Fatal pulmonary hemorrhage, pneumothorax and skin necrosis caused by IRIS to an Aspergillus flavus infection in a young patient with metamizole associated agranulocytosis.

We report the case of a young female with steroid-dependent ulcerative colitis (UC) who developed a complex systemic infection with Aspergillus flavus. This occurred following a UC relapse while vacationing in the Middle East, leading to extended use of metamizole and subsequent agranulocytosis. On her return to Germany, she was hospitalized for neutropenic sepsis and later transferred to our hospital due to persistent cytopenia and suspected Hemophagocytic Lymphohistiocytosis (HLH). Despite initial stabilization with targeted treatment for pulmonary Aspergillus flavus infection, her condition rapidly deteriorated following the onset of an Immune Reconstitution Inflammatory Syndrome (IRIS), which manifested as skin necrosis and pneumothorax after the replenishment of neutrophil granulocytes. The patient eventually died from an unmanageable pulmonary hemorrhage. Microscopy of skin necroses showed a massive presence of Aspergillus flavus, but tissue culture remained negative, suggesting effective antifungal treatment yet delayed phagocytosis due to agranulocytosis. This case underscores the need to consider IRIS in immunosuppressed patients who worsen despite aggressive and appropriately targeted treatment, highlighting its potential beyond the commonly recognized context in HIV-positive patients.

Prognostication of neurologic outcome using gray-white-matter-ratio in comatose patients after cardiac arrest.

BACKGROUND: This study aimed to assess the prognostic value regarding neurologic outcome of CT neuroimaging based Gray-White-Matter-Ratio measurement in patients after resuscitation from cardiac arrest. METHODS: We retrospectively evaluated CT neuroimaging studies of 91 comatose patients resuscitated from cardiac arrest and 46 non-comatose controls. We tested the diagnostic performance of Gray-White-Matter-Ratio compared with established morphologic signs of hypoxic-ischaemic brain injury, e. g. loss of distinction between gray and white matter, and laboratory parameters, i. e. neuron-specific enolase, for the prediction of poor neurologic outcomes after resuscitated cardiac arrest. Primary endpoint was neurologic function assessed with cerebral performance category score 30 days after the index event. RESULTS: Gray-White-Matter-Ratio showed encouraging interobserver variability (ICC 0.670 [95% CI: 0.592-0.741] compared to assessment of established morphologic signs of hypoxic-ischaemic brain injury (Fleiss kappa 0.389 [95% CI: 0.320-0.457]) in CT neuroimaging studies. It correlated with cerebral performance category score with lower Gray-White-Matter-Ratios associated with unfavourable neurologic outcomes. A cut-off of 1.17 derived from the control population predicted unfavourable neurologic outcomes in adult survivors of cardiac arrest with 100% specificity, 50.3% sensitivity, 100% positive predictive value, and 39.3% negative predictive value. Gray-White-Matter-Ratio prognostic power depended on the time interval between circulatory arrest and CT imaging, with increasing sensitivity the later the image acquisition was executed. CONCLUSIONS: A reduced Gray-White-Matter-Ratio is a highly specific prognostic marker of poor neurologic outcomes early after resuscitation from cardiac arrest. Sensitivity seems to be dependent on the time interval between circulatory arrest and image acquisition, with limited value within the first 12 h.

Percutaneous support of the failing left and right ventricle-recommendations for the use of mechanical device therapy.

Patients in cardiogenic shock and acute heart failure show high mortality and morbidity despite aggressive and invasive methods such as percutaneous coronary intervention and the use of mechanical support devices. Percutaneous implantation of active hemodynamic support is often the only option for hemodynamic stabilization of patients in cardiogenic shock. Therefore, current guidelines support the use of these devices. Standardized protocols and clinical algorithms for the use of these support devices decrease mortality in these patients. The aim of this review is an overview of current therapies of cardiogenic shock with special focus on mechanical support devices and the suggestion of a clinical algorithm for the differential use of current devices as well as the hemodynamic monitoring of such patients in order to reduce mortality in cardiogenic shock.

Increased Serum Levels of Fetal Tenascin-C Variants in Patients with Pulmonary Hypertension: Novel Biomarkers Reflecting Vascular Remodeling and Right Ventricular Dysfunction?

Pulmonary vascular remodeling is a pathophysiological feature that common to all classes of pulmonary hypertension (PH) and right ventricular dysfunction, which is the major prognosis-limiting factor. Vascular, as well as cardiac tissue remodeling are associated with a re-expression of fetal variants of cellular adhesion proteins, including tenascin-C (Tn-C). We analyzed circulating levels of the fetal Tn-C splicing variants B⁺ and C⁺ Tn-C in serum of PH patients to evaluate their potential as novel biomarkers reflecting vascular remodeling and right ventricular dysfunction. Serum concentrations of B⁺ and C⁺ Tn-C were determined in 80 PH patients and were compared to 40 healthy controls by enzyme-linked immunosorbent assay. Clinical, laboratory, echocardiographic, and functional data were correlated with Tn-C levels. Serum concentrations of both Tn-C variants were significantly elevated in patients with PH (p < 0.05). Significant correlations could be observed between Tn-C and echocardiographic parameters, including systolic pulmonary artery pressure (B⁺ Tn-C: r = 0.31, p < 0.001, C⁺ Tn-C: r = 0.26, p = 0.006) and right atrial area (B⁺ Tn-C: r = 0.46, p < 0.001, C⁺ Tn-C: r = 0.49, p < 0.001), and laboratory values like BNP (B⁺ Tn-C: r = 0.45, p < 0.001, C⁺ Tn-C: r = 0.42, p < 0.001). An inverse correlation was observed between Tn-C variants and 6-minute walk distance as a functional parameter (B⁺ Tn-C: r = -0.54, p < 0.001, C⁺ Tn-C: r = -0.43, p < 0.001). In a multivariate analysis, B⁺ Tn-C, but not C⁺ Tn-C, was found to be an independent predictor of pulmonary hypertension. Both fetal Tn-C variants may represent novel biomarkers that are capable of estimating both pulmonary vascular remodeling and right ventricular load. The potential beneficial impact of Tn-C variants for risk stratification in patients with PH needs further investigation.

Decreased regulatory T cells in vulnerable atherosclerotic lesions: imbalance between pro- and anti-inflammatory cells in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the arterial wall in which presentation of autoantigens by dendritic cells (DCs) leads to the activation of T cells. Anti-inflammatory cells like Tregs counterbalance inflammation in atherogenesis. In our study, human carotid plaque specimens were classified as stable (14) and unstable (15) according to established morphological criteria. Vessel specimens (n = 12) without any signs of atherosclerosis were used as controls. Immunohistochemical staining was performed to detect different types of DCs (S100, fascin, CD83, CD209, CD304, and CD123), proinflammatory T cells (CD3, CD4, CD8, and CD161), and anti-inflammatory Tregs (FoxP3). The following results were observed: in unstable lesions, significantly higher numbers of proinflammatory cells like DCs, T helper cells, cytotoxic T cells, and natural killer cells were detected compared to stable plaques. Additionally, there was a significantly higher expression of HLA-DR and more T cell activation (CD25, CD69) in unstable lesions. On the contrary, unstable lesions contained significantly lower numbers of Tregs. Furthermore, a significant inverse correlation between myeloid DCs and Tregs was shown. These data suggest an increased inflammatory state in vulnerable plaques resulting from an imbalance of the frequency of local pro- and anti-inflammatory immune cells.

Increased arginase levels contribute to impaired perfusion after cardiopulmonary resuscitation.

OBJECTIVES: The postcardiac arrest syndrome occurs after global hypoxia leading to microcirculatory impairment. Nitric oxide (NO) is a key molecule regulating microvascular function. The enzyme arginase has been suggested to modulate microvascular function by regulating NO metabolism. Therefore, we investigated whether arginase increases following global hypoxia and resuscitation and tested whether arginase inhibition influences altered microcirculation in resuscitated patients. METHODS: To determine the effect of global hypoxia on circulating arginase levels, fourteen healthy subjects were exposed to hypoxia in a normobaric hypoxia chamber (FiO² = 9·9%). In addition, 31 resuscitated patients were characterized clinically, and arginase 1 was measured on days 1 and 3. In eight resuscitated patients, a microcirculatory analysis was performed using a sidestream darkfield microcirculation camera. Perfused capillary density (PCD) was recorded before and after sublingual incubation of N-omega-hydroxy-nor-l-arginine (nor-NOHA) alone or together with the NOS inhibitor NG-monomethyl-l-arginine (l-NMMA). RESULTS: Circulating arginase 1 levels increased in healthy volunteers following global hypoxia in the hypoxic chamber (P < 0·01). In addition, arginase 1 levels were higher on day 1 (69·1 ± 83·3 ng/mL) and on day 3 (44·2 ± 65·6 ng/mL) after resuscitation than in control subjects (P < 0·001). Incubation of the sublingual mucosa with nor-NOHA increased microcirculatory perfusion (P < 0·001). This effect was inhibited by co-incubation with K-NMMA. CONCLUSIONS: Circulating arginase 1 levels are increased following exposure to global hypoxia and in patients who have been successfully resuscitated after cardiac arrest. Topical arginase inhibition improves microcirculatory perfusion following resuscitation. This is of potential therapeutic importance for the postcardiac arrest syndrome.

Serum levels of tenascin-C variants in congestive heart failure patients: comparative analysis of ischemic, dilated, and hypertensive cardiomyopathy.

BACKGROUND: Tissue remodelling in ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), and hypertensive heart disease (HHD) is accompanied by the re-occurrence of fetal tenascin-C (Tn-C) variants. The study was aimed to comparatively analyze the serum levels of Tn-C containing the FNIIIB (B+ Tn-C) or FNIIIC (C+ Tn-C) domain in heart failure patients due to ICM, DCM, and HHD. METHODS: 119 male patients with congestive heart failure (45 with ICM, 43 with DCM, 31 with HHD) were included. Measurement of serum levels of B+ and C+ Tn-C was performed using Enzyme Linked Immunosorbent Assay (ELISA). Results were correlated to clinical, laboratory, echocardiographic, and spiroergometric parameters. RESULTS: Analysis of Tn-C concentrations according to heart failure etiology revealed no significant differences. There was an association of C+ Tn-C serum levels to enlargement of the left atrium in DCM (p < 0.01) and the left ventricle in HHD (p < 0.05). In patients with ICM, C+ Tn-C showed a strong negative correlation to the stress test performance (p = 0.002, R2: -0.691). Most strikingly, there was a strong correlation between BNP and B+ Tn-C (p = 0.038, R2: 0.466) as well as C+ Tn-C (p = 0.001, R2: 0.814) in DCM patients. CONCLUSIONS: The present study highlights the impact of Tn-C variants as biomarkers reflecting the extent of cardiac remodeling in heart failure patients. Furthermore, B+ Tn-C can be suggested as an additional tool to estimate ICM performance in patients. Especially in combination with BNP, analysis of Tn-C might pave the way for a more precise evaluation of heart failure patients.

The Jena Method: Perfusionist Independent, Standby Wet-Primed Extracorporeal Membrane Oxygenation (ECMO) Circuit for Immediate Catheterization Laboratory and/or Hybrid Operating Room Deployment.

Background: The timely initiation of extracorporeal membrane oxygenation (ECMO) is crucial for providing life support. However, delays can occur when perfusionists are not readily available. The Jena Method aims to address this issue by offering a wet-primed ECMO system that can be rapidly established without the perfusionist's presence. Methods: The goal was to ensure prompt ECMO initiation while maintaining patient safety. The method focuses on meeting hygienic standards, safe primed storage of the circuit, staff training, and providing clear step-by-step instructions for the ECMO unit. Results: Since implementing the Jena Method in 2015, 306 patients received VA-ECMO treatment. Bacterial tests confirmed the sterility of the primed ECMO circuits during a 14-day period. The functionality of all the components of the primed ECMO circuit after 14 days, especially the pump and oxygenator, were thoroughly checked and no malfunction was found to this day. To train staff for independent ECMO initiation, a step-by-step system involves safely bringing the ECMO unit to the intervention site and establishing all connections. This includes powering up, managing recirculation, de-airing the system, and preparing it for cannula connection. A self-developed picture-based guide assists in this process. New staff members learn from colleagues and receive quarterly training sessions by perfusionists. After ECMO deployment, the perfusionist provides a new primed system for a potential next patient. Conclusions: Establishing a permanently wet-primed on-demand extracorporeal life support circuit without direct perfusionist support is feasible and safe. The Jena Method enables rapid ECMO deployment and has the potential to be adopted in emergency departments as well.

Effect of Hemolysis Regarding the Characterization and Prognostic Relevance of Neuron Specific Enolase (NSE) after Cardiopulmonary Resuscitation with Extracorporeal Circulation (eCPR).

BACKGROUND: Hemolysis, a common adverse event associated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO), may affect neuron-specific enolase (NSE) levels and potentially confound its prognostic value in predicting neurological outcomes in resuscitated patients without return of spontaneous circulation (ROSC) that require extracorporeal cardiopulmonary resuscitation (eCPR). Therefore, a better understanding of the relationship between hemolysis and NSE levels could help to improve the accuracy of NSE as a prognostic marker in this patient population. METHODS: We retrospectively analyzed the records of patients who received a VA-ECMO for eCPR between 2004 and 2021 and were treated in the medical intensive care unit (ICU) of the University Hospital Jena. The outcome was measured clinically by using the Cerebral Performance Category Scale (CPC) four weeks after eCPR. The serum concentration of NSE (baseline until 96 h) was analyzed by enzyme-linked immunosorbent assay (ELISA). To evaluate the ability of individual NSE measurements to discriminate, receiver operating characteristic (ROC) curves were calculated. Serum-free hemoglobin (fHb, baseline until 96 h) served as a marker for identifying a confounding effect of parallel hemolysis. RESULTS: 190 patients were included in our study. A total of 86.8% died within 4 weeks after ICU admission or remained unconscious (CPC 3-5), and 13.2% survived with a residual mild to moderate neurological deficit (CPC 1-2). Starting 24h after CPR, NSE was significantly lower and continued to decrease in patients with CPC 1-2 compared to the group with an unfavorable outcome of CPC 3-5. In addition, when evaluating on the basis of receiver operating characteristic curves (ROC), relevant and stable area under the curve (AUC) values for NSE could be calculated (48 h: 0.85 // 72 h: 0.84 // 96 h: 0.80; p < 0.01), and on the basis of a binary logistic regression model, relevant odds ratios for the NSE values were found even after adjusting for fHb regarding the prediction of an unfavorable outcome of CPC 3-5. The respective adjusted AUCs of the combined predictive probabilities were significant (48 h: 0.79 // 72 h: 0.76 // 96 h: 0.72; p ≤ 0.05). CONCLUSIONS: Our study confirms NSE as a reliable prognostic marker for poor neurological outcomes in resuscitated patients receiving VA-ECMO therapy. Furthermore, our results demonstrate that potential hemolysis during VA-ECMO does not significantly impact NSE's prognostic value. These findings are crucial for clinical decision making and prognostic assessment in this patient population.

Impact of a VA-ECMO in Combination with an Extracorporeal Cytokine Hemadsorption System in Critically Ill Patients with Cardiogenic Shock-Design and Rationale of the ECMOsorb Trial.

BACKGROUND: Cardiogenic shock and arrest present as critical, life-threatening emergencies characterized by severely compromised tissue perfusion and inadequate oxygen supply. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) serves as a mechanical support system for patients suffering shock refractory to conventional resuscitation. Despite the utilization of VA-ECMO, clinical deterioration due to systemic inflammatory response syndrome (SIRS) resulting from the underlying shock and exposure of blood cells to the artificial surfaces of the ECMO circuit may occur. To address this issue, cytokine adsorbers offer a valuable solution by eliminating blood proteins, thereby controlling SIRS and potentially improving hemodynamics. Consequently, a prospective, randomized, blinded clinical trial will be carried out with ECMOsorb. METHODS AND STUDY DESIGN: ECMOsorb is a single-center, controlled, randomized, triple-blinded trial that will compare the hemodynamic effects of treatment with a VA-ECMO in combination with a cytokine adsorber (CytoSorb®, intervention) to treatment with VA-ECMO only (control) in patients with cardiogenic shock (with or without prior cardiopulmonary resuscitation (CPR)) requiring extracorporeal, hemodynamic support. Fifty-four patients will be randomized in a 1:1 fashion to the intervention or control group over a 36-month period. The primary endpoint of ECMOsorb is the improvement of the Inotropic Score (IS) 72 h after the intervention. Prognostic indicators, including mortality rates, hemodynamic parameters, laboratory findings, echocardiographic assessments, quality of life measurements, and clinical parameters, will serve as secondary outcome measures. The safety evaluation encompasses endpoints such as air embolisms, allergic reactions, peripheral ischemic complications, vascular complications, bleeding incidents, and stroke occurrences. CONCLUSIONS: The ECMOsorb trial seeks to assess the efficacy of a cytokine adsorber (CytoSorb®; CytoSorbents Europe GmbH, Berlin, Germany) in reducing SIRS and improving hemodynamics in patients with cardiogenic shock who are receiving VA-ECMO. We hypothesize that a reduction in cytokine levels can lead to faster weaning from inotropic and mechanical circulatory support, and ultimately to improved recovery.

Recruitment of circulating dendritic cell precursors into the infarcted myocardium and pro-inflammatory response in acute myocardial infarction.

DC (dendritic cells) play an important role in the immune system. They invade peripheral tissues to detect harmful antigens, inducing a local immune response. Studies suggest that DCPs (dendritic cell precursors) might be reduced in AMI (acute myocardial infarction); however, the reason for their reduction is unknown yet. In the present study, circulating mDCPs (myeloid DCPs), pDCPs (plasmacytoid DCPs), tDCPs (total DCPs) and serum levels of TNFα (tumour necrosis factor α), IL (interleukin)-2, -4, -5, -6, -10 and -12 were analysed by flow cytometry in blood of patients with NSTEMI [non-STEMI (ST-segment elevation myocardial infarction)] (n=44) and STEMI (n=34) compared with controls with excluded CAD (coronary artery disease) (n=45). Post-mortem myocardial specimens of patients with AMI (n=12) and healthy myocardium of accident victims (n=10) were immunostained for mDCs (myeloid dendritic cells) T-cells and macrophages. Compared with controls, in patients with AMI a significant decrease in circulating mDCPs, pDCPs and tDCPs was observed (each P<0.0001). The extent of the decrease was higher in STEMI than NSTEMI patients. Serum levels were significantly higher in patients with AMI compared with controls for IL-6, -10, -12 and TNFα (each P<0.03). Immunostaining revealed significantly higher number of DCs, T-cells and macrophages (each P<0.002) in infarcted than control myocardium. We show that circulating DCPs are significantly reduced in AMI, with a pronounced reduction in STEMI patients. This was accompanied by a significant increase of inflammatory serum cytokines in patients with AMI. Immunohistochemical analysis unravelled that the reduction of circulating DCPs might be due to recruitment into the infarcted myocardium.

Testosterone deficiency in male heart failure patients and its effect on endothelial progenitor cells.

BACKGROUND: Endothelial progenitor cells (EPCs) are thought to contribute to reendothelialization and neoangiogenesis. Since it is known that EPCs express a testosterone receptor, we wanted to assess the prevalence of testosterone deficiency in patients with CHF and its impact on circulating EPCs. METHODS: 137 male patients with chronic heart failure (CHF) were included (age 61 ± 13 years; BMI 29 ± 5 kg/m(2); New York Heart Association classification (NYHA) I: n = 47, NYHA II: n = 51, NYHA III: n = 39). Numbers of different populations of circulating EPCs were quantified using flow cytometry. Levels of free testosterone and EPC-regulating cytokines were determined using ELISA. RESULTS: The prevalence of testosterone deficiency in our University CHF clinic was 39%. However, there was no difference between patients with and without testosterone deficiency regarding their levels of EPCs. Testosterone levels were inversely correlated with age (R(2) = -0.32, p = 0.001) and NYHA status (R(2) = 0.28, p = 0.001) and correlated with cardiorespiratory capacity (R(2) = 0.26, p = 0.03). CONCLUSION: Testosterone deficiency is frequent in male patients with CHF but does not appear to impact the regenerative EPCs.

Impact of diabetes mellitus on quality of life in patients with congestive heart failure.

OBJECTIVES: Congestive heart failure (CHF) and diabetes mellitus (DM) are increasing in prevalence. There are conflicting data regarding the crosstalk of DM and CHF with respect to the prognostic impact for the patients. Health-related quality of life (Hr-QoL) has been reported to be useful for risk stratification. The purpose of this study was to investigate the impact of DM on Hr-QoL in a CHF population. METHODS: 325 consecutive patients with CHF were retrospectively analyzed (age 49 ± 12 years, 74.2% male, 18% had diabetes). After a median follow-up time of 7.4 years, we compared Hr-QoL of patients with and without DM. Hr-QoL was assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Kaplan-Meier curves were used to compare survival. RESULTS: The presence of DM reduced Hr-QoL in patients with CHF, indicated by a higher overall MLHFQ score (43.5 vs. 21, P = 0.013). Kaplan-Meier survival curves showed a significant survival difference (P = 0.024). Survival rates of both groups differed significantly after 3 (P = 0.031), 5 (P = 0.006), and 10 years (P = 0.047) favoring the group without DM. CONCLUSIONS: In patients with CHF, the coexistence of DM is associated with a reduced Hr-QoL and a particularly poor long-term survival. Our results indicate that CHF patients with DM are at increased risk.

Immunomodulatory effects of cardiotrophin-1 on in vitro cytokine production of monocytes & CD4 + T-lymphocytes.

BACKGROUND & OBJECTIVES: In congestive heart failure (CHF), increased concentrations of several cytokines including cardiotrophin-1 (CT-1) and immunactivation are found. This study was performed to evaluate whether CT-1 can induce in vitro cytokines in monocytes and CD4 + T-lymphocytes of healthy volunteers. METHODS: The study was performed in vitro to see whether CT-1 can modulate monocyte or CD4 + T-lymphocyte interleukin (IL)-1ß, -2, -4, -5, -10, interferon γ (IFNγ), and tumour necrosis factor α (TNFα) expression by flow cytometry following stimulation with CT-1 alone or together with lipopolysaccharide (LPS) or phorbol myristate acetate (PMA)/ionomycine (iono). RESULTS: CT-1 increased the number of TNFα and IL-1ß positive monocytes. LPS induced IL-10, TNFα, and IL-1ß in monocytes but only IL-2 in CD4+ T-lymphocytes, whereas PMA/iono induced all cytokines besides IL-5 in monocytes and IL-1ß in CD4+ T-lymphocytes. In LPS activated monocytes, CT-1 induced a concentration-dependent reduction in the number of TNFα positive monocytes. After LPS activation, CT-1 decreased the number of CD4+ lymphocytes positive for IL-2, IL-4, and IL-5. In addition, following PMA/iono stimulation, CT-1 initiated a concentration-dependent decrease of CD4 + T-lymphocytes positive for TNFα, IL-4, IL-5, and IL-10. INTERPRETATION & CONCLUSIONS: The present data show that in vitro CT-1 can activate monocytes and modulate cytokine production of activated CD4 + T-lymphocytes. We speculate that CT-1 may at least be partly responsible for immunactivation in CHF.

Recurrent Disseminated Intravascular Coagulation in Metastatic Castration-Resistant Prostate Cancer: A Case Report.

Disseminated intravascular coagulation (DIC) is a systemic disease characterized by simultaneous thrombosis, bleeding, and partially excessive fibrinolysis. Systemic shock, trauma, bacterial toxins, and procoagulants-expressing solid and hematologic malignancies are common causes of this life-threatening hemorrhagic complication and often require treatment in intensive care units. We describe a case of an elderly man with recurrent severe bleeding events in the cause of DIC, including epistaxis, hemoptysis, hematuria, and gastrointestinal bleeding. Laboratory investigations revealed elevated prostate-specific antigen (PSA), suggesting an underlying prostate cancer. Despite intensified coagulatory therapy, the coagulation disorder could not be stabilized. A single injection of degarelix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, led to rapid stabilization of the coagulation and decreased PSA within days. One year after initiating androgen-deprivation therapy, there were recurrent transfusion-requiring bleeding events, and a concomitant PSA increase occurred, suggesting metastatic castration-resistant disease associated with DIC. This case emphasizes DIC as a possible primary phenomenon and indicator for the progression of the underlying malignancy, as well as the importance of etiological therapies in the management of DIC.

EKOS™ Jena Experience: Safety, Feasibility, and Midterm Outcomes of Percutaneous Ultrasound-Assisted Catheter-Directed Thrombolysis in Patients with Intermediate-High-Risk or High-Risk Pulmonary Embolism.

Background: Percutaneous catheter-based ultrasound-assisted thrombolysis (UACDT) is recommended for patients with intermediate-high-risk or high-risk pulmonary embolism (PE) in whom systemic thrombolysis has failed or is contraindicated. Aim: To evaluate the safety and efficiency of UACDT in patients with intermediate-high-risk or high-risk PE. Methods: Between October 2017 and January 2020, we performed UACDT using the EkoSonic™ Endovascular System (EKOS™) in 51 patients (21 males, age 63 ± 18 years) with a sPESI of 1.3 ± 0.7. The EKOS™-catheter was implanted within 24 h after admission. Over 15 hours, 11.5 mg of alteplase was administered per catheter. We evaluated right ventricular stress and cardiac biomarkers before and after UACDT. Results: 24 h post-UACDT, median RV/LV ratio decreased from 1.13 to 0.96 (p < 0.001) and the mean sPAP decreased from 47 ± 3 to 32 ± 2 mmHg + CVP (p < 0.0002). There were 6 major bleeding events resulting in transfusion. No stroke, myocardial infarction, right heart decompensation, or recurrent PE occurred. 31 patients (63%) were discharged without any signs of right ventricular stress. After at least 3 months, 73% of our patients did not show any signs of right ventricular dysfunction. The mean RV/LV ratio decreased to 0.75 ± 0.03 (p < 0.0001) in comparison with pre-UACDT, sPAP to 23 mmHg + CVP (p < 0.0001), and BNP to 40 pg/ml (p < 0.0001). Conclusions: The treatment with UACDT reduced right heart stress during the first 24 hours and midterm in patients with intermediate-high-risk or high-risk PE at an acceptable rate of severe complications.

Rationale and Design of JenaMACS-Acute Hemodynamic Impact of Ventricular Unloading Using the Impella CP Assist Device in Patients with Cardiogenic Shock.

INTRODUCTION: Cardiogenic shock due to myocardial infarction or heart failure entails a reduction in end organ perfusion. Patients who cannot be stabilized with inotropes and who experience increasing circulatory failure are in need of an extracorporeal mechanical support system. Today, small, percutaneously implantable cardiac assist devices are available and might be a solution to reduce mortality and complications. A temporary, ventricular, continuous flow propeller pump using magnetic levitation (Impella®) has been approved for that purpose. METHODS AND STUDY DESIGN: JenaMACS (Jena Mechanical Assist Circulatory Support) is a monocenter, proof-of-concept study to determine whether treatment with an Impella CP® leads to improvement of hemodynamic parameters in patients with cardiogenic shock requiring extracorporeal, hemodynamic support. The primary outcomes of JenaMACS are changes in hemodynamic parameters measured by pulmonary artery catheterization and changes in echocardiographic parameters of left and right heart function before and after Impella® implantation at different support levels after 24 h of support. Secondary outcome measures are hemodynamic and echocardiographic changes over time as well as clinical endpoints such as mortality or time to hemodynamic stabilization. Further, laboratory and clinical safety endpoints including severe bleeding, stroke, neurological outcome, peripheral ischemic complications and occurrence of sepsis will be assessed. JenaMACS addresses essential questions of extracorporeal, mechanical, cardiac support with an Impella CP® device in patients with cardiogenic shock. Knowledge of the acute and subacute hemodynamic and echocardiographic effects may help to optimize therapy and improve the outcome in those patients. CONCLUSION: The JenaMACS study will address essential questions of extracorporeal, mechanical, cardiac support with an Impella CP® assist device in patients with cardiogenic shock. Knowledge of the acute and subacute hemodynamic and echocardiographic effects may help to optimize therapy and may improve outcome in those patients. ETHICS AND DISSEMINATION: The protocol was approved by the institutional review board and ethics committee of the University Hospital of Jena. Written informed consent will be obtained from all participants of the study. The results of this study will be published in a renowned international medical journal, irrespective of the outcomes of the study. Strengths and Limitations: JenaMACS is an innovative approach to characterize the effect of additional left ventricular mechanical unloading during cardiogenic shock via a minimally invasive cardiac assist system (Impella CP®) 24 h after onset and will provide valuable data for acute interventional strategies or future prospective trials. However, JenaMACS, due to its proof-of-concept design, is limited by its single center protocol, with a small sample size and without a comparison group.

Impact of short-term systemic hypoxia on phagocytosis, cytokine production, and transcription factor activation in peripheral blood cells.

Hypoxia frequently associated with certain physiologic and pathologic conditions influences numerous cellular functions. Because the effects of short-term hypoxia are incompletely understood, we examined phagocytosis and cytokine production as well as the activation of the transcription factors HIF-1 and NFκB in peripheral blood cells of healthy volunteers exposed to an oxygen concentration equivalent to that found at a height of 5500 m. Furthermore, we analysed plasma HIF-1 and serum concentrations of various HIF-1-dependent genes. Results showed that short-term hypoxia increased phagocytosis in neutrophils without affecting monocyte phagocytosis. Hypoxia decreased basal TNFα concentration in monocytes and basal interferon γ concentration in CD4(+) T lymphocytes. In contrast, plasma HIF and serum VEGF concentrations were not affected by hypoxia, although serum EPO concentration was raised. In PBMC, hypoxia increased cytosolic HIF-1 concentration without affecting nuclear HIF-1 concentration and led to a rise in the nuclear NFκB in PBMC. Our results show that short-term hypoxia affects immune functions in healthy individuals. Furthermore, we speculate that the effects of hypoxia are not due to HIF-1, but are caused by the activation of NFκB .

Circulating levels of interleukin-1 family cytokines in overweight adolescents.

OBJECTIVES: Obesity and related diseases are dramatically increasing problems, particularly in children and adolescents. We determined circulating levels of different interleukin (IL)-1 family members in normal weight and overweight adolescents. METHODS: Seventy male, Caucasian adolescents (13-17 years) were recruited. Thirty-five had a body-mass index (BMI) above the 90th age-specific percentile. IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1ra), and IL-18 were determined using multiplex-technology. RESULTS: IL-18 concentrations were higher in the overweight group compared to normal weight (161.6 +/- 40.7 pg/ml versus 134.7 +/- 43.4 pg/ml, P = .009). Concentrations of circulating IL-1beta levels were below the detection threshold. IL-18 (R2:0.355, P < .01) and IL-1ra (R2:0.287, P < .05) correlated with BMI, whereas IL-1alpha did not. CONCLUSIONS: Accumulating data indicate the importance of the endocrine function of adipose tissue for the pathophysiological consequences of obesity-related co-morbidities. Since IL-18 is involved in the pathogenesis of different cardiovascular diseases, we conclude that IL-18 may represent a link between obesity and related co-morbidities in children and adolescents.

Anthropometric indices as predictors of the metabolic syndrome and its components in adolescents.

BACKGROUND: Overweight and related health problems are becoming increasingly recognized, especially in children and adolescents. For early screening, different anthropometrical measurements of obesity have been proposed to identify individuals at risk. We compared body mass index (BMI), BMI standard deviation score, waist circumference, waist-to-hip ratio (WHR), and waist/height ratio with respect to their power to predict the metabolic syndrome, its components and low-grade inflammation. METHODS: A total of 79 male Caucasian German adolescents (13-17 years) were studied. All anthropometrical measurements of obesity were recorded and blood samples drawn. Predictive power was estimated using receiver operating characteristic curves, by comparing the area under the curve (AUC). RESULTS: Except for WHR, all tested anthropometrical measurements of obesity showed comparably good AUC values for correct prediction, with the highest AUC for BMI (P < 0.001, AUC = 0.885 +/- 0.039). Superior prediction power was not observed for BMI standard deviation score, waist circumference, WHR or waist/height ratio. Furthermore, BMI was the best predictor of elevated C-reactive protein levels as a marker for low-grade inflammation (P < 0.001, AUC = 0.786 +/- 0.064). CONCLUSIONS: In this cross-sectional study the well-established parameter BMI was shown to have the best predictive power to identify metabolic syndrome, its components and markers for low-grade inflammation. Newly developed parameters did not provide superior values. Future longitudinal studies are needed to compare these anthropometrical markers in larger cohorts, incorporating different age groups and ethnic backgrounds.