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Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.

Objectives: International guidelines recommend IV crystalloid as the primary fluid for sepsis resuscitation, with 5% human albumin solution (HAS) as the second line. However, it is unclear which fluid has superior clinical effectiveness. We conducted a trial to assess the feasibility of delivering a randomized controlled trial comparing balanced crystalloid against 5% HAS as sole early resuscitation fluid in patients with sepsis presenting to hospital., Design: Multicenter, open, parallel-group randomized feasibility trial., Setting: Emergency departments (EDs) in 15 U.K. National Health Service (NHS) hospitals., Patients: Adult patients with sepsis and a National Early Warning Score 2 greater than or equal to five requiring IV fluids withing one hour of randomization., Interventions: IV fluid resuscitation with balanced crystalloid or 5% HAS for the first 6 hours following randomization., Measurements and Main Results: Primary feasibility outcomes were recruitment rate and 30-day mortality. We successfully recruited 301 participants over 12 months. Mean ( sd ) age was 69 years (± 16 yr), and 151 (50%) were male. From 1303 participants screened; 502 participants were potentially eligible and 300 randomized to receive trial intervention with greater than 95% of participants receiving the intervention. The median number of participants per site was 19 (range, 1-63). Thirty-day mortality was 17.9% ( n = 53). Thirty-one participants died (21.1%) within 30 days in the 5% HAS arm, compared with 22 participants (14.8%) in the crystalloid arm (adjusted odds ratio, 1.50; 95% CIs, 0.84-2.83)., Conclusions: Our results suggest it is feasible to recruit critically ill patients to a fluid resuscitation trial in U.K. EDs using 5% HAS as a primary resuscitation fluid. There was lower mortality in the balanced crystalloid arm. Given these findings, a definitive trial is likely to be deliverable, but the point estimates suggest such a trial would be unlikely to demonstrate a significant benefit from using 5% HAS as a primary resuscitation fluid in sepsis., Competing Interests: Dr. Bell is supported by the National Institute of Applied Research Collaboration Northwest London. Dr. Gray’s, Ms. Oatey’s, Dr. Irvine’s, Mr. Kennel’s, Dr. Norrie’s, Dr. Walsh’s, and Dr. Hall’s institutions received funding from the John Moulton Charitable Trust. Dr. Gray, Ms. Grahamslaw, and Dr. Appelboam received support for article research from the John Moulton Charitable Trust. Ms. Oatey disclosed work for hire. Dr. Cafferkey’s institution received funding from the Royal College of Emergency Medicine and the Sepsis FEAT Charity. Dr. Horner’s institution received funding from the National Institute for Health Research (132594). Mr. Skipworth received funding from Helsinn, Faraday Pharmaceuticals, Actimed Therapeutics, and Pfizer. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: To use the ventricular pressure-volume relationship and time-varying elastance model to provide a foundation for understanding cardiovascular physiology and pathophysiology, interpreting advanced hemodynamic monitoring, and for illustrating the physiologic basis and hemodynamic effects of therapeutic interventions. We will build on this foundation by using a cardiovascular simulator to illustrate the application of these principles in the care of patients with severe sepsis, cardiogenic shock, and acute mechanical circulatory support., Data Sources: Publications relevant to the discussion of the time-varying elastance model, cardiogenic shock, and sepsis were retrieved from MEDLINE. Supporting evidence was also retrieved from MEDLINE when indicated., Study Selection, Data Extraction, and Synthesis: Data from relevant publications were reviewed and applied as indicated., Conclusions: The ventricular pressure-volume relationship and time-varying elastance model provide a foundation for understanding cardiovascular physiology and pathophysiology. We have built on this foundation by using a cardiovascular simulator to illustrate the application of these important principles and have demonstrated how complex pathophysiologic abnormalities alter clinical parameters used by the clinician at the bedside., Competing Interests: Dr. Gomez’s institution received funding from the National Institute of Diabetes and Digestive and Kidney Diseases, Baxter, and bioMérieux; he received funding from Trilinear Bioventures, AclRx, Novartis, and the National Kidney Foundation. Dr. Burkhoff received funding from PVLoops. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Echocardiography is commonly used for hemodynamic assessment in sepsis, but data regarding its association with outcome are conflicting. The aim of this study was to evaluate the association between echocardiography and outcomes in patients with septic shock using the Medical Information Mart for Intensive Care IV database., Design: Retrospective cohort study comparing patients who did or did not undergo transthoracic echocardiography within the first 5 days of admission for the primary outcome of 28-day mortality., Setting: Admissions to the Beth Israel Deaconess Medical Center intensive care from 2008 to 2019., Patients: Adults 16 years old or older with septic shock requiring vasopressor support within 48 hours of admission. Readmissions and patients admitted to the coronary care unit or cardiovascular intensive care were excluded, as well as patients with ST-elevation myocardial infarction or cardiac arrest., Interventions: None., Measurements and Main Results: Echocardiography was performed in 1,515 (27%) of 5,697 eligible admissions. The primary outcome was analyzed using a marginal structural model and rolling entry matching to adjust for baseline and time-varying confounders. Patients who underwent echocardiography showed no significant difference in 28-day mortality (adjusted hazard ratio 1.09; 95% CI, 0.95-1.25; p = 0.24). This was consistent across multiple sensitivity analyses. Secondary outcomes were changes in management instituted within 4 hours of imaging. Treatment changes occurred in 493 patients (33%) compared with 431 matched controls (29%), with the most common intervention being the administration of a fluid bolus., Conclusions: Echocardiography in sepsis was not associated with a reduction in 28-day mortality based on observational data. These findings do not negate the utility of echo in cases of diagnostic uncertainty or inadequate response to initial treatment., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: This study aimed to conduct a comprehensive and updated systematic review with network meta-analysis (NMA) to assess the outcome benefits of various blood purification modalities for adult patients with severe infection or sepsis., Data Sources: We conducted a search of PubMed, MEDLINE, clinical trial registries, Cochrane Library, and Embase databases with no language restrictions., Study Selection: Only randomized controlled trials (RCTs) were selected., Data Extraction: The primary outcome was overall mortality. The secondary outcomes were the length of mechanical ventilation (MV) days and ICU stay, incidence of acute kidney injury (AKI), and kidney replacement therapy requirement., Data Synthesis: We included a total of 60 RCTs with 4,595 participants, comparing 16 blood purification modalities with 17 interventions. Polymyxin-B hemoperfusion (relative risk [RR]: 0.70; 95% CI, 0.57-0.86) and plasma exchange (RR: 0.61; 95% CI, 0.42-0.91) were associated with low mortality (very low and low certainty of evidence, respectively). Because of the presence of high clinical heterogeneity and intransitivity, the potential benefit of polymyxin-B hemoperfusion remained inconclusive. The analysis of secondary outcomes was limited by the scarcity of available studies. HA330 with high-volume continuous venovenous hemofiltration (CVVH), HA330, and standard-volume CVVH were associated with shorter ICU stay. HA330 with high-volume CVVH, HA330, and standard-volume CVVH were beneficial in reducing MV days. None of the interventions showed a significant reduction in the incidence of AKI or the need for kidney replacement therapy., Conclusions: Our NMA suggests that plasma exchange and polymyxin-B hemoperfusion may provide potential benefits for adult patients with severe infection or sepsis/septic shock when compared with standard care alone, but most comparisons were based on low or very low certainty evidence. The therapeutic effect of polymyxin-B hemoperfusion remains uncertain. Further RCTs are required to identify the specific patient population that may benefit from extracorporeal blood purification., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Objectives: Regionalized sepsis care could improve sepsis outcomes by facilitating the interhospital transfer of patients to higher-capability hospitals. There are no measures of sepsis capability to guide the identification of such hospitals, although hospital case volume of sepsis has been used as a proxy. We evaluated the performance of a novel hospital sepsis-related capability (SRC) index as compared with sepsis case volume., Design: Principal component analysis (PCA) and retrospective cohort study., Setting: A total of 182 New York (derivation) and 274 Florida and Massachusetts (validation) nonfederal hospitals, 2018., Patients: A total of 89,069 and 139,977 adult patients (≥ 18 yr) with sepsis were directly admitted into the derivation and validation cohort hospitals, respectively., Interventions: None., Measurements and Main Results: We derived SRC scores by PCA of six hospital resource use characteristics (bed capacity, annual volumes of sepsis, major diagnostic procedures, renal replacement therapy, mechanical ventilation, and major therapeutic procedures) and classified hospitals into capability score tertiles: high, intermediate, and low. High-capability hospitals were mostly urban teaching hospitals. Compared with sepsis volume, the SRC score explained more variation in hospital-level sepsis mortality in the derivation (unadjusted coefficient of determination [ R2 ]: 0.25 vs 0.12, p < 0.001 for both) and validation (0.18 vs 0.05, p < 0.001 for both) cohorts; and demonstrated stronger correlation with outward transfer rates for sepsis in the derivation (Spearman coefficient [ r ]: 0.60 vs 0.50) and validation (0.51 vs 0.45) cohorts. Compared with low-capability hospitals, patients with sepsis directly admitted into high-capability hospitals had a greater number of acute organ dysfunctions, a higher proportion of surgical hospitalizations, and higher adjusted mortality (odds ratio [OR], 1.55; 95% CI, 1.25-1.92). In stratified analysis, worse mortality associated with higher hospital capability was only evident among patients with three or more organ dysfunctions (OR, 1.88 [1.50-2.34])., Conclusions: The SRC score has face validity for capability-based groupings of hospitals. Sepsis care may already be de facto regionalized at high-capability hospitals. Low-capability hospitals may have become more adept at treating less complicated sepsis., Competing Interests: Dr. Ofoma’s institution received funding from the National Institute on Aging. Drs. Ofoma and Maddox received support for article research from the National Institutes of Health (NIH). Dr. Mohr’s institution received funding from Endpoint Health. Dr. Maddox’s institution received funding from the NIH; she received funding from Humana and Centene. Dr. Kollef is supported by the Barnes-Jewish Hospital Foundation. Dr. Joynt Maddox receives research support from the National Heart, Lung, and Blood Institute (R01HL143421 and R01HL164561), the National Institute of Nursing Research (U01NR020555), the National Institute on Aging (R01AG060935, R01AG063759, and R21AG065526), and from Humana. She also serves on the Health Policy Advisory Council for the Centene Corporation (St. Louis, MO). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: To assess the association between levels of intensive care and in-hospital mortality in patients hospitalized for sepsis, stratified by Sequential Organ Failure Assessment (SOFA) score at admission., Design: A nationwide, propensity score-matched, retrospective cohort study., Setting: A Japanese national inpatient database with data on 70-75% of all ICU and high-dependency care unit (HDU) beds in Japan., Patients: Adult patients hospitalized for sepsis with SOFA scores greater than or equal to 2 on their day of admission between April 1, 2018, and March 31, 2021, were recruited. Propensity score matching was performed to compare in-hospital mortality, and patients were stratified into 10 groups according to SOFA scores., Interventions: Two exposure and control groups according to treatment unit on day of admission: 1) ICU + HDU versus general ward and 2) ICU versus HDU., Measurements and Main Results: Of 97,070 patients, 19,770 (20.4%), 23,066 (23.8%), and 54,234 (55.9%) were treated in ICU, HDU, and general ward, respectively. After propensity score matching, the ICU + HDU group had significantly lower in-hospital mortality than the general ward group, among cohorts with SOFA scores greater than or equal to 6. There were no significant differences in in-hospital mortality among cohorts with SOFA scores 3-5. The ICU + HDU group had significantly higher in-hospital mortality than the general ward among cohorts with SOFA scores of 2. The ICU group had lower in-hospital mortality than the HDU group among cohorts with SOFA scores greater than or equal to 12. There were no significant differences in in-hospital mortality among cohorts with SOFA scores 5-11. The ICU group had significantly higher in-hospital mortality than the general ward group among cohorts with SOFA scores less than or equal to 4., Conclusions: Patients hospitalized for sepsis with SOFA scores greater than or equal to 6 in the ICU or HDU had lower in-hospital mortality than those in the general ward, as did those with SOFA scores greater than or equal to 12 in the ICU versus HDU., Competing Interests: Dr. Yasunaga’s institution received funding from the Ministry of Health, Labour and Welfare, Japan and the Ministry of Education, Culture, Sports, Science and Technology, Japan. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Competing Interests: Dr. Wardi received funding from Northwest Anesthesia and Medicolegal consulting. Drs. Wardi, Malhotra, and Nemati received support for article research from the National Institutes of Health (NIH). Dr. Malhotra’s institution received funding from ResMed; he received funding from the NIH, Livanova, Eli Lilly, Zoll, and Jazz. Drs. Malhotra and Nemati disclosed that they are cofounders and equity shareholders in Healcisio, Inc. Dr. Josef received funding from Healcisio, Inc. Dr. Longhurst disclosed that he is an equity shareholder in Doximity. Dr. Owens has disclosed that he does not have any potential conflicts of interest.

Competing Interests: Dr. Hagiya has disclosed that he does not have any potential conflicts of interest.

Objectives: Sepsis awareness and understanding are important aspects of prevention, recognition, and clinical management of sepsis. We conducted a scoping review to identify and map the literature related to sepsis awareness, general knowledge, and information-seeking behaviors with a goal to inform future sepsis research and knowledge translation campaigns., Design: Scoping review., Setting: Using Arksey and O'Malley's methodological framework, we conducted a systematic search on May 3, 2021, across four databases (MEDLINE, EMBASE, CINAHL, and Education Research Complete). Title/abstract and full-text screening was done in duplicate. One researcher extracted the data for each included article, and a second researcher checked data accuracy. The protocol was registered on Open Science Framework ( https://doi.org/10.17605/OSF.IO/YX7AU )., Subjects: Articles related to sepsis awareness, knowledge, and information seeking behaviors among patients, public, and healthcare professionals., Interventions: None., Measurements and Main Results: Of 5,927 unique studies, 80 reported on patient ( n = 13/80;16.3%), public ( n = 15/80;18.8%), or healthcare professional (nurses, physicians, emergency medical technicians) ( n = 48/80; 60%) awareness and knowledge of sepsis. Healthcare professional awareness and knowledge of sepsis is high compared with patients/public. The proportion of patients/public who had heard of the term sepsis ranged from 2% (Japan) to 88.6% (Germany). The proportions of patients/public who correctly identified the definition of sepsis ranged from 4.2% (Singapore) to 92% (Sweden). The results from the included studies appear to suggest that patient/public awareness of sepsis gradually improved over time. We found that the definition of sepsis was inconsistent in the literature and that few studies reported on patient, public, or healthcare professional knowledge of sepsis risk factors. Most patient/public get their sepsis information from the internet, whereas healthcare professionals get it from their role in healthcare through job training or educational training., Conclusions: Patient, public, and healthcare professional awareness and knowledge of sepsis vary globally. Future research may benefit from a consistent definition as well as country-specific data to support targeted public awareness campaigns., Competing Interests: Dr. Fox-Robichaud’s institution received funding from the Canadian Institutes of Health Research (CIHR), New Frontiers Research Fund, and Hamilton Academic Health Sciences Organization. She has received research grants from the CIHR, the Natural Sciences and Engineering Research Council, and Hamilton Academic Health Sciences Organization and is President of the Canadian Sepsis Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Objectives: To test the hypothesis that forced-air warming of critically ill afebrile sepsis patients improves immune function compared to standard temperature management., Design: Single-center, prospective, open-label, randomized controlled trial., Setting: One thousand two hundred-bed academic medical center., Patients: Eligible patients were mechanically ventilated septic adults with: 1) a diagnosis of sepsis within 48 hours of enrollment; 2) anticipated need for mechanical ventilation of greater than 48 hours; and 3) a maximum temperature less than 38.3°C within the 24 hours prior to enrollment. Primary exclusion criteria included: immunologic diseases, immune-suppressing medications, and any existing condition sensitive to therapeutic hyperthermia (e.g., brain injury). The primary outcome was monocyte human leukocyte antigen (HLA)-DR expression, with secondary outcomes of CD3/CD28-induced interferon gamma (IFN-γ) production, mortality, and 28-day hospital-free days., Interventions: External warming using a forced-air warming blanket for 48 hours, with a goal temperature 1.5°C above the lowest temperature documented in the previous 24 hours., Measurements and Main Results: We enrolled 56 participants in the study. No differences were observed between the groups in HLA-DR expression (692 vs 2,002; p = 0.396) or IFN-γ production (31 vs 69; p = 0.678). Participants allocated to external warming had lower 28-day mortality (18% vs 43%; absolute risk reduction, 25%; 95% CI, 2-48%) and more 28-day hospital-free days (difference, 2.6 d; 95% CI, 0-11.6)., Conclusions: Participants randomized to external forced-air warming did not have a difference in HLA-DR expression or IFN-γ production. In this pilot study, however, 28-day mortality was lower in the intervention group. Future research should seek to better elucidate the impact of temperature modulation on immune and nonimmune organ failure pathways in sepsis., Competing Interests: Drs. Drewry’s and Hotchkiss’s (R35GM126928) institutions received funding from the National Institutes of Health (NIH). Drs. Drewry’s and Mohr’s (K08HS025753) institutions received funding from the Agency for Healthcare Research and Quality. Dr. Drewry was supported by the Washington University Institute of Clinical and Translational Sciences (UL1TR000448, KL2TR000450) and the NIH (K23GM129660). Dr. Ablordeppey was supported by the Department of Anesthesiology, Division of Clinical and Translational Research at Washington University and the K12 Mentored Training in Implementation Science award (K12HL137942). Drs. Drewry, Mohr, Dalton, and Hotchkiss received support for article research from the NIH. Dr. Hotchkiss’s institution received funding from the National Institute of General Medical Sciences; he disclosed that he holds a patent for the Enzyme-Linked Immunospot assay, which was used for immune phenotyping in this article. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Sepsis is a life-threatening medical emergency. There is a paucity of information on whether quality improvement approaches reduce the in-hospital sepsis caseload or save lives and decrease the healthcare system and society's cost at the provincial/national levels. This study aimed to assess the outcomes and economic impact of a province-wide quality improvement initiative in Canada., Design: Retrospective population-based study with interrupted time series and return on investment analyses., Setting: The sepsis cases and deaths averted over time for British Columbia were calculated and compared with the rest of Canada (excluding Quebec and three territories)., Patients: Aggregate data were obtained from the Canadian Institute for Health Information on risk-adjusted in-hospital sepsis rates and sepsis mortality in acute care sites across Canada., Interventions: In 2012, the British Columbia Sepsis Network was formed to reduce sepsis occurrence and mortality through education, knowledge translation, and quality improvement., Measurements and Main Results: A return on investment analysis compared the financial investment for the British Columbia Sepsis Network with the savings from averted sepsis occurrence and mortality. An estimated 981 sepsis cases and 172 deaths were averted in the post-British Columbia Sepsis Network period (2014-2018). The total cost, including the development and implementation of British Columbia Sepsis Network, was $449,962. Net savings due to cases averted after program costs were considered were $50.6 million in 2018. This translates into a return of $112.5 for every dollar invested., Conclusions: British Columbia Sepsis Network appears to have averted a greater number of sepsis cases and deaths in British Columbia than the national average and yielded a positive return on investment. Our findings strengthen the policy argument for targeted quality improvement initiatives for sepsis care and provide a model of care for other provinces in Canada and elsewhere globally., Competing Interests: Dr. Khowaja received support for article research from the Michael Smith Foundation for Health Research (18164). Ms. Krause received funding from the University of British Columbia. Mr. Ridout and Ms. Kennedy disclosed they are employees of the British Columbia Patient Safety & Quality Council. Mr. Young disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Competing Interests: Dr. Biban received funding from Chiesi Pharmaceutical and Getinge. Dr. Marlow received funding from Novartis, Takeda, and Royal Society of Medicine Consulting. Dr. Fanaroff received support for article research from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Objectives: To describe the epidemiology of sepsis in critical care by applying the Sepsis-3 criteria to electronic health records., Design: Retrospective cohort study using electronic health records., Setting: Ten ICUs from four U.K. National Health Service hospital trusts contributing to the National Institute for Health Research Critical Care Health Informatics Collaborative., Patients: A total of 28,456 critical care admissions (14,332 emergency medical, 4,585 emergency surgical, and 9,539 elective surgical)., Measurements and Main Results: Twenty-nine thousand three hundred forty-three episodes of clinical deterioration were identified with a rise in Sequential Organ Failure Assessment score of at least 2 points, of which 14,869 (50.7%) were associated with antibiotic escalation and thereby met the Sepsis-3 criteria for sepsis. A total of 4,100 episodes of sepsis (27.6%) were associated with vasopressor use and lactate greater than 2.0 mmol/L, and therefore met the Sepsis-3 criteria for septic shock. ICU mortality by source of sepsis was highest for ICU-acquired sepsis (23.7%; 95% CI, 21.9-25.6%), followed by hospital-acquired sepsis (18.6%; 95% CI, 17.5-19.9%), and community-acquired sepsis (12.9%; 95% CI, 12.1-13.6%) (p for comparison less than 0.0001)., Conclusions: We successfully operationalized the Sepsis-3 criteria to an electronic health record dataset to describe the characteristics of critical care patients with sepsis. This may facilitate sepsis research using electronic health record data at scale without relying on human coding., Competing Interests: Drs. Shah’s, Watkinson’s, and Brett’s institutions received funding from the National Institute for Health Research (NIHR). Dr. Shah is supported by a postdoctoral fellowship funded by the Health Foundation's grant to the University of Cambridge for The Healthcare Improvement Studies Institute. Dr. Palmer received funding from the Medical Research Council and The London Clinic. Dr. Hetherington’s institution received funding from the United Kingdom Government; he received funding from Turing Institute and the Department of Health and Social Care; he received support for article research from Research Councils UK; he disclosed work for hire. Dr. Shi disclosed work for hire. Dr. Watkinson’s institution received funding from Wellcome and Sesnyne Health; he disclosed that he was the Chief Medical Officer for Sesnyne Health. Dr. Ashworth disclosed that he is an employee of Imperial College Healthcare National Health Service (NHS) Trust and the Clinical Director of Critical Care. Dr. Beale’s institution received funding from the Philips Medical Systems Medical Advisory Board; he disclosed that he is on the Steering Committee of the Surviving Sepsis Campaign. Dr. Singer’s institution received funding from Roche, Deltex, NewB, GE Healthcare, Pfizer, and Biomerieux. The views expressed are those of the authors and are not necessarily those of the NIHR, the NHS, or the United Kingdom Department of Health and Social Care. The remaining authors have disclosed that they do not have any potential conflicts of interest, (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Competing Interests: Dr. Martin serves as president of the Society of Critical Care Medicine (SCCM). Drs. Kane-Gill, Nadkarni, Sorce, and Kaplan serve as members of the Society of Critical Care Medicine Executive Committee. Drs. Cecconi, Azoulay, Teboul, Forni and Kesecioglu serve as members of the ESICM Executive Committee. Drs. Martin, Kane-Gill, Cecconi, and Azoulay serve as members of the Surviving Sepsis Campaign Executive Committee. Dr. Kaplan received funding from SCCM. Dr. Cecconi received funding from Edwards Lifesciences and Directed Systems. Dr. Azoulay’s institution received funding from Fisher & Paykel, Jazz Pharma, MSD, and Alexion; he received funding from Pfizer, Sanofi, Alexion, and Gilead. Drs. Azoulay and Forni received funding from Baxter Medical. Dr. Teboul received funding from Getinge. Dr. Forni received funding from Exthera Medical and Biomerieux. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Competing Interests: Dr. Alhazzani is the Chair of the Guidelines Chapter for the Saudi Critical Care Society and is the chair of the guidelines in intensive care, development and evaluation (GUIDE) Group, McMaster University Canada. Dr. Antonelli received funding from GE, Toray-Estor, Baxter, Pfizer, Orion, Maquet, and Fisher and Paykel; he was on the board of Baxter and Pfizer, and is a member of the executive committee and past president of Società Italiana di Anestesia Rianimazione e Terapia Intensiva (SIAARTI). Dr. French contributed to the ANZICS Guidelines and the National COVID-19 Guidelines. Dr. Machado is a member of the Executive Committee for the Basics Study (for which Baxter provided the drugs and logistics) and AMIB. Dr. McIntyre is a member of the Canadian Critical Care Society and serves on the Surviving Sepsis Campaign Steering Committee. Dr. Ostermann is a council member of the Intensive Care Society UK and member of the Renal Association UK and World Sepsis Alliance. Dr. Prescott is a member of the ATS Critical Care Program Committee. Dr. Simpson is the president-elect and Chair of CHEST, is a member of the board of directors and medical director of Sepsis Alliance, and Chair of the Sepsis Institute Advisory Board. Dr. Wiersinga is a member of ISF, ESCIMID, and SWAB. Dr. Angus received funding from Ferring Pharmaceuticals, Inc and ALung Technologies, Inc. Dr. Beale provides consultancy services for Philips Healthcare with his time billed by his institution. Dr. Beilman is the president of the Surgical Infection Society. Dr. Belley-Cote received grants from Roche and Bayer and is a panel member on the Saudi Critical Care Society COVID-19 Thrombosis Guidelines. Dr. Cecconi is a consultant for Edwards Lifesciences, Cheetah Medical, and Directed Systems and is President of the European Society of Intensive Care Medicine. Dr. Coz is a board member of the American College of Chest Physicians. Dr. De Waele consulted for Accelerate, Bayer, Grifols, Pfizer, and MSD with all honoraria paid to Ghent University; he is a Senior Clinical Investigator with the Research Foundation Flanders. Dr. Dellinger serves as an expert witness on occasional medical legal case reviews. Dr. Doi is a member of the Japanese Society of Intensive Care Medicine. Dr. Du is a member of the Chinese Society of Critical Care Medicine and the Chinese College of Intensive Care Medicine. Dr. Ferrer received funding from Grifols, MSD, Pfizer, Shionogi, Toray, Jafron, and Cytosorbents; he is a member of SEMICYUC. Dr. Gomersall is a member of an educational subgroup of the International Forum of Acute Care Trialists. Dr. Hodgson is a member of the Australian National Health and Medical Research Council guidelines (COVID-19) and leading funded trials in early rehabilitation and ECMO. Dr. Møller contributed to guideline work for DASAIM, SSAI, GUIDE, and ESA. Dr. Iwashyna is a member of the ATS, the NIH, and an informal (unincorporated) organization called the Critical and Acute Illness Recovery Organization. Dr. Jacob co-directs the African Research Collaboration on Sepsis (ARCS, funded by UK National Institute for Health Research, sponsored by Liverpool School of Tropical Medicine), he is Secretary General for the African Sepsis Alliance, and is a technical expert for the World Health Organization panels. Dr. Kleinpell is a board member of the World Federation of Intensive and Critical Care, American Nurses Credentialing Center, and the Tennessee Nurses Association Political Action Committee. Dr. Klompas received funding from Up-to-Date; he is a member of the guidelines committees of the Infectious Disease Society of America (IDSA) and Society of Healthcare Epidemiologists of America (SHEA). Dr. Koh is a member of The Korean Society of Critical Care Medicine, The Korean Academy of Tuberculosis and Respiratory Diseases, The Korean Society of Medical Ethics, and the Asia Ventilation Forum. Dr. Kumar served as an expert witness regarding a lethal dose of narcotics. Dr. Kwizera is president of the Intensive Care Society of Uganda and PRO for the Association of Anesthesiologists of Uganda. Dr. Lobo received funding from Pfizer, MSD, Edwards, and Nestle; she is the principal investigator in new antibiotics research led by CROs/industry; she is a member of the AMIB Executive Board and was elected president for 2020-2021. Dr. McGloughlin is a member of ANZICS (Australian New Zealand Intensive Care Society). Dr. Mehta participated in two non-interventional studies by ISCCM-Hermes and Indicaps. Dr. Mer has been an invited speaker for educational talks in industry-sponsored symposia for which honoraria was received; he is the current Vice President of the Southern African Society of Thrombosis and Haemostasis (SASTH), and is involved in annual congress organization; he is an invited author of the Global guidelines for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Dr. Nunnally is the treasurer of SOCCA, committee member of ASA, NYSSA, IARS, AUA, and SAAAPM and serves on the American College of Critical Care Medicine Board of Regents. Dr. Oczkowski is a member of the European Respiratory Society, and contributed to the High Flow Nasal Cannula Guidelines, the Non-Invasive Ventilation in COPD Guidelines. Dr. Osborn received funding from Viven Inc, Inflammatrix, Beckman, and the Foundation for Barnes Jewish Hospital; she is on the advisory board for Beckman, Inflammatix, and Viven; she is a member of the American College of Emergency Physicians, American College of Chest Physicians, American Medical Association, Society of Academic Emergency Medicine, and American Academy of Emergency Physicians; she served as an expert witness in a case related to viral as compared to bacterial sepsis. Dr. Papathanassoglou is a member of the World Federation of Critical Care Nurses (Editor of Journal) and the Canadian Association of Critical Care Nurses. Dr. Perner received a research grant from Pfizer Denmark. Dr. Puskarich is the co-inventor of a patent to assess L0carnitine drug responsiveness in sepsis (USPO 10330685); he is a member of the Society for Academic Emergency Medicine, American College of Emergency Physicians (ACEP); he was invited to a recently gathered ACEP early sepsis treatment policy task force asked to develop specialty recommendations for early sepsis treatment. Dr. Roberts received funding from MSD, The Medicines Company, Cardeas Pharma, Biomerieux, QPEX, Cipla, and Pfizer; he consulted for MSD, QPEX, Discuva Ltd, Accelerate Diagnostics, Bayer, Biomerieux, UptoDate, and Australian Therapeutic Guidelines; he is a member of the Society of Hospital Pharmacists of Australia Leadership Committees for Critical Care and Infectious Diseases and the Lead of Sepsis Working group for the International Society of Anti-infective Chemotherapy. Dr. Schweickert is a paid consultant to the American College of Physicians (last performed in Spring, 2019). Dr. Seckel volunteers for AACN and is a paid consultant to revise online Critical Care Orientation. Dr. Sevransky received funding from the Marcus Foundation- PI VICTAS Trial and serves on the American College of Critical Care Medicine Board of Regents. Dr. Welte received funding from Astellas, AstraZeneca, Boehringer, Basilea, Bayer, Berlin-Chemie, Grifols, Infectopharm, Mundipharma, MSD, Novartis, Pfizer, DFG, EU, BMBF, and Insmed; he is on the advisory board for AstraZeneca, Boehringer, Bayer, Gilead, GSK, Insmed, Novartis, Pfizer, Roche; he is a member of the European Respiratory Society, German Society of Pneumology, and Paul Ehrlich Gesellschaft. Dr. Zimmerman is a member of the ACP, AACP, and WFPICCS. Dr. Levy is a legal consultant for a few cases involving sepsis and serves as co-chair of the Surviving Sepsis Campaign Steering Committee. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Competing Interests: Dr. Alhazzani is the Chair of the Guidelines Chapter for the Saudi Critical Care Society and is the chair of the guidelines in intensive care, development and evaluation (GUIDE) Group, McMaster University Canada. Dr. Antonelli received funding from GE, Toray-Estor, Baxter, Pfizer, Orion, Maquet, and Fisher and Paykel; he was on the board of Baxter and Pfizer, and is a member of the executive committee and past president of Società Italiana di Anestesia Rianimazione e Terapia Intensiva (SIAARTI). Dr. French contributed to the ANZICS Guidelines and the National COVID-19 Guidelines. Dr. Machado is a member of the Executive Committee for the Basics Study (for which Baxter provided the drugs and logistics) and AMIB. Dr. McIntyre is a member of the Canadian Critical Care Society and serves on the Surviving Sepsis Campaign Steering Committee. Dr. Ostermann is a council member of the Intensive Care Society UK and member of the Renal Association UK and World Sepsis Alliance. Dr. Prescott is a member of the ATS Critical Care Program Committee. Dr. Simpson is the president-elect and Chair of CHEST, is a member of the board of directors and medical director of Sepsis Alliance, and Chair of the Sepsis Institute Advisory Board. Dr. Wiersinga is a member of ISF, ESCIMID, and SWAB. Dr. Angus received funding from Ferring Pharmaceuticals, Inc and ALung Technologies, Inc. Dr. Beale provides consultancy services for Philips Healthcare with his time billed by his institution. Dr. Beilman is the president of the Surgical Infection Society. Dr. Belley-Cote received grants from Roche and Bayer and is a panel member on the Saudi Critical Care Society COVID-19 Thrombosis Guidelines. Dr. Cecconi is a consultant for Edwards Lifesciences, Cheetah Medical, and Directed Systems and is President of the European Society of Intensive Care Medicine. Dr. Coz is a board member of the American College of Chest Physicians. Dr. De Waele consulted for Accelerate, Bayer, Grifols, Pfizer, and MSD with all honoraria paid to Ghent University; he is a Senior Clinical Investigator with the Research Foundation Flanders. Dr. Dellinger serves as an expert witness on occasional medical legal case reviews. Dr. Doi is a member of the Japanese Society of Intensive Care Medicine. Dr. Du is a member of the Chinese Society of Critical Care Medicine and the Chinese College of Intensive Care Medicine. Dr. Ferrer received funding from Grifols, MSD, Pfizer, Shionogi, Toray, Jafron, and Cytosorbents; he is a member of SEMICYUC. Dr. Gomersall is a member of an educational subgroup of the International Forum of Acute Care Trialists. Dr. Hodgson is a member of the Australian National Health and Medical Research Council guidelines (COVID-19) and leading funded trials in early rehabilitation and ECMO. Dr. Møller contributed to guideline work for DASAIM, SSAI, GUIDE, and ESA. Dr. Iwashyna is a member of the ATS, the NIH, and an informal (unincorporated) organization called the Critical and Acute Illness Recovery Organization. Dr. Jacob co-directs the African Research Collaboration on Sepsis (ARCS, funded by UK National Institute for Health Research, sponsored by Liverpool School of Tropical Medicine), he is Secretary General for the African Sepsis Alliance, and is a technical expert for the World Health Organization panels. Dr. Kleinpell is a board member of the World Federation of Intensive and Critical Care, American Nurses Credentialing Center, and the Tennessee Nurses Association Political Action Committee. Dr. Klompas received funding from Up-to-Date; he is a member of the guidelines committees of the Infectious Disease Society of America (IDSA) and Society of Healthcare Epidemiologists of America (SHEA). Dr. Koh is a member of The Korean Society of Critical Care Medicine, The Korean Academy of Tuberculosis and Respiratory Diseases, The Korean Society of Medical Ethics, and the Asia Ventilation Forum. Dr. Kumar served as an expert witness regarding a lethal dose of narcotics. Dr. Kwizera is president of the Intensive Care Society of Uganda and PRO for the Association of Anesthesiologists of Uganda. Dr. Lobo received funding from Pfizer, MSD, Edwards, and Nestle; she is the principal investigator in new antibiotics research led by CROs/industry; she is a member of the AMIB Executive Board and was elected president for 2020-2021. Dr. McGloughlin is a member of ANZICS (Australian New Zealand Intensive Care Society). Dr. Mehta participated in two non-interventional studies by ISCCM-Hermes and Indicaps. Dr. Mer has been an invited speaker for educational talks in industry-sponsored symposia for which honoraria was received; he is the current Vice President of the Southern African Society of Thrombosis and Haemostasis (SASTH), and is involved in annual congress organization; he is an invited author of the Global guidelines for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Dr. Nunnally is the treasurer of SOCCA, committee member of ASA, NYSSA, IARS, AUA, and SAAAPM and serves on the American College of Critical Care Medicine Board of Regents. Dr. Oczkowski is a member of the European Respiratory Society, and contributed to the High Flow Nasal Cannula Guidelines, the Non-Invasive Ventilation in COPD Guidelines. Dr. Osborn received funding from Viven Inc, Inflammatrix, Beckman, and the Foundation for Barnes Jewish Hospital; she is on the advisory board for Beckman, Inflammatix, and Viven; she is a member of the American College of Emergency Physicians, American College of Chest Physicians, American Medical Association, Society of Academic Emergency Medicine, and American Academy of Emergency Physicians; she served as an expert witness in a case related to viral as compared to bacterial sepsis. Dr. Papathanassoglou is a member of the World Federation of Critical Care Nurses (Editor of Journal) and the Canadian Association of Critical Care Nurses. Dr. Perner received a research grant from Pfizer Denmark. Dr. Puskarich is the co-inventor of a patent to assess L0carnitine drug responsiveness in sepsis (USPO 10330685); he is a member of the Society for Academic Emergency Medicine, American College of Emergency Physicians (ACEP); he was invited to a recently gathered ACEP early sepsis treatment policy task force asked to develop specialty recommendations for early sepsis treatment. Dr. Roberts received funding from MSD, The Medicines Company, Cardeas Pharma, Biomerieux, QPEX, Cipla, and Pfizer; he consulted for MSD, QPEX, Discuva Ltd, Accelerate Diagnostics, Bayer, Biomerieux, UptoDate, and Australian Therapeutic Guidelines; he is a member of the Society of Hospital Pharmacists of Australia Leadership Committees for Critical Care and Infectious Diseases and the Lead of Sepsis Working group for the International Society of Anti-infective Chemotherapy. Dr. Schweickert is a paid consultant to the American College of Physicians (last performed in Spring, 2019). Dr. Seckel volunteers for AACN and is a paid consultant to revise online Critical Care Orientation. Dr. Sevransky received funding from the Marcus Foundation- PI VICTAS Trial and serves on the American College of Critical Care Medicine Board of Regents. Dr. Welte received funding from Astellas, AstraZeneca, Boehringer, Basilea, Bayer, Berlin-Chemie, Grifols, Infectopharm, Mundipharma, MSD, Novartis, Pfizer, DFG, EU, BMBF, and Insmed; he is on the advisory board for AstraZeneca, Boehringer, Bayer, Gilead, GSK, Insmed, Novartis, Pfizer, Roche; he is a member of the European Respiratory Society, German Society of Pneumology, and Paul Ehrlich Gesellschaft. Dr. Zimmerman is a member of the ACP, AACP, and WFPICCS. Dr. Levy is a legal consultant for a few cases involving sepsis and serves as co-chair of the Surviving Sepsis Campaign Steering Committee. The remaining authors have disclosed that they do not have any potential conflicts of interest.

The authors reflect on a study which discusses the timing of corticosteroid administration in refractory septic shock among critically ill patients. Topics include the use of corticosteroid in septic shock patients, the recommended administration of hydrocortisone, and the suspected adrenal insufficiency for the patients.

Objectives: The National Early Warning Score, Modified Early Warning Score, and quick Sepsis-related Organ Failure Assessment can predict clinical deterioration. These scores exhibit only moderate performance and are often evaluated using aggregated measures over time. A simulated prospective validation strategy that assesses multiple predictions per patient-day would provide the best pragmatic evaluation. We developed a deep recurrent neural network deterioration model and conducted a simulated prospective evaluation., Design: Retrospective cohort study., Setting: Four hospitals in Pennsylvania., Patients: Inpatient adults discharged between July 1, 2017, and June 30, 2019., Interventions: None., Measurements and Main Results: We trained a deep recurrent neural network and logistic regression model using data from electronic health records to predict hourly the 24-hour composite outcome of transfer to ICU or death. We analyzed 146,446 hospitalizations with 16.75 million patient-hours. The hourly event rate was 1.6% (12,842 transfers or deaths, corresponding to 260,295 patient-hours within the predictive horizon). On a hold-out dataset, the deep recurrent neural network achieved an area under the precision-recall curve of 0.042 (95% CI, 0.04-0.043), comparable with logistic regression model (0.043; 95% CI 0.041 to 0.045), and outperformed National Early Warning Score (0.034; 95% CI, 0.032-0.035), Modified Early Warning Score (0.028; 95% CI, 0.027- 0.03), and quick Sepsis-related Organ Failure Assessment (0.021; 95% CI, 0.021-0.022). For a fixed sensitivity of 50%, the deep recurrent neural network achieved a positive predictive value of 3.4% (95% CI, 3.4-3.5) and outperformed logistic regression model (3.1%; 95% CI 3.1-3.2), National Early Warning Score (2.0%; 95% CI, 2.0-2.0), Modified Early Warning Score (1.5%; 95% CI, 1.5-1.5), and quick Sepsis-related Organ Failure Assessment (1.5%; 95% CI, 1.5-1.5)., Conclusions: Commonly used early warning scores for clinical decompensation, along with a logistic regression model and a deep recurrent neural network model, show very poor performance characteristics when assessed using a simulated prospective validation. None of these models may be suitable for real-time deployment., Competing Interests: Mr. Shah’s institution received funding from America Thoracic Society Research Foundation and the National Institutes of Health (NIH), and he received funding from Medical Student Health Services and Policy Research Summer Research Fellowship through the Master of Science in Health Policy Research Program at the Perelman School of Medicine, University of Pennsylvania. Dr. Ungar received support for article research from the NIH. Dr. Weissman was supported in part by NIH K23HL141639 and a grant from the America Thoracic Society Research Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Evaluating whether there is a clinical benefit of using extracorporeal cytokine adsorption therapy in two indications., Design: Systematic review., Setting: Search on four databases, Medline, Embase, The Cochrane Library, and the European Network for Health Technology Assessment planned and ongoing projects database., Patients: Patients with sepsis/septic shock; patients undergoing cardiac surgery., Interventions: Cytokine adsorption., Measurements and Main Results: Randomized controlled trials and prospective studies with concurrent control were eligible for the evidence synthesis. The quality of the individual studies and the strength of the available evidence were assessed using the Cochrane risk of bias tool and the Grading of Recommendations, Assessment, Development, and Evaluation approach, respectively. For the preventive treatment of extracorporeal cytokine adsorption therapy in patients undergoing cardiac surgery, we found very low-quality inconclusive evidence for mortality (five randomized controlled trials, n = 163), length of stay in the ICU (five randomized controlled trials, n = 163), and length of hospitalization (three randomized controlled trials, n = 101). Very low-quality inconclusive evidence was found for (serious) adverse events (four randomized controlled trials, n = 148). For the therapeutic treatment of extracorporeal cytokine adsorption therapy in patients with sepsis/septic shock, we found very low-quality inconclusive evidence for mortality up to 60-day follow-up (two randomized controlled trials, n = 117), organ function (two randomized controlled trials, n = 117) and length of stay in the ICU (one randomized controlled trial, n = 20). Very low-quality inconclusive evidence was found for (serious) adverse events (two randomized controlled trials, n = 117)., Conclusions: Given the available evidence, the efficacy and safety of extracorporeal cytokine adsorption therapy in combination with standard care in the investigated indications was not established. We strongly recommend considering well-powered studies with patient-relevant endpoints instead of investing further research funds on studies that may not shed light on the clinical benefit of extracorporeal cytokine adsorption therapy., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care., Competing Interests: Dr. DeMerle’s institution received funding from R35 GM119519-03 and T32HL007820. Dr. Calfee is supported in part by grants from the National Institutes of Health (NIH; HL140026). Dr. Carcillo is supported in part by grants from the National Institutes of Health (R01GM108618). Dr. DeMerle is supported in part by grants from the National Institutes of Health (T32HL007820). Dr. Angus received funding from Ferring Pharmaceuticals, Bristol-Myers Squibb, Bayer AG, and Alung Technologies. Drs. Angus, Brant, Carcillo, Chang, Dickson, Kennedy, Lindsell, Liu, Randolph, Thompson, Tsalik, Wong, and Seymour received support for article research from the NIH. Dr. Baillie received support for article research from Wellcome Trust/Charity Open Access Fund (COAF), and Research Councils UK. Dr. Calfee’s institution received funding from Roche/Genentech and Bayer, and she received funding from Roche/Genentech, Quark, CSL Behring, Bayer, Gen1e Life Sciences, and Vasomune. Drs. Carcillo’s and Seymour’s institutions received funding from the National Institute of General Medical Sciences. Drs. Chang’s, Lindsell’s, Liu’s, Randolph’s, Shapiro’s, and Wong’s institutions received funding from the NIH. Dr. Gordon’s institution received funding from the National Institute for Health Research (NIHR) Research Professorship (RP-2015-06-18), NIHR Imperial Biomedical Research Centre, GlaxoSmithKline, and Bristol Myers Squibb. Dr. Knight received support for article research from Wellcome Trust/COAF. Dr. Lindsell’s institution received funding from the Centers for Disease Control and Prevention (CDC), Department of Defense, Marcus Foundation, Entegrion, Endpoint Health, and bioMerieux, and he disclosed he is a coinventor on patents related to risk stratification in septic shock. Dr. Marshall received funding from AM Pharma, AKPA Pharma, and the Society of Critical Care Medicine (Critical Care Medicine Associate Editor). Dr. Randolph’s institution received funding from the CDC, and she received funding from La Jolla Pharma. Dr. Shapiro’s institution received funding from rapid pathogen screening, Baxter, and Inflammatix, and he received funding from Diagnostic Robotics. Dr. Sweeney received funding from Inflammatix. Dr. Thompson’s institution received funding from the National Heart, Lung, and Blood Institute, and he received funding from Bayer and Thetis. Dr. Tsalik disclosed that he is a founder and holds equity in Predigen; he receives salary support from the Durham VA Healthcare System and Duke University; and he has received salary support and/or grant funding (paid to his university) from the NIH, DARPA, DTRA, Karius, and Sanofi US. Dr. Wong disclosed that he and his institutions hold U.S. patents for sepsis biomarkers. Dr. Yende received funding from serving as consultant for expert testimony and he disclosed government work. Dr. Knight is supported by a Wellcome Trust Investigator Award (204969/Z/16/Z) and the NIHR Oxford Biomedical Research Centre. Dr. Lindsell was supported in part by grants from the National Institutes of Health (R35GM126943, R01HL149422), a research grant to VUMC from Endpoint Health, and is also listed as co-inventor on patents for endotyping and risk-stratification in pediatric septic shock. Dr. Liu is supported in part by grants from the National Institutes of Health (R35GM128672). Dr. Marshall is supported in part by grants from the Canadian Institutes of Health Research. Dr. Randolph is supported in part by grants from the National Institutes of Health (R21HD095228). Dr. Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (CS-2016-16-011). Dr. Wong is supported in part by grants from the National Institutes of Health (R35 GM126943). Dr. Sweeney is an employee of, and shareholder in, Inflammatix. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: To identify research priorities in the management, pathophysiology, and host response of coronavirus disease 2019 in critically ill patients., Design: The Surviving Sepsis Research Committee, a multiprofessional group of 17 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine, was virtually convened during the coronavirus disease 2019 pandemic. The committee iteratively developed the recommendations and subsequent document., Methods: Each committee member submitted a list of what they believed were the most important priorities for coronavirus disease 2019 research. The entire committee voted on 58 submitted questions to determine top priorities for coronavirus disease 2019 research., Results: The Surviving Sepsis Research Committee provides 13 priorities for coronavirus disease 2019. Of these, the top six priorities were identified and include the following questions: 1) Should the approach to ventilator management differ from the standard approach in patients with acute hypoxic respiratory failure?, 2) Can the host response be modulated for therapeutic benefit?, 3) What specific cells are directly targeted by severe acute respiratory syndrome coronavirus 2, and how do these cells respond?, 4) Can early data be used to predict outcomes of coronavirus disease 2019 and, by extension, to guide therapies?, 5) What is the role of prone positioning and noninvasive ventilation in nonventilated patients with coronavirus disease?, and 6) Which interventions are best to use for viral load modulation and when should they be given?, Conclusions: Although knowledge of both biology and treatment has increased exponentially in the first year of the coronavirus disease 2019 pandemic, significant knowledge gaps remain. The research priorities identified represent a roadmap for investigation in coronavirus disease 2019., Competing Interests: Dr. Deutschman is past president of the Society of Critical Care Medicine, is a scientific editor for Critical Care Medicine, and is a consultant for Enlivex and Lowell Therapeutics; his institution received funding from National Institute of General Medical Sciences; he received funding from the Society of Critical Care Medicine, Elsevier, Enlivex, Sage Therapeutics, and La Jolla Pharmaceuticals; and he received support for article research from the National Institutes of Health (NIH). Dr. Evans disclosed that she serves as the cochair of the Surviving Sepsis Committee and as the adult Surviving Sepsis Campaign Guidelines for the management of sepsis and septic shock. Dr. Ferrer received funding from MSD, Pfizer, and Gilead. Dr. Kesecioglu is president of the European Society of Intensive Care Medicine. Dr. Kissoon is the pediatrics guidelines cochair of the Surviving Sepsis Committee. Dr. Martin-Loeches received honoraria from MSD, Gilead, and Aspen. Dr. Nunnally is Treasurer of the Society of Critical Care Anesthesiologists. Dr. Prescott is the sepsis lead for a Michigan statewide sepsis quality improvement initiative sponsored by Blue Cross Blue Shield of Michigan, and his institution received funding from Agency for Healthcare Research and Quality, the Department of Veterans Affairs, and the NIH, and she disclosed government work. Dr. Rhodes is the adult guidelines cochair of the Surviving Sepsis Committee and a member of the Executive Committee. Dr. Talmor received speaking fees from Hamilton Medical, Clew, and Mindray. Dr. Tissieres is president of the European Society of Pediatric and Neonatal Intensive Care, is the pediatrics guidelines cochair of the Surviving Sepsis Committee, and has received consulting fees or research grant from Baxter, bioMerieux, Sanofi. Dr. DeBacker is past president of the European Society of Intensive Care Medicine and has received consulting fees from Fresenius Kabi. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objective: Expand upon the priorities of fluid resuscitation and vasopressor therapy research priorities identified by a group of experts assigned by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine., Data Sources: Original article, literature search., Study Selection: Several members of the original task force with expertise specific to the area of fluid resuscitation and vasopressor therapy., Data Extraction: None., Data Synthesis: None., Conclusion: In the second of a series of manuscripts subsequent to the original article, members with expertise in the subjects expound upon the three identified priorities related to fluid resuscitation and vasopressor therapies. This analysis summarizes what is known and what were identified as ongoing and future research., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Objectives: To assess whether Black race is associated with a higher rate of all-cause readmission compared with White race following community-onset sepsis., Design: Retrospective cohort study., Setting: One-thousand three-hundred bed urban academic medical centers., Patients: Three-thousand three-hundred ninety patients hospitalized with community-onset sepsis between January 1, 2010, and December 31, 2017., Interventions: Community-onset sepsis was defined as patients admitted through the emergency department with an International Classification of Disease, ninth revision, Clinical Modification code for either severe sepsis (995.92) or septic shock (785.52). Beginning in 2015, we used International Classification of Disease, Tenth Revision, Clinical Modification codes R65.20 (severe sepsis) and R65.21 (septic shock). We excluded those individuals hospitalized at another acute care facility that were transferred to our facility. Race was abstracted electronically, and patients who expired or self-identified as a race other than Black or White race were excluded. Patients who experienced a subsequent hospitalization at our facility were considered to be readmitted., Measurements and Main Results: Compared with White race, Black race demonstrated a significantly higher rate of all-cause readmission (60.8% vs 71.1%; p < 0.001), including a higher rate of readmission for sepsis (14.0% vs 19.8%; p < 0.001). Black patients also resided in zip codes with a lower median household income and were more likely to use public insurance compared with White race. Similar rates of comorbid diseases and disease burden were observed between the two groups, but vasopressors were less likely to be administered to Black patients. Multivariable analysis showed that Black race was associated with a 50% increased odds (odds ratio, 1.52, 99% CI, 1.25-1.84) in all-cause readmission risk compared with White race., Conclusions: Black race was associated with a higher rate of all-cause and sepsis readmission, possibly as a result of unaddressed health disparities, compared with White race. Programs addressing healthcare disparities should use readmission as another marker of equity., Competing Interests: Dr. Betthauser received funding from La Jolla Pharmaceutical Company. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: To examine long-term mortality, resource utilization, and healthcare costs in sepsis patients compared to hospitalized nonsepsis controls., Design: Propensity-matched population-based cohort study using administrative data., Setting: Ontario, Canada., Patients: We identified a cohort of adults (≥ 18) admitted to hospitals in Ontario between April 1, 2012, and March 31, 2016, with follow-up to March 31, 2017. Sepsis patients were flagged using a validated International Classification of Diseases, 10th Revision-coded algorithm (Sepsis-2 definition), including cases with organ dysfunction (severe sepsis) and without (nonsevere). Remaining hospitalized patients were potential controls. Cases and controls were matched 1:1 on propensity score, age, sex, admission type, and admission date., Interventions: None., Measurements and Main Results: Differences in mortality, rehospitalization, hospital length of stay, and healthcare costs were estimated, adjusting for remaining confounders using Cox regression and generalized estimating equations. Of 270,669 sepsis cases, 196,922 (73%) were successfully matched: 64,204 had severe and 132,718 nonsevere sepsis (infection without organ dysfunction). Over follow-up (median 2.0 yr), severe sepsis patients had higher mortality rates than controls (hazard ratio, 1.66; 95% CI, 1.63-1.68). Both severe and nonsevere sepsis patients had higher rehospitalization rates than controls (hazard ratio, 1.53; 95% CI, 1.50-1.55 and hazard ratio, 1.41; 95% CI, 1.40-1.43, respectively). Incremental costs (Canadian dollar 2018) in sepsis cases versus controls at 1-year were: $29,238 (95% CI, $28,568-$29,913) for severe and $9,475 (95% CI, $9,150-$9,727) for nonsevere sepsis., Conclusions: Severe sepsis was associated with substantially higher long-term risk of death, rehospitalization, and healthcare costs, highlighting the need for effective postdischarge care for sepsis survivors., Competing Interests: Ms. Farrah's and Dr. Thavorn's institution received funding from The Ottawa Hospital Academic Medical Organization. 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.)

Competing Interests: Dr. Sevransky’s institution has received funding from the Marcus Foundation for a sepsis clinical trial and from the Centers for Disease Control and Prevention Foundation. Dr. Rochwerg is supported by the Hamilton Health Sciences Early Career Award. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Great efforts are being made worldwide to identify the specific clinical characteristics of infected critically ill patients that mediate the associated pathogenesis, including vascular dysfunction, thrombosis, dysregulated inflammation, and respiratory complications. Recently, coronavirus disease 2019 has been closely related to sepsis, which suggests that most deaths in ICUs in infected patients are produced by viral sepsis. Understanding the physiopathology of the disease that lead to sepsis after severe acute respiratory syndrome coronavirus 2 infection is a current clinical need to improve intensive care-applied therapies applied to critically ill patients. Although the whole representative data characterizing the immune and inflammatory status in coronavirus disease 2019 patients are not completely known, it is clear that hyperinflammation and coagulopathy contribute to disease severity. Here, we present some common features shared by severe coronavirus disease 2019 patients and sepsis and describe proposed anti-inflammatory therapies for coronavirus disease 2019 which have been previously evaluated in sepsis.

Objectives: To describe the Children's Hospital Association's Improving Pediatric Sepsis Outcomes sepsis definitions and the identified patients; evaluate the definition using a published framework for evaluating sepsis definitions., Design: Observational cohort., Setting: Multicenter quality improvement collaborative of 46 hospitals from January 2017 to December 2018, excluding neonatal ICUs., Patients: Improving Pediatric Sepsis Outcomes Sepsis was defined by electronic health record evidence of suspected infection and sepsis treatment or organ dysfunction. A more severely ill subgroup, Improving Pediatric Sepsis Outcomes Critical Sepsis, was defined, approximating septic shock., Interventions: Participating hospitals identified patients, extracted data, and transferred de-identified data to a central data warehouse. The definitions were evaluated across domains of reliability, content validity, construct validity, criterion validity, measurement burden, and timeliness., Measurements and Main Results: Forty hospitals met data quality criteria across four electronic health record platforms. There were 23,976 cases of Improving Pediatric Sepsis Outcomes Sepsis, including 8,565 with Improving Pediatric Sepsis Outcomes Critical Sepsis. The median age was 5.9 years. There were 10,316 (43.0%) immunosuppressed or immunocompromised patients, 4,135 (20.3%) with central lines, and 2,352 (11.6%) chronically ventilated. Among Improving Pediatric Sepsis Outcomes Sepsis patients, 60.8% were admitted to intensive care, 26.4% had new positive-pressure ventilation, and 19.7% received vasopressors. Median hospital length of stay was 6.0 days (3.0-13.0 d). All-cause 30-day in-hospital mortality was 958 (4.0%) in Improving Pediatric Sepsis Outcomes Sepsis; 541 (6.3%) in Improving Pediatric Sepsis Outcomes Critical Sepsis. The Improving Pediatric Sepsis Outcomes Sepsis definitions demonstrated strengths in content validity, convergent construct validity, and criterion validity; weakness in reliability. Improving Pediatric Sepsis Outcomes Sepsis definitions had significant initial measurement burden (median time from case completion to submission: 15 mo [interquartile range, 13-18 mo]); timeliness improved once data capture was established (median, 26 d; interquartile range, 23-56 d)., Conclusions: The Improving Pediatric Sepsis Outcomes Sepsis definitions demonstrated feasibility for large-scale data abstraction. The patients identified provide important information about children treated for sepsis. When operationalized, these definitions enabled multicenter identification and data aggregation, indicating practical utility for quality improvement.