Hans-Jörg Busch

Arteriogenesis in hypoperfused rat brain

Experimental and clinical studies have provided evidence for spontaneous and therapeutically induced arteriogenesis after occlusion of major peripheral or cardiac vessels. Such evidence is lacking for the cerebrovascular system. In halothane-anesthetized rats, different degrees of brain hypoperfusion were induced by one- to four-vessel occlusion, that is, one or both common carotid arteries in combination with or without bilateral vertebral artery occlusion. The flow decline was monitored by laser Doppler flowmetry, the residual hemodynamic reserve by testing flow reactivity to ventilation with 6% CO2 and arteriogenesis by intravascular latex infusion and immunohistochemistry of vascular proliferation and monocyte adhesion. The optimum condition for induction of arteriogenesis was three-vessel (one carotid plus both vertebral arteries) occlusion, which led to reduction of blood flow to about 50% and complete suppression of CO2 reactivity, but no histologic injury. One week after three-vessel occlusion, the ipsilateral posterior cerebral artery significantly enlarged by 39%, and after 3 weeks by 72%, paralleled by the partial return of CO2 reactivity and the appearance of immunohistochemical markers of arteriogenesis. Three-vessel occlusion is a reliable model for the induction of arteriogenesis in the adult brain and is a new approach for exploring the potentials of arteriogenesis for the prevention of progressing brain ischemia.

Severe endothelial injury and subsequent repair in patients after successful cardiopulmonary resuscitation

IntroductionIschemia and reperfusion after cardiopulmonary resuscitation (CPR) induce endothelial activation and systemic inflammatory response, resulting in post-resuscitation disease. In this study we analyzed direct markers of endothelial injury, circulating endothelial cells (CECs) and endothelial microparticles (EMPs), and endothelial progenitor cells (EPCs) as a marker of endothelial repair in patients after CPR.MethodsFirst we investigated endothelial injury in 40 patients after CPR, 30 controls with stable coronary artery disease (CAD), and 9 healthy subjects, who were included to measure CECs and EMPs. In a subsequent study, endothelial repair was assessed by EPC measurement in 15 CPR, 9 CAD, and 5 healthy subjects. Blood samples were drawn immediately and 24 hours after ROSC and analyzed by flow cytometry. For all statistical analyses P < 0.05 was considered significant.ResultsThere was a massive rise in CEC count in resuscitated patients compared to CAD (4,494.1 ± 1,246 versus 312.7 ± 41 cells/mL; P < 0.001) and healthy patients (47.5 ± 3.7 cells/mL; P < 0.0005). Patients after prolonged CPR (≥30 min) showed elevated CECs compared to those resuscitated for <30 min (6,216.6 ± 2,057 versus 2,340.9 ± 703.5 cells/mL; P = 0.13/ns). There was a significant positive correlation of CEC count with duration of CPR (R2= 0.84; P < 0.01). EMPs were higher immediately after CPR compared to controls (31.2 ± 5.8 versus 19.7 ± 2.4 events/μL; P = 0.12 (CAD); versus 15.0 ± 5.2 events/μL; P = 0.07 (healthy)) but did not reach significance until 24 hours after CPR (69.1 ± 12.4 versus 22.0 ± 3.0 events/μL; P < 0.005 (CAD); versus 15.4 ± 4.4 events/μL; P < 0.001 (healthy)). EPCs were significantly elevated in patients on the second day after CPR compared to CAD (1.16 ± 0.41 versus 0.02 ± 0.01% of lymphocytes; P < 0.005) and healthy (0.04 ± 0.01; P < 0.005).ConclusionsIn the present study we provide evidence for a severe endothelial damage after successful CPR. Our results point to an ongoing process of endothelial injury, paralleled by a subsequent endothelial regeneration 24 hours after resuscitation.

Induction of cerebral arteriogenesis leads to early-phase expression of protease inhibitors in growing collaterals of the brain

Cerebral arteriogenesis constitutes a promising therapeutic concept for cerebrovascular ischaemia; however, transcriptional profiles important for therapeutic target identification have not yet been investigated. This study aims at a comprehensive characterization of transcriptional and morphologic activation during early-phase collateral vessel growth in a rat model of adaptive cerebral arteriogenesis. Arteriogenesis was induced using a three-vessel occlusion (3-VO) rat model of nonischaemic cerebral hypoperfusion. Collateral tissue from growing posterior cerebral artery (PCA) and posterior communicating artery (Pcom) was selectively isolated avoiding contamination with adjacent tissue. We detected differential gene expression 24 h after 3-VO with 164 genes significantly deregulated. Expression patterns contained gene transcripts predominantly involved in proliferation, inflammation, and migration. By using scanning electron microscopy, morphologic activation of the PCA endothelium was detected. Furthermore, the PCA showed induced proliferation (PCNA staining) and CD68+ macrophage staining 24 h after 3-VO, resulting in a significant increase in diameter within 7 days after 3-VO, confirming the arteriogenic phenotype. Analysis of molecular annotations and networks associated with differentially expressed genes revealed that early-phase cerebral arteriogenesis is characterised by the expression of protease inhibitors. These results were confirmed by quantitative real-time reverse transcription-PCR, and in situ hybridisation localised the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and kininogen to collateral arteries, showing that TIMP-1 and kininogen might be molecular markers for early-phase cerebral arteriogenesis.

Circulating annexin V positive microparticles in patients after successful cardiopulmonary resuscitation

IntroductionIschemia/reperfusion after cardiopulmonary resuscitation (CPR) induces systemic inflammatory response and activation of endothelium and coagulation, resulting in a post-cardiac arrest syndrome. We analysed circulating (annexin V+) microparticles and their conjugates in resuscitated patients.Methods36 patients after successful resuscitation, 20 control patients with stable cardiac disease and 15 healthy subjects were included prospectively. Two blood samples were drawn, one immediately and one 24 hours after return of spontaneous circulation (ROSC) to detect (annexin V+) monocyte-derived microparticles (MMPs) or procoagulant (annexin V+) platelet-derived microparticles (PMPs) and conjugates of endothelial-derived (annexin V+) microparticles (EMPs) with monocytes (EMP-MC) or platelets (EMP-PC). Measurements were performed by flow cytometric analysis. Additionally, the effect of isolated microparticles on cultured endothelial cells was assessed by ELISA.ResultsMMPs were significantly elevated immediately after ROSC compared to the cardiological control group (control; p < 0.01) and healthy subjects (healthy; p < 0.05) and persisted to be elevated in the following 24 hours after CPR (p < 0.05 vs. control and healthy, respectively). Procoagulant PMPs increased within the first 24 hours after ROSC (p < 0.01 vs. control and p < 0.005 vs. healthy). Conjugates of EMP with monocytes and platelets were both significantly elevated immediately after CPR (EMP-MC: p < 0.05 vs. control and p < 0.05 vs. healthy; EMP-PC: p < 0.05 vs. control and p < 0.05 vs. healthy), while only EMP-MC showed persisting high levels within 24 hours after CPR (p < 0.05 vs. control and p < 0.01 vs. healthy). MMP levels of ≥1.0/μL 24 hours after CPR predicted adverse outcome at 20 days (p < 0.05). Furthermore, isolated microparticles circulating in CPR patients early after ROSC led to enhanced endothelial apoptosis ex vivo compared to those of the healthy controls (p < 0.005).ConclusionsResuscitated patients show substantially increased levels of different (annexin V+) microparticles and their conjugates immediately and 24 hours after cardiopulmonary resuscitation, suggesting an early onset of inflammation, an ongoing endothelial activation and a procoagulatory state. Additionally, microparticles of CPR patients may contribute to endothelial apoptosis. These results point to an involvement of microparticles in the development of the post-cardiac arrest syndrome.

Mac-1 directly binds to the endothelial protein C-receptor: a link between the protein C anticoagulant pathway and inflammation?

Objective The endothelial protein C-receptor (EPCR) is an endothelial transmembrane protein that binds protein C and activated protein C (APC) with equal affinity, thereby facilitating APC formation. APC has anticoagulant, antiapoptotic and antiinflammatory properties. Soluble EPCR, released by the endothelium, may bind activated neutrophils, thereby modulating cell adhesion. EPCR is therefore considered as a possible link between the anticoagulant properties of protein C and the inflammatory response of neutrophils. In the present study, we aimed to provide proof of concept for a direct binding of EPCR to the β2 –integrin Mac-1 on monocytic cells under static and physiological flow conditions. Measurements and Main Results Under static conditions, human monocytes bind soluble EPCR in a concentration dependent manner, as demonstrated by flow cytometry. Binding can be inhibited by specific antibodies (anti-EPCR and anti-Mac-1). Specific binding was confirmed by a static adhesion assay, where a transfected Mac-1 expressing CHO cell line (Mac-1+ cells) bound significantly more recombinant EPCR compared to Mac-1+ cells blocked by anti-Mac-1-antibody and native CHO cells. Under physiological flow conditions, monocyte binding to the endothelium could be significantly blocked by both, anti-EPCR and anti-Mac-1 antibodies in a dynamic adhesion assay at physiological flow conditions. Pre-treatment of endothelial cells with APC (drotrecogin alfa) diminished monocyte adhesion significantly in a comparable extent to anti-EPCR. Conclusions In the present study, we demonstrate a direct binding of Mac-1 on monocytes to the endothelial protein C receptor under static and flow conditions. This binding suggests a link between the protein C anticoagulant pathway and inflammation at the endothelium side, such as in acute vascular inflammation or septicaemia.

Endovaskuläre Kühlung oder Oberflächenkühlung

INTRODUCTION Time course, time necessary to achieve the target temperature and stable maintenance, as well as a controlled rewarming period are important factors influencing the outcome of patients after successful cardiopulmonary resuscitation. METHODS After successful cardiopulmonary resuscitation a total of 49 patients were cooled via an endovascular or external cooling device to a target temperature of 33 degrees C. Relevant cooling parameters, such as time between admission and initiation of cooling, achievement of target temperature and stable maintenance of cooling therapy, were compared between both groups. RESULTS In the endovascular cooling group the target temperature was reached significantly faster (154 +/- 97 min vs. 268 +/- 95 min, p = 0.0002) and showed stable and controlled maintenance of cooling therapy (deviation from target temperature: 0.189 +/- 0.23 degrees C vs 0.596 +/- 0.61 degrees C, p = 0.00006). The rewarming phase was better controlled and length of ICU stay was shorter in the group with endovascular cooling (8.8 +/- 3 vs. 12.9 +/- 6 days). CONCLUSION Endovascular cooling offers the possibility to reach the target temperature significantly faster and a stable maintenance of therapeutic hypothermia. It is capable of a more controlled rewarming period and shortens the length of ICU stay.

[Endovascular or surface cooling?: therapeutic hypothermia after cardiac arrest].

INTRODUCTION Time course, time necessary to achieve the target temperature and stable maintenance, as well as a controlled rewarming period are important factors influencing the outcome of patients after successful cardiopulmonary resuscitation. METHODS After successful cardiopulmonary resuscitation a total of 49 patients were cooled via an endovascular or external cooling device to a target temperature of 33 degrees C. Relevant cooling parameters, such as time between admission and initiation of cooling, achievement of target temperature and stable maintenance of cooling therapy, were compared between both groups. RESULTS In the endovascular cooling group the target temperature was reached significantly faster (154 +/- 97 min vs. 268 +/- 95 min, p = 0.0002) and showed stable and controlled maintenance of cooling therapy (deviation from target temperature: 0.189 +/- 0.23 degrees C vs 0.596 +/- 0.61 degrees C, p = 0.00006). The rewarming phase was better controlled and length of ICU stay was shorter in the group with endovascular cooling (8.8 +/- 3 vs. 12.9 +/- 6 days). CONCLUSION Endovascular cooling offers the possibility to reach the target temperature significantly faster and a stable maintenance of therapeutic hypothermia. It is capable of a more controlled rewarming period and shortens the length of ICU stay.

Klug-entscheiden-Empfehlungen in der internistischen Intensivmedizin

ZusammenfassungDie internistische Intensivmedizin ist ein wichtiger und integraler Bestandteil der Inneren Medizin. Die Intensivmedizin ermöglicht heutzutage das Überleben vieler Patienten mit schweren und lebensbedrohlichen internistischen Erkrankungen in akuten Krisensituationen. Entscheidend für den Therapieerfolg ist oft nicht die Anwendung besonders aufwendiger und kostspieliger Hochtechnologie, sondern die rasche Erkennung der führenden medizinischen Probleme, gekoppelt mit der raschen und kompetenten Anwendung von medizinischen Standardbehandlungen. Von zentraler Bedeutung ist ein personell angemessen ausgestattetes und gut organisiertes interprofessionelles Team. Bei der Anwendung der Standardtherapie hat sich zunehmend erwiesen, dass weniger oft mehr ist und schonende Therapieverfahren mit an die Pathophysiologie des kritisch Kranken angepassten Therapiezielen bessere Ergebnisse liefern können als aggressive Therapien mit zu hoch gesteckten Therapiezielen. Der erweiterte Vorstand der Deutschen Gesellschaft für Internistische Intensivmedizin und Notfallmedizin (DGIIN) hat in Anlehnung an die Choosing-Wisely-Empfehlungen der amerikanischen intensivmedizinischen Fachgesellschaften jeweils fünf Positiv- und Negativempfehlungen formuliert, in denen diese Prinzipien zum Ausdruck kommen sollen. Bei der hier vorgestellten Publikation handelt es sich um eine ergänzte und aktualisierte Version der ursprünglich im Deutschen Ärzteblatt veröffentlichten Empfehlungen. Bei der Anwendung der Empfehlungen ist zu berücksichtigen, dass Intensivpatienten sehr komplex sind und die Anwendung dieser Prinzipien immer individuell hinterfragt und ggf. an den einzelnen Patienten angepasst werden muss.AbstractIntensive care medicine is an important and integral part of internal medicine. Modern intensive care medicine permits survival of many patients with severe and life-threatening internal diseases in acute situations. Decisive for therapeutic success is often not the application of complicated and expensive medical technologies, but rather the rapid diagnosis and identification of core issues, with immediate and competent initiation of standard treatment regimens. An adequately staffed, well-organized interprofessional team is of central importance. With the application of standard therapies, it has been increasingly demonstrated that “less is more”, and that personalized treatment concepts are better than aggressive strategies with higher therapeutic goals. In accordance with the Choosing wisely recommendations of the American societies for intensive care medicine, the extended board of the Deutsche Gesellschaft für Internistische Intensivmedizin und Notfallmedizin (DGIIN) has formulated five positive and five negative recommendations reflecting these principles. The current paper is an updated version of the manuscript originally published in the Deutsches Ärzteblatt. When applying these recommendations, it is important to consider that intensive care patients are very complex; therefore, the applicability of these principles must be assessed on an individual basis and, where necessary, modified appropriately.

Strukturen der Akut- und Notfallmedizin

The timely medical treatment of the population in emergency situations is an enormous challenge for the healthcare system and is becoming increasingly more important. Due to this development clinical acute and emergency medicine has undergone enormous progress and is in the process of further professionalization. Various specialist societies and medical associations have published essential position papers in recent years and demanded fundamentally new healthcare structures and assignments. Additionally, emergency medical healthcare structures and centers have already been established on the initiative of individual emergency medical specialist disciplines. The future challenge is the nationwide establishment, grouping and integration of the structures and processes within definitive healthcare centers. The main objective of all involved must be the optimal care of emergency patients.ZusammenfassungDie zeitgerechte medizinische Versorgung der Bevölkerung in Notfallsituationen ist eine enorme Herausforderung des Gesundheitswesens und gewinnt zunehmend an Bedeutung. Durch diese Entwicklung hat sich die klinische Akut- und Notfallmedizin enorm weiterentwickelt und ist dabei, sich weiter zu professionalisieren. Verschiedene Fachgesellschaften und medizinische Vereinigungen haben in den letzten Jahren wesentliche Positionspapiere publiziert und grundlegend neue Versorgungsstrukturen und -aufträge gefordert. Daneben wurden durch die Initiative einzelner notfallmedizinischer Fachgebiete schon notfallmedizinische Versorgungsstrukturen und Zentren erfolgreich etabliert. Die Herausforderung der Zukunft ist die flächendeckende Etablierung, Bündelung und Integration dieser Strukturen und Prozessen innerhalb definitiver Versorgungszentren. Das zentrale Anliegen aller Beteiligten muss die optimale Versorgung von Notfallpatienten sein.AbstractThe timely medical treatment of the population in emergency situations is an enormous challenge for the healthcare system and is becoming increasingly more important. Due to this development clinical acute and emergency medicine has undergone enormous progress and is in the process of further professionalization. Various specialist societies and medical associations have published essential position papers in recent years and demanded fundamentally new healthcare structures and assignments. Additionally, emergency medical healthcare structures and centers have already been established on the initiative of individual emergency medical specialist disciplines. The future challenge is the nationwide establishment, grouping and integration of the structures and processes within definitive healthcare centers. The main objective of all involved must be the optimal care of emergency patients.

Einsatz unbemannter Drohnen zur Bereitstellung eines automatischen externen Defibrillators beim prähospitalen Herz-Kreislauf-Stillstand

Hintergrund. Einer der wichtigsten Faktoren für die Prognose des Patienten mit prähospitalem Herz-Kreislauf-Stillstand („out-of-hospital cardiac arrest“, OHCA) mit primär schockbarem Herzrhythmus ist die frühe Defibrillation. Unbemannte Luftfahrzeuge (Drohnen) können mit einem automatischen externen Defibrillator (AED) ausgerüstet und imFall eines OHCAdurchdenLeitstellendisponenten aktiviert und zum Standort des Anrufers entsandt werden. Dort kann der Ersthelfer den AED herausnehmen und anwenden. Ein solches Szenario hatten die Autoren mithilfe eines geographischen Modells im Vorfeld für das Umland von Stockholm berechnet. Sie konnten zeigen, dass dieses Vorgehen die Dauer bis zur Defibrillation in ländlichen Gebieten potenziell reduzieren könnte [2]. In der vorliegenden Studie wurde nun im Rahmen einer Simulation die Dauer bis zur Auslieferung des AED durch die Drohne gemessen. Methoden. Eine 8-Rotor-Drohne mit einem Gewicht von 5,7 kg und einer maximalen Geschwindigkeit von 75 km/h mit GPSund Autopilotsystem wurde mit einem 763 g schweren AED ausgerüstet. Die Drohne wurde in einer ländlichenGemeinde nahe Stockholm stationiert und im Rahmen einer Simulation innerhalb eines 10 km-Radius an Orte versandt, an denen sich zwischen den Jahren2006und2014einOHCAereignet hatte. Primärer Endpunkt war die Dauer vom Ausgang des AED bis zu dessen Ankunft am Zielort verglichen mit der historischen Auslieferungszeit des Rettungsdiensts („emergency medical service“; EMS) im jeweiligen realen Fall.