crystalloidal and colloidal infusion preparations on coronary vascular integrity, interstitial oedema and cardiac performance in isolated hearts.

INTRODUCTION: Recent data suggested an interaction between plasma constituents and the endothelial glycocalyx to be relevant for vascular barrier function. This might be negatively influenced by infusion solutions, depending on ionic composition, pH and binding properties. The present study evaluated such an influence of current artificial preparations. METHODS: Isolated guinea pig hearts were prepared in a modified Langendorff mode and perfused with Krebs-Henseleit buffer augmented with 1g% human albumin. After equilibration the perfusion was switched to replacement of one half buffer by either isotonic saline (NaCl), ringer's acetate (Ri-Ac), 6% and 10% hydroxyethyl starch (6% and 10% HES, resp.), or 4% gelatine (Gel), the artificial colloids having been prepared in balanced solution. We analysed glycocalyx shedding, functional integrity of the vascular barrier and heart performance. RESULTS: While glycocalyx shedding was not observed, diluting albumin concentration towards 0.5g% by artificial solutions was associated with a marked functional breakdown of vascular barrier competence. This effect was biggest with isotonic saline and significantly attenuated with artificial colloids, the difference in the pressure dependent transvascular fluid filtration (basal vs. during infusion in groups NaCl, Ri-Ac, 6% HES, 10% HES and Gel, n = 6 each) being 0.31 ± 0.03 vs. 1.00 ± 0.04; 0.27 ± 0.03 vs. 0.81 ± 0.03; 0.29 ± 0.03 vs. 0.68 ± 0.02; 0.32 ± 0.03 vs. 0.59 ± 0.08 and 0.31 ± 0.04 vs. 0.61 ± 0.03 g/5min, respectively. Heart performance was directly related to pH value (7.38 ± 0.06, 7.33 ± 0.03, 7.14 ± 0.04, 7.08 ± 0.04, 7.25 ± 0.03), the change in the rate pressure product being 21,702 ± 1969 vs. 21,291 ± 2,552; 22,098 ± 2,115 vs. 14,114 ± 3,386; 20,897 ± 2,083 vs. 10,671 ± 1,948; 21,822 ± 2,470 vs. 10,047 ± 2,320 and 20,955 ± 2,296 vs. 15,951 ± 2,755 mmHg × bpm, respectively. CONCLUSIONS: It appears important to maintain the pH value within a physiological range to maintain optimal myocardial contractility. Using colloids prepared in calcium-containing, balanced solutions for volume replacement therapy may attenuate the breakdown of vascular barrier competence in the critically ill.

The Effect of Local Anesthetics on Neutrophils in the Context of Different Isolation Techniques.

Various functions of polymorphonuclear neutrophils (PMNs) are related to diseases and postoperative plasma changes. The influence of some local anesthetics (LAs) on PMNs obtained by conventional isolation methods and their functions has already been demonstrated. This study investigates the effect of selected LAs on PMNs, comparing a new isolation method with conventional ones. To obtain the PMNs, we performed either gelafundin sedimentation, hypotonic lysis or density gradient centrifugation. Subsequently, PMNs were mixed with different concentrations of bupivacaine, levobupivacaine, lidocaine or ropivacaine. Live cell imaging and flow cytometry were performed to quantify the migration, ROS production, NETosis and antigen expression of PMNs. We found the inhibition of chemotaxis and ROS production by LAs. PMNs showed a strong reduction in time to half maximal NETosis in response to bupivacaine and lidocaine, but not to levobupivacaine and ropivacaine. We also found distinct differences in survival time and migration duration between the isolation methods. This suggests that the careful selection of LAs has a short-term impact on in vitro PMNs.

The Effects of Analgesics on the Migration of Pancreatic Cancer Cells.

BACKGROUND/AIM: Adenocarcinoma of the pancreas is one of the most aggressive malignant diseases in humans. Characteristics of this tumour type are poor response to radiotherapy and chemotherapeutic agents as well as metastasis in the absence of an organ capsule. The best therapeutic option is surgical removal of the tumour followed by chemotherapy or radiotherapy. Yet, even after surgical R0-resection, the 5-year survival probability is only about 20% because of the high recurrence rate of this tumour and complications due to metastases. Furthermore, recent studies have shown that the perioperative period is a particularly vulnerable phase, during which tumour progression and metastasis may be facilitated. The effects of analgesics administered during the perioperative period are still unknown. The present work investigated the effects of analgesics on pancreatic cancer cell migration in vitro. MATERIALS AND METHODS: The migratory potential of pancreatic cancer cells was analysed using a Cell Migration Assay Kit with a Boyden chamber, in which cells migrate through a semi-permeable membrane under different stimuli. Cell concentration was measured by reading fluorescence (Ex/Em=530/590 nm) in a plate reader. RESULTS: Migration in PANC-1 pancreatic cancer cells was significantly decreased after 24 h stimulation with 100 µM of ropivacaine, 100 nM of sufentanil, 1,000 µM of ropivacaine and 1,000 nM of sufentanil. In the PaTu 8988t cell line, incubation with 10 µM of ropivacaine caused a slight but statistically significant increase in migration, whereas lidocaine, metamizole and paracetamol did not significantly affect migration. CONCLUSION: The risk of tumour progression and metastasis seems to be increased during major oncological surgical interventions. The recent advances in the molecular and biological understanding of pathogenesis of pancreatic cancer have not yet significantly improved patient outcome. Therefore, further studies are needed to identify the underlying mechanisms of this aggressive tumour and establish new therapeutic options for the future.

Effect of Propofol and Etomidate on the Proliferation, Cell-cycle Distribution, Apoptosis and Necrosis of Pancreatic Tumour Cells.

BACKGROUND/AIM: The influence of surgical interventions and anaesthesiological procedures on tumour progression was investigated as early as the 1920s. In current cancer management, the perioperative phase is increasingly being considered a vulnerable period with an increased risk of tumour cell dissemination due to medication, surgical manipulation, and immunosuppression. The extent to which narcotics administered in the perioperative setting influence the oncological outcomes of patients with pancreatic cancer is still unclear. MATERIALS AND METHODS: To investigate the effect of propofol and etomidate on the proliferation, cell-cycle distribution, apoptosis, and necrosis of pancreatic tumour cells in vitro, PaTu 8988t and Panc-1 pancreatic cancer cells were treated with 0-1,000 µM propofol or etomidate for 24 h each. Cell proliferation was measured with enzyme-linked immunosorbent-bromodeoxyuridine assay. The apoptosis rate was analysed with annexin V staining and the cell-cycle distribution with flow cytometry. RESULTS: Propofol at 1,000 µM induced apoptosis and inhibited cell proliferation. The cell cycle showed an increased S-phase and reduced cells in the G1-phase. At 100 µM, propofol significantly inhibited proliferation of the pancreatic cancer cell line PaTu 8988t and reduced cells in the G2-phase in the cell cycle. Etomidate had no effects on cell-cycle distribution, proliferation, apoptosis, and necrosis at the concentrations used. CONCLUSION: In this study, propofol was shown to have anticancer effects by induction of apoptosis and inhibition of cell proliferation, while etomidate did not affect pancreatic cancer cells. However, it is too early to make any recommendation for changes in clinical practice and further clinical studies are warranted to investigate the effect of anaesthetics on cancer progression.

Hemoadsorption in the critically ill-Final results of the International CytoSorb Registry.

The aim of the current paper is to summarize the results of the International CytoSorb Registry. Data were collected on patients of the intensive care unit. The primary endpoint was actual in-hospital mortality compared to the mortality predicted by APACHE II score. The main secondary endpoints were SOFA scores, inflammatory biomarkers and overall evaluation of the general condition. 1434 patients were enrolled. Indications for hemoadsorption were sepsis/septic shock (N = 936); cardiac surgery perioperatively (N = 172); cardiac surgery postoperatively (N = 67) and "other" reasons (N = 259). APACHE-II-predicted mortality was 62.0±24.8%, whereas observed hospital mortality was 50.1%. Overall SOFA scores did not change but cardiovascular and pulmonary SOFA scores decreased by 0.4 [-0.5;-0.3] and -0.2 [-0.3;-0.2] points, respectively. Serum procalcitonin and C-reactive protein levels showed significant reduction: -15.4 [-19.6;-11.17] ng/mL; -17,52 [-70;44] mg/L, respectively. In the septic cohort PCT and IL-6 also showed significant reduction: -18.2 [-23.6;-12.8] ng/mL; -2.6 [-3.0;-2.2] pg/mL, respectively. Evaluation of the overall effect: minimal improvement (22%), much improvement (22%) and very much improvement (10%), no change observed (30%) and deterioration (4%). There was no significant difference in the primary outcome of mortality, but there were improvements in cardiovascular and pulmonary SOFA scores and a reduction in PCT, CRP and IL-6 levels. Trial registration: ClinicalTrials.gov Identifier: NCT02312024 (retrospectively registered).

Potential Impact of Local Anesthetics Inducing Granulocyte Arrest and Altering Immune Functions on Perioperative Outcome.

INTRODUCTION: Local anesthetics (LAs) are frequently used during anesthesia; however, they may influence granulocyte function which in turn could modify immune responses in the perioperative period. Therefore, the aim of this study was to investigate the impact of clinically used doses of bupivacaine and lidocaine on granulocyte function with regard to migration, reactive oxygen species (ROS) production, neutrophil extracellular traps (NETosis) formation, and viability. METHODS: A total of 38 granulocyte-enriched samples from healthy subjects were obtained by whole blood lysis. Polymorphonuclear neutrophil (PMN) samples were incubated simultaneously with different concentrations of either bupivacaine (0.03-3.16 mmol/L) or lidocaine (0.007-14.21 mmol/L), or without drug (control). Live cell imaging was conducted in order to observe granulocyte chemotaxis, migration, ROS production, and NETosis. Flow cytometry was used to analyze viability and antigen expression. RESULTS: The track length (TL) of PMNs exposed to bupivacaine concentrations of 0.16 mmol/L and above significantly decreased compared to the control. Low concentrations of lidocaine were associated with slight but significant increases in TL, whereas this changed with concentrations above 1.4 mmol/L, showing a significant decrease in TL. PMN incubated with bupivacaine concentrations of 1.58 mmol/L and above or lidocaine concentrations of at least 3.6 mmol/L showed no migration or chemotaxis at all. Time to onset of maximal ROS production and time for half-maximal NETosis decreased in a dose-dependent manner for both substances. Equipotency in NETosis induction was reached by bupivacaine (1.1 mmol/L) at significantly lower concentrations than lidocaine (7.96 mmol/L). Cell viability and oxidative burst were unaffected by LAs. CONCLUSION: Local anesthetics in clinically used doses ameliorate granulocyte defense mechanisms, thus indicating their potentially decisive effect during the perioperative period.

Butyrylcholinesterase as a perioperative complication marker in patients after transcatheter aortic valve implantation: a prospective observational study.

OBJECTIVES: Transcatheter aortic valve implantation (TAVI) is performed in elderly patients with severe aortic valve stenosis and increased operative risks. We tested the hypothesis that acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) have a predictive value for prevalent complications after TAVI and could serve as indicators of systemic inflammation in the early postoperative period. DESIGN: Prospective observational study. SETTING: This study is a secondary analysis of multicentre CESARO- study. PARTICIPANTS: 48 patients with TAVI were included and 43 obtained the complete assessment. PRIMARY AND SECONDARY OUTCOME MEASURES: Patients' clinical parameters, demographic data, peripheral AChE and BChE activities and routine blood markers were assessed throughout the perioperative period using bedside point-of-care measurements for AChE and BChE. Postoperative complication screening was conducted up to the third postoperative day and included infections, delirium and heart-rhythm disturbances. After assessment, the patients were divided into complication and noncomplication group. RESULTS: Of 43 patients, 24 developed postsurgical complications (55.8%). Preoperative assessment showed no significant differences regarding demographic data and laboratory markers, but preoperative BChE levels were significantly lower in patients who developed postoperative complications (complication group 2589.2±556.4 vs noncomplication group 3295.7±628.0, Cohen's r=0.514, p<0.001). In complication group, we observed an early, sustained reduction in BChE activity from preoperative to postoperative period. In complication group, BChE levels were significantly lower at each time point compared with noncomplication group. AChE activity showed no significant difference between both groups. Complication group also had longer stay in hospital overall. CONCLUSION: BChE could be a useful perioperative biomarker to identify patients with a higher risk for postoperative complications after TAVI. By using point-of-care measurements, the levels of BChE are fast available and can lead to an early targeted therapy. Predicting the length of the hospital stay might play an important role in staff and resource management for these patients. TRIAL REGISTRATION NUMBER: NCT01964274; Post-results.

Propofol Ameliorates Exaggerated Human Neutrophil Activation in a LPS Sepsis Model.

BACKGROUND: Sepsis is a leading cause of morbidity and mortality worldwide. Many patients suffering from sepsis are treated on intensive care units and many of them require mechanical ventilation under sedation or general anesthesia. Propofol, a drug used for these purposes, is known to interact with polymorphonuclear granulocytes (PMNs). Therefore, the aim of this study was to investigate the influence of propofol on PMN functions after experimental Gram-negative induced sepsis using lipopolysaccharide (LPS) stimulation. METHODS: A total of 34 granulocyte-enriched samples were collected from healthy subjects. PMNs were isolated by density gradient centrifugation and incubated simultaneously with either 6 µg/mL or 60 µg/mL propofol, or none (control). Additionally, the experimental sepsis samples were incubated with either 40 pg/mL or 400 pg/mL LPS. Live cell imaging was conducted in order to observe granulocyte chemotactic migration, ROS production, and NETosis. Flow cytometry was used to analyze viability and antigen expression. RESULTS: Propofol led to significantly reduced PMN track length (p < 0.001) and track speed (p < 0.014) after LPS-induced sepsis in a dose-dependent manner. NETosis (p = 0.018) and ROS production (p = 0.039) were accelerated by propofol without LPS incubation, indicating improved immune function. Propofol also ameliorated LPS-induced increased NETosis and ROS-production. Antigen expression for CD11b, CD62l and CD66b was unaffected by propofol. CONCLUSION: Propofol improves LPS-induced exaggerated PMN activation in an ex vivo model. Beneficial effects due to restored immune function in septic patients might be possible, but needs further investigation.

Postoperative acute respiratory dysfunction and the influence of antibiotics after acute type A aortic dissection surgery: A retrospective analysis.

OBJECTIVES: Surgery for acute type A aortic dissection is associated with several perioperative complications, such as acute respiratory dysfunction (ARD). The aim of this study was to investigate perioperative risk factors involved in the development of ARD and whether antibiotic treatment has an impact. METHODS: 243 patients underwent surgery for acute type A aortic dissection between 2008 and 2017. The patients were retrospectively divided into the ARD and NON-ARD group. ARD was defined as PaO2/FiO2 ≤ 200 mmHg (PF ratio) within 48 hours after surgery. All patients received either narrow- or broad-spectrum antibiotics. RESULTS: After the exclusion of 42 patients, 201 patients were analyzed. The PF ratio of the ARD group was significantly lower than of the NON-ARD group within the first 7 days. ARD patients (n = 111) were significantly older (p = .031) and had a higher body mass index (BMI) (p = .017). ARD patients required longer postoperative ventilation (2493 vs. 4695 [min], p = .006) and spent more days in the intensive care unit (7.0 vs. 8.9 [days], p = .043) compared to NON-ARD. The mortality was significantly lower for ARD than for NON-ARD patients (p = .030). The incidence of pneumonia was independent of the antibiotic treatment regime (p = .391). Renal and neurological complication rate was higher in patients treated with broad-spectrum antibiotic. CONCLUSION: ARD is the main complication (55%) that occurs approximately 24 hours after surgery for acute type A aortic dissection. The preoperative risk factors for ARD were higher age and increased BMI. Patients on broad-spectrum antibiotics did not show an improved postoperative outcome compared to patients with narrow-spectrum antibiotics.

Recurrent necrotizing cellulitis, multi-organ autoimmune disease and humoral immunodeficiency due to a novel NFKB1 frameshift mutation.

BACKGROUND: Mutations in NFKB1(nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) are associated with a variety of clinical symptoms, including lymphadenopathy, splenomegaly, hepatomegaly, autoimmune haemolytic anaemia, arthralgia, recurrent respiratory tract infections and post-operative necrotizing cellulitis. CASE PRESENTATION: We describe a case of a 47-year-old man, who presented with deep necrotizing cellulitis after incision of a submucous abscess by a dentist. Surgical intervention led to a massive progress. Pyoderma gangraenosum (PG) was diagnosed clinically and confirmed histopathologically. High dose corticosteroids and intravenous immunoglobulins (IVIG) improved wound healing dramatically. Until now, immune mediated inflammation events not only affected the skin, but also multiple inner organs, i.e. the heart, lungs and gut. Sequencing of all coding exons of NFKB1 revealed a heterozygous 1bp deletion in exon 23 predicting a frameshift starting at codon Ala891 and resulting in a subsequent stop codon at position 6 in the new reading frame: NM_003998.4: c.2671del; p.(Ala891Glnfs*6) Acute episodes were always successfully treated with corticosteroids, IVIG and concomitant antibiotics. To prevent further exacerbations, the patient receives IVIG once a month, low-dose corticosteroids and methotrexate. CONCLUSION: This is the first case of a patient with recurrent necrotizing cellulitis and immune mediated multi-organ involvement (heart, lungs, intestine) carrying the novel frameshift mutation c.2671del (p.Ala891Glnfs*6) in NFKB1 effectively treated with IVIG, low-dose corticosteroids and methotrexate.

Therapeutic Anticoagulation with Argatroban and Heparins Reduces Granulocyte Migration: Possible Impact on ECLS-Therapy?

INTRODUCTION: Anticoagulants such as argatroban and heparins (low-molecular-weight and unfractionated) play an immense role in preventing thromboembolic complications in clinical practice. Nevertheless, they can also have a negative effect on the immune system. This study is aimed at investigating the influence of these substances on polymorphonuclear neutrophils (PMNs), whose nonspecific defense mechanisms can promote thrombogenesis. METHODS: Blood samples from 30 healthy volunteers were investigated, whereby PMNs were isolated by density gradient centrifugation and incubated with 0.8 µg/mL of argatroban, 1.0 U/mL of low-molecular-weight heparin (LMWH), 1.0 U/mL of unfractionated heparin (UFH), or without drug (control). A collagen-cell mixture was prepared and filled into 3D µ-slide chemotaxis chambers (IBIDI® GmbH, Germany). Stimulation was initiated by using a chemokine gradient of n-formyl-methionine-leucyl-phenylalanine (fMLP), and microscopic observation was conducted for 4.5 hours. The cells' track length and track straightness, as well as the number of attracted granulocytes, level of ROS (reactive oxygen species) production, and NET (neutrophil extracellular traps) formation, were analyzed and categorized into migration distances and time periods. RESULTS: All three anticoagulants led to significantly reduced PMN track lengths, with UFH having the biggest impact. The number of tracks observed in the UFH group were significantly reduced compared to the control group. Additionally, the UFH group demonstrated a significantly lower track straightness compared to the control. ROS production and NET formation were unaffected. CONCLUSION: Our data provide evidence that anticoagulants have an inhibitory effect on the extent of PMN migration and chemotactic migration efficiency, thus indicating their potential immune-modulatory and prothrombotic effects.

Early fasciotomies and plastic-surgical reconstruction may enhance preservation of functional extremity length in purpura fulminans.

BACKGROUND: Purpura fulminans (PF) is a distinct form of rare meningococcal septicaemia mostly in childhood which is characterized by high lethality, extensive necroses and mutilations of extremities. Other ethiologies are idiopathic forms or purpura neonatorum, which is marked by deficiency of Protein-C. PF is caused by micro-embolism of the vascular system, followed by quickly spreading necroses of skin and different organs.Modern concepts of intensive care treatment of the acute phase of this disease and early surgical intervention lead to a rising number of surviving patients requiring limb salvage.Aim of this study is to evaluate a possible lower morbidity and the grade of lower loss of function because of early surgical intervention. PATIENTS AND METHODS: Between the years 1998 and 2017 eight cases of PF at two large centers for critical wound care, the department of plastic-, hand- and reconstructive surgery of the university hospital of Regensburg and the department of plastic-, hand- and reconstructive surgery of the BG-clinic Ludwigshafen were included into our study.We retrospectively examined patients with PF who were stabilized by intensive care medicine and received surgical interventions. After survival of the acute phase (10 days), patients received plastic surgical reconstructions. RESULTS: A total number of eight patients could be included into our study. All patients survived the initial phase (10 days). All patients required plastic-surgical interventions to address extensive skin and soft tissue defects. Flap operations were judged necessary in five cases. Hereby four defects could be reconstructed by free tissue transfer, one with a local flap. Flap survival was 100 percent. One flap required revision of the arterial anastomosis of the flap arteria. Another flap got partial necrosis. One patient died due to multiorgan failure.Early debridements with consequent fasciotomies and secondary plastic-surgical reconstruction achieved good functional results. Limb salvage was accomplished in three patients. One patient died due to fulminant progress of the disease. CONCLUSION: Management of PF requires a multidisciplinary approach and close communication between the different subspecialties. Early debridements with consequent fasciotomies showed good results in salvaging subfascial muscle tissue in the extremities with satisfying functional results. Early surgical intervention is an important factor for improved limb salvage and survival.

Staurosporine induces apoptosis in pancreatic carcinoma cells PaTu 8988t and Panc-1 via the intrinsic signaling pathway.

BACKGROUND: Cancer, one of the leading causes of death worldwide, develops when the normal balance between mitosis and apoptosis is disrupted. The subsequently increased proliferation rate or decreased apoptosis rate of cells leads to uncontrolled cellular growth. Thus, the current aim of cancer research is to increase the apoptosis rate in tumor cells-while limiting the concurrent death of healthy cells-and to induce controlled apoptosis in abnormal cells. Staurosporine is a very potent inducer of apoptosis because it inhibits many different kinases. So far, many different kinase pathways of staurosporine-induced apoptosis have been discussed for various tumor entities. AIMS: To identify the effect of staurosporine in pancreatic and colorectal carcinoma cells and its apoptosis-inducing signaling pathway. METHODS: The apoptosis rate in pancreatic and colorectal carcinoma cells was analyzed by annexin V staining after staurosporine administration. Staurosporine stimulation and its effects on the expression of Bcl2, BAX, Bad, caspase-8, and caspase-9 were investigated with immunoblot. RESULTS: Staurosporine significantly increased apoptosis in pancreatic carcinoma cells. Western blot analysis showed activation of caspase-9 in PaTu 8988t and Panc-1 cells with 1 µM staurosporine. In addition, expression of Bcl2 and Bad was decreased in PaTu 8988t cells. In colorectal carcinoma cells SW 480, staurosporine stimulation did not induce apoptosis. CONCLUSION: Modern therapeutic strategies for tumor diseases target the efficient modulation of specific signaling and transcription pathways. In this respect, the therapeutic potential of protein kinase inhibitors has been repeatedly discussed. Our study showed that staurosporine induces apoptosis in pancreatic carcinoma cells via the intrinsic signaling pathway. Thus, staurosporine is a suitable positive control for in vitro apoptosis tests for the pancreatic cancer cell lines PaTu 8988t and Panc-1. Further clinical studies should analyze the impact of this finding on cancer treatment.