[Update on fast-track concepts in operative medicine : Improved outcome and higher patient satisfaction through interdisciplinary multimodal treatment concepts]. / Update zu "Fast-track"-Konzepten in der operativen Medizin : Verbessertes Outcome und höhere Patientenzufriedenheit durch interdisziplinäre, multimodale Behandlungskonzepte.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have been propagated in general surgery since the mid-1990s due to medical and health economic advantages for patients as well as hospitals. A comprehensive implementation in Germany is not yet established, although the demographic change requires more than ever concepts for the safe treatment of multimorbid frail patients. The aim of this review is to present modern ERAS concepts, to discuss an extension to prehabilitation measures for frail patients and to present aspects of structural feasibility. MATERIAL AND METHOD: A selective literature search in the PubMed database was performed and national as well as international guidelines up to the cut-off date of 1 July 2022 were considered. RESULTS: From an anesthesiological point of view, preoperative optimization, individual anesthesia management and postoperative analgesia are prioritized. The implementation of ERAS protocols requires a high degree of interdisciplinarity and needs in addition to medical know-how, appropriate information systems and structures. Modern ERAS concepts can reduce hospital costs and improve patient outcome. CONCLUSION: The implementation of ERAS protocols is beneficial for patients as well as economically and should be further promoted. In addition, the benefit of an extension of ERAS concepts, e.g. in older multimorbid patients, should be further scientifically analyzed.

Hypoxia briefly increases diuresis but reduces plasma volume by fluid redistribution in women.

We have recently reported that hypobaric hypoxia (HH) reduces plasma volume (PV) in men by decreasing total circulating plasma protein (TCPP). Here, we investigated whether this applies to women and whether an inflammatory response and/or endothelial glycocalyx shedding could facilitate the TCCP reduction. We further investigated whether acute HH induces a short-lived diuretic response that was overlooked in our recent study, where only 24-h urine volumes were evaluated. In a strictly controlled crossover protocol, 12 women underwent two 4-day sojourns in a hypobaric chamber: one in normoxia (NX) and one in HH equivalent to 3,500-m altitude. PV, urine output, TCPP, and markers for inflammation and glycocalyx shedding were repeatedly measured. Total body water (TBW) was determined pre- and postsojourns by deuterium dilution. PV was reduced after 12 h of HH and thereafter remained 230-330 mL lower than in NX (P < 0.0001). Urine flow was 45% higher in HH than in NX throughout the first 6 h (P = 0.01) but lower during the second half of the first day (P < 0.001). Twenty-four-hour urine volumes (P ≥ 0.37) and TBW (P ≥ 0.14) were not different between the sojourns. TCPP was lower in HH than in NX at the same time points as PV (P < 0.001), but inflammatory or glycocalyx shedding markers were not consistently increased. As in men, and despite initially increased diuresis, HH-induced PV contraction in women is driven by a loss of TCPP and ensuing fluid redistribution, rather than by fluid loss. The mechanism underlying the TCPP reduction remains unclear but does not seem to involve inflammation or glycocalyx shedding.NEW & NOTEWORTHY This study is the first to investigate the mechanisms underlying plasma volume (PV) contraction in response to hypoxia in women while strictly controlling for confounders. PV contraction in women has a similar time course and magnitude as in men and is driven by the same mechanism, namely, oncotically driven redistribution rather than loss of fluid. We further report that hypoxia facilitates an increase in diuresis, that is, however, short-lived and of little relevance for PV regulation.

Functional Testing for Tranexamic Acid Duration of Action Using Modified Viscoelastometry.

INTRODUCTION: Tranexamic acid (TXA) is the standard medication to prevent or treat hyperfibrinolysis. However, prolonged inhibition of lysis (so-called "fibrinolytic shutdown") correlates with increased mortality. A new viscoelastometric test enables bedside quantification of the antifibrinolytic activity of TXA using tissue plasminogen activator (TPA). MATERIALS AND METHODS: Twenty-five cardiac surgery patients were included in this prospective observational study. In vivo, the viscoelastometric TPA test was used to determine lysis time (LT) and maximum lysis (ML) over 96 h after TXA bolus. Additionally, plasma concentrations of TXA and plasminogen activator inhibitor 1 (PAI-1) were measured. Moreover, dose effect curves from the blood of healthy volunteers were performed in vitro. Data are presented as median (25-75th percentile). RESULTS: In vivo TXA plasma concentration correlated with LT (r = 0.55; p < 0.0001) and ML (r = 0.62; p < 0.0001) at all time points. Lysis was inhibited up to 96 h (LTTPA-test: baseline: 398 s [229-421 s] vs. at 96 h: 886 s [626-2,175 s]; p = 0.0013). After 24 h, some patients (n = 8) had normalized lysis, but others (n = 17) had strong lysis inhibition (ML <30%; p < 0.001). The high- and low-lysis groups differed regarding kidney function (cystatin C: 1.64 [1.42-2.02] vs. 1.28 [1.01-1.52] mg/L; p = 0.002) in a post hoc analysis. Of note, TXA plasma concentration after 24 h was significantly higher in patients with impaired renal function (9.70 [2.89-13.45] vs.1.41 [1.30-2.34] µg/mL; p < 0.0001). In vitro, TXA concentrations of 10 µg/mL effectively inhibited fibrinolysis in all blood samples. CONCLUSIONS: Determination of antifibrinolytic activity using the TPA test is feasible, and individual fibrinolytic capacity, e.g., in critically ill patients, can potentially be measured. This is of interest since TXA-induced lysis inhibition varies depending on kidney function.

Viscoelastometry for detecting oral anticoagulants.

BACKGROUND: Determination of anticoagulant therapy is of pronounced interest in emergency situations. However, routine tests do not provide sufficient insight. This study was performed to investigate the impact of anticoagulants on the results of viscoelastometric assays using the ClotPro device. METHODS: This prospective, observational study was conducted in patients receiving dabigatran, factor Xa (FXa)-inhibitors, phenprocoumon, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (local ethics committee approval number: 17-525-4). Healthy volunteers served as controls. Viscoelastometric assays were performed, including the extrinsic test (EX-test), intrinsic test (IN-test) Russel's viper venom test (RVV-test), ecarin test (ECA-test), and the tissue plasminogen activator test (TPA-test). RESULTS: 70 patients and 10 healthy volunteers were recruited. Clotting time in the EX-test (CTEX-test) was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon. CTIN-test was prolonged by dabigatran, FXa inhibitors and UFH. Dabigatran, FXa inhibitors and UFH significantly prolonged CTRVV-test in comparison with controls (median 200, 207 and 289 vs 63 s, respectively; all p < 0.0005). Only dabigatran elicited a significant increase in CTECA-test compared to controls (median 307 vs 73 s; p < 0.0001). CTECA-test correlated strongly with dabigatran plasma concentration (measured by anti-IIa activity; r = 0.9970; p < 0.0001) and provided 100% sensitivity and 100% specificity for detecting dabigatran. Plasma concentrations (anti-XA activity) of FXa inhibitors correlated with CTRVV-test (r = 0.7998; p < 0.0001), and CTRVV-test provided 83% sensitivity and 64% specificity for detecting FXa inhibitors. CONCLUSIONS: In emergency situations, ClotPro viscoelastometric assessment of whole-blood samples may help towards determining the presence and type of anticoagulant class that a patient is taking. TRIAL REGISTRATION: German clinical trials database ID: DRKS00015302 .

Real-time detection and differentiation of direct oral anticoagulants (rivaroxaban and dabigatran) using modified thromboelastometric reagents.

INTRODUCTION: Timely measurement of direct oral anticoagulants (DOACs) is challenging, though clinically important. We tested the hypotheses, that thromboelastometry is able to detect dabigatran and rivaroxaban and discriminates between dabigatran and rivaroxaban as representatives of the two groups of DOACs. METHODS AND MATERIALS: We conducted a prospective-observational study: In-vitro dose-effect-curves for rivaroxaban and dabigatran were performed (n = 10). Ex-vivo: Patients with indication of DOAC treatment (stroke; dabigatran/rivaroxaban) were included (n = 21). Blood samples were analyzed before first intake, at first estimated peak level and at 24 h after first but before following intake and 3 h after 24 h-intake. Standard and modified thromboelastometric-assays, using low tissue factor concentrations (TFTEM) or ecarin (ECATEM) were used. Receiver-operating-characteristics-curve-analysis (ROC), regression-analysis and two-way-ANOVA were performed. RESULTS: In-vitro: TFTEM detected dabigatran and rivaroxaban (ROC_AUC: 0.99; sensitivity/specificity: 100%/98%) but could not discriminate. Dabigatran prolongs CTECATEM whereas rivaroxaban did not. Clotting Time (CT)-ratio TFTEM/ECATEM discriminated highly sensitive (100%) and specific (100%) between dabigatran and rivaroxaban even at very low concentrations (ROC_AUC:1.0). CTECATEM correlated with dabigatran spiked concentrations (r = 0.9985; p < 0.001) and CTTFTEM (r = 0.9363; p = 0.006) with rivaroxaban. Similarly results could be demonstrated with patient data: We confirmed the performance for the differentiation of CT-ratio TFTEM/ECATEM (sensitivity 100%/specificity 100%) at any time after first intake of either DOAC. CONCLUSION: The thromboelastometric tests TFTEM and ECATEM detect and differentiate rivaroxaban and dabigatran. Further investigations evaluate the other DOACs and the differentiation to phenprocoumon. However, results need to be confirmed in a larger study, and especially cut off values for differentiation need to be calculated from a larger sample size.

Effects of balanced hydroxyethyl starch 6% (130/0.4) and albumin 5% on clot formation and glycocalyx shedding: Subgroup analysis of a prospective randomized trial.

BACKGROUND: Intravenous fluids can impair coagulation and affect the endothelial glycocalyx, whereas glycocalyx shedding itself can cause an impairment of clot formation and firmness. We hypothesized that hydroxyethyl starch 6% (130/0.4) has a more distinct effect on coagulation and glycocalyx shedding than albumin 5%. METHODS: Presented data derive from an exploratory subgroup analysis of a prospective randomized, single-blinded trial comparing albumin 5% versus balanced hydroxyethyl starch 6% (130/0.4). Patients between 46 and 85 years undergoing cystectomy were included. Prothrombin time, plasma fibrinogen concentration, partial thromboplastin time, thrombelastometry and platelet function were analyzed before and after surgery. Glycocalyx components were assessed before and after surgery, 2 to 4 h after surgery and at 1st and 3rd postoperative day. Primary outcome parameter was the change of thrombelastometric variables at the end of surgery. Further variables included calculated blood loss, infusion amount and transfusion rate. RESULTS: 55 patients (albumin group n = 28; hydroxyethyl starch group n = 27) were included. Thrombelastometric variables were significantly more compromised in the hydroxyethyl starch than in the albumin group whereas platelet function, glycocalyx shedding, partial thromboplastin time, prothrombin time and fibrinogen were not different between groups. Mean intraoperative calculated blood loss was higher in the hydroxyethyl starch group (1557 ±â€¯825 ml versus 1245 ±â€¯709 ml; p = 0.042). Transfusion requirements did not differ. CONCLUSION: Rotational thrombelastometric variables were significantly more reduced when hydroxyethyl starch was used compared to albumin 5%. This effect was independent from a shedding of the endothelial glycocalyx. However, results presented here are from a subgroup analysis and must be considered with caution. Trial registration EudraCT number 2010-018343-34.

Changes of hemodynamic and cerebral oxygenation after exercise in normobaric and hypobaric hypoxia: associations with acute mountain sickness.

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 (FiO2 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, rScO2), 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.

NFKB1 Promoter DNA from nt+402 to nt+99 Is Hypomethylated in Different Human Immune Cells.

Sepsis, with a persistently high 90-day mortality of about 46%, is the third most frequent cause of death in intensive care units worldwide. Further understanding of the inflammatory signaling pathways occurring in sepsis is important for new efficient treatment options. Key regulator of the inflammatory response is the transcription factor NFκB. As we have recently shown, the -94 Ins/Del NFKB1 promoter polymorphism influences sepsis mortality. However, a molecular explanation is still missing. Thus, promoter activity might be varying depending on the NFKB1 genotype, explaining the genotype dependent mortality from sepsis, and one likely mechanism is the degree of promoter methylation. Therefore, we tested the hypothesis that NFκB mRNA expression is regulated by promoter methylation in human cell lines and primary immune cell cultures. First, we examined the methylation of the NFKB1 promoter in U937, REH and HL-60 cells. In the promoter region of nt+99/+229 methylation in all analyzed cell lines was below 1%. Following incubation with bacterial cell wall components, no significant changes in the frequency of promoter methylation in U937 and REH cells were measured and the methylation frequency was under 1%. However, NFκB1 mRNA expression was two-fold increased in U937 cells after 24 h incubation with LPS. By contrast, demethylation by 5-Aza-2'-deoxycytidine incubation enhanced NFκB1 expression significantly. In addition, we analyzed NFKB1 promoter methylation in primary cells from healthy volunteers depending on the NFKB1-94 Ins/Del genotype. Methylation in the promoter region from nt+402 to nt+99 was below 1%. Genotype dependent differences occurred in neutrophil cells, where DD-genotype was significantly more methylated compared to II genotype at nt+284/+402. Besides in the promoter region from nt-227/-8 in ID-genotypes methylation of neutrophils was significantly decreased compared to lymphocytes and in II-genotypes methylation in neutrophils was significantly decreased compared to lymphocytes and monocytes. In addition, CHART-PCR showed that the hypomethylated promoter regions are highly accessible. Therefore we assume that the demethylated regions are very important for NFKB1 promoter activity.

Aquaporin 1 and 5 expression evoked by the ß2 adrenoreceptor agonist terbutaline and lipopolysaccharide in mice and in the human monocytic cell line THP-1 is differentially regulated.

Aquaporin 1 (AQP1) and AQP5 expression may impact on key mechanisms in sepsis. However, it is unclear whether these AQPs are expressed to an equal extent or regulated differentially. Accordingly, we investigated the time-dependent expression of AQP1 and AQP5 following stimulation with lipopolysaccharide (LPS) in cultured human THP-1 cells and in the lungs of mice injected with LPS. Furthermore, we tested the hypothesis that the ß2 adrenoreceptor agonist terbutaline or its downstream effector cyclic adenosine monophosphate (cAMP) mitigates LPS-evoked changes of AQP expression. THP-1 cells were stimulated with either LPS (1 µg/mL; serotype O127:B8), 8-Br-cAMP (1 mM), or both, and RNA and protein were extracted at baseline and after 2, 6, and 24 h. C57BL/6 mice that received LPS (20 mg/kg i.p.), terbutaline (2.5 mg/kg), or both were killed 8 h later, and lungs were excised for RNA extraction and lung wet weight determination. Real-time polymerase chain reaction and Western blot analysis show that LPS increased AQP1 (3 h, P < 0.0001) but not AQP5 mRNA and protein expression in THP-1 cells. cAMP increased AQP1 (6 h, P < 0.0001) but not AQP5 mRNA and protein expression. Incubation with both substances accelerated the increase in AQP1 (2 h, P = 0.001) expression, whereas AQP5 expression decreased after 2 h but increased after 24 h (P = 0.0148). In mice lungs, LPS decreased AQP1 (P = 0.0082) but not AQP5 mRNA expression and increased lung wet weight. Terbutaline increased AQP1 mRNA expression twice (P = 0.0005) but not AQP5 mRNA expression. Terbutaline did neither abolish the LPS-induced decrease in AQP1 and AQP5 expression nor increase lung weight. Thus, AQP1 and AQP5 expression is differentially regulated following exposure to LPS, the ß2 adrenoreceptor agonist terbutaline, and cAMP. Furthermore, neither terbutaline nor cAMP mitigated the LPS-evoked change of AQP1 and AQP5 expression.