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Purpose: The European Society of Intensive Care Medicine (ESICM) Green Paper aims to address the challenge of environmental sustainability in intensive care and proposes actionable strategies for integrating sustainability into intensive care unit (ICU) stakeholder actions., Methods: The ESICM Executive Committee appointed a task force of topic experts and ESICM committee representatives to develop the ESICM Green Paper. The task force convened biweekly from January to June 2024, identifying key domains for environmental sustainability and prioritizing actions. Drafts were iteratively refined and approved by the ESICM Executive Committee., Results: Climate change will impact activities in intensive care in many ways, but also the impact of ICU activities on the environment is considerable; drivers for this include extensive resource use and waste generation in ICUs from energy consumption, use of disposable items, and advanced therapies for critically ill patients. The ESICM Green Paper outlines a structured approach for ICUs to reduce their environmental impact, emphasizing energy efficiency, waste reduction, and sustainable procurement. Furthermore, it endorses the need for awareness and education among healthcare professionals, integration of sustainability into research, and sustainable policies within scientific societies., Conclusions: The ESICM Green Paper reviewed the relevance of climate change to intensive care and provided suggestions for clinical practice, research, education, and ESICM organizational domains. It underscores that reducing intensive care's ecological footprint can coexist with high-quality patient care. Promoting a resilient, responsible healthcare system is a joint responsibility of all ICU stakeholders., (© 2024. The Author(s).)

Background: Pancreatic stone protein (PSP) exhibits potential as a plasma biomarker for infection diagnosis and risk stratification in critically ill patients, but its significance in nosocomial infection and intensive care unit (ICU)-acquired bloodstream infection (BSI) remains unclear. This study explores the temporal responses of PSP in ICU-acquired BSI caused by different pathogens., Methods: From a large cohort of ICU patients, we selected episodes of ICU-acquired BSI caused by Gram-negative rods (GNRs), enterococci, or Candida species. Events were matched on length of ICU stay at infection onset, Severe Organ Failure Assessment (SOFA) score, presence of immune deficiency, and use of renal replacement therapy. PSP concentrations were measured at infection onset (T0) and at 24, 48 and 72 h prior to infection onset as defined by the first occurrence of a positive blood culture. Absolute and trend differences in PSP levels between pathogen groups were analysed using one-way analysis of variance. Sensitivity analyses were performed in events with a new or worsening systematic inflammatory response based on C-reactive protein, white cell count and fever., Results: We analysed 30 BSI cases per pathogen group. Median (IQR) BSI onset was on day 9 (6-12). Overall, PSP levels were high (381 (237-539) ng/ml), with 18% of values exceeding the assay's measurement range. Across all 90 BSI cases, there was no clear trend over time (median change 34 (- 75-189) ng/ml from T-72 to T0). PSP concentrations at infection onset were 406 (229-497), 350 (223-608), and 480 (327-965) ng/ml, for GNR, enterococci, and Candida species, respectively (p = 0.32). At every time point, absolute PSP levels and trends did not differ significantly between pathogens. PSP values at T0 correlated with SOFA scores. Eighteen (20%) of 90 BSI events did not exhibit a systemic inflammatory response, primarily in Candida species. No clear change in PSP concentration before BSI onset or between-group differences were found in sensitivity analyses of 72 cases., Conclusions: Against a background of overall (very) high plasma PSP levels in critically ill patients, we did not find clear temporal patterns or any pathogen-specific differences in PSP response in the days preceding onset of ICU-acquired BSI., (© 2024. The Author(s).)

While several effective therapies for critically ill patients with COVID-19 have been identified in large, well-conducted trials, the mechanisms underlying these therapies have not been investigated in depth. Our aim is to investigate the association between various immunosuppressive therapies (corticosteroids, tocilizumab and anakinra) and the change in endothelial host response over time in critically ill COVID-19 patients. We conducted a pre-specified multicenter post-hoc analysis in a Dutch cohort of COVID-19 patients admitted to the ICU between March 2020 and September 2021 due to hypoxemic respiratory failure. A panel of 18 immune response biomarkers in the complement, coagulation and endothelial function domains were measured using ELISA or Luminex. Biomarkers were measured on day 0-1, day 2-4 and day 6-8 after start of COVID-19 treatment. Patients were categorized into four treatment groups: no immunomodulatory treatment, corticosteroids, anakinra plus corticosteroids, or tocilizumab plus corticosteroids. The association between treatment group and the change in concentrations of biomarkers was estimated with linear mixed-effects models, using no immunomodulatory treatment as reference group. 109 patients with a median age of 62 years [IQR 54-70] of whom 72% (n = 78) was male, were included in this analysis. Both anakinra plus corticosteroids (n = 22) and tocilizumab plus corticosteroids (n = 38) were associated with an increase in angiopoietin-1 compared to no immune modulator (n = 23) (beta of 0.033 [0.002-0.064] and 0.041 [0.013-0.070] per day, respectively). These treatments, as well as corticosteroids alone (n = 26), were further associated with a decrease in the ratio of angiopoietin-2/angiopoietin-1 (beta of 0.071 [0.034-0.107], 0.060 [0.030-0.091] and 0.043 [0.001-0.085] per day, respectively). Anakinra plus corticosteroids and tocilizumab plus corticosteroids were associated with a decrease in concentrations of complement complex 5b-9 compared to no immunomodulatory treatment (0.038 [0.006-0.071] and 0.023 [0.000-0.047], respectively). Currently established treatments for critically ill COVID-19 patients are associated with a change in biomarkers of the angiopoietin and complement pathways, possibly indicating a role for stability of the endothelium. These results increase the understanding of the mechanisms of interventions and are possibly useful for stratification of patients with other inflammatory conditions which may potentially benefit from these treatments., (© 2024. The Author(s).)

Background: Anemia is a hallmark of critical illness, which is largely inflammatory driven. We hypothesized that the use of anti-inflammatory agents limits the development of anemia and reduces the need for red blood cell (RBC) transfusions in patients with a hyper-inflammatory condition due to COVID-19., Methods: An observational cohort (n = 772) and a validation cohort (a subset of REMAP-CAP, n = 119) of critically ill patients with hypoxemic respiratory failure due to COVID-19 were analyzed, who either received no treatment, received steroids or received steroids plus IL-6 blocking agents. The trajectory of hemoglobin (Hb) decline and the need for RBC transfusions were compared using descriptive statistics as well as multivariate modeling., Results: In both cohorts, Hb level was higher in the treated groups compared to the untreated group at all time points. In the observational cohort, incidence and number of transfused patients were lower in the group receiving the combination treatment compared to the untreated groups. In a multivariate analysis controlling for baseline Hb imbalance and mechanical ventilation, receipt of steroids remained associated with a slower decline in Hb level and the combination treatment remained associated with a slower decline of Hb and with less transfusions. Results remained the same in the validation cohort., Conclusion: Immunomodulatory treatment was associated with a slower decline in Hb level in critically ill patients with COVID-19 and with less transfusion. Findings point toward inflammation as an important cause for the occurrence of anemia in the critically ill., (© 2024. The Author(s).)

Sepsis is a common and deadly condition. Within the current model of sepsis immunobiology, the framing of dysregulated host immune responses into proinflammatory and immunosuppressive responses for the testing of novel treatments has not resulted in successful immunomodulatory therapies. Thus, the recent focus has been to parse observable heterogeneity into subtypes of sepsis to enable personalised immunomodulation. In this Personal View, we highlight that many fundamental immunological concepts such as resistance, disease tolerance, resilience, resolution, and repair are not incorporated into the current sepsis immunobiology model. The focus for addressing heterogeneity in sepsis should be broadened beyond subtyping to encompass the identification of deterministic molecular networks or dominant mechanisms. We explicitly reframe the dysregulated host immune responses in sepsis as altered homoeostasis with pathological disruption of immune-driven resistance, disease tolerance, resilience, and resolution mechanisms. Our proposal highlights opportunities to identify novel treatment targets and could enable successful immunomodulation in the future., Competing Interests: Declaration of interests MS-H is supported by the UK National Institute for Health and Care Research (NIHR) Clinician Scientist Award (CS-2016-16-011; 2017–2023). MPS's laboratory is supported by the Calouste Gulbenkian Foundation, La Caixa Foundation (HR18-00502), Fundação para a Ciência e a Tecnologia (GlucoInfect, 5723/2014; FEDER029411, FEDER/29411/2017; Infectenergy, PTDC/MED-FSL/4681/2020; MalBil, 2022.02426.PTDC), the Oeiras–European Research Council Frontier Research Incentive Awards, SymbNET Research Grants (H2020-WIDESPREAD-2020-5-952537), and Congento (LISBOA-01-0145-FEDER-022170). MPS is an associate member of the Deutsche Forschungsgemeinschaft (DFG) Balance of the Microverse initiative (EXC 2051; 390713860). MB is principal investigator of the DFG Balance of the Microverse initiative (EXC 2051; 390713860). JCK is supported by the Medical Research Council (MR/V002503/1), a Wellcome Trust Investigator Award (204969/Z/16/Z), and Wellcome Trust grants (090532/Z/09/Z and 203141/Z/16/Z) to the Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, and the NIHR Oxford Biomedical Research Centre. JM reports grants from the Canadian Institutes of Health Research and has served as chair of data and safety monitoring boards for AM Pharma and Adrenomed. CWS reports grants from the US National Institutes of Health National Institute of General Medical Sciences, during the conduct of the study, and personal fees from Inotrem and Beckman Coulter, outside of the submitted work. IBM has received funding or consultancy fees from Abbvie, Amgen, Bristol Myers Squibb, Cabaletta, Causeway, Eli Lilly, Evelo, GSK, Janssen, Moonlake, Novartis, Pfizer, and UCB. TvdP has received grants from the EU's Horizon 2020 research and innovation funding programme (grant agreements: Flagellin Aerosol Therapy in Treatment of Drug-resistant Bacterial Pneumonia, 847786; ImmunoSEP, 847422). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Impaired intestinal barrier function can enable passage of enteric microorganisms into the bloodstream and lead to nosocomial bloodstream infections during critical illness. We aimed to determine the relative importance of gut translocation as a source for ICU-acquired enterococcal bacteremia of unknown origin., Methods: We conducted a nested case-control study in two mixed medical-surgical tertiary ICUs in the Netherlands among patients enrolled between 2011 and 2018. We selected 72 cases with ICU-acquired bacteremia due to enterococci (which are known gastrointestinal tract commensals) and 137 matched controls with bacteremia due to coagulase-negative staphylococci (CoNS) (which are of non-intestinal origin). We measured intestinal fatty acid-binding protein, trefoil factor-3, and citrulline 48 h before bacteremia onset. A composite measure for Gut Barrier Injury (GBI) was calculated as the sum of standardized z-scores for each biomarker plus a clinical gastrointestinal failure score., Results: No single biomarker yielded statistically significant differences between cases and controls. Median composite GBI was higher in cases than in controls (0.58, IQR - 0.36-1.69 vs. 0.32, IQR - 0.53-1.57, p = 0.33) and higher composite measures of GBI correlated with higher disease severity and ICU mortality (p < 0.001). In multivariable analysis, higher composite GBI was not significantly associated with increased occurrence of enterococcal bacteremia relative to CoNS bacteremia (adjusted OR 1.12 95% CI 0.93-1.34, p = 0.22)., Conclusions: We could not demonstrate an association between biomarkers of gastrointestinal barrier dysfunction and an increased occurrence of bacteremia due to gut compared to skin flora during critical illness, suggesting against bacterial translocation as a major vector for acquisition of nosocomial bloodstream infections in the ICU., (© 2024. The Author(s).)

The aim of this Intensive Care Medicine Rapid Practice Guideline (ICM-RPG) was to provide evidence-based clinical guidance about the use of higher versus lower oxygenation targets for adult patients in the intensive care unit (ICU). The guideline panel comprised 27 international panelists, including content experts, ICU clinicians, methodologists, and patient representatives. We adhered to the methodology for trustworthy clinical practice guidelines, including the use of the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence, and used the Evidence-to-Decision framework to generate recommendations. A recently published updated systematic review and meta-analysis constituted the evidence base. Through teleconferences and web-based discussions, the panel provided input on the balance and magnitude of the desirable and undesirable effects, the certainty of evidence, patients' values and preferences, costs and resources, equity, feasibility, acceptability, and research priorities. The updated systematic review and meta-analysis included data from 17 randomized clinical trials with 10,248 participants. There was little to no difference between the use of higher versus lower oxygenation targets for all outcomes with available data, including all-cause mortality, serious adverse events, stroke, functional outcomes, cognition, and health-related quality of life (very low certainty of evidence). The panel felt that values and preferences, costs and resources, and equity favored the use of lower oxygenation targets. The ICM-RPG panel issued one conditional recommendation against the use of higher oxygenation targets: "We suggest against the routine use of higher oxygenation targets in adult ICU patients (conditional recommendation, very low certainty of evidence). Remark: an oxygenation target of SpO 2 88%-92% or PaO 2 8 kPa/60 mmHg is relevant and safe for most adult ICU patients.", (© 2023 Acta Anaesthesiologica Scandinavica Foundation.)

Background: Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the efficacy of therapeutic heparin including its comparative effect relative to intermediate-dose anticoagulation., Objectives: The authors performed 2 complementary secondary analyses of a completed randomized clinical trial: 1) a prespecified per-protocol analysis; and 2) an exploratory dose-based analysis to compare the effect of therapeutic-dose heparin with low- and intermediate-dose heparin., Methods: Patients who received initial anticoagulation dosed consistently with randomization were included. The primary outcome was organ support-free days (OSFDs), a combination of in-hospital death and days free of organ support through day 21., Results: Among 2,860 participants, 1,761 (92.8%) noncritically ill and 857 (89.1%) critically ill patients were treated per-protocol. Among noncritically ill per-protocol patients, the posterior probability that therapeutic-dose heparin improved OSFDs as compared with usual care was 99.3% (median adjusted OR: 1.36; 95% credible interval [CrI]: 1.07-1.74). Therapeutic heparin had a high posterior probability of efficacy relative to both low- (94.6%; adjusted OR: 1.26; 95% CrI: 0.95-1.64) and intermediate- (99.8%; adjusted OR: 1.80; 95% CrI: 1.22-2.62) dose thromboprophylaxis. Among critically ill per-protocol patients, the posterior probability that therapeutic heparin improved outcomes was low., Conclusions: Among noncritically ill patients hospitalized for COVID-19 who were randomized to and initially received therapeutic-dose anticoagulation, heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support. Therapeutic heparin appeared superior to both low- and intermediate-dose thromboprophylaxis., Competing Interests: The ACTIV-4a platform was sponsored by the 10.13039/100000050National Heart, Lung, and Blood Institute, 10.13039/100000002National Institutes of Health, Bethesda and administered through OTA-20 to 011. The research was, in part, funded by the 10.13039/100000002National Institutes of Health (NIH) Agreement 1OT2HL156812 through the 10.13039/100000050National Heart, Lung, and Blood Institute (NHLBI) CONNECTS program. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the NIH. The ATTACC platform was supported by grants from the 10.13039/501100000024Canadian Institutes of Health Research, 10.13039/100012357LifeArc, Thistledown Foundation, Peter Munk Cardiac Centre, 10.13039/100008794Research Manitoba, 10.13039/100009395CancerCare Manitoba Foundation, 10.13039/501100023238Victoria General Hospital Foundation, and the 10.13039/501100000226Ontario Ministry of Health. The REMAP-CAP platform was supported by the European Union—through FP7-HEALTH-2013-INNOVATION: the Platform for European Preparedness Against (Re)emerging Epidemics (PREPARE) consortium (602525), and 10.13039/100010661Horizon 2020 research and innovation program: the Rapid European Covid-19 Emergency Research response (RECOVER) consortium (101003589)—and by the Australian 10.13039/501100000925National Health and Medical Research Council (APP1101719), the 10.13039/501100001505Health Research Council of New Zealand (16/631), the 10.13039/501100000024Canadian Institutes of Health Research (Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant - 158584, and COVID-19 Rapid Research Operating Grant - 447335), the U.K. NIHR and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (PHRC-20-0147), the Minderoo Foundation, Amgen, Eisai, the Global Coalition for Adaptive Research, and the Wellcome Trust Innovations Project (215522). Dr Godoy is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Research Award) from the 10.13039/501100000024Canadian Institutes of Health Research. Dr Neal has received grants from the 10.13039/100000002National Institutes of Health and 10.13039/100000005United States Department of Defense; has received research support from Haemonetics, Janssen and Instrumentation Laboratories; has received honoraria from Haemonetics, 10.13039/100005565Janssen, and 10.13039/501100014255CSL Behring; and serves on the Scientific Advisory Board of Haima Therapeutics. Dr Goligher has received personal fees and nonfinancial support from Getinge, nonfinancial support from Timpel, outside the submitted work. Dr Cushman has received personal fees from the 10.13039/100000002National Institutes of Health, during the conduct of the study. Dr Bradbury has received personal fees from BMS Pfizer; nonfinancial support from 10.13039/100002429Amgen; personal fees and nonfinancial support from Bayer; personal fees and nonfinancial support from 10.13039/100004336Novartis; personal fees from Janssen; personal fees from Portola; and personal fees from Ablynx, outside the submitted work. Dr Tritschler is a member of the Canadian Venous Thromboembolism Research Network (CanVECTOR); the network receives grant funding from the 10.13039/501100000024Canadian Institutes of Health Research (CDT-142654). Dr Kahn is supported by a Tier 1 10.13039/501100001804Canada Research Chair. Dr L. Berry has received grants from PREPARE Network, 10.13039/501100000780European Commission through University Antwerp, grants from OPTIMISE CAP. She reports Australia funding through Monash University; grants from REMAP-CAP; New Zealand funding through Medical Research Institute of New Zealand; grants from Global Coalition for Adaptive Research (GCAR); United States funding through grants from ATTACC; Canada funding through 10.13039/100009663University Health Network, grants from ACTIV-4; and reports IP funding, 10.13039/100007921University of Pittsburgh, during the conduct of the study. Dr Lorenzi has received grants from PREPARE in EU (University Antwerp), grants from OPTIMISE-CAP in Australia (Monash University), grants from REMAP-CAP in New Zealand (Medical Research Institute of New Zealand (MRINZ)), grants from REMAP-COVID in the US (GCAR), grants from ATTACC in Canada (10.13039/100009663University Health Network), grants from ACTIV-4 IP in the U.S. (10.13039/100007125University of Pittsburgh), during the conduct of the study. Dr Higgins has received grants from 10.13039/501100000925National Health and Medical Research Council, grants from 10.13039/501100016056Minderoo Foundation, during the conduct of the study. Dr Berger has received grants from 10.13039/100000002National Institutes of Health - 10.13039/100000050NHLBI, during the conduct of the study; personal fees from Astra Zeneca, personal fees from Janssen, personal fees from Amgen, outside the submitted work. Dr Gong has received grants from 10.13039/100000050NHLBI, during the conduct of the study. Dr Castellucci has received unrelated honoraria received from Bayer, BMS-Pfizer Alliance, The Academy, LEO Pharma, Sanofi, Servier, and Valeo; and holds a Heart and Stroke Foundation of Canada National New Investigator Award, and a Tier 2 research Chair in Thrombosis and Anticoagulation Safety from the University of Ottawa. Dr Le Gal holds a Heart and Stroke Foundation of Canada National Clinician-Scientist Award, and the Chair on Diagnosis of Venous Thromboembolism from the University of Ottawa. Dr Rosenson has a patent EFSID 40934007 pending. Dr Derde has received grants from EU FP7-HEALTH-2013-INNOVATION-1, grant number 602525, grants from H2020 RECOVER grant agreement No 101003589, during the conduct of the study; COVID-19 guideline committee SCCM/ESICM/ SSC, ESICM COVID-19 taskforce, Dutch intensivists (NVIC) taskforce infectious threats, outside the submitted work. Dr Kumar has received grants from Merck, outside the submitted work. Dr McVerry has received grants from 10.13039/100000002NIH - National Heart, Lung and Blood Institute, during the conduct of the study; grants from Bayer Pharmaceuticals, Inc, outside the submitted work. Dr Nicolau has received personal fees from AMGEN, grants from 10.13039/100004325AstraZeneca, grants and personal fees from Bayer, grants from 10.13039/501100022336Esperion, grants from CLS Behring, personal fees from Daiichi-Sankyo, grants from Dalcor, grants from Janssen, grants and personal fees from Novartis, grants from NovoNordisk, grants and personal fees from Sanofi, personal fees from Servier, grants from Vifor, outside the submitted work. Dr Huang has received grants from the 10.13039/100000002NIH, during the conduct of the study. Dr Reynolds has received grants from 10.13039/100000050National Heart, Lung and Blood Institute, during the conduct of the study; nonfinancial support from 10.13039/100011949Abbott Vascular, nonfinancial support from BioTelemetry Inc, nonfinancial support from 10.13039/100004340Siemens, outside the submitted work. Dr Carrier has received grants from 10.13039/100004319Pfizer, grants from 10.13039/501100000024Canadian Institutes of Health Research, grants from 10.13039/100002491BMS, during the conduct of the study; grants and personal fees from Leo Pharma, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Bayer, personal fees from Sanofi Aventis, personal fees from Pfizer, outside the submitted work. Dr S. Berry reports grants from PREPARE Network, grants from Optimise-CAP, grants from REMAP-CAP, grants from GCAR, grants from 10.13039/100009663University Health Network, grants from 10.13039/100007125University of Pittsburgh, during the conduct of the study. Dr Webb reports grants from 10.13039/501100000925National Health and Medical Research Council, grants from 10.13039/501100016056Minderoo Foundation, during the conduct of the study. Dr Turgeon reports grants from 10.13039/100022992Canadian Institutes of Health Research, during the conduct of the study. Dr McArthur has received grants from 10.13039/501100001505Health Research Council of New Zealand, during the conduct of the study. Dr Farkouh has received grants from 10.13039/100002429Amgen, grants from Novo Nordisk, grants from 10.13039/100004336Novartis, outside the submitted work. Dr Hochman is a principal investigator for the ISCHEMIA trial which, in addition to funding by 10.13039/100000002NIH, received support in the form of devices and medications provided by: Medtronic, Inc; Abbott Vascular, Inc (formerly St. Jude Medical, Inc); Royal Philips NV (formerly Volcano Corporation); Arbor Pharmaceuticals, LLC; AstraZeneca Pharmaceuticals, LP; Merck Sharp & Dohme Corp; Omron Healthcare, Inc; Sunovion Pharmaceuticals, Inc; Espero BioPharma; and Amgen Inc; and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. Dr Zarychanski has received unrelated grant funding from the 10.13039/501100000024Canadian Institutes of Health Research, 10.13039/100009395CancerCare Manitoba Foundation, and 10.13039/100008794Research Manitoba and receives operating support as the Lyonel G. Israels Research Chair in Hematology at the 10.13039/100010318University of Manitoba. Dr Lawler has received unrelated consulting fees from Novartis, CorEvitas, and Brigham and Women’s Hospital, and unrelated royalties from McGraw-Hill Publishing; and is supported by a Heart and Stroke Foundation of Canada National New Investigator career award. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear., Methods: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2)., Results: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control., Conclusions: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose: Antibiotic therapy is commonly prescribed longer than recommended in intensive care patients (ICU). We aimed to provide insight into the decision-making process on antibiotic therapy duration in the ICU., Methods: A qualitative study was conducted, involving direct observations of antibiotic decision-making during multidisciplinary meetings in four Dutch ICUs. The study used an observation guide, audio recordings, and detailed field notes to gather information about the discussions on antibiotic therapy duration. We described the participants' roles in the decision-making process and focused on arguments contributing to decision-making., Results: We observed 121 discussions on antibiotic therapy duration in sixty multidisciplinary meetings. 24.8% of discussions led to a decision to stop antibiotics immediately. In 37.2%, a prospective stop date was determined. Arguments for decisions were most often brought forward by intensivists (35.5%) and clinical microbiologists (22.3%). In 28.9% of discussions, multiple healthcare professionals participated equally in the decision. We identified 13 main argument categories. While intensivists mostly used arguments based on clinical status, clinical microbiologists used diagnostic results in the discussion., Conclusions: Multidisciplinary decision-making regarding the duration of antibiotic therapy is a complex but valuable process, involving different healthcare professionals, using a variety of argument-types to determine the duration of antibiotic therapy. To optimize the decision-making process, structured discussions, involvement of relevant specialties, and clear communication and documentation of the antibiotic plan are recommended., Competing Interests: Declaration of Competing Interest The authors have no financial interest or any other conflict of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain., Objective: To determine whether vitamin C improves outcomes for patients with COVID-19., Design, Setting, and Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents., Interventions: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses)., Main Outcomes and Measures: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility., Results: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy., Conclusions and Relevance: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival., Trial Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

Importance: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19., Objective: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19., Design, Setting, and Participants: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022)., Interventions: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days., Main Outcomes and Measures: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes., Results: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively)., Conclusions and Relevance: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Importance: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown., Objective: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes., Design, Setting, and Participants: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022., Interventions: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401)., Main Outcomes and Measures: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83., Results: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies., Conclusions and Relevance: Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Background: A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence., Methods: Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation. Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomisation were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence., Findings: One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0·82 [0·71-0·95, p = 0·008]] and sarilumab [0·80 [0·61-1·04, p = 0·09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 [95%CI 0·81-1·32, p = 0·80]. The p-value for the global test of inconsistency was 0·28., Conclusions: Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist., Competing Interests: LPGD is a member of the COVID-19 guideline committee for the Society of Critical Care Medicine/European Society of Intensive Care Medicine/Surviving Sepsis Campaign. ACG has received personal fees from Thirty Respiratory Ltd and GlaxoSmithKline. JCM received personal fees from AM Pharma (for serving as the chair of a data and safety monitoring board), Gilead (for serving as a consultant), and Critical Care Medicine (for serving as associate editor). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Pulmonary embolism (PE) occurs in one-third of critically-ill COVID-19 patients. Although prior studies identified several pathways contributing to thrombogenicity, it is unknown whether this is COVID-19-specific or also occurs in ARDS patients with another infection., Objective: To compare pathway activity among patients having COVID-19 with PE (C19PE+), COVID-19 without PE (C19PE-), and influenza-associated ARDS (IAA) using a targeted proteomics approach., Methods: We exploited an existing biorepository containing daily plasma samples to carefully match C19PE+ cases to C19PE- and IAA controls on mechanical ventilation duration, PEEP, FiO2, and cardiovascular-SOFA (n = 15 per group). Biomarkers representing various thrombosis pathways were measured using proximity extension- and ELISA-assays. Summed z-scores of individual biomarkers were used to represent total pathway activity., Results: We observed no relevant between-group differences among 22 biomarkers associated with activation of endothelium, platelets, complement, coagulation, fibrinolysis or inflammation, except sIL-1RT2 and sST2, which were lower in C19PE- than IAA (log2-Foldchange -0.67, p = .022 and -1.78, p = .022, respectively). However, total pathway analysis indicated increased activation of endothelium (z-score 0.2 [-0.3-1.03] vs. 0.98 [-2.5--0.3], p = .027), platelets (1.0 [-1.3-3.0] vs. -3.3 [-4.1--0.6], p = .023) and coagulation (0.8 [-0.5-2.0] vs. -1.0 [-1.6-1.0], p = .023) in COVID-19 patients (C19PE+/C19PE- groups combined) compared to IAA., Conclusion: We observed only minor differences between matched C19PE+, C19PE-, and IAA patients, which suggests individual biomarkers mostly reflect disease severity. However, analysis of total pathway activity suggested upregulation of some distinct processes in COVID-19 could be etiologically related to increased PE-risk., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain., Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19., Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021)., Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis., Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions., Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm)., Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Randomised clinical trials (RCTs) are the gold standard for providing unbiased evidence of intervention effects. Here, we provide an overview of the history of RCTs and discuss the major challenges and limitations of current critical care RCTs, including overly optimistic effect sizes; unnuanced conclusions based on dichotomization of results; limited focus on patient-centred outcomes other than mortality; lack of flexibility and ability to adapt, increasing the risk of inconclusive results and limiting knowledge gains before trial completion; and inefficiency due to lack of re-use of trial infrastructure. We discuss recent developments in critical care RCTs and novel methods that may provide solutions to some of these challenges, including a research programme approach (consecutive, complementary studies of multiple types rather than individual, independent studies), and novel design and analysis methods. These include standardization of trial protocols; alternative outcome choices and use of core outcome sets; increased acceptance of uncertainty, probabilistic interpretations and use of Bayesian statistics; novel approaches to assessing heterogeneity of treatment effects; adaptation and platform trials; and increased integration between clinical trials and clinical practice. We outline the advantages and discuss the potential methodological and practical disadvantages with these approaches. With this review, we aim to inform clinicians and researchers about conventional and novel RCTs, including the rationale for choosing one or the other methodological approach based on a thorough discussion of pros and cons. Importantly, the most central feature remains the randomisation, which provides unparalleled restriction of confounding compared to non-randomised designs by reducing confounding to chance., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm., Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes., Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts., Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria., Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality., Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days., Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16)., Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality., Trial Registration: PROSPERO Identifier: CRD42021230155.

Purpose: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19)., Methods: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable., Results: We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (- 1 to 15), 0 (- 1 to 9) and-1 (- 1 to 7), respectively, compared to 6 (- 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively)., Conclusion: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive proinflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis revealed no specific inflammatory endotypes in COVID-19 patients. Functional assays revealed abrogated adaptive cytokine production (interferon-γ, interleukin-17, and interleukin-22) and prominent T-cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlights potential biomarkers of disease severity., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: Although the Surviving Sepsis Campaign bundle recommends obtaining blood cultures within 1 hour of sepsis recognition, adherence is suboptimal in many settings. We, therefore, implemented routine blood culture collection for all nonelective ICU admissions (regardless of infection suspicion) and evaluated its diagnostic yield., Design: A before-after analysis., Setting: A mixed-ICU of a tertiary care hospital in the Netherlands., Patients: Patients acutely admitted to the ICU between January 2015 and December 2018., Measurements and Main Results: Automatic orders for collecting a single set of blood cultures immediately upon ICU admission were implemented on January 1, 2017. Blood culture results and the impact of contaminated blood cultures were compared for 2015-2016 (before period) and 2017-2018 (after period). Positive blood cultures were categorized as bloodstream infection or contamination. Blood cultures were obtained in 573 of 1,775 patients (32.3%) and in 1,582 of 1,871 patients (84.5%) in the before and after periods, respectively (p < 0.0001), and bloodstream infection was diagnosed in 95 patients (5.4%) and 154 patients (8.2%) in both study periods (relative risk 1.5; 95% CI 1.2-2.0; p = 0.0006). The estimated number needed to culture for one additional patient with bloodstream infection was 17. Blood culture contamination occurred in 40 patients (2.3%) and 180 patients (9.6%) in the before period and after period, respectively (relative risk 4.3; 95% CI 3.0-6.0; p < 0.0001). Rate of vancomycin use or presumed episodes of catheter-related bloodstream infections treated with antibiotics did not differ between both study periods., Conclusions: Implementation of routine blood cultures was associated with a 1.5-fold increase of detected bloodstream infection. The 4.3-fold increase in contaminated blood cultures was not associated with an increase in vancomycin use in the ICU., Competing Interests: Dr. Verboom’s and Bonten’s institutions received funding from the Innovative Medicine Initiative, European Union’s Seventh Framework Programme (FP7/2007–2013), and European Federation of Pharmaceutical Industries and Associations companies’ in-kind contribution (Combatting Bacterial resistance in Europe-Carbapenem-Resistance, grant agreement 115 620). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Introduction: Coronavirus disease (COVID-19) is associated with a high incidence of thrombosis and mortality despite standard anticoagulant thromboprophylaxis. There is equipoise regarding the optimal dose of anticoagulant intervention in hospitalized patients with COVID-19 and consequently, immediate answers from high-quality randomized trials are needed., Methods: The World Health Organization's International Clinical Trials Registry Platform was searched on June 17, 2020 for randomized controlled trials comparing increased dose to standard dose anticoagulant interventions in hospitalized COVID-19 patients. Two authors independently screened the full records for eligibility and extracted data in duplicate., Results: A total of 20 trials were included in the review. All trials are open label, 5 trials use an adaptive design, 1 trial uses a factorial design, 2 trials combine multi-arm parallel group and factorial designs in flexible platform trials, and at least 15 trials have multiple study sites. With individual target sample sizes ranging from 30 to 3000 participants, the pooled sample size of all included trials is 12 568 participants. Two trials include only intensive care unit patients, and 10 trials base patient eligibility on elevated D-dimer levels. Therapeutic intensity anticoagulation is evaluated in 14 trials. All-cause mortality is part of the primary outcome in 14 trials., Discussion: Several trials evaluate different dose regimens of anticoagulant interventions in hospitalized patients with COVID-19. Because these trials compete for sites and study participants, a collaborative effort is needed to complete trials faster, conduct pooled analyses and bring effective interventions to patients more quickly., (© 2020 International Society on Thrombosis and Haemostasis.)

A novel multiplex real-time PCR for bloodstream infections (BSI-PCR) detects pathogens directly in blood. This study aimed at determining the positive predictive value (PPV) of BSI-PCR in critically ill patients with sepsis. We included consecutive patients with presumed sepsis upon admission to the intensive care unit (ICU). The multiplexed BSI-PCR included 17 individual PCRs for a broad panel of species- and genus-specific DNA targets. BSI-PCR results were compared with a reference diagnosis for which plausibility of infection and causative pathogen(s) had been prospectively assessed by trained observers, based on available clinical and microbiological evidence. PPV and false positive proportion (FPP) were calculated. Clinical plausibility of discordant positive results was adjudicated by an expert panel. Among 325 patients, infection likelihood was categorized as confirmed, uncertain, and ruled out in 210 (65%), 88 (27%), and 27 (8%) subjects, respectively. BSI-PCR identified one or more microorganisms in 169 (52%) patients, of whom 104 (61%) had at least one detection in accordance with the reference diagnosis. Discordant positive PCR results were observed in 95 patients, including 30 subjects categorized as having an "unknown" pathogen. Based on 5525 individual PCRs yielding 295 positive results, PPV was 167/295 (57%) and FPP was 128/5525 (2%). Expert adjudication of the 128 discordant PCR findings resulted in an adjusted PPV of 68% and FPP of 2%. BSI-PCR was all-negative in 156 patients, including 79 (51%) patients in whom infection was considered ruled out. BSI-PCR may complement conventional cultures and expedite the microbiological diagnosis of sepsis in ICU patients, but improvements in positive predictive value of the test are warranted before its implementation in clinical practice can be considered.

Background: The global emergence of infections caused by Enterobacteriaceae resistant to expanded-spectrum cephalosporins (ESCs) in intensive care units (ICUs) is, at least partly, driven by cross-transmission. Yet, individual transmission capacities of bacterial species have not been quantified., Methods: In this post hoc analysis of a multicenter study in 13 European ICUs, prospective surveillance data and a mathematical model were used to estimate transmission capacities and single-admission reproduction numbers (RA) of Escherichia coli and non-E. coli Enterobacteriaceae (non-EcE), all being ESC resistant. Surveillance was based on a chromogenic selective medium for ESC-resistant Enterobacteriaceae, allowing identification of E. coli and of Klebsiella, Enterobacter, Serratia, and Citrobacter species, grouped as non-EcE., Results: Among 11420 patients included, the admission prevalence was 3.8% for non-EcE (74% being Klebsiella pneumoniae) and 3.3% for E. coli. Acquisition rates were 7.4 and 2.6 per 100 admissions at risk for non-EcE and E. coli, respectively. The estimated transmission capacity of non-EcE was 3.7 (95% credibility interval [CrI], 1.4-11.3) times higher than that of E. coli, yielding single-admission reproduction numbers (RA) of 0.17 (95% CrI, .094-.29) for non-EcE and 0.047 (95% CrI, .018-.098) for E. coli., Conclusions: In ICUs, non-EcE, mainly K. pneumoniae, are 3.7 times more transmissible than E. coli. Estimated RA values of these bacteria were below the critical threshold of 1, suggesting that in these ICUs outbreaks typically remain small with current infection control policies., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Intensive care units (ICUs) are high-risk areas for transmission of antimicrobial-resistant bacteria, but no controlled study has tested the effect of rapid screening and isolation of carriers on transmission in settings with best-standard precautions. We assessed interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in European ICUs., Methods: We did this study in three phases at 13 ICUs. After a 6 month baseline period (phase 1), we did an interrupted time series study of universal chlorhexidine body-washing combined with hand hygiene improvement for 6 months (phase 2), followed by a 12-15 month cluster randomised trial (phase 3). ICUs were randomly assigned by computer generated randomisation schedule to either conventional screening (chromogenic screening for meticillin-resistant Staphylococcus aureus [MRSA] and vancomycin-resistant enterococci [VRE]) or rapid screening (PCR testing for MRSA and VRE and chromogenic screening for highly resistant Enterobacteriaceae [HRE]); with contact precautions for identified carriers. The primary outcome was acquisition of resistant bacteria per 100 patient-days at risk, for which we calculated step changes and changes in trends after the introduction of each intervention. We assessed acquisition by microbiological surveillance and analysed it with a multilevel Poisson segmented regression model. We compared screening groups with a likelihood ratio test that combined step changes and changes to trend. This study is registered with ClinicalTrials.gov, number NCT00976638., Findings: Seven ICUs were assigned to rapid screening and six to conventional screening. Mean hand hygiene compliance improved from 52% in phase 1 to 69% in phase 2, and 77% in phase 3. Median proportions of patients receiving chlorhexidine body-washing increased from 0% to 100% at the start of phase 2. For trends in acquisition of antimicrobial-resistant bacteria, weekly incidence rate ratio (IRR) was 0·976 (0·954-0·999) for phase 2 and 1·015 (0·998-1·032) for phase 3. For step changes, weekly IRR was 0·955 (0·676-1·348) for phase 2 and 0·634 (0·349-1·153) for phase 3. The decrease in trend in phase 2 was largely caused by changes in acquisition of MRSA (weekly IRR 0·925, 95% CI 0·890-0·962). Acquisition was lower in the conventional screening group than in the rapid screening group, but did not differ significantly (p=0·06)., Interpretation: Improved hand hygiene plus unit-wide chlorhexidine body-washing reduced acquisition of antimicrobial-resistant bacteria, particularly MRSA. In the context of a sustained high level of compliance to hand hygiene and chlorhexidine bathings, screening and isolation of carriers do not reduce acquisition rates of multidrug-resistant bacteria, whether or not screening is done with rapid testing or conventional testing., Funding: European Commission., (Copyright © 2014 Derde et al. Open Access article distributed under the terms of CC BY-NC-SA. Published by Elsevier Ltd. All rights reserved.)