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Abstract Background Intracellular sensing of lipopolysaccharide (LPS) is essential for the immune response against gram-negative bacteria and results in activation of caspase-11 and pyroptotic cell death with fatal consequences in sepsis. We found the neuronal guidance receptor plexin C1 (PLXNC1) influences the intracellular response to LPS. Methods We employed a murine model of sepsis via cecal ligation and binding (CLP), using PLXNC1-/- mice and littermate controls, and additionally transfected murine bone-marrow-derived macrophages (BMDMs) from both genotypes with LPS to achieve activation of the noncanonical inflammasome ex vivo. Additionally, we transfected the PLXNC1 ligand SL4c-d in vivo and ex vivo to examine its effect on intracellular LPS response. Results We found the neuronal guidance receptor PLXNC1 dampens the intracellular response to LPS by interacting with adenylate cyclase 4 (ADCY4) and protein kinase A activity, which in turn diminishes caspase-11 expression. The absence of PLXNC1 results in excessive inflammation marked by increased cytokine release, increased secondary organ injury and reduced sepsis survival in a murine sepsis model induced by CLP. Notably, administration of SL4c-d—peptide ligand of PLXNC1—reduces the inflammatory response during CLP-induced sepsis and improves survival. Conclusions These results elucidate a previously unknown mechanism for PLXNC1 suppressing excessive noncanonical inflammasome activity and offer a new potential target for treatment of sepsis with its detrimental effects.

Abstract Background Risk stratification and outcome prediction are crucial for intensive care resource planning. In addressing the large data sets of intensive care unit (ICU) patients, we employed the Explainable Boosting Machine (EBM), a novel machine learning model, to identify determinants of acute kidney injury (AKI) in these patients. AKI significantly impacts outcomes in the critically ill. Methods An analysis of 3572 ICU patients was conducted. Variables such as average central venous pressure (CVP), mean arterial pressure (MAP), age, gender, and comorbidities were examined. This analysis combined traditional statistical methods with the EBM to gain a detailed understanding of AKI risk factors. Results Our analysis revealed chronic kidney disease, heart failure, arrhythmias, liver disease, and anemia as significant comorbidities influencing AKI risk, with liver disease and anemia being particularly impactful. Surgical factors were also key; lower GI surgery heightened AKI risk, while neurosurgery was associated with a reduced risk. EBM identified four crucial variables affecting AKI prediction: anemia, liver disease, and average CVP increased AKI risk, whereas neurosurgery decreased it. Age was a progressive risk factor, with risk escalating after the age of 50 years. Hemodynamic instability, marked by a MAP below 65 mmHg, was strongly linked to AKI, showcasing a threshold effect at 60 mmHg. Intriguingly, average CVP was a significant predictor, with a critical threshold at 10.7 mmHg. Conclusion Using an Explainable Boosting Machine enhance the precision in AKI risk factors in ICU patients, providing a more nuanced understanding of known AKI risks. This approach allows for refined predictive modeling of AKI, effectively overcoming the limitations of traditional statistical models.

Introduction Herpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients and is associated with a worse outcome. The aim of this study is to determine whether antiviral therapy in HSV-positive patients improves outcome.Methods and analysis Prospective, multicentre, open-label, randomised, controlled trial in parallel-group design. Adult, mechanically ventilated patients with pneumonia and HSV type 1 detected in bronchoalveolar lavage (≥105 copies/mL) are eligible for participation and will be randomly allocated (1:1) to receive acyclovir (10 mg/kg body weight every 8 hours) for 10 days (or until discharge from the intensive care unit if earlier) or no intervention (control group). The primary outcome is mortality measured at day 30 after randomisation (primary endpoint) and will be analysed with Cox mixed-effects model. Secondary endpoints include ventilator-free and vasopressor-free days up to day 30. A total of 710 patients will be included in the trial.Ethics and dissemination The trial was approved by the responsible ethics committee and by Germany’s Federal Institute for Drugs and Medical Devices. The clinical trial application was submitted under the new Clinical Trials Regulation through CTIS (The Clinical Trials Information System). In this process, only one ethics committee, whose name is unknown to the applicant, and Germany’s Federal Institute for Drugs and Medical Devices are involved throughout the entire approval process. Results will be published in a journal indexed in MEDLINE and CTIS. With publication, de-identified, individual participant data will be made available to researchers.Trial registration number NCT06134492.

Abstract Background Venovenous extracorporeal membrane oxygenation (vvECMO) is used to treat hypoxia in patients with severe acute respiratory distress syndrome (ARDS). Nevertheless, uncertainty exists regarding the optimal timing of initiation of vvECMO therapy. We aimed to investigate the association between number of days of invasive mechanical ventilation (IMV) prior to vvECMO implantation and mortality. Methods In this retrospective observational study, we included patients treated at an academic intensive care unit with vvECMO for severe ARDS. The primary outcome was all-cause 28-day mortality. We conducted a multivariate logistic regression analysis to estimate the association between number of days of IMV prior to vvECMO implantation and mortality after adjustment for confounders. Results Out of 274 patients who underwent ECMO for severe ARDS, 158 patients (median age: 58 years) with relevant data were included in the analysis. The mean duration of IMV prior to vvECMO was significantly shorter in survivors than in nonsurvivors [survivors median: 1; interquartile range: 1–3; non-survivors median 4; interquartile range: 1–5.75; p = 0.0001). Logistic regression showed an association between the duration of ventilation prior to vvECMO and patient mortality. The odds ratio for the all-cause 28-day mortality and in-hospital mortality was significantly reduced in patients who received vvECMO within the first 5 days of IMV. Conclusions Early vvECMO implantation may be associated with lower mortality in ARDS.

IntroductionThe study explores the role of endothelial Semaphorin 7A (SEMA7A) in inflammatory processes. SEMA7A is known for enhancing inflammation during tissue hypoxia and exhibiting anti-inflammatory properties in the intestinal system during colitis. This research extends the understanding of SEMA7A's function by examining its role in inflammatory peritonitis and intestinal inflammation.MethodsThe research involved inducing peritonitis in SEMA7A knockout (SEMA7A-/-) and wild-type (WT) animals through Zymosan A (ZyA) injection. The inflammatory response was assessed by measuring cell count and cytokine release. In parallel, the study investigated the expression of SEMA7A in intestinal epithelial cells under inflammatory stimuli and its impact on interleukin 10 (IL-10) production using an in vitro co-culture model of monocytes and epithelial cells. Additionally, the distribution of SEMA7A target receptors, particularly ITGAV/ITGB1 (CD51/CD29), was analyzed in WT animals.ResultsThe results revealed that SEMA7A-/- animals exhibited increased inflammatory peritonitis compared to the WT animals. Inflammatory conditions in intestinal epithelial cells led to the induction of SEMA7A. The co-culture experiments demonstrated that SEMA7A induced IL-10 production, which depended on integrin receptors and was independent of PLXNC1 expression. Furthermore, ITGAV/ITGB1 emerged as the predominant SEMA7A receptor in the intestinal area of WT animals.DiscussionThese findings underscore the multifaceted role of SEMA7A in inflammatory processes. The differential responses in peritonitis and intestinal inflammation suggest that SEMA7A's function is significantly influenced by the expression and distribution of its target receptors within different organ systems. The study highlights the complex and context-dependent nature of SEMA7A in mediating inflammatory responses.

Abstract Background Acute respiratory distress syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS. Methods We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride (Placebo). The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events. Results Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n = 73) or sodium chloride (n = 77). Data from 144 patients were analyzed. The baseline PaO2/FiO2 ratio did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than Placebo (p = 0.17). Secondary analysis showed that the oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p = 0.04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups. Conclusions The primary result of our study was negative. Our data suggest that inhaled prostacyclin might be beneficial treatment in patients with COVID-19 induced ARDS. Trial registration: The study was approved by the Institutional Review Board of the Research Ethics Committee of the University of Tübingen (899/2018AMG1) and the corresponding ethical review boards of all participating centers. The trial was also approved by the Federal Institute for Drugs and Medical Devices (BfArM, EudraCT No. 2016003168-37) and registered at clinicaltrials.gov (NCT03111212) on April 6th 2017.

Abstract Rationale Health-related quality of life after surviving acute respiratory distress syndrome has come into focus in recent years, especially during the coronavirus disease 2019 pandemic. Objectives A total of 144 patients with acute respiratory distress syndrome caused by COVID-19 or of other origin were recruited in a randomized multicenter trial. Methods Clinical data during intensive care treatment and data up to 180 days after study inclusion were collected. Changes in the Sequential Organ Failure Assessment score were used to quantify disease severity. Disability was assessed using the Barthel index on days 1, 28, 90, and 180. Measurements Mortality rate and morbidity after 180 days were compared between patients with and without COVID-19. Independent risk factors associated with high disability were identified using a binary logistic regression. Main results The SOFA score at day 5 was an independent risk factor for high disability in both groups, and score dynamic within the first 5 days significantly impacted disability in the non-COVID group. Mortality after 180 days and impairment measured by the Barthel index did not differ between patients with and without COVID-19. Conclusions Resolution of organ dysfunction within the first 5 days significantly impacts long-term morbidity. Acute respiratory distress syndrome caused by COVID-19 was not associated with increased mortality or morbidity.

OBJECTIVES:. To determine the feasibility, safety, and efficacy of a biomarker-guided implementation of a kidney-sparing sepsis bundle (KSSB) of care in comparison with standard of care (SOC) on clinical outcomes in patients with sepsis. DESIGN:. Adaptive, multicenter, randomized clinical trial. SETTING:. Five University Hospitals in Europe and North America. PATIENTS:. Adult patients, admitted to the ICU with an indwelling urinary catheter and diagnosis of sepsis or septic shock, without acute kidney injury (acute kidney injury) stage 2 or 3 or chronic kidney disease. INTERVENTIONS:. A three-level KSSB based on Kidney Disease: Improving Global Outcomes (KDIGOs) recommendations guided by serial measurements of urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 used as a combined biomarker [TIMP2]•[IGFBP7]. MEASUREMENTS AND MAIN RESULTS:. The trial was stopped for low enrollment related to the COVID-19 pandemic. Nineteen patients enrolled in five sites over 12 months were randomized to the SOC (n = 8, 42.0%) or intervention (n = 11, 58.0%). The primary outcome was feasibility, and key secondary outcomes were safety and efficacy. Adherence to protocol in patients assigned to the first two levels of KSSB was 15 of 19 (81.8%) and 19 of 19 (100%) but was 1 of 4 (25%) for level 3 KSSB. Serious adverse events were more frequent in the intervention arm (4/11, 36.4%) than in the control arm (1/8, 12.5%), but none were related to study interventions. The secondary efficacy outcome was a composite of death, dialysis, or progression of greater than or equal to 2 stages of acute kidney injury within 72 hours after enrollment and was reached by 3 of 8 (37.5%) patients in the control arm, and 0 of 11 (0%) patients in the intervention arm. In the control arm, two patients experienced progression of acute kidney injury, and one patient died. CONCLUSIONS:. Although the COVID-19 pandemic impeded recruitment, the actual implementation of a therapeutic strategy that deploys a KDIGO-based KSSB of care guided by risk stratification using urinary [TIMP2]•[IGFBP7] seems feasible and appears to be safe in patients with sepsis.

Abstract Background A profound inflammation-mediated lung injury with long-term acute respiratory distress and high mortality is one of the major complications of critical COVID-19. Immunoglobulin M (IgM)-enriched immunoglobulins seem especially capable of mitigating the inflicted inflammatory harm. However, the efficacy of intravenous IgM-enriched preparations in critically ill patients with COVID-19 is largely unclear. Methods In this retrospective multicentric cohort study, 316 patients with laboratory-confirmed critical COVID-19 were treated in ten German and Austrian ICUs between May 2020 and April 2021. The primary outcome was 30-day mortality. Analysis was performed by Cox regression models. Covariate adjustment was performed by propensity score weighting using machine learning-based SuperLearner to overcome the selection bias due to missing randomization. In addition, a subgroup analysis focusing on different treatment regimens and patient characteristics was performed. Results Of the 316 ICU patients, 146 received IgM-enriched immunoglobulins and 170 cases did not, which served as controls. There was no survival difference between the two groups in terms of mortality at 30 days in the overall cohort (HRadj: 0.83; 95% CI: 0.55 to 1.25; p = 0.374). An improved 30-day survival in patients without mechanical ventilation at the time of the immunoglobulin treatment did not reach statistical significance (HRadj: 0.23; 95% CI: 0.05 to 1.08; p = 0.063). Also, no statistically significant difference was observed in the subgroup when a daily dose of ≥ 15 g and a duration of ≥ 3 days of IgM-enriched immunoglobulins were applied (HRadj: 0.65; 95% CI: 0.41 to 1.03; p = 0.068). Conclusions Although we cannot prove a statistically reliable effect of intravenous IgM-enriched immunoglobulins, the confidence intervals may suggest a clinically relevant effect in certain subgroups. Here, an early administration (i.e. in critically ill but not yet mechanically ventilated COVID-19 patients) and a dose of ≥ 15 g for at least 3 days may confer beneficial effects without concerning safety issues. However, these findings need to be validated in upcoming randomized clinical trials. Trial registration DRKS00025794 , German Clinical Trials Register, https://www.drks.de . Registered 6 July 2021.

BackgroundIn cases of terrorism, disasters, or mass casualty incidents, far-reaching life-and-death decisions about prioritizing patients are currently made using triage algorithms that focus solely on the patient’s current health status rather than their prognosis, thus leaving a fatal gap of patients who are under- or overtriaged. ObjectiveThe aim of this proof-of-concept study is to demonstrate a novel approach for triage that no longer classifies patients into triage categories but ranks their urgency according to the anticipated survival time without intervention. Using this approach, we aim to improve the prioritization of casualties by respecting individual injury patterns and vital signs, survival likelihoods, and the availability of rescue resources. MethodsWe designed a mathematical model that allows dynamic simulation of the time course of a patient’s vital parameters, depending on individual baseline vital signs and injury severity. The 2 variables were integrated using the well-established Revised Trauma Score (RTS) and the New Injury Severity Score (NISS). An artificial patient database of unique patients with trauma (N=82,277) was then generated and used for analysis of the time course modeling and triage classification. Comparative performance analysis of different triage algorithms was performed. In addition, we applied a sophisticated, state-of-the-art clustering method using the Gower distance to visualize patient cohorts at risk for mistriage. ResultsThe proposed triage algorithm realistically modeled the time course of a patient’s life, depending on injury severity and current vital parameters. Different casualties were ranked by their anticipated time course, reflecting their priority for treatment. Regarding the identification of patients at risk for mistriage, the model outperformed the Simple Triage And Rapid Treatment’s triage algorithm but also exclusive stratification by the RTS or the NISS. Multidimensional analysis separated patients with similar patterns of injuries and vital parameters into clusters with different triage classifications. In this large-scale analysis, our algorithm confirmed the previously mentioned conclusions during simulation and descriptive analysis and underlined the significance of this novel approach to triage. ConclusionsThe findings of this study suggest the feasibility and relevance of our model, which is unique in terms of its ranking system, prognosis outline, and time course anticipation. The proposed triage-ranking algorithm could offer an innovative triage method with a wide range of applications in prehospital, disaster, and emergency medicine, as well as simulation and research.

Platelets are anucleate blood cells derived from megakaryocytes. They link the fundamental functions of hemostasis, inflammation and host defense. They undergo intracellular calcium flux, negatively charged phospholipid translocation, granule release and shape change to adhere to collagen, fibrin and each other, forming aggregates, which are key to several of their functions. In all these dynamic processes, the cytoskeleton plays a crucial role. Neuronal guidance proteins (NGPs) form attractive and repulsive signals to drive neuronal axon navigation and thus refine neuronal circuits. By binding to their target receptors, NGPs rearrange the cytoskeleton to mediate neuron motility. In recent decades, evidence has indicated that NGPs perform important immunomodulatory functions and influence platelet function. In this review, we highlight the roles of NGPs in platelet formation and activation.

Background: Veno-arterial extracorporeal membrane oxygenation (vaECMO) removal reflects a critical moment and factors of adverse outcomes are incompletely understood. Thus, we studied various patient-related factors during vaECMO removal to determine their association with outcomes. Methods: A total of 58 patients from a university hospital were included retrospectively. Demographic, clinical, and echocardiographic parameters were recorded while under vaECMO support, as well as the need for inotropic and vasoactive-inotropic scores (VIS). Successful weaning was defined as 28-day survival without reinitiation of vaECMO. Results: Patient age differed significantly between patients with a successful and a failed vaECMO weaning (54 ± 14 vs. 62 ± 12 years, p = 0.029). In univariable logistic regression, age (OR 0.952 (0.909–0.997), p = 0.038), the necessities for inotropic agents at the time of echocardiography (OR 0.333 (0.113–0.981), p = 0.046), and vaECMO removal (OR 0.266 (0.081–0.877), p = 0.030) as well as the dobutamine dose during removal (OR 0.649 (0.473–0.890), p = 0.007), were significantly associated with a successful weaning from vaECMO. Age (HR 1.048 (1.006–1.091), p = 0.024) and the VIS (HR 1.030 (1.004–1.056), p = 0.025) at the time of vaECMO removal were independently associated with survival in bivariable Cox regression. In Kaplan–Meier analysis, a VIS of >5.1 at vaECMO removal was associated with impaired survival (log-rank p = 0.025). Conclusions: In this cohort, age and the extent of vasoactive-inotropic agents were associated with adverse outcomes following vaECMO, whereas echocardiographic biventricular function during vaECMO support was not.

Abstract Background Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. Methods 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. Results Most patients were between 50 and 70 years of age. PaO2/FiO2 ratio prior to ECMO was 72 mmHg (IQR: 58–99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41–0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28–1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to

Introduction Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation.Methods and analysis The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage.Ethics and dissemination The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration number NCT04647396.

Abstract Background A peripheral venous catheter (PVC) is the most widely used device for obtaining vascular access, allowing the administration of fluids and medication. Up to 25% of adult patients, and 50% of pediatric patients experience a first-attempt cannulation failure. In addition to patient and clinician characteristics, device features might affect the handling and success rates. The objective of the study was to compare the first-attempt cannulation success rate between PVCs with wings and a port access (Vasofix® Safety, B. Braun, abbreviated hereon in as VS) with those without (Introcan® Safety, B. Braun, abbreviated hereon in as IS) in an anesthesiological cohort. Methods An open label, multi-center, randomized trial was performed. First-attempt cannulation success rates were examined, along with relevant patient, clinician, and device characteristics with univariate and multivariate analyses. Information on handling and adherence to use instructions was gathered, and available catheters were assessed for damage. Results Two thousand three hundred four patients were included in the intention to treat analysis. First-attempt success rate was significantly higher with winged and ported catheters (VS) than with the non-winged, non-ported design (IS) (87.5% with VS vs. 78.2% with IS; P Chi

Blood flow through left ventricular assist devices (LVAD) may induce activation and dysfunction of platelets. Dysfunctional platelets cause coagulation disturbances and form platelet-neutrophil conjugates (PNC), which contribute to inflammatory tissue damage. This prospective observational cohort study investigated patients, who underwent implantation of a LVAD (either HeartMate II (HM II) (n = 7) or HeartMate 3 (HM 3) (n = 6)) and as control patients undergoing coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) (n = 10). We performed platelet and leukocyte flow cytometry, analysis of platelet activation markers, and platelet aggregometry. Platelet CD42b expression was reduced at baseline and perioperatively in HM II/3 compared to CABG/AVR patients. After surgery the platelet activation marker β-thromboglobulin and platelet microparticles increased in all groups while platelet aggregation decreased. Platelet aggregation was more significantly impaired in LVAD compared to CABG/AVR patients. PNC were higher in HM II compared to HM 3 patients. We conclude that LVAD implantation is associated with platelet dysfunction and proinflammatory platelet-leukocyte binding. These changes are less pronounced in patients treated with the newer generation LVAD HM 3. Future research should identify device-specific LVAD features, which are associated with the least amount of platelet activation to further improve LVAD therapy.

Abstract Background Disaster medicine is a component of the German medical education since 2003. Nevertheless, studies have shown some inconsistencies within the implementation of the national curriculum, and limits in the number of students trained over the years. Recently, the SARS-CoV-2 pandemic and other disasters have called attention to the importance of training medical students in disaster medicine on a coordinated basis. The aim of this study is to present and evaluate the disaster medicine and humanitarian assistance course, which was developed in the University of Tübingen, Germany. Methods The University Clinic for Anesthesiology and Intensive Care Medicine in Tübingen expanded the existing curriculum of undergraduate disaster medicine training with fundamentals of humanitarian medicine, integrating distance learning, interactive teaching and simulation sessions in a 40 h course for third-, fourth- and fifth- year medical students. This prospective and cross-sectional study evaluates the Disaster Medicine and Humanitarian Assistance course carried out over five semesters during the period between 2018 and 2020. Three survey tools were used to assess participants’ previous experiences and interest in the field of disaster medicine, to compare the subjective and objective level of knowledge before and after training, and to evaluate the course quality. Results The total number of medical students attending the five courses was n = 102 of which n = 60 females (59%) and n = 42 males (41%). One hundred two students entered the mandatory knowledge assessment, with the rate of correct answers passing from 73.27% in the pre-test to 95.23% in the post-test (t [101] = 18.939, p

BACKGROUND Results of many randomized trials on COVID-19 convalescent plasma (CCP) have been reported, but information on long-term outcome after CCP treatment is limited. The objectives of this extended observation of the randomized CAPSID trial are to assess long-term outcome and disease burden in patients initially treated with or without CCP.METHODS Of 105 randomized patients, 50 participated in the extended observation. Quality of life (QoL) was assessed by questionnaires and a structured interview. CCP donors (n = 113) with asymptomatic to moderate COVID-19 were included as a reference group.RESULTS The median follow-up of patients was 396 days, and the estimated 1-year survival was 78.7% in the CCP group and 60.2% in the control (P = 0.08). The subgroup treated with a higher cumulative amount of neutralizing antibodies showed a better 1-year survival compared with the control group (91.5% versus 60.2%, P = 0.01). Medical events and QoL assessments showed a consistent trend for better results in the CCP group without reaching statistical significance. There was no difference in the increase in neutralizing antibodies after vaccination between the CCP and control groups.CONCLUSION The trial demonstrated a trend toward better outcome in the CCP group without reaching statistical significance. A predefined subgroup analysis showed a significantly better outcome (long-term survival, time to discharge from ICU, and time to hospital discharge) among those who received a higher amount of neutralizing antibodies compared with the control group. A substantial long-term disease burden remains after severe COVID-19.Trial registration EudraCT 2020-001310-38 and ClinicalTrials.gov NCT04433910.Funding Bundesministerium für Gesundheit (German Federal Ministry of Health).

BackgroundShock increases mortality in the critically ill and the mainstay of therapy is the administration of vasopressor agents to achieve hemodynamic targets. In the past, studies have found that the NO-pathway antagonist methylene blue improves hemodynamics. However, the optimal dosing strategy remains elusive. Therefore, we investigated the hemodynamic and ICU outcome parameters of three different dosing strategies for methylene blue.MethodsWe performed a retrospective cohort study of patients in shock treated with methylene blue. Shock was defined as norepinephrine dose >0.1 μg/kg/min and serum lactate level >2 mmol/l at the start of methylene blue administration. Different demographic variables, ICU treatment, and outcome parameters were evaluated. To compare the differences in the administration of vasopressors or inotropes, the vasoactive inotropic score (VIS) was calculated at different time points after starting the administration of methylene blue. Response to methylene blue or mortality at 28 days were assessed.Results262 patients from July 2014 to October 2019 received methylene blue. 209 patients met the inclusion criteria. Three different dosing strategies were identified: bolus injection followed by continuous infusion (n = 111), bolus injection only (no continuous infusion; n = 59) or continuous infusion only (no bolus prior; n = 39). The groups did not differ in demographics, ICU scoring system, or comorbidities. In all groups, VIS decreased over time, indicating improved hemodynamics. Cardiogenic shock and higher doses of norepinephrine increased the chance of responding to methylene blue, while bolus only decreased the chance of responding to methylene blue treatment. 28-day mortality increased with higher SAPSII scores and higher serum lactate levels, while bolus injection followed by continuous infusion decreased 28-day mortality. No severe side effects were noted.ConclusionIn this cohort, methylene blue as a bolus injection followed by continuous infusion was associated with a reduced 28-day mortality in patients with shock. Prospective studies are needed to systematically evaluate the role of methylene blue in the treatment of shock.

Abstract Background Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. Methods A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. Results 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict “survival”. Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients’ age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. Conclusions Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration “ClinicalTrials” (clinicaltrials.gov) under NCT04455451.

Acute kidney injury increases morbidity and mortality, and previous studies have shown that remote ischemic preconditioning (RIPC) reduces the risk of acute kidney injury after cardiac surgery. RIPC increases urinary high mobility group box protein-1 (HMGB1) levels in patients, and this correlates with kidney protection. Here, we show that RIPC reduces renal ischemia-reperfusion injury and improves kidney function in mice. Mechanistically, RIPC increases HMGB1 levels in the plasma and urine, and HMGB1 binds to TLR4 on renal tubular epithelial cells, inducing transcriptomic modulation of renal tubular epithelial cells and providing renal protection, whereas TLR4 activation on nonrenal cells was shown to contribute to renal injury. This protection is mediated by activation of induction of AMPKα and NF-κB; this induction contributes to the upregulation of Sema5b, which triggers a transient, protective G1 cell cycle arrest. In cardiac surgery patients at high risk for postoperative acute kidney injury, increased HMGB1 and Sema5b levels after RIPC were associated with renal protection after surgery. The results may help to develop future clinical treatment options for acute kidney injury.

Daptomycin is a cyclic lipopeptide antibiotic with bactericidal effects against multidrug-resistant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). For critically ill patients, especially in the presence of implants, daptomycin is an important therapeutic option. Left ventricle assist devices (LVADs) can be utilized for intensive care patients with end-stage heart failure as a bridge to transplant. We conducted a single-center prospective trial with critically ill adults with LVAD who received prophylactic anti-infective therapy with daptomycin. Our study aimed to evaluate the pharmacokinetics of daptomycin in the blood serum and wound fluids after LVAD implantation. Daptomycin concentration were assessed over three days using high-performance liquid chromatography (HPLC). We detected a high correlation between blood serum and wound fluid daptomycin concentration at 12 h (IC95%: 0.64 to 0.95; r = 0.86; p < 0.001) and 24 h (IC95%: −0.38 to 0.92; r = 0.76; p < 0.001) after antibiotic administration. Our pilot clinical study provides new insights into the pharmacokinetics of daptomycin from the blood into wound fluids of critically ill patients with LVADs.

Abstract Background Sepsis is associated with capillary leakage and vasodilatation and leads to hypotension and tissue hypoperfusion. Early plasma volume replacement is required to achieve haemodynamic stability (HDS) and maintain adequate tissue oxygenation. The right choice of fluids to be used for plasma volume replacement (colloid or crystalloid solutions) is still a matter of debate, and large trials investigating the use of colloid solutions containing gelatine are missing. This study aims to investigate the efficacy and safety of plasma volume replacement using either a combined gelatine-crystalloid regime (1:1 ratio) or a pure crystalloid regime. Methods This is a prospective, controlled, randomized, double-blind, international, multicentric phase IV study with two parallel groups that is planned to be conducted at European intensive care units (ICUs) in a population of patients with hypovolaemia in severe sepsis/septic shock. A total of 608 eligible patients will be randomly assigned to receive either a gelatine-crystalloid regime (Gelaspan® 4% and Sterofundin® ISO, B. Braun Melsungen AG, in a 1:1 ratio) or a pure crystalloid regime (Sterofundin® ISO) for plasma volume replacement. The primary outcome is defined as the time needed to achieve HDS. Plasma volume replacement will be target-controlled, i.e. fluids will only be administered to volume-responsive patients. Volume responsiveness will be assessed through passive leg raising or fluid challenges. The safety and efficacy of both regimens will be assessed daily for 28 days or until ICU discharge (whichever occurs first) as the secondary outcomes of this study. Follow-up visits/calls will be scheduled on day 28 and day 90. Discussion This study aims to generate evidence regarding which regimen—a gelatine-crystalloid regimen or a pure crystalloid regimen—is more effective in achieving HDS in critically ill patients with hypovolaemia. Study participants in both groups will benefit from the increased safety of target-controlled plasma volume replacement, which prevents fluid administration to already haemodynamically stable patients and reduces the risk of harmful fluid overload. Trial registration The European clinical trial database EudraCT 2015-000057-20 and the ClinicalTrials.gov Protocol Registration and Results System ClinicalTrials.gov NCT02715466 . Registered on 17 March 2016.

Background: Left atrioventricular valve (LAVV) stenosis following an atrioventricular septal defect (AVSD) repair is a rare but potentially life-threatening complication. While echocardiographic quantification of diastolic transvalvular pressure gradients is paramount in the evaluation of a newly corrected valve function, it is hypothesized that these measured gradients are overestimated immediately following a cardiopulmonary bypass (CPB) due to the altered hemodynamics when compared to postoperative valve assessments using awake transthoracic echocardiography (TTE) upon recovery after surgery. Methods: Out of the 72 patients screened for inclusion at a tertiary center, 39 patients undergoing an AVSD repair with both intraoperative transesophageal echocardiograms (TEE, performed immediately after a CPB) and an awake TTE (performed prior to hospital discharge) were retrospectively selected. The mean (MPGs) and peak pressure gradients (PPGs) were quantified using a Doppler echocardiography and other measures of interest were recorded (e.g., a non-invasive surrogate of the cardiac output and index (CI), left ventricular ejection fraction, blood pressures and airway pressures). The variables were analyzed using the paired Student’s t-tests and Spearman’s correlation coefficients. Results: The MPGs were significantly higher in the intraoperative measurements when compared to the awake TTE (3.0 ± 1.2 vs. 2.3 ± 1.1 mmHg; p < 0.01); however, the PPGs did not significantly differ (6.6 ± 2.7 vs. 5.7 ± 2.8 mmHg; p = 0.06). Although the assessed intraoperative heart rates (HRs) were also higher (132 ± 17 vs. 114 ± 21 bpm; p < 0.001), there was no correlation found between the MPG and the HR, or any other parameter of interest, at either time-point. In a further analysis, a moderate to strong correlation was observed in the linear relationship between the CI and the MPG (r = 0.60; p < 0.001). During the in-hospital follow-up period, no patients died or required an intervention due to LAVV stenosis. Conclusions: The Doppler-based quantification of diastolic transvalvular LAVV mean pressure gradients using intraoperative transesophageal echocardiography seems to be prone to overestimation due to altered hemodynamics immediately after an AVSD repair. Thus, the current hemodynamic state should be taken into consideration during the intraoperative interpretation of these gradients.

In critically ill patients, hemodynamic disturbances are common and often lead to a detrimental outcome. Frequently, invasive hemodynamic monitoring is required for patients who are hemodynamically unstable. Although the pulmonary artery catheter enables a comprehensive assessment of the hemodynamic profile, this technique carries a substantial inherent risk of complications. Other less invasive techniques do not offer a full range of results to guide detailed hemodynamic therapies. An alternative with a lower risk profile is transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE). After training, intensivists can obtain similar parameters on the hemodynamic profile using echocardiography, such as stroke volume and ejection fraction of the right and left ventricles, an estimate of the pulmonary artery wedge pressure, and cardiac output. Here, we will review individual echocardiography techniques that will help the intensivist obtain a comprehensive assessment of the hemodynamic profile using echocardiography.

BackgroundThe assessment of right ventricular (RV) function in patients undergoing elective cardiac surgery is paramount for providing optimal perioperative care. The role of regional RV function assessment employing sophisticated state-of-the-art cardiac imaging modalities has not been investigated in this cohort. Hence, this study investigated the association of 3D echocardiography-based regional RV volumetry with short-term outcomes.Materials and MethodsIn a retrospective single-center study, patients undergoing elective cardiac surgery were included if they underwent 3D transesophageal echocardiography prior to thoracotomy. A dedicated software quantified regional RV volumes of the inflow tract, apical body and RV outflow tract employing meshes derived from 3D speckle-tracking. Echocardiographic, clinical and laboratory data were entered into univariable and multivariable logistic regression analyses to determine association with the endpoint (in-hospital mortality or the need for extracorporeal circulatory support).ResultsOut of 357 included patients, 25 (7%) reached the endpoint. Inflow RV ejection fraction (RVEF, 32 ± 8% vs. 37 ± 11%, p = 0.01) and relative stroke volume (rel. SV) were significantly lower in patients who reached the endpoint (44 ± 8 vs. 48 ± 9%, p = 0.02), while the rel. SV of the apex was higher (38 ± 10% vs. 33 ± 8%, p = 0.01). Global left and right ventricular function including RVEF and left ventricular global longitudinal strain did not differ. In univariable logistic regression, tricuspid regurgitation grade ≥ 2 [odds ratio (OR) 4.24 (1.66–10.84), p < 0.01], inflow RVEF [OR 0.95 (0.92–0.99), p = 0.01], inflow rel. SV [OR 0.94 (0.90–0.99), p = 0.02], apex rel. SV [OR 1.07 (1.02–1.13), p < 0.01] and apex to inflow rel. SV ratio [OR 5.81 (1.90–17.77), p < 0.01] were significantly associated with the endpoint. In a multivariable model, only the presence of tricuspid regurgitation [OR 4.24 (1.66–10.84), p < 0.01] and apex to inflow rel. SV ratio [OR 6.55 (2.09–20.60), p < 0.001] were independently associated with the endpoint.ConclusionsRegional RV function is associated with short-term outcomes in patients undergoing elective cardiac surgery and might be helpful for optimizing risk stratification.

Abstract Background Right ventricular (RV) function is an important prognostic indicator. The acute effects of cardiac interventions or cardiac surgery on global and longitudinal RV function are not entirely understood. In this study, acute changes of RV function during mitral valve surgery (MVS), percutaneous mitral valve repair (PMVR) and off-pump coronary artery bypass surgery (OPCAB) were investigated employing 3D echocardiography. Methods Twenty patients scheduled for MVS, 23 patients scheduled for PMVR and 25 patients scheduled for OPCAB were included retrospectively if patients had received 3D transesophageal echocardiography before and immediately after MVS, PMVR or OPCAB, respectively. RV global and longitudinal function was assessed using a 3D multiparameter set consisting of global right ventricular ejection fraction (RVEF), tricuspid annular plane systolic excursion (TAPSE), longitudinal contribution to RVEF (RVEFlong) and free wall longitudinal strain (FWLS). Results Longitudinal RV function was significantly depressed immediately after MVS, as reflected by all parameters (RVEFlong: 20 ± 5% vs. 13 ± 6%, p

Abstract Background With the following report we want to present an unusual case of a patient suffering from acute respiratory distress syndrome with early discovery of bacterial pathogens in bronchoalveolar liquid samples that developed a fatal undiscovered disseminated fungal infection. Case presentation A 67-year-old man was admitted to our university hospital with dyspnea. Progressive respiratory failure developed leading to admission to the intensive care unit, intubation and prone positioning was necessary. To ensure adequate oxygenation and lung protective ventilation veno-venous extracorporeal membrane oxygenation was established. Despite maximal therapy and adequate antiinfective therapy of all discovered pathogens the condition of the patient declined further and he deceased. Postmortem autopsy revealed Mucor and Aspergillus mycelium in multiple organs such as lung, heart and pancreas as the underlying cause of his deterioration and death. Conclusion Routine screening re-evaluation of every infection is essential for adequate initiation and discontinuation of every antiinfective therapy. In cases with unexplained deterioration and unsuccessful sampling the possibility for diagnostic biopsies should be considered.

Reperfusion injury following myocardial ischemia is aggravated by inflammation and platelet–neutrophil complex formation. Here the authors show that semaphorin 7A binds to platelet GPIb, enhancing platelet–neutrophil interaction and increasing post-ischemic myocardial tissue injury, and that blockage of semaphorin 7A is protective.

Abstract Background Acute respiratory distress syndrome (ARDS) is caused by rapid-onset (within hours) acute inflammatory processes in lung tissue, and it is a life-threatening condition with high mortality. The treatment of ARDS to date is focused on the prevention of further iatrogenic damage of the lung rather than the treatment of the initial inflammatory process. Several preclinical studies have revealed a beneficial effect of iloprost on the control of pulmonary inflammation, and in a small number of patients with ARDS, iloprost treatment resulted in improved oxygenation. Therefore, we plan to conduct a large multicenter trial to evaluate the effect of iloprost on ARDS. Methods The Therapeutic Iloprost during ARDS trial (ThIlo trial) is a multicenter, randomized, single blinded, clinical phase II trial assessing the efficacy of inhaled iloprost for the prevention of the development and progression of ARDS in critically ill patients. One hundred fifty critically ill patients suffering from acute ARDS will be treated either by nebulized iloprost or NaCl 0.9% for 5 days. Blood samples will be drawn at defined time points to elucidate the serum levels of iloprost and inflammatory markers during treatment. Mechanical ventilation will be standardized. In follow-up visits at days 28 and 90 as well as 6 months after enrollment, functional status according to the Barthel Index and a health care-related questionnaire, and frailty (Vulnerable Elders Survey) will be evaluated. The primary endpoint is the improvement of oxygenation, defined as the ratio of PaO2/FiO2. Secondary endpoints include 90-day all-cause mortality, Sequential Organ Failure Assessment scores during the study period up to day 90, the duration of mechanical ventilation, the length of intensive care unit (ICU) stay, ventilator-associated pneumonia, delirium, ICU-acquired weakness, and discharge localization. The study will be conducted in three university ARDS centers in Germany. Discussion The results of the ThIlo trial will highlight the anti-inflammatory effect of iloprost on early inflammatory processes during ARDS, resulting in the improvement of outcome parameters in patients with ARDS. Trial registration EUDRA-CT: 2016-003168-37. Registered on 12 April 2017. ClinicalTrials.gov: NCT03111212. Registered on 4 June 2017.

Abstract Background In the critically ill, catheter-related bloodstream infection can result from bacterial contamination of infusion hubs of intravascular catheters. Needle-free connectors (NFC) have been suggested to reduce the rate of bacterial contamination and subsequent catheter-related bloodstream infection (CRBSI), but data remains ambiguous. Thus, we tested if a novel NFC would reduce bacterial contamination and subsequent CRBSI. Results In a prospective, randomized controlled trial, surgical ICU patients were randomized to three-way hubs closed by caps or Bionecteur® (Vygon, Inc.) of central venous catheters. Every 72 h, infusion lines were renewed and microbiological samples were taken. Bacterial growth was analyzed by blinded microbiologists. Incidence of bacterial contamination and CRSBI were assessed. Outcome parameters like length of stay on ICU and outcome were retrospectively assessed. Two thousand seven hundred patients were screened, 111 were randomized to the NFC, and 109 into the control group. Finally, 24 patients in the NFC and 23 control patients were analyzed. The majority of samples (NFC 77%; control 70%) found no bacterial growth. Coagulase-negative staphylococci were most commonly detected on CVC samples (NFC 17%; control 21%). We found CRBSI (defined as identical pathogens in blood culture and catheter line tip culture, and clinical manifestations of infection) in two control patients and one patient of the NFC group. Their length of ICU stay did not differ between groups (NFC 19 days; control 23 days). Conclusion The use of NFC does not influence the rate of bacterial contamination of infusion hubs of central venous catheters. Trial registration Clinicaltrials.gov , NCT02134769 . Registered 09 May 2014.

Abstract Background General anesthesia induction with the initiation of positive pressure ventilation creates a vulnerable phase for patients. The impact of positive intrathoracic pressure on cardiac performance has been studied but remains controversial. 3D echocardiography is a valid and MRI-validated bed-side tool to evaluate the right ventricle (RV). The aim of this study was to assess the impact of anesthesia induction (using midazolam, sufentanil and rocuronium, followed by sevoflurane) with positive pressure ventilation (PEEP 5, tidal volume 6–8 ml/kg) on 2D and 3D echocardiography derived parameters of RV function. Methods A prospective observational study on fifty-three patients undergoing elective cardiac surgery in a tertiary care university hospital was designed. Transthoracic echocardiography exams were performed before and immediately after anesthesia induction and were recorded together with hemodynamic parameters and ventilator settings. Results After anesthesia induction TAPSE (mean difference − 1.6 mm (95% CI − 2.6 mm to − 0.7 mm; p = 0.0013) as well as the Tissue Doppler derived tricuspid annulus peak velocity (TDITVs’) were significantly reduced (mean difference − 1.9% (95% CI: − 2.6 to − 1.2; p

Background: Lower body perfusion (LBP) may be a strategy for maintaining organ perfusion during congenital heart disease surgery. It is hypothesized that renal and lower limb oxygen supply during LBP is superior to off-pump surgery and comparable to that of a standard cardiopulmonary bypass (CPB). Methods: in this prospective single-center study, patients aged 2), hemoglobin amount (Hb), blood velocity (Velo), and blood flow (Flow) were measured noninvasively. Results: A total of 23 patients were included (group 1, n = 9; group 2, n = 5; group 3, n = 9). Compared to the baseline values, rSO2 and pSO2 decreased significantly in group 2 compared to groups 1 and 3. Conversely, rHB significantly increased in group 2 compared to groups 1 and 3, reflecting abdominal venous stasis. Compared to group 3, group 1 showed a significantly lower pFlow during CPB; however, rFlow, pFlow, and pVelo did not differ. Conclusion: according to these observations, LBP results in an improved renal oxygen supply compared to off-pump surgery and may prove to be a promising alternative to conventional CPB.

Ischemic events are associated with severe inflammation and are here referred to as ischemic inflammatory response (IIR). Recent studies identified the formation of platelet–neutrophil complexes (PNC) as key players in IIR. We investigated the role of extracellular platelet nucleotide signaling in the context of IIR and defined a cybernetic circle, including description of feedback loops. Cybernetic circles seek to integrate different levels of information to understand how biological systems function. Our study specifies the components of the cybernetic system of platelets in IIR and describes the theoretical progression of IIR passing the cybernetic cycle with positive and negative feedback loops based on nucleotide-dependent signaling and functional regulation. The cybernetic components and feedback loops were explored by cytometry, immunohistological staining, functional blocking antibodies, and ADP/ATP measurements. Using several ex vivo and in vivo approaches we confirmed cybernetic parameters, such as controller, sensor, and effector (VASP phosphorylation, P2Y12, ADORAs and GPIIb/IIIa activity), as well as set points (ADP, adenosine) and interfering control and disturbance variables (ischemia). We demonstrate the impact of the regulated platelet–neutrophil complex (PNC) formation in blood and the resulting damage to the affected inflamed tissue. Taken together, extracellular nucleotide signaling, PNC formation, and tissue damage in IIR can be integrated in a controlled cybernetic circle of platelet function, as introduced through this study.

Objective: This systematic-review and meta-analysis aimed to assess the prevalence of cardiovascular comorbidities and complications in ICU-admitted coronavirus disease 2019 (COVID-19) patients. Data sources: PubMed and Web of Science databases were referenced until November 25, 2020. Data extraction: We extracted retrospective and prospective observational studies on critically ill COVID-19 patients admitted to an intensive care unit. Only studies reporting on cardiovascular comorbidities and complications during ICU therapy were included. Data synthesis: We calculated the pooled prevalence by a random-effects model and determined heterogeneity by Higgins’ I 2 test. Results: Of the 6346 studies retrieved, 29 were included in this review. The most common cardiovascular comorbidity was arterial hypertension (50%; 95% confidence interval [CI], 0.42-058; I 2 = 94.8%, low quality of evidence). Among cardiovascular complications in the ICU, shock (of any course) was most common, being present in 39% of the patients (95% CI, 0.20-0.59; I 2 = 95.6%; 6 studies). Seventy-four percent of patients in the ICU required vasopressors to maintain target blood pressure (95% CI, 0.58-0.88; I 2 = 93.6%; 8 studies), and 30% of patients developed cardiac injury in the ICU (95% CI, 0.19-0.42; I 2 = 91%; 14 studies). Severe heterogeneity existed among the studies. Conclusions: Cardiovascular complications are common in patients admitted to the intensive care unit for COVID-19. However, the existing evidence is highly heterogeneous in terms of study design and outcome measurements. Thus, prospective, observational studies are needed to determine the impact of cardiovascular complications on patient outcome in critically ill COVID-19 patients.

Background. Extracorporeal membrane oxygenation (ECMO) serves as a rescue therapy when systemic hypoxia persists despite conventional care for severe acute respiratory distress syndrome (ARDS). Due to the extracorporeal gas exchange, the paO2/FiO2 ratio cannot be used as the primary marker for disease severity and progression. Therefore, we performed a propensity score-matched analysis to identify other potential predictors of outcomes in patients supported by ECMO therapy. Results. Between December 2014 and May 2018, 105 patients underwent venovenous ECMO in our institution. From these patients, we identified 28 who died during ECMO therapy and assigned 28 control patients using propensity score matching based on the following criteria: age, ARDS severity, and SAPSII score at admission. A statistical evaluation of the patient characteristics, intensive care data, morbidities, respiratory system variables, and outcomes was performed. The baseline patient characteristics did not differ between groups and ECMO was placed on day 1 in all patients. The analyzed variables of respiratory mechanics, such as the plateau pressure, positive end-expiratory pressure, and tidal volume, did not differ between groups. The driving pressure before ECMO was equal between the nonsurvivors and the controls. Twelve hours after initiation of ECMO therapy, the driving pressure decreased by 40.8% in the survivors but by only 20.1% in the nonsurvivors. Conclusions. We report that very early driving pressure changes can serve as an indicator of disease severity and predict patient survival following ECMO therapy.

Introduction: In this study, we evaluated right ventricular (RV) function before and after percutaneous mitral valve repair (PMVR) using conventional echocardiographic parameters and novel 3DE data sets acquired prior to and directly after the procedure. Patients and methods: Observational study on 45 patients undergoing PMVR at an university hospital. Results: In the overall collective, the 3D RV-EF before and after PMVR showed no significant change (p = 0.16). While there was a significant increase of the fractional area change (FAC, from 23 [19–29] % to 28 [24–33] %, p = 0.001), no significant change of the tricuspid annular plane systolic excursion (TAPSE, from 17 ± 6 mm to 18 ± 5 mm (standard deviation), p = 0.33) was observed. Regarding patients with a reduced RV-EF (< 35%), a significant RV-EF improvement was observed (from 27 [23–34] % to 32.5 [30–39] % (p = 0.001). 71.4% of patients had an improved clinical outcome (improvement in 6-minute walk test and/or improvement in NYHA class of more than one grade), whereas clinical outcome did not improve in 28.6% of patients. Using univariate logistic regression analysis, the post-PMVR RV-EF (OR 1.15: 95% CI 1.02–1.29; p = 0.02) and the change in RV-EF (OR 1.13: 95% CI 1.02–1.25; p = 0.02) were significant predictors for improved clinical outcome at 6 months follow up. Conclusion: Thus, RV function may be an important non-invasive parameter to add to the predictive parameters indicating a potential clinical benefit from treatment of severe mitral regurgitation using PMVR. Keywords: Mitral regurgitation, Percutaneous mitral valve repair, Echocardiography, 3D-echocardiography, RV function, Outcome

Uterus transplantation (UTx) can provide a route to motherhood for women with Mayer–Rokitansky–Küster–Hauser syndrome (MRKHS), a congenital disorder characterized by uterovaginal aplasia, but with functional ovaries. Based on our four successful living-donor transplantations and two resulting births, this analysis presents parameters relevant to standardizing recipient/donor selection, UTx surgery, and postoperative treatment, and their implementation in routine settings. We descriptively analyzed prospectively collected observational data from our four uterus recipients, all with MRKHS, their living donors, and the two newborns born to two recipients, including 1-year postnatal follow-ups. Analysis included only living-donor/recipient pairs with completed donor/recipient surgery. Two recipients, both requiring ovarian restimulation under immunosuppression after missed pregnancy loss in one case and no pregnancy in the other, each delivered a healthy boy by cesarean section. We conclude that parameters crucial to successful transplantation, pregnancy, and childbirth include careful selection of donor/recipient pairs, donor organ quality, meticulous surgical technique, a multidisciplinary team approach, and comprehensive follow-up. Surgery duration and blood vessel selection await further optimization, as do the choice and duration of immunosuppression, which are crucial to timing the first embryo transfer. Data need to be collected in an international registry due to the low prevalence of MRKHS.

BACKGROUND:Patients after transcatheter aortic valve replacement (TAVR) and persistent severe mitral regurgitation (MR) are increasingly treated with percutaneous edge-to-edge mitral valve repair (PMVR). The impact of a former TAVR on PMVR procedures is not clear. METHODS AND RESULTS:We retrospectively analyzed 332 patients undergoing PMVR using the MitraClip system with respect to procedural and clinical outcome. 21 of these 332 patients underwent TAVR before PMVR. Intra-procedural transthoracic (TTE) and transesophageal echocardiograms (TEE) immediately before and after clip implantation as well as invasive hemodynamic measurements were evaluated. At baseline, we found a significantly smaller mitral valve anterior-posterior diameter in the TAVR cohort (p < 0.001). A reduction of MR by at least three grades was achieved in a smaller fraction in the TAVR cohort as compared to the cohort with a native aortic valve (p = 0.02). Accordingly, we observed a smaller post-procedural cardiac output in the TAVR cohort (p = 0.02). CONCLUSION:PMVR in patients who had a TAVR before, is associated with altered MR anatomy before and a reduced improvement of MR after the procedure. Future larger and prospective studies will have to determine, whether a previous TAVR influences long-term clinical outcome of patients undergoing PMVR.

BackgroundPercutaneous edge‐to‐edge mitral valve repair (PMVR) has become an established treatment option for mitral regurgitation in patients not eligible for surgical repair. Currently, most procedures are performed under general anesthesia (GA). An increasing number of centers, however, are performing the procedure under deep sedation (DS). Here, we compared patients undergoing PMVR with GA or DS. Methods and ResultsA total of 271 consecutive patients underwent PMVR at our institution between May 2014 and December 2016. Seventy‐two procedures were performed under GA and 199 procedures under DS. We observed that in the DS group, doses of propofol (743±228 mg for GA versus 369±230 mg for DS, P

BACKGROUND:The objective of this study was to evaluate the outcome of left ventricular assist device (LVAD) implantation after initial extracorporeal life support (ECLS) in patients with cardiogenic shock and the incidence of post implantation right ventricular failure. METHODS & RESULTS:All patients on ECLS therapy for cardiogenic shock prior to LVAD implantation (n = 15) between October 2011 and January 2014 were analyzed. Baseline patient characteristics, as well as detailed pre-operative treatment and postoperative outcome data were collected retrospectively. At time of admission to our unit all patients were classified INTERMACS II or higher (12 [80%] INTERMACS I). Improvement to INTERMACS III temporary cardiac support (TCS) at time of LVAD implantation was successful in 14 patients (93.3%). End-organ function recovered during ECLS support. No patient needed ongoing ECLS or additional right ventricular support after LVAD implantation. Both in-hospital and 30-day mortality was 6.7% (n = 1). The median duration of LVAD support was 687.9 ± 374.5 days. At the end of the study (follow-up 810.7 +/- 338.9 days), 13 (86.7%) patients were alive. The majority of patients (10 [66.7%]) remained on LVAD support. Transplantation could be performed in 1 (6.7%) patient, 2 (13.3%) patients could be successfully weaned. CONCLUSION:LVAD implantation in ECLS patients leads to improvement of INTERMACS level to INTERMACS III TCS status. Excellent mid-term survival comparable to true INTERMACS III-IV patients could be shown. ECLS prior to LVAD as a bridge-to-bridge therapy may help to lower mortality in primarily unstable patients.

The extent of pulmonary inflammation during lung injury ultimately determines patient outcome. Pulmonary inflammation is initiated by the migration of neutrophils into the alveolar space. Recent work has demonstrated that the guidance protein semaphorin 7A (SEMA7A) influences the migration of neutrophils into hypoxic tissue sites, yet, its role during lung injury is not well understood. Here, we report that the expression of SEMA7A is induced in vitro through pro-inflammatory cytokines. SEMA7A itself induces the production of pro-inflammatory cytokines in endothelial and epithelial cells, enhancing pulmonary inflammation. The induction of SEMA7A facilitates the transendothelial migration of neutrophils. In vivo, animals with deletion of SEMA7A expression showed reduced signs of pulmonary inflammatory changes following lipopolysaccharide challenge. We define here the role of SEMA7A in the development of lung injury and identify a potential pathway to interfere with these detrimental changes. Future anti-inflammatory strategies for the treatment of lung injury might be based on this finding.

Intraaortic balloon pump counterpulsation (IABP) is often used in patients with acute coronary syndrome for its favourable effects on left ventricular (LV) systolic function and coronary perfusion. However, the effects of IABP on LV diastolic function have not been comprehensively investigated. Acute diastolic dysfunction has been linked to increased morbidity and mortality. The aim of this study was to examine the influence of IABP on LV diastolic dysfunction using standard TEE derived parameters.Intraoperative TEE was performed in 10 patients (mean age 65 ± 11 yrs) undergoing urgent coronary artery bypass graft surgery (CABG), who had received an IABP preoperatively. TEE derived measures of diastolic dysfunction included early to late transmitral Doppler inflow velocity ratio (E/A), deceleration time (Dt), pulmonary venous systolic to diastolic Doppler velocity ratio (S/D), transmitral propagation velocity (Vp), and the ratio of early to late mitral annular tissue Doppler velocities (e'/a'). Statistical analyses included the Wilcoxon Sign-Rank test, and a p

Organ dysfunction or failure after the first days of ICU treatment and subsequent mortality with respect to the type of intensive care unit (ICU) admission is poorly elucidated. Therefore we analyzed the association of ICU mortality and admission for medical (M), scheduled surgery (ScS) or unscheduled surgery (US) patients mirrored by the occurrence of organ dysfunction/failure (OD/OF) after the first 72h of ICU stay.For this retrospective cohort study (23,795 patients; DIVI registry; German Interdisciplinary Association for Intensive Care Medicine (DIVI)) organ dysfunction or failure were derived from the Sequential Organ Failure Assessment (SOFA) score (excluding the Glasgow Coma Scale). SOFA scores were collected on admission to ICU and 72h later. For patients with a length of stay of at least five days, a multivariate analysis was performed for individual OD/OF on day three.M patients had the lowest prevalence of cardiovascular failure (M 31%; ScS 35%; US 38%), and the highest prevalence of respiratory (M 24%; ScS 13%; US 17%) and renal failure (M 10%; ScS 6%; US 7%). Risk of death was highest for M- and ScS-patients in those with respiratory failure (OR; M 2.4; ScS 2.4; US 1.4) and for surgical patients with renal failure (OR; M 1.7; ScS 2.7; US 2.4).The dynamic evolution of OD/OF within 72h after ICU admission and mortality differed between patients depending on their types of admission. This has to be considered to exclude a systematic bias during multi-center trials.

G-protein-coupled receptors (GPCRs) are the most abundant receptors in the heart and therefore are common targets for cardiovascular therapeutics. The activated GPCRs transduce their signals via heterotrimeric G-proteins. The four major families of G-proteins identified so far are specified through their α-subunit: Gαi, Gαs, Gαq and G12/13. Gαi-proteins have been reported to protect hearts from ischemia reperfusion injury. However, determining the individual impact of Gαi2 or Gαi3 on myocardial ischemia injury has not been clarified yet. Here, we first investigated expression of Gαi2 and Gαi3 on transcriptional level by quantitative PCR and on protein level by immunoblot analysis as well as by immunofluorescence in cardiac tissues of wild-type, Gαi2-, and Gαi3-deficient mice. Gαi2 was expressed at higher levels than Gαi3 in murine hearts, and irrespective of the isoform being knocked out we observed an up regulation of the remaining Gαi-protein. Myocardial ischemia promptly regulated cardiac mRNA and with a slight delay protein levels of both Gαi2 and Gαi3, indicating important roles for both Gαi isoforms. Furthermore, ischemia reperfusion injury in Gαi2- and Gαi3-deficient mice exhibited opposite outcomes. Whereas the absence of Gαi2 significantly increased the infarct size in the heart, the absence of Gαi3 or the concomitant upregulation of Gαi2 dramatically reduced cardiac infarction. In conclusion, we demonstrate for the first time that the genetic ablation of Gαi proteins has protective or deleterious effects on cardiac ischemia reperfusion injury depending on the isoform being absent.

The UNC5 receptor family are chemorepulsive neuronal guidance receptors with additional functions outside the central nervous system. Previous studies have implicated that the UNC5B receptor influences the migration of leukocytes into sites of tissue inflammation. Given that this process is a critical step during the pathophysiology of myocardial ischemia followed by reperfusion (IR) we investigated the role of UNC5B during myocardial IR. In initial in-vitro experiments, the functional inhibition of UNC5B resulted in a significant reduction of chemotactic migration of neutrophils. In-vivo, using a model of acute myocardial ischemia in UNC5B(+/-) and wild type (WT) animals, we found a significant reduction of infarct sizes in UNC5B(+/-) animals. This was associated with significantly reduced levels of troponin-I and IL-6 in UNC5B(+/-) mice. The repression of UNC5B using siRNA and the functional inhibition of UNC5B significantly dampened the extent of myocardial IR injury. Following depletion of neutrophils, we were not able to observe any further reduction in infarct size through functional inhibition of UNC5B in WT and UNC5B(+/-) mice. In summary our studies demonstrate an important role for UNC5B during myocardial IR injury, and that UNC5B might be a potential therapeutic target to control reperfusion injury in the future.

Neuronal guidance proteins (NGP) were originally described in the context of axonal growth and migration. Yet recent work has demonstrated that NGPs also serve as guidance cues for immune competent cells. A crucial target receptor for NGPs during embryonic development is the neogenin receptor, however its role during acute inflammation is unknown. We report here that neogenin is abundantly expressed outside the nervous system and that animals with endogenous repression of neogenin (Neo1(-/-)) demonstrate attenuated changes of acute inflammation. Studies using functional inhibition of neogenin resulted in a significant attenuation of inflammatory peritonitis. In studies employing bone marrow chimeric animals we found the hematopoietic presence of Neo1(-/-) to be responsible for the attenuated inflammatory response. Taken together our studies suggest that the guidance receptor neogenin holds crucial importance for the propagation of an acute inflammatory response and further define mechanisms shared between the nervous and the immune system.

Recent evidence has demonstrated additional roles for the neuronal guidance protein receptor UNC5B outside the nervous system. Given the fact that ischemia reperfusion injury (IRI) of the liver is a common source of liver dysfunction and the role of UNC5B during an acute inflammatory response we investigated the role of UNC5B on acute hepatic IRI. We report here that UNC5B(+/-) mice display reduced hepatic IRI and neutrophil (PMN) infiltration compared to WT controls. This correlated with serum levels of lactate dehydrogenase (LDH), aspartate- (AST) and alanine- (ALT) aminotransferase, the presence of PMN within ischemic hepatic tissue, and serum levels of inflammatory cytokines. Moreover, injection of an anti-UNC5B antibody resulted in a significant reduction of hepatic IR injury. This was associated with reduced parameters of liver injury (LDH, ALT, AST) and accumulation of PMN within the injured hepatic tissue. In conclusion our studies demonstrate a significant role for UNC5B in the development of hepatic IRI and identified UNC5B as a potential drug target to prevent liver dysfunction in the future.