Antibiotic stewardship and nosocomial infection prevention in critically ill patients: a quality improvement program.

OBJECTIVE: The objective of this study was to evaluate the impact of the implementation of a bundle of interventions through a "Program for Antibiotic Management and Nosocomial Infection Prevention" in the intensive care unit on antibiotic and devices use and healthcare-associated infections. METHODS: This was a quasi-experimental study of consecutive series of cases in periods before and after the establishment of protocols and checklists for the use of antibiotics as well as other measures to prevent healthcare-associated infection as part of a quality improvement program. Antimicrobial consumption was assessed by the defined daily dose. RESULTS: A total of 1,056 and 1,323 admissions in the pre-intervention and post-intervention phases, respectively, were evaluated. The defined daily dose per 100 patient-day decreased from 89±8 to 77±11 (p=0.100), with a decrease in carbapenems, glycopeptides, polymyxins, penicillins, and cephalosporins. The rates of ventilator and central venous catheter use decreased from 52.8 to 44.1% and from 76 to 70%, respectively. The rates of healthcare-associated infection decreased from 19.2 to 15.5%. CONCLUSION: Quality improvement actions focused primarily on antimicrobial management and prevention of healthcare-associated infection are feasible and have the potential to decrease antibiotic use and healthcare-associated infection rates.

Efficacy of oral 20-hydroxyecdysone (BIO101), a MAS receptor activator, in adults with severe COVID-19 (COVA): a randomized, placebo-controlled, phase 2/3 trial.

Background: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19. Methods: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728). Findings: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group. Interpretation: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19. Funding: Biophytis.

Measurements of I-FABP and citrulline in the postoperative period of non-cardiac surgeries with gastrointestinal complications: A prospective cohort observational study.

BACKGROUND: Acute Gastrointestinal Injury (AGI) is associated with adverse clinical outcomes, including increased mortality. We aimed to investigate the potential of citrulline and intestinal fatty acid binding protein (I-FABP) as biomarkers for early AGI diagnosis and predicting outcomes in surgical patients. METHODS: Prospective cohort study involving patients who underwent non-cardiac surgeries and were admitted to Intensive Care Units. AGI diagnosis was based on specific criteria, and severity was categorised following established guidelines. Statistical analyses were performed to assess the diagnostic accuracy of the biomarkers and their association with outcomes, P significant when <0.05. RESULTS: AGI was identified in 40.3% of patients with varying severity. Mortality rates were significantly higher in the AGI group in the ICU (19.4% vs. 0%, p = 0.001) and hospital (22.6% vs. 2.17%, p = 0.003). Urinary I-FABP levels on days 3 and 7 showed reasonable and good accuracy for AGI diagnosis (AUC 0.732 and 0.813, respectively). Urinary I-FABP levels on days 2 and 3 accurately predict sepsis. Urinary citrulline levels on day one predicted mortality (AUC 0.87) furthermore urinary I-FABP levels on day 2 showed reasonable accuracy (sensitivity 83.3%, specificity 92.4%). CONCLUSION: Urinary I-FABP and citrulline levels are promising diagnostic and prognostic markers in ICU patients following non-cardiac surgeries.

Choosing immunomodulating therapies for the treatment of COVID-19: recommendations based on placebo-controlled trial evidence.

BACKGROUND: Immunomodulatory therapy has been extensively studied in randomized clinical trials for the treatment of patients hospitalized for COVID-19 with inconsistent findings. Guideline committees, reviewing the same clinical trial data, have generated different recommendations for immunomodulatory therapy. OBJECTIVES: We hypothesize that trial design differences, specifically whether the study utilized an open-label or placebo-controlled design, accounted for the inconsistent mortality effects reported in clinical trials of immunomodulator therapies for COVID-19. SOURCES: We reviewed COVID-19 treatment guidelines (World Health Organization [WHO], Infectious Diseases Society of America [IDSA] and The National Institutes of Health [NIH]) and identified the meta-analyses associated with glucocorticoids, IL-6 inhibitors, JAK kinase inhibitors, and complement C5a inhibitors that were available to the guideline authors at the time recommendations were either made or updated. CONTENT: We identified a meta-analysis for each of the immunomodulator classes that are included in current COVID-19 treatment guidelines: glucocorticoids [WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA. 2021;326:499-518] (cited 419), IL-6 antagonists [WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA. 2021;326:499-518] (cited 419), JAK inhibitors [Kramer A, Prinz C, Fichtner F, Fischer AL, Thieme V, Grundeis F, et al. Janus kinase inhibitors for the treatment of COVID-19. Cochrane Database Syst Rev. 2022;6:CD015209] (cited 34), and complement C5a inhibitors [Tsai CL, Lai CC, Chen CY, Lee HS. The efficacy and safety of complement C5a inhibitors for patients with severe COVID-19: A systematic review and meta-analysis. Expert Rev Anti Infect Ther. 2023;21:77-86] (cited 1). Using the same randomized clinical trials, we evaluated the four meta-analyses accounting for trial design: placebo-controlled or open-label. Glucocorticoids (Risk Ratio [RR] 0.91 [95% CI, 0.49-1.69]), IL-6 inhibitors sarilumab (RR 1.17 [95% CI, 0.96-01.43]), and tocilizumab (RR 0.95 [95% CI, 0.76-1.19]) did not reduce mortality in placebo-controlled trials, whereas baricitinib did confer a large survival benefit (RR 0.65 [95% CI, 0.52-0.81]). The complement C5a inhibitor, vilobelimab, also reduced mortality in a single placebo-controlled trial (RR 0.76 [95% CI, 0.57-1.0]). IMPLICATIONS: Placebo-controlled trial evidence indicates that baricitinib should be the first choice immunomodulator for patients hospitalized for COVID-19 who require any form of oxygen support-low- or high-flow oxygen, non-invasive or invasive ventilation. Vilobelimab warrants study in a large placebo-controlled trial. Treatment guidelines for future pandemics should prioritize the results of placebo-controlled trials.

Improving perioperative care in low-resource settings with goal-directed therapy: a narrative review.

Perioperative Goal-Directed Therapy (PGDT) has significantly showed to decrease complications and risk of death in high-risk patients according to numerous meta-analyses. The main goal of PGDT is to individualize the therapy with fluids, inotropes, and vasopressors, during and after surgery, according to patients' needs in order to prevent organic dysfunction development. In this opinion paper we aimed to focus a discussion on possible alternatives to invasive hemodynamic monitoring in low resource settings.

The II Brazilian Guidelines for the pharmacological treatment of patients hospitalized with COVID-19 Joint Guidelines of the Associação Brasileira de Medicina de Emergência, Associação de Medicina Intensiva Brasileira, Associação Médica Brasileira, Sociedade Brasileira de Angiologia e Cirurgia Vascular, Sociedade Brasileira de Infectologia, Sociedade Brasileira de Pneumologia e Tisiologia and Sociedade Brasileira de Reumatologia.

OBJECTIVE: To update the recommendations to support decisions regarding the pharmacological treatment of patients hospitalized with COVID-19 in Brazil. METHODS: Experts, including representatives of the Ministry of Health and methodologists, created this guideline. The method used for the rapid development of guidelines was based on the adoption and/or adaptation of existing international guidelines (GRADE ADOLOPMENT) and supported by the e-COVID-19 RecMap platform. The quality of the evidence and the preparation of the recommendations followed the GRADE method. RESULTS: Twenty-one recommendations were generated, including strong recommendations for the use of corticosteroids in patients using supplemental oxygen and conditional recommendations for the use of tocilizumab and baricitinib for patients on supplemental oxygen or on noninvasive ventilation and anticoagulants to prevent thromboembolism. Due to suspension of use authorization, it was not possible to make recommendations regarding the use of casirivimab + imdevimab. Strong recommendations against the use of azithromycin in patients without suspected bacterial infection, hydroxychloroquine, convalescent plasma, colchicine, and lopinavir + ritonavir and conditional recommendations against the use of ivermectin and remdesivir were made. CONCLUSION: New recommendations for the treatment of hospitalized patients with COVID-19 were generated, such as those for tocilizumab and baricitinib. Corticosteroids and prophylaxis for thromboembolism are still recommended, the latter with conditional recommendation. Several drugs were considered ineffective and should not be used to provide the best treatment according to the principles of evidence-based medicine and to promote resource economy.

Dapagliflozin in patients with critical illness: rationale and design of the DEFENDER study.

BACKGROUND: Critical illness is a major ongoing health care burden worldwide and is associated with high mortality rates. Sodium-glucose cotransporter-2 inhibitors have consistently shown benefits in cardiovascular and renal outcomes. The effects of sodium-glucose cotransporter-2 inhibitors in acute illness have not been properly investigated. METHODS: DEFENDER is an investigator-initiated, multicenter, randomized, open-label trial designed to evaluate the efficacy and safety of dapagliflozin in 500 adult participants with acute organ dysfunction who are hospitalized in the intensive care unit. Eligible participants will be randomized 1:1 to receive dapagliflozin 10mg plus standard of care for up to 14 days or standard of care alone. The primary outcome is a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and intensive care unit length of stay, up to 28 days. Safety will be strictly monitored throughout the study. CONCLUSION: DEFENDER is the first study designed to investigate the use of a sodium-glucose cotransporter-2 inhibitor in general intensive care unit patients with acute organ dysfunction. It will provide relevant information on the use of drugs of this promising class in critically ill patients. CLINICALTRIALS.GOV REGISTRY: NCT05558098.

Trends in perioperative practices of high-risk surgical patients over a 10-year interval.

INTRODUCTION: In Brazil, data show an important decrease in morbi-mortality of high-risk surgical patients over a 10-year high. The objective of this post-hoc study was to evaluate the mechanism explaining this trend in high-risk surgical patients admitted to Brazilian ICUs in two large Brazilian multicenter cohort studies performed 10 years apart. METHODS: The patients included in the 2 cohorts studies published in 2008 and 2018 were compared after a (1:1) propensity score matching. Patients included were adults who underwent surgeries and admitted to the ICU afterwards. RESULTS: After matching, 704 patients were analyzed. Compared to the 2018 cohort, 2008 cohort had more postoperative infections (OR 13.4; 95%CI 6.1-29.3) and cardiovascular complications (OR 1.5; 95%CI 1.0-2.2), as well as a lower survival ICU stay (HR = 2.39, 95% CI: 1.36-4.20) and hospital stay (HR = 1.64, 95% CI: 1.03-2.62). In addition, by verifying factors strongly associated with hospital mortality, it was found that the risk of death correlated with higher intraoperative fluid balance (OR = 1.03, 95% CI 1.01-1.06), higher creatinine (OR = 1.31, 95% CI 1.1-1.56), and intraoperative blood transfusion (OR = 2.32, 95% CI 1.35-4.0). By increasing the mean arterial pressure, according to the limits of sample values from 43 mmHg to 118 mmHg, the risk of death decreased (OR = 0.97, 95% CI 0.95-0.98). The 2008 cohort had higher fluid balance, postoperative creatinine, and volume of intraoperative blood transfused and lower mean blood pressure at ICU admission and temperature at the end of surgery. CONCLUSION: In this sample of ICUs in Brazil, high-risk surgical patients still have a high rate of complications, but with improvement over a period of 10 years. There were changes in the management of these patients over time.

Dapagliflozin in patients with critical illness: rationale and design of the DEFENDER study / Dapagliflozina em pacientes com doença crítica: justificativa e desenho do estudo DEFENDER

ABSTRACT Background: Critical illness is a major ongoing health care burden worldwide and is associated with high mortality rates. Sodium-glucose cotransporter-2 inhibitors have consistently shown benefits in cardiovascular and renal outcomes. The effects of sodium-glucose cotransporter-2 inhibitors in acute illness have not been properly investigated. Methods: DEFENDER is an investigator-initiated, multicenter, randomized, open-label trial designed to evaluate the efficacy and safety of dapagliflozin in 500 adult participants with acute organ dysfunction who are hospitalized in the intensive care unit. Eligible participants will be randomized 1:1 to receive dapagliflozin 10mg plus standard of care for up to 14 days or standard of care alone. The primary outcome is a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and intensive care unit length of stay, up to 28 days. Safety will be strictly monitored throughout the study. Conclusion: DEFENDER is the first study designed to investigate the use of a sodium-glucose cotransporter-2 inhibitor in general intensive care unit patients with acute organ dysfunction. It will provide relevant information on the use of drugs of this promising class in critically ill patients. ClinicalTrials.gov registry: NCT05558098

RESUMO Antecedentes: A doença crítica é um importante ônus permanente da assistência médica em todo o mundo e está associada a altas taxas de mortalidade. Os inibidores do cotransportador de sódio-glicose do tipo 2 têm demonstrado consistentemente benefícios nos desfechos cardiovasculares e renais. Os efeitos dos inibidores do cotransportador de sódio-glicose do tipo 2 em doenças agudas ainda não foram devidamente investigados. Métodos: O DEFENDER é um estudo de iniciativa do investigador, multicêntrico, randomizado, aberto, desenhado para avaliar a eficácia e a segurança da dapagliflozina em 500 participantes adultos com disfunção orgânica aguda hospitalizados na unidade de terapia intensiva. Os participantes aptos serão randomizados 1:1 para receber 10mg de dapagliflozina e o tratamento padrão por até 14 dias ou apenas o tratamento padrão. O desfecho primário é um composto hierárquico de mortalidade hospitalar, início de terapia renal substitutiva e tempo de internação na unidade de terapia intensiva, até 28 dias. O monitoramento da segurança será rigoroso durante todo o estudo. Conclusão: O DEFENDER é o primeiro estudo desenvolvido para investigar o uso de um inibidor do cotransportador de sódio-glicose do tipo 2 em pacientes de unidade de terapia intensiva geral com disfunção orgânica aguda. O estudo fornecerá informações relevantes sobre o uso de medicamentos dessa classe promissora em pacientes críticos. Registro ClincalTrials.gov: NCT05558098

The II Brazilian Guidelines for the pharmacological treatment of patients hospitalized with COVID-19 Joint Guidelines of the Associação Brasileira de Medicina de Emergência, Associação de Medicina Intensiva Brasileira, Associação Médica Brasileira, Sociedade Brasileira de Angiologia e Cirurgia Vascular, Sociedade Brasileira de Infectologia, Sociedade Brasileira de Pneumologia e Tisiologia and Sociedade Brasileira de Reumatologia / II Diretrizes Brasileiras para o tratamento farmacológico de pacientes hospitalizados com COVID-19 Diretriz conjunta da Associação Brasileira de Medicina de Emergência, Associação de Medicina Intensiva Brasileira, Associação Médica Brasileira, Sociedade Brasileira de Angiologia e Cirurgia Vascular, Sociedade Brasileira de Infectologia, Sociedade Brasileira de Pneumologia e Tisiologia e Sociedade Brasileira de Reumatologia

ABSTRACT Objective: To update the recommendations to support decisions regarding the pharmacological treatment of patients hospitalized with COVID-19 in Brazil. Methods: Experts, including representatives of the Ministry of Health and methodologists, created this guideline. The method used for the rapid development of guidelines was based on the adoption and/or adaptation of existing international guidelines (GRADE ADOLOPMENT) and supported by the e-COVID-19 RecMap platform. The quality of the evidence and the preparation of the recommendations followed the GRADE method. Results: Twenty-one recommendations were generated, including strong recommendations for the use of corticosteroids in patients using supplemental oxygen and conditional recommendations for the use of tocilizumab and baricitinib for patients on supplemental oxygen or on noninvasive ventilation and anticoagulants to prevent thromboembolism. Due to suspension of use authorization, it was not possible to make recommendations regarding the use of casirivimab + imdevimab. Strong recommendations against the use of azithromycin in patients without suspected bacterial infection, hydroxychloroquine, convalescent plasma, colchicine, and lopinavir + ritonavir and conditional recommendations against the use of ivermectin and remdesivir were made. Conclusion: New recommendations for the treatment of hospitalized patients with COVID-19 were generated, such as those for tocilizumab and baricitinib. Corticosteroids and prophylaxis for thromboembolism are still recommended, the latter with conditional recommendation. Several drugs were considered ineffective and should not be used to provide the best treatment according to the principles of evidence-based medicine and to promote resource economy.

RESUMO Objetivo: Atualizar as recomendações para embasar as decisões para o tratamento farmacológico de pacientes hospitalizados com COVID-19 no Brasil. Métodos: A elaboração desta diretriz foi feita por especialistas, incluindo representantes do Ministério da Saúde e metodologistas. O método utilizado para o desenvolvimento rápido de diretrizes baseou-se na adoção e/ou adaptação de diretrizes internacionais existentes (GRADE ADOLOPMENT) e contou com o apoio da plataforma e-COVID-19 RecMap. A qualidade das evidências e a elaboração das recomendações seguiram o método GRADE. Resultados: Chegaram-se a 21 recomendações, incluindo recomendações fortes quanto ao uso de corticosteroides em pacientes em uso de oxigênio suplementar e recomendações condicionais para o uso de tocilizumabe e baricitinibe, em pacientes com oxigênio suplementar ou ventilação não invasiva, e de anticoagulantes, para prevenção de tromboembolismo. Devido à suspensão da autorização de uso, não foi possível fazer recomendações para o tratamento com casirivimabe + imdevimabe. Foram feitas recomendações fortes contra o uso de azitromicina em pacientes sem suspeita de infecção bacteriana, hidroxicloroquina, plasma convalescente, colchicina e lopinavir + ritonavir, além de recomendações condicionais contra o uso de ivermectina e rendesivir. Conclusão: Foram criadas novas recomendações para o tratamento de pacientes hospitalizados com COVID-19, como as recomendações de tocilizumabe e baricitinibe. Ainda são recomendados corticosteroides e profilaxia contra tromboembolismo, esta em caráter condicional. Vários medicamentos foram considerados ineficazes e não devem ser usados, no intuito de proporcionar o melhor tratamento segundo os princípios da medicina baseada em evidências e promover a economia de recursos.

Diagnostic accuracy of a set of clinical and radiological criteria for screening of COVID-19 using RT-PCR as the reference standard.

BACKGROUND: The gold-standard method for establishing a microbiological diagnosis of COVID-19 is reverse-transcriptase polymerase chain reaction (RT-PCR). This study aimed to evaluate the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a set of clinical-radiological criteria for COVID-19 screening in patients with severe acute respiratory failure (SARF) admitted to intensive care units (ICUs), using reverse-transcriptase polymerase chain reaction (RT-PCR) as the reference standard. METHODS: Diagnostic accuracy study including a historical cohort of 1009 patients consecutively admitted to ICUs across six hospitals in Curitiba (Brazil) from March to September, 2020. The sample was stratified into groups by the strength of suspicion for COVID-19 (strong versus weak) using parameters based on three clinical and radiological (chest computed tomography) criteria. The diagnosis of COVID-19 was confirmed by RT-PCR (referent). RESULTS: With respect to RT-PCR, the proposed criteria had 98.5% (95% confidence interval [95% CI] 97.5-99.5%) sensitivity, 70% (95% CI 65.8-74.2%) specificity, 85.5% (95% CI 83.4-87.7%) accuracy, PPV of 79.7% (95% CI 76.6-82.7%) and NPV of 97.6% (95% CI 95.9-99.2%). Similar performance was observed when evaluated in the subgroups of patients admitted with mild/moderate respiratory disfunction, and severe respiratory disfunction. CONCLUSION: The proposed set of clinical-radiological criteria were accurate in identifying patients with strong versus weak suspicion for COVID-19 and had high sensitivity and considerable specificity with respect to RT-PCR. These criteria may be useful for screening COVID-19 in patients presenting with SARF.

Prevalence, outcomes, and predictors of multidrug-resistant nosocomial lower respiratory tract infections among patients in an ICU.

OBJECTIVE: To determine the prevalence, outcomes, and predictors of multidrug-resistant nosocomial lower respiratory tract infections (LRTI) in patients in an ICU. METHODS: This was an observational cohort study involving patients with nosocomial LRTI (health care-associated pneumonia, hospital-acquired pneumonia, or ventilator-associated pneumonia). Data were prospectively collected between 2015 and 2019. The multidrug-resistant pathogens (MDRPs) identified in the isolates studied included resistant to extended-spectrum cephalosporin-resistant and carbapenem-resistant Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, and methicillin-resistant Staphylococcus aureus at microbiological diagnosis. RESULTS: During the study period, 267 patients in the ICU were diagnosed with LRTI, microbiological confirmation of LRTI having been obtained in 237. Of these, 146 (62%) had at least one MDRP isolate. Patients infected with MDRP were found to have poorer outcomes than patients infected with susceptible strains, such as prolonged mechanical ventilation (18.0 days vs. 12.0 days; p < 0.001), prolonged ICU length of stay (23.0 days vs.16.0 days; p < 0.001), and higher mortality (73% vs. 53%; p < 0.001) when compared with patients infected with susceptible strains. Hospital length of stay ≥ 5 days (OR = 3.20; 95% CI: 1.39-7.39; p = 0.005) and prolonged use vasoactive drugs (OR = 3.15; 95% CI: 1.42-7.01; p = 0.004) were independent predictors of LRTI caused by MDRPs (LRTI-MDRP). The presence of LRTI-MDRP was found to be an independent predictor of death (OR = 2.311; 95% CI: 1.091-4.894; p = 0.028). CONCLUSIONS: Prolonged use of vasoactive drugs and prolonged hospital length of stay were independent predictors of LRTI-MDRP in this population of critically ill patients with very poor outcomes.

Prevalence, outcomes, and predictors of multidrug-resistant nosocomial lower respiratory tract infections among patients in an ICU / Prevalência, desfechos e preditores de infecções nosocomiais do trato respiratório inferior multirresistentes em pacientes em uma UTI

ABSTRACT Objective: To determine the prevalence, outcomes, and predictors of multidrug-resistant nosocomial lower respiratory tract infections (LRTI) in patients in an ICU. Methods: This was an observational cohort study involving patients with nosocomial LRTI (health care-associated pneumonia, hospital-acquired pneumonia, or ventilator-associated pneumonia). Data were prospectively collected between 2015 and 2019. The multidrug-resistant pathogens (MDRPs) identified in the isolates studied included resistant to extended-spectrum cephalosporin-resistant and carbapenem-resistant Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, and methicillin-resistant Staphylococcus aureus at microbiological diagnosis. Results: During the study period, 267 patients in the ICU were diagnosed with LRTI, microbiological confirmation of LRTI having been obtained in 237. Of these, 146 (62%) had at least one MDRP isolate. Patients infected with MDRP were found to have poorer outcomes than patients infected with susceptible strains, such as prolonged mechanical ventilation (18.0 days vs. 12.0 days; p < 0.001), prolonged ICU length of stay (23.0 days vs.16.0 days; p < 0.001), and higher mortality (73% vs. 53%; p < 0.001) when compared with patients infected with susceptible strains. Hospital length of stay ≥ 5 days (OR = 3.20; 95% CI: 1.39-7.39; p = 0.005) and prolonged use vasoactive drugs (OR = 3.15; 95% CI: 1.42-7.01; p = 0.004) were independent predictors of LRTI caused by MDRPs (LRTI-MDRP). The presence of LRTI-MDRP was found to be an independent predictor of death (OR = 2.311; 95% CI: 1.091-4.894; p = 0.028). Conclusions: Prolonged use of vasoactive drugs and prolonged hospital length of stay were independent predictors of LRTI-MDRP in this population of critically ill patients with very poor outcomes.

RESUMO Objetivo: Determinar a prevalência, os desfechos e os preditores de infecções do trato respiratório inferior (ITRI) nosocomiais em pacientes em uma UTI. Métodos: Estudo observacional de coorte com pacientes com ITRI nosocomiais (pneumonia associada à assistência à saúde, pneumonia adquirida no hospital ou pneumonia associada à ventilação mecânica). Os dados foram coletados prospectivamente entre 2015 e 2019. Os patógenos multirresistentes (PMR) identificados nos isolados estudados incluíram Acinetobacter baumannii, Klebsiella pneumoniae e Pseudomonas aeruginosa resistentes a cefalosporinas de espectro estendido e carbapenêmicos, enterobactérias resistentes a carbapenêmicos e Staphylococcus aureus resistente à meticilina no diagnóstico microbiológico. Resultados: Durante o período do estudo, 267 pacientes internados na UTI foram diagnosticados com ITRI, 237 dos quais tiveram confirmação microbiológica de ITRI. Destes, 146 (62%) apresentaram pelo menos um isolado de PMR. Os pacientes infectados por PMR tiveram piores desfechos do que os infectados por cepas sensíveis, como ventilação mecânica prolongada (18,0 dias vs. 12,0 dias; p < 0,001), tempo prolongado de internação na UTI (23,0 dias vs. 16,0 dias; p < 0,001) e maior mortalidade (73% vs. 53%; p < 0,001). Tempo de internação hospitalar ≥ 5 dias (OR = 3,20; IC95%: 1,39-7,39; p = 0,005) e uso prolongado de drogas vasoativas (OR = 3,15; IC95%: 1,42-7,01; p = 0,004) foram preditores independentes de ITRI por PMR (ITRI-PMR). A presença de ITRI-PMR foi um preditor independente de óbito (OR = 2,311; IC95%: 1,091-4,894; p = 0,028). Conclusões: O uso prolongado de drogas vasoativas e o tempo prolongado de internação hospitalar foram preditores independentes de ITRI-PMR nesta população de pacientes críticos com desfechos muito ruins.

Lesão miocárdica e complicações cardiovasculares na COVID-19: estudo de coorte em pacientes graves e críticos / Myocardial injury and cardiovascular complications in COVID-19: a cohort study in severe and critical patients

RESUMO Objetivo: Caracterizar a lesão miocárdica e as complicações cardiovasculares e seus preditores em pacientes graves e críticos com COVID-19 admitidos à unidade de terapia intensiva. Métodos: Este foi um estudo de coorte observacional em pacientes graves e críticos com COVID-19 admitidos à unidade de terapia intensiva. A lesão miocárdica foi definida como níveis sanguíneos de troponina cardíaca acima do limite de referência superior ao percentil 99. Os eventos cardiovasculares considerados foram combinação de trombose venosa profunda, embolia pulmonar, acidente vascular cerebral, infarto do miocárdio, isquemia aguda de membros, isquemia mesentérica, insuficiência cardíaca e arritmia cardíaca. Regressão logística univariada e multivariada ou modelos de risco proporcional de Cox foram utilizados para determinar os preditores de lesão miocárdica. Resultados: Foram admitidos à unidade de terapia intensiva 567 pacientes graves e críticos com COVID-19, dos quais 273 (48,1%) apresentavam lesão miocárdica. Dos 374 pacientes críticos com COVID-19, 86,1% tinham lesão miocárdica, além de apresentarem mais disfunção orgânica e maior mortalidade aos 28 dias (56,6% versus 27,1%; p < 0,001). Foram preditores de lesão miocárdica idade avançada, hipertensão arterial e uso de imunomoduladores. Complicações cardiovasculares ocorreram em 19,9% dos pacientes graves e críticos com COVID-19 admitidos à unidade de terapia intensiva, e a maioria dos eventos deu-se em pacientes com lesão miocárdica (28,2% versus 12,2%; p < 0,001). A ocorrência de evento cardiovascular precoce durante internação em unidade de terapia intensiva estava associada à maior mortalidade aos 28 dias em comparação com eventos tardios ou inexistentes (57,1% versus 34,0% versus 41,8%; p = 0,01). Conclusão: Pacientes com formas graves e críticas de COVID-19 admitidos à unidade de terapia intensiva foram comumente diagnosticados com lesão miocárdica e complicações cardiovasculares, e ambas estavam associadas à maior mortalidade nesses pacientes.

ABSTRACT Objective: To characterize myocardial injury and cardiovascular complications and their predictors in severe and critical COVID-19 patients admitted to the intensive care unit. Methods: This was an observational cohort study of severe and critical COVID-19 patients admitted to the intensive care unit. Myocardial injury was defined as blood levels of cardiac troponin above the 99th percentile upper reference limit. Cardiovascular events considered were the composite of deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, acute limb ischemia, mesenteric ischemia, heart failure and arrhythmia. Univariate and multivariate logistic regression or Cox proportional hazard models were used to determine predictors of myocardial injury. Results: Of 567 patients with severe and critical COVID-19 admitted to the intensive care unit, 273 (48.1%) had myocardial injury. Of the 374 patients with critical COVID-19, 86.1% had myocardial injury, and also showed more organ dysfunction and higher 28-day mortality (56.6% versus 27.1%, p < 0.001). Advanced age, arterial hypertension and immune modulator use were predictors of myocardial injury. Cardiovascular complications occurred in 19.9% of patients with severe and critical COVID-19 admitted to the intensive care unit, with most events occurring in patients with myocardial injury (28.2% versus 12.2%, p < 0.001). The occurrence of an early cardiovascular event during intensive care unit stay was associated with higher 28-day mortality compared with late or no events (57.1% versus 34% versus 41.8%, p = 0.01). Conclusion: Myocardial injury and cardiovascular complications were commonly found in patients with severe and critical forms of COVID-19 admitted to the intensive care unit, and both were associated with increased mortality in these patients.

Surging ICU during COVID-19 pandemic: an overview.

PURPOSE OF REVIEW: The coronavirus disease 2019 (COVID-19) pandemic has posed great challenges to intensive care units (ICUs) across the globe. The objective of this review is to provide an overview on how ICU surging was managed during COVID-19 pandemic, with a special focus on papers published in the last 18 months. RECENT FINDINGS: From the onset of the COVID-19 pandemic, it was apparent that the biggest challenge was the inequity of access to an adequately equipped and staffed ICU bed. The first wave was overwhelming; large surge of patients required critical care, resources were limited and non-COVID-19 care processes were severely compromised. Various approaches were used to address ICU staffing shortage and to expand the physical ICU space capacity. Because of restrictions to family visitations in most ICUs, the pandemic posed a threat to communication and family-centered ICU care. The pandemic, especially during the first wave, was accompanied by a high level of apprehension in the community, many uncertainties about clinical course and therapy and an influx of speculations and misinformation. SUMMARY: Although healthcare systems learned how to face some of the challenges with subsequent waves, the pandemic had persistent effects on healthcare systems.

Hospitalizations for COVID-19 in a tertiary hospital in Brazil: a parallel with vaccination.

This study aimed to evaluate the COVID-19 hospitalizations in a tertiary hospital by age group and month, considering the introduction and the advance of the vaccination against the disease. The laboratory-confirmed COVID-19-associated hospitalizations among people aged 20 years or older, that occurred between March 2020 and June 2021, were distributed by month of symptom onset and age group. The proportion of hospitalizations by age group was calculated for the year 2021. The proportions were compared using the chi-square test for trends. The marks of vaccination advances among different age groups were taken from the official website LocalizaSUS. In 2020, hospitalizations among people aged 60-80 years old were the most frequent (39.1%). From January-June 2021, when the vaccination commenced, while hospitalizations of patients aged 20 to < 40 and 40 to 60 years old showed an increasing trend, the older age groups and those with vaccination recommendations (from 60 to < 80 and from 80 or over) showed a downward trend. As of June 2021, with widespread vaccination, a drop in hospitalizations was observed in > 60 years old. At 20 to <40 and 40 to < 60, an increase in hospitalizations was observed. It demonstrates the important role of vaccination in combating the COVID-19 pandemic.

Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population. METHODS: This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO2/FiO2 ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using Kaplan-Meier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420. FINDINGS: From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis (full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0·73, 95% CI 0·50-1·06; p=0·094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0·67, 95% CI 0·48-0·96; p=0·027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group. INTERPRETATION: In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections. FUNDING: InflaRx and the German Federal Government.

The effects of vasopressors with and without dobutamine on haemodynamics, metabolism and gut injury during endotoxic shock in rabbits. A controlled study.

INTRODUCTION: Vasopressors increase arterial pressure but they may have deleterious effects on mesenteric blood flow. We aimed to evaluate the response of gut biomarkers and superior mesenteric blood flow to different vasopressors with and without dobutamine. MATERIAL AND METHODS: Thirty New Zealand rabbits were included and randomly allocated to 5 groups: group A - sham group; group B - norepinephrine; group C - norepinephrine plus dobutamine; group D - vasopressin; and group E - vasopressin plus dobutamine. Mean arterial pressure (MAP) target was greater than 60 mmHg. Endotoxic shock was induced by intra-venous injection of lipopolysaccharide (LPS) in four of the five groups. Aortic blood flow (Qao), superior mesenteric artery flow (QSMA) and lactate were measured after LPS injection. Enterocyte damage was evaluated by measurements of serum citrulline and intestinal fatty acid-binding protein (I-FABP) after 4 h. RESULTS: The largest reduction in Qao occurred in group D (64 ± 17.3 to 38 ± 7.5 mL min-1; P = 0.04). QSMA also declined significantly in groups D and E and remained lower than in the other groups over 4 h (group D - baseline: 65 ± 31; 1 h: 37 ± 10; 2 h: 38 ± 10; 3 h: 46 ± 26; and 4 h: 48 ± 15 mL min-1; P < 0.005; group E - baseline: 73 ± 14; 1 h: 28 ± 4.0; 2 h: 37 ± 6.4; 3 h: 40 ± 11; and 4 h: 48 ± 11; P < 0.005; all in mL min-1). Serum citrulline was significantly lower in groups D (P = 0.014) and E (P = 0.019) in comparison to group A. The fluid administration regimen was similar in all groups. CONCLUSIONS: Vasopressin seems to negatively impact gut enterocyte function during endotoxic shock despite the association of an inodilator and adequate fluid replacement.

Brazilian Guidelines for the pharmacological treatment of patients hospitalized with COVID-19: Joint guideline of Associação Brasileira de Medicina de Emergência, Associação de Medicina Intensiva Brasileira, Associação Médica Brasileira, Sociedade Brasileira de Angiologia e Cirurgia Vascular, Sociedade Brasileira de Infectologia, Sociedade Brasileira de Pneumologia e Tisiologia, Sociedade Brasileira de Reumatologia. / Diretrizes Brasileiras para o tratamento farmacológico de pacientes hospitalizados com COVID-19: Diretriz conjunta da Associação Brasileira de Medicina de Emergência, Associação de Medicina Intensiva Brasileira, Associação Médica Brasileira, Sociedade Brasileira de Angiologia e Cirurgia Vascular, Sociedade Brasileira de Infectologia, Sociedade Brasileira de Pneumologia e Tisiologia e Sociedade Brasileira de Reumatologia.

OBJECTIVE: Several therapies are being used or proposed for COVID-19, and many lack appropriate evaluations of their effectiveness and safety. The purpose of this document is to develop recommendations to support decisions regarding the pharmacological treatment of patients hospitalized with COVID-19 in Brazil. METHODS: A group of 27 experts, including representatives of the Ministry of Health and methodologists, created this guideline. The method used for the rapid development of guidelines was based on the adoption and/or adaptation of existing international guidelines (GRADE ADOLOPMENT) and supported by the e-COVID-19 RecMap platform. The quality of the evidence and the preparation of the recommendations followed the GRADE method. RESULTS: Sixteen recommendations were generated. They include strong recommendations for the use of corticosteroids in patients using supplemental oxygen, the use of anticoagulants at prophylactic doses to prevent thromboembolism and the nonuse of antibiotics in patients without suspected bacterial infection. It was not possible to make a recommendation regarding the use of tocilizumab in patients hospitalized with COVID-19 using oxygen due to uncertainties regarding the availability of and access to the drug. Strong recommendations against the use of hydroxychloroquine, convalescent plasma, colchicine, lopinavir + ritonavir and antibiotics in patients without suspected bacterial infection and also conditional recommendations against the use of casirivimab + imdevimab, ivermectin and rendesivir were made. CONCLUSION: To date, few therapies have proven effective in the treatment of hospitalized patients with COVID-19, and only corticosteroids and prophylaxis for thromboembolism are recommended. Several drugs were considered ineffective and should not be used to provide the best treatment according to the principles of evidence-based medicine and promote economical resource use.

OBJETIVOS: Há diversas terapias sendo utilizadas ou propostas para a COVID-19, muitas carecendo de apropriada avaliação de efetividade e segurança. O propósito deste documento é elaborar recomendações para subsidiar decisões sobre o tratamento farmacológico de pacientes hospitalizados com COVID-19 no Brasil. MÉTODOS: Um grupo de 27 membros, formado por especialistas, representantes do Ministério da Saúde e metodologistas, integra essa diretriz. Foi utilizado o método de elaboração de diretrizes rápidas, tomando por base a adoção e/ou a adaptação de recomendações a partir de diretrizes internacionais existentes (GRADE ADOLOPMENT), apoiadas pela plataforma e-COVID-19 RecMap. A qualidade das evidências e a elaboração das recomendações seguiram o método GRADE. RESULTADOS: Foram geradas 16 recomendações. Entre elas, estão recomendações fortes para o uso de corticosteroides em pacientes em uso de oxigênio suplementar, para o uso de anticoagulantes em doses de profilaxia para tromboembolismo e para não uso de antibacterianos nos pacientes sem suspeita de infecção bacteriana. Não foi possível fazer uma recomendação quanto à utilização do tocilizumabe em pacientes hospitalizados com COVID-19 em uso de oxigênio, pelas incertezas na disponibilidade e de acesso ao medicamento. Foi feita recomendação para não usar azitromicina, casirivimabe + imdevimabe, cloroquina, colchicina, hidroxicloroquina, ivermectina, lopinavir/ ritonavir, plasma convalescente e rendesivir. CONCLUSÃO: Até o momento, poucas terapias se provaram efetivas no tratamento do paciente hospitalizado com COVID-19, sendo recomendados apenas corticosteroides e profilaxia para tromboembolismo. Diversos medicamentos foram considerados ineficazes, devendo ser descartados, de forma a oferecer o melhor tratamento pelos princípios da medicina baseada em evidências e promover economia de recursos não eficazes.