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Purpose: During the initial phase of the pandemic, healthcare professionals faced difficulties due to the limited availability of comprehensive learning resources on managing patients affected with coronavirus disease 2019 (COVID-19). The COVID-19 Skills Preparation Course (C19&#95;SPACE) was tailored to meet the overwhelming demand for specialized training. The primary objective of this study was to assess the efficacy and impact of this program on enhancing clinical knowledge and to identify factors affecting this improvement., Methods: As part of the project, data were collected prospectively to measure the baseline knowledge. After the descriptive statistics, multiple and multivariate logistic regression models were executed to identify the factors associated with knowledge increase., Results: The final sample included 3140 medical doctors (MDs) and 3090 nurses (RNs). For the primary analysis, the mean value of the baseline knowledge test score of MDs was 62.41 (standard deviation, SD = 13.48), and it significantly (p < 0.001) increased to 84.65 (SD = 11.95). Factors influencing overall knowledge scores were female sex (AOR = 1.34 [1.04-1.73]), being a specialist qualified for intensive care medicine (adjusted odds ratio, AOR = 0.56, [0.33-0.96]), and performance on the pre-test (AOR = 0.91, [0.90-0.92]). As for the RNs, the mean value of the total knowledge score was 63.25 (SD = 13.53), which significantly (p < 0.001) increased to 81.51 (SD = 14.21). Factor associated with knowledge was performance on the pre-test (AOR = 0.92 [0.92-0.93])., Conclusions: C19&#95;SPACE effectively increased the clinical knowledge of doctors and nurses. The effect was more pronounced in the program's target group of healthcare workers with less experience in the intensive care unit (ICU). Other factors associated with knowledge enhancement were sex and being a specialist in intensive care., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Severe community-acquired pneumonia (sCAP) is associated with high morbidity and mortality, and whilst European and non-European guidelines are available for community-acquired pneumonia, there are no specific guidelines for sCAP., Methods: The European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and Latin American Thoracic Association (ALAT) launched a task force to develop the first international guidelines for sCAP. The panel comprised a total of 18 European and four non-European experts, as well as two methodologists. Eight clinical questions for sCAP diagnosis and treatment were chosen to be addressed. Systematic literature searches were performed in several databases. Meta-analyses were performed for evidence synthesis, whenever possible. The quality of evidence was assessed with GRADE (Grading of Recommendations, Assessment, Development and Evaluation). Evidence to Decision frameworks were used to decide on the direction and strength of recommendations., Results: Recommendations issued were related to diagnosis, antibiotics, organ support, biomarkers and co-adjuvant therapy. After considering the confidence in effect estimates, the importance of outcomes studied, desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention and implications to health equity, recommendations were made for or against specific treatment interventions., Conclusions: In these international guidelines, ERS, ESICM, ESCMID, and ALAT provide evidence-based clinical practice recommendations for diagnosis, empirical treatment, and antibiotic therapy for sCAP, following the GRADE approach. Furthermore, current knowledge gaps have been highlighted and recommendations for future research have been made., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: Although elective surgery is generally safe, some procedures remain associated with an increased risk of complications. Improved preoperative risk stratification and earlier recognition of these complications may ameliorate postoperative recovery and improve long-term outcomes. The perioperative longitudinal study of complications and long-term outcomes (PLUTO) cohort aims to establish a comprehensive biorepository that will facilitate research in this field. In this profile paper, we will discuss its design rationale and opportunities for future studies., Participants: Patients undergoing elective intermediate to high-risk non-cardiac surgery are eligible for enrolment. For the first seven postoperative days, participants are subjected to daily bedside visits by dedicated observers, who adjudicate clinical events and perform non-invasive physiological measurements (including handheld spirometry and single-channel electroencephalography). Blood samples and microbiome specimens are collected at preselected time points. Primary study outcomes are the postoperative occurrence of nosocomial infections, major adverse cardiac events, pulmonary complications, acute kidney injury and delirium/acute encephalopathy. Secondary outcomes include mortality and quality of life, as well as the long-term occurrence of psychopathology, cognitive dysfunction and chronic pain., Findings to Date: Enrolment of the first participant occurred early 2020. During the inception phase of the project (first 2 years), 431 patients were eligible of whom 297 patients consented to participate (69%). Observed event rate was 42% overall, with the most frequent complication being infection., Future Plans: The main purpose of the PLUTO biorepository is to provide a framework for research in the field of perioperative medicine and anaesthesiology, by storing high-quality clinical data and biomaterials for future studies. In addition, PLUTO aims to establish a logistical platform for conducting embedded clinical trials., Trial Registration Number: NCT05331118., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections., (© 2022. Springer Nature America, Inc.)

Importance: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive., Objective: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19., Design, Setting, and Participants: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021., Interventions: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916)., Main Outcomes and Measures: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events., Results: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group., Conclusions and Relevance: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Background: The coronavirus disease 2019 pandemic continues to affect millions worldwide. Given the rapidly growing evidence base, we implemented a living guideline model to provide guidance on the management of patients with severe or critical coronavirus disease 2019 in the ICU., Methods: The Surviving Sepsis Campaign Coronavirus Disease 2019 panel has expanded to include 43 experts from 14 countries; all panel members completed an electronic conflict-of-interest disclosure form. In this update, the panel addressed nine questions relevant to managing severe or critical coronavirus disease 2019 in the ICU. We used the World Health Organization's definition of severe and critical coronavirus disease 2019. The systematic reviews team searched the literature for relevant evidence, aiming to identify systematic reviews and clinical trials. When appropriate, we performed a random-effects meta-analysis to summarize treatment effects. We assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach, then used the evidence-to-decision framework to generate recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility., Results: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued nine statements (three new and six updated) related to ICU patients with severe or critical coronavirus disease 2019. For severe or critical coronavirus disease 2019, the panel strongly recommends using systemic corticosteroids and venous thromboprophylaxis but strongly recommends against using hydroxychloroquine. In addition, the panel suggests using dexamethasone (compared with other corticosteroids) and suggests against using convalescent plasma and therapeutic anticoagulation outside clinical trials. The Surviving Sepsis Campaign Coronavirus Diease 2019 panel suggests using remdesivir in nonventilated patients with severe coronavirus disease 2019 and suggests against starting remdesivir in patients with critical coronavirus disease 2019 outside clinical trials. Because of insufficient evidence, the panel did not issue a recommendation on the use of awake prone positioning., Conclusion: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued several recommendations to guide healthcare professionals caring for adults with critical or severe coronavirus disease 2019 in the ICU. Based on a living guideline model the recommendations will be updated as new evidence becomes available., Competing Interests: Dr. Evans has disclosed that she is a PI on a multi-center observational cohort study of hospitalized patients with severe acute respiratory infection, funded by the CDC Foundation. Drs. Prescott, Chertow, and Mammen disclosed government work. Dr. Fan received funding from Lung Technologies, MC3 Cardiopulmonary, and Fresenius Medical Care. Dr. Derde’s institution received funding from ZonMw (Den Haag, Europe) grant number 10150062010003, the Canadian Institutes of Health Research (CIHR), and from Rapid European COVID-19 Emergency Research response (RECOVER) (Europe, H2020) grant agreement No 101003589, and her institution has agreements with Faron (interferon), SOBI (anakinra), and Abbvie (lopinavir/r) to supply drugs for the above-funded studies. Dr. Du’s institution received funding from the Ministry of Science and Technology for a COVID-19–related study (NCT04244591). Dr. Crowther received funding from Servier Canada, Asahi Kasei, Precision Biologicals, Hemostasis Reference Laboratory, Pfizer, CSL Behring, Diagnostica Stago, and he disclosed that he undertakes significant amounts of both medical malpractice and product work in the general areas of hematology and thromboembolism. Dr. Belley-Cote received funding from CIHR, Roche, and Bayer as a principal investigator for the ACT trial that evaluates hydroxychloroquine, interferon beta, colchicine, aspirin, and rivaroxaban in patients with COVID-19. Dr. Zarychanski received operating grants from CIHR, LifeArc Foundation, Thistledown Foundation, and Research Manitoba for grants related to anticoagulation in COVID-19. Dr. McGreer’s institution received funding from Appili Therapeutics. Dr. Hayden disclosed he is a nonpaid consultant for multiple companies involved in developing COVID-19 countermeasures (Arcturus, Cidara, Gilead, GSK, resTORbio, Regeneron, SAB Biotherapeutics, Takeda, Vir), and he is a DSMB member for CytoDyn. Dr. Martin received funding from serving on a clinical trial data monitoring board. Dr. Antonelli received funding from consulting for Intersurgical and ESTOR. Dr. Waleed Alhazzani is the principal investigator on awake proning trial in COVID-19 COVI-PRONE. Dr. Yaseen Arabi is the principal investigator on a clinical trial for lopinavir/ritonavir and interferon in Middle East respiratory syndrome (MERS) and he was a nonpaid consultant on antiviral active for MERS-coronavirus (CoV) for Gilead Sciences and SAB Biotherapeutics. He is an investigator on REMAP-CAP trial and is a Board Members of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). He is a co-investigator on the REMAP-CAP trial and on an awake proning trial in COVID-19 (COVI-PRONE). Dr. Maurizio Cecconi declared consultancy work with Edwards Lifesciences, Directed Systems, and Cheetah Medical: Dr. Lennie Derde is an investigator on REMAP-CAP trial, the NVIC (Dutch National ICU society) chair of Taskforce Infectious Diseases (standing committee), member of ESICM Coronavirus Taskforce (started with this outbreak), and chair of the ESICM Clinical Training Committee; all are unpaid positions. Dr. Laura Evans is the team leader for the critical care section of the NIH COVID-19 management guideline. Dr. Eddy Fan declared receiving consultancy fees from ALung Technologies and MC3 Cardiopulmonary. Dr. Frederick Hayden is a noncompensated consultant to Gilead Sciences, Regeneron, Cidara, Fujifilm, Ridgeback, Merck, Roche/Genentech, GSK, Vir, resTORbio, and SAB Biotherapeutics, and he is a DSMB member for CytoDyn therapeutic clinical trial: Dr. Manoj J. Mammen is an investigator for the U.S. NIH PASSive Immunity Trial for Our Nation (PassItOn) trial: Dr. Greg Martin is a member of the NIH COVID-19 treatment guidelines, principal investigator for COVID-19 diagnostic testing (U.S. NIH RADx program) and has served as a research consultant to Genentech, Grifols, Regeneron and Siemens. Dr. Massimo Antonelli declared consultancy with Toray/Estor and Fisher and Pykel and research grant from GE. Dr. Flavia Machado is member of the executive committee for the CODEX study. Dr. Sheila Nainan Myatra is on the steering committee of the COVID Steroid 2 Trial (ClinicalTrials.gov Identifier: NCT04509973) and the HydrOxychloroquine Prophylaxis Evaluation (HOPE) Trial (CTRI registration No.CTRI/2020/05/025067). Dr Naomi Hammond is on the steering committee of the COVID Steroid 2 Trial (ClinicalTrials.gov Identifier: NCT04509973) and the HydrOxychloroquine Prophylaxis Evaluation (HOPE) Trial (CTRI registration No.CTRI/2020/05/025067). Dr. Emilie Belley-Cote reports grants from Bayer, grants from Roche outside the submitted work. She is a principal investigator for the ACT trial: 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.)

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited., Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19., Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020., Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108)., Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%)., Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively., Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Purpose: To survey healthcare workers (HCW) on availability and use of personal protective equipment (PPE) caring for COVID-19 patients in the intensive care unit (ICU)., Materials and Method: A web-based survey distributed worldwide in April 2020., Results: We received 2711 responses from 1797 (67%) physicians, 744 (27%) nurses, and 170 (6%) Allied HCW. For routine care, most (1557, 58%) reportedly used FFP2/N95 masks, waterproof long sleeve gowns (1623; 67%), and face shields/visors (1574; 62%). Powered Air-Purifying Respirators were used routinely and for intubation only by 184 (7%) and 254 (13%) respondents, respectively. Surgical masks were used for routine care by 289 (15%) and 47 (2%) for intubations. At least one piece of standard PPE was unavailable for 1402 (52%), and 817 (30%) reported reusing single-use PPE. PPE was worn for a median of 4 h (IQR 2, 5). Adverse effects of PPE were associated with longer shift durations and included heat (1266, 51%), thirst (1174, 47%), pressure areas (1088, 44%), headaches (696, 28%), Inability to use the bathroom (661, 27%) and extreme exhaustion (492, 20%)., Conclusions: HCWs reported widespread shortages, frequent reuse of, and adverse effects related to PPE. Urgent action by healthcare administrators, policymakers, governments and industry is warranted., Competing Interests: Declaration of Competing Interest Dr. Tabah has nothing to disclose, Dr. Ramanan has nothing to disclose, Prof. Laupland has nothing to disclose, Dr. Buetti has nothing to disclose, Dr. Cortegiani has nothing to disclose, Mr. Mellinghoff has nothing to disclose, Dr. Conway Morris reports grants from Wellcome Trust, during the conduct of the study; Dr. Camporota has nothing to disclose, Dr. Zappella has nothing to disclose, Dr. Vidal has nothing to disclose, Dr. Elhadi has nothing to disclose, Dr. Povoa reports personal fess from Orion, personal fees from Pfizer and personal fees from Technofage, Dr. Amrein reports grants, personal fees and other from Fresenius Kabi, personal fees from Vifor Pharma, personal fees from Shire now part of Takeda, outside the submitted work, Dr. Derde reports grants from European Union, grants from ZonMw, outside the submitted work, Guy Francoishas nothing to disclose, Dr. Bassetti reports grants and personal fees from Pfizer, grants and personal fees from MSD, grants and personal fees from Menarini, grants and personal fees from Angelini, personal fees from Astellas, personal fees from Nabriva, grants and personal fees from Paratek, personal fees from Gilead, personal fees from Basilea, personal fees from Cidara, personal fees from Molteni, outside the submitted work; Dr. Ssi Yan Kai has nothing to disclose, Dr. De Waelereports grants from Research Foundation Flanders, during the conduct of the study; other from Bayer, other from Pfizer, other from MSD, other from Grifols, other from Accelerate, outside the submitted work;., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)