Hypertone Kochsalzlösungen in der Therapie des Schädel-Hirn-Traumas und des traumatisch hämorrhagischen Schocks - Systematische Übersichtsarbeit und Metaanalyse mit Trial Sequential Analysis

Fragestellung Hypertone Kochsalzlösungen und Mannitol werden in der intensivmedizinischen Therapie des Schädel-Hirn-Traumas verwendet. Die Überlegenheit einer der Substanzen konnte bisher nicht gezeigt werden. Die präklinische Infusion hypertoner Kochsalzlösungen kann bei Patienten mit einem Schädel-Hirn-Trauma zu einer verbesserten zerebralen Perfusion sowie bei Patienten im traumatisch hämorrhagischen Schock zur Wiederherstellung von Kreislauffunktionen und einer suffizienten Organperfusion beitragen. Diese theoretischen Vorteile konnten durch klinische Studien bisher nicht bestätigt werden. Es ist unklar, ob die Infusion hypertoner Kochsalzlösungen derzeitigen Standardtherapien überlegen ist. Um diese Fragestellung zu beantworten, wurden Metaanalysen zu den klinischen Fragestellungen „Hypertone Kochsalzlösungen versus Mannitol bei Schädel-Hirn-Trauma“, „Hypertone Kochsalzlösungen versus konventionelle Volumentherapie bei Schädel-Hirn-Trauma“ und „Hypertone Kochsalzlösungen versus konventionelle Volumentherapie bei traumatisch hämorrhagischem Schock“ durchgeführt. Methoden Vorliegende Arbeit zeigt Metaanalysen randomisierter kontrollierter Studien zur Effektivität und Sicherheit hypertoner Kochsalzlösungen versus Mannitol bzw. versus eine konventionelle Volumentherapie in der Therapie des Schädel-Hirn-Traumas oder traumatisch hämorrhagischen Schocks. Das Protokoll für die Literatursuche in den Datenbanken Medline, Embase und Central, die Qualitätsbewertung, die Endpunkte (Mortalität, neurologisches Langzeitoutcome, zerebrale Perfusionsparameter, hämodynamische, klinische, physiologische und laborchemische Parameter) sowie der statistische Auswerteplan samt einer Trial Sequential Analysis wurden prospektiv festgelegt und in der PROSPERO-Datenbank publiziert. In Ergänzung dazu wurden die Ergebnisse aller Metaanalysen unter Einschluss nichtrandomisierter kontrollierter Studien berichtet. Zur Analyse unerwünschter Wirkungen wurden zudem nichtkontrollierte Studien hinzugezogen. Ergebnisse Insgesamt wurden 126 Studien an 15 327 Patienten eingeschlossen. Im Vergleich hypertoner Kochsalzlösungen versus Mannitol bestand, trotz einer Tendenz zur Überlegenheit hypertoner Kochsalzlösungen, kein signifikanter Unterschied in der Mortalität (relatives Risiko [RR], 95 %-Konfidenzintervall 0,69 [0,45; 1,04]; p = 0,08). Ebenfalls bestand kein signifikanter Unterschied im neurologischen Outcome (RR 1,28 [0,86; 1,90]; p = 0,23). Während 30–60 min nach Therapie kein signifikanter Unterschied im intrakraniellen Druck bestand (Mittelwertsdifferenz [MD], 95 %-Konfidenzintervall -0,19 [-0,54; 0,17]; p = 0,30), war der intrakranielle Druck 90–120 min nach Therapie signifikant geringer nach hypertoner Kochsalzlösung verglichen mit Mannitol (-2,31 mmHg [-3,17; -1,50]; p < 0,00001). Der zerebrale Perfusionsdruck war nach hypertoner Kochsalzlösung signifikant höher als nach Mannitol-Therapie nach 30–60 min (MD 5,48 [4,84; 6,12]; p < 0,00001) und 90–120 min (9,08 [7,54; 10,62]; p < 0,00001). In der Rate der Therapieversagen bestand eine nicht signifikante Tendenz zur Überlegenheit von hypertoner Kochsalzlösung (RR 0,71 [0,51; 1,00]; p = 0,05). Es bestand kein Unterschied in der Dauer des täglich erhöhten intrakraniellen Drucks zwischen Therapie- und Kontrollgruppe (MD 0,41 [-4,52; 5,34]; p = 0,87). Im Vergleich hypertoner Kochsalzlösungen versus eine konventionelle Volumentherapie in der Therapie des Schädel-Hirn-Traumas bestand kein signifikanter Unterschied in Mortalität (RR 0,90 [0,78; 1,04]; p = 0,16) oder neurologischem Outcome (RR 0,97 [0,86; 1,10]; p = 0,65). Ebenso war die Dauer der maschinellen Beatmung nicht signifikant unterschiedlich (MD 0,02 [-1,25; -1,29]; p = 0,98). Die Katecholamintherapie war in der mit hypertoner Kochsalzlösung therapierten Gruppe signifikant kürzer (MD -1,00 [-1,88; -0,12]; p = 0,03). Es bestand kein signifikanter Unterschied im systolischen Blutdruck nach 30–60 min bzw. bei Krankenhausaufnahme nach präklinischer Therapie (MD -2,04 [-6,43; 2,36]; p = 0,36). Im Vergleich hypertoner Kochsalzlösungen versus eine konventionelle Volumentherapie in der Therapie des traumatisch hämorrhagischen Schocks bestanden keine signifikanten Unterschiede in der Langzeitmortalität (RR 0,94 [0,80; 1,11]; p = 0,47) oder der 24 h-Mortalität (RR 0,94 [0,75; 1,18]; p = 0,60). Die Beatmungsdauer war nicht signifikant unterschiedlich (MD 0,73 [-0,87; -2,33]; p = 0,37). Die Katecholamintherapie war in der mit hypertoner Kochsalzlösung therapierten Gruppe signifikant kürzer (MD -1,00 [-1,88; -0,12]; p = 0,03). Die Therapie mit hypertonen Kochsalzlösungen führte zu einem signifikant höheren systolischen Blutdruck nach 30–60 min bzw. bei Krankenhausaufnahme nach präklinischer Therapie (MD 6,22 [0,73; 11,71]; p = 0,03). Es bestand kein signifikanter Unterschied im Laktatwert bei Krankenhausaufnahme nach präklinischer Therapie (MD -0,25 [-1,14; 0,64]; p = 0,58) oder in der Inzidenz von Multiorganversagen (RR 0,52 [0,11; 2,51]; p = 0,41). In einer Trial Sequential Analysis zeigte sich für 4 von 6 primären Endpunkten, dass die Daten nicht ausreichen, um die Resultate mit der gewünschten statistischen Power von 80 % zu bestätigen. In den Vergleichen versus eine konventionelle Volumentherapie konnte in der Therapie des Schädel-Hirn-Traumas eine relative Risikoreduktion von -20 % für ein gutes neurologisches Outcome und in der Therapie des hämorrhagischen Schocks eine relative Risikoreduktion von 20 % für Langzeitmortalität mit der statistischen Power von 80 % ausgeschlossen werden. Kontrollierte Studien zu hypertonen Kochsalzlösungen bei Traumapatienten, die nicht die Einschlusskriterien der Metaanalysen erfüllten, wurden in einer deskriptiven Übersicht dargestellt. Unerwünschte Ereignisse waren selten und gleichmäßig auf die Therapiegruppen verteilt. Schlussfolgerung Es gibt Hinweise darauf, dass in der intensivmedizinischen Therapie erhöhten intrakraniellen Drucks durch ein Schädel-Hirn-Trauma hypertone Kochsalzlösungen Mannitol überlegen sein könnten. Ebenso zeigten sich, verglichen mit einer konventionellen Volumentherapie, Vorteile in klinischen und hämodynamischen Parametern durch – vor allem präklinisch applizierte – hypertone Kochsalzlösungen. Für belastbare Aussagen liegen jedoch nicht genügend Daten vor und weitere Studien sind daher notwendig. Vor allem bei der Kombination von Schädel-Hirn-Trauma und hämorrhagischem Schock wären günstige Effekte zu erwarten

The shift in the myocardial adenine nucleotide translocator isoform expression pattern is associated with an enteroviral infection in the absence of an active T-cell dependent immune response in human inflammatory heart disease

AbstractOBJECTIVESThis study evaluates the relevance of an enteroviral infection and the intramyocardial T-cell immune response for the alteration in the adenine nucleotide translocator isoform transcription pattern (ANTitp) in patients suspected of having myocardial inflammation.BACKGROUNDThe ANT, the only mitochondrial carrier for ADP and ATP, plays a significant role in the energy metabolism and is involved in the apoptosis process. Its function and expression were found to be altered in the myocardium of patients with dilated cardiomyopathy and myocarditis.METHODSThe ANTitp was analyzed in endomyocardial biopsies from 53 patients with clinically suspected inflammatory heart disease (csIHD). Enteroviral RNA was detected in the biopsies using the reverse transcripted polymerase chain reaction technique. The activation of the cellular immune system was assessed by the quantification of T-lymphocytes employing immunohistochemistry.RESULTSThe ANTitp was found to be altered in 21 csIHD patients. Enteroviral genome was found in the heart of 71.4% of these patients, but only 37.5% of the patients with a normal ANTitp were virus-positive (p < 0.02). The infiltration with CD3+, CD45R0+ and CD8+ T-cells was substantially lower in myocardial specimens with an altered ANTitp than in biopsies with a normal ANTitp. Combining the data, an altered ANTitp was primarily found in virus-positive heart tissue, which was less infiltrated with lymphocytes or not at all.CONCLUSIONSAn enteroviral infection is linked to changes in the ANT isoform expression in human heart tissue, which shows little or no evidence of an active T-cell dependent immune response. These results make a contribution to a better understanding of the pathophysiology of enterovirus-induced human inflammatory heart disease

A virtual reality paradigm to assess episodic memory: Validation-dataset for six parallel versions and a structured behavioral assessment

In the epilepsy monitoring unit of the Department of Neurology at the University Clinic of Salzburg 20 adult patients were recruited to participate in a validation of 6 parallel versions of the virtual reality test for episodic memory. Patients were tested up to 7 times, i.e. twice a day, in the morning and evening, beginning on Monday evening. Each session consisted of learning a new town and immediate recall for this town. All sessions but the first one included also delayed recall of the previously learned town and a recognition test. Recall included the sub-scales what, details, when, egocentric where and allocentric where. Recognition memory was tested by presenting the patients 30 sentences of which 15 were true and 15 were false. While not all patients completed the full testing schedule, at immediate recall for 9 patients a full data set (7 sessions) is available. All patients were free of antiepileptic medication (N = 19) or medication was kept constant across the week (N = 1). This data can be used to demonstrate the feasibility to use the virtual reality test in the epilepsy monitoring unit e.g. to monitor effects of seizures or medication on episodic memory.Yvonne Höller's research was funded by the Austrian Science Fund (FWF) : T 798-B27 and by the Research Fund of the Paracelsus Medical University : A-16/02/021-HÖL .Peer reviewe

Association of cytokines with endothelium dependent flow mediated vasodilation (FMD) of systemic arteries in patients with non-ischemic cardiomyopathy

<p>Abstract</p> <p>Background</p> <p>Aim of this study was to elucidate the relation between localised inflammatory heart disease and endothelial dysfunction in the peripheral circulation, considering circulating cytokines as a potential link.</p> <p>Methods</p> <p>In 38 patients with non-ischemic heart disease, myocardial biopsies were examined for myocardial inflammation (immunohistology) and virus persistence (PCR). Cytokines (sIL-4, IFN-g, IFN-b, IFN-a, sIL-12p7, TNF-a) were measured by ELISA in venous serum. Endothelial function of the radial artery was examined by ultrasound, measuring diameter changes in response to reactive hyperemia (FMD), compared to glyceroltrinitrate (GTN-MD). Patients with EF < 35% were excluded.</p> <p>Results</p> <p>Age 44 ± 14 years, 19 male, 19 female, EF 63.5[16]%. FMD 4.38 [4.82]%. 30 patients had myocardial inflammation (8 not), 23 virus persistence (15 not). FMD correlated significantly with sIL-12p7 (p = 0.024, r = -0.365), but not with other cytokines. sIL-12p7 levels were significantly higher in patients with severely impaired FMD (n = 17), compared with normal FMD (n = 21): 10.70 [10.72] vs. 4.33 [7.81] pg/ml (p = 0.002). Endothelium independent vasodilation (GTN-MD 23.67 [8.21]%) was not impaired.</p> <p>Conclusion</p> <p>Endothelial dysfunction of peripheral arteries in patients with non-ischemic cardiomyopathy is associated with elevated serum concentrations of sIL-12p7, but not of other cytokines. Circulating sIL-12p7 may partly explain, that endothelial dysfunction is not restricted to the coronary circulation, but involves systemic arteries.</p

Acute viral myocarditis

Acute myocarditis is one of the most challenging diagnosis in cardiology. At present, no diagnostic gold standard is generally accepted, due to the insensitivity of traditional diagnostic tests. This leads to the need for new diagnostic approaches, which resulted in the emergence of new molecular tests and a more detailed immunohistochemical analysis of endomyocardial biopsies. Recent findings using these new diagnostic tests resulted in increased interest in inflammatory cardiomyopathies and a better understanding of its pathophysiology, the recognition in overlap of virus-mediated damage, inflammation, and autoimmune dysregulation. Novel results also pointed towards a broader spectrum of viral genomes responsible for acute myocarditis, indicating a shift of enterovirus and adenovirus to parvovirus B19 and human herpes virus 6. The present review proposes a general diagnostic approach, focuses on the viral aetiology and associated autoimmune processes, and reviews treatment options for patients with acute viral myocarditis

Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

Background and purpose: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). Methods: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3&nbsp;years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Results: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0&nbsp;years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79–2.03), major bleeding 0.59 (0.40–0.88), myocardial infarction 0.68 (0.40–1.16), and all-cause death 0.86 (0.67–1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76–1.78), myocardial infarction 0.84 (0.48–1.46), major bleeding 0.98 (0.63–1.52) and all-cause death 1.01 (0.79–1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52–1.19), myocardial infarction 0.96 (0.63–1.45), major bleeding 1.54 (1.14–2.08), and all-cause death 0.97 (0.80–1.19). Conclusions: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013

Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation. the GLORIA-AF registry

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores &gt;2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores &gt;2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score &gt;2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores &gt;2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores &gt;2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007