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Abstract Thromboembolism is a major cause of death in cancer patients. The association between paraneoplastic hypercoagulability of oncological patients and long-term central venous catheters (CVC) may result in CVC associated thrombosis. Patent Foramen Ovale (PFO), especially when associated with atrial septal aneurysm (ASA) is a risk factor for paradoxical embolism. We report a case of paradoxical embolism with stroke in an oncological patient with a huge CVC thrombus playing "ping-pong" with an hypermobile ASA with a PFO. We review the management of hypercoagulability in oncologic patients and discuss the potential role of routine transthoracic echocardiography before the implantation of long term central venous catheters to identify predisposing conditions to paradoxical embolism and select patients for anticoagulant therapy.

Objective: To evaluate the prevalence of burnout among the intensive care unit team of a university hospital after the second wave of COVID-19 and identify the key factors associated with its development., Methods: This single-center study included 395 employees from a multidisciplinary team. The participants completed a questionnaire based on the Maslach Burnout Inventory. Multivariate analysis was used to identify the factors associated with burnout., Results: Of 395 participants, 220 responded to the questionnaire (response rate: 56%). The prevalence of Burnout syndrome, defined as a severe score in at least one dimension, was 64.5% (142/220). Emotional distress was the most prevalent dimension, with a severe score affecting 50.5% (111/220) of the participants, followed by depersonalization at 39.1% (86/220). Only 5.9% (13/220) had severe scores in all three dimensions. Multivariate analysis revealed that being a physician was significantly associated with severe burnout symptoms in at least one dimension (odds ratio (OR), 1.32; 95% confidence interval (95%CI): 1.57-9.05; p=0.003). Additionally, having two or more jobs was associated with burnout in the three dimensions (OR=1.65; 95%CI=1.39-19.59; p=0.01)., Conclusion: This study highlights the alarming prevalence of burnout among intensive care unit teams, particularly among physicians, following the second wave of COVID-19. This emphasizes the need for targeted interventions and support systems to mitigate burnout and reduce its negative impact on healthcare professionals' well-being and patient care.

Nanotechnology involves the utilization of nanomaterials, including polymeric nanocapsules (NCs) that are drug carriers. For modify drug release and stability, nanoformulations can feature different types of polymers as surface coatings: Polysorbate 80 (P80), Polyethylene glycol (PEG), Chitosan (CS) and Eudragit (EUD). Although nanoencapsulation aims to reduce side effects, these polymers can interact with living organisms, inducing events in the antioxidant system. Thus far, little has been described about the impacts of chronic exposure, with Drosophila melanogaster being an in vivo model for characterizing the toxicology of these polymers. This study analyzes the effects of chronic exposure to polymeric NCs with different coatings. Flies were exposed to 10, 50, 100, and 500 μL of NCP80, NCPEG, NCCS, or EUD. The survival rate, locomotor changes, oxidative stress markers, cell viability, and Nrf2 expression were evaluated. Between the coatings, NCPEG had minimal effects, as only 500 μL affected the levels of reactive species (RS) and the enzymatic activities of catalase (CAT) and glutathione S-transferase (GST) without reducing Nrf2 expression. However, NCEUD significantly impacted the total flies killed, RS, CAT, and Superoxide dismutase from 100 μL. In part, the toxicity mechanisms of these coatings can be explained by the imbalance of the antioxidant system. This research provided initial evidence on the chronic toxicology of these nanomaterials in D. melanogaster to clarify the nanosafety profile of these polymers in future nanoformulations. Further investigations are essential to characterize possible biochemical pathways involved in the toxicity of these polymeric coatings., Competing Interests: Declaration of competing interest The authors declare that this research was conducted in the absence of any financial or commercial relationships, therefore there is no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Ventilator-associated tracheobronchitis is a common condition among invasively ventilated patients in intensive care units, for which the best treatment strategy is currently unknown. We designed the VATICAN (Ventilator-Associated Tracheobronchitis Initiative to Conduct Antibiotic Evaluation) trial to assess whether a watchful waiting antibiotic treatment strategy is noninferior to routine antibiotic treatment for ventilator-associated tracheobronchitis regarding days free of mechanical ventilation., Methods: VATICAN is a randomized, controlled, open-label, multicenter noninferiority trial. Patients with suspected ventilator-associated tracheobronchitis without evidence of ventilator-associated pneumonia or hemodynamic instability due to probable infection will be assigned to either a watchful waiting strategy, without antimicrobial administration for ventilator-associated tracheobronchitis and prescription of antimicrobials only in cases of ventilator-associated pneumonia, sepsis or septic shock, or another infectious diagnosis, or to a routine antimicrobial treatment strategy for seven days. The primary outcome will be mechanical ventilation-free days at 28 days, and a key secondary outcome will be ventilator-associated pneumonia-free survival. Through an intention-to-treat framework with a per-protocol sensitivity analysis, the primary outcome analysis will address noninferiority with a 20% margin, which translates to a 1.5 difference in ventilator-free days. Other analyses will follow a superiority analysis framework., Conclusion: The VATICAN trial will follow all national and international ethical standards. We aim to publish the trial in a high-visibility general journal and present it at critical care and infectious disease conferences for dissemination. These results will likely be immediately applicable to the bedside upon trial completion and will provide information with a low risk of bias for guideline development.

Objective: Patients with acute respiratory failure often require mechanical ventilation to reduce the work of breathing and improve gas exchange; however, this may exacerbate lung injury. Protective ventilation strategies, characterized by low tidal volumes (≤ 8mL/kg of predicted body weight) and limited plateau pressure below 30cmH2O, have shown improved outcomes in patients with acute respiratory distress syndrome. However, in the transition to spontaneous ventilation, it can be challenging to maintain tidal volume within protective levels, and it is unclear whether low tidal volumes during spontaneous ventilation impact patient outcomes. We developed a study protocol to estimate the prevalence of low tidal volume ventilation in the first 24 hours of spontaneous ventilation in patients with hypoxemic acute respiratory failure and its association with ventilator-free days and survival., Methods: We designed a multicenter, multinational, cohort study with a 28-day follow-up that will include patients with acute respiratory failure, defined as a partial oxygen pressure/fraction of inspired oxygen ratio < 300mmHg, in transition to spontaneous ventilation in intensive care units in Latin America., Results: We plan to include 422 patients in ten countries. The primary outcomes are the prevalence of low tidal volume in the first 24 hours of spontaneous ventilation and ventilator-free days on day 28. The secondary outcomes are intensive care unit and hospital mortality, incidence of asynchrony and return to controlled ventilation and sedation., Conclusion: In this study, we will assess the prevalence of low tidal volume during spontaneous ventilation and its association with clinical outcomes, which can inform clinical practice and future clinical trials.

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.)

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.)

Introduction: Cerebral palsy (CP) is a nonprogressive neuropathological condition that requires lifelong neurocognitive-motor rehabilitation. Evidences indicate that the use of new technologies to assist in rehabilitation processes, such as serious games in virtual reality (VR), have served as adjuncts to therapy and capable of promoting engagement, motivation, and motor activation for these patients. Objective: To investigate the usability of a serious game in VR to help with the stability and balance of the head and trunk of children with CP, focusing on the perception and experience of health professionals. Methods: The collection was carried out with health professionals, and the results were comprehensively evaluated through viability by means of the total score, number of correct answers, number of errors, and level of difficulty during the execution of the game, which were collected from the performance report generated by the application. System satisfaction was also verified by the System Usability Scale (SUS). Results: The mean obtained from the total score of the SUS was 82.10 ± 12.66 points, being considered of high usability for the suggested purpose. The professionals' opinion about the usability of the system did not change due to the performance during the game. Conclusion: The study demonstrated that the developed rehabilitation program has successfully delivered the experience to exercise the head control and trunk balance of subjects with CP.

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., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear., Objective: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia., Methods: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance., Outcomes: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide., Conclusion: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.

Background: The effect of balanced crystalloids compared with that of saline in critically ill patients overall and in specific subgroups is unclear. We aimed to assess whether use of balanced solutions, compared with 0·9% sodium chloride (saline), decreased in-hospital mortality in adult patients in intensive care units (ICUs)., Methods: For this systematic review and individual patient data meta-analysis, we searched PubMed, Embase, and CENTRAL databases from inception until March 1, 2022 (updated Sept 1, 2023) for individually randomised and cluster-randomised trials comparing balanced solutions with saline for adult patients in the ICU. Eligible trials were those that allocated patients to receive balanced solutions or saline for fluid resuscitation and maintenance fluids, or for maintenance fluids only; and administered the allocated fluid throughout ICU admission or, for trials using landmark mortality as their primary outcome, until the timepoint at which mortality was assessed (if ≥28 days). Authors of eligible trials were contacted to request individual patient data. Data obtained from eligible trials were merged, checked for accuracy, and centrally analysed by use of Bayesian regression models. The primary outcome was in-hospital mortality. Prespecified subgroups included patients with traumatic brain injury. This study was registered with PROSPERO (CRD42022299282)., Findings: Our search identified 5219 records, yielding six eligible randomised controlled trials. Data obtained for 34 685 participants from the six trials, 17 407 assigned to receive balanced crystalloids and 17 278 to receive saline, were included in the analysis. The mean age of participants was 58·8 years (SD 17·5). Of 34 653 participants with available data, 14 579 (42·1%) were female and 20 074 (57·9%) were male. Among patients who provided consent to report in-hospital mortality, 2907 (16·8%) of 17 313 assigned balanced solutions and 2975 (17·3%) of 17 166 assigned saline died in hospital (odds ratio [OR] 0·962 [95% CrI 0·909 to 1·019], absolute difference -0·4 percentage points [-1·5 to 0·2]). The posterior probability that balanced solutions reduced mortality was 0·895. In patients with traumatic brain injury, 191 (19·1%) of 999 assigned balanced and 141 (14·7%) of 962 assigned saline died (OR 1·424 [1·100 to 1·818], absolute difference 3·2 percentage points [0·7 to 8·7]). The probability that balanced solutions increased mortality in patients with traumatic brain injury was 0·975. In an independent risk of bias assessment, two trials were deemed to be at low risk of bias and four at high risk of bias., Interpretation: The probability that using balanced solutions in the ICU reduces in-hospital mortality is high, although the certainty of the evidence was moderate and the absolute risk reduction was small. In patients with traumatic brain injury, using balanced solutions was associated with increased in-hospital mortality., Funding: HCor (Brazil) and The George Institute for Global Health (Australia)., Competing Interests: Declaration of interests FGZ reports receiving consulting fees from Baxter (USA) and Bactiguard (Sweden), and grants, paid to his institution from Ionis Pharmaceuticals (USA), and receiving logistical support and donation of study materials from Baxter Hospitalar for the BaSICS trial. ABC reports receiving logistical support and donation of study materials from Baxter Hospitalar for the BaSICS trial. GLDT reports receiving consulting fees from Gilead paid to his then employer (The George Institute for Global Health) for work outside the scope of this paper. LPD reports receiving fees for statistical analysis from Nestlé and Endpoint Health, all unrelated to the scope of this study. NEH reports research funding and donation of study materials from Baxter Healthcare related to intravenous fluid therapy, research funding from Endpoint Health, and consulting fees from RevImmune unrelated to fluid therapy, all paid to her employer; and competitive research grants from the Australian National Health and Medical Research Council and Medical Research Future Fund. FRM reports receiving consulting fees from Baxter and receiving logistical support and donation of study materials from Baxter Hospitalar for the BaSICS trial. SM declares no competing interests. JM reports research funding and donation of study materials from Baxter Healthcare related to intravenous fluid therapy, paid to his employer; research funding from Endpoint Health unrelated to fluid therapy; and competitive research grants from the Australian National Health and Medical Research Council and Medical Research Future Fund. MR reports donation of study materials from Baxter Healthcare related to intravenous fluid therapy and competitive research grants from the Australian Medical Research Future Fund. BV reports donation of study materials from Baxter Healthcare related to intravenous fluid therapy, research funding from Endpoint Health unrelated to fluid therapy, and consulting fees from RevImmune unrelated to fluid therapy, all paid to his institution; and competitive research grants from the Australian National Health and Medical Research Council. TWR reports receiving consulting fees received from Cumberland Pharmaceuticals and Cytovale and fees for serving as a data safety and monitoring board member from Sanofi, all unrelated to the scope of this paper; and grants from the US National Institutes for Health, Centers for Disease Control, and Department of Defence, all paid to his institution. MWS reports receiving grants from the US National Institutes for Health and Department of Defence unrelated to the current work; and consulting fees and honoraria from Baxter Healthcare related to intravenous fluid therapy. PJY reports receiving competitive grants from the Health Research Council of New Zealand unrelated to this work; consulting fees from AM Pharma unrelated to this work; and consulting fees from Baxter Healthcare related to intravenous fluid therapy. SF reports competitive research grants from the Australian National Health and Medical Research Council, research funding and consulting fees from Baxter Healthcare related to intravenous fluid therapy, research funding and consulting fees from RevImmune unrelated to fluid therapy, and research funding from Endpoint Health unrelated to fluid therapy, all paid to his institution; and owning stock options in Sepsis Scout, unrelated to fluid therapy., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest Dr. Furtado reports research grants and personal fees from AstraZeneca, Bayer, Servier, and Apsen and research grants (received from his institution) from Pfizer, Libbs, Brazilian Ministry of Health, and University Health Network. Dr. Fonseca received research grants from AstraZeneca, Pfizer, Essity, Aché, Colgate, BioGen, and Brazilian Ministry of Health. Dr. Barros e Silva reports reports fees and research grants from Pfizer, Roche Diagnostics, and Bayer. Dr. Pereira reports research grants from Brazilian Ministry of Health through PROADI-SUS Program (not related to this article). Dr. Polanczyk received research grants and professional fees from AstraZeneca, Bayer, Pfizer, Novartis, Roche, Sanofi, and Brazilian Ministry of Health through PROADI Programs. Dr. Veiga received grants from Brazilian Ministry of Health through PROADI-SUS Program. Dr. Rosa received research grants from Pfizer, Merck Sharp & Dohme, and Brazilian Ministry of Health. Dr. Azevedo received professional fees from Baxter, Nestle, and Merck Sharp & Dohme not related to the present work and research grants from Brazilian Ministry of Health through PROADI-SUS Program. Dr. Avezum reports research grants from Bayer, Sanofi-Pasteur, and Population Health Research Institute. Dr. Cavalcanti reports research grants from Bayer. Dr. Lopes reports research support from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer and consulting fees from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, and Portola. Dr. Berwanger report research grants from Bayer, Pfizer, AstraZeneca, Servier, Novartis, and Boehringer-Ingelheim. The remaining authors have no competing interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The optimal amount for initial fluid resuscitation is still controversial in sepsis and the contribution of non-resuscitation fluids in fluid balance is unclear. We aimed to investigate the main components of fluid intake and fluid balance in both survivors and non-survivor patients with septic shock within the first 72 hours., Methods: In this prospective observational study in two intensive care units, we recorded all fluids administered intravenously, orally, or enterally, and losses during specific time intervals from vasopressor initiation: T1 (up to 24 hours), T2 (24 to 48 hours) and T3 (48 to 72 hours). Logistic regression and a mathematical model assessed the association with mortality and the influence of severity of illness., Results: We included 139 patients. The main components of fluid intake varied across different time intervals, with resuscitation and non-resuscitation fluids such as antimicrobials and maintenance fluids being significant contributors in T1 and nutritional therapy in T2/T3. A positive fluid balance both in T1 and T2 was associated with mortality (p = 0.049; p = 0.003), while nutritional support in T2 was associated with lower mortality (p = 0.040). The association with mortality was not explained by severity of illness scores., Conclusions: Non-resuscitation fluids are major contributors to a positive fluid balance within the first 48 hours of resuscitation. A positive fluid balance in the first 24 and 48 hours seems to independently increase the risk of death, while higher amount of nutrition seems protective. This data might inform fluid stewardship strategies aiming to improve outcomes and minimize complications in sepsis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Sociedade Brasileira de Anestesiologia. Published by Elsevier España S.L.U. All rights reserved.)