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The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) controls tryptophan metabolism and is induced by pro-inflammatory stimuli. We investigated whether immunostimulatory treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) influences IDO activity and tryptophan metabolism in sepsis. Thirty-six patients with severe sepsis/septic shock and sepsis-associated immunosuppression (assessed using monocytic human leukocyte antigen-DR (mHLA-DR) expression) were assessed in a controlled trial of GM-CSF or placebo treatment for 8 days. Using tandem mass spectrometry, levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid, 5-hydroxytryptophan, serotonin, and estimated IDO activity were determined in a blinded fashion over a 9-day interval. At baseline, tryptophan and metabolite levels did not differ between the study groups. Although tryptophan levels were unchanged in both groups over the treatment interval (all p>0.8), IDO activity was markedly reduced after GM-CSF treatment (35.4 ± 21.0 vs 21.6 ±9.9 (baseline vs day 9), p = 0.02). IDO activity differed significantly between the 2 groups after therapy ( p = 0.03). Metabolites downstream of IDO (kynurenine, quinolinic acid, kynurenic acid) were all induced in sepsis and declined in the GM-CSF group, but not in controls. Serotonin pathway metabolites remained unchanged in both groups (all p>0.15). Moreover, IDO activity correlated with procalcitonin ( p< 0.0001, r = 0.56) and mHLA-DR levels ( p = 0.005, r = -0.28) in the overall samples group. Thus, GM-CSF therapy is associated with decreased IDO activity and reduced kynurenine pathway catabolites in sepsis. This may be due to an improved antibacterial defence. [ABSTRACT FROM AUTHOR]

It has recently been shown that an increased plasma level of the tryptophan catabolite kynurenine is an early indicator for the development of sepsis in major trauma patients. We examined the predictive value of kynurenine pathway activity for ongoing sepsis in patients being admitted to a surgical intensive care unit for different reasons. In addition, we asked whether an accumulation of kynurenines in patients' plasma depends on reduced renal clearance. We conducted a prospective observational study including 100 consecutive patients and monitored laboratory variables, physiological and adverse events, sepsis and outcome. Using tandem mass spectrometry, we quantified the five indoleamines tryptophan, serotonin (5-HT), kynurenine, quinolinic acid and kynurenic acid at baseline and twice a week during the intensive care unit stay. Among the patients enrolled, 50 did not develop sepsis in the intensive care unit (non-septic), 18 patients did not have sepsis at baseline but developed sepsis later on (pre-septic) and 32 patients already fulfilled the criteria of severe sepsis and septic shock at baseline (septic). In general, non-septic critically ill patients showed activation of the kynurenine pathway, but septic shock coincided with an exacerbation of kynurenine pathway activity even in the absence of renal failure. Importantly, plasma concentrations of quinolinic acid (area under the curve 0.832 [95% confidence interval 0.710 to 0.954]) and the Quin/Trp ratio (area under the curve 0.835 [95% confidence interval; 0.719 to 0.952]) showed the best discrimination between non-septic and pre-septic patients at baseline. These findings open new avenues for further investigations on the pathophysiology of sepsis. [ABSTRACT FROM AUTHOR]

RATIONALE: Sustained sepsis-associated immunosuppression is associated with uncontrolled infection, multiple organ dysfunction, and death. OBJECTIVES: In the first controlled biomarker-guided immunostimulatory trial in sepsis, we tested whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reverses monocyte deactivation, a hallmark of sepsis-associated immunosuppression (primary endpoint), and improves the immunological and clinical course of patients with sepsis. METHODS: In a prospective, randomized, double-blind, placebo-controlled, multicenter trial, 38 patients (19/group) with severe sepsis or septic shock and sepsis-associated immunosuppression (monocytic HLA-DR [mHLA-DR] <8,000 monoclonal antibodies (mAb) per cell for 2 d) were treated with GM-CSF (4 microg/kg/d) or placebo for 8 days. The patients' clinical and immunological course was followed up for 28 days. MEASUREMENTS AND MAIN RESULTS: Both groups showed comparable baseline mHLA-DR levels (5,609 +/- 3,628 vs. 5,659 +/- 3,332 mAb per cell), which significantly increased within 24 hours in the GM-CSF group. After GM-CSF treatment, mHLA-DR was normalized in 19/19 treated patients, whereas this occurred in 3/19 control subjects only (P < 0.001). GM-CSF also restored ex-vivo Toll-like receptor 2/4-induced proinflammatory monocytic cytokine production. In patients receiving GM-CSF, a shorter time of mechanical ventilation (148 +/- 103 vs. 207 +/- 58 h, P = 0.04), an improved Acute Physiology and Chronic Health Evaluation-II score (P = 0.02), and a shorter length of both intrahospital and intensive care unit stay was observed (59 +/- 33 vs. 69 +/- 46 and 41 +/- 26 vs. 52 +/- 39 d, respectively, both not significant). Side effects related to the intervention were not noted. CONCLUSIONS: Biomarker-guided GM-CSF therapy in sepsis is safe and effective for restoring monocytic immunocompetence. Use of GM-CSF may shorten the time of mechanical ventilation and hospital/intensive care unit stay. A multicenter trial powered for the improvement of clinical parameters and mortality as primary endpoints seems indicated. Clinical trial registered with www.clinicaltrials.gov (NCT00252915). [ABSTRACT FROM AUTHOR]

Background: Enteral nutrition may affect risks of gastrointestinal bleeding, pneumonia and mortality in critically ill patients and may also modify the effects of pharmacological stress ulcer prophylaxis. We undertook post hoc analyses of the stress ulcer prophylaxis in the intensive care unit trial to assess for any associations and interactions between enteral nutrition and pantoprazole., Methods: Extended Cox models with time-varying co-variates and competing events were used to assess potential associations, adjusted for baseline severity of illness. Potential interactions between daily enteral nutrition and allocation to pantoprazole on outcomes were similarly assessed., Results: Enteral nutrition was associated with lower risk of clinically important gastrointestinal bleeding (cause-specific hazard ratio [HR]: 0.29, 95% confidence interval: [CI] 0.19-0.44, p < .001), higher risk of pneumonia (HR: 1.44, 95% CI: 1.14-1.82, p = .003), and lower risk of all-cause mortality (HR: 0.22, 95% CI: 0.18-0.27, p < .001). Enteral nutrition with allocation to pantoprazole was associated with a lower risk of mortality (HR: 0.27, 95% CI: 0.21-0.35, p < .001), similar to enteral nutrition with allocation to placebo (HR: 0.17, 95% CI: 0.13-0.23, p < .001). Allocation to pantoprazole with no enteral nutrition had little effect on mortality (HR: 0.83, 95% CI: 0.63-1.09, p = .179), whilst allocation to pantoprazole and receipt of enteral nutrition was mostly compatible with increased all-cause mortality (HR: 1.27, 95% CI: 0.99-1.64, p = .061). The test of interaction between enteral nutrition and pantoprazole treatment allocation for all-cause mortality was statistically significant (p = .024)., Conclusions: Enteral nutrition was associated with an increased risk of pneumonia and a reduced risk of gastrointestinal bleeding. The interaction between pantoprazole and enteral nutrition suggesting an increased risk of mortality requires further study., (© 2024 The Author(s). Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Postoperative fluid overload (FO) after cardiac surgery is common and affects recovery. Predicting FO could help optimize fluid management. This post-hoc analysis of the HERACLES randomized controlled trial evaluated the predictive value of MR-proADM for FO post-cardiac surgery. MR-proADM levels were measured at four different timepoints in 33 patients undergoing elective cardiac surgery. Patients were divided into FO (> 5% weight gain) and no-FO at ICU discharge. The primary outcome was the predictive power of MR-proADM at ICU admission for FO at discharge. Secondary outcomes included the predictive value of MR-proADM for FO on day 6 post-surgery and changes over time. The association between MR-proADM and FO at ICU discharge or day 6 post-surgery was not significant (crude odds ratio (cOR): 4.3 (95% CI 0.5-40.9, p = 0.201) and cOR 1.1 (95% CI 0.04-28.3, p = 0.954)). MR-proADM levels over time did not differ significantly between patients with and without FO at ICU discharge (p = 0.803). MR-proADM at ICU admission was not associated with fluid overload at ICU discharge in patients undergoing elective cardiac surgery. MR-proADM levels over time were not significantly different between groups, although elevated levels were observed in patients with FO., (© 2024. The Author(s).)

Objectives: Intensive care unit acquired weakness (ICUAW) is a clinical diagnosis and an umbrella term for acquired weakness due to neuromuscular disorders such as critical illness myopathy (CIM) but also muscular inactivity/atrophy. Without a clear understanding of the distinct aetiology, it seems difficult to predict outcomes of ICUAW and to test and apply effective future treatments. The present study contrasts ICUAW with CIM and assesses the diagnostic and clinical relevance for affected patients., Methods: Data from a previous prospective cohort study investigating critically ill COVID-19 patients was analysed in a retrospective fashion. Patients were examined ten days after intubation with clinical assessment, nerve conduction studies, electromyography and muscle biopsy. Mortality was assessed during critical illness and at three months after hospital discharge. ICUAW and CIM were diagnosed according to the current diagnostic guidelines., Results: In this patient sample (n = 22), 92 % developed ICUAW, 55 % developed ICUAW and CIM, and 36 % had ICUAW but did not develop CIM. Overall, 27 % patients died during their stay in the intensive care unit. At three months after discharge, there were no further deaths, but in 14 % of patients the outcome was unknown. The diagnosis of CIM was more strongly associated with death during critical illness than ICUAW. No patient with ICUAW who did not fulfil the criteria for CIM died. Both clinical and electrophysiological criteria showed excellent sensitivity for CIM diagnosis, but only electrophysiological criteria had a high specificity. Determination of the myosin:actin ratio showed neither high sensitivity nor specificity for the diagnosis of CIM., Conclusions: The results of the present study support that ICUAW is a non-specific clinical diagnosis of low predictive power with regard to mortality. Further, diagnosing "ICUAW" seems also of little research value for both exploring the aetiology and pathophysiology of muscle weakness in critically ill patients and for evaluating potential treatment effects. Thus, more specific diagnoses such as CIM are more appropriate. Within the different diagnostic criteria for CIM, electrophysiological studies are the most sensitive and specific examinations compared to clinical and muscle tissue assessment., Significance: Avoiding an overarching diagnosis of "ICUAW" and instead focusing on specific diagnoses appears to have several relevant consequences: more precise diagnosis making, more accurate referral to aetiology and pathophysiology, improved outcome prediction, and development of more appropriate treatments., Competing Interests: BR, JCS and WJZ report no competing interests., (© 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Sepsis is characterised by a dysregulated host immune response to infection. Despite recognition of its significance, immune status monitoring is not implemented in clinical practice due in part to the current absence of direct therapeutic implications. Technological advances in immunological profiling could enhance our understanding of immune dysregulation and facilitate integration into clinical practice. In this Review, we provide an overview of the current state of immune profiling in sepsis, including its use, current challenges, and opportunities for progress. We highlight the important role of immunological biomarkers in facilitating predictive enrichment in current and future treatment scenarios. We propose that multiple immune and non-immune-related parameters, including clinical and microbiological data, be integrated into diagnostic and predictive combitypes, with the aid of machine learning and artificial intelligence techniques. These combitypes could form the basis of workable algorithms to guide clinical decisions that make precision medicine in sepsis a reality and improve patient outcomes., Competing Interests: Declaration of interests SC reports personal fees from Pfizer, AstraZeneca, Swedish Orphan Biovitrum (SOBI), GSK, and Merck Sharp & Dohme (MSD). MK reports personal fees from ARTCLINE, Atriva, AOP pharma, Inflammatix, and 4TEEN4; and discloses institutional funding from MediSieve, 4TEEN4, Adrenomed, Spinghotec, Cytosorbents, and Inflammatix. MAW reports personal fees from MSD, Gilead, Pfizer, Shionogi, Eumedica, Coulter, Biotest, Sedana, SOBI, and Böhringer; and patent EPA17198330 “Delta-Like Ligand 1 for diagnosing severe infections”. IM-L reports personal fees from MSD, Pfizer, and Gilead. GL reports personal fees from SOBI. EJG-B discloses institutional funding from Abbott, bioMérieux, InflaRx, Johnson & Johnson, MSD, SOBI, XBiotech, Horizon 2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy”, Horizon 2020 European Grants ImmunoSep and RISCinCOVID, and Horizon Health European Grants EPIC-CROWN-2. MSW has received unrestricted funding from Sartorius and reports personal fees from GRIFOLS, Gilead, and Amomed. MO is president of the European Shock Society and Deputy Editor of Intensive Care Medicine Experimental. JFB-M reports personal fees from GSK, PROFARMA programme, Ministry of Industry Spain, GSK-MODUS programme, and Inflammatix; and patents on the following biomarkers related to management of severe infections: PCT/EP2018/064363 “MMP-8 as a marker for identifying infectious disease”, PCT/EP2018/052499 “Pro-ADM as marker indicating an adverse event”, WO2020030745 “Pro-ADM for prognosing the risk of a medical condition requiring hospitalisation in patients with symptoms of infectious disease”, and EP20383140.9 “In vitro method for predicting mortality in COVID-19 patients” (based on detecting N-antigenaemia of SARS-CoV-2 in plasma). JCS discloses institutional funding from Orion Pharma, Abbott Nutrition International, B Braun Medical, CSEM, Edwards Lifesciences Services, Kenta Biotech, Maquet Critical Care, Omnicare Clinical Research, Nestle, Pierre Fabre Pharma, Pfizer, Bard Medica, Abbott, Anandic Medical Systems, Pan Gas Healthcare, Bracco, Hamilton Medical, Fresenius Kabi, Getinge Group Maquet, Dräger, Teleflex Medical, GSK, MSD, Eli Lilly and Company, Baxter, Astellas, AstraZeneca, CSL Behring, Novartis, Covidien, Philips Medical, Prolong Pharmaceuticals and Nycomed, Phagenesis, and Cytel, outside of the submitted work. JCS is Chair of the Clinical Advisory Board of Hemotune. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Premorbid conditions influence the outcome of acutely ill adult patients aged 80 years and over who are admitted to the ICU. The aim of this study was to determine the influence of such premorbid conditions on 6 month survival., Methods: Prospective cohort study in 242 ICUs from 22 countries including patients 80 years or above, admitted over a 6 months period to an ICU between May 2018 and May 2019. Only emergency (acute) ICU admissions in adult patients ≥ 80 years of age were eligible. Patients who were admitted after planned/elective surgery were excluded. We measured the Clinical Frailty Scale (CFS), the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), disability with the Katz activities of daily living (ADL) score, comorbidities and a Polypharmacy Score (CPS)., Results: Overall, the VIP2 study included 3920 patients. During ICU stay 1191 patients died (30.9%), and another 436 patients (11.1%) died after ICU discharge but within the first 30 days of admission, and an additional 895 patients died hereafter but within the first 6 months after admission (22.8%). The 6 months mortality was 64%. The median CFS was 4 (IQR 3-6). Frailty (CFS ≥ 5) was present in 26.6%. Cognitive decline (IQCODE above 3.5) was found in 30.2%. The median IQCODE was 3.19. A Katz ADL of 4 or less was present in 27.7%. Patients who surviving > 6 months were slightly younger (median age survivors 84 with IQR 81-86) than patients dying within the first 6 months (median age 84, IQR 82-87, p = 0.013), were less frequently frail (CFS > 5 in 19% versus 34%, p < 0.01) and were less dependent based on their Katz activities of daily living measurement (median Katz score 6, IQR 5-6 versus 6 points, IQR 3-6, p < 0.01)., Conclusions: We found that Clinical Frailty Scale, age, and SOFA at admission were independent prognostic factors for 6 month mortality after ICU admission in patients age 80 and above. Adding other geriatric syndromes and scores did not improve the model. This information can be used in shared-decision making., Clinicaltrials: gov: NCT03370692., (© 2024. The Author(s).)

Background: Dysphagia is common in intensive care unit (ICU) patients, yet it remains underrecognized and often unmanaged despite being associated with life-threatening complications, prolonged ICU stays and hospitalization., Purpose: To propose an expert opinion for the diagnosis and management of dysphagia developed from evidence-based clinical recommendations and practitioner insights., Methods: A multinational group of dysphagia and critical care experts conducted a literature review using a modified ACCORD methodology. Based on a fusion of the available evidence and the panel's clinical experience, an expert opinion on best practice management was developed., Results: The panel recommends adopting clinical algorithms intended to promote standardized, high-quality care that triggers timely systematic dysphagia screening, assessment, and treatment of extubated and tracheostomized patients in the ICU., Conclusions: Given the lack of robust scientific evidence, two clinical management algorithms are proposed for use by multidisciplinary teams to improve early systematic detection and effective management of dysphagia in ICU patients. Additionally, emerging therapeutic options such as neurostimulation have the potential to improve the quality of ICU dysphagia care., Competing Interests: Declaration of Competing Interest This publication has been supported by Phagenesis, Ltd. JCS reports that Phagenesis, LTD is the sponsor of the randomized controlled clinical PHINEST trial (NCT03840395). This ongoing clinical study is investigating pharyngeal electrical stimulation in ICU patients and JCS is the principal investigator of this trial., (Copyright © 2023. Published by Elsevier Inc.)

BackgroundWomen are overrepresented among individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Biological (sex) as well as sociocultural (gender) differences between women and men might account for this imbalance, yet their impact on PASC is unknown.AimWe assessed the impact of sex and gender on PASC in a Swiss population.MethodOur multicentre prospective cohort study included 2,856 (46% women, mean age 44.2 ± 16.8 years) outpatients and hospitalised patients with PCR-confirmed SARS-CoV-2 infection.ResultsAmong those who remained outpatients during their first infection, women reported persisting symptoms more often than men (40.5% vs 25.5% of men; p < 0.001). This sex difference was absent in hospitalised patients. In a crude analysis, both female biological sex (RR = 1.59; 95% CI: 1.41-1.79; p < 0.001) and a score summarising gendered sociocultural variables (RR = 1.05; 95% CI: 1.03-1.07; p < 0.001) were significantly associated with PASC. Following multivariable adjustment, biological female sex (RR = 0.96; 95% CI: 0.74-1.25; p = 0.763) was outperformed by feminine gender-related factors such as a higher stress level (RR = 1.04; 95% CI: 1.01-1.06; p = 0.003), lower education (RR = 1.16; 95% CI: 1.03-1.30; p = 0.011), being female and living alone (RR = 1.91; 95% CI: 1.29-2.83; p = 0.001) or being male and earning the highest income in the household (RR = 0.76; 95% CI: 0.60-0.97; p = 0.030).ConclusionSpecific sociocultural parameters that differ in prevalence between women and men, or imply a unique risk for women, are predictors of PASC and may explain, at least in part, the higher incidence of PASC in women. Once patients are hospitalised during acute infection, sex differences in PASC are no longer evident.

Background: When caring for mechanically ventilated adults with acute hypoxaemic respiratory failure (AHRF), clinicians are faced with an uncertain choice between ventilator modes allowing for spontaneous breaths or ventilation fully controlled by the ventilator. The preferences of clinicians managing such patients, and what motivates their choice of ventilator mode, are largely unknown. To better understand how clinicians' preferences may impact the choice of ventilatory support for patients with AHRF, we issued a survey to an international network of intensive care unit (ICU) researchers., Methods: We distributed an online survey with 32 broadly similar and interlinked questions on how clinicians prioritise spontaneous or controlled ventilation in invasively ventilated patients with AHRF of different severity, and which factors determine their choice., Results: The survey was distributed to 1337 recipients in 12 countries. Of these, 415 (31%) completed the survey either fully (52%) or partially (48%). Most respondents were identified as medical specialists (87%) or physicians in training (11%). Modes allowing for spontaneous ventilation were considered preferable in mild AHRF, with controlled ventilation considered as progressively more important in moderate and severe AHRF. Among respondents there was strong support (90%) for a randomised clinical trial comparing spontaneous with controlled ventilation in patients with moderate AHRF., Conclusions: The responses from this international survey suggest that there is clinical equipoise for the preferred ventilator mode in patients with AHRF of moderate severity. We found strong support for a randomised trial comparing modes of ventilation in patients with moderate AHRF., (© 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Purpose: Intensive care unit (ICU) hospitalization is challenging for the family members of the patients. Most family members report some level of anxiety and depression, sometimes even resulting in post-traumatic stress disorder (PTSD). An association has been reported between lack of information and PTSD. This study had three aims: to quantify the psychological burden of family members of critically ill patients, to explore whether a website with specific information could reduce PTSD symptoms, and to ascertain whether a website with information about intensive care would be used., Method: A multicenter double-blind, randomized, placebo-controlled trial was carried out in Austria and Switzerland., Results: In total, 89 members of families of critically ill patients (mean age 47.3 ± 12.9 years, female n = 59, 66.3%) were included in the study. 46 relatives were allocated to the intervention website and 43 to the control website. Baseline Impact of Event Scale (IES) score was 27.5 ± 12.7. Overall, 50% showed clinically relevant PTSD symptoms at baseline. Mean IES score for the primary endpoint (~ 30 days after inclusion, T1) was 24 ± 15.8 (intervention 23.9 ± 17.9 vs. control 24.1 ± 13.5, p = 0.892). Hospital Anxiety and Depression Scale (HADS - Deutsch (D)) score at T1 was 12.2 ± 6.1 (min. 3, max. 31) and did not differ between groups. Use of the website differed between the groups (intervention min. 1, max. 14 vs. min. 1, max. 3; total 1386 "clicks" on the website, intervention 1021 vs. control 365). Recruitment was prematurely stopped in February 2020 due to coronavirus disease 2019 (COVID-19)., Conclusion: Family members of critically ill patients often have significant PTSD symptoms and online information on critical illness did not result in reduced PTSD symptoms., (© 2023. The Author(s).)

Purpose: Religious beliefs affect end-of-life practices in intensive care units (ICUs). Changes over time in end-of-life practices were not investigated regarding religions., Methods: Twenty-two European ICUs (3 regions: Northern, Central, and Southern Europe) participated in both Ethicus-1 (years 1999-2000) and Ethicus-2 studies (years 2015-2016). Data of ICU patients who died or had limitations of life-sustaining therapy were analysed regarding changes in end-of-life practices and patient/physician religious affiliations. Frequencies, timing of decision-making, and religious affiliations of physicians/patients were compared using the same definitions., Results: In total, 4592 adult ICU patients (n = 2807 Ethicus-1, n = 1785 Ethicus-2) were analysed. In both studies, patient and physician religious affiliations were mostly Catholic, Greek Orthodox, Jewish, Protestant, or unknown. Treating physicians (but not patients) commonly reported no religious affiliation (18%). Distribution of end-of-life practices with respect to religion and geographical regions were comparable between the two studies. Withholding [n = 1143 (40.7%) Ethicus-1 and n = 892 (50%) Ethicus-2] and withdrawing [n = 695 (24.8%) Ethicus-1 and n = 692 (38.8%) Ethicus-2] were most commonly decided. No significant changes in end-of-life practices were observed for any religion over 16 years. The number of end-of-life discussions with patients/ families/ physicians increased, while mortality and time until first decision decreased., Conclusions: Changes in end-of-life practices observed over 16 years appear unrelated to religious affiliations of ICU patients or their treating physicians, but the effects of religiosity and/or culture could not be assessed. Shorter time until decision in the ICU and increased numbers of patient and family discussions may indicate increased awareness of the importance of end-of-life decision-making in the ICU., (© 2023. The Author(s).)

Background: Several studies have found an association between diabetes mellitus, disease severity and outcome in COVID-19 patients. Old critically ill patients are particularly at risk. This study aimed to investigate the impact of diabetes mellitus on 90-day mortality in a high-risk cohort of critically ill patients over 70 years of age., Methods: This multicentre international prospective cohort study was performed in 151 ICUs across 26 countries. We included patients ≥ 70 years of age with a confirmed SARS-CoV-2 infection admitted to the intensive care unit from 19th March 2020 through 15th July 2021. Patients were categorized into two groups according to the presence of diabetes mellitus. Primary outcome was 90-day mortality. Kaplan-Meier overall survival curves until day 90 were analysed and compared using the log-rank test. Mixed-effect Weibull regression models were computed to investigate the influence of diabetes mellitus on 90-day mortality., Results: This study included 3420 patients with a median age of 76 years were included. Among these, 37.3% (n = 1277) had a history of diabetes mellitus. Patients with diabetes showed higher rates of frailty (32% vs. 18%) and several comorbidities including chronic heart failure (20% vs. 11%), hypertension (79% vs. 59%) and chronic kidney disease (25% vs. 11%), but not of pulmonary comorbidities (22% vs. 22%). The 90-day mortality was significantly higher in patients with diabetes than those without diabetes (64% vs. 56%, p < 0.001). The association of diabetes and 90-day mortality remained significant (HR 1.18 [1.06-1.31], p = 0.003) after adjustment for age, sex, SOFA-score and other comorbidities in a Weibull regression analysis., Conclusion: Diabetes mellitus was a relevant risk factor for 90-day mortality in old critically ill patients with COVID-19., Study Registration: NCT04321265, registered March 19th, 2020., (© 2023. The Author(s).)

Background: Fluid overload is associated with excess mortality in septic shock. Current approaches to reduce fluid overload include restrictive administration of fluid or active removal of accumulated fluid. However, evidence on active fluid removal is scarce. The aim of this study is to assess the efficacy and feasibility of an early de-resuscitation protocol in patients with septic shock., Methods: All patients admitted to the intensive care unit (ICU) with a septic shock are screened, and eligible patients will be randomised in a 1:1 ratio to intervention or standard of care., Intervention: Fluid management will be performed according to the REDUCE protocol, where resuscitation fluid will be restricted to patients showing signs of poor tissue perfusion. After the lactate has peaked, the patient is deemed stable and assessed for active de-resuscitation (signs of fluid overload). The primary objective of this study is the proportion of patients with a negative cumulative fluid balance at day 3 after ICU. Secondary objectives are cumulative fluid balances throughout the ICU stay, number of patients with fluid overload, feasibility and safety outcomes and patient-centred outcomes. The primary outcome will be assessed by a logistic regression model adjusting for the stratification variables (trial site and chronic renal failure) in the intention-to-treat population., Ethics and Dissemination: The study was approved by the respective ethical committees (No 2020-02197). The results of the REDUCE trial will be published in an international peer-reviewed medical journal regardless of the results., Trial Registration Number: ClinicalTrials.gov, NCT04931485., Competing Interests: Competing interests: The Department of Intensive Care, University Hospital, Inselspital (AM, JW, DB, CAP and JCS) reports grants from Orion Pharma, Abbott Nutrition International, B. Braun Medical AG, CSEM AG, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd, Maquet Critical Care AB, Omnicare Clinical Research AG, Nestle, Pierre Fabre Pharma AG, Pfizer, Bard Medica S.A., Abbott AG, Anandic Medical Systems, Pan Gas AG Healthcare, Bracco, Hamilton Medical AG, Fresenius Kabi, Getinge Group Maquet AG, Dräger AG, Teleflex Medical GmbH, GlaxoSmithKline, Merck Sharp and Dohme AG, Eli Lilly and Company, Baxter, Astellas, AstraZeneca, CSL Behring, Novartis, Covidien, Phagenesis, Cytel and Nycomed outside the project. The money was paid into departmental funds; no personal financial gain applied. All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Non-invasive ventilation (NIV) has been commonly used to treat acute respiratory failure due to COVID-19. In this study we aimed to compare outcomes of older critically ill patients treated with NIV before and during the COVID-19 pandemic., Methods: We analysed a merged cohort of older adults admitted to intensive care units (ICUs) due to respiratory failure. Patients were enrolled into one of two prospective observational studies: before COVID-19 (VIP2-2018 to 2019) and admitted due to COVID-19 (COVIP-March 2020 to January 2023). The outcomes included: 30-day mortality, intubation rate and NIV failure (death or intubation within 30 days)., Results: The final cohort included 1986 patients (1292 from VIP2, 694 from COVIP) with a median age of 83 years. NIV was used as a primary mode of respiratory support in 697 participants (35.1%). ICU admission due to COVID-19 was associated with an increased 30-day mortality (65.5% vs. 36.5%, HR 2.18, 95% CI 1.71 to 2.77), more frequent intubation (36.9% vs. 17.5%, OR 2.63, 95% CI 1.74 to 3.99) and NIV failure (76.2% vs. 45.3%, OR 4.21, 95% CI 2.84 to 6.34) compared to non-COVID causes of respiratory failure. Sensitivity analysis after exclusion of patients in whom life supporting treatment limitation was introduced during primary NIV confirmed higher 30-day mortality in patients with COVID-19 (52.5% vs. 23.4%, HR 2.64, 95% CI 1.83 to 3.80)., Conclusion: The outcomes of patients aged ≥80 years treated with NIV during COVID-19 pandemic were worse compared then those treated with NIV in the pre-pandemic era., (© 2023. La Société de Réanimation de Langue Francaise = The French Society of Intensive Care (SRLF).)

Background: Exposure to elevated sound pressure levels within the intensive care unit is known to negatively affect patient and staff health. In the past, interventions to address this problem have been unsuccessful as there is no conclusive evidence on the severity of each sound source and their role on the overall sound pressure levels. Therefore, the goal of the study was to perform a continuous 1 week recording to characterize the sound pressure levels and identify negative sound sources in this setting., Methods: In this prospective, systematic, and quantitative observational study, the sound pressure levels and sound sources were continuously recorded in a mixed medical-surgical intensive care unit over 1 week. Measurements were conducted using four sound level meters and a human observer present in the room noting all sound sources arising from two beds., Results: The mean 8 h sound pressure level was significantly higher during the day (52.01 ± 1.75 dBA) and evening (50.92 ± 1.66 dBA) shifts than during the night shift (47.57 ± 2.23; F (2, 19) = 11.80, p  < 0.001). No significant difference was found in the maximum and minimum mean 8 h sound pressure levels between the work shifts. However, there was a significant difference between the two beds in the based on location during the day ( F (3, 28) = 3.91, p  = 0.0189) and evening ( F (3, 24) = 5.66, p  = 0.00445) shifts. Cleaning of the patient area, admission and discharge activities, and renal interventions (e.g., dialysis) contributed the most to the overall sound pressure levels, with staff talking occurring most frequently., Conclusion: Our study was able to identify that continuous maintenance of the patient area, patient admission and discharge, and renal interventions were responsible for the greatest contribution to the sound pressure levels. Moreover, while staff talking was not found to significantly contribute to the sound pressure levels, it was found to be the most frequently occurring activity which may indirectly influence patient wellbeing. Overall, identifying these sound sources can have a meaningful impact on patients and staff by identifying targets for future interventions, thus leading to a healthier environment., Competing Interests: M-MJ, BZ, and JS report grants from Orion Pharma, Abbott Nutrition International, B. Braun Medical AG, CSEM AG, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd., Maquet Critical Care AB, Omnicare Clinical Research AG, Nestle, Pierre Fabre Pharma AG, Pfizer, Bard Medica S.A., Abbott AG, Anandic Medical Systems, Pan Gas AG Healthcare, Bracco, Hamilton Medical AG, Fresenius Kabi, Getinge Group Maquet AG, Dräger AG, Teleflex Medical GmbH, Glaxo Smith Kline, Merck Sharp and Dohme AG, Eli Lilly, and Company, Baxter, Astellas, Astra Zeneca, CSL Behring, Novartis, Covidien, Hemotune, Phagenesis, Philips Medical, Prolong Pharmaceuticals, and Nycomed outside the submitted work. The money received was paid into departmental funds. No personal financial gain was applied. 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., (Copyright © 2023 Naef, Knobel, Ruettgers, Rossier, Jeitziner, Zante, Müri, Schefold, Nef and Gerber.)

Critically ill patients are at risk of gastrointestinal (GI) bleeding. Counter measures to minimise this risk include the use of pharmacological stress ulcer prophylaxis (SUP). The effect of enteral nutrition as SUP on GI bleeding event rates is unknown. There are conflicting data describing the effect of co-administration of enteral nutrition with pharmacological SUP, and there is substantial variation in practice. We aim to conduct an exploratory post hoc analysis to evaluate the association of enteral nutrition with clinically important GI bleed rates in ICU patients included in the SUP-ICU trial, and to explore any interactions between enteral nutrition and pharmacologic SUP on patient outcomes. The SUP-ICU trial dataset will be used to assess if enteral nutrition is associated with the outcomes of interest. Extended Cox models will be used considering relevant competing events, including treatment allocation (SUP or placebo) and enteral nutrition as a daily time-varying covariate, with additional adjustment for severity of illness (SAPS II). Results will be presented as adjusted hazard ratios for treatment allocation and enteral nutrition, and for treatment allocation and enteral nutrition considering potential interactions with the other variable, all with 95% confidence intervals and p-values for the tests of interaction. All results will be considered as exploratory only. This post hoc analysis may yield important insights to guide practice and inform the design of future randomised clinical trial investigating the effect of enteral nutrition on GI bleeding., (© 2023 Acta Anaesthesiologica Scandinavica Foundation.)

Objectives: This study assessed opinions and experiences of healthcare professionals, former patients and family members during the first wave of the COVID-19 pandemic and focuses on challenges in family-centred care for intensive care unit patients and affected families., Research Methodology/design: A two-round modified Delphi process assessed the opinions and experiences of experts such as healthcare professionals, former patients and their families (n = 151)., Setting: This study was conducted across four countries in Europe., Results: In total, 121 participants (response rate 80.13%) answered the first Delphi round; the second was answered by 131 participants (response rate 86.75%). Participants perceived family support in the intensive care unit as highly important during the COVID-19 pandemic. Enabling contact amongst patients, families and clinicians is regarded as essential to build hope and confidence in the treatment and the recovery process. The extraordinary situation led to the implementation of new communication structures such as video calls and websites., Conclusion: A consensus was reached between healthcare professionals that virtual contact is essential for patients with COVID-19 and their families during visit restrictions. This should be done to establish confidence in the treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: To investigate the predictive validity of the Chelsea Critical Care Physical Assessment tool (CPAx) at intensive care unit (ICU) discharge in critically ill adults for their 90-day outcomes., Materials and Methods: This prospective clinimetric study investigated four theory-driven, a-priori hypotheses in critically ill adults recruited within 72-144 h of mechanical ventilation. The primary hypothesis was a moderate accuracy (AUROC = 0.750) in predicting residence at home within 90 days. Secondary hypotheses included discrimination between hospital discharge destinations, correlation with subsequent health-related quality of life and length of ICU stay., Results: We observed a good accuracy (AUROC = 0.778) of the CPAx at ICU discharge in predicting a return to home within 90 days. The CPAx score significantly increased between the discharge groups "undesirable" ≤ "rehabilitation" ≤ "home" ( p  < 0.001), but was not associated with 90-day health-related quality of life (physical: r  = 0.261, mental: r  = 0.193). Measured at baseline, CPAx scores correlated as expected with length of ICU stay ( r = -0.443)., Conclusions: The CPAx at ICU discharge had a good predictive validity in projecting residence at home within 90 days and general discharge destinations. The CPAx might therefore have clinical value in prediction, though it does not seem useful to predict subsequent health-related quality of life. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) identification number: DRKS00012983, registered on September 20, 2017IMPLICATIONS FOR REHABILITATIONThe CPAx is a valid and reliable measurement instrument to evaluate critically ill adults' physical function and activity, in addition the CPAx might be useful to predict rehabilitation needs.The CPAx had a moderate to good predictive validity with three out of four a-priori hypotheses accepted.A CPAx score of ≥18 at critical care discharge has a sensitivity of 80% and a specificity of 70% in predicting a return to home within 90 days.The CPAx might consequently be valuable to identify critically ill adults' rehabilitation needs, to advise on their potential trajectory of recovery or to screen patients for follow-up after hospital discharge.

Severe COVID-19 is characterized by systemic inflammation and multiple organ dysfunction syndrome (MODS). Arterial and venous thrombosis are involved in the pathogenesis of MODS and fatality in COVID-19. There is evidence that complement and neutrophil activation in the form of neutrophil extracellular traps are main drivers for development of microvascular complications in COVID-19. Plasma and serum samples were collected from 83 patients infected by SARS-CoV-2 during the two first waves of COVID-19, before the availability of SARS-CoV-2 vaccination. Samples were collected at enrollment, day 11, and day 28; and patients had differing severity of disease. In this comprehensive study, we measured cell-free DNA, neutrophil activation, deoxyribonuclease I activity, complement activation, and D-dimers in longitudinal samples of COVID-19 patients. We show that all the above markers, except deoxyribonuclease I activity, increased with disease severity. Moreover, we provide evidence that in severe disease there is continued neutrophil and complement activation, as well as D-dimer formation and nucleosome release, whereas in mild and moderate disease all these markers decrease over time. These findings suggest that neutrophil and complement activation are important drivers of microvascular complications and that they reflect immunothrombosis in these patients. Neutrophil activation, complement activation, cell-free DNA, and D-dimer levels have the potential to serve as reliable biomarkers for disease severity and fatality in COVID-19. They might also serve as suitable markers with which to monitor the efficacy of therapeutic interventions in COVID-19., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Purpose: The noise levels in intensive care units have been repeatedly reported to exceed the recommended guidelines and yield negative health outcomes among healthcare professionals. However, it is unclear which sound sources within this environment are perceived as disturbing. Therefore, this study aimed to evaluate how healthcare professionals in Germany, Switzerland, and Austria perceive the sound levels and the associated sound sources within their work environment and explore sound reduction strategies., Material and Methods: An online survey was conducted among 350 healthcare professionals working in intensive care units. The survey consisted of items on demographic and hospital data and questions about the perception of the sound levels [1 (strongly disagree) to 5 (strongly agree)], disturbance from sound sources [1 (not disturbing at all) to 5 (very disturbing)], and implementation potential, feasibility, and motivation to reduce sound reduction measures [1 (not high at all) to 5 (very high)]., Results: Approximately 69.3% of the healthcare professionals perceived the sound levels in the ICUs as too high. Short-lasting human sounds (e.g. moans or laughs) [mean (M) ± standard deviation (SD) = 3.30 ± 0.81], devices and alarms (M ± SD = 2.67 ± 0.59), and short-lasting object sounds (M ± SD = 2.55 ± 0.68) were perceived as the most disturbing sounds. Reducing medical equipment alarms was considered to have greater implementation potential [M ± SD = 3.62 ± 0.92, t(334) = -7.30, p < 0.001], feasibility [M ± SD = 3.19 ± 0.93, t(334) = -11.02, p < 0.001], and motivation [M ± SD = 3.85 ± 0.89, t(334) = -10.10, p < 0.001] for reducing the sound levels., Conclusion: This study showed that healthcare professionals perceive short-lasting human sounds as most disturbing and rated reducing medical equipment alarms as the best approach to reduce the sound levels in terms of potential, feasibility, and motivation for implementation., Competing Interests: This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2022 Ruettgers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: In the early COVID-19 pandemic concerns about the correct choice of analgesics in patients with COVID-19 were raised. Little data was available on potential usefulness or harmfulness of prescription free analgesics, such as paracetamol. This international multicentre study addresses that lack of evidence regarding the usefulness or potential harm of paracetamol intake prior to ICU admission in a setting of COVID-19 disease within a large, prospectively enrolled cohort of critically ill and frail intensive care unit (ICU) patients., Methods: This prospective international observation study (The COVIP study) recruited ICU patients ≥ 70 years admitted with COVID-19. Data on Sequential Organ Failure Assessment (SOFA) score, prior paracetamol intake within 10 days before admission, ICU therapy, limitations of care and survival during the ICU stay, at 30 days, and 3 months. Paracetamol intake was analysed for associations with ICU-, 30-day- and 3-month-mortality using Kaplan Meier analysis. Furthermore, sensitivity analyses were used to stratify 30-day-mortality in subgroups for patient-specific characteristics using logistic regression., Results: 44% of the 2,646 patients with data recorded regarding paracetamol intake within 10 days prior to ICU admission took paracetamol. There was no difference in age between patients with and without paracetamol intake. Patients taking paracetamol suffered from more co-morbidities, namely diabetes mellitus (43% versus 34%, p < 0.001), arterial hypertension (70% versus 65%, p = 0.006) and had a higher score on Clinical Frailty Scale (CFS; IQR 2-5 versus IQR 2-4, p < 0.001). Patients under prior paracetamol treatment were less often subjected to intubation and vasopressor use, compared to patients without paracetamol intake (65 versus 71%, p < 0.001; 63 versus 69%, p = 0.007). Paracetamol intake was not associated with ICU-, 30-day- and 3-month-mortality, remaining true after multivariate adjusted analysis., Conclusion: Paracetamol intake prior to ICU admission was not associated with short-term and 3-month mortality in old, critically ill intensive care patients suffering from COVID-19., Trial Registration: This prospective international multicentre study was registered on ClinicalTrials.gov with the identifier "NCT04321265" on March 25, 2020., (© 2022. The Author(s).)

Objective: Post-extubation dysphagia in critically ill patients is known to affect about 18 per cent of mixed medical-surgical intensive care unit patients. This study investigated the incidence of post-extubation dysphagia in adult intensive care unit patients with coronavirus disease 2019., Method: This study was a retrospective analysis of consecutive intensive care unit patients prospectively screened for dysphagia. Systematic screening of all extubated intensive care unit patients at our tertiary centre was performed using the Bernese intensive care unit dysphagia algorithm. The primary outcome measure was the incidence of post-extubation dysphagia., Results: A total of 231 critically ill adult coronavirus disease 2019 positive patients were included, and 81 patients remained in the final analysis after exclusion criteria were applied (e.g. patients transferred). Dysphagia screening positivity was 25 of 81 (30.9 per cent), with 28.2 per cent (22 of 78) having confirmed dysphagia by specialist examination within 24 hours ( n = 3 lost to follow up)., Conclusion: In this observational study, it was observed that the incidence of dysphagia in adult critically ill coronavirus disease 2019 patients was about 31 per cent (i.e. increased when compared with a historical pre-pandemic non-coronavirus disease 2019 intensive care unit cohort).

Background: The coronavirus disease 2019 (COVID-19) pandemic demands reliable prognostic models for estimating the risk of long COVID. We developed and validated a prediction model to estimate the probability of known common long COVID symptoms at least 60 days after acute COVID-19., Methods: The prognostic model was built based on data from a multicentre prospective Swiss cohort study. Included were adult patients diagnosed with COVID-19 between February and December 2020 and treated as outpatients, at ward or intensive/intermediate care unit. Perceived long-term health impairments, including reduced exercise tolerance/reduced resilience, shortness of breath and/or tiredness (REST), were assessed after a follow-up time between 60 and 425 days. The data set was split into a derivation and a geographical validation cohort. Predictors were selected out of twelve candidate predictors based on three methods, namely the augmented backward elimination (ABE) method, the adaptive best-subset selection (ABESS) method and model-based recursive partitioning (MBRP) approach. Model performance was assessed with the scaled Brier score, concordance c statistic and calibration plot. The final prognostic model was determined based on best model performance., Results: In total, 2799 patients were included in the analysis, of which 1588 patients were in the derivation cohort and 1211 patients in the validation cohort. The REST prevalence was similar between the cohorts with 21.6% (n = 343) in the derivation cohort and 22.1% (n = 268) in the validation cohort. The same predictors were selected with the ABE and ABESS approach. The final prognostic model was based on the ABE and ABESS selected predictors. The corresponding scaled Brier score in the validation cohort was 18.74%, model discrimination was 0.78 (95% CI: 0.75 to 0.81), calibration slope was 0.92 (95% CI: 0.78 to 1.06) and calibration intercept was -0.06 (95% CI: -0.22 to 0.09)., Conclusion: The proposed model was validated to identify COVID-19-infected patients at high risk for REST symptoms. Before implementing the prognostic model in daily clinical practice, the conduct of an impact study is recommended., (© 2022. The Author(s).)

Aims of the Study: To describe reasons for medical emergency team (MET) activation over time, to analyse outcomes, and to describe the circadian distribution of MET calls and Intensive Care Unit (ICU) admissions following MET activation., Methods: Monocentric retrospective observational study of prospectively collected data on all MET calls between 1 st of January 2012 until 31 st of May 2019. We analysed data on baselines, referring wards, and disposition of all MET patients. In addition, we allocated all MET calls to the hourly intervals over the 24-hour cycle of the day in order to identify peak times of team activation., Results: A total of 4068 calls in 3277 patients (37% female, n = 1210) were analysed. The mean age was 65.9 years (± 15.7). The MET dose (defined as MET calls/1000 hospital admissions) remained relatively stable over the years with a median of 8.0 calls/1000 hospitalisations (interquartile range [IQR] 7.0-10.0). A total of 2526 calls (62%) occurred out of hours (17:00 to 8:00). The hourly rate of MET activations was greatest during the evening shift (33.8% of calls in seven hours), followed by the day shift (35.8% calls in nine hours) and night shift (30.4% in eight hours). Over the years, staff concern was the main reason for a MET call (n = 1192, 34%), followed by low peripheral oxygen saturation (SpO 2 ) not responding to oxygen therapy (n = 776, 22%). Abnormal respiratory rate was a trigger to call the MET in 44 cases (1.3%), and was not documented prior to 2017. Overall, in-hospital mortality was 22%., Conclusion: While most common reasons for MET calls over the years were staff concern and low SpO 2 , abnormal respiratory rate was the least frequent, but increased after the introduction of the quick sequential organ failure assessment (qSOFA) in 2016. Most MET calls occurred out of hours with peak hours during the evening shift, highlighting the importance of resource allocation during this shift when planning to introduce a MET system in a hospital. In-hospital mortality after a MET call was 22%.

Background: COVID-19 remains a complex disease in terms of its trajectory and the diversity of outcomes rendering disease management and clinical resource allocation challenging. Varying symptomatology in older patients as well as limitation of clinical scoring systems have created the need for more objective and consistent methods to aid clinical decision making. In this regard, machine learning methods have been shown to enhance prognostication, while improving consistency. However, current machine learning approaches have been limited by lack of generalisation to diverse patient populations, between patients admitted at different waves and small sample sizes., Objectives: We sought to investigate whether machine learning models, derived on routinely collected clinical data, can generalise well i) between European countries, ii) between European patients admitted at different COVID-19 waves, and iii) between geographically diverse patients, namely whether a model derived on the European patient cohort can be used to predict outcomes of patients admitted to Asian, African and American ICUs., Methods: We compare Logistic Regression, Feed Forward Neural Network and XGBoost algorithms to analyse data from 3,933 older patients with a confirmed COVID-19 diagnosis in predicting three outcomes, namely: ICU mortality, 30-day mortality and patients at low risk of deterioration. The patients were admitted to ICUs located in 37 countries, between January 11, 2020, and April 27, 2021., Results: The XGBoost model derived on the European cohort and externally validated in cohorts of Asian, African, and American patients, achieved AUC of 0.89 (95% CI 0.89-0.89) in predicting ICU mortality, AUC of 0.86 (95% CI 0.86-0.86) for 30-day mortality prediction and AUC of 0.86 (95% CI 0.86-0.86) in predicting low-risk patients. Similar AUC performance was achieved also when predicting outcomes between European countries and between pandemic waves, while the models showed high calibration quality. Furthermore, saliency analysis showed that FiO2 values of up to 40% do not appear to increase the predicted risk of ICU and 30-day mortality, while PaO2 values of 75 mmHg or lower are associated with a sharp increase in the predicted risk of ICU and 30-day mortality. Lastly, increase in SOFA scores also increase the predicted risk, but only up to a value of 8. Beyond these scores the predicted risk remains consistently high., Conclusion: The models captured both the dynamic course of the disease as well as similarities and differences between the diverse patient cohorts, enabling prediction of disease severity, identification of low-risk patients and potentially supporting effective planning of essential clinical resources., Trial Registration Number: NCT04321265., Competing Interests: JCS report grants from Orion Pharma, Abbott Nutrition International, B. Braun Medical AG, CSEM AG, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd, Maquet Critical Care AB, Omnicare Clinical Research AG, Nestle, Pierre Fabre Pharma AG, Pfizer, Bard Medica S.A., Abbott AG, Anandic Medical Systems, Pan Gas AG Healthcare, Bracco, Hamilton Medical AG, Fresenius Kabi, Getinge Group Maquet AG, Dräger AG, Teleflex Medical GmbH, Glaxo Smith Kline, Merck Sharp and Dohme AG, Eli Lilly and Company, Baxter, Astellas, Astra Zeneca, CSL Behring, Novartis, Covidien, Phagenesis, and Nycomed outside the submitted work. The money was paid into departmental funds. No personal financial gain applied. The other authors declare no Competing Financial or Non-Financial Interests., (Copyright: © 2022 Mamandipoor et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Older critically ill patients with COVID-19 have been the most vulnerable during the ongoing pandemic, with men being more prone to hospitalization and severe disease than women. We aimed to explore sex-specific differences in treatment and outcome after intensive care unit (ICU) admission in this cohort., Methods: We performed a sex-specific analysis in critically ill patients ≥ 70 yr of age with COVID-19 who were included in the international prospective multicenter COVIP study. All patients were analyzed for ICU admission and treatment characteristics. We performed a multilevel adjusted regression analysis to elucidate associations of sex with 30-day mortality., Results: A total of 3,159 patients (69.8% male, 30.2% female; median age, 75 yr) were included. Male patients were significantly fitter than female patients as determined by the Clinical Frailty Scale (fit, 67% vs 54%; vulnerable, 14% vs 19%; frail, 19% vs 27%; P < 0.001). Male patients more often underwent tracheostomy (20% vs 14%; odds ratio [OR], 1.57; P < 0.001), vasopressor therapy (69% vs 62%; OR, 1.25; P = 0.02), and renal replacement therapy (17% vs 11%; OR, 1.96; P < 0.001). There was no difference in mechanical ventilation, life-sustaining treatment limitations, and crude 30-day mortality (50% male vs 49% female; OR, 1.11; P = 0.19), which remained true after adjustment for disease severity, frailty, age and treatment limitations (OR, 1.17; 95% confidence interval, 0.94 to 1.45; P = 0.16)., Conclusion: In this analysis of sex-specific treatment characteristics and 30-day mortality outcomes of critically ill patients with COVID-19 ≥ 70 yr of age, we found more tracheostomy and renal replacement therapy in male vs female patients, but no significant association of patient sex with 30-day mortality., Study Registration: www., Clinicaltrials: gov (NCT04321265); registered 25 March 2020)., (© 2022. The Author(s).)

During analysis of a prospective multinational observation study of critically ill patients ≥80 years of age, the VIP2 study, we also studied the effects of differences in country consent for study inclusion. This is a post hoc analysis where the ICUs were analyzed according to requirement for study consent. Group A: ICUs in countries with no requirement for consent at admission but with deferred consent in survivors. Group B: ICUs where some form of active consent at admission was necessary either from the patient or surrogates. Patients' characteristics, the severity of disease and outcome variables were compared. Totally 3098 patients were included from 21 countries. The median age was 84 years (IQR 81-87). England was not included because of changing criteria for consent during the study period. Group A (7 countries, 1200 patients), and group B (15 countries, 1898 patients) were comparable with age and gender distribution. Cognition was better preserved prior to admission in group B. Group A suffered from more organ dysfunction at admission compared to group B with Sequential Organ Failure Assessment score median 8 and 6 respectively. ICU survival was lower in group A, 66.2% compared to 78.4% in group B (p<0.001). We hence found profound effects on outcomes according to differences in obtaining consent for this study. It seems that the most severely ill elderly patients were less often recruited to the study in group B. Hence the outcome measured as survival was higher in this group. We therefore conclude that consent likely is an important confounding factor for outcome evaluation in international studies focusing on old patients., Competing Interests: Joerg C. Schefold declares that the Dept. of Intensive Care Medicine Bern has/ had research and/or development/consulting contracts with (full disclosure): Orion Corporation, Abbott Nutrition International, B. Braun Medical AG, CSEM SA, Edwards Lifesciences Services GmbH/SA, Kenta Biotech Ltd, Maquet Critical Care AB, Omnicare Clinical Research AG, and Nestlé. Educational grants were received from Fresenius Kabi; GSK; MSD; Lilly; Baxter; Astellas; AstraZeneca; B. Braun Medical AG, CSL Behring, Maquet, Novartis, Covidien, Nycomed, Pierre Fabre Pharma (Roba Pharma); Pfizer, Orion Pharma. The money went into departmental funds. No personal financial gain applies. This does not alter our adherence to PLOS ONE policies on sharing data and materials All other authors do not have any conflict of interest to declare related to this manuscript.

In Europe, tax-based healthcare systems (THS) and social health insurance systems (SHI) coexist. We examined differences in 30-day mortality among critically ill patients aged ≥ 70 years treated in intensive care units in a THS or SHI. Retrospective cohort study. 2406 (THS n = 886; SHI n = 1520) critically ill ≥ 70 years patients in 129 ICUs. Generalized estimation equations with robust standard errors were chosen to create population average adjusted odds ratios (aOR). Data were adjusted for patient-specific variables, organ support and health economic data. The primary outcome was 30-day-mortality. Numerical differences between SHI and THS in SOFA scores (6 ± 3 vs. 5 ± 3; p = 0.002) were observed, but clinical frailty scores were similar (> 4; 17% vs. 14%; p = 0.09). Higher rates of renal replacement therapy (18% vs. 11%; p < 0.001) were found in SHI (aOR 0.61 95%CI 0.40-0.92; p = 0.02). No differences regarding intubation rates (68% vs. 70%; p = 0.33), vasopressor use (67% vs. 67%; p = 0.90) and 30-day-mortality rates (47% vs. 50%; p = 0.16) were found. Mortality remained similar between both systems after multivariable adjustment and sensitivity analyses. The retrospective character of this study. Baseline risk and mortality rates were similar between SHI and THS. The type of health care system does not appear to have played a role in the intensive care treatment of critically ill patients ≥ 70 years with COVID-19 in Europe., (© 2022. The Author(s).)

Aims: Continuous-flow left ventricular assist devices (CF-LVADs) have become a standard of care in end-stage heart failure. Limited data exist comparing outcomes of HeartMate3 (HM3) and HeartWare HVAD (HW). We aimed to compare midterm outcomes of these devices., Methods and Results: Investigator-initiated retrospective-observational comparative analysis of all patients who underwent primary LVAD implantation of either HM3 or HW at our centre between January 2010 and December 2020. Data were derived from a prospective registry. Primary endpoints were all-cause mortality and heart transplantation. Secondary endpoints included device-related major adverse cardiac and cerebrovascular events, which included major bleeding, major neurological dysfunction (defined as persisting neurological impairment for ≥24 h), device-related major infection (excluding driveline infections), major device malfunctions leading to re-intervention or partial device exchange (pump failure, outflow-graft twist or failure, controller failure, battery failure, patient cable failure, but excluding pump thrombosis), and pump thrombosis. Further secondary endpoints included right heart failure, gastrointestinal bleeding, driveline infections, and surgical re-interventions. The secondary outcomes were analysed not only for the first event but also for recurrent events. The analysis included competing risks analysis and recurrent event regression analysis, with adjustment for confounders age, gender, body mass index (BMI), and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level. Out of 106 primary CF-LVAD implantations, 36 (34%) received HM3 and 70 (66%) received HW. Median follow-up was 1.48 years [interquartile range 0.67, 2.41]. HM3 was more often implanted in men (91.7% vs. 72.9%, P = 0.024); patients were older (median 61 years [54, 66.5] vs. 52.5 years [43, 60], P < 0.001), had a higher BMI (median 26.7 kg/m 2 [23.4, 29.0] vs. 24.3 kg/m 2 [20.7, 27.4], P = 0.013), had more comorbidities, and were more likely targeted for destination therapy (36.1% vs. 14.3%, P = 0.010). Death occurred in 33.3% of HM3 patients, compared with 22.9% of HW patients, P = 0.247 (probability of survival at 4 years, 54.7% vs. 74.1%, P = 0.296). After adjustment for confounders, we observed a significant six-fold risk increase in device malfunctions for HW [hazard ratio (HR) 6.49, 95% confidence interval (CI) [1.89, 22.32], P = 0.003], but no significant differences in pump thrombosis (P = 0.173) or overall survival (P = 0.801)., Conclusions: Comparing midterm outcomes between HM3 and HW for LVAD support from a prospective registry, HW patients had a significantly higher risk of device malfunctions. No significant differences were evident between devices in overall survival and in respect to most outcomes., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Previous studies reported regional differences in end-of-life care (EoLC) for critically ill patients in Europe., Objectives: The purpose of this post-hoc analysis of the prospective multicentre COVIP study was to investigate variations in EoLC practices among older patients in intensive care units during the coronavirus disease 2019 pandemic., Methods: A total of 3105 critically ill patients aged 70 years and older were enrolled in this study (Central Europe: n = 1573; Northern Europe: n = 821; Southern Europe: n = 711). Generalised estimation equations were used to calculate adjusted odds ratios (aORs) to population averages. Data were adjusted for patient-specific variables (demographic, disease-specific) and health economic data (gross domestic product, health expenditure per capita). The primary outcome was any treatment limitation, and 90-day mortality was a secondary outcome., Results: The frequency of the primary endpoint (treatment limitation) was highest in Northern Europe (48%), intermediate in Central Europe (39%) and lowest in Southern Europe (24%). The likelihood for treatment limitations was lower in Southern than in Central Europe (aOR 0.39; 95% confidence interval [CI] 0.21-0.73; p = 0.004), even after multivariable adjustment, whereas no statistically significant differences were observed between Northern and Central Europe (aOR 0.57; 95%CI 0.27-1.22; p = 0.15). After multivariable adjustment, no statistically relevant mortality differences were found between Northern and Central Europe (aOR 1.29; 95%CI 0.80-2.09; p = 0.30) or between Southern and Central Europe (aOR 1.07; 95%CI 0.66-1.73; p = 0.78)., Conclusion: This study shows a north-to-south gradient in rates of treatment limitation in Europe, highlighting the heterogeneity of EoLC practices across countries. However, mortality rates were not affected by these results., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background: The objective was to investigate the role of gene expression and plasma levels of the muscular protein myostatin in intensive care unit-acquired weakness (ICUAW). This was performed to evaluate a potential clinical and/or pathophysiological rationale of therapeutic myostatin inhibition., Methods: A retrospective analysis from pooled data of two prospective studies to assess the dynamics of myostatin plasma concentrations (day 4, 8 and 14) and myostatin gene (MSTN) expression levels in skeletal muscle (day 15) was performed. Associations of myostatin to clinical and electrophysiological outcomes, muscular metabolism and muscular atrophy pathways were investigated., Results: MSTN gene expression (median [IQR] fold change: 1.00 [0.68-1.54] vs. 0.26 [0.11-0.80]; p = 0.004) and myostatin plasma concentrations were significantly reduced in all critically ill patients when compared to healthy controls. In critically ill patients, myostatin plasma concentrations increased over time (median [IQR] fold change: day 4: 0.13 [0.08/0.21] vs. day 8: 0.23 [0.10/0.43] vs. day 14: 0.40 [0.26/0.61]; p < 0.001). Patients with ICUAW versus without ICUAW showed significantly lower MSTN gene expression levels (median [IQR] fold change: 0.17 [0.10/0.33] and 0.51 [0.20/0.86]; p = 0.047). Myostatin levels were directly correlated with muscle strength (correlation coefficient 0.339; p = 0.020) and insulin sensitivity index (correlation coefficient 0.357; p = 0.015). No association was observed between myostatin plasma concentrations as well as MSTN expression levels and levels of mobilization, electrophysiological variables, or markers of atrophy pathways., Conclusion: Muscular gene expression and systemic protein levels of myostatin are downregulated during critical illness. The previously proposed therapeutic inhibition of myostatin does therefore not seem to have a pathophysiological rationale to improve muscle quality in critically ill patients., Trial Registration: ISRCTN77569430 -13th of February 2008 and ISRCTN19392591 17th of February 2011., (© 2022. The Author(s).)

Purpose: Six to 19% of critically ill COVID-19 patients display circulating auto-antibodies against type I interferons (IFN-AABs). Here, we establish a clinically applicable strategy for early identification of IFN-AAB-positive patients for potential subsequent clinical interventions., Methods: We analyzed sera of 430 COVID-19 patients from four hospitals for presence of IFN-AABs by ELISA. Binding specificity and neutralizing activity were evaluated via competition assay and virus-infection-based neutralization assay. We defined clinical parameters associated with IFN-AAB positivity. In a subgroup of critically ill patients, we analyzed effects of therapeutic plasma exchange (TPE) on the levels of IFN-AABs, SARS-CoV-2 antibodies and clinical outcome., Results: The prevalence of neutralizing AABs to IFN-α and IFN-ω in COVID-19 patients from all cohorts was 4.2% (18/430), while being undetectable in an uninfected control cohort. Neutralizing IFN-AABs were detectable exclusively in critically affected (max. WHO score 6-8), predominantly male (83%) patients (7.6%, 18/237 for IFN-α-AABs and 4.6%, 11/237 for IFN-ω-AABs in 237 patients with critical COVID-19). IFN-AABs were present early post-symptom onset and at the peak of disease. Fever and oxygen requirement at hospital admission co-presented with neutralizing IFN-AAB positivity. IFN-AABs were associated with lower probability of survival (7.7% versus 80.9% in patients without IFN-AABs). TPE reduced levels of IFN-AABs in three of five patients and may increase survival of IFN-AAB-positive patients compared to those not undergoing TPE., Conclusion: IFN-AABs may serve as early biomarker for the development of severe COVID-19. We propose to implement routine screening of hospitalized COVID-19 patients for rapid identification of patients with IFN-AABs who most likely benefit from specific therapies., (© 2022. The Author(s).)

Purpose: To translate and cross-culturally adapt the Chelsea Critical Care Physical Assessment tool from English to German (CPAx-GE) and to examine its validity and reliability., Materials and Methods: Following a forward-backward translation including an expert round table discussion, the measurement properties of the CPAx-GE were explored in critically ill, mechanically ventilated adults. We investigated construct, cross-sectional, and cross-cultural validity of the CPAx-GE with other measurement instruments at pre-specified timepoints, analysed relative reliability with intraclass correlation coefficients (ICCs) and determined absolute agreement with the Bland-Altman plots., Results: Consensus for the translated CPAx-GE was reached. Validity was excellent with >80% of the pre-specified hypotheses accepted at baseline, critical care, and hospital discharge. Interrater reliability was high (ICCs > 0.8) across all visits. Limit of agreement ranged from -2 to 2 points. Error of measurement was small, floor, and ceiling effects limited., Conclusions: The CPAx-GE demonstrated excellent construct, cross-sectional, and cross-cultural validity as well as high interrater reliability in critically ill adults with prolonged mechanical ventilation at baseline, critical care, and hospital discharge. Consequently, the CPAx-GE can be assumed equal to the original and recommended in the German-speaking area to assess physical function and activity of critically ill adults across the critical care and hospital stay. Trial registration: German Clinical Trials Register (DRKS) identification number: DRKS00012983 (https://www.drks.de/drks&#95;web/navigate.do?navigationId=trial.HTML&TRIAL&#95;ID=DRKS00012983), registered on 20 September 2017, first patient enrolled on 21 November 2017.Implications for rehabilitationEarly rehabilitation of critically ill patients is recommended to prevent and treat the subsequent functional disability, but a suitable measurement instrument for the German-speaking area is lacking.The translated, cross-culturally adapted German CPAx demonstrated excellent validity and reliability in assessing physical function and activity in critically ill adults.Cross-sectional validity of the CPAx has been newly established and allows the use of this tool at clinically relevant time-points in the course of a critical illness.The CPAx-GE can therefore be used in clinical practice by German-speaking therapists to assess physical function and activity during early rehabilitation in the ICU and hospital.

Numerous patient-related clinical parameters and treatment-specific variables have been identified as causing or contributing to the severity of peritonitis. We postulated that a combination of clinical and surgical markers and scoring systems would outperform each of these predictors in isolation. To investigate this hypothesis, we developed a multivariable model to examine whether survival outcome can reliably be predicted in peritonitis patients treated with open abdomen. This single-center retrospective analysis used univariable and multivariable logistic regression modeling in combination with repeated random sub-sampling validation to examine the predictive capabilities of domain-specific predictors (i.e., demography, physiology, surgery). We analyzed data of 1,351 consecutive adult patients (55.7% male) who underwent open abdominal surgery in the study period (January 1998 to December 2018). Core variables included demographics, clinical scores, surgical indices and indicators of organ dysfunction, peritonitis index, incision type, fascia closure, wound healing, and fascial dehiscence. Postoperative complications were also added when available. A multidomain peritonitis prediction model (MPPM) was constructed to bridge the mortality predictions from individual domains (demographic, physiological and surgical). The MPPM is based on data of n = 597 patients, features high predictive capabilities (area under the receiver operating curve: 0.87 (0.85 to 0.90, 95% CI)) and is well calibrated. The surgical predictor "skin closure" was found to be the most important predictor of survival in our cohort, closely followed by the two physiological predictors SAPS-II and MPI. Marginal effects plots highlight the effect of individual outcomes on the prediction of survival outcome in patients undergoing staged laparotomies for treatment of peritonitis. Although most single indices exhibited moderate performance, we observed that the predictive performance was markedly increased when an integrative prediction model was applied. Our proposed MPPM integrative prediction model may outperform the predictive power of current models., (© 2021. The Author(s).)