Antisense therapy to block the Kallikrein-kinin pathway in COVID-19: The ASKCOV randomized controlled trial.

PURPOSE: To assess the effect of antisense therapy to block kallikrein-kinin pathway in COVID-19 patients. MATERIAL AND METHODS: Randomized, placebo-controlled, double blind, controlled trial enrolling hospitalized COVID-19 patients that required supplementary oxygen to sustain peripheral oxygen saturation. Key exclusion criteria included use of mechanical ventilation or vasopressors, and patients with more than 10 days since symptom onset or more than 48 h of oxygen use. Patients were randomized to either one subcutaneous dose of ISIS721744, an antisense that blocks prekallikrein, or placebo. The primary outcome was the number of days alive and free of oxygen support up to 15 days (DAFOR15). Secondary endpoints included organ failure score, need and duration of mechanical ventilation up to 15 days, and all-cause mortality at 30 days. Exploratory endpoints included physiological parameters, biomarkers, and quality of life. RESULTS: From October 10, 2020, to December 09, 2020, 111 patients were randomized at thirteen sites in Brazil (56 to treatment and 55 to control group). Average age was 57.5 years, and most patients were male (68.5%). There were no significant differences in DAFOR15 between groups (5.9 ± 5.2 days for the intervention arm and 7.7 ± 5.1 for the control group; mean difference - 0.65, 95% confidence intervals from -2.95 to 1.36, p = 0.520). CONCLUSION: Antisense therapy designed to block the kallikrein-kinin pathway did not demonstrate clinical benefits in increasing days-alive without respiratory support at 15 days in patients with COVID-19 during the first wave in 2020. GOV IDENTIFIER: NCT04549922.

Boarding in the emergency department: challenges and mitigation strategies.

PURPOSE OF REVIEW: Herein, we conducted a review of the literature to better understand the issue of prolonged emergency department (ED) boarding by providing an overview of the current evidence on the available causes, consequences, and mitigation strategies. RECENT FINDINGS: Severely ill patients awaiting transfer to intensive care units (ICU) imposes additional burdens on the emergency care team from both a clinical and management perspective. The reasons for prolonged ED boarding are multifactorial. ED boarding compromises patients' safety and outcomes, and is associated with increased team burnout and dissatisfaction. Mitigation strategies include the optimization of patients' flow, the establishment of resuscitative care units, deployment of mobile critical care teams, and improvements in training. Staffing adjustments, changes in hospital operations, and quality improvement initiatives are required to improve this situation, while active bed management and implementation of capacity command centers may also help. SUMMARY: Considering the characteristics of healthcare systems, such as funding mechanisms, organizational structures, delivery models, access and quality of care, the challenge of ED boarding of critically ill patients requires a nuanced and adaptable approach. Solutions are complex but must involve the entirety of the hospital system, emergency department, staff adjustment, and education.

Cardiovascular Safety of Azithromycin in Patients Hospitalized With COVID-19: A Prespecified Pooled Analysis of the COALITION I and COALITION II Randomized Clinical Trials.

The cardiovascular safety from azithromycin in the treatment of several infectious diseases has been challenged. In this prespecified pooled analysis of 2 multicenter randomized clinical trials, we aimed to assess whether the use of azithromycin might lead to corrected QT (QTc) interval prolongation or clinically relevant ventricular arrhythmias. In the COALITION COVID Brazil I trial, 667 patients admitted with moderate COVID-19 were randomly allocated to hydroxychloroquine, hydroxychloroquine plus azithromycin, or standard of care. In the COALITION COVID Brazil II trial, 447 patients with severe COVID-19 were randomly allocated to hydroxychloroquine alone versus hydroxychloroquine plus azithromycin. The principal end point for the present analysis was the composite of death, resuscitated cardiac arrest, or ventricular arrhythmias. The addition of azithromycin to hydroxychloroquine did not result in any prolongation of the QTc interval (425.8 ± 3.6 ms vs 427.9 ± 3.9 ms, respectively, mean difference -2.1 ms, 95% confidence interval -12.5 to 8.4 ms, p = 0.70). The combination of azithromycin plus hydroxychloroquine compared with hydroxychloroquine alone did not result in increased risk of the primary end point (proportion of patients with events at 15 days 17.2% vs 16.0%, respectively, hazard ratio 1.08, 95% confidence interval 0.78 to 1.49, p = 0.65). In conclusion, in patients hospitalized with COVID-19 already receiving standard-of-care management (including hydroxychloroquine), the addition of azithromycin did not result in the prolongation of the QTc interval or increase in cardiovascular adverse events. Because azithromycin is among the most commonly prescribed antimicrobial agents, our results may inform clinical practice. Clinical Trial Registration: NCT04322123, NCT04321278.

Predictors of prolonged ventilator weaning and mortality in critically ill patients with COVID-19 / Preditores de desmame ventilatório prolongado e mortalidade em pacientes críticos com COVID-19

ABSTRACT Objective: To identify factors associated with prolonged weaning and mortality in critically ill COVID-19 patients admitted to ICUs and under invasive mechanical ventilation. Methods: Between March of 2020 and July of 2021, we retrospectively recorded clinical and ventilatory characteristics of critically ill COVID-19 patients from the day of intubation to the outcome. We classified the patients regarding the weaning period in accordance with established criteria. A logistic regression analysis was performed to identify variables associated with prolonged weaning and mortality. Results: The study involved 303 patients, 100 of whom (33.0%) had a prolonged weaning period. Most of the patients were male (69.6%), 136 (44.8%) had more than 50% of pulmonary involvement on chest CT, and 93 (30.6%) had severe ARDS. Within the prolonged weaning group, 62% died within 60 days. Multivariate analysis revealed that lung involvement greater than 50% on CT and delay from intubation to the first separation attempt from mechanical ventilation were significantly associated with prolonged weaning, whereas age and prolonged weaning were significantly associated with mortality. Conclusions: Prolonged weaning can be used as a milestone in predicting mortality in critically ill COVID-19 patients. Lung involvement greater than 50% on CT and delay from intubation to the first separation attempt from mechanical ventilation were identified as significant predictors of prolonged weaning. These results might provide valuable information for healthcare professionals when making clinical decisions regarding the management of critically ill COVID-19 patients who are on mechanical ventilation.

RESUMO Objetivo: Identificar fatores associados ao desmame prolongado e à mortalidade em pacientes críticos com COVID-19 admitidos em UTI e sob ventilação mecânica invasiva. Métodos: Entre março de 2020 e julho de 2021, registramos retrospectivamente as características clínicas e ventilatórias de pacientes críticos com COVID-19 desde o dia da intubação até o desfecho. Os pacientes foram classificados quanto ao período de desmame de acordo com critérios estabelecidos. Foi realizada análise de regressão logística para identificar variáveis associadas ao desmame prolongado e à mortalidade. Resultados: O estudo incluiu 303 pacientes, 100 dos quais (33,0%) apresentaram período de desmame prolongado. A maioria dos pacientes era do sexo masculino (69,6%), 136 (44,8%) apresentaram mais de 50% de acometimento pulmonar na TC de tórax, e 93 (30,6%) apresentaram SDRA grave. No grupo desmame prolongado, 62% foram a óbito em 60 dias. A análise multivariada revelou que o acometimento pulmonar maior que 50% na TC e a demora na primeira tentativa de retirada da ventilação mecânica após a intubação apresentaram associação significativa com o desmame prolongado, enquanto a idade e o desmame prolongado apresentaram associação significativa com a mortalidade. Conclusões: O desmame prolongado pode ser utilizado como marco na predição de mortalidade em pacientes críticos com COVID-19. O acometimento pulmonar maior que 50% na TC e a demora na primeira tentativa de retirada da ventilação mecânica após a intubação foram identificados como preditores significativos de desmame prolongado. Esses resultados podem fornecer informações valiosas para os profissionais de saúde na tomada de decisões clínicas sobre o manejo de pacientes críticos com COVID-19 e em ventilação mecânica.

Balanced Crystalloids versus Saline in Critically Ill Adults - A Systematic Review with Meta-Analysis.

BACKGROUND: The comparative efficacy and safety of balanced crystalloid solutions and saline for fluid therapy in critically ill adults remain uncertain. METHODS: We systematically reviewed randomized clinical trials (RCTs) comparing the use of balanced crystalloids with saline in critically ill adults. The primary outcome was 90-day mortality after pooling data from low-risk-of-bias trials using a random-effects model. We also performed a Bayesian meta-analysis to describe the primary treatment effect in probability terms. Secondary outcomes included the incidence of acute kidney injury (AKI), new treatment with renal replacement therapy (RRT), and ventilator-free and vasopressor-free days to day 28. RESULTS: We identified 13 RCTs, comprising 35,884 participants. From six trials (34,450 participants) with a low risk of bias, the risk ratio (RR) for 90-day mortality with balanced crystalloids versus saline was 0.96 (95% confidence interval [CI], 0.91 to 1.01; I2 = 12.1%); using vague priors, the posterior probability that balanced crystalloids reduce mortality was 89.5%. The RRs of developing AKI and of being treated with RRT with balanced crystalloids versus saline were 0.96 (95% CI, 0.89 to 1.02) and 0.95 (95% CI, 0.81 to 1.11), respectively. Ventilator-free days (mean difference, 0.18 days; 95% CI, −0.45 to 0.81) and vasopressor-free days (mean difference, 0.19 days; 95% CI, −0.14 to 0.51) were similar between groups. CONCLUSIONS: The estimated effect of using balanced crystalloids versus saline in critically ill adults ranges from a 9% relative reduction to a 1% relative increase in the risk of death, with a high probability that the average effect of using balanced crystalloids is to reduce mortality. (PROSPERO number, CRD42021243399.)

A living WHO guideline on drugs for COVID-19

What is the role of drug interventions in the treatment of patients with covid-19? The latest version of this WHO living guidance focuses on remdesivir, following the 15 October 2020 preprint publication of results from the WHO SOLIDARITY trial. It contains a weak or conditional recommendation against the use of remdesivir in hospitalised patients with covid-19 The first version on this living guidance focused on corticosteroids. The strong recommendation for systemic corticosteroids in patients with severe and critical covid-19, and a weak or conditional recommendation against systemic corticosteroids in patients with non-severe covid-19 are unchanged.

Late recognition and illness severity are determinants of early death in severe septic patients

OBJECTIVE: To identify the independent variables associated with death within 4 days after the first sepsis-induced organ dysfunction. METHODS: In this prospective observational study, severe sepsis and septic shock patients were classified into 3 groups: Group 1, survivors; Group 2, late non-survivors; and Group 3, early non-survivors. Early death was defined as death occurring within 4 days after the first sepsis-induced organ dysfunction. Demographic, clinical and laboratory data were collected and submitted to univariate and multinomial analyses. RESULTS: The study included 414 patients: 218 (52.7%) in Group 1, 165 (39.8%) in Group 2, and 31 (7.5%) in Group 3. A multinomial logistic regression analysis showed that age, Acute Physiology and Chronic Health Evaluation II score, Sepsis-related Organ Failure Assessment score after the first 24 hours, nosocomial infection, hepatic dysfunction, and the time elapsed between the onset of organ dysfunction and the sepsis diagnosis were associated with early mortality. In contrast, Black race and a source of infection other than the urinary tract were associated with late death. Among the non-survivors, early death was associated with Acute Physiology and Chronic Health Evaluation II score, chronic renal failure, hepatic dysfunction Sepsis-related Organ Failure Assessment score after 24 hours, and the duration of organ dysfunction. CONCLUSION: Factors related to patients' intrinsic characteristics and disease severity as well as the promptness of sepsis recognition are associated with early death among severe septic patients. .

Avaliação de teste de tubo T como estratégia inicial de suspensão da ventilação mecânica / Evaluation of T tube trial as a strategy of weaning from mechanical ventilation

JUSTIFICATIVA E OBJETIVOS: A retirada precoce da ventilação mecânica (VM) é importante para reduzir a morbimortalidade de pacientes internados em Unidades de Terapia Intensiva. O objetivo deste estudo foi avaliar a utilização do teste de Tubo T (TT) como método de retirada de VM. MÉTODO: Foram incluídos neste estudo os pacientes admitidos na UTI que apresentavam os seguintes critérios: VM > 24 horas, ausência de doença neuromuscular, relação PaO2/FiO2 > 200, estabilidade hemodinâmica, reversão da causa da intubação traqueal e drive respiratório adequado. Todos foram submetidos ao teste de tubo T. Considerou-se falha a ocorrência de FR > 30 irpm, hipoxemia, taquicardia, disritmias cardíacas, hipertensão ou hipotensão arterial. Após 2 horas de teste TT sem critérios de falha, os pacientes foram extubados. Considerou-se como sucesso na retirada da VM a manutenção por 48 horas de autonomia ventilatória. RESULTADOS: Foram incluídos 49 pacientes com idade média de 51,8 ± 21,7 anos. As incidências de SDRA e choque séptico foram 26,5 por cento e 32,7 por cento e o tempo médio de VM foi 11,9 ± 13 dias. A retirada da VM ocorreu em 79,2 por cento, re-intubação em 31,6 por cento, com tempo médio 13 ± 8,7 horas, sendo 75 por cento devido à falência respiratória. Não houve correlação entre extubação e níveis de hemoglobina, PaO2/FiO2, idade, sexo, SDRA ou choque séptico prévios. O sucesso da retirada da VM (48 horas de autonomia) não se correlacionou com nenhuma das variáveis descritas. Os resultados foram considerados significativos se p < 0,05. CONCLUSÕES: O tubo T mostrou ser método adequado para a retirada da VM na maioria dos pacientes. Entretanto, a taxa de re-intubação foi elevada, podendo ser conseqüência do longo tempo do TT, da ventilação mecânica prévia ou da falha dos critérios de indicação de extubação traqueal.

BACKGROUND AND OBJECTIVES: Weaning from mechanical ventilation (MV) is an important strategy to reduce morbidity and mortality in critical care patients. In this setting, this study aimed at evaluation of T-tube trial (TT) in weaning from MV. METHODS: Patient admitted in the ICU were included if they present the following inclusion criteria: MV > 24 hours, no neuromuscular disorders, PaO2/FiO2 ratio >200, hemodynamic stability, reversion of the cause of respiratory failure, adequate respiratory drive. All were submitted to TT. Failure was defined by the presence of one of these symptoms: RR > 30 ipm, hypoxemia, tachycardia, arrhythmia, hypertension or hypotension. After two hours of TT, patients without failure criteria were extubated. After 48 hours of adequate spontaneous respiration the patient was considered successful weaned. Results were considered significant if p < 0.05. RESULTS: Forty-nine patients were included with a mean age 51.8 ± 21.7 years. The incidence of ARDS and septic shock were 26.5 percent and 32.7 percent and mean duration of MV was 11.9 ± 13 days. Discontinuation of MV occurred in 79.2 percent, reintubation in 31.6 percent, in a mean time of 13 ± 8.7 hours and in 75 percent of the cases it was due to respiratory failure. There was no correlation between success in TT and hemoglobin levels, PaO2/FiO2 ratio, age, gender, prior ARDS or septic shock. Weaning success was not correlated with none of the above variables. CONCLUSIONS: TT was adequated for weaning from mechanical ventilation in the majority of the cases. However, reintubation rate was high. Possible causes are the long period of TT, prior mechanical ventilation or the failure in the criteria used to indicate extubation.

Treatment of nosocomial pneumoniae: an experience with meropenem

This study aimed at evaluating the efficacy and safety of meropenem as first choice treatment for nosocomial pneumonia (NP) in intensive care units (ICU) in Hospital das Clínicas (HC) - University of Säo Paulo; a hospital with high incidence of antimicrobial resistence. Prospective, open, and non-comparative trial with meropenem were done in patients with ventilator-assiciated or aspiration NP in 2 ICUs at HC - University od Säo Paulo. Etiologic investigation was done through bronchoalveolar lavage and blood cultures prior to study entry. Twenty-five (25) critically ill patients with NP were enrolled (mean age 40 years). Ventilator-acquired pneumonia was responsible for 76 percent of cases and aspiration NP for 24 percent. Specific etiologic agents were identified and considered to be clinically and temporally responsible for NP in 11 (44 percent) patients. A.baumanii was responsible for 6 cases (55 percent), P.aeruginosa for 3 (27 percent), and S.aureus for 2 (18 percent). At completion of treatment, 19 patients (76 percent) showed either cure (48 percent) or improvement (28 percent) after use of meropenem therapy. Mortality was 12 percent at the end therapy (8 perecent after excluding 1 non-evaluable patient). After 4 to 6 weeks of follow-up, 12 (48 percent) patients has improved or been totally cured, and overall mortality was 24 percent. Clinical complications were observed in 11 patients (44 percent), with none of them definitely related to the study drug. Meropenem as monotherapy was effective and well-tolerated in most NP patients in our ICU. The low mortality rate in this study might have been due to first choice use of this drug. Controlled, drug comparative clinical trials are needed to support this preliminary observation.