Dynamics of Vascular Protective and Immune Supportive Sphingosine-1-Phosphate During Cardiac Surgery.

Introduction: Sphingosine-1-phosphate (S1P) is a signaling lipid and crucial in vascular protection and immune response. S1P mediated processes involve regulation of the endothelial barrier, blood pressure and S1P is the only known inducer of lymphocyte migration. Low levels of circulatory S1P correlate with severe systemic inflammatory syndromes such as sepsis and shock states, which are associated with endothelial barrier breakdown and immunosuppression. We investigated whether S1P levels are affected by sterile inflammation induced by cardiac surgery. Materials and Methods: In this prospective observational study we included 46 cardiac surgery patients, with cardiopulmonary bypass (CPB, n=31) and without CPB (off-pump, n=15). Serum-S1P, S1P-sources and carriers, von-Willebrand factor (vWF), C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) were measured at baseline, post-surgery and at day 1 (POD 1) and day 4 (POD 4) after surgical stimulus. Results: Median S1P levels at baseline were 0.77 nmol/mL (IQR 0.61-0.99) and dropped significantly post-surgery. S1P was lowest post-surgery with median levels of 0.37 nmol/mL (IQR 0.31-0.47) after CPB and 0.46 nmol/mL (IQR 0.36-0.51) after off-pump procedures (P<0.001). The decrease of S1P was independent of surgical technique and observed in all individuals. In patients, in which S1P levels did not recover to preoperative baseline ICU stay was longer and postoperative inflammation was more severe. S1P levels are associated with its sources and carriers and vWF, as a more specific endothelial injury marker, in different phases of the postoperative course. Determination of S1P levels during surgery suggested that also the anticoagulative effect of heparin might influence systemic S1P. Discussion: In summary, serum-S1P levels are disrupted by major cardiac surgery. Low S1P levels post-surgery may play a role as a new marker for severity of cardiac surgery induced inflammation. Due to well-known protective effects of S1P, low S1P levels may further contribute to the observed prolonged ICU stay and worse clinical status. Moreover, we cannot exclude a potential inhibitory effect on circulating S1P levels by heparin anticoagulation during surgery, which would be a new pro-inflammatory pleiotropic effect of high dose heparin in patients undergoing cardiac surgery.

Understanding Why All Types of Motivation Are Necessary in Advanced Anaesthesiology Training Levels and How They Influence Job Satisfaction: Translation of the Self-Determination Theory to Healthcare.

Studies applying the self-determination theory have shown that intrinsic motivation and autonomous regulation lead to job satisfaction and to better job performance. What has not been worked out clearly yet are the effects of extrinsic motivation and controlled regulation on affect, job performance and job satisfaction. However, it has been described that controlled regulation is often necessary for mundane tasks. In anaesthesiology, routine daily tasks can be perceived as mundane by those who have achieved a certain level of training (e.g., consultants). Therefore, it was hypothesised that consultants have high expressions of all motivational qualities. Furthermore, it was hypothesised that job satisfaction of anaesthesiologists is correlated with autonomous motivation. The hypotheses were tested in a cross-sectional study design within a group of anaesthesiologists. The study participants reported the same pattern throughout the motivational continuum. Consultants reported the highest levels of all motivational qualities, including controlled regulation, as well as the highest levels of job satisfaction. Junior residents reported high levels of amotivation and extrinsic regulation. The lowest levels of identified regulation and job satisfaction were reported by the group of attendings. Job satisfaction was positively correlated with intrinsic motivation and negatively correlated with amotivation. Therefore, our findings from the field of anaesthesiology show that the expressions of high levels of controlled regulation might be necessary for specialists to engage in mundane daily tasks. Intrinsic motivation and autonomous regulation are necessary for job satisfaction and the presence of controlled regulation and extrinsic behavioural regulation have no declining effects. Furthermore, the decrease of amotivation will lead to enhanced job satisfaction and the resulting consequences will be extensive. Junior residents need to be supported with the aim to enhance their feeling of autonomy and competence in order to decrease amotivation and to foster autonomous regulation and hence to increase job satisfaction and well-being. Further special focus should be on attendings to counteract their lacking identification with the job. Hereby, the provision of feedback and professional perspectives might foster the process of re-identification.

Establishment of an enhanced recovery after surgery protocol in minimally invasive heart valve surgery.

Protocols for "Enhanced recovery after surgery (ERAS)" are on the rise in different surgical disciplines and represent one of the most important recent advancements in perioperative medical care. In cardiac surgery, only few ERAS protocols have been described in the past. At University Heart Center Hamburg, Germany, we invented an ERAS protocol for patients undergoing minimally invasive cardiac valve surgery. In this retrospective single center study, we aimed to describe the implementation of our ERAS program and to evaluate the results of the first 50 consecutive patients. Our ERAS protocol was developed according to a modified Kern cycle by an expert group, literature search, protocol creation and pilot implementation in the clinical practice. Data of the first 50 consecutive patients undergoing minimally invasive cardiac valve surgery were analysed retrospectively. The key features of our multidisciplinary ERAS protocol are physiotherapeutic prehabilitation, minimally invasive valve surgery techniques, modified cardiopulmonary bypass management, fast-track anaesthesia with on- table extubation and early mobilisation. A total of 50 consecutive patients (mean age of 51.9±11.9 years, mean STS score of 0.6±0.3) underwent minimally-invasive mitral or aortic valve surgery. The adherence to the ERAS protocol was high and neither protocol related complications nor in-hospital mortality occurred. 12% of the patients developed postoperative atrial fibrillation, postoperative delirium emerged in two patients and reintubation was required in one patient. Intensive care unit stay was 14.0±7.4 hours and total hospital stay 6.2±2.9 days. Our ERAS protocol is feasible and safe in minimally-invasive cardiac surgery setting and has a clear potential to improve patients outcome.

Human leucocyte antigen (HLA-DR) gene expression is reduced in sepsis and correlates with impaired TNFα response: A diagnostic tool for immunosuppression?

BACKGROUND: Sepsis is defined as a dysregulated immune response to infection. Impaired immune response in sepsis, often described as endotoxin tolerance, is characterized by unresponsiveness of monocytes on lipopolysaccharide (LPS) stimulation to release tumor necrosis factor α (TNFα). Furthermore, decreased monocyte surface protein expression of human leucocyte antigen DR (HLA-DR) is a marker for changes of the innate immune response during sepsis. Quantitative polymerase chain reaction (qPCR) and flow-cytometry (FACS) have been used to measure protein or gene expression of HLA-DR. We aimed to determine whether changes in mRNA expression of HLA-DR are associated with impaired TNFα response in human sepsis. METHODS: Surface protein together with mRNA expression of HLA-DR were measured by FACS and qPCR in a cohort of 9 sepsis patients and compared to 10 pre-operative control patients in a prospective study. In addition, 20 patients with post-surgical inflammation, 20 patients with sepsis or septic shock were included and TNFα was determined following ex vivo stimulation of whole blood with 500 pg/mL LPS. Total RNA was prepared from whole blood and subjected to qPCR analysis for expression analysis of HLA-DR alpha (HLA-DRA) to correlate TNFα response with HLA-DRA expression. RESULTS: Patients with sepsis presented higher numbers of monocytes in peripheral blood (P<0.001) but decreased surface protein and mRNA HLA-DR levels when compared to controls. In all patients mRNA expression of HLA-DRA was decreased by approximately 70% compared to controls (P<0.01) and was lowest in patients with sepsis or septic shock (P<0.01). TNFα response to LPS was decreased in all patients (median 319 pg/mL versus controls 1256 pg/mL; P<0.01) and lowest in patients with sepsis or septic shock (median 128 pg/mL; P<0.01). HLA-DRA correlated positively with TNFα response in all study participants (r +0.60, P<0.001) and within patients (r +0.67, P<0.001). The TNFα:HLA-DRA ratio correlated negatively with severity and the Sequential Organ Failure Assessment (SOFA) score (Spearman's rho -0.59, P<0.001). CONCLUSION: In this study, HLA-DRA expression was associated with a functional assay of the innate immune response. Future interventional studies aimed at the immune response during sepsis could make use of these methods for optimizing target groups based on biological plausibility and intervention effectiveness.

Markers of nitric oxide are associated with sepsis severity: an observational study.

BACKGROUND: Nitric oxide (NO) regulates processes involved in sepsis progression, including vascular function and pathogen defense. Direct NO measurement in patients is unfeasible because of its short half-life. Surrogate markers for NO bioavailability are substrates of NO generating synthase (NOS): L-arginine (lArg) and homoarginine (hArg) together with the inhibitory competitive substrate asymmetric dimethylarginine (ADMA). In immune cells ADMA is cleaved by dimethylarginine-dimethylaminohydrolase-2 (DDAH2). The aim of this study was to investigate whether concentrations of surrogate markers for NO bioavailability are associated with sepsis severity. METHOD: This single-center, prospective study involved 25 controls and 100 patients with surgical trauma (n = 20), sepsis (n = 63), or septic shock (n = 17) according to the Sepsis-3 definition. Plasma lArg, hArg, and ADMA concentrations were measured by mass spectrometry and peripheral blood mononuclear cells (PBMCs) were analyzed for DDAH2 expression. RESULTS: lArg concentrations did not differ between groups. Median (IQR) hArg concentrations were significantly lower in patient groups than controls, being 1.89 (1.30-2.29) µmol/L (P < 0.01), with the greatest difference in the septic shock group, being 0.74 (0.36-1.44) µmol/L. In contrast median ADMA concentrations were significantly higher in patient groups compared to controls, being 0.57 (0.46-0.65) µmol/L (P < 0.01), with the highest levels in the septic shock group, being 0.89 (0.56-1.39) µmol/L. The ratio of hArg:ADMA was inversely correlated with disease severity as determined by the Sequential Organ Failure Assessment (SOFA) score. Receiver-operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for the hArg:ADMA ratio compared to the SOFA score. DDAH2 expression was lower in patients than controls and lowest in the subgroup of patients with increasing SOFA. CONCLUSIONS: In patients with sepsis, plasma hArg concentrations are decreased and ADMA concentrations are increased. Both metabolites affect NO metabolism and our findings suggest reduced NO bioavailability in sepsis. In addition, reduced expression of DDAH2 in immune cells was observed and may not only contribute to blunted NO signaling but also to subsequent impaired pathogen defense.

Decreased serum concentrations of sphingosine-1-phosphate in sepsis.

INTRODUCTION: Sphingosine-1-phosphate (S1P) is a signaling lipid that regulates pathophysiological processes involved in sepsis progression, including endothelial permeability, cytokine release, and vascular tone. The aim of this study was to investigate whether serum-S1P concentrations are associated with disease severity in patients with sepsis. METHODS: This single-center prospective-observational study includes 100 patients with systemic inflammatory response syndrome (SIRS) plus infection (n = 40), severe sepsis (n = 30), or septic shock (n = 30) and 214 healthy blood donors as controls. Serum-S1P was measured by mass spectrometry. Blood parameters, including C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), lactate, and white blood cells (WBCs), were determined by routine assays. The Sequential Organ Failure Assessment (SOFA) score was generated and used to evaluate disease severity. RESULTS: Serum-S1P concentrations were lower in patients than in controls (P < 0.01), and the greatest difference was between the control and the septic shock groups (P < 0.01). Serum-S1P levels were inversely correlated with disease severity as determined by the SOFA score (P < 0.01) as well as with IL-6, PCT, CRP, creatinine, lactate, and fluid balance. A receiver operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for S1P compared with the SOFA score. In a multivariate logistic regression model calculated for prediction of septic shock, S1P emerged as the strongest predictor (P < 0.001). CONCLUSIONS: In patients with sepsis, serum-S1P levels are dramatically decreased and are inversely associated with disease severity. Since S1P is a potent regulator of endothelial integrity, low S1P levels may contribute to capillary leakage, impaired tissue perfusion, and organ failure in sepsis.