Research Group Translational Critical Care Medicine

 

We are an interdisciplinary group of intensivists with a wide background of nephrology, gastroenterology/hepatology as well as pulmonary medicine focusing on Translational Critical Care Medicine. Our experimental focus lies on endothelial permeability, injury to the endothelial glycocalyx and microcirculatory dysfunction in critical illness.

As a clinical focus, we initiated several prospective studies that investigate novel treatment options for septic shock (EXCHANGE), ARDS (SPARE-14), non-occlusive mesenteric ischemia (REPERFUSE) and CAR-T-cell associated Cytokine relase syndrome (CYTORELEASE-Ex).

From a translational aspect, we investigate from „bedside to bench“ in patients included in these studies the effect of extracorporeal treatment approaches on endothelial permeability, glycocalyx and microcirculation.

   

Experimental Focus of Research

Our group is interested in molecular mechanisms regulating endothelial barrier function in response to inflammation. We have been focusing on the Angiopoietin (Angpt) / Tie ligand receptor system over the last ten years. Tie2 is a transmembrane receptor tyrosinekinase that is essential for embryonic vessel development. In mature organisms its function shifts toward maintenance of endothelial homeostasis and reaction to insults. Angpt-1 is the major circulating Tie2 agonist that promotes protective anti-permeability signals, whereas Angpt-2 has antagonistic properties. Our group was the first to proof in a murine knockout model that Angpt-2 directly contributes to sepsis morbidity and mortality.

Based on this finding we have conducted a series of experiments exploring potential therapeutic strategies (antibody, siRNA etc.) to eliminate or block the injurious Angpt-2 protein in sepsis models. We are also conducting drug repurposing screens to identify potential off-target Angpt-2 regulators (T. Pape).

Recently, we have gained much attention in the regulation of the Tie2 receptor expression per se and are currently working on the underlying mechanisms of posttranslational Tie2 modifications (T. Idowu).

MicroRNAs might be involved in Tie2 processing in disease as well so that we are studying the potential of MIRs in inflammatory diseases (V. Etzrodt).

We are also interested in the interaction between endothelial cells and pericytes – both with regard to Angiopoietin signaling and bioactive adrenomedullin (bioADM) (P. Gronski).

Another focus lies in the investigation of the endothelial glycocalyx both in vivo (SDF imaging) and in-vitro (endothelial microperfusion chip model). As injury of the endothelial glycocalyx can be found early in critical illness and substantially contributes to endothelial dysfunction we, together with the AG Haller, investigate regulation of glycocalyx degradation both in septic shock (U. Hillebrand) as well as severe COVID-19 (P. Gronski).

   

Clinical Focus of Research

A major interest of our clinical research is focused on questions regarding medical critical care mostly in the context of sepsis and septic shock. In a prospective non-randomized pilot study, we could demonstrate that early therapeutic plasma exchange (TPE) improves hemodynamics and endothelial permeability as well as reduced inflammatory cytokines in patients with severe septic shock (EXCHANGE Pilot, published). We are currently conducting a randomized controlled trial together with the University Hospital Bonn (Dr. Bode/Putensen) to analyze the role of TPE in early septic shock on hemodynamic stability (EXCHANGE I, NCT04231994). Funding for a German multicenter RCT with a clinically meaningful endpoint is under review at the DFG (EXCHANGE II).

In order to better understand sepsis and ARDS we are collecting human biomaterials (bronchoalveolar lavage and blood) and clinical characteristics of sepsis +/- ARDS patients. This Sepsis and ARDS Register (SPARE-14) will help to translate experimental findings of our basic research group from bench to bedside.

Support of non-intubated patients with both chronic and acute lung failure with extra-corporeal membrane oxygenation, termed Awake ECMO, is an innovative strategy that has been first established at Hannover medical school as it potentially completely avoids the multiple potential side effects of invasive ventilation. We continue to explore this strategy in selected patient cohorts such as patients with PcP associated ARDS. ECMO support in special patient cohorts, e.g. patients with diffuse alveolar hemorrhage, and conditions, e.g. heparin free ECMO, are further clinical interests of our group.

We are also conducting research on extracorporeal cytokine removal in patients treated with CAR-T cells suffering from severe cytokine release syndrome (CytoreleaseEx, NCT04048434). This project is financially supported by Cytosorbents.

We are currently running a prospective observational trial to analyze intra-arterial  prostaglandine infusion into the superior mesenteric artery in non-occlusive mesenteric ischemia (NOMI) patients (REPERFUSE, NCT04235634) . This project is conducted together with our Department of Interventional Radiology.

High volume TPE in acute liver failure has been shown to improve survival. We investigate more feasible low volume TPE strategies in both acute- and acute on chronic liver failure.

   

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