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Background: Endotype classification becomes the cornerstone of understanding sepsis pathogenesis. Macrophage activation-like syndrome (MALS) and immunoparalysis are the best recognized major endotypes, so far. Interferon-gamma (IFNγ) action on tissue macrophages stimulates the release of the cytotoxic chemokine CXCL9. It was investigated if this mechanism may be an independent sepsis endotype., Methods: In this cohort study, 14 patient cohorts from Greece, Germany and Italy were studied. The cohorts were 2:1 randomly split into discovery and validation sets. Sepsis was defined by the Sepsis-3 definitions and blood was sampled the first 24 h from meeting the Sepsis-3 definitions. Concentrations of IFNγ, CXCL9, IP-10 (IFNγ induced protein-10), soluble CD163 and ferritin were measured. The endotype of IFNγ-driven sepsis (IDS) was defined in the discovery set as the combination of a) blood IFNγ above a specified cut-off associated with the minimal risk for immunoparalysis (defined as ≥8000 HLA-DR receptors on CD45/CD14-monoytes); and b) increase of CXCL9. Results were compared to the validation set., Findings: 5503 patients were studied; 3670 in the discovery set and 1833 in the validation set. IDS was defined as IFNγ more than 3 pg/ml and CXCL9 more than 2200 pg/ml. The frequency of IDS in the discovery set was 19.9% (732 patients; 95% confidence intervals-CIs 18.7-21.3%) and in the validation set 20.0% (366 patients; 95% CIs 18.2-21.9%). Soluble CD163, a marker of macrophage activation, was greater in IDS and IDS had features distinct from MALS. The mortality in IDS patients was 43.0% (315 patients; 95% CIs 39.5-46.6%) in the discovery set and 40.4% in the validation set (148 patients; 95% CIs 35.5-45.5%) (p = 0.44 compared to patients of the discovery set). IDS was an independent risk factor for death in the presence of other endotypes, severity scores and organ dysfunctions of the multivariate model [hazard ratio 1.71 (95% CIs 1.45-2.01) in the discovery set and 1.70 (95% CIs 1.34-2.16) in the validation set]. Decreases of IFNγ and CXCL9 blood levels within the first 72 h were associated with better outcome., Interpretation: IDS is a new sepsis endotype independently associated with unfavorable outcome., Funding: Hellenic Institute for the Study of Sepsis; Horizon 2020 project ImmunoSep; Swedish Orphan BioVitrum AB (publ) and German Federal Ministry of Education and Research., Competing Interests: Declaration of interests EJG-B reports honoraria and consultation fees from Abbott Products Operations, bioMérieux, Brahms GmbH, GSK and Sobi (granted to the National and Kapodistrian University of Athens); independent educational grants from AbbVie, InCyte, Novartis and UCB (granted to the National and Kapodistrian University of Athens) and from Abbott Products Operations, bioMérieux Inc, Johnson & Johnson, MSD, and Swedish Orphan Biovitrum AB (granted to the Hellenic Institute for the Study of Sepsis); and funding from the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grants EPIC-CROWN-2, POINT and Homi-Lung (granted to the Hellenic Institute for the Study of Sepsis). MA reports Honoraria for Board Participation from Shionogi, Pfizer and Menarini and unrestricted research grants from GE and Fisher and Paykel. AJR is a full-time employee of Sobi. The authors FB and DT-R were supported by the German Federal Ministry of Education and Research (BMBF; grant number 01KU2209) within the ERA PerMed project iRECORDS. MK is inventor of a patent covering a method for quantification of C-terminal peptides of AAT (applicant: Jena University Hospital) (JUH); EP4224163A1; status: application), and the inventor of other patents covering C-terminal AAT peptides in inflammation (applicant: Jena University Hospital (JUH): Method for determining the origin of an infection (EP3239712B1 [granted]) and Diagnosis of Sepsis and Systemic Inflammatory Response Syndrome (EP2592421B1, EP2780719B1, CN104204808B, US10712350B2, JP6308946B2 [all granted]). MB is cofounder of SmartDyeLivery GmbH, Jena, and declares receipt of independent educational grants from B.R.A.H.M.S/Thermofisher, Swedish Orphan Biovitrum AB; and funding from the Horizon 2020 European Grants ImmunoSep and by the German Federal Ministry of Education and Research (BMBF; grant number 01KU2209) within the ERA PerMed project iRECORDS and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project Number 316213987—SFB 1278 “PolyTarget” (Project C06). The other authors do not declare any conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The treatment of acute life-threatening conditions in intensive care and emergency medicine requires in-depth training and education, with initial training playing a key role., Research Question: What is the structure and quality of the initial training of physicians and nurses in intensive care units and emergency departments in Germany?, Methods: With the help of survey software, an online questionnaire comprising 40 questions in German on the aforementioned topic was designed. It was distributed via the website of the German Society for Internal Intensive Care and Emergency Medicine (DGIIN) and via pertinent social media channels., Results: In total, 103 nurses and 125 physicians participated in the survey. The average work experience of the participating nurses and physicians was 8.5 ± 5.1 and 3.0 ± 3.1 years, respectively. The majority of participants worked primarily in intensive care units (59%) or in emergency departments (22%). On average, the initial training lasted 45 ± 27 and 13 ± 13 days for nurses and physicians, respectively. Only 20% of the initial training comprised seminars or hands-on workshops taught outside of routine clinical care. In all, 47% of the participants stated that they were not able to complete the entire initial training period. Only 49% had been officially certified for usage of the technical equipment in their department. A total of 35% reported feeling confident or somewhat confident in handling predictable tasks after initial training, but only 15% in handling acute emergencies., Discussion: The present study revealed that initial training in intensive care and emergency medicine is frequently incomplete, unstructured, as well as inadequate and bears both safety and liability risks. New concepts are needed to improve the initial training across clinics., (© 2024. The Author(s).)

Background/purpose: Several periprocedural adjuncts for elective surgical aneurysm treatment have been introduced over the last 20 years to increase safety and efficacy. Besides the introduction of IONM in the late-1990s, ICG-videoangiography (ICG-VAG) since the mid-2000s and intraoperative CT-angiography/-perfusion (iCT-A/-P) since the mid-2010s are available. We aimed to clarify whether the introduction of ICG-VAG and iCT-A/-P resulted in our department in a stepwise improvement in the rate of radiologically detected postoperative ischemia, complete aneurysm occlusion and postoperative new deficits., Methods: Patients undergoing microsurgical clip occlusion for unruptured anterior circulation aneurysms between 2000 and 2019 were included, with ICG-VAG since 2009 and iCT-A/-P (for selected cases) since 2016. Baseline characteristics and treatment-related morbidity/outcome focusing on differences between the three distinct cohorts (cohort-I: pre-ICG-VAG-era, cohort-II: ICG-VAG-era, cohort-III: ICG-VAG&iCT-A/-P-era) were analyzed., Results: 1391 patients were enrolled (n = 74 were excluded), 779 patients were interventionally treated, 538 patients were surgically clipped by a specialized vascular team (cohort-I n = 167, cohort-II n = 284, cohort-III n = 87). Aneurysm size was larger in cohort-I (8.9 vs. 7.5/6.8 mm; p < 0.01) without differences concerning age (mean:55years), gender distribution (m: f = 1:2.6) and aneurysm location (MCA:61%, ICA:18%, ACA/AcomA:21%). There was a stepwise improvement in the rate of radiologically detected postoperative ischemia (16.2vs.12.0vs.8.0%; p = 0.161), complete aneurysm occlusion (68.3vs.83.6vs.91.0%; p < 0.01) and postoperative new deficits (10.8vs.7.7vs.5.7%; p = 0.335) from cohort-I to -III. After a mean follow-up of 12months, a median modified Rankin scale of 0 was achieved in all cohorts., Discussion: Associated with periprocedural technical achievements, surgical outcome in elective anterior circulation aneurysm surgery has improved in our service during the past 20 years., (© 2024. The Author(s).)

Purpose: Inadequate piperacillin (PIP) exposure in intensive care unit (ICU) patients threatens therapeutic success. Model-informed precision dosing (MIPD) might be promising to individualize dosing; however, the transferability of published models to external populations is uncertain. This study aimed to externally evaluate the available PIP population pharmacokinetic (PopPK) models., Methods: A multicenter dataset of 561 ICU patients (11 centers/3654 concentrations) was used for the evaluation of 24 identified models. Model performance was investigated for a priori (A) predictions, i.e., considering dosing records and patient characteristics only, and for Bayesian forecasting, i.e., additionally including the first (B1) or first and second (B2) therapeutic drug monitoring (TDM) samples per patient. Median relative prediction error (MPE) [%] and median absolute relative prediction error (MAPE) [%] were calculated to quantify accuracy and precision., Results: The evaluation revealed a large inter-model variability (A: MPE - 135.6-78.3% and MAPE 35.7-135.6%). Integration of TDM data improved all model predictions (B1/B2 relative improvement vs. A: |MPE| median&#95;all&#95;models 45.1/67.5%; MAPE median&#95;all&#95;models 29/39%). The model by Kim et al. was identified to be most appropriate for the total dataset (A/B1/B2: MPE - 9.8/- 5.9/- 0.9%; MAPE 37/27.3/23.7%), Udy et al. performed best in patients receiving intermittent infusion, and Klastrup et al. best predicted patients receiving continuous infusion. Additional evaluations stratified by sex and renal replacement therapy revealed further promising models., Conclusion: The predictive performance of published PIP models in ICU patients varied considerably, highlighting the relevance of appropriate model selection for MIPD. Our differentiated external evaluation identified specific models suitable for clinical use, especially in combination with TDM., (© 2023. The Author(s).)

The revised and redefined "International Guidelines for Management of Sepsis and Septic Shock 2021" of the Surviving Sepsis Campaign were published on 4 October 2021. As in the previous version from 2016, the focus of these international guidelines is on the diagnosis and acute treatment measures in sepsis. The topics long-term outcome and treatment targets for rehabilitation are extensively discussed and accompanied by specific recommendations. These recommendations and the underlying studies reflect the increasing awareness about the long-term consequences of severe diseases requiring intensive medical care. This article summarizes the updates in a clearly comprehensible form., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objectives: To compare noninvasive pulse-pressure variation (PPV) measurements obtained from a new high-fidelity upper arm cuff using a hydraulic coupling technique to corresponding intraarterial PPV measurements., Design: The authors used prospective multicenter comparison and development studies for the new high-fidelity upper arm cuff., Setting: The study was performed in the departments of Anesthesiology at the Ludwig-Maximilians-Universität München Hospital, the University Hospital of Bonn, and the RoMed Hospital in Rosenheim (all Germany)., Participants: A total of 153 patients were enrolled, undergoing major abdominal surgery or neurosurgery with mechanical ventilation. For the evaluation of PPV, 1,467 paired measurements in 107 patients were available after exclusion due to predefined quality criteria., Interventions: Simultaneous measurements of PPV were performed from a reference femoral arterial catheter (PPV ref ) and the high-fidelity upper arm cuff (PPV cuff ). The new device uses a semirigid conical shell. It incorporates a hydraulic sensor pad with a pressure transducer, leading to a tissue pressure-pulse contour with all characteristics of an arterial- pulse contour., Measurements and Main Results: The comparative analysis of the included measurements showed that PPV ref and PPV cuff were closely correlated (r = 0.92). The mean of the differences between PPV ref and PPV cuff was 0.1 ± 2.0%, with 95% limits of agreement between -4.1% and 3.9%. To track absolute changes in PPV >2%, the concordance rate between the 2 methods was 93%., Conclusions: The new high-fidelity upper arm cuff method provided a clinically reliable estimate of PPV., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: In patients with severe aneurysmal subarachnoid hemorrhage (SAH) deep sedation is often used early in the course of the disease in order to control brain edema formation and thus intracranial hypertension. However, some patients do not reach an adequate sedation depth despite high doses of common intravenous sedatives. Balanced sedation protocols incorporating low-dose volatile isoflurane administration might improve insufficient sedation depth in these patients., Methods: We retrospectively analyzed ICU patients with severe aneurysmal SAH who received isoflurane in addition to intravenous anesthetics in order to improve insufficient sedation depth. Routinely recorded data from neuromonitoring, laboratory and hemodynamic parameters were compared before and up to 6 days after initiation of isoflurane., Results: Sedation depth measured using the bispectral index improved in thirty-six SAH patients (-15.16; p  = 0.005) who received additional isoflurane for a mean period of 9.73 ± 7.56 days. Initiation of isoflurane sedation caused a decline in mean arterial pressure (-4.67 mmHg; p  = 0.014) and cerebral perfusion pressure (-4.21 mmHg; p  = 0.013) which had to be balanced by increased doses of vasopressors. Patients required increased minute ventilation in order to adjust for the increase in PaCO 2 (+2.90 mmHg; p  < 0.001). We did not detect significant increases in mean intracranial pressure. However, isoflurane therapy had to be terminated prematurely in 25% of the patients after a median of 30 h due to episodes of intracranial hypertension or refractory hypercapnia., Discussion: A balanced sedation protocol including isoflurane is feasible for SAH patients experiencing inadequately shallow sedation. However, therapy should be restricted to patients without impaired lung function, hemodynamic instability and impending intracranial hypertension., 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 Müller, Terpolilli, Schwarzmaier, Briegel and Huge.)

Arterial blood pressure is one of the vital signs monitored mandatory in anaesthetised patients. Even short episodes of intraoperative hypotension are associated with increased risk for postoperative organ dysfunction such as acute kidney injury and myocardial injury. Since there is little evidence whether higher alarm thresholds in patient monitors can help prevent intraoperative hypotension, we analysed the blood pressure data before (group 1) and after (group 2) the implementation of altered hypotension alarm settings. The study was conducted as a retrospective observational cohort study in a large surgical centre with 32 operating theatres. Alarm thresholds for hypotension alarm for mean arterial pressure (MAP) were altered from 60 (before) to 65 mmHg for invasive measurement and 70 mmHg for noninvasive measurement. Blood pressure data from electronic anaesthesia records of 4222 patients (1982 and 2240 in group 1 and 2, respectively) with 406,623 blood pressure values undergoing noncardiac surgery were included. We analysed (A) the proportion of blood pressure measurements below the threshold among all measurements by quasi-binomial regression and (B) whether at least one blood pressure measurement below the threshold occurred by logistic regression. Hypotension was defined as MAP < 65 mmHg. There was no significant difference in overall proportions of hypotensive episodes for mean arterial pressure before and after the adjustment of alarm settings (mean proportion of values below 65 mmHg were 6.05% in group 1 and 5.99% in group 2). The risk of ever experiencing a hypotensive episode during anaesthesia was significantly lower in group 2 with an odds ratio of 0.84 (p = 0.029). In conclusion, higher alarm thresholds do not generally lead to less hypotensive episodes perioperatively. There was a slight but significant reduction of the occurrence of intraoperative hypotension in the presence of higher thresholds for blood pressure alarms. However, this reduction only seems to be present in patients with very few hypotensive episodes., (© 2022. The Author(s).)

Background: Sepsis and septic shock are frequently accompanied by coagulopathy. Since the sepsis-induced coagulopathy (SIC) score was first described, subsequent studies from Asia revealed a SIC prevalence of 40-60%. In Europe, however, SIC prevalence in patients fulfilling sepsis criteria according to the third international consensus definition (SEPSIS-3) has not yet been evaluated., Methods: The Critical Care Trials Group of the German Sepsis Competence Network (SepNet) conducted a secondary analysis of two randomized controlled trials. Only patients fulfilling sepsis criteria according SEPSIS-3 were included in this secondary analysis. In a two step approach, SIC prevalence was determined in 267 patients with sepsis but not septic shock (at the time of inclusion) from the "Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis" (HYPRESS) trial. Then, we estimated SIC prevalence in 1,018 patients from the "Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock" (SISPCT) trial using a simplified SIC score based on the platelet-SIC-subscore (PSSC). Study aims were to assess (i) the prevalence of SIC in patients with SEPSIS-3, (ii) the association of SIC with 90-day mortality and morbidity, (iii) the time when patients become SIC positive during the course of sepsis, and (iv) the value of the PSSC for predicting SIC., Results: In the HYPRESS trial, SIC prevalence was 22.1% (95% confidence interval [CI] 17.5-27.5%). The estimated SIC prevalence in the SISPCT trial was 24.2% (95% CI 21.6-26.9%). In the HYPRESS trial, SIC was associated with significantly higher 90-day mortality (13.9% vs. 26.8%, p = 0.027) and morbidity. Logistic regression analysis adjusted for age, sex, treatment arm, and (SIC-adapted) SOFA score confirmed the negative association of SIC with survival (p = 0.011). In the SISPCT trial, increased PSSCs were associated with higher 90-day mortality (PSSC 0: 34.4%, PSSC 1: 40.5%, PSSC 2: 53.3%; p < 0.001). In both trials, SIC was already present at sepsis diagnosis or occurred during the following 4 days., Conclusions: SIC is a clinically relevant complication of sepsis. Although it might be less frequent than previously reported, its occurrence is associated with higher morbidity and mortality and should be interpreted as an early warning sign., (© 2023. The Author(s).)