Long-Term Venovenous Connection for Extracorporeal Carbon Dioxide Removal (ECCO2R)-Numerical Investigation of the Connection to the Common Iliac Veins.

PURPOSE: Currently used cannulae for extracorporeal carbon dioxide removal (ECCO2R) are associated with complications such as thrombosis and distal limb ischemia, especially for long-term use. We hypothesize that the risk of these complications is reducible by attaching hemodynamically optimized grafts to the patient's vessels. In this study, as a first step towards a long-term stable ECCO2R connection, we investigated the feasibility of a venovenous connection to the common iliac veins. To ensure its applicability, the drainage of reinfused blood (recirculation) and high wall shear stress (WSS) must be avoided. METHODS: A reference model was selected for computational fluid dynamics, on the basis of the analysis of imaging data. Initially, a sensitivity analysis regarding recirculation was conducted using as variables: blood flow, the distance of drainage and return to the iliocaval junction, as well as the diameter and position of the grafts. Subsequently, the connection was optimized regarding recirculation and the WSS was evaluated. We validated the simulations in a silicone model traversed by dyed fluid. RESULTS: The simulations were in good agreement with the validation measurements (mean deviation 1.64%). The recirculation ranged from 32.1 to 0%. The maximum WSS did not exceed 5.57 Pa. The position and diameter of the return graft show the highest influence on recirculation. A correlation was ascertained between recirculation and WSS. Overall, an inflow jet directed at a vessel wall entails not only high WSS, but also a flow separation and thereby an increased recirculation. Therefore, return grafts aligned to the vena cava are crucial. CONCLUSION: In conclusion, a connection without recirculation could be feasible and therefore provides a promising option for a long-term ECCO2R connection.

[Liquid biopsy in human non-small-cell lung cancer : Blood-based analysis of ctDNA methylation]. / Liquid Biopsy im nicht-kleinzelligen Lungenkarzinom : Die blutbasierte Analyse der ctDNA-Methylierung.

BACKGROUND: Use of liquid biopsy for minimal invasive follow-up diagnostics of non-small-cell lung carcinomas (NSCLCs). OBJECTIVES: Systematic search for new putative blood-based hypermethylation biomarkers to discriminate NSCLC patients from patients without a malign disease. METHODS: Quantitative analysis of gene promoter DNA methylation of potential biomarkers from cfDNA (plasma) with pyrosequencing. RESULTS: cfDNA hypermethylation in plasma confirmed significant higher methylation frequencies of the candidate gene CFTR of the NSCLC patients compared to the combined control groups and to NSCLC patients after curative therapy of primary NSCLC (post-NSCLC). ROC-analysis of the best discriminatory CpGs of the CFTR promotor (CpG1-2-4) revealed a sensitivity of 52% in NSCLC patients and a specificity of 90% in the post-NSCLC group (AUC: 0.69; p < 0.05). CONCLUSIONS: Promotor hypermethylation of the potential biomarker CFTR shows a discriminatory potential for differentiation of NSCLC patients to patients without a malign disease and should further be investigated.

Inflammatory response in transapical transaortic valve replacement.

OBJECTIVE: Transapical aortic valve implantation (TA-AVI) has become a fast growing alternative to conventional aortic valve replacement (cAVR) particularly for patients burdened with serious comorbidities. We investigated whether the inflammatory response triggered by TA-AVI reflects the less invasive nature of this procedure. METHOD: In this prospective observational study 25 patients undergoing aortic valve replacement (AVR; 15 cAVR and 10 TA-AVI) were included. Serial plasma cytokine concentrations (IL-6, IL-8, and IL-10) were measured by commercially available enzyme-linked immunosorbent assay kits at six different time points before, during, and after surgery. RESULTS: Plasma levels of all three cytokines increased during and after both procedures and returned to baseline before the patient's discharge. Peak values of IL-6 were 258 ± 113 pg/mL in AVR patients versus 111 ± 101 pg/mL in TA-AVI patients and were reached 12 hours after surgery. For IL-8, peak values were 51 ± 29 pg/mL 1 hour after surgery in AVR patients versus 15 ± 20 pg/mL on wound closure in TA-AVI patients. Plasma levels of IL-6 and IL-8 were significantly reduced in the TA-AVI group as compared with cAVR. IL-10 is markedly activated in both groups yet its induction is more prominent in AVR patients with peak values of 51 ± 28 pg/mL for AVR versus 24 ± 18 pg/mL for TA-AVI on wound closure. CONCLUSION: TA-AVI compared with cAVR results in a significant reduction but not elimination of a systemic inflammatory response, which is attributable to cardiopulmonary bypass-dependent and bypass-independent factors.

Influence of aortic dimensions on the hemodynamic performance of small aortic valve prostheses: impact on patient/prosthesis mismatch.

BACKGROUND: Since Doppler echocardiography takes no account of pressure recovery, the true hemodynamic burden of aortic valve prostheses remains vague. The purpose of this study was to elucidate the methodological error of Doppler gradient estimation by means of a model demonstrating the different influence of aortic root diameters on net and Doppler gradients, respectively. This matters especially in small valves and the related patient/prosthesis mismatch calculation. METHODS: Two bileaflet small aortic valve prostheses (19 mm SJM Regent® and On-X® valve) were tested using a pulsatile circulatory mock loop simulator with two different aortic models: one with statistically normal diameters according to annular size, another one simulating an aortic aneurysm of 50 mm. Doppler and simultaneously recorded net gradients as well as systolic energy losses were obtained for different hemodynamic conditions. RESULTS: In all measurements a significant amount of pressure recovery was observed. In cases of aortic aneurysm systolic energy loss increased significantly for each cardiac output at each heart rate ( P < 0.0028), reflected by a significant ( P < 0.0001) increase in net gradients. The corresponding Doppler gradients were unchanged. This indicates significantly less pressure recovery ( P < 0.0001) in the aneurysmatic aorta. CONCLUSIONS: Geometry of the ascending aorta considerably alters aortic valve hemodynamic parameters. The hemodynamic function of small aortic valve prostheses, especially with corresponding normal outflow dimensions, is much better than expected from Doppler gradients. Thus, calculation of a patient/prosthesis mismatch can be misleading.

Late bilateral diaphragmatic rupture: challenging diagnostic and surgical repair.

A 67-year-old man was referred to our department, after a vehicle accident, with multiple bone fractures and a left blunt diaphragmatic rupture. An emergency laparatomy was performed, and the left diaphragmatic defect directly sutured. Postoperatively, a delayed right diaphragmatic rupture occurred due to progressive inflammation and muscle devitalisation. The diagnosis was challenging because the right rupture became clinically evident later after extubation. Diaphragmatic reconstruction was performed through a right thoracotomy. A high index of suspicion should always be observed for missed or delayed bilateral diaphragmatic ruptures.

Tumor necrosis factor-alpha production in whole blood after cardiopulmonary bypass: downregulation caused by circulating cytokine-inhibitory activities.

OBJECTIVES: Cardiopulmonary bypass is associated with the release of proinflammatory cytokines (tumor necrosis factor alpha, interleukin 1beta, interleukin 6, and interleukin 8) and anti-inflammatory cytokines (interleukin 10 and transforming growth factor beta(1)). On the one hand this cytokine release is related to the postoperative systemic inflammatory response syndrome, and on the other hand it is related to deterioration of the immune system, for example in monocyte or polymorphonuclear neutrophil function, leading to an increased susceptibility to infections. To gain further insight into the alterations of immune cell reactivity and possible regulatory mechanisms, we studied lipopolysaccharide-induced tumor necrosis factor alpha synthesis in whole blood from cardiac surgical patients. METHODS: Fifteen patients undergoing elective heart surgery with cardiopulmonary bypass were included in the study. Ex vivo lipopolysaccharide-induced tumor necrosis factor alpha synthesis was measured in a whole blood assay before, during, and after bypass. Corresponding tumor necrosis factor alpha messenger RNA levels were determined by semiquantitative reverse transcriptase-polymerase chain reaction. In addition, the influence of patient serum on whole blood responsiveness and its relationship to anti-inflammatory cytokines were evaluated in vitro. RESULTS: Tumor necrosis factor alpha synthesis was significantly reduced after 30 minutes of cardiopulmonary bypass and showed the lowest values at the end of bypass (mean +/- SD 0.109 +/- 0.105 ng/10(6) white blood cells after 30 minutes of bypass and 0.050 +/- 0.065 ng/10(6) white blood cells at the end of bypass, vs 0.450 +/- 0.159 ng/10(6) white blood cells preoperatively, P <.001). As a further indication of reduced cytokine biosynthesis, diminished messenger RNA levels for tumor necrosis factor alpha were detected. Serum withdrawn from patients at the end of cardiopulmonary bypass reduced tumor necrosis factor alpha synthesis in heterologous blood from healthy volunteers highly significantly to 39.93% +/- 23.18% relative to control serum (P =.005) and preoperatively drawn serum (P =.024). This effect was dose dependent and was not specific for lipopolysaccharide-induced tumor necrosis factor alpha synthesis. Anesthesia and heparin administration did not influence tumor necrosis factor alpha production significantly. Ex vivo tumor necrosis factor alpha synthesis was negatively related to interleukin 10 serum levels, positively but weakly related to interleukin 4, and was not related to transforming growth factor beta(1) (Spearman correlation coefficients -0.565, P <.001, 0.362, P <.001, and -0.062, P =.460, respectively). However, interleukin 10 levels in patient serum after cardiopulmonary bypass were 300-fold below the quantities needed for half-maximal inhibition of tumor necrosis factor alpha synthesis in vitro. Moreover, the inhibitory activity could not be removed by immune absorption of interleukin 10. CONCLUSIONS: These results suggest that during cardiac operations cytokine-inhibitory serum activities are released or newly formed. These activities could not be explained by the actions of interleukins 4 and 10 or transforming growth factor beta(1). Although their exact nature remains undetermined, these substances may contribute to the diminished immune cell functions after cardiopulmonary bypass and thus need further characterization.

Lipopolysaccharide-binding protein (LBP) and markers of acute-phase response in patients with multiple organ dysfunction syndrome (MODS) following open heart surgery.

Cardiopulmonary bypass (CPB) is associated with an immunological injury that may cause pathophysiological alterations in the form of a systemic inflammatory response syndrome (SIRS) or a multiple organ dysfunction syndrome (MODS). Previous studies on this issue have reported different changes of immunological parameters during and after CPB, but there are no reports about the lipopolysaccharide-binding protein (LBP) in relationship to other markers of inflammation in patients with MODS following cardiovascular surgery. In the present study, we investigated the acute-phase response of patients with MODS of infectious and non-infectious origin following open-heart-surgery. Plasma levels of procalcitonin (PCT), c-reactive protein (CRP), interleukin-6 (IL-6), and LBP were measured in the first four postoperative days in 12 adult male patients with the signs of SIRS and two or more organ dysfunctions after myocardial revascularization (MODS-group), and 12 patients without organ insufficiencies (SIRS-group). There were no significant differences regarding age, weight, height, preoperative NYHA-classification, preoperative LVEDP, or the number of anastomosis. Patients with MODS had a significantly longer operation time, duration of ischemia, and duration of extracorporeal circulation. None of the patients in the SIRS group died, whereas in the MODS group, 4 patients died due to septic multiorgan failure. Plasma PCT and IL-6 concentrations were significantly elevated in all MODS patients. CRP and LBP showed no differences between the MODS and the SIRS group. Comparing the MODS patients with and without positive microbial findings, we found significantly elevated levels of PCT and LBP in those patients with documented infections. Our results indicate that LBP may be a new marker for the differentiation between a severe non-infectious SIRS and an ongoing bacterial sepsis in the early postoperative course following CPB, while a microbiological result is still missing.

Ischemic pre-conditioning of 5 minutes but not of 10 minutes improves lung function after warm ischemia in a canine model.

BACKGROUND: Protection from reperfusion injury by ischemic pre-conditioning (IPC) before prolonged ischemia has been proven for the heart and the liver. We now assess the efficacy of IPC to protect lungs from reperfusion injury. METHODS: Eighteen foxhounds (25 to 30 kg) were anesthetized, intubated, and ventilated with a fraction of inspired oxygen of 0.3 at a volume-controlled mode to maintain arterial pCO2 of 30 to 40 mm Hg. After left thoracotomy, we performed warm ischemia for 3 hours by clamping the left hilus, and followed with 8 hours of reperfusion (control, n = 6). In the treated groups, IPC was performed either for 5 minutes followed by 15-minute reperfusion (n = 6, IPC-5), or by 2 successive cycles of 10-minute ischemia, followed by 10-minute reperfusion (n = 6, IPC-10) before prior to the 3-hours warm-ischemia period. Pulmonary compliance and gas exchange were determined separately for each lung, and we recorded pulmonary and systemic hemodynamics. We performed bronchoalveolar lavage (BAL) at the end of the experiment and determined total protein concentration as well as tumor necrosis factor alpha (TNF-alpha) mRNA expression in cell-free supernatant and in BAL cells, respectively. We also assessed the wet/dry ratio of the lung. RESULTS: In the controls, on reperfusion, we encountered a progressive deterioration of gas exchange, especially of the reperfused left lung, which we could largely avoid using the IPC-5 protocol. Similarly, pulmonary compliance steadily declined but was much better in the ICP-5 group. Parallel to the improvement of gas exchange and lung mechanics, we found less total alveolar protein content and TNF-alpha mRNA expression in BAL cells in the IPC-5 than in the controls. However, we did not find IPC-10 to be paralleled by a significant improvement of lung function. Neither IPC-5 nor IPC-10 influenced the pulmonary vascular resistance index or the fluid accumulation in the lung. CONCLUSION: The major finding of the present study was that 5 minutes of IPC improved lung function after 3 hours of warm ischemia of the lung.