Postoperative Delirium (POD) is the most common complication of elderly patients after surgery associated with increased postoperative morbidity, persistent care dependency and even mortality. ...Prevention of POD requires detection of patients at high risk prior to surgery. PROPDESC intends to provide an instrument for preoperative routine screening of patients' risk for POD.
PROPDESC is a monocentric prospective observatory trial including 1000 patients older than 60 years from various disciplines of a university hospital planned for surgery of at least 60 min. To develop a score predicting the risk for POD, anesthesiological stratifications, laboratory values, medication and known risk factors as well as quality of life and cognitive performance are taken into account. POD assessment is performed daily on the first five days after the operation respectively the end of sedation in the intensive care units and normal wards. The score is evaluated from 600 data sets and subsequently validated internally. The most appropriate predictors are determined by a component-wise gradient boosting approach.
Based on retrospective investigations, etiology of POD is considered multifactorial. By a prospective analysis of various factors, PROPDESC intends to provide an applicable tool to predict the risk for POD from preoperative routine data and assessment of cognitive function. Objective is to establish an automatically generating score in preoperative routine to screen patients for increased risk of POD as starting point for POD reduction and management. Model compilation requires a high significance and enhancement within compound as well as regular availability of the selected predictors.
DRKS, DRKS00015715. Registered 13 December 2018 - Retrospectively registered, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015715.
In transgenic animal models of sepsis, members of the Bcl-2 family of proteins regulate lymphocyte apoptosis and survival of sepsis. This study investigates the gene regulation of pro-apoptotic and ...anti-apoptotic members of the Bcl-2 family of proteins in patients with early stage severe sepsis.
In this prospective case-control study, patients were recruited from three intensive care units (ICUs) in a university hospital. Sixteen patients were enrolled when they fulfilled the criteria of severe sepsis. Ten critically ill but non-septic patients and 11 healthy volunteers served as controls. Blood samples were immediately obtained at inclusion. To confirm the presence of accelerated apoptosis in the patient groups, caspase-3 activation and phosphatidylserine externalisation in CD4+, CD8+ and CD19+ lymphocyte subsets were assessed using flow cytometry. Specific mRNAs of Bcl-2 family members were quantified from whole blood by real-time PCR. To test for statistical significance, Kruskal-Wallis testing with Dunn's multiple comparison test for post hoc analysis was performed.
In all lymphocyte populations caspase-3 (p < 0.05) was activated, which was reflected in an increased phosphatidylserine externalisation (p < 0.05). Accordingly, lymphocyte counts were decreased in early severe sepsis. In CD4+ T-cells (p < 0.05) and B-cells (p < 0.001) the Bcl-2 protein was decreased in severe sepsis. Gene expression of the BH3-only Bim was massively upregulated as compared with critically ill patients (p < 0.001) and 51.6-fold as compared with healthy controls (p < 0.05). Bid was increased 12.9-fold compared with critically ill patients (p < 0.001). In the group of mitochondrial apoptosis inducers, Bak was upregulated 5.6-fold, while the expression of Bax showed no significant variations. By contrast, the pro-survival members Bcl-2 and Bcl-xl were both downregulated in severe sepsis (p < 0.001 and p < 0.05, respectively).
In early severe sepsis a gene expression pattern with induction of the pro-apoptotic Bcl-2 family members Bim, Bid and Bak and a downregulation of the anti-apoptotic Bcl-2 and Bcl-xl proteins was observed in peripheral blood. This constellation may affect cellular susceptibility to apoptosis and complex immune dysfunction in sepsis.
Aim was to elucidate the specific role of pattern recognition receptors in vascular dysfunction during polymicrobial sepsis (colon ascendens stent peritonitis, CASP).
Vascular contractility of ...C57BL/6 (wildtype) mice and mice deficient for Toll-like receptor 2/4/9 (TLR2-D, TLR4-D, TLR9-D) or CD14 (CD14-D) was measured 18 h following CASP. mRNA expression of pro- (Tumor Necrosis Factor-α (TNFα), Interleukin (IL)-1β, IL-6) and anti-inflammatory cytokines (IL-10) and of vascular inducible NO-Synthase (iNOS) was determined using RT-qPCR. Wildtype mice exhibited a significant loss of vascular contractility after CASP. This was aggravated in TLR2-D mice, blunted in TLR4-D animals and abolished in TLR9-D and CD14-D animals. TNF-α expression was significantly up-regulated after CASP in wildtype and TLR2-D animals, but not in mice deficient for TLR4, -9 or CD14. iNOS was significantly up-regulated in TLR2-D animals only. TLR2-D animals showed significantly higher levels of TLR4, -9 and CD14. Application of H154-ODN, a TLR9 antagonist, attenuated CASP-induced cytokine release and vascular dysfunction in wildtype mice.
Within our model, CD14 and TLR9 play a decisive role for the development of vascular dysfunction and thus can be effectively antagonized using H154-ODN. TLR2-D animals are more prone to polymicrobial sepsis, presumably due to up-regulation of TLR4, 9 and CD14.
The molecular mechanisms that mediate gram-negative sepsis-associated myocardial dysfunction remain elusive. Myocardial expression of inflammatory mediators is Toll-like receptor 4 (TLR4) dependent. ...However, it remains to be elucidated whether TLR4, expressed on cardiac myocytes, mediates impairment of cardiac contractility after lipopolysaccharide (LPS) application. Cardiac myocyte contractility, measured as sarcomere shortening of isolated cardiac myocytes from C3H/HeJ (with nonfunctional TLR4) and C3H/HeN (control), were recorded at stimulation frequencies between 0.5 and 10 Hz and after incubation with 1 and 10 mug/mL LPS for up to 8 h. Control cells treated with LPS were investigated with and without a competitive LPS inhibitor (E5564) and a specific inducible nitric oxide synthase (iNOS) inhibitor S-methylisothiourea. In control mice, LPS reduced sarcomere shortening amplitude and prolonged duration of relaxation, whereas sarcomere shortening of C3H/HeJ cells was insensitive to LPS. NFkappaB and iNOS were upregulated after LPS application in control mice compared with C3H/HeJ. Inhibition of TLR4 by E5564 as well as inhibition of iNOS prevented the influence of LPS on contractile activity in control myocytes. LPS-dependent suppression of cardiac myocyte contractility was significantly blunted in C3H/HeJ mice. Competitive inhibition of functional TLR4 with E5564 protects cardiac myocyte contractility against LPS. These findings suggest that TLR4, expressed on cardiac myocytes, contributes to sepsis-induced myocardial dysfunction. E5564, currently under investigation in two clinical phase II trials, seems to be a new therapeutic option for the treatment of myocardial dysfunction in sepsis associated with endotoxemia.
Bacterial DNA containing motifs of unmethylated CpG dinucleotides (CpG-ODN) initiate an innate immune response mediated by the pattern recognition receptor Toll-like receptor 9 (TLR9). This leads in ...particular to the expression of proinflammatory mediators such as tumor necrosis factor (TNF-alpha) and interleukin-1beta (IL-1beta). TLR9 is expressed in human and murine pulmonary tissue and induction of proinflammatory mediators has been linked to the development of acute lung injury. Therefore, the hypothesis was tested whether CpG-ODN administration induces an inflammatory response in the lung via TLR9 in vivo.
Wild-type (WT) and TLR9-deficient (TLR9-D) mice received CpG-ODN intraperitoneally (1668-Thioat, 1 nmol/g BW) and were observed for up to 6 hrs. Lung tissue and plasma samples were taken and various inflammatory markers were measured.
In WT mice, CpG-ODN induced a strong activation of pulmonary NFkappaB as well as a significant increase in pulmonary TNF-alpha and IL-1beta mRNA/protein. In addition, cytokine serum levels were significantly elevated in WT mice. Increased pulmonary content of lung myeloperoxidase (MPO) was documented in WT mice following application of CpG-ODN. Bronchoalveolar lavage (BAL) revealed that CpG-ODN stimulation significantly increased total cell number as well as neutrophil count in WT animals. In contrast, the CpG-ODN-induced inflammatory response was abolished in TLR9-D mice.
This study suggests that bacterial CpG-ODN causes lung inflammation via TLR9.
Approximate entropy, a measure of signal complexity and regularity, quantifies electroencephalogram changes during anesthesia. With increasing doses of anesthetics, burst-suppression patterns occur. ...Because of the high-frequency bursts, spectrally based parameters such as median electroencephalogram frequency and spectral edge frequency 95 do not decrease, incorrectly suggesting lightening of anesthesia. The authors investigated whether the approximate entropy algorithm correctly classifies the occurrence of burst suppression as deepening of anesthesia.
Eleven female patients scheduled for elective major surgery were studied. After propofol induction, anesthesia was maintained with isoflurane only. Before surgery, the end-tidal isoflurane concentration was varied between 0.6 and 1.3 minimum alveolar concentration. The raw electroencephalogram was continuously recorded and sampled at 128 Hz. Approximate entropy, electroencephalogram median frequency, spectral edge frequency 95, burst-suppression ratio, and burst-compensated spectral edge frequency 95 were calculated offline from 8-s epochs. The relation between burst-suppression ratio and approximate entropy, electroencephalogram median frequency, spectral edge frequency 95, and burst-compensated spectral edge frequency 95 was analyzed using Pearson correlation coefficient.
Higher isoflurane concentrations were associated with higher burst-suppression ratios. Electroencephalogram median frequency (r = 0.34) and spectral edge frequency 95 (r = 0.29) increased, approximate entropy (r = -0.94) and burst-compensated spectral edge frequency 95 (r = -0.88) decreased with increasing burst-suppression ratio.
Electroencephalogram approximate entropy, but not electroencephalogram median frequency or spectral edge frequency 95 without burst compensation, correctly classifies the occurrence of burst-suppression pattern as increasing anesthetic drug effect.
Summary Background and purpose In experimental studies infusion of hypertonic saline during cardiopulmonary resuscitation (CPR) increased resuscitation success rate and improved myocardial and ...cerebral reperfusion during CPR. We tested the feasibility and the safety of this new therapeutic measure in a randomised, preclinical pilot study. Methods The study was performed in the EMS system of Bonn after approval of the local ethical committee. Study inclusion criteria were out-of-hospital cardiac arrest (CA) of non-traumatic origin, age ≥18 years, application of adrenaline (epinephrine) during CPR, duration of CA ≤ 15 min, and estimated body weight ≤125 kg. Patients randomly received 2 ml/kg/10 min HHS (7.2% NaCl with 6% hydroxy ethyl starch 200,000/0.5 HES) or HES alone. Haemoglobin, blood gases, plasma sodium and potassium concentrations were measured before and 10 min after infusion, and after admission to hospital. Feasibility and safety of the new fluid management was evaluated by looking for side effects and determination of resuscitation success and admission rates. Results Sixty-six patients were included. After infusion of HHS, plasma sodium concentration increased to 168 ± 29 mmol/l at 10 min after application but already decreased to near normal (147 ± 5.5 mmol/l) at admission to hospital. Patients receiving HHS showed a trend to higher resuscitation success and hospital admission rates (ROSC: HHS 66.7%, HES 51.5%, p = 0.21; admission: HHS 57.6%, HES 39.4%, p = 0.14). The benefit of HHS was more pronounced if duration of untreated CA was >6 min or if initial rhythm was asystole or pulseless electrical activity (PEA). Negative side-effects were not observed after HHS. Conclusions HHS after CA is feasible and safe and might improve short term survival after CPR. However, whether giving HHS could be a useful measure to increase resuscitation success after out-of-hospital CA requires a larger preclinical trial.
The prospective observational European multicentre cohort study (POPULAR) of postoperative pulmonary complications (NCT01865513) did not demonstrate that adherence to the recommended train-of-four ...ratio (TOFR) of 0.9 before extubation was associated with better pulmonary outcomes from the first postoperative day up to hospital discharge. We re-analysed the POPULAR data as to whether there existed a better threshold for TOFR recovery before extubation to reduce postoperative pulmonary complications in patients who had quantitative neuromuscular monitoring (87% acceleromyography).
To identify the optimal TOFR, the complete case cohort of patients with quantitative neuromuscular monitoring (n=3150) was split into several pairs of sub-cohorts related to TOFR values from 0.86 to 0.96; values of 0.97 and higher could not be used as the sub-cohorts were too small. The optimal TOFR was considered to have the lowest P-value from multivariate logistic regression calculated for each of the TOFR values. Data are presented as adjusted absolute risk reduction or median difference with 95% confidence interval.
Extubating patients with TOFR >0.95 rather than >0.9 reduced the adjusted risk of postoperative pulmonary complications by 3.5% (0.7–6.0%) from that reported in POPULAR (11.3%). Increasing the recommended TOFR from 0.9 to 0.95 reduced the adjusted risk by 4.9% (1.2–8.5%). Sub-cohorts resulting from 1:1 propensity score matching revealed that sugammadex had been given in higher doses by 0.30 (0.13–0.48) mg kg−1 in the sub-cohort with TOFR > 0.95.
A post hoc analysis of patients receiving quantitative monitoring of neuromuscular function suggests that postoperative pulmonary complications are reduced for TOFR > 0.95 before tracheal extubation compared with TOFR > 0.9.
NCT01865513.
We report the case of a 72-year-old woman with signs of pulmonary embolism and right heart failure. Echocardiographic imaging and computed tomography revealed a mass within the inferior vena cava ...reaching from the head of the pancreas to the right ventricle. From standard imaging procedures and clinical findings alone, differentiation of a cardiac thrombus from a metastatic tumor mass was difficult. After resection of the intravascular tumor, histopathologic analysis confirmed a metastasis of primary ductal pancreatic adenocarcinoma. This is a report of a case of mucinous adenocarcinoma of the pancreas reaching the heart by continuous intravascular spreading.
The Shannon entropy is a standard measure for the order state of sequences. It quantifies the degree of skew of the distribution of values. Increasing hypnotic drug concentrations increase ...electroencephalographic amplitude. The probability density function of the amplitude values broadens and flattens, thereby changing from a skew distribution towards equal distribution. We investigated the dose-response relation of the Shannon entropy of the electroencephalographic amplitude values during desflurane monoanesthesia in comparison with previously used electroencephalographic parameters.
Electroencephalographic records previously obtained in 12 female patients during gynecologic laparotomies were reanalyzed. Between opening and closure of the peritoneum, desflurane vapor settings were varied between 0.5 and 1.6 minimum alveolar concentration. Electroencephalographic Shannon entropy, approximate entropy, median electroencephalographic frequency, SEF 95, total power, log total power, and Bispectral Index were determined, and their correlations with the desflurane effect compartment concentration, obtained by simultaneous pharmacokinetic-pharmacodynamic modeling, were compared.
The electroencephalographic Shannon entropy increased continuously over the observed concentration range of desflurane. The correlation of the Shannon entropy (R2 = 0.84+/-0.08, mean +/- SD) with the desflurane effect compartment concentrations is similar to approximate entropy (R2 = 0.85+/-0.12), SEF 95 (R2 = 0.85+/-0.10), and Bispectral Index (R2 = 0.82+/-0.13) and is more statistically significant than median frequency (R2 = 0.72+/-0.17), total power (R2 = 0.67+/-0.18), and log total power (R2 = 0.80+/-0.09).
The Shannon entropy seems to be a useful electroencephalographic measure of anesthetic drug effect.
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