Identification of Distinct Clinical Phenotypes of Critically Ill COVID-19 Patients: Results from a Cohort Observational Study.

Purpose: COVID-19 presents complex pathophysiology, and evidence collected points towards an intricate interaction between viral-dependent and individual immunological mechanisms. Identifying phenotypes through clinical and biological markers may provide a better understanding of the subjacent mechanisms and an early patient-tailored characterization of illness severity. Methods: A multicenter prospective cohort study was performed in 5 hospitals in Portugal and Brazil for one year between 2020-2021. All adult patients with an Intensive Care Unit admission with SARS-CoV-2 pneumonia were eligible. COVID-19 was diagnosed using clinical and radiologic criteria with a SARS-CoV-2 positive RT-PCR test. A two-step hierarchical cluster analysis was made using several class-defining variables. Results: 814 patients were included. The cluster analysis revealed a three-class model, allowing for the definition of three distinct COVID-19 phenotypes: 407 patients in phenotype A, 244 patients in phenotype B, and 163 patients in phenotype C. Patients included in phenotype A were significantly older, with higher baseline inflammatory biomarkers profile, and a significantly higher requirement of organ support and mortality rate. Phenotypes B and C demonstrated some overlapping clinical characteristics but different outcomes. Phenotype C patients presented a lower mortality rate, with consistently lower C-reactive protein, but higher procalcitonin and interleukin-6 serum levels, describing an immunological profile significantly different from phenotype B. Conclusions: Severe COVID-19 patients exhibit three different clinical phenotypes with distinct profiles and outcomes. Their identification could have an impact on patients' care, justifying different therapy responses and inconsistencies identified across different randomized control trial results.

Perceptions and practices regarding light sedation in mechanically ventilated patients: a survey on the attitudes of Brazilian critical care physicians. / Percepções e práticas sobre sedação superficial em pacientes sob ventilação mecânica: um inquérito sobre as atitudes de médicos intensivistas brasileiros.

OBJECTIVE: To characterize the knowledge and perceived attitudes toward pharmacologic interventions for light sedation in mechanically ventilated patients and to understand the current gaps comparing current practice with the recommendations of the Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the Intensive Care Unit. METHODS: This was a cross-sectional cohort study based on the application of an electronic questionnaire focused on sedation practices. RESULTS: A total of 303 critical care physicians provided responses to the survey. Most respondents reported routine use of a structured sedation scale (281; 92.6%). Almost half of the respondents reported performing daily interruptions of sedation (147; 48.4%), and the same percentage of participants (48.0%) agreed that patients are often over sedated. During the COVID-19 pandemic, participants reported that patients had a higher chance of receiving midazolam compared to before the pandemic (178; 58.8% versus 106; 34.0%; p = 0.05), and heavy sedation was more common during the COVID-19 pandemic (241; 79.4% versus 148; 49.0%; p = 0.01). CONCLUSION: This survey provides valuable data on the perceived attitudes of Brazilian intensive care physicians regarding sedation. Although daily interruption of sedation was a well-known concept and sedation scales were often used by the respondents, insufficient effort was put into frequent monitoring, use of protocols and systematic implementation of sedation strategies. Despite the perception of the benefits linked with light sedation, there is a need to identify improvement targets to propose educational strategies to improve current practices.

OBJETIVO: Caracterizar o conhecimento e as atitudes percebidas em relação às intervenções farmacológicas para sedação superficial em pacientes sob ventilação mecânica e entender as lacunas atuais, comparando a prática atual com as recomendações das Diretrizes de Prática Clínica para a Prevenção e Tratamento da Dor, Agitação/Sedação, Delirium, Imobilidade e Interrupção do Sono em Pacientes Adultos na Unidade de Terapia Intensiva. MÉTODOS: Trata-se de estudo de coorte transversal baseado na aplicação de um questionário eletrônico centrado nas práticas de sedação. RESULTADOS: Responderam ao inquérito 303 médicos intensivistas. A maioria dos entrevistados relatou uso de rotina de uma escala de sedação estruturada (281; 92,6%). Quase metade dos entrevistados relatou realizar interrupções diárias da sedação (147; 48,4%), e a mesma percentagem de participantes (48,0%) concordou com a afirmação de que os pacientes costumam ser sedados em excesso. Durante a pandemia da COVID-19, os participantes relataram que os pacientes tinham maior chance de receber midazolam do que antes da pandemia (178; 58,8% versus 106; 34,0%; p = 0,05); além disso, a sedação profunda foi mais comum durante a pandemia da COVID-19 (241; 79,4% versus 148; 49,0%; p = 0,01). CONCLUSÃO: Este inquérito fornece dados valiosos sobre as atitudes percebidas dos médicos intensivistas brasileiros em relação à sedação. Embora a interrupção diária da sedação fosse um conceito bem conhecido e as escalas de sedação fossem frequentemente utilizadas pelos entrevistados, foi colocado esforço insuficiente no monitoramento frequente, no uso de protocolos e na implementação sistemática de estratégias de sedação. Apesar da percepção dos benefícios associados à sedação superficial, há necessidade de identificar metas de melhoria para se proporem estratégias educacionais que melhorem as práticas atuais.

Dapagliflozin and Kidney Outcomes in Hospitalized Patients with COVID-19 Infection: An Analysis of the DARE-19 Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Patients who were hospitalized with coronavirus disease 2019 (COVID-19) infection are at high risk of AKI and KRT, especially in the presence of CKD. The Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial showed that in patients hospitalized with COVID-19, treatment with dapagliflozin versus placebo resulted in numerically fewer participants who experienced organ failure or death, although these differences were not statistically significant. We performed a secondary analysis of the DARE-19 trial to determine the efficacy and safety of dapagliflozin on kidney outcomes in the overall population and in prespecified subgroups of participants defined by baseline eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The DARE-19 trial randomized 1250 patients who were hospitalized (231 [18%] had eGFR <60 ml/min per 1.73 m2) with COVID-19 and cardiometabolic risk factors to dapagliflozin or placebo. Dual primary outcomes (time to new or worsened organ dysfunction or death, and a hierarchical composite end point of recovery [change in clinical status by day 30]), and the key secondary kidney outcome (composite of AKI, KRT, or death), and safety were assessed in participants with baseline eGFR <60 and ≥60 ml/min per 1.73 m2. RESULTS: The effect of dapagliflozin versus placebo on the primary prevention outcome (hazard ratio, 0.80; 95% confidence interval, 0.58 to 1.10), primary recovery outcome (win ratio, 1.09; 95% confidence interval, 0.97 to 1.22), and the composite kidney outcome (hazard ratio, 0.74; 95% confidence interval, 0.50 to 1.07) were consistent across eGFR subgroups (P for interaction: 0.98, 0.67, and 0.44, respectively). The effects of dapagliflozin on AKI were also similar in participants with eGFR <60 ml/min per 1.73 m2 (hazard ratio, 0.71; 95% confidence interval, 0.29 to 1.77) and ≥60 ml/min per 1.73 m2 (hazard ratio, 0.69; 95% confidence interval, 0.37 to 1.29). Dapagliflozin was well tolerated in participants with eGFR <60 and ≥60 ml/min per 1.73 m2. CONCLUSIONS: The effects of dapagliflozin on primary and secondary outcomes in hospitalized participants with COVID-19 were consistent in those with eGFR below/above 60 ml/min per 1.73 m2. Dapagliflozin was well tolerated and did not increase the risk of AKI in participants with eGFR below or above 60 ml/min per 1.73 m2.

COVID-19 Infection in Rheumatic Patients on Chronic Antimalarial Drugs: A Systematic Review and Meta-Analysis.

The ongoing chronic use of hydroxychloroquine or chloroquine (HCQ/CQ) in rheumatic patients might impact their outcomes after a SARS-CoV-2 infection. Therefore, we sought to assess the mortality in rheumatic patients with chronic HCQ/CQ use who developed a COVID-19 infection through a comparison between individuals chronically using HCQ/CQ with those not taking these drugs. We performed a systematic review and meta-analysis of studies on PubMed, Embase, and Cochrane Central. We included full-length reports, prospective observational cohorts, and clinical trials of adult patients (aged ≥ 18 years) who were diagnosed with a COVID-19 infection. Case studies, case series, letters, comments, and editorials were excluded. The main outcome was all-cause mortality. This study is registered with PROSPERO (CRD42022341678). We identified 541 studies, of which 20 studies were included, comprising 236,997 patients. All-cause mortality was significantly lower in patients with prior chronic use of HCQ/CQ compared to those with no previous usage (OR 0.76; 95% CI 0.62-0.94; p = 0.01). There was a considerably lower incidence of hospitalization among patients with chronic HCQ/CQ use compared to their counterparts without HCQ/CQ usage (OR 0.80; 95% CI 0.65-0.99; p = 0.04). All-cause mortality and hospitalization were significantly lower in rheumatic patients with chronic HCQ/CQ use who developed a COVID-19 infection.

Clinical outcomes and lung mechanics characteristics between COVID-19 and non-COVID-19-associated acute respiratory distress syndrome: a propensity score analysis of two major randomized trials. / Desfechos clínicos e características da mecânica pulmonar entre a síndrome do desconforto respiratório agudo associada à COVID-19 e a não associada à COVID-19: uma análise de escore de propensão de dois importantes ensaios randomizados.

OBJECTIVE: To compare the lung mechanics and outcomes between COVID-19-associated acute respiratory distress syndrome and non-COVID-19-associated acute respiratory distress syndrome. METHODS: We combined data from two randomized trials in acute respiratory distress syndrome, one including only COVID-19 patients and the other including only patients without COVID-19, to determine whether COVID-19-associated acute respiratory distress syndrome is associated with higher 28-day mortality than non-COVID-19 acute respiratory distress syndrome and to examine the differences in lung mechanics between these two types of acute respiratory distress syndrome. RESULTS: A total of 299 patients with COVID-19-associated acute respiratory distress syndrome and 1,010 patients with non-COVID-19-associated acute respiratory distress syndrome were included in the main analysis. The results showed that non-COVID-19 patients used higher positive end-expiratory pressure (12.5cmH2O; SD 3.2 versus 11.7cmH2O SD 2.8; p < 0.001), were ventilated with lower tidal volumes (5.8mL/kg; SD 1.0 versus 6.5mL/kg; SD 1.2; p < 0.001) and had lower static respiratory compliance adjusted for ideal body weight (0.5mL/cmH2O/kg; SD 0.3 versus 0.6mL/cmH2O/kg; SD 0.3; p = 0.01). There was no difference between groups in 28-day mortality (52.3% versus 58.9%; p = 0.52) or mechanical ventilation duration in the first 28 days among survivors (13 [IQR 5 - 22] versus 12 [IQR 6 - 26], p = 0.46). CONCLUSION: This analysis showed that patients with non-COVID-19-associated acute respiratory distress syndrome have different lung mechanics but similar outcomes to COVID-19-associated acute respiratory distress syndrome patients. After propensity score matching, there was no difference in lung mechanics or outcomes between groups.

OBJETIVO: Comparar a mecânica pulmonar e os desfechos entre a síndrome do desconforto respiratório agudo associada à COVID-19 e a síndrome do desconforto respiratório agudo não associada à COVID-19. MÉTODOS: Combinamos dados de dois ensaios randomizados sobre a síndrome do desconforto respiratório agudo, um incluindo apenas pacientes com COVID-19 e o outro incluindo apenas pacientes sem COVID-19, para determinar se a síndrome do desconforto respiratório agudo associada à COVID-19 está associada à maior mortalidade aos 28 dias do que a síndrome do desconforto respiratório agudo não associada à COVID-19 e também examinar as diferenças na mecânica pulmonar entre esses dois tipos de síndrome do desconforto respiratório agudo. RESULTADOS: Foram incluídos na análise principal 299 pacientes com síndrome do desconforto respiratório agudo associada à COVID-19 e 1.010 pacientes com síndrome do desconforto respiratório agudo não associada à COVID-19. Os resultados mostraram que os pacientes sem COVID-19 utilizaram pressão positiva expiratória final mais alta (12,5cmH2O; DP 3,2 versus 11,7cmH2O; DP 2,8; p < 0,001), foram ventilados com volumes correntes mais baixos (5,8mL/kg; DP 1,0 versus 6,5mL/kg; DP 1,2; p < 0,001) e apresentaram menor complacência respiratória estática ajustada para o peso ideal (0,5mL/cmH2O/kg; DP 0,3 versus 0,6mL/cmH2O/kg; DP 0,3; p = 0,01). Não houve diferença entre os grupos quanto à mortalidade aos 28 dias (52,3% versus 58,9%; p = 0,52) ou à duração da ventilação mecânica nos primeiros 28 dias entre os sobreviventes (13 [IQ 5 - 22] dias versus 12 [IQ 6 - 26] dias; p = 0,46). CONCLUSÃO: Esta análise mostrou que os pacientes com síndrome do desconforto respiratório agudo não associada à COVID-19 têm mecânica pulmonar diferente, mas desfechos semelhantes aos dos pacientes com síndrome do desconforto respiratório agudo associada à COVID-19. Após pareamento por escore de propensão, não houve diferença na mecânica pulmonar e nem nos desfechos entre os grupos.

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. METHODS: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3-0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. FINDINGS: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. INTERPRETATION: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. FUNDING: Coalition COVID-19 Brazil, Bayer SA.

Clinical course and outcomes of critically ill patients with COVID-19 infection: a systematic review.

OBJECTIVES: Coronavirus disease 19 (COVID-19) is a major cause of hospital admission and represents a challenge for patient management during intensive care unit (ICU) stay. We aimed to describe the clinical course and outcomes of COVID-19 pneumonia in critically ill patients. METHODS: We performed a systematic search of peer-reviewed publications in MEDLINE, EMBASE and the Cochrane Library up to 15th August 2020. Preprints and reports were also included if they met the inclusion criteria. Study eligibility criteria were full-text prospective, retrospective or registry-based publications describing outcomes in patients admitted to the ICU for COVID-19, using a validated test. Participants were critically ill patients admitted in the ICU with COVID-19 infection. RESULTS: From 32 articles included, a total of 69 093 patients were admitted to the ICU and were evaluated. Most patients included in the studies were male (76 165/128 168, 59%, 26 studies) and the mean patient age was 56 (95%CI 48.5-59.8) years. Studies described high ICU mortality (21 145/65 383, 32.3%, 15 studies). The median length of ICU stay was 9.0 (95%CI 6.5-11.2) days, described in five studies. More than half the patients admitted to the ICU required mechanical ventilation (31 213/53 465, 58%, 23 studies) and among them mortality was very high (27 972/47 632, 59%, six studies). The duration of mechanical ventilation was 8.4 (95%CI 1.6-13.7) days. The main interventions described were the use of non-invasive ventilation, extracorporeal membrane oxygenation, renal replacement therapy and vasopressors. CONCLUSIONS: This systematic review, including approximately 69 000 ICU patients, demonstrates that COVID-19 infection in critically ill patients is associated with great need for life-sustaining interventions, high mortality, and prolonged length of ICU stay.