Extracellular Vesicles as Possible Plasma Markers and Mediators in Patients with Sepsis-Associated Delirium-A Pilot Study.

Patients with sepsis-associated delirium (SAD) show severe neurological impairment, often require an intensive care unit (ICU) stay and have a high risk of mortality. Hence, useful biomarkers for early detection of SAD are urgently needed. Extracellular vesicles (EVs) and their cargo are known to maintain normal physiology but also have been linked to numerous disease states. Here, we sought to identify differentially expressed proteins in plasma EVs from SAD patients as potential biomarkers for SAD. Plasma EVs from 11 SAD patients and 11 age-matched septic patients without delirium (non-SAD) were isolated by differential centrifugation, characterized by nanoparticle tracking analysis, transmission electron microscopy and Western blot analysis. Differential EV protein expression was determined by mass spectrometry and the resulting proteomes were characterized by Gene Ontology term and between-group statistics. As preliminary results because of the small group size, five distinct proteins showed significantly different expression pattern between SAD and non-SAD patients (p ≤ 0.05). In SAD patients, upregulated proteins included paraoxonase-1 (PON1), thrombospondin 1 (THBS1), and full fibrinogen gamma chain (FGG), whereas downregulated proteins comprised immunoglobulin (IgHV3) and complement subcomponent (C1QC). Thus, plasma EVs of SAD patients show significant changes in the expression of distinct proteins involved in immune system regulation and blood coagulation as well as in lipid metabolism in this pilot study. They might be a potential indicator for to the pathogenesis of SAD and thus warrant further examination as potential biomarkers, but further research is needed to expand on these findings in longitudinal study designs with larger samples and comprehensive polymodal data collection.

Liver-Support Therapies in Critical Illness-A Comparative Analysis of Procedural Characteristics and Safety.

Extracorporeal liver-support therapies remain controversial in critically ill patients, as most studies have failed to show an improvement in outcomes. However, heterogeneous timing and inclusion criteria, an insufficient number of treatments, and the lack of a situation-dependent selection of available liver-support modalities may have contributed to negative study results. We retrospectively investigated the procedural characteristics and safety of the three liver-support therapies CytoSorb, Molecular Adsorbent Recirculating System (MARS) and therapeutic plasma exchange (TPE). Whereas TPE had its strengths in a shorter treatment duration, in clearing larger molecules, affecting platelet numbers less, and improving systemic coagulation and hemodynamics, CytoSorb and MARS were associated with a superior reduction in particularly small protein-bound and water-soluble substances. The clearance magnitude was concentration-dependent for all three therapies, but additionally related to the molecular weight for CytoSorb and MARS therapy. Severe complications did not appear. In conclusion, a better characterization of disease-driving as well as beneficial molecules in critically ill patients with acute liver dysfunction is crucial to improve the use of liver-support therapy in critically ill patients. TPE may be beneficial in patients at high risk for bleeding complications and impaired liver synthesis and hemodynamics, while CytoSorb and MARS may be considered for patients in whom the elimination of smaller toxic compounds is a primary objective.

suPAR links a dysregulated immune response to tissue inflammation and sepsis-induced acute kidney injury.

Acute kidney injury (AKI) secondary to sepsis results in poor outcomes and conventional kidney function indicators lack diagnostic value. Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune-derived molecule implicated in inflammatory organ damage. We characterized the diagnostic ability of longitudinal serum suPAR levels to discriminate severity and course of sepsis-induced AKI (SI-AKI) in 200 critically ill patients meeting Sepsis-3 criteria. The pathophysiologic relevance of varying suPAR levels in SI-AKI was explored in a polymicrobial sepsis model in WT, (s)uPAR-knockout, and transgenic suPAR-overexpressing mice. At all time points studied, suPAR provided a robust classification of SI-AKI disease severity, with improved prediction of renal replacement therapy (RRT) and mortality compared with established kidney biomarkers. Patients with suPAR levels of greater than 12.7 ng/mL were at highest risk for RRT or death, with an adjusted odds ratio of 7.48 (95% CI, 3.00-18.63). suPAR deficiency protected mice against SI-AKI. suPAR-overexpressing mice exhibited greater kidney damage and poorer survival through inflamed kidneys, accompanied by local upregulation of potent chemoattractants and pronounced kidney T cell infiltration. Hence, suPAR allows for an innate immune-derived and kidney function-independent staging of SI-AKI and offers improved longitudinal risk stratification. suPAR promotes T cell-based kidney inflammation, while suPAR deficiency improves SI-AKI.

High resolution propagation-based lung imaging at clinically relevant X-ray dose levels.

Absorption-based clinical computed tomography (CT) is the current imaging method of choice in the diagnosis of lung diseases. Many pulmonary diseases are affecting microscopic structures of the lung, such as terminal bronchi, alveolar spaces, sublobular blood vessels or the pulmonary interstitial tissue. As spatial resolution in CT is limited by the clinically acceptable applied X-ray dose, a comprehensive diagnosis of conditions such as interstitial lung disease, idiopathic pulmonary fibrosis or the characterization of small pulmonary nodules is limited and may require additional validation by invasive lung biopsies. Propagation-based imaging (PBI) is a phase sensitive X-ray imaging technique capable of reaching high spatial resolutions at relatively low applied radiation dose levels. In this publication, we present technical refinements of PBI for the characterization of different artificial lung pathologies, mimicking clinically relevant patterns in ventilated fresh porcine lungs in a human-scale chest phantom. The combination of a very large propagation distance of 10.7 m and a photon counting detector with [Formula: see text] pixel size enabled high resolution PBI CT with significantly improved dose efficiency, measured by thermoluminescence detectors. Image quality was directly compared with state-of-the-art clinical CT. PBI with increased propagation distance was found to provide improved image quality at the same or even lower X-ray dose levels than clinical CT. By combining PBI with iodine k-edge subtraction imaging we further demonstrate that, the high quality of the calculated iodine concentration maps might be a potential tool for the analysis of lung perfusion in great detail. Our results indicate PBI to be of great value for accurate diagnosis of lung disease in patients as it allows to depict pathological lesions non-invasively at high resolution in 3D. This will especially benefit patients at high risk of complications from invasive lung biopsies such as in the setting of suspected idiopathic pulmonary fibrosis (IPF).

Case report: Resuscitative endovascular balloon occlusion after iatrogenic injury of the common iliac artery during neurosurgical dorsal lumbar microdiscectomy.

Introduction and importance: This case report describes resuscitative endovascular balloon occlusion (REBOA) of the aorta in a patient with life-threatening iatrogenic bleeding of the right common iliac artery during elective dorsal lumbar spine surgery. REBOA is an emergency procedure for temporary intra-aortic balloon occlusion being increasingly reported and published since its inauguration in 1954. The interdisciplinary management of hemorrhage and technical notes for a successful REBOA procedure will be presented. Case presentation: A 53-year-old female patient was admitted to the neurosurgery clinic suffering from left-sided L5 radiculopathy. During surgery, the anterior longitudinal ligament was perforated and an arterial vessel was lacerated. The patient became hemodynamically unstable demanding prompt supine repositioning and cardiopulmonary resuscitation (CPR). REBOA enabled cardiovascular stabilization after 90 min of CPR and laparotomy with vascular reconstruction and contributed to the survival of the patient without major clinical deficits. The patient was discharged from the ICU after 7 days. Clinical discussion: Resuscitative endovascular balloon occlusion of the aorta is an emergency procedure to control life-threatening hemorrhage. REBOA should be available on-scene and applied by well-trained vascular surgery personnel to control vascular complications or extend to emergency laparotomy and thoracotomy with aortic cross-clamping in case of in-hospital non-controllable hemorrhages. In case of ongoing CPR, we recommend surgical groin incision, open puncture of the pulseless common femoral artery, and aortic balloon inflation in REBOA zone I. Hereby, fast access and CPR optimization for heart and brain perfusion are maintained. Conclusion: Training for REBOA is the decisive factor to control selected cases of in-house and outpatient massive arterial abdominal bleeding complications.

Implementation of a spontaneous awakening/spontaneous breathing trial protocol in a surgical intensive care unit: a before and after study.

BACKGROUND: Prolonged invasive mechanical ventilation (IMV) influences patient outcome in multiple ways. In this regard the early weaning from IMV is a major goal to be achieved in the treatment of ICU patients. Adopting a weaning protocol that incorporates a Spontaneous Awakening Trial (SAT) and a Spontaneous Breathing Trial (SBT) seems to be essential to reach this goal. Most studies investigating the effectiveness of SAT/SBT protocols in ICU patients' outcomes have focused mainly on medical or mixed (medical and surgical), but not on exclusively surgical patient populations. Surgical patients usually experience more complications and often undergo revision surgeries, therefore needing longer sedation periods and adequate analgo-sedation therapy. Moreover, the longer IMV times make the weaning process more arduous. METHODS: Our retrospective data analysis therefore investigates the effectiveness of a SAT/SBT protocol implementation in the surgical ICU of Heidelberg University Hospital, focusing exclusively on surgical patients and their outcome related to the weaning process. The SAT/SBT protocol was adopted in Heidelberg ICU starting from 05/2019. We therefore analyzed the time period before and after the implementation between 03/2018 and 08/2020. Adult patients who required invasive ventilation for at least 48 hours were screened for study entry. Demographic data, clinical data and SOFA Score on admission, were collected to define the baseline characteristics of the two groups. Only patients with full adherence to the protocol were included. The primary outcome was defined as the successful extubation, intended as an extubation not followed by successive re-intubations until discharge from the ICU. We performed an univariate analysis to evaluate the rate of successful extubations between the two groups. RESULTS: In total, 199 patients were included in the analysis, 98 of which before the SAT/SBT protocol implementation (control group) and 101 after the SAT/SBT protocol implementation (intervention group). The successful extubation rate in the intervention group resulted in 82% (83/101 patients) compared to 64% (63/98 patients) in the control group (P<0.004). CONCLUSIONS: We conclude that even for an exclusively surgical patient population, the implementation of a SAT/SBT protocol could result in a higher rate of successful extubation.

Pumpless Extracorporeal Hemadsorption Technique (pEHAT): A Proof-of-Concept Animal Study.

Background: Extracorporeal hemadsorption eliminates proinflammatory mediators in critically ill patients with hyperinflammation. The use of a pumpless extracorporeal hemadsorption technique allows its early usage prior to organ failure and the need for an additional medical device. In our animal model, we investigated the feasibility of pumpless extracorporeal hemadsorption over a wide range of mean arterial pressures (MAP). Methods: An arteriovenous shunt between the femoral artery and femoral vein was established in eight pigs. The hemadsorption devices were inserted into the shunt circulation; four pigs received CytoSorb® and four Oxiris® hemadsorbers. Extracorporeal blood flow was measured in a range between mean arterial pressures of 45-85 mmHg. Mean arterial pressures were preset using intravenous infusions of noradrenaline, urapidil, or increased sedatives. Results: Extracorporeal blood flows remained well above the minimum flows recommended by the manufacturers throughout all MAP steps for both devices. Linear regression resulted in CytoSorb® blood flow [mL/min] = 4.226 × MAP [mmHg] - 3.496 (R-square 0.8133) and Oxiris® blood flow [mL/min] = 3.267 × MAP [mmHg] + 57.63 (R-square 0.8708), respectively. Conclusion: Arteriovenous pumpless extracorporeal hemadsorption resulted in sufficient blood flows through both the CytoSorb® and Oxiris® devices over a wide range of mean arterial blood pressures and is likely an intriguing therapeutic option in the early phase of septic shock or hyperinflammatory syndromes.

Increased prevalence of clonal hematopoiesis of indeterminate potential in hospitalized patients with COVID-19.

Clonal hematopoiesis of indeterminate potential (CHIP) leads to higher mortality, carries a cardiovascular risk and alters inflammation. All three aspects harbor overlaps with the clinical manifestation of COVID-19. This study aimed to identify the impact of CHIP on COVID-19 pathophysiology. 90 hospitalized patients were analyzed for CHIP. In addition, their disease course and outcome were evaluated. With a prevalence of 37.8%, the frequency of a CHIP-driver mutation was significantly higher than the prevalence expected based on median age (17%). CHIP increases the risk of hospitalization in the course of the disease but has no age-independent impact on the outcome within the group of hospitalized patients. Especially in younger patients (45 - 65 years), CHIP was associated with persistent lymphopenia. In older patients (> 65 years), on the other hand, CHIP-positive patients developed neutrophilia in the long run. To what extent increased values of cardiac biomarkers are caused by CHIP independent of age could not be elaborated solely based on this study. In conclusion, our results indicate an increased susceptibility to a severe course of COVID-19 requiring hospitalization associated with CHIP. Secondly, they link it to a differentially regulated cellular immune response under the pressure of SARS-CoV-2 infection. Hence, a patient's CHIP-status bears the potential to serve as biomarker for risk stratification and to early guide treatment of COVID-19 patients.

Plasma Transfusion in Septic Shock-A Secondary Analysis of a Retrospective Single-Center Cohort.

In sepsis, both beneficial and detrimental effects of fresh frozen plasma (FFP) transfusion have been reported. The aim of this study was to analyze the indication for and effect of FFP transfusion in patients with septic shock. We performed a secondary analysis of a retrospective single-center cohort of all patients treated for septic shock at the interdisciplinary surgical intensive care unit (ICU) of the Heidelberg University Hospital. Septic shock was defined according to sepsis-3 criteria. To assess the effects of FFP administration in the early phase of septic shock, we compared patients with and without FFP transfusion during the first 48 h of septic shock. Patients who died during the first 48 h of septic shock were excluded from the analysis. Primary endpoints were 30- and 90-day mortality. A total of 261 patients were identified, of which 100 (38.3%) received FFP transfusion within the first 48 h after septic shock onset. The unmatched analysis showed a trend toward higher 30- and 90-d mortality in the FFP group (30 d: +7% p = 0.261; 90 d: +11.9% p = 0.061). In the propensity-matched analysis, 30- and 90-day mortality were similar between groups. Plasma administration did not influence fluid or vasopressor need, lactate levels, ICU stay, or days on a ventilator. We found no significant harm or associated benefit of FFP use in the early phase of septic shock. Finally, plasma should only be used in patients with a strong indication according to current recommendations, as a conclusive evaluation of the risk-benefit ratio for plasma transfusion in septic shock cannot be made based on the current data.

Rapid Development of Cefiderocol Resistance in Carbapenem-resistant Enterobacter cloacae During Therapy Is Associated With Heterogeneous Mutations in the Catecholate Siderophore Receptor cirA.

We report a case of resistance development toward cefiderocol in a patient with intra-abdominal and bloodstream infections caused by carbapenemase-producing Enterobacter cloacae within 21 days of cefiderocol therapy. Whole genome sequencing revealed heterogeneous mutations in the cirA gene, encoding a catecholate siderophore receptor, conferring phenotypic resistance to cefiderocol.

Hyperspectral imaging for perioperative monitoring of microcirculatory tissue oxygenation and tissue water content in pancreatic surgery - an observational clinical pilot study.

BACKGROUND: Hyperspectral imaging (HSI) could provide extended haemodynamic monitoring of perioperative tissue oxygenation and tissue water content to visualize effects of haemodynamic therapy and surgical trauma. The objective of this study was to assess the capacity of HSI to monitor skin microcirculation and possible relations to perioperative organ dysfunction in patients undergoing pancreatic surgery. METHODS: The hyperspectral imaging TIVITA® Tissue System was used to evaluate superficial tissue oxygenation (StO2), deeper layer tissue oxygenation (near-infrared perfusion index (NPI)), haemoglobin distribution (tissue haemoglobin index (THI)) and tissue water content (tissue water index (TWI)) in 25 patients undergoing pancreatic surgery. HSI parameters were measured before induction of anaesthesia (t1), after induction of anaesthesia (t2), postoperatively before anaesthesia emergence (t3), 6 h after emergence of anaesthesia (t4) and three times daily (08:00, 14:00, 20:00 ± 1 h) at the palm and the fingertips until the second postoperative day (t5-t10). Primary outcome was the correlation of HSI with perioperative organ dysfunction assessed with the perioperative change of SOFA score. RESULTS: Two hundred and fifty HSI measurements were performed in 25 patients. Anaesthetic induction led to a significant increase of tissue oxygenation parameters StO2 and NPI (t1-t2). StO2 and NPI decreased significantly from t2 until the end of surgery (t3). THI of the palm showed a strong correlation with haemoglobin levels preoperatively (t2: r = 0.83, p < 0.001) and 6 h postoperatively (t4: r = 0.71, p = 0.001) but not before anaesthesia emergence (t3: r = 0.35, p = 0.10). TWI of the palm and the fingertip rose significantly between pre- and postoperative measurements (t2-t3). Higher blood loss, syndecan level and duration of surgery were associated with a higher increase of TWI. The perioperative change of HSI parameters (∆t1-t3) did not correlate with the perioperative change of the SOFA score. CONCLUSION: This is the first study using HSI skin measurements to visualize tissue oxygenation and tissue water content in patients undergoing pancreatic surgery. HSI was able to measure short-term changes of tissue oxygenation during anaesthetic induction and pre- to postoperatively. TWI indicated a perioperative increase of tissue water content. Perioperative use of HSI could be a useful extension of haemodynamic monitoring to assess the microcirculatory response during haemodynamic therapy and major surgery. TRIAL REGISTRATION: German Clinical Trial Register, DRKS00017313 on 5 June 2019.

Hyperspectral Imaging for the Evaluation of Microcirculatory Tissue Oxygenation and Perfusion Quality in Haemorrhagic Shock: A Porcine Study.

BACKGROUND: The ultimate goal of haemodynamic therapy is to improve microcirculatory tissue and organ perfusion. Hyperspectral imaging (HSI) has the potential to enable noninvasive microcirculatory monitoring at bedside. METHODS: HSI (Tivita® Tissue System) measurements of tissue oxygenation, haemoglobin, and water content in the skin (ear) and kidney were evaluated in a double-hit porcine model of major abdominal surgery and haemorrhagic shock. Animals of the control group (n = 7) did not receive any resuscitation regime. The interventional groups were treated exclusively with either crystalloid (n = 8) or continuous norepinephrine infusion (n = 7). RESULTS: Haemorrhagic shock led to a drop in tissue oxygenation parameters in all groups. These correlated with established indirect markers of tissue oxygenation. Fluid therapy restored tissue oxygenation parameters. Skin and kidney measurements correlated well. High dose norepinephrine therapy deteriorated tissue oxygenation. Tissue water content increased both in the skin and the kidney in response to fluid therapy. CONCLUSIONS: HSI detected dynamic changes in tissue oxygenation and perfusion quality during shock and was able to indicate resuscitation effectivity. The observed correlation between HSI skin and kidney measurements may offer an estimation of organ oxygenation impairment from skin monitoring. HSI microcirculatory monitoring could open up new opportunities for the guidance of haemodynamic management.

Plasma Exchange in Patients With Severe Coronavirus Disease 2019: A Single-Center Experience.

IMPORTANCE: Recent evidence suggests a multilevel inflammatory syndrome as a driving factor in some of the most severely ill coronavirus disease 2019 patients with overlapping features to other hyperinflammatory or autoimmune diseases. Therefore, plasma exchange is considered as potential therapy in these patients. OBJECTIVES: We characterize the longitudinal therapeutic efficacy and safety profile of plasma exchange in critically ill patients with clinical and laboratory evidences of coronavirus disease 2019-related immunopathology. DESIGN SETTING AND PARTICIPANTS: A retropsective case-control study of critically ill coronavirus disease 2019 patients treated with plasma exchange at Heidelberg University Hospital between March and December 2020. Plasma exchange-treated patients were compared with coronavirus disease 2019 patients on standard therapy matched for age, gender, disease severity, and features of hyperinflammatory syndrome. MAIN OUTCOME AND MEASURES: Mortality rate and course of clinical and laboratory parameters in response to plasma exchange were assessed in coronavirus disease 2019 patients and in patients on standard care. A plasma volume of 50 mL per kg body weight or a maximum of 4 L was exchanged. RESULTS: In total, 28 critically ill coronavirus disease 2019 patients were treated with a median of three plasma exchange procedures per patient. No relevant complications occurred during plasma exchange therapy. Inflammatory and biochemical markers of end-organ damage and endothelial activation were significantly reduced following plasma exchange together with normalization of body temperature, improved pulmonary function, and reduced vasopressor demand. Most importantly, these improvements were maintained after the last plasma exchange. In contrast, no such effects were observed in the control group, although baseline clinical and laboratory parameters were comparable. Kaplan-Meier analysis showed improved 30-day survival in the plasma exchange group compared with the control group (67.9% vs 42.9%; p = 0.044). In a multivariable analysis, the hazard ratio for death was 0.27 (95% CI, 0.11-0.68; p = 0.005) with plasma exchange versus standard care. CONCLUSIONS AND RELEVANCE: Our data provide further evidence for plasma exchange as a novel therapeutic strategy in a subset of critically ill coronavirus disease 2019 patients by potentially reversing the complex coronavirus disease 2019 immunopathology. Randomized controlled trials are underway to confirm these positive results.

Prolonged Infusion of ß-Lactams Decreases Mortality in Patients with Septic Shock: A Retrospective before-and-after Study.

Septic shock substantially alters the pharmacokinetic properties of ß-lactams with a subsequently high risk of insufficiently low serum concentrations and treatment failure. Considering their pharmacokinetic (PK)/pharmacodynamic (PD) index, prolonged infusions (PI) of ß-lactams extend the time that the unbound fraction of the drug remains above the minimal inhibitory concentration MIC (ft >MIC) and may improve patient survival. The present study is a monocentric, retrospective before-and-after analysis of septic shock patients treated with ß-lactams. Patients of the years 2015-2017 received intermittent bolus application whereas patients of 2017-2020 received PI of ß-lactams. The primary outcome was mortality at day 30 and 90 after diagnosis of septic shock. Mortality rates in the PI group were significantly lower on day 30 (PI: 41%, n = 119/290 vs. IB: 54.8%, n = 68/114; p = 0.0097) and day 90 (PI: 47.9%, n = 139/290 vs. IB: 62.9%, n = 78/124; p = 0.005). After propensity-score matching, 30- and 90-day mortality remained lower for the PI group (-10%, p = 0.14). PI was further associated with a reduction in the duration of invasive ventilation and a stronger decrease in SOFA scores within a 14 day-observation period. PI of ß-lactams was associated with a significant reduction of mortality in patients with septic shock and may have beneficial effects on invasive ventilation and recovery from sepsis-related organ failure.

Conservative management of COVID-19 associated hypoxaemia.

This correspondence argues that data presented previously cannot justify a novel approach for treating hypoxic patients with severe #COVID19 https://bit.ly/3dLaPlk.

Pumpless Extracorporeal Hemadsorption Technique: A New Method for Early Cytokine Elimination?

In recent years, extracorporeal hemadsorption (HA) techniques capable of adsorbing pro- and anti-inflammatory cytokines are increasingly used in various clinical situations. The therapeutic benefit of cytokine elimination likely depends on timing. Although treatment seems to be most effective when started within the first 24 h, therapy is often delayed as it must be combined with another extracorporeal circuit. Thus, using a pumpless extracorporeal HA technique might be a valuable option in order to expedite the commencement of cytokine elimination in critically ill patients.