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Systemic diseases characterized by elevated levels of C-reactive protein (CRP), such as sepsis or systemic inflammatory response syndrome, are usually associated with hardly controllable haemodynamic instability. We therefore investigated whether CRP itself influences blood pressure and heart rate. Immediately after intravenous injection of purified human CRP (3.5 mg CRP/kg body weight) into anesthetized rabbits, blood pressure dropped critically in all animals, while control animals injected with bovine serum albumin showed no response. Heart rate did not change in either group. Approaching this impact on a cellular level, we investigated the effect of CRP in cell lines expressing adrenoceptors (CHO-α1A and DU-145). CRP caused a Ca(2+)signaling being dependent on the CRP dose. After complete activation of the adrenoceptors by agonists, CRP caused additional intracellular Ca(2+)mobilization. We assume that CRP interacts with hitherto unknown structures on the surface of vital cells and thus interferes with the desensitization of adrenoceptors.

Acute kidney injury (AKI) corrupts the outcome of about 50% of all critically ill patients. We investigated the possible contribution of the pathology acidemia on the development of AKI. Pigs were exposed to acidemia, acidemia plus hypoxemia or a normal acid-base balance in an experimental setup, which included mechanical ventilation and renal replacement therapy to facilitate biotrauma caused by extracorporeal therapies. Interestingly, extensive histomorphological changes like a tubular loss of cell barriers occurred in the kidneys after just 5 hours exposure to acidemia. The additional exposure to hypoxemia aggravated these findings. These 'early' microscopic pathologies opposed intra vitam data of kidney function. They did not mirror cellular or systemic patterns of proinflammatory molecules (like TNF-α or IL 18) nor were they detectable by new, sensitive markers of AKI like Neutrophil gelatinase-associated lipocalin. Instead, the data suggest that the increased renal proton excretion during acidemia could be an 'early' first hit in the multifactorial pathogenesis of AKI.

Habilitationsschrift, In der Intensivmedizin finden zunehmend verschiedene Aphereseverfahren Anwendung. Neben der Varianz der Membrantrennprozesse von nieder zu hochmolekularer Filtration kommt eine ausgeprägte Variation bei der Hämorheologie hinzu. Letztere wird durch das jeweilige Krankheitsbild sowie durch die begleitenden Therapieregime geprägt. Interessanterweise kommt es auch bei Patienten mit einer funktionell entgleisten Gerinnung und Blutungskomplikationen oftmals zu einer Blockade der Filterkapillaren. Die Paradoxität einer intra vitam ausbleibenden Gerinnung bei gleichzeitig hocheffektiver Gerinnung (Clotting) in biokompatiblen Filtern unter Heparinisierung wurde in dieser Arbeit aufgegriffen. Stufenweise aufeinander aufbauende in vitro und in vivo Studien zeigten, dass nicht die Gerinnung des Blutes in der Filterkapillaren zu einer Stase des Blutflusses führt. Vielmehr verursachen unzureichende Strömungsgeschwindigkeiten bei niedrigen Blutflußraten, gesteigerte Erythrozytenaggregation des Blutes und zu hohe Strömungswiderstände im blutrückführenden Schenkel des Gesamtsystems eine Stase des Blutes mit folgender Erythrozytensedimentation und unwiederbringlich blockierter Filterkapillare (Clogging). Unter Nutzung biokompatibler Polymermembranen mit hoher hydraulischer Kapazität ist eine nicht kontrollierbare Aktivierung des Gerinnungssystems eher die Konsequenz als die Ursache für Kapillarmembranfilter-Blockaden. Es konnte gezeigt werden, dass die Auswahl kolloidaler Infusionslösungen, welche die Erythrozytenaggregation reduzieren, bereits im Rahmen der Begleittherapie Ansätze zur Clogging- Prävention gegeben sind. Auch die Berücksichtigung von Katheterwiderständen im venösen Schenkel bieten eine wesentliche Option zur verbesserten Filterclearance und Standzeit. Insgesamt erscheint es wesentlich, Biokompatibilität und Systemclearance nicht auf Membranmaterial oder Antikoagulationsregime zu reduzieren. Vielmehr muß darauf geachtet werden, dass die Umstellung von Filtergrößen oder zwischen den verschiedenen Varianten der Membrantrennverfahren auch eine spezifisch ausgerichtete Adaptation der Einzelkomponenten eines Apheresesystems erfolgen muß., Applying extracorporeal systems in the critically ill patient is quite often associated with high risks such as nosocomial infections and bleeding complications. The filter modules (hemo- and plasma filters used for renal replacement therapies or extracorporeal detoxification) often tend towards a fast blockage. A decrease in sieving performance due to membrane fouling may be tolerable for quite some time. In contrast, the complete blockage of high percentages of hollow fibers, which is commonly assigned to membrane clotting , is a severe problem often requiring immediate exchange of the filter system. Extracorporeal detoxification and high clearance renal replacement regimes both require high blood flow and filtration rates. As a consequence, filter clotting and anticoagulation-associated bleedings are the most sensitive aspect in this topic. We were interested in the paradox phenomenon of intra vitam bleeding in the patients occurring in parallel to filter clotting. Therefore, we performed stepwise investigations based on in vitro and animal experiments. The results identified a stasis of blood flow followed by blood cell sedimentation and aggregation ( clogging ) as the main factor of hollow fiber blockage in hemo- and plasma filters. As a result, various aspects increasing the risk of stasis of blood flow inside the hollow fibers were investigated, i.e. hemorheology as provided by the patient s individual conditions, configuration of an extracorporeal treatment system including interaction of catheter features with the filtration procedure, and aspects arising from the basic treatment such as the colloidal volume substitutes. The final result was the formulation of an etiological triad for membrane clogging. This triad is giving hints for a first level prevention of membrane clogging instead of looking for interventional options with anticoagulation strategies.