The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group IMPORTANCE Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.OBJECTIVE To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.DATA SOURCES Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.STUDY SELECTION Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. DATA EXTRACTION AND SYNTHESISIn this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I 2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. MAIN OUTCOMES AND MEASURESThe primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.RESULTS A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). CONCLUSIONS AND RELEVANCEIn this prospective meta-analysis of clinical trials of patients hosp...
OBJECTIVES: The infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) spreads worldwide and is considered a pandemic. The most common manifestation of SARS-CoV2 infection (Coronavirus disease 2019 - COVID-19) is viral pneumonia with varying degrees of respiratory compromise and up to 40% of hospitalized patients might develop Acute Respiratory Distress Syndrome (ARDS). Several clinical trials evaluated the role of corticosteroids in non-COVID-19 ARDS with conflicting results. We designed a trial to evaluate the effectiveness of early intravenous dexamethasone administration on the number of days alive and free of mechanical ventilation within 28 days after randomization in adult patients with moderate or severe ARDS due to confirmed or probable COVID-19. METHODS: This is a pragmatic, prospective, randomized, stratified, multicenter, open-label, controlled trial including 350 patients with early-onset (less than 48h before randomization) moderate or severe ARDS, defined by the Berlin criteria, due to COVID-19. Eligible patients will be randomly allocated to either standard treatment plus dexamethasone (intervention group) or standard treatment without dexamethasone (control group). Patients in the intervention group will receive dexamethasone 20mg IV once daily for 5 days, followed by dexamethasone 10mg IV once daily for additional 5 days or until Intensive Care Unit (ICU) discharge, whichever occurs first. The primary outcome is ventilator-free days within 28 days after randomization, defined as days alive and free from invasive mechanical ventilation. Secondary outcomes are all-cause mortality rates at day 28, evaluation of the clinical status at day 15 assessed with a 6-level ordinal scale, mechanical ventilation duration from randomization to day 28, Sequential Organ Failure Assessment (SOFA) Score evaluation at 48h, 72h and 7 days and ICU-free days within 28. ETHICS AND DISSEMINATION: This trial was approved by the Brazilian National Committee of Ethics in Research (Comissão Nacional de Ética em Pesquisa - CONEP) and National Health Surveillance Agency (ANVISA). An independent data monitoring committee will perform interim analyses and evaluate adverse events throughout the trial. Results will be submitted for publication after enrolment and follow-up are complete.
Objective To contribute to updating the recommendations for brain-dead potential organ donor management. Method A group of 27 experts, including intensivists, transplant coordinators, transplant surgeons, and epidemiologists, joined a task force formed by the General Coordination Office of the National Transplant System/Brazilian Ministry of Health (CGSNT-MS), the Brazilian Association of Intensive Care Medicine (AMIB), the Brazilian Association of Organ Transplantation (ABTO), and the Brazilian Research in Intensive Care Network (BRICNet). The questions were developed within the scope of the 2011 Brazilian Guidelines for Management of Adult Potential Multiple-Organ Deceased Donors. The topics were divided into mechanical ventilation, hemodynamic support, endocrine-metabolic management, infection, body temperature, blood transfusion, and use of checklists. The outcomes considered for decision-making were cardiac arrest, number of organs recovered or transplanted per donor, and graft function/survival. Rapid systematic reviews were conducted, and the quality of evidence of the recommendations was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Two expert panels were held in November 2016 and February 2017 to classify the recommendations. A systematic review update was performed in June 2020, and the recommendations were reviewed through a Delphi process with the panelists between June and July 2020. Results A total of 19 recommendations were drawn from the expert panel. Of these, 7 were classified as strong (lung-protective ventilation strategy, vasopressors and combining arginine vasopressin to control blood pressure, antidiuretic hormones to control polyuria, serum potassium and magnesium control, and antibiotic use), 11 as weak (alveolar recruitment maneuvers, low-dose dopamine, low-dose corticosteroids, thyroid hormones, glycemic and serum sodium control, nutritional support, body temperature control or hypothermia, red blood cell transfusion, and goal-directed protocols), and 1 was considered a good clinical practice (volemic expansion). Conclusion Despite the agreement among panel members on most recommendations, the grade of recommendation was mostly weak. The observed lack of robust evidence on the topic highlights the importance of the present guideline to improve the management of brain-dead potential organ donors.
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