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Competing Interests: Interessenkonflikt: C.J. Reuß, M. Bernhard, C. Beynon, M.O. Fiedler-Kalenka, A. Hecker, C. Jungk, C. Nusshag, D. Michalski, F.C.F. Schmitt, T. Brenner, M.A. Weigand und M. Dietrich geben an, dass kein Interessenkonflikt besteht.

Purpose: Early recognition of sepsis is critical to patient outcome, with mortality increasing with every hour of delay in treatment. The aim of this study was to investigate the use of a point-of-care molecular host response assay to differentiate sepsis from inflammation after surgery., Methods: Three molecular host response assays (SeptiCyte® RAPID) were performed in 61 patients after major abdominal surgery with admission to the intensive care unit and drawn blood cultures. The first (T0) was taken ± 3 h around the time of obtaining blood cultures, the second 24 h later (T24) and the third at discharge from the intensive care unit (Tex). The primary endpoint was the agreement of SeptiCyte® RAPID results with the diagnosis of sepsis. SeptiScore® indicates sepsis probability (low risk 0 - high risk 15). Patients were retrospectively classified into sepsis and inflammation by three blinded experts., Results: 25 (42.4%) patients were categorized as "inflammation" and 34 (57.6%) patients as "sepsis". At T0 and T24 septic patients showed significantly higher mean SeptiScores® of 8.0 (± 2.2 SD) vs. 6.3 (± 2.1 SD) and 8.5 (± 2.1 SD) vs. 6.2 (± 1.8 SD), respectively. The Receiver Operating Curves (ROC) for the ability to discriminate between sepsis and inflammation had an Area Under the Curve (AUC) of 0.71 (T0) and 0.80 (T24)., Conclusion: Embedded in a comprehensive diagnostic algorithm molecular host response analysis could broaden the possibilities for infection diagnostics to differentiate between sepsis and inflammatory response after surgery. But validation in larger cohorts is needed., Competing Interests: Declarations. Competing interests: Beside the funding of the study, the authors declare to have no conflict of interest., (© 2024. The Author(s).)

Background : At present, there is a paucity of data in the literature pertaining to the impact of radiotherapy (RT) on the success of tracheal intubation in patients with nasopharyngeal cancer (NPC). The aim of this study is to investigate the frequency of difficult tracheal intubation in patients with NPC following RT. Methods : Patients with NPC who underwent RT followed by surgery between 2012 and April 2024 at the University Hospital Heidelberg were retrospectively analyzed. Results : Twenty-three patients, predominantly males (73.9%) with a mean age of 52.9 years, were enrolled. Overall, 65.2% of the patients had an American Society of Anesthesiologists (ASA) class of III. The mean total laryngeal dose was 53.5 Gy for the main and boost plan, and the maximum total laryngeal dose was 66.61 Gy. Direct laryngoscopy was performed in 69.6% of cases, followed by 26.1% videolaryngoscopy, and 4.2% required fiberoptic intubation. In total, 47.8% of the patients had a Cormack/Lehane grade of I, followed by 43.5% with grade II and 8.7% with grade III. Overall, 87% of patients were successfully intubated on the first attempt. Conclusions : It has been demonstrated by previous studies that RT has the potential to enhance complications and difficulties encountered during airway management. While the results must be interpreted with caution, our study provides no evidence of severe impairment in advanced airway management in patients with nasopharyngeal cancer who have undergone radiotherapy.

Background: Hepatic chemosaturation for inoperable liver tumors is a palliative treatment option with a beneficial effect on survival. However, the procedure regularly leads to circulatory failure during the filtration phase, and hemodynamic management is challenging. Our study aimed to compare two different strategies for hemodynamic management during chemosaturation to develop hypotheses for improving patient care and reducing peri-interventional morbidity. Methods: We conducted a single-center retrospective cohort study including 66 procedures of chemosaturation between May 2016 and March 2024. Procedures were divided into two groups: group 1 was managed with norepinephrine as the only vasopressor and liberal use of hydroxyethyl starch (HES). Group 2 was managed with norepinephrine and vasopressin and the preferred use of balanced crystalloids. We compared these two groups with respect to hemodynamic parameters, laboratory values, and post-interventional complications. Results: The heart rate was highest and the mean arterial pressure (MAP) was lowest during the filtration phase in both groups ( p = 0.868, p = 0.270). The vasoactive inotropic score (VIS) was significantly higher in group 2 during the filtration phase (31.5 vs. 89, p < 0.001). Group 1 received significantly more HES overall (1000 mL vs. 0 mL, p < 0.001). Lactate levels at admission to the ICU were higher in group 1 (22.9 vs. 14.45 mg/dL, p = 0.041). Platelet counts were lower in group 2 from directly after chemosaturation through day 2 ( p = 0.022, p = 0.001, p = 0.032). The INR differed significantly directly after chemosaturation (1.13 vs. 1.26, p = 0.015). Overall, group 1 received significantly more blood products peri-interventionally. There were two bleedings and one ischemic stroke in the overall cohort. There was no peri-interventional mortality. Conclusions: Advanced hemodynamic management ensures low peri-interventional mortality and morbidity. High-dose vasopressors, including vasopressin and the preferred use of balanced crystalloids, are sufficient to stabilize circulatory function during chemosaturation.

Introduction: Viscoelastic hemostatic assays (VHA) are integral in contemporary hemostatic resuscitation, offering insights into clot formation, firmness, and lysis for rapid diagnosis and targeted therapy. Large animal models, particularly swine, provide anatomical and physiological analogies for coagulation research. Despite the growing use of VHAs, the ClotPro ® device's applicability in porcine models remains unexplored. This study investigates ClotPro ® in a porcine model of abdominal surgery, severe hemorrhage, and resuscitation, comparing it with the established ROTEM ® delta system., Methods: Twenty-seven healthy pigs underwent abdominal surgery, hemorrhage and resuscitation. ClotPro ® and ROTEM ® were used to assess viscoelastic hemostatic properties at baseline, after surgery, 60 min after shock induction, 60 and 120 min after resuscitation., Results: Clotting times in extrinsically and intrinsically stimulated assays exhibited fair to moderate correlation. Clot firmness in extrinsically stimulated tests could be used interchangeably while fibrin polymerization assays revealed significant differences between the devices. Fibrin polymerization assays in ClotPro ® consistently yielded higher values than ROTEM ® . Furthermore, the study evaluated the ClotPro ® TPA-test's applicability in porcine blood, revealing failure of lysis induction in porcine blood samples., Conclusion: This research contributes valuable insights into the use of ClotPro ® in porcine models of hemorrhage and coagulopathy, highlighting both its applicability and limitations in comparison to ROTEM ® delta. The observed differences, especially in fibrin polymerization assays, emphasize the importance of understanding device-specific characteristics when interpreting results. Due to its inapplicability, TPA-test should not be used in porcine blood to evaluate fibrinolytic potential. The study provides a foundation for future investigations into the use of different viscoelastic hemostatic assays in porcine animal models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gruneberg, Dietrich, Studier-Fischer, Petersen, von der Forst, Özdemir, Schöchl, Nickel, Weigand and Schmitt.)

(1) Background: Currently, no data are available in the literature investigating the influence of radiotherapy (RT) on endotracheal intubation success in patients with esophageal cancer. This study aims to evaluate the impact of RT on endotracheal intubation quality metrics in patients with esophageal cancer. (2) Methods: Patients with esophageal cancer who underwent RT followed by surgery between 2012 and 2023 at the University Hospital Heidelberg, Germany, were retrospectively analyzed. (3) Results: Fifty-five patients, predominantly males 65.5% with a mean age of 64 years, were enrolled. Overall, 81.8% of the patients had an ASA class of III, followed by 27.2% ASA II. The mean prescribed cumulative total dose to the primary tumor and lymph node metastasis was 48.2 Gy with a mean single dose of 1.8 Gy. The mean laryngeal total dose was 40.0 Gy. Direct laryngoscopy was performed in 80.0% of cases, followed by 12.1% videolaryngoscopy, and 7.2% required fiberoptic intubation. Overall, 96.4% of patients were successfully intubated on the first attempt. (4) Conclusions: It has been demonstrated that post-RT effects can increase the risk of airway management difficulties and complications. The results of our study did not indicate any evidence of impaired advanced airway management in patients with esophageal cancer who had undergone RT.

Introduction: Oncologic esophagectomy is a two-cavity procedure with considerable morbidity and mortality. Complex anatomy and the proximity to major vessels constitute a risk for massive intraoperative hemorrhage. Currently, there is no conclusive consensus on the ideal anesthesiologic countermeasure in case of such immense blood loss. The objective of this work was to identify the most promising anesthesiologic management in case of intraoperative hemorrhage with regards to tissue perfusion of the gastric conduit during esophagectomy using hyperspectral imaging (HSI)., Material and Methods: An established live porcine model (n=32) for esophagectomy was used with gastric conduit formation and simulation of a linear stapled side-to-side esophagogastrostomy. After a standardized procedure of controlled blood loss of about 1 L per pig, the four experimental groups (n=8 each) differed in anesthesiologic intervention i.e. (I) permissive hypotension, (II) catecholamine therapy using noradrenaline, (III) crystalloid volume supplementation and (IV) combined crystalloid volume supplementation with noradrenaline therapy. HSI tissue oxygenation (StO2) of the gastric conduit was evaluated and correlated with systemic perfusion parameters. Measurements were conducted before (T0) and after (T1) laparotomy, after hemorrhage (T2) and 60 minutes (T3) and 120 minutes (T4) after anesthesiologic intervention., Results: StO2 values of the gastric conduit showed significantly different results between the four experimental groups with 63.3% (±7.6%) after permissive hypotension (I), 45.9% (±6.4%) after catecholamine therapy (II), 70.5% (±6.1%) after crystalloid volume supplementation (III) and 69.0% (±3.7%) after combined therapy (IV). StO2 values correlated strongly with systemic lactate values (r=-0.67; CI -0.77 to -0.54), which is an established prognostic factor., Conclusion: Crystalloid volume supplementation (III) yields the highest StO2 values and lowest systemic lactate values and therefore appears to be the superior primary treatment strategy after hemorrhage during esophagectomy with regards to microcirculatory tissue oxygenation of the gastric conduit., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Acute kidney injury (AKI) is a common complication in patients undergoing major vascular surgery. Despite significant research efforts in this area, the incidence of AKI remains high, posing a significant challenge to healthcare systems, especially in situations where resources are limited. Early prediction of AKI severity and individualized postoperative care is therefore essential., Methods: The primary objective of this exploratory study was to assess the diagnostic value of urine cell-cycle arrest biomarkers [(TIMP-2) × (IGFBP7)] and soluble urokinase plasminogen activator receptor (suPAR) for predicting moderate or severe AKI within 24 h after open aortic surgery, and compared to routine kidney biomarkers. Seventy-five patients undergoing elective aortic surgery were included. Clinical parameters, urine and blood samples were collected preoperatively, immediately postoperatively, and 24 h later. AKI was defined using KDIGO criteria. Individual and combined diagnostic performance of biomarkers were evaluated., Results: Of the 75 patients, 61% developed AKI, of which 28% developed moderate or severe AKI within 24 h of surgery. Baseline demographics, comorbidities and kidney parameters did not differ between patients with moderate or severe AKI (AKI II/III) and none or mild AKI (AKI 0/I), except for higher preoperative suPAR levels in later AKI II/III patients. Urine osmolality, Cystatin C and serum creatinine had the highest predictive power for AKI II/III with AUCs of 0.75-0.72. (TIMP-2) × (IGFBP7), and neither (TIMP-2) × (IGFBP7) nor suPAR individually showed superior diagnostic value. Combining CysC or SCr with urine osmolality and 6 h urine output gave the best performance with AUCs of 0.86 (95% CI, 0.74-0.96) and 0.85 (95% CI, 0.75-0.95) respectively., Conclusion: Our study suggests that routine parameters like urine osmolality, CysC, SCr and 6 h urine output perform best in predicting postoperative AKI after aortic surgery compared to the new biomarkers (TIMP-2) × (IGFBP7) and suPAR. Combining biomarkers, particularly CysC or SCr with urine output, urine osmolality, may enhance diagnostic accuracy. Further validation in larger cohorts and clinical settings is warranted to establish their clinical utility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nusshag, Theobald, Wortmann, Kaimann, Dietrich, Gruneberg, Tourelle, von der Forst, Weigand, Bischoff, Böckler and Schmitt.)

Purpose: Infections are common complications in patients following liver transplantation (LTX). The early diagnosis and prognosis of these infections is an unmet medical need even when using routine biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT). Therefore, new approaches are necessary., Methods: In a prospective, observational pilot study, we monitored 30 consecutive patients daily between days 0 and 13 following LTX using the 29-mRNA host classifier IMX-BVN-3b that determine the likelihood of bacterial infections and viral infections. True infection status was determined using clinical adjudication. Results were compared to the accuracy of CRP and PCT for patients with and without bacterial infection due to clinical adjudication., Results: Clinical adjudication confirmed bacterial infections in 10 and fungal infections in 2 patients. 20 patients stayed non-infected until day 13 post-LTX. IMX-BVN-3b bacterial scores were increased directly following LTX and decreased until day four in all patients. Bacterial IMX-BVN-3b scores detected bacterial infections in 9 out of 10 patients. PCT concentrations did not differ between patients with or without bacterial, whereas CRP was elevated in all patients with significantly higher levels in patients with bacterial infections., Conclusion: The 29-mRNA host classifier IMX-BVN-3b identified bacterial infections in post-LTX patients and did so earlier than routine biomarkers. While our pilot study holds promise future studies will determine whether these classifiers may help to identify post-LTX infections earlier and improve patient management., Clinical Trial Notation: German Clinical Trials Register: DRKS00023236, Registered 07 October 2020, https://drks.de/search/en/trial/DRKS00023236., (© 2024. The Author(s).)

Background: Medical research aims to improve patient safety and efficiency in the perioperative setting. One critical aspect of patient safety is the intrahospital transfer of patients. Also, reliable monitoring of vital signs is crucial to support the medical staff. This study was conducted to assess two monitoring systems in terms of the handover time and staff satisfaction., Methods: To assess several aspects, two monitoring systems were compared: an organizational unit-related monitoring system that needs to be changed and brought back to the initial organizational unit after the patient transfer and a patient-specific monitoring system that accompanies the patient during the whole perioperative process., Results: In total, 243 patients were included, and 375 transfers were examined to analyze economic factors, including differences in handover times and user-friendliness. To this end, 30 employees of the Heidelberg University Hospital were asked about their satisfaction with the two monitoring systems based on a systematic questionnaire. It could be shown that, especially during transfers from the operating theater to the intensive care unit or the recovery room, the time from arrival to fully centralized monitoring and the total handover time were significantly shorter with the patient-specific monitoring system (p < 0.001). Furthermore, the staff was more satisfied with the patient-specific monitor system in terms of flexibility, cleanability and usability., Conclusion: The increased employee satisfaction and significant time benefits during intrahospital transports may increase patient safety and efficiency of patient care, reduce employee workload, and reduce costs in the overall context of patient care., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Tourelle et al.)

Purpose of Review: Direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic events. Thus, trauma care providers are facing a steadily raising number of injured patients on DOACs., Recent Findings: Despite a predictable pharmacokinetic profile, the resulting plasma levels of trauma patients upon admission and bleeding risks remain uncertain. Therefore, recent guidelines recommend the measurement of DOAC plasma concentrations in injured patients. Alternatively, DOAC specific visco-elastic tests assays can be applied to identify DOAC patients at bleeding risk.Bleeding complications in trauma patients on DOACs are generally higher compared to nonanticoagulated subjects, but comparable to vitamin K antagonists (VKAs). In particular, a traumatic brain injury does not carry an increased risk of intracranial bleeding due to a DOAK intake compared to VKAs. Current studies demonstrated that up to 14% of patients with a hip fracture are on DOACs prior to surgery. However, the majority can be operated safely within a 24h time window without an increased bleeding rate.Specific antagonists facilitate rapid reversal of patients on DOACs. Idarucizumab for dabigatran, and andexanet alfa for apixaban and rivaroxaban have been approved for life threatening bleeding. Alternatively, prothrombin complex concentrate can be used. Dialysis is a potential treatment option for dabigatran and haemoabsorption with special filters can be applied in patients on FXa-inhibitors., Summary: Current guidelines recommend the measurement of DOAC plasma levels in trauma patients. Compared to VKAs, DOACs do not carry a higher bleeding risk. DOAC specific antagonists facilitate the individual bleeding management., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Viscoelastic test (VET) procedures suitable for point-of-care (POC) testing are in widespread clinical use. Due to the expanded range of available devices and in particular due to the development of new test approaches and methods, the authors believe that an update of the current treatment algorithms is necessary. The aim of this article is to provide an overview of the currently available VET devices and the associated reagents. In addition, two treatment algorithms for the VET devices most commonly used in German-speaking countries are presented., (© 2024. The Author(s).)

Trauma-induced coagulopathy (TIC) is a complex hemostatic disturbance that can develop early after a major injury. There is no universally accepted definition of TIC. However, TIC primarily refers to the inability to achieve sufficient hemostasis in severely injured trauma patients, resulting in diffuse microvascular and life-threatening bleeding. Endogenous TIC is driven by the combination of hypovolemic shock and substantial tissue injury, resulting in endothelial damage, glycocalyx shedding, upregulated fibrinolysis, fibrinogen depletion, altered thrombin generation, and platelet dysfunction. Exogenous factors such as hypothermia, acidosis, hypokalemia, and dilution due to crystalloid and colloid fluid administration can further exacerbate TIC. Established TIC upon emergency room admission is a prognostic indicator and is strongly associated with poor outcomes. It has been shown that patients with TIC are prone to higher bleeding tendencies, increased requirements for allogeneic blood transfusion, higher complication rates such as multi-organ failure, and an almost fourfold increase in mortality. Thus, early recognition and individualized treatment of TIC is a cornerstone of initial trauma care. However, patients who survive the initial insult switch from hypocoagulability to hypercoagulability, also termed "late TIC," with a high risk of developing thromboembolic complications., Competing Interests: HS: Consulting fees: Octapharm, Alexion; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: CSL Behring, Bristol Mayers Squipp, Haemonetics.FCFS: Consulting fees: CSL Behring, Roche Diabetes; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: CSL Behring, AstraZeneca, LFBMM: Grants or contracts from any entity: Astra Zeneca, Baxter, Bayer, Biotest, CSL Behring, LFB Biomedicaments, IL-Werfen, TEM International, Octapharma, Portola; Consulting fees: Astra Zeneca, Baxter, Bayer, Biotest, CSL Behring, LFB Biomedicaments, IL-Werfen, TEM International, Octapharma, Portola; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Astra Zeneca, Baxter, Bayer, Biotest, CSL Behring, LFB Biomedicaments, IL-Werfen, TEM International, Octapharma, Portola; Support for attending meetings and/or travel: Astra Zeneca, CSL Behring, LFB Biomedicaments, IL-Werfen, TEM International, Octapharma; Participation on a Data Safety Monitoring Board or Advisory Board: Astra Zeneca, Baxter, Bayer, Biotest, CSL Behring, LFB Biomedicaments, IL-Werfen, TEM International, Octapharma, Portola., (Thieme. All rights reserved.)

Background : Viscoelastic hemostatic assays (VHAs) have become an integral diagnostic tool in guiding hemostatic therapy, offering new opportunities in personalized hemostatic resuscitation. This study aims to assess the interchangeability of ClotPro® and ROTEM® delta in the unique context of parturient women. Methods : Blood samples from 217 parturient women were collected at three timepoints. A total of 631 data sets were eligible for our final analysis. The clotting times were analyzed via extrinsic and intrinsic assays, and the clot firmness parameters A5, A10, and MCF were analyzed via extrinsic, intrinsic, and fibrin polymerization assays. In parallel, the standard laboratory coagulation statuses were obtained. Device comparison was assessed using regression and Bland-Altman plots. The best cutoff calculations were used to determine the VHA values corresponding to the established standard laboratory cutoffs. Results : The clotting times in the extrinsic and intrinsic assays showed notable differences between the devices, while the extrinsic and intrinsic clot firmness results demonstrated interchangeability. The fibrinogen assays revealed higher values in ClotPro ® compared to ROTEM ® . An ROC analysis identified VHA parameters with high predictive values for coagulopathy exclusion and yet low specificity. Conclusions : In the obstetric setting, the ROTEM ® and ClotPro ® parameters demonstrate a significant variability. Device- and indication-specific transfusion algorithms are essential for the accurate interpretation of measurements and adequate hemostatic therapy.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor and plays a critical role in the immune response. TREM-1 activation leads to the production and release of proinflammatory cytokines, chemokines, as well as its own expression and circulating levels of the cleaved soluble extracellular portion of TREM-1 (sTREM-1). Because patients with sepsis and septic shock show elevated sTREM-1 levels, TREM-1 has attracted attention as an important contributor to the inadequate immune response in this often-deadly condition. Since 2001, when the first blockade of TREM-1 in sepsis was performed, many potential TREM-1 inhibitors have been established in animal models. However, only one of them, nangibotide, has entered clinical trials, which have yielded promising data for future treatment of sepsis, septic shock, and other inflammatory disease such as COVID-19. This review discusses the TREM-1 pathway and important ligands, and highlights the development of novel inhibitors as well as their clinical potential for targeted treatment of various inflammatory conditions., (© 2024. The Author(s).)

Purpose of Review: The purpose of this review is to consider the clinical value of point-of-care (POC) testing in coagulopathic trauma patients with traumatic brain injury (TBI) and trauma-induced coagulopathy (TIC)., Recent Findings: Patients suffering from severe TBI or TIC are at risk of developing pronounced haemostatic disorders. Standard coagulation tests (SCTs) are insufficient to reflect the complexity of these coagulopathies. Recent evidence has shown that viscoelastic tests (VETs) identify haemostatic disorders more rapidly and in more detail than SCTs. Moreover, VET results can guide coagulation therapy, allowing individualised treatment, which decreases transfusion requirements. However, the impact of VET on mortality remains uncertain. In contrast to VETs, the clinical impact of POC platelet function testing is still unproven., Summary: POC SCTs are not able to characterise the complexity of trauma-associated coagulopathy. VETs provide a rapid estimation of underlying haemostatic disorders, thereby providing guidance for haemostatic therapy, which impacts allogenic blood transfusion requirements. The value of POC platelet function testing to identify platelet dysfunction and guide platelet transfusion is still uncertain., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Postpartum hemorrhage (PPH) is still the leading cause of maternal morbidity and mortality worldwide. While impaired fibrin polymerization plays a crucial role in the development and progress of PPH, recent approaches using viscoelastic measurements have failed to sensitively detect early changes in fibrinolysis in PPH. This study aimed to evaluate whether women experiencing PPH show alterations in POC-VET fibrinolytic potential during childbirth and whether fibrinolytic potential offers benefits in the prediction and treatment of PPH., Methods: Blood samples were collected at three different timepoints: T0 = hospital admission (19 h ± 18 h prepartum), T1 = 30-60 min after placental separation, and T2 = first day postpartum (19 h ± 6 h postpartum). In addition to standard laboratory tests, whole-blood impedance aggregometry (Multiplate) and viscoelastic testing (VET) were performed using the ClotPro system, which included the TPA-test lysis time, to assess the POC-VET fibrinolytic potential, and selected coagulation factors were measured. The results were correlated with blood loss and clinical outcome markers. Severe PPH was defined as a hemoglobin drop > 4g/dl and/or the occurrence of shock or the need for red blood cell transfusion., Results: Blood samples of 217 parturient women were analyzed between June 2020 and December 2020 at Heidelberg University Women's Hospital, and 206 measurements were eligible for the final analysis. Women experiencing severe PPH showed increased fibrinolytic potential already at the time of hospital admission. When compared to non-PPH, the difference persisted 30-60 min after placental separation. A higher fibrinolytic potential was accompanied by a greater drop in fibrinogen and higher d-dimer values after placental separation. While 70% of women experiencing severe PPH showed fibrinolytic potential, 54% of those without PPH showed increased fibrinolytic potential as well., Conclusion: We were able to show that antepartal and peripartal fibrinolytic potential was elevated in women experiencing severe PPH. However, several women showed high fibrinolytic potential but lacked clinical signs of PPH. The findings indicate that high fibrinolytic potential is a risk factor for the development of coagulopathy, but further conditions are required to cause PPH., Competing Interests: HS has received honoraria for participation in advisory board meetings for Alexion, Bayer Healthcare, Boehringer Ingelheim, Haemonetics and Vifor, and has received study grants and speaker's honorarium from CSL Behring. FS has received research support from CSL Behring and Philips, as well as speaker honorarium from CSL Behring and AstraZeneca and he is a consultant in an advisory board for CSL Behring. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Enicor (consumables). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2023 Gruneberg, Braun, Schöchl, Nachtigall-Schmitt, von der Forst, Tourelle, Dietrich, Wallwiener, Wallwiener, Weigand, Fluhr, Spratte, Hofer and Schmitt.)

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.

Sepsis is defined as organ failure caused by dysregulated host response to infection. While early antibiotic treatment in patients with acute infection is essential, treating non-infectious patients must be avoided. Current guidelines recommend procalcitonin (PCT) to guide discontinuation of antibiotic treatment. For initiation of therapy, there is currently no recommended biomarker. In this study, we evaluated Host-Derived Delta-like Canonical Notch Ligand 1 (DLL1), a monocyte membrane ligand that has shown promising results in differentiating infectious from non-infectious critically ill patients. Soluble DLL1 levels were measured in plasma samples of six different cohorts. The six cohorts comprise two cohorts with non-infectious inflammatory auto-immune diseases (Hidradenitis Suppurativa, Inflammatory Bowel Disease), one cohort of bacterial skin infection, and three cohorts of suspected systemic infection or sepsis. In total, soluble DLL1 plasma levels of 405 patients were analyzed. Patients were divided into three groups: inflammatory disease, infection, and sepsis (defined according to the Sepsis-3 definition), followed by the evaluation of its diagnostic performance via Area Under the Receiver Operating Characteristics (AUROC) analyses. Patients of the sepsis group showed significantly elevated plasma DLL1 levels compared to patients with uncomplicated infections and sterile inflammation. However, patients with infections had significantly higher DLL1 levels than patients with inflammatory diseases. Diagnostic performance was evaluated and showed better performance for DLL1 for the recognition of sepsis (AUC: 0.823; CI 0.731-0.914) than C-reactive protein (AUC 0.758; CI 0.658-0.857), PCT (AUC 0.593; CI 0.474-0.711) and White Blood Cell count (AUC 0.577; CI 0.46-0.694). DLL1 demonstrated promising results for diagnosing sepsis and was able to differentiate sepsis from other infectious and inflammatory diseases., Competing Interests: Markus A. Weigand holds patent EP/25.10.17/EPA17198330 Delta like ligand for diagnosing severe infections and is co-founder of the Delta Theragnostics GmbH. All other authors declare no conflict of interest.

Impaired consciousness is a frequent phenomenon after general anesthesia. In addition to the classical causes (e.g., overhang of sedatives), an impairment of consciousness can also be an adverse side effect of drugs. Many drugs used in anesthesia can trigger these symptoms. Alkaloids, such as atropine can trigger a central anticholinergic syndrome, opioids can promote the occurrence of serotonin syndrome and the administration of a neuroleptic can lead to neuroleptic malignant syndrome. These three syndromes are difficult to diagnose due to the individually very heterogeneous symptoms. Mutual symptoms, such as impaired consciousness, tachycardia, hypertension and fever further complicate the differentiation between the syndromes; however, more individual symptoms, such as sweating, muscle tension or bowl sounds can be helpful in distinguishing these syndromes. The time from the trigger event can also help to differentiate the syndromes. The central anticholinergic syndrome is the fastest to appear, usually taking just a few of hours from trigger to clinical signs, serotonin syndrome takes several hours up to 1 day to show and neuroleptic malignant syndrome usually takes days. The clinical symptoms can range from mild to life-threatening. Generally, mild cases are treated with discontinuation of the trigger and extended observation. More severe cases can require specific antidotes. The specific treatment recommended for central anticholinergic syndrome is physostigmine with an initial dose of 2 mg (0.04 mg/kg body weight, BW) administered over 5 min. For serotonin syndrome an initial dose of 12 mg cyproheptadine followed by 2 mg every 2 h is recommended (maximum 32 mg/day or 0.5 mg/kgBW day -1 ) but this medication is only available in Germany as an oral formulation. For neuroleptic malignant syndrome 25-120 mg dantrolene (1-2.5 mg/kgBW maximum 10 mg/kgBW day -1 ) is the recommended treatment., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fiedler, Böckler, Giese, Popp, Schmitt, Weigand and Erhart.)

Impaired consciousness is a frequent phenomenon after general anesthesia. In addition to the classical causes (e.g., overhang of sedatives), an impairment of consciousness can also be an adverse side effect of drugs. Many drugs used in anesthesia can trigger these symptoms. Alkaloids, such as atropine can trigger a central anticholinergic syndrome, opioids can promote the occurrence of serotonin syndrome and the administration of a neuroleptic can lead to neuroleptic malignant syndrome. These three syndromes are difficult to diagnose due to the individually very heterogeneous symptoms. Mutual symptoms, such as impaired consciousness, tachycardia, hypertension and fever further complicate the differentiation between the syndromes; however, more individual symptoms, such as sweating, muscle tension or bowl sounds can be helpful in distinguishing these syndromes. The time from the trigger event can also help to differentiate the syndromes. The central anticholinergic syndrome is the fastest to appear, usually taking just a few of hours from trigger to clinical signs, serotonin syndrome takes several hours up to 1 day to show and neuroleptic malignant syndrome usually takes days. The clinical symptoms can range from mild to life-threatening. Generally, mild cases are treated with discontinuation of the trigger and extended observation. More severe cases can require specific antidotes. The specific treatment recommended for central anticholinergic syndrome is physostigmine with an initial dose of 2 mg (0.04 mg/kg body weight, BW) administered over 5 min. For serotonin syndrome an initial dose of 12 mg cyproheptadine followed by 2 mg every 2 h is recommended (maximum 32 mg/day or 0.5 mg/kgBW day -1 ) but this medication is only available in Germany as an oral formulation. For neuroleptic malignant syndrome 25-120 mg dantrolene (1-2.5 mg/kgBW maximum 10 mg/kgBW day -1 ) is the recommended treatment., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, ein Teil von Springer Nature 2023.)

Infants and children with complex chronic diseases have lifelong, life-threatening conditions and for many, early death is an unavoidable outcome of their disease process. But not all chronic diseases in children are fatal when treated well. Cardiopulmonary resuscitation is more common in children with chronic diseases than in healthy children. Resuscitation of infants and children presents significant challenges to physicians and healthcare providers. Primarily, these situations occur only rarely and are therefore not only medically demanding but also associated with emotional stress. In case of resuscitation in infants and children with chronic diseases these challenges become much more complex. The worldwide valid Pediatric Advanced Life Support Guidelines do not give clear recommendations how to deal with periarrest situations in chronically ill infants and children. For relevant life-limiting illnesses, a "do not resuscitate" order should be discussed early, taking into account medical, ethical, and emotional considerations. The decision to terminate resuscitative efforts in cardiopulmonary arrest in infants and children with chronic illnesses such as severe lung disease, heart disease, or even incurable cancer is complex and controversial among physicians and parents. Judging the "outcome" of resuscitation as a "good" outcome becomes complex because for some, life extension itself and for others, quality of life is a goal. Physicians often decide that a healthy child is more likely to have a reversible condition and thereby have a better outcome than a child with multiple comorbidities and chronic health care needs. Major challenges in resuscitation infants and children are that clinicians need to individualize resuscitation strategies in light of each chronic disease, anatomy and physiology. This review aims to highlight terms of resuscitation infants and children with complex chronic diseases, considering resuscitation-related factors, parent-related factors, patient-related factors, and physician-related factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Uzun, Lang, Saur, Weigand and Schmitt.)

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.

Within the approved indications direct oral anticoagulants (DOAC) are increasingly gaining acceptance instead of vitamin K antagonists (VKA). In the last 12 months 5 guidelines relevant to the perioperative management of DOACs have been updated. This article summarizes the current recommendations for the perioperative management of treatment with DOACs. The available substances and their pharmacological properties as well as the possibilities for specific laboratory diagnostics of the effect of DOAC are explained. Special focus is placed on anesthesiologically important aspects of substance-specific preoperative and postoperative intermission intervals, the procedure for neuraxial regional anesthesia and antagonization with specific antidotes in cases of life-threatening bleeding., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

In this observational prospective multicenter study conducted between October 2016 and October 2018, we tested the hypothesis that the use of prehospital non-invasive ventilation (phNIV) to treat patients with acute respiratory insufficiency (ARI) caused by severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and acute cardiopulmonary oedema (ACPE) is effective, time-efficient and safe. The data were collected at four different physician response units and three admitting hospitals in a German EMS system. Patients with respiratory failure due to acute exacerbation of chronic obstructive pulmonary disease and acute cardiopulmonary oedema were enrolled. A total of 545 patients were eligible for the final analysis. Patients were treated with oxygen supplementation, non-invasive ventilation or invasive mechanical ventilation. The primary outcomes were defined as changes in the clinical parameters and the in-hospital course. The secondary outcomes included time efficiency, peri-interventional complications, treatment failure rate, and side-effects. Oxygenation under phNIV improved equally to endotracheal intubation (ETI), and more effectively in comparison to standard oxygen therapy (SOT) (paO2 SOT vs. non-invasive ventilation (NIV) vs. ETI: 82 mmHg vs. 125 mmHg vs. 135 mmHg, p-value SOT vs. NIV < 0.0001). In a matched subgroup analysis phNIV was accompanied by a reduced time of mechanical ventilation (phNIV: 1.8 d vs. ETI: 4.2 d) and a shortened length of stay at the intensive care unit (3.4 d vs. 5.8 d). The data support the hypothesis that the treatment of severe AECOPD/ACPE-induced ARI using prehospital NIV is effective, time efficient and safe. Compared to ETI, a matched comparison supports the hypothesis that prehospital implementation of NIV may provide benefits for an in-hospital course.

Factor XIII (FXIII) is a protein involved in blood clot stabilisation which also plays an important role in processes including trauma, wound healing, tissue repair, pregnancy, and even bone metabolism. Following surgery, low FXIII levels have been observed in patients with peri-operative blood loss and FXIII administration in those patients was associated with reduced blood transfusions. Furthermore, in patients with low FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing. Increasing awareness of potentially low FXIII levels in specific patient populations could help identify patients with acquired FXIII deficiency; although opinions and protocols vary, a cut-off for FXIII activity of ~ 60-70% may be appropriate to diagnose acquired FXIII deficiency and guide supplementation. This narrative review discusses altered FXIII levels in trauma, surgery and wound healing, diagnostic approaches to detect FXIII deficiency and clinical guidance for the treatment of acquired FXIII deficiency., (© 2022. The Author(s).)

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.

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., (© 2021. The Author(s).)

Next-generation sequencing (NGS) has been further optimised during the last years and has given us new insights into the human microbiome. The 16S rDNA sequencing, especially, is a cheap, fast, and reliable method that can reveal significantly more microorganisms compared to culture-based diagnostics. It might be a useful method for patients suffering from severe sepsis and at risk of organ failure because early detection and differentiation between healthy and harmful microorganisms are essential for effective therapy. In particular, the gut and lung microbiome in critically ill patients have been probed by NGS. For this review, an iterative approach was used. Current data suggest that an altered microbiome with a decreased alpha-diversity compared to healthy individuals could negatively influence the individual patient's outcome. In the future, NGS may not only contribute to the diagnosis of complications. Patients at risk could also be identified before surgery or even during their stay in an intensive care unit. Unfortunately, there is still a lack of knowledge to make precise statements about what constitutes a healthy microbiome, which patients exactly have an increased perioperative risk, and what could be a possible therapy to strengthen the microbiome. This work is an iterative review that presents the current state of knowledge in this field.

The therapy of gastrointestinal carcinomas includes surgery, chemo- or immunotherapy, and radiation with diverse complications such as surgical-site infection and enteritis. In recent years, the microbiome's influence on different diseases and complications has been studied in more detail using methods such as next-generation sequencing. Due to the relatively simple collectivisation, the gut microbiome is the best-studied so far. While certain bacteria are sometimes associated with one particular complication, it is often just the loss of alpha diversity linked together. Among others, a strong influence of Fusobacterium nucleatum on the effectiveness of chemotherapies is demonstrated. External factors such as diet or specific medications can also predispose to dysbiosis and lead to complications. In addition, there are attempts to treat developed dysbiosis, such as faecal microbiota transplant or probiotics. In the future, the underlying microbiome should be investigated in more detail for a better understanding of the precipitating factors of a complication with specific therapeutic options.

Introduction: Microcirculatory alterations are key mechanisms in sepsis pathophysiology leading to tissue hypoxia, edema formation, and organ dysfunction. Hyperspectral imaging (HSI) is an emerging imaging technology that uses tissue-light interactions to evaluate biochemical tissue characteristics including tissue oxygenation, hemoglobin content and water content. Currently, clinical data for HSI technologies in critical ill patients are still limited., Methods and Analysis: TIVITA® Tissue System was used to measure Tissue oxygenation (StO2), Tissue Hemoglobin Index (THI), Near Infrared Perfusion Index (NPI) and Tissue Water Index (TWI) in 25 healthy volunteers and 25 septic patients. HSI measurement sites were the palm, the fingertip, and a suprapatellar knee area. Septic patients were evaluated on admission to the ICU (E), 6 h afterwards (E+6) and three times a day (t3-t9) within a total observation period of 72 h. Primary outcome was the correlation of HSI results with daily SOFA-scores., Results: Serial HSI at the three measurement sites in healthy volunteers showed a low mean variance expressing high retest reliability. HSI at E demonstrated significantly lower StO2 and NPI as well as higher TWI at the palm and fingertip in septic patients compared to healthy volunteers. StO2 and TWI showed corresponding results at the suprapatellar knee area. In septic patients, palm and fingertip THI identified survivors (E-t4) and revealed predictivity for 28-day mortality (E). Fingertip StO2 and THI correlated to SOFA-score on day 2. TWI was consistently increased in relation to the TWI range of healthy controls during the observation time. Palm TWI correlated positively with SOFA scores on day 3., Discussion: HSI results in septic patients point to a distinctive microcirculatory pattern indicative of reduced skin oxygenation and perfusion quality combined with increased blood pooling and tissue water content. THI might possess risk-stratification properties and TWI could allow tissue edema evaluation in critically ill patients., Conclusion: HSI technologies could open new perspectives in microcirculatory monitoring by visualizing oxygenation and perfusion quality combined with tissue water content in critically ill patients - a prerequisite for future tissue perfusion guided therapy concepts in intensive care medicine., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Septic shock substantially alters the pharmacokinetic properties of β-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 β-lactams extend the time that the unbound fraction of the drug remains above the minimal inhibitory concentration MIC ( f t >MIC ) and may improve patient survival. The present study is a monocentric, retrospective before-and-after analysis of septic shock patients treated with β-lactams. Patients of the years 2015-2017 received intermittent bolus application whereas patients of 2017-2020 received PI of β-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 β-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.

Changes in the gut microbiome have already been associated with postoperative complications in major abdominal surgery. However, it is still unclear whether these changes are transient or a long-lasting effect. Therefore, the aim of this prospective clinical pilot study was to examine long-term changes in the gut microbiota and to correlate these changes with the clinical course of the patient. Methods: In total, stool samples of 62 newly diagnosed colorectal cancer patients undergoing primary tumor resection were analyzed by 16S-rDNA next-generation sequencing. Stool samples were collected preoperatively in order to determine the gut microbiome at baseline as well as at 6, 12, and 24 months thereafter to observe longitudinal changes. Postoperatively, the study patients were separated into two groups-patients who suffered from postoperative complications ( n = 30) and those without complication ( n = 32). Patients with postoperative complications showed a significantly stronger reduction in the alpha diversity starting 6 months after operation, which does not resolve, even after 24 months. The structure of the microbiome was also significantly altered from baseline at six-month follow-up in patients with complications ( p = 0.006). This was associated with a long-lasting decrease of a large number of species in the gut microbiota indicating an impact in the commensal microbiota and a long-lasting increase of Fusobacterium ulcerans . The microbial composition of the gut microbiome shows significant changes in patients with postoperative complications up to 24 months after surgery.

Acquired FXIII deficiency is a relevant complication in the perioperative setting; however, we still have little evidence about the incidence and management of this rarely isolated coagulopathy. This study aims to help find the right value for the substitution of patients with an acquired mild FXIII deficiency. In this retrospective single-center cohort study, we enrolled critically ill patients with mild acquired FXIII deficiency (>5% and ≤70%) and compared clinical and laboratory parameters, as well as pro-coagulatory treatments. The results of the present analysis of 104 patients support the clinical relevance of FXIII activity out of the normal range. Patients with lower FXIII levels, beginning at <60%, had lower minimum and maximum hemoglobin values, corresponding to the finding that patients with a minimum FXIII activity of <50% needed significantly more packed red blood cells. FXIII activity correlated significantly with general coagulation markers such as prothrombin time, activated partial thromboplastin time, and fibrinogen. Nevertheless, comparing the groups with a cut-off of 50%, the amount of fresh frozen plasma, thrombocytes, PPSB, AT-III, and fibrinogen given did not differ. These results indicate that a mild FXIII deficiency occurring at any point of intensive care unit stay is also probably relevant for the total need of packed red blood cells, independent of pro-coagulatory management. In alignment with the ESAIC guidelines, the measurement of FXIII in critically ill patients with the risk of bleeding and early management, with the substitution of FXIII at levels <50%-60%, could be suggested.

Background: Patients with sepsis-induced Acute Respiratory Distress Syndrome (ARDS) are hallmarked by high mortality rates. Early, targeted antibiotic therapy is crucial for patients' survival. The clinical use of a Next Generation Sequencing (NGS)-based approach for pathogen identification may lead to an improved diagnostic performance. Therefore, the objective of this study was to examine changes in the pulmonary-microbiome and resulting influences on patients' outcome in septic ARDS, but also to compare NGS- and culture-based diagnostic methods for pathogen identification., Methods: In total, 30 patients in two groups were enrolled in the study: (1) 15 septic ARDS patients following major abdominal surgery and (2) 15 patients undergoing oesophageal resection serving as controls. In the ARDS group, blood samples were collected at ARDS onset as well as 5 days and 10 days afterwards. At the same timepoints, bronchoalveolar lavages (BAL) were performed to collect epithelial lining fluid for culture-, as well as NGS-based analyses and to evaluate longitudinal changes in the pulmonary microbiome. In the control group, only one BAL and one blood sample were collected., Results: ARDS patients showed a significantly reduced α-diversity (p=0.007**) and an increased dominance (p=0.012*) in their pulmonary-microbiome. The α-diversity-index correlated with the length of stay in the intensive care unit (p-value=0.015) and the need for mechanical ventilation (p-value=0.009). In 42.9% of all ARDS patients, culture-based results were negative, while NGS findings indicated bacterial colonization., Conclusion: Sepsis-induced ARDS is associated with a significant dysbiosis of patients' pulmonary-microbiome, which is closely correlated with the clinical course of the disease., Trial Registration: This prospective, observational pilot study was approved by the Ethics Committee of the Medical Faculty of Heidelberg (trial code no. S-063/2015) and was prospectively registered in the German clinical trials register (DRKS-ID: DRKS00008317 prospectively registered: 28.10.2015). All study patients or their legal representatives signed written informed consent., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Sepsis is a life-threatening syndrome, resulting from a dysbalanced host response to infection. However, especially the early, pro-inflammatory immune response in sepsis is similar to other inflammatory conditions without infectious cause, e.g., trauma or surgery. This aspect challenges the value of current biomarkers for diagnosis, as these are often broadly induced. We earlier identified Delta-like Protein 1 (DLL1), a canonical Notch ligand, to be released from monocytes upon bacterial stimulation. Considering the importance of monocytes in the pathophysiology of sepsis, we hypothesized that this mechanism might occur also in the clinical setting and DLL1 might serve as a biomarker of life-threatening bacterial infection. Methods: We combined samples from three different studies, including subgroups of patients with sepsis ( n = 80), surgical patients ( n = 50), trauma patients ( n = 36), as well as healthy controls ( n = 50). We assessed plasma concentrations of DLL1 using ELISA. We performed Area-under-receiver-operator-curve (AUROC) analysis to evaluate the diagnostic performance of DLL1 compared to leucocytes, C-reactive protein (CRP), and procalcitonin (PCT). Results: Plasma concentrations of DLL1 were strongly elevated already at sepsis onset and maintained elevated until day 7. In contrast, neither surgical patients nor patients after severe trauma presented with elevated levels, while conventional biomarkers of inflammation (e.g., leucocytes and CRP), responded. AUROC analysis revealed a cut-off of 30 ng/ml associated with the best diagnostic performance, yielding a superior accuracy of 91% for DLL1, compared to 75, 79, and 81% for CRP, leucocytes, and PCT. Conclusion: DLL1 is a novel host-derived biomarker for the diagnosis of sepsis with a better performance compared to established ones, most likely due to its high robustness in non-infectious inflammatory responses. Clinical Trial Registration: POCSEP-Trial DRKS00008090; MIRSI DRKS00005463; SPRINT DRKS00010991.

Purpose: Despite antifungal prophylaxis following liver transplantation (LTX), patients are at risk for the development of subsequent opportunistic infections, such as an invasive fungal disease (IFD). However, culture-based diagnostic procedures are associated with relevant weaknesses., Methods: Culture and next-generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of ß-D-glucan (BDG), galactomannan (GM), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, -4, -6, -10, -17A and mid-regional proadrenomedullin (MR-proADM) were evaluated in 93 patients at 6 consecutive time points within 28 days following LTX., Results: A NGS-based diagnostic approach was shown to be suitable for the early identification of fungal pathogens in patients following LTX. Moreover, MR-proADM and IL-17A in plasma proved suitable for the identification of patients with an IFD., Conclusion: Plasma measurements of MR-proADM and IL-17A as well as a NGS-based diagnostic approach were shown to be attractive methodologies to attenuate the weaknesses of routinely used culture-based diagnostic procedures for the determination of an IFD in patients following LTX. However, an additional confirmation within a larger multicenter trial needs to be recommended., Trial Registration: German Clinical Trials Register: DRKS00005480 .

Background: Postoperative complications are of great relevance in daily clinical practice, and the gut microbiome might play an important role by preventing pathogens from crossing the intestinal barrier. The two aims of this prospective clinical pilot study were: (1) to examine changes in the gut microbiome following pancreatic surgery, and (2) to correlate these changes with the postoperative course of the patient., Results: In total, 116 stool samples of 32 patients undergoing pancreatic surgery were analysed by 16S-rRNA gene next-generation sequencing. One sample per patient was collected preoperatively in order to determine the baseline gut microbiome without exposure to surgical stress and/or antibiotic use. At least two further samples were obtained within the first 10 days following the surgical procedure to observe longitudinal changes in the gut microbiome. Whenever complications occurred, further samples were examined. Based on the structure of the gut microbiome, the samples could be allocated into three different microbial communities (A, B and C). Community B showed an increase in Akkermansia, Enterobacteriaceae and Bacteroidales as well as a decrease in Lachnospiraceae, Prevotella and Bacteroides. Patients showing a microbial composition resembling community B at least once during the observation period were found to have a significantly higher risk for developing postoperative complications (B vs. A, odds ratio = 4.96, p < 0.01**; B vs. C, odds ratio = 2.89, p = 0.019*)., Conclusions: The structure of the gut microbiome is associated with the development of postoperative complications.

Background: Septic coagulopathy represents a very dynamic disease entity, tilting from initial hypercoagulability towards a subsequent hypocoagulable disease state, entitled overt disseminated intravascular coagulation. Acute fibrinolysis shutdown has recently been described to be a crucial component of initial hypercoagulability in critically ill patients, although the underlying pathomechanisms, the specific temporal kinetics and its outcome relevance in patients with sepsis remain to be determined., Methods: In total, 90 patients (30 with septic shock, 30 surgical controls and 30 healthy volunteers) were enrolled. Blood samples were collected at sepsis onset or prior and immediately after the surgical procedure as well as 3 h, 6 h, 12 h, 24 h, 48 h and 7 d later, whereas blood samples from healthy volunteers were collected once. Besides viscoelastic and aggregometric point-of-care testing (POCT), enzyme-linked immunosorbent and thrombin generation assays and liquid chromatography-mass spectrometry-based measurements were performed., Results: As assessed by viscoelastic POCT, fibrinolysis shutdown occurred early in sepsis. Significant increases in tissue plasminogen activator had no effect on thromboelastometrical lysis indices (LIs). Contrariwise, plasminogen activator inhibitor-1 was already significantly increased at sepsis onset, which was paralleled by significantly increased LIs in patients suffering from septic shock in comparison with both control groups. This effect persisted throughout the 7-day observation period and was most pronounced in severely ill as well as non-surviving septic patients. Thromboelastometrical LI, therefore, proved to be suitable for early diagnosis [e.g. LI 45 min: area under the curve (AUC) up to 0.933] as well as prognosis (e.g. LI 60 min: AUC up to 1.000) of septic shock., Conclusions: Early inhibition of plasminogen activation leads to acute fibrinolysis shutdown with improved clot stability and is associated with increased morbidity and mortality in septic patients. Trial registration This study was approved by the local ethics committee (Ethics Committee of the Medical Faculty of Heidelberg; Trial-Code No. S247-2014/German Clinical Trials Register (DRKS)-ID: DRKS00008090; retrospectively registered: 07.05.2015). All study patients or their legal representatives signed written informed consent.

A prolonged cold ischaemia time (CIT) is suspected to be associated with an increased ischaemia and reperfusion injury (IRI) resulting in an increased damage to the graft. In total, 91 patients were evaluated for a delayed graft function within 7 days after kidney transplantation (48 deceased, 43 living donors). Blood and urine samples were collected before, immediately after the operation, and 1, 3, 5, 7 and 10 days later. Plasma and/or urine levels of total keratin 18 (total K18), caspase-cleaved keratin 18 (cc K18), the soluble receptor for advanced glycation end products (sRAGE), tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP7) were measured. As a result of prolonged CIT and increased IRI, deceased donor transplantations were shown to suffer from a more distinct cell cycle arrest and necrotic cell death. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 were therefore demonstrated to be of value for the detection of a delayed graft function (DGF), as they improved the diagnostic performance of a routinely used clinical scoring system. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 measurements are potentially suitable for early identification of patients at high risk for a DGF following kidney transplantation from deceased or living donors., (© 2018 Steunstichting ESOT.)

Accidents in which a person is run over are often associated with multiple serious injuries. Immediate bleeding control is crucial. Pressure and shear stress at the borders of subcutaneous tissue to the muscle fascia can cause hypoperfusion and the emergence of blood-filled cavities that are associated with a high risk of infection and necrosis, a so-called Morel-Lavallée lesion. Insufficient therapy can lead to local complications and furthermore to live-threatening sepsis.

Bacterial RNA serves an important function as activator of the innate immune system. In humans bacterial RNA is sensed by the endosomal receptors TLR7 and TLR8. Differences in the posttranscriptional modification profile of prokaryotic when compared with eukaryotic RNA allow innate immune cells to discriminate between "host" and "foreign" RNA. Ribose 2'- O -methylation is of particular importance and has been reported to antagonize TLR7/8 activation. Yet, the exact sequence context in which 2'- O -methylation has to occur to mediate its inhibitory activity remains largely undefined. On the basis of a naturally occurring 2'- O -methylated RNA sequence, we performed a systematic permutation of the methylated nucleotide as well as adjacent bases and hereby identify two minimal trinucleotide motifs within a 9-mer oligoribonucleotide that are necessary and sufficient to antagonize TLR7 and TLR8 activation, respectively. Given the growing interest in the development of inhibitors of nucleic acid-sensing TLRs for therapeutic purposes, these results will facilitate the rational design of such antagonists in the future., (© 2017 Schmitt et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)