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Background: Shorter courses of antimicrobial therapy have been shown to be non-inferior to longer durations for the management of several infections. However, data on critically ill patients with severe infections by multidrug-resistant Gram-negative bacteria (MDR-GNB) are scarce. In the duratiOn of theraPy in severe infecTIons by MultIdrug-reSistant gram-nEgative bacteria (OPTIMISE) trial, we assessed the non-inferiority of 7-day versus 14-day antimicrobial therapy for patients with intensive care unit (ICU)-acquired severe infections by MDR-GNB., Methods: This was a randomised multicenter, open-label, parallel controlled, non-inferiority trial. Adult patients with severe infections by MDR-GNB initiated ≥ 48 h of ICU admission were eligible if they were hemodynamically stable and without fever > 48 h on the 7th day of appropriate antimicrobial therapy. Patients were 1:1 randomised to discontinue antimicrobial therapy on the 7th (± 1) day or to continue for a total of 14 (± 1) days. The primary outcome was clinical failure, defined as death or relapse of infection within 28 days of randomisation. An upper edge of the two-tailed 95% confidence interval (CI) of the delta between the clinical failure rate in the 7- and the 14-day lower than 10% in both intention-to-treat (ITT) and per protocol (PP) analyses was set as the non-inferiority criteria., Results: A total of 106 patients composed the ITT population: 59 and 47 allocated to 7- and 14-day groups, respectively. The PP population included 75 patients: 47 and 28 in the 7- and 14-day groups, respectively. Clinical failure occurred in 42.4% and 44.7% of the ITT population in 7- and 14-day groups, respectively, (risk difference (RD) - 2.3, 95%CI - 21.3 to 16.7), and in 46.8% and 50.0% of the PP population in 7- and 14-day groups, respectively (RD - 3.2, 95%CI - 26.6 to 20.2).  Most infections were of the respiratory tract (73/68.9%) and caused by carbapenem-resistant Enterobacterales (42/39.6%). The study was interrupted before reaching planned sample size due to low recruitment rate., Conclusion: The OPTIMISE trial could not determine the non-inferiority of 7-day compared to 14-day therapy for severe infections caused by MDR-GNB due to early termination related to the low recruitment rate., Trial Registration: NCT05210387 on January 13, 2022., Competing Interests: Declarations. Ethics approval and consent to participate: The study protocol and amendments were approved by the research ethics committee (institutional review board, IRB) of the coordinating centre (Hospital Moinhos de Vento), as well as IRBs from all other participant sites. Written informed consent was obtained from the patients (or from a legal representative, if the patient was not capable of providing it at that moment). Consent for publication: Not applicable. Competing interests: BA received support for attending meetings and/or travel by MSD. G.M.N received payment for lectures for Pfizer and MSD and received support for attending meetings and/or travel by Pfizer. A.P.Z. is a research fellow of the National Council for Scientific and Technological Development (CNPq), Ministry of Science and Technology, Brazil. All other authors have no conflicts to declare., (© 2024. The Author(s).)

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., Competing Interests: Declaration of competing interest None. This study was funded by Ionis Pharmaceutical, US, through a grant provided to HCor. The sponsor reviewed and agreed with the protocol, but had no role in any other aspect of the trial execution. MJ and GB were Ionis employees at the time this study was designed and provided relevant feedback on design of the trial and reviewed the final manuscript for intellectually relevant content. FGZ has received consulting fees from Baxter, unrelated to the scope of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To elucidate the impact of lymphopenia on critical COVID-19 patient outcomes., Methods: We conducted a multicenter prospective cohort study across five hospitals in Portugal and Brazil from 2020 to 2021. The study included adult patients admitted to the intensive care unit with SARS-CoV-2 pneumonia. Patients were categorized into two groups based on their lymphocyte counts within 48 hours of intensive care unit admission: the Lymphopenia Group (lymphocyte serum count < 1 × 109/L) and the Nonlymphopenia Group. Multivariate logistic regression, propensity score matching, Kaplan‒Meier survival curve analysis and Cox proportional hazards regression analysis were used., Results: A total of 912 patients were enrolled, with 191 (20.9%) in the Nonlymphopenia Group and 721 (79.1%) in the Lymphopenia Group. Lymphopenia patients displayed significantly elevated disease severity indices, including Sequential Organ Failure Assessment and Simplified Acute Physiology Score 3 scores, at intensive care unit admission (p = 0.001 and p < 0.001, respectively). Additionally, they presented heightened requirements for vasopressor support (p = 0.045) and prolonged intensive care unit and in-hospital stays (both p < 0.001). Multivariate logistic regression analysis after propensity score matching revealed a significant contribution of lymphopenia to mortality, with an odds ratio of 1,621 (95%CI: 1,275 - 2,048; p < 0.001). Interaction models revealed an increase of 8% in mortality for each decade of longevity in patients with concomitant lymphopenia. In the subanalysis utilizing three-group stratification, the Severe Lymphopenia Group had the highest mortality rate, not only in direct comparisons but also in Kaplan‒Meier survival analysis (log-rank test p = 0.0048)., Conclusion: Lymphopenia in COVID-19 patients is associated with increased disease severity and an increased risk of mortality, underscoring the need for prompt support for critically ill high-risk patients. These findings offer important insights into improving patient care strategies for COVID-19 patients.

Therapeutic anticoagulation showed inconsistent results in hospitalized patients with COVID-19 and selection of the best patients to use this strategy still a challenge balancing the risk of thrombotic and hemorrhagic outcomes. The present post-hoc analysis of the ACTION trial evaluated the variables independently associated with both bleeding events (major bleeding or clinically relevant non-major bleeding) and the composite outcomes thrombotic events (venous thromboembolism, myocardial infarction, stroke, systemic embolism, or major adverse limb events). Variables were assessed one by one with independent logistic regressions and final models were chosen based on Akaike information criteria. The model for bleeding events showed an area under the curve of 0.63 (95% confidence interval [CI] 0.53 to 0.73), while the model for thrombotic events had an area under the curve of 0.72 (95% CI 0.65 to 0.79). Non-invasive respiratory support was associated with thrombotic but not bleeding events, while invasive ventilation was associated with both outcomes (Odds Ratio of 7.03 [95 CI% 1.95 to 25.18] for thrombotic and 3.14 [95% CI 1.11 to 8.84] for bleeding events). Beyond respiratory support, creatinine level (Odds Ratio [OR] 1.01 95% CI 1.00 to 1.02 for every 1.0 mg/dL) and history of coronary disease (OR 3.67; 95% CI 1.32 to 10.29) were also independently associated to the risk of thrombotic events. Non-invasive respiratory support, history of coronary disease, and creatinine level may help to identify hospitalized COVID-19 patients at higher risk of thrombotic complications.ClinicalTrials.gov: NCT04394377., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To investigate the impact of delirium severity in critically ill COVID-19 patients and its association with outcomes., Methods: This prospective cohort study was performed in two tertiary intensive care units in Rio de Janeiro, Brazil. COVID-19 patients were evaluated daily during the first 7 days of intensive care unit stay using the Richmond Agitation Sedation Scale, Confusion Assessment Method for Intensive Care Unit (CAM-ICU) and Confusion Method Assessment for Intensive Care Unit-7 (CAM-ICU-7). Delirium severity was correlated with outcomes and one-year mortality., Results: Among the 277 COVID-19 patients included, delirium occurred in 101 (36.5%) during the first 7 days of intensive care unit stay, and it was associated with a higher length of intensive care unit stay in days (IQR 13 [7 - 25] versus 6 [4 - 12]; p < 0.001), higher hospital mortality (25.74% versus 5.11%; p < 0.001) and additional higher one-year mortality (5.3% versus 0.6%, p < 0.001). Delirium was classified by CAM-ICU-7 in terms of severity, and higher scores were associated with higher in-hospital mortality (17.86% versus 34.38% versus 38.46%, 95%CI, p value < 0.001). Severe delirium was associated with a higher risk of progression to coma (OR 7.1; 95%CI 1.9 - 31.0; p = 0.005) and to mechanical ventilation (OR 11.09; 95%CI 2.8 - 58.5; p = 0.002) in the multivariate analysis, adjusted by severity and frailty., Conclusion: In patients admitted with COVID-19 in the intensive care unit, delirium was an independent risk factor for the worst prognosis, including mortality. The delirium severity assessed by the CAM-ICU-7 during the first week in the intensive care unit was associated with poor outcomes, including progression to coma and to mechanical ventilation.

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.

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.

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.

Objective: To describe the IMPACTO-MR, a Brazilian nationwide intensive care unit platform study focused on the impact of health care-associated infections due to multidrug-resistant bacteria., Methods: We described the IMPACTO-MR platform, its development, criteria for intensive care unit selection, characterization of core data collection, objectives, and future research projects to be held within the platform., Results: The core data were collected using the Epimed Monitor System® and consisted of demographic data, comorbidity data, functional status, clinical scores, admission diagnosis and secondary diagnoses, laboratory, clinical, and microbiological data, and organ support during intensive care unit stay, among others. From October 2019 to December 2020, 33,983 patients from 51 intensive care units were included in the core database., Conclusion: The IMPACTO-MR platform is a nationwide Brazilian intensive care unit clinical database focused on researching the impact of health care-associated infections due to multidrug-resistant bacteria. This platform provides data for individual intensive care unit development and research and multicenter observational and prospective trials.

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 m 2 ) 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 m 2 ., 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 m 2 (hazard ratio, 0.71; 95% confidence interval, 0.29 to 1.77) and ≥60 ml/min per 1.73 m 2 (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 m 2 ., 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 m 2 . 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 m 2 ., (Copyright © 2022 by the American Society of Nephrology.)

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., Competing Interests: Declaration of interests JHA reports grants and personal fees from Bristol-Myers Squibb and CSL Behring; grants from AstraZeneca, CryoLife, US Food & Drug Administration, US National Institutes of Health, Sanofi, VoluMetrix, and Boehringer Ingelheim; personal fees from Pfizer, AbbVie Pharmaceuticals, Portola Pharmaceuticals, Quantum Genetics, Teikoku Pharmaceuticals, VA Cooperative Studies Program, and Zafgen, outside of the submitted work. AA reports consultant and lecture fees from Bayer, NovoNordisk, and LillyBaxter; lecture fees from Daichii-Sankyo; and research grants from Bayer, EMS Pharma, and the Population Health Research Institute, outside of the submitted work. LCPA reports personal fees from Baxter, Pfizer, and Halex-Istar; and grants from Ache Laboratorios Farmaceuticos, outside of the submitted work. OB reports grants from AstraZeneca, Pfizer, Bayer, Boehringer Ingelheim, Servier, and Amgen, and advisory board and personal fees from Novartis, outside of the submitted work. ABC reports grants from Bayer outside of the submitted work. GEC-S reports grants from Novartis and Air Liquide, outside of the submitted work. PGMdBeS reports grants from Bayer, Roche, and Pfizer, outside of the submitted work. MDAD reports personal fees, non-financial support, and other (advisory board participation) from Pfizer; personal fees and non-financial support from Bayer; personal fees and other (advisory board participation) from Servier; and personal fees from Boehringer Ingelheim, Daiichi Sankyo, and AstraZeneca, outside of the submitted work. RHMF reports grants from Bayer during the conduct of the study; and grants and personal fees from AstraZeneca and Servier, personal fees and non-financial support from Bayer, grants and non-financial support from EMS Pharma, and grants from Aché, Health Canada, and the Brazilian Ministry of Health, outside of the submitted work. MBG reports personal fees from COALITION COVID-19 Brazil and Bayer during the conduct of the study. RDL reports grants and personal fees from Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Medtronic PLC, and Sanofi; and personal fees from Amgen, Bayer, and Boehringer Ingelheim, outside of the submitted work. AVSM reports personal fees, non-financial support, and other (advisory board participation) from Bayer and Pfizer; personal fees and other (advisory board participation) from Novartis; personal fees and non-financial support from Zodiac; and personal fees from Ferring, Janssen, Sanofi, and AstraZeneca, outside of the submitted work. FCN reports grants and personal fees from Boehringer Ingelheim; and personal fees from Bayer and Pfizer, outside of the submitted work. ER reports grants and consulting fees from Bayer and Pfizer; grants from the Brazilian Ministry of Science and Technology; and personal fees from Aspen Pharma, Biomm Pharma, and Daiichi Sankyo, outside of the submitted work. ATR reports personal fees from Sanofi and Bayer, outside of the submitted work. VCV reports grants from Aspen Pharma, Pfizer, and Cristalia, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Acute brain dysfunction (ABD) is a frequent and severe syndrome occurring in critically ill patients and early identification of high-risk patients is paramount. In the present analysis, we propose a clinically applicable model for early phenotype identification of ABD at the bedside in mechanically ventilated patients, improving the recognition of patients with prolonged ABD.Prospective cohort with 629 mechanically ventilated patients in two medical-surgical intensive care units at academic centers. We applied cluster analysis to identify phenotypes using clinical and biological data. We then tested the association of phenotypes and its respective clinical outcomes. We performed a validation on a new cohort of patients select on subsequent patients admitted to the participants intensive care units.A model with 3 phenotypes best described the study population. A 4-variable model including medical admission, sepsis diagnosis, simplified acute physiologic score II and basal serum C-reactive protein (CRP) accurately classified each phenotype (area under curve 0.82; 95% CI, 0.79-0.86). Phenotype A had the shorter duration of ABD (median, 1 day), while phenotypes B and C had progressively longer duration of ABD (median, 3 and 6 days, respectively; P < .0001). There was an association between the duration of ABD and the baseline CRP levels and simplified acute physiology score II score (sensitivity and specificity of 80%). To increase the sensitivity of the model, we added CRP kinetics. By day 1, a CRP < 1.0 times the initial level was associated with a shorter duration of ABD (specificity 0.98).A model based on widely available clinical variables could provide phenotypes associated with the duration of ABD. Phenotypes with longer duration of ABD (phenotypes B and C) are characterized by more severe inflammation and by significantly worse clinical outcomes.

Ventilator-associated lower respiratory tract infection is one of the most frequent complications in mechanically ventilated patients. Ventilator-associated tracheobronchitis has been considered a disease that does not warrant antibiotic treatment by the medical community for many years. In the last decade, several studies have shown that tracheobronchitis could be considered an intermediate process that leads to ventilator-associated pneumonia. Furthermore, ventilator-associated tracheobronchitis has a limited impact on overall mortality but shows a significant association with increased patient costs, length of stay, antibiotic use, and duration of mechanical ventilation. Although we still need clear evidence, especially concerning treatment modalities, the present study on ventilator-associated tracheobronchitis highlights that there are important impacts of including this condition in clinical management and epidemiological and infection surveillance.

Background: Although patients with advanced or metastatic lung cancer have poor prognosis, admission to the ICU for management of life-threatening complications has increased over the years. Patients with newly diagnosed lung cancer appear as good candidates for ICU admission, but more robust information to assist decisions is lacking. The aim of our study was to evaluate the prognosis of newly diagnosed unresectable lung cancer patients., Methods: A retrospective multicentric study analyzed the outcome of patients admitted to the ICU with a newly diagnosed lung cancer (diagnosis within the month) between 2010 and 2013., Results: Out of the 100 patients, 30 had small cell lung cancer (SCLC) and 70 had non-small cell lung cancer. (Thirty patients had already been treated with oncologic treatments.) Mechanical ventilation (MV) was performed for 81 patients. Seventeen patients received emergency chemotherapy during their ICU stay. ICU, hospital, 3- and 6-month mortality were, respectively, 47, 60, 67 and 71%. Hospital mortality was 60% when invasive MV was used alone, 71% when MV and vasopressors were needed and 83% when MV, vasopressors and hemodialysis were required. In multivariate analysis, hospital mortality was associated with metastatic disease (OR 4.22 [1.4-12.4]; p = 0.008), need for invasive MV (OR 4.20 [1.11-16.2]; p = 0.030), while chemotherapy in ICU was associated with survival (OR 0.23, [0.07-0.81]; p = 0.020)., Conclusion: This study shows that ICU management can be appropriate for selected newly diagnosed patients with advanced lung cancer, and chemotherapy might improve outcome for patients with SCLC admitted for cancer-related complications. Nevertheless, tumors' characteristics, numbers and types of organ dysfunction should be taken into account in the decisional process before admitting these patients in ICU.

Purpose of Review: Nosocomial pneumonia is a frequent and severe nosocomial infection divided in two distinct groups: hospital-acquired pneumonia and ventilator-associated pneumonia (VAP). In this context, the VAP is notoriously difficult to diagnose clinically, resulting from the lack of a 'gold standard' method of diagnosis., Recent Findings: The use of biomarkers may potentially improve the early diagnosis of infections allowing earlier and better identification and treatment. An exhausting list of biomarkers has been studied and although far from perfect, procalcitonin (PCT) and C-reactive protein (CRP) are the most studied biomarkers used in clinical practice. Data coming from literature suggests the use of PCT for VAP prognosis and as a based algorithm tool for the reduction of duration of pneumonia therapy, as well as, the use of the CRP dynamics to the early prediction of VAP and the response to the antibiotics., Summary: The evidence for the use of biomarkers to diagnose nosocomial pneumonia as a stand-alone tool is low to moderate. Improved performance for both PCT and CRP can be obtained by using them in association with clinical features or scoring systems but prospective studies are still needed to validate this hypothesis.

Delirium is the most frequent and severe clinical presentation of brain dysfunction in critically ill septic patients with an incidence ranging from 9% to 71%. Delirium represents a significant burden for patients and relatives, as well as to the health care system, resulting in higher costs, long-term cognitive impairment and significant risk of death after 6 months. Current interventions for the prevention of delirium typically involve early recognition and amelioration of modifiable risk factors and treatment of underlying conditions that predisposes the individual to delirium. Several pharmacological interventions to prevent and treat delirium have been tested, although their effectiveness remains uncertain, especially in larger and more homogeneous subgroups of ICU patients, like in patients with sepsis. To date, there is inconsistent and conflicting data regarding the efficacy of any particular pharmacological agent, thus substantial attention has been paid to non-pharmacological interventions and preventive strategies should be applied to every patient admitted in the ICU. Future trials should be designed to evaluate the impact of these pharmacologic interventions on the prevention and treatment of delirium on clinically relevant outcomes such as length of stay, hospital mortality and long-term cognitive function. The role of specific medications like statins in delirium prevention is also yet to be evaluated.

Background: Detailed information about lung cancer patients requiring admission to intensive care units (ICUs) is mostly restricted to single-center studies. Our aim was to evaluate the clinical characteristics and outcomes of lung cancer patients admitted to ICUs., Patients and Methods: Prospective multicenter study in 449 patients with lung cancer (small cell, n = 55; non-small cell, n = 394) admitted to 22 ICUs in six countries in Europe and South America during 2011. Multivariate Cox proportional hazards frailty models were built to identify characteristics associated with 30-day and 6-month mortality., Results: Most of the patients (71%) had newly diagnosed cancer. Cancer-related complications occurred in 56% of patients; the most common was tumoral airway involvement (26%). Ventilatory support was required in 53% of patients. Overall hospital, 30-day, and 6-month mortality rates were 39%, 41%, and 55%, respectively. After adjustment for type of admission and early treatment-limitation decisions, determinants of mortality were organ dysfunction severity, poor performance status (PS), recurrent/progressive cancer, and cancer-related complications. Mortality rates were far lower in the patient subset with nonrecurrent/progressive cancer and a good PS, even those with sepsis, multiple organ dysfunctions, and need for ventilatory support. Mortality was also lower in high-volume centers. Poor PS predicted failure to receive the initially planned cancer treatment after hospital discharge., Conclusions: ICU admission was associated with meaningful survival in lung cancer patients with good PS and non-recurrent/progressive disease. Conversely, mortality rates were very high in patients not fit for anticancer treatment and poor PS. In this subgroup, palliative care may be the best option., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Sedation overuse is frequent and possibly associated with poor outcomes in the intensive care unit (ICU) patients. However, the association of early oversedation with clinical outcomes has not been thoroughly evaluated. The aim of this study was to assess the association of early sedation strategies with outcomes of critically ill adult patients under mechanical ventilation (MV)., Methods: A secondary analysis of a multicenter prospective cohort conducted in 45 Brazilian ICUs, including adult patients requiring ventilatory support and sedation in the first 48 hours of ICU admissions, was performed. Sedation depth was evaluated after 48 hours of MV. Multivariate analysis was used to identify variables associated with hospital mortality., Results: A total of 322 patients were evaluated. Overall, ICU and hospital mortality rates were 30.4% and 38.8%, respectively. Deep sedation was observed in 113 patients (35.1%). Longer duration of ventilatory support was observed (7 (4 to 10) versus 5 (3 to 9) days, P = 0.041) and more tracheostomies were performed in the deep sedation group (38.9% versus 22%, P = 0.001) despite similar PaO2/FiO2 ratios and acute respiratory distress syndrome (ARDS) severity. In a multivariate analysis, age (Odds Ratio (OR) 1.02; 95% confidence interval (CI) 1.00 to 1.03), Charlson Comorbidity Index >2 (OR 2.06; 95% CI, 1.44 to 2.94), Simplified Acute Physiology Score 3 (SAPS 3) score (OR 1.02; CI 95%, 1.00 to 1.04), severe ARDS (OR 1.44; CI 95%, 1.09 to 1.91) and deep sedation (OR 2.36; CI 95%, 1.31 to 4.25) were independently associated with increased hospital mortality., Conclusions: Early deep sedation is associated with adverse outcomes and constitutes an independent predictor of hospital mortality in mechanically ventilated patients.

Introduction: Delirium and coma are a frequent source of morbidity for ICU patients. Several factors are associated with the prognosis of mechanically ventilated (MV) cancer patients, but no studies evaluated delirium and coma (acute brain dysfunction). The present study evaluated the frequency and impact of acute brain dysfunction on mortality., Methods: The study was performed at National Cancer Institute, Rio de Janeiro, Brazil. We prospectively enrolled patients ventilated >48 h with a diagnosis of cancer. Acute brain dysfunction was assessed during the first 14 days of ICU using RASS/CAM-ICU. Patients were followed until hospital discharge. Univariate and multivariable analysis were performed to evaluate factors associated with hospital mortality., Results: 170 patients were included. 73% had solid tumors, age 65 [53-72 (median, IQR 25%-75%)] years. SAPS II score was 54[46-63] points and SOFA score was (7 [6-9]) points. Median duration of MV was 13 (6-21) days and ICU stay was 14 (7.5-22) days. ICU mortality was 54% and hospital mortality was 66%. Acute brain dysfunction was diagnosed in 161 patients (95%). Survivors had more delirium/coma-free days [4(1,5-6) vs 1(0-2), p<0.001]. In multivariable analysis the number of days of delirium/coma-free days were associated with better outcomes as they were independent predictors of lower hospital mortality [0.771 (0.681 to 0.873), p<0.001]., Conclusions: Acute brain dysfunction in MV cancer patients is frequent and independently associated with increased hospital mortality. Future studies should investigate means of preventing or mitigating acute brain dysfunction as they may have a significant impact on clinical outcomes.

Introduction: Contemporary information on mechanical ventilation (MV) use in emerging countries is limited. Moreover, most epidemiological studies on ventilatory support were carried out before significant developments, such as lung protective ventilation or broader application of non-invasive ventilation (NIV). We aimed to evaluate the clinical characteristics, outcomes and risk factors for hospital mortality and failure of NIV in patients requiring ventilatory support in Brazilian intensive care units (ICU)., Methods: In a multicenter, prospective, cohort study, a total of 773 adult patients admitted to 45 ICUs over a two-month period requiring invasive ventilation or NIV for more than 24 hours were evaluated. Causes of ventilatory support, prior chronic health status and physiological data were assessed. Multivariate analysis was used to identifiy variables associated with hospital mortality and NIV failure., Results: Invasive MV and NIV were used as initial ventilatory support in 622 (80%) and 151 (20%) patients. Failure with subsequent intubation occurred in 54% of NIV patients. The main reasons for ventilatory support were pneumonia (27%), neurologic disorders (19%) and non-pulmonary sepsis (12%). ICU and hospital mortality rates were 34% and 42%. Using the Berlin definition, acute respiratory distress syndrome (ARDS) was diagnosed in 31% of the patients with a hospital mortality of 52%. In the multivariate analysis, age (odds ratio (OR), 1.03; 95% confidence interval (CI), 1.01 to 1.03), comorbidities (OR, 2.30; 95% CI, 1.28 to 3.17), associated organ failures (OR, 1.12; 95% CI, 1.05 to 1.20), moderate (OR, 1.92; 95% CI, 1.10 to 3.35) to severe ARDS (OR, 2.12; 95% CI, 1.01 to 4.41), cumulative fluid balance over the first 72 h of ICU (OR, 2.44; 95% CI, 1.39 to 4.28), higher lactate (OR, 1.78; 95% CI, 1.27 to 2.50), invasive MV (OR, 2.67; 95% CI, 1.32 to 5.39) and NIV failure (OR, 3.95; 95% CI, 1.74 to 8.99) were independently associated with hospital mortality. The predictors of NIV failure were the severity of associated organ dysfunctions (OR, 1.20; 95% CI, 1.05 to 1.34), ARDS (OR, 2.31; 95% CI, 1.10 to 4.82) and positive fluid balance (OR, 2.09; 95% CI, 1.02 to 4.30)., Conclusions: Current mortality of ventilated patients in Brazil is elevated. Implementation of judicious fluid therapy and a watchful use and monitoring of NIV patients are potential targets to improve outcomes in this setting., Trial Registration: ClinicalTrials.gov NCT01268410.

Background: The prognostic effect of neutropenia in cancer patients admitted to intensive care units (ICUs) was addressed exclusively in cohort studies with conflicting results. Our aim was to address this question using a matched case-control study., Patients and Methods: Ninety-four neutropenic patients and 94 non-neutropenic controls were matched for age, cancer type, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment score, and need for mechanical ventilation and vasopressors. Conditional logistic regression was used to identify factors associated with hospital mortality., Results: The ICU (66% versus 66%, P = 0.999) and hospital (73% versus 78%, P = 0.611) mortality rates were similar in neutropenic and non-neutropenic patients. Adjusting for the type of admission and length of hospital stay before ICU admission, the characteristics associated with increased mortality were the severity of acute disease and organ failures, compromised performance status and sepsis diagnosis. The impact of both previous chemotherapy and neutropenia on the outcomes was not significant., Conclusions: Using a matched case-control study design, our results provide additional evidence that the presence of neutropenia is no longer associated with worse outcomes in critically ill patients with cancer. Moreover, our results also corroborate that recent exposure to chemotherapy is not associated with increased risk for death.

Introduction: Several biomarkers have been studied in febrile neutropenia. Our aim was to assess C-reactive protein (CRP) concentration in septic critically ill cancer patients and to compare those with and without neutropenia., Methods: A secondary analysis of a matched case-control study conducted at an oncologic medical-surgical intensive care unit (ICU) was performed, segregating patients with severe sepsis/septic shock. The impact of neutropenia on CRP concentrations at admission and during the first week of ICU stay was assessed., Results: A total of 154 critically ill septic cancer patients, 86 with neutropenia and 68 without, were included in the present study. At ICU admission, the CRP concentration of neutropenic patients was significantly higher than in non-neutropenic patients, 25.9 ± 11.2 mg/dL vs. 19.7 ± 11.4 mg/dL (P = 0.009). Among neutropenic patients, CRP concentrations at ICU admission were not influenced by the severity of neutropenia (< 100/mm3 vs. ≥ 100/mm3 neutrophils), 25.1 ± 11.6 mg/dL vs. 26.9 ± 10.9 mg/dL (P = 0.527). Time dependent analysis of CRP from Day 1 to Day 7 of antibiotic therapy showed an almost parallel decrease in both groups (P = 0.335), though CRP of neutropenic patients was, on average, always higher in comparison to that of non-neutropenic patients., Conclusions: In septic critically ill cancer patients CRP concentrations are more elevated in those with neutropenia. However, the CRP course seems to be independent from the presence or absence of neutropenia.