Christian Skrabal

Enhanced thoracic gene delivery by magnetic nanobead-mediated vector

Systemic gene delivery is limited by the adverse hydrodynamic conditions on the collection of gene carrier particles to the specific area. In the present study, a magnetic field was employed to guide magnetic nanobead (MNB)/polymer/DNA complexes after systemic administration to the left side of the mouse thorax in order to induce localized gene expression.

Minimizing cardiopulmonary bypass attenuates myocardial damage after cardiac surgery.

The standard heart-lung machine is deemed a major trigger of systemic inflammatory reactions, potentially inducing organ failure. The strict reduction of blood–artificial surface and blood-air contact might represent meaningful improvements of the extracorporeal technology with respect to organ preservation. In this study, we assessed perioperative myocardial damage by using a novel minimal extracorporeal circuit (MECC) and a conventional cardiopulmonary bypass (CPB) system. Sixty patients scheduled for coronary artery bypass surgery were randomly assigned to either the MECC or the standard CPB system. Myocardial markers were determined by specific immunoassays 6, 12, and 24 hours after CPB initiation. Results were corrected for hemodilution. Demographics, hemodynamics, the number of anastomoses, CPB, and cross-clamp time were comparable between the groups. MECC patients demonstrated significantly lower levels of Troponin T (ng/ml) at 6, 12, and 24 hours (0.07 ± 0.01 vs. 0.16 ± 0.04, p < 0.005; 0.12 ± 0.03 vs. 0.28 ± 0.08, p < 0.008; 0.21 ± 0.05 vs. 0.35 ± 0.09, p < 0.03, respectively) and creatine kinase-MB (U/l) at 6 and 12 hours (22.5 ± 1.5 vs. 40.6 ± 3.3, p < 0.0001; 23.3 ± 3.4 vs. 40.8 ± 8.0, p < 0.001, respectively). Creatine kinase-MB at 24 hours tended to lower values in the MECC group but did not quite reach statistical significance. The MECC system may not only provide a less invasive solution to meet the requirements during cardiac surgery but also a more organ-preserving alternative to standard CPB.

Endothelial NOS is required for SDF-1α/CXCR4-mediated peripheral endothelial adhesion of c-kit+ bone marrow stem cells

In the era of intravascular approaches for regenerative cell therapy, the underlying mechanisms of stem cell migration to non-marrow tissue have not been clarified. We hypothesized that next to a local inflammatory response implying adhesion molecule expression, endothelial nitric oxide synthase (eNOS)-dependent signaling is required for stromal- cell-derived factor-1 alpha (SDF-1α)-induced adhesion of c-kit+ cells to the vascular endothelium. SDF-1α/tumor necrosis factor-alpha (TNF-α)-induced c-kit+-cell shape change and migration capacity was studied in vitro using immunohistochemistry and Boyden chamber assays. In vivo interaction of c-kit+ cells from bone marrow with the endothelium in response to SDF-1α/TNF-α stimulation was visualized in the cremaster muscle microcirculation of wild-type (WT) and eNOS (−/−) mice using intravital fluorescence microscopy. In addition, NOS activity was inhibited with N-nitro-L-arginine-methylester-hydrochloride in WT mice. To reveal c-kit+-specific adhesion behavior, endogenous leukocytes (EL) and c-kit+ cells from peripheral blood served as control. Moreover, intercellular adhesion molecule-1 (ICAM-1) and CXCR4 were blocked systemically to determine their role in inflammation-related c-kit+-cell adhesion. In vitro, SDF-1α enhanced c-kit+-cell migration. In vivo, SDF-1α alone triggered endothelial rolling—not firm adherence—of c-kit+ cells in WT mice. While TNF-α alone had little effect on adhesion of c-kit+ cells, it induced maximum endothelial EL adherence. However, after combined treatment with SDF-1α+TNF-α, endothelial adhesion of c-kit+ cells increased independent of their origin, while EL adhesion was not further incremented. Systemic treatment with anti-ICAM-1 and anti-CXCR4-monoclonal antibody completely abolished endothelial c-kit+-cell adhesion. In N-nitro-L-arginine-methylester-hydrochloride-treated WT mice as well as in eNOS (−/−) mice, firm endothelial adhesion of c-kit+ cells was entirely abrogated, while EL adhesion was significantly increased. The chemokine SDF-1α mediates firm adhesion c-kit+ cells only in the presence of TNF-α stimulation via an ICAM-1- and CXCR4-dependent mechanism. The presence of eNOS appears to be a crucial and specific factor for firm c-kit+-cell adhesion to the vascular endothelium.

Pericardial suction blood separation attenuates inflammatory response and hemolysis after cardiopulmonary bypass

Objectives. Retransfusion of pericardial suction blood (PSB) is critically considered under the aspect of the biocompatibility of the cardiopulmonary bypass (CPB). We investigated various indicators of inflammation and blood cell activation associated with CPB and re-transfusion of PSB during cardiac surgery. Design. Thirty-five patients undergoing elective coronary artery bypass grafting were prospectively randomized into two groups. In group A (n = 15, retransfusion group) the pericardial suction blood was continuously retransfused during CPB, in group B (n = 20, no-retransfusion group) the suction blood was separated. Parameters indicating the status of the inflammation and blood cell activation were analyzed before and at the end of CPB, latest after 90 minutes on CPB. Results. Patients’ perioperative data did not differ between groups. The inflammatory markers C-reactive protein, PMN-Elastase and Interleukin-6 increased in both groups after CPB (p < 0.04) with significantly lower values in the no-retransfusion group (p < 0.02). Leukocytes and platelet activation markers β-Thromboglobulin and soluble P-Selectin also experienced a significant elevation during observation time (p < 0.02) without any difference between the groups. Free hemoglobin and LDH tremendously increased during CPB with lower values in the no-retransfusion group. Conclusions. Cardiotomy suction is a major cause of hemolysis and contributes significantly to the systemic inflammatory response.

Treatment of post-cardiopulmonary bypass SIRS by hemoadsorption: a case series.

The use of cardiopulmonary bypass (CPB) in cardiothoracic surgery results in a well-known activation of the immunologic response. In some cases, however, this triggered immunologic response may be excessive, leading to a severe systemic inflammatory response syndrome (SIRS) and induced organ dysfunction. For example, patients frequently develop hemodynamic instability with hypotension and low systemic vascular resistance. To date, different therapeutic approaches, such as steroids, have been tried to control this maladaptive postoperative SIRS response, yet definitive proof of clinical efficacy is missing. A new cytokine adsorber device (CytoSorb; CytoSorbents) may be a useful approach to control hyperinflammatory systemic reactions by reducing a broad range of proinflammatory cytokines and other inflammatory mediators. This may, in turn, help to reestablish a physiologic immune response and help to restore deranged clinical parameters in these patients. In this retrospective case series study, we describe 16 cardiac surgery patients following prolonged CPB with post-CPB SIRS and subsequent acute kidney injury, who were then treated with hemoadsorption using CytoSorb in combination with continuous renal replacement therapy (CRRT). Treatment of patients with CytoSorb who presented with severe post-CPB SIRS resulted in a reduction of elevated cytokine levels, which was associated with a clear stabilization of deranged hemodynamic, metabolic, and organ function parameters. Treatment was well tolerated and safe, with no device-related adverse events occurring. CytoSorb therapy combined with CRRT is a potentially promising new treatment approach to achieve hemodynamic stability, cytokine reduction, and improved organ function in cardiac surgery patients who develop post-CPB SIRS.

Effects of poly-2-methoxyethylacrylate (PMEA)-coating on CPB circuits.

Objectives. In this study, the immuno- and neuroprotective effect of a novel cardiopulmonary bypass coating was investigated. Design. Thirty nine patients scheduled for elective coronary artery bypass grafting were randomly assigned to either PMEA-coated (n = 19) or non-coated CPB circuits (n = 20). Pericardial suction blood was separated and retransfused only if needed at the end of operation. Neurocognitive functions were examined preoperatively and 7–10 days postoperatively using a standard neuropsychological test battery. Assuming an inflammatory etiology, the most cogent inflammatory markers were perioperatively analyzed. Results. Postoperatively, patients of the PMEA-coated group performed better in Go/NoGo and Mini-Mental-test than patients of the non-coated group (p < 0.04). Other neurocognitive testing did not reveal significant differences between the groups. Although most inflammatory parameters showed a significant intraindividual increase during or shortly after CPB, there was no difference in inflammatory alteration between the groups. Conclusions. PMEA-coating of cardiopulmonary bypass surfaces revealed some minor benefits in preservation of neurocognitive functions after surgery. The immediate inflammatory response remained mostly unaffected. Suction blood separation may additionally contribute to proper postoperative outcome.

Papillary fibroelastoma of the aortic wall with partial occlusion of the right coronary ostium.

Papillary fibroelastomas are the most common cardiac valve tumors, although they represent less than 10% of all cardiac tumors. These benign tumors are increasingly incidentally discovered as the result of the widespread use of echocardiography. After a definitive diagnosis has been made, surgical resection is strongly advocated due to the risk of cardioembolic complications. We present a very rare finding of an aortic wall papillary fibroelastoma with a resultant partial occlusion of the right coronary ostium.

Cytokine Reduction in the Setting of an ARDS-Associated Inflammatory Response with Multiple Organ Failure

A 45-year-old male was admitted to our hospital with a small bowel obstruction due to torsion and was immediately scheduled for surgical intervention. At anesthesia induction, the patient aspirated and subsequently developed a severe SIRS with ARDS and multiple organ failure requiring the use of ECMO, CRRT, antibiotics, and low dose steroids. Due to a rapid deterioration in clinical status and a concurrent surge in inflammatory biomarkers, an extracorporeal cytokine adsorber (CytoSorb) was added to the CRRT blood circuit. The combined treatment resulted in a rapid and significant reduction in the levels of circulating inflammatory mediators. This decrease was paralleled by marked clinical stabilization of the patient including a significant improvement in hemodynamic stability and a reduced need for norepinephrine and improved respiratory function as measured by PaO2/FIO2, ventilator parameters, lung mechanics, and indirect measures of capillary leak syndrome. The patient could be discharged to a respiratory weaning unit where successful respiratory weaning could be achieved later on. We attribute the clinical improvement to the rapid control of the hyperinflammatory response and the reduction of inflammatory mediators using a combination of CytoSorb and these other therapies. CytoSorb treatment was safe and well tolerated, with no device-related adverse effects observed.

Evaluation of coated oxygenators in cardiopulmonary bypass systems and their impact on neurocognitive function

Introduction: Coronary artery bypass graft surgery (CABG) using cardiopulmonary bypass (CPB) is assumed to be associated with a decline of neurocognitive functions. This study was designed to analyse the neurocognitive function of patients with coronary heart disease before and after CABG and to determine possible protective effects of oxygenator surface coating on neurological outcome. Methods: Forty patients scheduled for selective CABG were prospectively randomized into two groups of 20 patients each according to the type of hollow-fibre membrane oxygenator used. Non-coated oxygenators (Group A) were compared to phosphorylcholine (PC)- coated oxygenators (Group B). A battery of six neurological tests was administered preoperatively, 7 - 10 days and 4 - 6 months after surgery. Results: One patient of Group A suffered from a perioperative stroke and died on postoperative day 3, presumably because of sudden heart failure. Two patients of Group A (10%) developed a symptomatic transitory delirious psychotic syndrome (STPT) on postoperative days 3 and 5. None of the patients of Group B had perioperative complications. The test analysis revealed a trend of declined neurocognitive function early after CABG, but did not show any difference in neurocognitive outcome between the two groups. Discussion: PC coating of the oxygenators did not show any significant benefit on neurocognitive function after CABG using CPB.

Aortic valve endocarditis due to abiotrophia defectiva: a rare etiology.

ZusammenfassungAortenklappenendokarditis durch Abiotrophia defectiva ist ein seltene Ursache der bakteriellen Endokarditis. Diese Entität ist neben häufig negativen Blutkulturen durch eine schwierige Behandlung, hohe Rezidivraten und höhere Sterblichkeit als die Endokarditiden durch die anderen Viridans-Streptokokken gekennzeichnet. Wir präsentieren hier die medikamentöse und chirurgische Therapie einer Aortenklappenendokarditis durch Abiotrophia defectiva bei einem 19-Jahre alten Patienten. Dieser Fall ist nach unserer Kenntnis der erste Fall einer Aortenklappenendokarditis durch Abiotrophia defectiva bei einem Patienten mit Down Syndrom, der mit einem Aortenklappenersatz behandelt wurde.SummaryAbiotrophia defectiva is a rare cause of infective endocarditis. Besides an association with often negative blood cultures and difficult treatment, high rates of relapse and higher mortality than endocarditis caused by other viridans streptococci are known features of this entity. We report on the surgical and medical management of the aortic valve endocarditis caused by Abiotrophia defectiva in a 19-year-old patient. To the best of our knowledge, this is the first case of a patient to have Down syndrome and Abiotrophia defectiva endocarditis requiring aortic valve replacement.