Prognostic Value of Early S100 Calcium Binding Protein B and Neuron-Specific Enolase in Patients with Poor-Grade Aneurysmal Subarachnoid Hemorrhage: A Pilot Study.

BACKGROUND: This prospective study was undertaken to investigate the value of early S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE) in prognosticating outcome in patients with poor-grade aneurysmal subarachnoid hemorrhage and to develop a statistical model and cutoff values for clinical practice. METHODS: Between 2012 and 2014, patients with poor-grade subarachnoid hemorrhage (Hunt and Hess grade 3-5) who were admitted within 24 hours after hemorrhage were prospectively enrolled. Serum NSE and S100B levels were assayed once daily during the first 3 days after hemorrhage. Patient characteristics, Glasgow Coma Scale score, Hunt and Hess grade, and Fisher grade at admission were recorded. Glasgow Outcome Scale (GOS) score was obtained at 6 months and dichotomized as poor (score 1-3) or good (score 4-5). Logistic regression and receiver operating characteristic curve were used to assess the value of S100B and NSE in predicting outcome, and cutoff values were calculated using conditional interference trees. RESULTS: The study included 52 patients. Hunt and Hess grade was 3 in 23 patients, 4 in 15 patients, and 5 in 14 patients. S100B range was 0.07-5.62 µg/L (mean 0.87 µg/L ± 1.06). NSE range was 5.7-94.2 µg/L (mean 16.1 µg/L ± 10.5). At 6-month follow-up, 23 patients (44.2%) had a poor outcome, and 29 patients (55.8%) had a good outcome. Both S100B at day 1 (P = 0.004; cutoff 0.202 µg/L) and NSE at day 1 (P = 0.047; cutoff 9.4 µg/L) predicted good outcome with a specificity of 100%. The specificity of mean S100B in detecting patients with poor outcome reached 100% (P = 0.003) when combined with mean NSE levels. CONCLUSIONS: S100B and NSE measured during the first 3 days after hemorrhage showed, separately and combined, a significant predictive value in prognosticating clinical outcome in patients with poor-grade subarachnoid hemorrhage. A multicenter study with a large patient cohort is necessary to validate the above-mentioned cutoff values for clinical practice.

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.

Coronary angiography and intervention during hypothermia can be performed safely without cardiac arrhythmia or vasospasm.

PURPOSE: Mild therapeutic hypothermia is a neuroprotective procedure after cardiac arrest. Therefore, it is increasingly used. Likewise, there is a growing demand for coronary angiography and percutaneous coronary interventions under hypothermia. Case studies suggested that hypothermia may be associated with coronary vasospasm, heart rhythm events and platelet dysfunction. In this study, it was evaluated whether vasospasm, arrhythmia or bleeding occur to a relevant degree during cardiac catheterization under concomitant hypothermia. METHODS: In this prospective, single-center, open-label, non-interventional study, 29 patients after resuscitation for cardiac arrest were treated with mild hypothermia and underwent cardiac catheterization (coronary angiography n = 11, coronary angiography plus percutaneous intervention n = 18). The incidence of vasospasm, cardiac arrhythmia and relevant bleeding at the puncture site were evaluated. RESULTS: Mean temperature at cardiac catheterization was 33.9 ± 0.76°C. The mean heart rate was 82 ± 26 bpm at hospital admission and 67 ± 17 bpm under hypothermia (p < 0.05). There was no patient with relevant bradycardia beyond the expected hypothermia-induced rate reduction during the procedure. There were no unexpected ventricular tachycardias or episodes of ventricular fibrillation which might have been attributed to hypothermia. Twenty-nine of 29 patients (100%) were free from coronary vasospasm. There was no patient with a relevant bleeding at the puncture site. Potassium levels were low in 52% of the patients, even after resuscitation, which was partially attributed to hypothermia. CONCLUSION: Coronary angiography and percutaneous coronary interventions under mild therapeutic hypothermia were safe in this small cohort and were performed without hypothermia-induced vasospasm, relevant rhythm events or bleeding complications. This result has to be confirmed in a large series of patients.