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Since the beginning of the severe acute respiratory syndrome coronavirus 2 pandemic, there has been a large increase in the consumption of antimicrobials, both as a form of treatment for viral pneumonia, which has been shown to be ineffective, and in the treatment of secondary infections that arise over the course of the severe presentation of coronavirus disease 2019 (COVID-19). This increase in consumption, often empirical, ends up causing an increase in the incidence of colonization and secondary infections by multi and pan-resistant germs.The presence of a hyperinflammatory condition induced by the primary infection, associated with the structural damage caused by viral pneumonia and by the greater colonization by bacteria, generally multiresistant, are important risk factors for the acquisition of secondary infections in COVID-19. Consequently, there is an increased prevalence of secondary infections, associated with a higher consumption of antimicrobials and a significant increase in the incidence of infections by multi and pan-resistant bacteria.Antimicrobial stewardship and improvement in diagnostic techniques, improving the accuracy of bacterial infection diagnosis, may impact the antibiotic consumption and the incidence of infections by resistant pathogens.

Rationale: Coated devices may reduce biofilm formation and reduce the occurrence of device-related infections in critically ill patients. A bundle of coated devices (an endotracheal tube [ETT], central venous catheter [CVC], and urinary catheter [UC]) simultaneously inserted may optimize benefits of coated devices in patients with the most severe illness. Objectives: To assess the feasibility of a randomized controlled trial on simultaneous insertion of gold/silver/palladium-coated devices versus uncoated devices in severely ill patients, which required sequential insertion of all three devices (an ETT, CVC, and UC) for support in the intensive care unit (ICU). Methods: This was a multicenter randomized controlled pilot trial. Patients who required simultaneous insertion of an ETT, CVC, and UC were randomized to treatment with coated versus uncoated devices, which were used as necessary for up to 28 days. The primary endpoint was feasibility, defined as the trial being able to enroll enough participants to have the sample size necessary for its secondary primary endpoint (estimating sepsis incidence in this population) in less than 1 year and for estimating the number of admitted patients who require simultaneous insertion of all three devices. Secondary endpoints included the incidence of sepsis and device-associated infections (ventilator-associated pneumonia, catheter-related bloodstream infection, and catheter-related urinary-tract infection) within each group as well as the number of days alive and free of antibiotics during the ICU stay. All events were adjudicated. Results: One hundred and three patients (48 in the coated-device group and 55 in the uncoated-device group) were included in the perprotocol analysis. The inclusion period was 8 months. There were 13 septic events in each group (26 in total), with an approximate incidence of sepsis of 32.3 (95% credible interval [CrI], 22.4-44.9) per 100 patient-days. The overall incidences of ventilator-associated pneumonia, catheter-related urinary-tract infection, and catheterrelated bloodstream infection were 15.2 (95% CrI, 7.8-26.4), 6.3 (95% CrI, 2.4-13.7), and 7.9 (95% CrI, 3.6-15.1) per 1,000 patient-days, and incidence rates were not statistically different between groups. Patients in the coated-device group had more days alive and free of antibiotics in the ICU (28.97 d vs. 19.62 d per 100 patient-days; mean ratio, 1.48; 95% CrI, 1.16-1.89). Conclusions: Use of a bundle of coated devices as the initial treatment for of severely ill patients is feasible. Coated devices may be associated with more days alive and free of antibiotics. Clinical trial registered with www.clinicaltrials.gov (NCT 03868241).

Summary Background The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19. Methods We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278. Findings 447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94–1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups. Interpretation In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. Funding COALITION COVID-19 Brazil and EMS.

To evaluate renal responsiveness in oliguric critically ill patients after a fluid challenge.We conducted a prospective observational study in one university intensive care unit. Patients with urine output0.5mL/kg/h for 3 hours with a mean arterial pressure60mmHg received a fluid challenge. We examined renal fluid responsiveness (defined as urine output0.5mL/kg/h for 3 hours) after fluid challenge.Forty-two patients (age 67 ± 13 years; APACHE II score 16 ± 6) were evaluated. Patient characteristics were similar between renal responders and renal nonresponders. Thirteen patients (31%) were renal responders. Hemodynamic or perfusion parameters were not different between those who did and those who did not increase urine output before the fluid challenge. The areas under the receiver operating characteristic curves were calculated for mean arterial pressure, heart rate, creatinine, urea, creatinine clearance, urea/creatinine ratio and lactate before the fluid challenge. None of these parameters were sensitive or specific enough to predict reversal of oliguria.After achieving hemodynamic stability, oliguric patients did not increase urine output after a fluid challenge. Systemic hemodynamic, perfusion or renal parameters were weak predictors of urine responsiveness. Our results suggest that volume replacement to correct oliguria in patients without obvious hypovolemia should be done with caution.Avaliar a responsividade renal após desafio hídrico em pacientes oligúricos na unidade de terapia intensiva.Conduzimos um estudo observacional prospectivo em uma unidade de terapia intensiva universitária. Pacientes com débito urinário inferior a 0,5mL/kg/hora por 3 horas, com pressão arterial média acima de 60mmHg receberam um desafio hídrico. Examinamos a responsividade renal aos fluidos (definida como débito urinário acima de 0,5mL/kg/hora por 3 horas) após o desafio hídrico.Avaliaram-se 42 pacientes (idade 67 ± 13 anos; APACHE II 16 ± 6). As características dos pacientes foram similares entre os respondedores e os não respondedores renais. Treze pacientes (31%) foram respondedores renais. Antes do desafio hídrico, os parâmetros hemodinâmicos e de perfusão não foram diferentes entre os pacientes que apresentaram aumento do débito urinário e os que não apresentaram. Calcularam-se as áreas sob a curva receiver operating characteristic para os níveis pré-desafio hídrico de pressão arterial média, frequência cardíaca, creatinina, ureia, depuração de creatinina, proporção ureia/creatinina e lactato. Nenhum desses parâmetros foi sensível ou suficientemente específico para predizer a reversão da oligúria.Após obtenção de estabilidade hemodinâmica, os pacientes oligúricos não alcançaram aumento do débito urinário em resposta ao desafio hídrico. Os parâmetros de hemodinâmica sistêmica, perfusão ou renais foram preditores fracos de responsividade urinária. Nossos resultados sugerem que a reposição de volume com objetivo de corrigir oligúria em pacientes sem hipovolemia óbvia deve ser realizada com cautela.

Corticosteroids have been used for decades in the adjunctive treatment of severe infections in intensive care. The most frequent scenario in intensive care is in septic shock, where low doses of glucocorticoids appear to restore vascular responsiveness to norepinephrine. There is a strong body of evidence suggesting that hydrocortisone reduces time on vasopressor, and may modulate the immune response. In this review, we explore the current evidence supporting the use of corticosteroids in septic shock, its benefits, and potential harms. In addition to landmark clinical trials, we will also describe new frontiers for the use of corticosteroids in septic shock which should be explored in future studies.

Importance Intravenous fluids are used for almost all intensive care unit (ICU) patients. Clinical and laboratory studies have questioned whether specific fluid types result in improved outcomes, including mortality and acute kidney injury. Objective To determine the effect of a balanced solution vs saline solution (0.9% sodium chloride) on 90-day survival in critically ill patients. Design, Setting, and Participants Double-blind, factorial, randomized clinical trial conducted at 75 ICUs in Brazil. Patients who were admitted to the ICU with at least 1 risk factor for worse outcomes, who required at least 1 fluid expansion, and who were expected to remain in the ICU for more than 24 hours were randomized between May 29, 2017, and March 2, 2020; follow-up concluded on October 29, 2020. Patients were randomized to 2 different fluid types (a balanced solution vs saline solution reported in this article) and 2 different infusion rates (reported separately). Interventions Patients were randomly assigned 1:1 to receive either a balanced solution (n = 5522) or 0.9% saline solution (n = 5530) for all intravenous fluids. Main Outcomes and Measures The primary outcome was 90-day survival. Results Among 11 052 patients who were randomized, 10 520 (95.2%) were available for the analysis (mean age, 61.1 [SD, 17] years; 44.2% were women). There was no significant interaction between the 2 interventions (fluid type and infusion speed;P = .98). Planned surgical admissions represented 48.4% of all patients. Of all the patients, 60.6% had hypotension or vasopressor use and 44.3% required mechanical ventilation at enrollment. Patients in both groups received a median of 1.5 L of fluid during the first day after enrollment. By day 90, 1381 of 5230 patients (26.4%) assigned to a balanced solution died vs 1439 of 5290 patients (27.2%) assigned to saline solution (adjusted hazard ratio, 0.97 [95% CI, 0.90-1.05];P = .47). There were no unexpected treatment-related severe adverse events in either group. Conclusion and Relevance Among critically ill patients requiring fluid challenges, use of a balanced solution compared with 0.9% saline solution did not significantly reduce 90-day mortality. The findings do not support the use of this balanced solution. Trial Registration ClinicalTrials.gov Identifier:NCT02875873

BackgroundThe effects of convalescent plasma (CP) therapy in hospitalised patients with coronavirus disease 2019 (COVID-19) remain uncertain. This study investigates the effect of CP on clinical improvement in these patients.MethodsThis is an investigator-initiated, randomised, parallel arm, open-label, superiority clinical trial. Patients were randomly (1:1) assigned to two infusions of CP plus standard of care (SOC) or SOC alone. The primary outcome was the proportion of patients with clinical improvement 28 days after enrolment.ResultsA total of 160 (80 in each arm) patients (66.3% critically ill, 33.7% severely ill) completed the trial. The median (interquartile range (IQR)) age was 60.5 (48–68) years; 58.1% were male and the median (IQR) time from symptom onset to randomisation was 10 (8–12) days. Neutralising antibody titres >1:80 were present in 133 (83.1%) patients at baseline. The proportion of patients with clinical improvement on day 28 was 61.3% in the CP+SOC group and 65.0% in the SOC group (difference −3.7%, 95% CI −18.8–11.3%). The results were similar in the severe and critically ill subgroups. There was no significant difference between CP+SOC and SOC groups in pre-specified secondary outcomes, including 28-day mortality, days alive and free of respiratory support and duration of invasive ventilatory support. Inflammatory and other laboratory marker values on days 3, 7 and 14 were similar between groups.ConclusionsCP+SOC did not result in a higher proportion of clinical improvement on day 28 in hospitalised patients with COVID-19 compared to SOC alone.

This is the twelfth version (eleventh update) of the living guideline, replacing earlier versions (available as data supplements). New recommendations will be published as updates to this guideline.What is the role of drugs in the treatment of patients with covid-19?The evidence base for therapeutics for covid-19 is evolving with numerous randomised controlled trials (RCTs) recently completed and under way. The emerging SARS-CoV-2 variants (such as omicron) and subvariants are also changing the role of therapeutics. This update provides updated recommendations for remdesivir, addresses the use of combination therapy with corticosteroids, interleukin-6 (IL-6) receptor blockers, and janus kinase (JAK) inhibitors in patients with severe or critical covid-19, and modifies previous recommendations for the neutralising monoclonal antibodies sotrovimab and casirivimab-imdevimab in patients with non-severe covid-19.• Remdesivir: a conditional recommendation for its use in patients with severe covid-19; and a conditional recommendation against its use in patients with critical covid-19. • Concomitant use of IL-6 receptor blockers (tocilizumab or sarilumab) and the JAK inhibitor baricitinib: these drugs may now be combined, in addition to corticosteroids, in patients with severe or critical covid-19. • Sotrovimab and casirivimab-imdevimab: strong recommendations against their use in patients with covid-19, replacing the previous conditional recommendations for their use.When moving from new evidence to updated recommendations, the Guideline Development Group (GDG) considered a combination of evidence assessing relative benefits and harms, values and preferences, and feasibility issues. For remdesivir, new trial data were added to a previous subgroup analysis and provided sufficiently trustworthy evidence to demonstrate benefits in patients with severe covid-19, but not critical covid-19. The GDG considered benefits of remdesivir to be modest and of moderate certainty for key outcomes such as mortality and mechanical ventilation, resulting in a conditional recommendation. For baricitinib, the GDG considered clinical trial evidence (RECOVERY) demonstrating reduced risk of death in patients already receiving corticosteroids and IL-6 receptor blockers. The GDG acknowledged that the clinical trials were not representative of the world population and that the risk-benefit balance may be less advantageous, particularly in patients who are immunosuppressed at higher risk of opportunistic infections (such as serious fungal, viral, or bacteria), those already deteriorating where less aggressive or stepwise addition of immunosuppressive medications may be preferred, and in areas where certain pathogens such as HIV or tuberculosis, are of concern. The panel anticipated that there would be situations where clinicians may opt for less aggressive immunosuppressive therapy or to combine medications in a stepwise fashion in patients who are deteriorating. The decision to combine the medications will depend on their availability, and the treating clinician's perception of the risk-benefit balance associated with combination immunosuppressive therapy, particularly in patient populations at risk of opportunistic infections who may have been under-represented in clinical trials. When making a strong recommendation against the use of monoclonal antibodies for patients with covid-19, the GDG considered in vitro neutralisation data demonstrating that sotrovimab and casirivimab-imdevimab evaluated in clinical trials have meaningfully reduced neutralisation activity of the currently circulating variants of SARS-CoV-2 and their subvariants. There was consensus among the panel that the absence of in vitro neutralisation activity strongly suggests absence of clinical effectiveness of these monoclonal antibodies. However, there was also consensus regarding the need for clinical trial evidence in order to confirm clinical efficacy of new monoclonal antibodies that reliably neutralise the circulating strains in vitro. Whether emerging new variants and subvariants might be susceptible to sotrovimab, casirivimab-imdevimab, or other anti-SARS-CoV-2 monoclonal antibodies cannot be predicted.• Recommended for patients with severe or critical covid-19—strong recommendations for systemic corticosteroids; IL-6 receptor blockers (tocilizumab or sarilumab) in combination with corticosteroids; and baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids. • Recommended for patients with non-severe covid-19 at highest risk of hospitalisation—a strong recommendation for nirmatrelvir/ritonavir; conditional recommendations for molnupiravir and remdesivir. • Not recommended for patients with non-severe covid-19—a conditional recommendation against systemic corticosteroids; a strong recommendation against convalescent plasma; a recommendation against fluvoxamine, except in the context of a clinical trial; and a strong recommendation against colchicine. • Not recommended for patients with non-severe covid-19 at low risk of hospitalisation—a conditional recommendation against nirmatrelvir/ritonavir. • Not recommended for patients with severe or critical covid-19—a recommendation against convalescent plasma except in the context of a clinical trial; and a conditional recommendation against the JAK inhibitors ruxolitinib and tofacitinib. • Not recommended, regardless of covid-19 disease severity—a strong recommendations against hydroxychloroquine and against lopinavir/ritonavir; and a recommendation against ivermectin except in the context of a clinical trial.This living guideline from the World Health Organization (WHO) incorporates new evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF, with a summary version here in The BMJ. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact.Recommendations on anticoagulation are planned for the next update to this guideline.

BACKGROUND: Handgrip strength is an alternative measure to assess peripheral muscle strength and is correlated with the Medical Research Council (MRC) scale, with promising values for diagnosing ICU-acquired weakness (ICUAW). Because ICUAW has been associated with delayed weaning from mechanical ventilation, we hypothesized that ICUAW evaluated with both the MRC scale score and handgrip strength are associated with failure of a spontaneous breathing trial (SBT) and duration of mechanical ventilation weaning. METHODS: We conducted a prospective observational study in 3 general ICUs with a total of 54 beds at 2 academic hospitals. Adult subjects with > 48 h of mechanical ventilation who were eligible for weaning were included in the study. RESULTS: In the evaluation before the first SBT, the MRC score (P < .001) and handgrip strength (P < .001) were significantly different between subjects extubated after a successful first SBT (simple weaning) and those extubated any time after a failed first SBT (difficult weaning). Only the MRC score discriminated between first SBT success or failure (P < .001); in multivariate analysis, the MRC score was significantly associated with first SBT failure (odds ratio 0.91, 95% CI 0.88–0.97, P < .001) and difficult weaning (odds ratio 0.91, 95% CI 0.87–0.96, P < .001). Handgrip strength exhibited good accuracy in identifying ICUAW. CONCLUSIONS: MRC score was independently associated with SBT failure and difficult or prolonged weaning.

Submitted by DSpace Unilasalle (dspace@unilasalle.edu.br) on 2021-09-13T16:53:54Z No. of bitstreams: 1 tclisboa.etal.pdf: 231184 bytes, checksum: ecd60ed6cb851e9549fc698e4fe5205b (MD5) Made available in DSpace on 2021-09-13T16:53:54Z (GMT). No. of bitstreams: 1 tclisboa.etal.pdf: 231184 bytes, checksum: ecd60ed6cb851e9549fc698e4fe5205b (MD5) Previous issue date: 2020

Introduction Acinetobacter species treatment often represents a challenge. The main objective of this study is identify predictors of ICU mortality in patients submitted to mechanical ventilation (MV). Materials and methods Retrospective cohort study. Patients with MV > 48 h who developed a respiratory tract positive culture for Acinetobacter were included, and distinguished among colonized, ventilator-associated pneumonia (VAP) or ventilator-associated tracheobronchitis (VAT) patients. Primary outcome was ICU mortality. Results 153 patients were in MV and presented positive culture for Acinetobacter calcoaceticus-baumanii complex, 70 of them with VAP, 59 with VAT and 24 patients were colonized. The factors related to ICU mortality were VAP (OR 2.2, 95% CI 1.1–4.5) and shock at the time of diagnosis (OR 4.8, 95% CI 1.8–2.3). In multivariate analysis, only SOFA score at the time of diagnosis (OR 1.06, 95% CI 1.03–1.09) was related with ICU mortality. A paired-matched analysis was performed to assess effect of dual therapy on outcomes, and no effect was found in terms of clinical cure, ICU or hospital mortality or duration of antimicrobial therapy. Conclusions Previous comorbidities and degree of associated organic injury seem to be more important factors in the prognosis than double antibiotic therapy in patients with Acinetobacter-related respiratory infection.

Made available in DSpace on 2022-04-29T08:30:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-04-01 National Health and Medical Research Council Objective: To describe fluid resuscitation practices in Brazilian intensive care units and to compare them with those of other countries participating in the Fluid-TRIPS. Methods: This was a prospective, international, cross-sectional, observational study in a convenience sample of intensive care units in 27 countries (including Brazil) using the Fluid-TRIPS database compiled in 2014. We described the patterns of fluid resuscitation use in Brazil compared with those in other countries and identified the factors associated with fluid choice. Results: On the study day, 3,214 patients in Brazil and 3,493 patients in other countries were included, of whom 16.1% and 26.8% (p < 0.001) received fluids, respectively. The main indication for fluid resuscitation was impaired perfusion and/or low cardiac output (Brazil: 71.7% versus other countries: 56.4%, p < 0.001). In Brazil, the percentage of patients receiving crystalloid solutions was higher (97.7% versus 76.8%, p < 0.001), and 0.9% sodium chloride was the most commonly used crystalloid (62.5% versus 27.1%, p < 0.001). The multivariable analysis suggested that the albumin levels were associated with the use of both crystalloids and colloids, whereas the type of fluid prescriber was associated with crystalloid use only. Conclusion: Our results suggest that crystalloids are more frequently used than colloids for fluid resuscitation in Brazil, and this discrepancy in frequencies is higher than that in other countries. Sodium chloride (0.9%) was the crystalloid most commonly prescribed. Serum albumin levels and the type of fluid prescriber were the factors associated with the choice of crystalloids or colloids for fluid resuscitation. Discipline of Anesthesiology Pain and Intensive Care Universidade Federal de São Paulo, Rua Napoleão de Barros, 737, 6ºandar Critical Care and Trauma Division George Institute for Global Health Hospital Sírio-Libanês Hospital das Clínicas Faculdade de Medicina Universidade de São Paulo Instituto de Pesquisa HCor - Hospital do Coração Instituto de Pesquisa Clínica Evandro Chagas Fundação Oswaldo Cruz Hospital de Clínicas Mário Lioni Hospital do Rim e Hipertensão Fundação Oswaldo Ramos Hospital Samaritano Hospital Paulistano Hospital São José Instituto D’Or de Ensino e Pesquisa Hospital Municipal São José Hospital Israelita Albert Einstein Hospital Santa Rita Hospital de Base Faculdade de Medicina de São Jose do Rio Preto Hospital Unimed de Belo Horizonte Hospital Santa Lúcia Hospital Evangélico de Sorocaba Hospital PIO XII Hospital São Camilo Pompéia Hospital Alvorada Brasília Hospital Ecoville Hospital do Trabalhador Hospital Vita Batel Hospital das Clínicas Faculdade de Medicina de Botucatu Universidade Estadual “Júlio de Mesquita Filho” Hospital Geral Dr. César Cals Hospital Copa D’Or Associação Beneficente Hospital Unimar Hospital Casa de Saúde de Santos Hospital Estadual Getúlio Vargas Hospital e Maternidade Otaviano Neves Instituto Estadual do Cérebro Paulo Niemeyer Hospital Universitário Universidade Federal de Juiz de Fora Lifecenter Hospital Geral de Fortaleza Hospital Municipal Dr. Moysés Deutsch (M’Boi Mirim) Santa Casa de Misericórdia de Presidente Prudente Hospital 9 de julho Hospital Estadual Rocha Faria Hospital Municipal Santa Isabel Hospital e Maternidade Municipal Dr. Odelmo Leão Carneiro Hospital Evangélico de Londrina Universidade Estadual de Londrina Hospital Samaritano João Pessoa Hospital de Caridade Astrogildo de Azevedo Vitória Apart Hospital Instituto de Ortopedia e Traumatologia Hospital do Subúrbio Hospital Renascentista Hospital Felício Rocho Hospital Municipal Irmã Dulce Hospital Universitário Júlio Müller Universidade Federal do Mato Grosso Hospital de Urgência Hospital Geral de Goiânia Fundação Doutor Amaral Carvalho Hospital Adventista de Belém Hospital Santa Juliana Hospital Dom Vicente Scherer Hospital Primavera Hospital Carlos da Silva Lacaz Hospital Escola Faculdade de Medicina de Jundiaí Hospital Sepaco Hospital Professor Edmundo Vasconcelos Hospital Paulo Sacramento Clínica Dom Rodrigo Complexo Hospitalar Ortotrauma de Mangabeira Hospital Nossa Senhora da Conceição Hospital Regional de Samambaia Hospital São Camilo Ipiranga Hospital da Restauração Instituto do Coração Hospital das Clínicas Faculdade de Medicina Universidade de São Paulo Hospital Estadual Jayme Santos Neves Hospital SOS Cárdio Hospital da Luz Vila Mariana Hospital Maternidade e Pronto-Socorro Santa Luci Santa Casa de Misericórdia de Vitória da Conquista Santa Casa de Misericórdia de Porto Alegre Hospital São Francisco de Assis Hospital Memorial São José Hospital Regional de Jundiaí Hospital Universitário Faculdade de Medicina de Jundiaí Hospital Regional de Presidente Prudente Santa Casa de Misericórdia de Assis Hospital de Clínicas Gaspar Vianna Hospital do Coração do Brasil Hospital Hélio Anjos Ortiz Hospital Vila da Serra Hospital Nereu Ramos Hospital Santa Maria Intensibarra Santa Casa de Misericórdia de Santo Amaro Santa Casa de Caridade de Don Pedrito Santa Casa de Misericórdia de Santana do Livramento Hospital Unimed de Macaé Hospital Municipal Pedro II Hospital Federal dos Servidores do Estado Hospital São Mateus Hospital IBR Hospital Uniclinic Santa Casa de Misericórdia de Paraguaçu Paulista Associação Hospitalar Beneficente São Vicente de Paulo Hospital do Servidor Público Municipal de São Paulo Hospital Santa Isabel Hospital Municipal Dr Jose Soares Hungria Hospital Fernandes Távora Hospital Distrital Evandro Ayres de Moura Hospital Saúde da Mulher Hospital Estadual de Urgência e Emergência de Vitória Samur Hospital e Pronto-Socorro 28 de Agosto Hospital Assunção Hospital Universitário de Santa Maria Hospital Universitário Cajuru Instituto do Câncer do Estado de São Paulo Hospital Unimed de Limeira Hospital Amecor Santa Casa de Caridade de Diamantina Hospital das Clínicas Faculdade Ribeirão Preto Universidade de São Paulo HCor - Hospital do Coração Hospital Goiânia Leste Hospital Ortopédico Hospital Santa Maria Hospital Municipal Dr. Munir Rafful Hospital Jardim Amália Hospital Madre Regina Prottman Hospital Universitário São Francisco de Paula Universidade Católica de Pelotas Hospital São Joao de Deus Hospital Nossa Senhora Monte Serrat Hospital Unimed Salto Hospital Moinhos de Vento Hospital Geral de Vitória da Conquista Hospital Marcelino Champagnat Hospital São Lucas Pontifícia Universidade Católica do Rio Grande do Sul Hospital Universitário Universidade Federal da Grande Dourados Hospital Português Hospital Brigadeiro Hospital Regional de Sousa Hospital das Clínicas Universidade Federal do Espírito Santo Santa Casa de Misericórdia de Ribeirão Preto Hospital Universitário Lauro Wanderley Santa Casa de Belo Horizonte Hospital Adventista de Manaus Santa Casa Maringá Universidade Estadual Maringá Hospital Total Cor Hospital Universitário Universidade de Santa Cruz do Sul Hospital Dom Hélder Hospital das Clínicas de Porto Alegre Universidade Federal do Rio Grande do Sul Hospital Anis Rassi Instituto de Infectologia Emílio Ribas II Hospital Unimed Rio de Janeiro Hospital Alemão Oswaldo Cruz Hospital Samaritano Rio de Janeiro São Bernardo Apart Hospital Hospital Nossa Senhora dos Prazeres Hospital Unimed ABC Hospital Municipal de Paracatu Hospital Municipal Padre Germano Lauck Hospital Santa Helena Hospital Santa Izabel Santa Casa de Misericórdia de São Paulo Hospital Tereza Ramos Hospital Alvorada Taguatinga Hospital Maternidade São José Hospital Universitário Ciências Médicas Fundação Educacional Lucas Machado Santa Casa de Belém do Pará Instituto Nacional de Cardiologia Hospital Novo Atibaia BP - A Beneficência Portuguesa de São Paulo Hospital Universitário Maria Aparecida Pedrossian Universidade Federal de Mato Grosso do Sul Hospital do Servidor Público Estadual “Francisco Morato de Oliveira” Hospital Norte D’Or Hospital Estadual Ipiranga Hospital Universitário de Maringá Universidade Estadual de Maringá Albert Sabin Hospital e Maternidade Casa de Caridade de Carangola Irmandade de Misericórdia de Guaxupé Disciplina de Emergências Clínicas Universidade Estadual de Campinas Hospital São Lucas Fundação Pio XII- Hospital de Câncer de Barretos Clínica Campo Grande Hospital das Clínicas Universidade Federal de Minas Gerais Casa de Saúde Santa Lúcia Hospital Regional de Itapetininga São Camilo Santa Casa de Angra dos Reis Grupo Hospitalar Nossa Senhora da Conceição Irmandade Misericórdia Hospital Santa Casa de Monte Alto Hospital São Marcos Hospital Unimed de Manaus Hospital Universitário Getúlio Vargas Universidade Federal do Amazonas Casa de Saúde Campinas Hospital e Maternidade Galileo Hospital das Clínicas Faculdade de Medicina de Botucatu Universidade Estadual “Júlio de Mesquita Filho” National Health and Medical Research Council: APP1039312

Clinical question What is the role of drugs in preventing covid-19? Why does this matter? There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. Recommendations The second version of this living guideline reiterates the previous strong recommendation against the use of hydroxychloroquine and includes a new conditional recommendation against the use of tixagevimab-cilgavimab in individuals who do not have covid-19. How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provides methodological support. A living systematic review with network analysis informs the recommendations. An international guideline development group (GDG) of content experts, clinicians, patients, an ethicist and methodologists produces recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Understanding the recommendations The living network meta-analysis informing this guideline included 12 trials (8379 participants) comparing hydroxychloroquine to standard care/placebo, and one trial (5197 participants) comparing tixagevimab-cilgavimab to standard care/placebo. When moving from evidence to the continued strong recommendation against the use of hydroxychloroquine, the GDG emphasised additional evidence suggesting no or little effect on mortality and hospital admission, and an increased risk of adverse effects. For the new conditional recommendation against the use of tixagevimab-cilgavimab, the GDG emphasised in vitro evidence reducing the applicability of available trial data. While trial results demonstrated modest reduction in the occurrence of laboratory confirmed symptomatic covid-19, lack of in vitro neutralisation of new SARS-CoV-2 sub-lineages was considered to have rendered these results obsolete. Updates This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. Readers note This is the second version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19 and living guidance regarding covid-19 related clinical management. When citing this article, please consider adding the update number and date of access for clarity.

Objective To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19). Design Randomised, open label trial. Setting Nine hospitals in Brazil, 8 May to 17 July 2020. Participants Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group. Interventions Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64). Main outcome measure The primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met. Results A total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab. Conclusions In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality. Trial registration ClinicalTrials.gov NCT04403685 .

Importance Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients. Objective To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19–associated ARDS. Design, Setting, and Participants Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients. Interventions Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148). Main Outcomes and Measures The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days. Results A total of 299 patients (mean [SD] age, 61 [14] years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38;P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, −1.16; 95% CI, −1.94 to −0.38;P= .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events. Conclusions and Relevance Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days. Trial Registration ClinicalTrials.gov Identifier:NCT04327401

The delivery of critical care is a major challenge for developing countries [1]. The inequity of access to an ICU bed, heterogeneous triage policies, a low staff/patient ratio and suboptimal adherence to evidence-based practices contribute to disproportionally high mortality of sepsis and acute respiratory distress syndrome in these countries [2,3,4,5]. In addition, limited step-down and specialized ward beds’ availability further widens the gap between critical and non-critical care inside hospitals. As the COVID-19 pandemic spreads through the world, developing countries are challenged with the surge of pneumonia cases where up to 30% of all hospitalized cases will require ICU admission [6]. In August 2020, Brazil is a hotspot of COVID-19 with more than 100,000 deaths. Other Latin American countries such as Mexico, Peru, Colombia, and Chile are also among the 10 countries with most cases worldwide. Several factors seem to have contributed to the dramatic progress of the epidemic in the country. Initial measures of social distancing were adopted at the beginning of the epidemic in several states. However, the lack of central coordination and, at a certain point, the denial of the pandemic by a populist government meant that more effective measures such as lockdown were not adopted whereas use of unproven therapies such as hydroxychloroquine was encouraged. Also, the low availability of tests and progression towards the interior and peripheries of large cities made the epidemic hard to control causing overwhelming hospitals and ICUs.

Submitted by DSpace Unilasalle (dspace@unilasalle.edu.br) on 2021-07-30T17:29:03Z No. of bitstreams: 1 Hydroxychloroquine with or without Azithromycin_NEJM.pdf: 657905 bytes, checksum: abd774ed0fca84d1bf82fc915cc48491 (MD5) Made available in DSpace on 2021-07-30T17:29:03Z (GMT). No. of bitstreams: 1 Hydroxychloroquine with or without Azithromycin_NEJM.pdf: 657905 bytes, checksum: abd774ed0fca84d1bf82fc915cc48491 (MD5) Previous issue date: 2020 BACKGROUND Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited. METHODS We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed. RESULTS A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P=1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P=1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. CONCLUSIONS Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.)

Introduction Hydroxychloroquine and its combination with azithromycin have been suggested to improve viral clearance in patients with COVID-19, but its effect on clinical outcomes remains uncertain. Methods and analysis We describe the rationale and design of an open-label pragmatic multicentre randomised (concealed) clinical trial of 7 days of hydroxychloroquine (400 mg BID) plus azithromycin (500 mg once daily), hydroxychloroquine 400 mg BID, or standard of care for moderately severe hospitalised patients with suspected or confirmed COVID-19 (in-patients with up to 4L/minute oxygen supply through nasal catheter). Patients are randomised in around 50 recruiting sites and we plan to enrol 630 patients with COVID-19. The primary endpoint is a 7-level ordinal scale measured at 15-days: 1)not hospitalised, without limitations on activities; 2)not hospitalised, with limitations on activities; 3)hospitalised, not using supplementary oxygen; 4)hospitalised, using supplementary oxygen; 5)hospitalised, using high-flow nasal cannula or non-invasive ventilation; 6)hospitalised, on mechanical ventilation; 7)death. Secondary endpoints are the ordinal scale at 7 days, need for mechanical ventilation and rescue therapies during 15 days, need of high-flow nasal cannula or non-invasive ventilation during 15 days, length of hospital stay, in-hospital mortality, thromboembolic events, occurrence of acute kidney injury, and number of days free of respiratory support at 15 days. Secondary safety outcomes include prolongation of QT interval on electrocardiogram, ventricular arrhythmias, and liver toxicity. The main analysis will consider all patients with confirmed COVID-19 in the groups they were randomly assigned. Ethics and dissemination This study has been approved by Brazil’s National Ethic Committee (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, as well as presented and reported to local health agencies. ClinicalTrials.gov identifier NCT04322123 Strengths and limitations of this study Pragmatic randomised controlled trial of 7 days of hydroxychloroquine plus azithromycin, hydroxychloroquine or standard of care for moderately severe in-patients with suspected or confirmed COVID-19 Multicentre: around 50 recruiting sites in Brazil with planned enrolment of 630 patients (1:1:1) The primary endpoint is a 7-level ordinal scale ([1] not hospitalised, without limitations on activities; [2] not hospitalised, with limitations on activities; [3] hospitalised, not using supplementary oxygen; [4] hospitalised, using supplementary oxygen; [5] hospitalised, using high-flow nasal cannula or non-invasive ventilation; [6] hospitalised, on mechanical ventilation; [7] death) measured at 15 days. Open label design (no placebo)

Submitted by DSpace Unilasalle (dspace@unilasalle.edu.br) on 2021-09-10T23:12:37Z No. of bitstreams: 1 The role of steroids in severe CAP.pdf: 232136 bytes, checksum: fc65c7581dcec5c29d337042cb681d4c (MD5) Made available in DSpace on 2021-09-10T23:12:37Z (GMT). No. of bitstreams: 1 The role of steroids in severe CAP.pdf: 232136 bytes, checksum: fc65c7581dcec5c29d337042cb681d4c (MD5) Previous issue date: 2020 Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality despite adequate antibiotic therapy. It is the single most common cause of infection-related mortality in the United States. An exaggerated host inflammatory response can potentially be harmful to both the lung and host, and has been associated with treatment failure and mortality. Modulation of inflammatory response may, therefore, be theoretically beneficial. The anti–inflammatory and immunosuppressive effects of steroids seem an attractive therapeutic option in severe CAP patients. Available datapoint to overall shorter time to clinical stability and decreased length-of-stay in CAP patients, with a potential mortality benefit in severe CAP. The level of evidence is, however, low to moderate regarding mortality due to high heterogeneity and insufficient power of data. Furthermore, steroids were deleterious in influenza pneumonia and in patients with pneumococcal pneumonia data suggest a lack of efficacy and potential harm. Both European and American guidelines recommend not using corticosteroids in CAP. Patients who might benefit and those that can be harmed from steroids remain to be clearly identified, as does the ideal steroid for CAP patients, based on pharmacokinetic and pharmacodynamic properties. It is essential for future studies to avoid the same methodological bias present in the available data so that high-quality evidence on the true role of steroids in CAP can be provided.

Rationale: Although proposed as a clinical prompt to sepsis based on predictive validity for mortality, the Quick Sepsis-related Organ Failure Assessment (qSOFA) score is often used as a screening tool, which requires high sensitivity.Objectives: To assess the predictive accuracy of qSOFA for mortality in Brazil, focusing on sensitivity.Methods: We prospectively collected data from two cohorts of emergency department and ward patients. Cohort 1 included patients with suspected infection but without organ dysfunction or sepsis (22 hospitals: 3 public and 19 private). Cohort 2 included patients with sepsis (54 hospitals: 24 public and 28 private). The primary outcome was in-hospital mortality. The predictive accuracy of qSOFA was examined considering only the worst values before the suspicion of infection or sepsis.Measurements and Main Results: Cohort 1 contained 5,460 patients (mortality rate, 14.0%; 95% confidence interval [CI], 13.1-15.0), among whom 78.3% had a qSOFA score less than or equal to 1 (mortality rate, 8.3%; 95% CI, 7.5-9.1). The sensitivity of a qSOFA score greater than or equal to 2 for predicting mortality was 53.9% and the 95% CI was 50.3 to 57.5. The sensitivity was higher for a qSOFA greater than or equal to 1 (84.9%; 95% CI, 82.1-87.3), a qSOFA score greater than or equal to 1 or lactate greater than 2 mmol/L (91.3%; 95% CI, 89.0-93.2), and systemic inflammatory response syndrome plus organ dysfunction (68.7%; 95% CI, 65.2-71.9). Cohort 2 contained 4,711 patients, among whom 62.3% had a qSOFA score less than or equal to 1 (mortality rate, 17.3%; 95% CI, 15.9-18.7), whereas in public hospitals the mortality rate was 39.3% (95% CI, 35.5-43.3).Conclusions: A qSOFA score greater than or equal to 2 has low sensitivity for predicting death in patients with suspected infection in a developing country. Using a qSOFA score greater than or equal to 2 as a screening tool for sepsis may miss patients who ultimately die. Using a qSOFA score greater than or equal to 1 or adding lactate to a qSOFA score greater than or equal to 1 may improve sensitivity.Clinical trial registered with www.clinicaltrials.gov (NCT03158493).

Background The routine use of empiric combination therapy with aminoglycosides during critical illness is associated with uncertain benefit and increased risk of acute kidney injury. This study aimed to assess the benefits of aminoglycosides in immunocompromised patients with suspected bacterial pneumonia and sepsis. Methods Secondary analysis of a prospective multicenter study. Adult immunocompromised patients with suspected bacterial pneumonia and sepsis or septic shock were included. Primary outcome was hospital mortality. Secondary outcomes were needed for renal replacement therapy (RRT). Mortality was also assessed in neutropenic patients and in those with confirmed bacterial pneumonia. Results were further analyzed in a cohort matched on risk of receiving aminoglycosides combination. Results Five hundred thirty-five patients were included in this analysis, of whom 187 (35%) received aminoglycosides in addition to another antibiotic effective against gram-negative bacteria. Overall hospital mortality was 59.6% (58.3% vs. 60.3% in patients receiving and not receiving combination therapy; P = 0.71). Lack of association between mortality and aminoglycosides was confirmed after adjustment for confounders and center effect (adjusted OR 1.14 [0.69-1.89]) and in a propensity matched cohort (adjusted OR = 0.89 [0.49-1.61]). No association was found between aminoglycosides and need for RRT (adjusted OR = 0.83 [0.49-1.39], P = 0.477), nor between aminoglycoside use and outcome in neutropenic patients or in patients with confirmed bacterial pneumonia (adjusted OR 0.66 [0.23-1.85] and 1.25 [0.61-2.57], respectively). Conclusion Aminoglycoside combination therapy was not associated with hospital mortality or need for renal replacement therapy in immunocompromised patients with pulmonary sepsis.

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.

To report the statistical analysis plan (first version) for the Balanced Solutions versus Saline in Intensive Care Study (BaSICS).BaSICS is a multicenter factorial randomized controlled trial that will assess the effects of Plasma-Lyte 148 versus 0.9% saline as the fluid of choice in critically ill patients, as well as the effects of a slow (333mL/h) versus rapid (999mL/h) infusion speed during fluid challenges, on important patient outcomes. The fluid type will be blinded for investigators, patients and the analyses. No blinding will be possible for the infusion speed for the investigators, but all analyses will be kept blinded during the analysis procedure.BaSICS will have 90-day mortality as its primary endpoint, which will be tested using mixed-effects Cox proportional hazard models, considering sites as a random variable (frailty models) adjusted for age, organ dysfunction and admission type. Important secondary endpoints include renal replacement therapy up to 90 days, acute renal failure, organ dysfunction at days 3 and 7, and mechanical ventilation-free days within 28 days.This manuscript provides details on the first version of the statistical analysis plan for the BaSICS trial and will guide the study's analysis when follow-up is finished.Relatar o plano de análise estatística (primeira versão) para o estudo Balanced Solutions versus Saline in Intensive Care Study (BaSICS).O estudo BaSICS é um ensaio multicêntrico fatorial e randomizado que avaliará os efeitos da administração dos fluidos Plasma-Lyte 148 em comparação com solução salina 0,9% como fluido de escolha em pacientes críticos, assim como os efeitos de uma velocidade de infusão lenta (333mL/hora) em comparação com uma velocidade de infusão rápida (999mL/hora) durante desafios com volume, em importantes desfechos do paciente. O tipo de fluido será mantido cego para os investigadores, pacientes e nas análises. Não será possível, entretanto, ocultar dos investigadores a velocidade de infusão, mas os procedimentos de análise serão mantidos cegos quanto a esse aspecto.O estudo BaSICS terá como parâmetro primário a mortalidade em 90 dias, que será testada com utilização de modelos de risco proporcional de Cox de efeitos mistos, considerando os centros de estudo como variável randômica (modelos de fragilidade) ajustada por idade, disfunção de órgãos e tipo de admissão. Os parâmetros secundários importantes incluem terapia de substituição renal até 90 dias, insuficiência renal aguda, disfunção de órgãos nos dias 3 e 7 e dias sem ventilação mecânica em 28 dias.Este artigo fornece detalhes referentes à primeira versão do plano de análise estatística para o estudo BaSICS e orientará a análise do estudo após a conclusão do seguimento.

Additional file 2. Declaration of competing interests.

Additional file 1. Working group and contributions of each participant.

Additional file 3. Checklist for clinical management of brain-dead potential organ donor.

Context: Determining which patients are ready for discharge from an Intensive Care Unit (ICU) presents a huge challenge, as ICU readmissions are associated with several negative outcomes such as increased mortality, length of stay, and cost compared to those patients who are not readmitted during their hospital stay. For these reasons, enhancing risk stratification in order to identify patients at high risk of clinical deterioration might benefit and improve the outcomes of critically ill hospitalized patients. Existing work on predicting ICU readmissions relies on information available at the time of discharge, however, in order to be more useful and to prevent complications, predictions need to be made earlier. Goals: In this work, we investigate the hypothesis that the basal characteristics and information collected at the time of the patient’s admission can enable accurate predictions of ICU readmission. Materials and Methods: We analyzed an anonymized dataset of 11,805 adult patients from three ICUs in a Brazilian university hospital. After excluding 1879 patients who died during their first ICU admission, our final dataset contained 9,926 patients. Of these, 658 patients (6.6%) had been readmitted to the ICU. The original dataset had 185 attributes, including demographics, length of stay prior to ICU admission, comorbidities, severity indexes, interventions, organ support care during ICU stay and laboratory results. The problem of predicting ICU readmissions was modeled as a binary classification task. We tested eight classification algorithms (including Bayesian algorithms, decision trees, rule-based, and ensemble methods) over different sets of attributes and evaluated their results based on six metrics. Results: Predictions made solely based on the attributes collected at the admission are highly accurate. Their quality in terms of prediction is no different from predictions made using the complete set of attributes for our dataset and for a subset of attributes selected by a feature selection method. Furthermore, our AUROC score of 0.91 (95% CI [0.89,0.92]) is higher than existing results published in the literature for other datasets. Discussion and Conclusion: The results confirm our hypothesis. Our findings suggest that early markers can be used to anticipate patients at high risk of clinical deterioration after ICU discharge.