Predictors of bleeding and thrombotic events among patients admitted to the hospital with COVID-19 and elevated D-dimer: insights from the ACTION randomized clinical trial.

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.

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.

Sepsis in patients hospitalized with coronavirus disease 2019: how often and how severe?

PURPOSE OF REVIEW: To discuss why severe COVID-19 should be considered sepsis and how co-infection and secondary infection can aggravate this condition and perpetuate organ dysfunction leading to high mortality rates. RECENT FINDINGS: In severe COVID-19, there is both direct viral toxicity and dysregulated host response to infection. Although both coinfection and/or secondary infection are present, the latest is of greater concern mainly in resource-poor settings. Patients with severe COVID-19 present a phenotype of multiorgan dysfunction that leads to death in an unacceptable high percentage of the patients, with wide variability around the world. Similarly to endemic sepsis, the mortality of COVID-19 critically ill patients is higher in low-income and middle-income countries as compared with high-income countries. Disparities, including hospital strain, resources limitations, higher incidence of healthcare-associated infections (HAI), and staffing issues could in part explain this variability. SUMMARY: The high mortality rates of critically ill patients with severe COVID-19 disease are not only related to the severity of patient disease but also to modifiable factors, such as the ICU strain, HAI incidence, and organizational aspects. Therefore, HAI prevention and the delivery of best evidence-based care for these patients to avoid additional damage is important. Quality improvement interventions might help in improving outcomes mainly in resource-limited settings.

Efficacy and Safety of a Nasopharyngeal Catheter for Selective Brain Cooling in Patients with Traumatic Brain Injury: A Prospective, Non-randomized Pilot Study.

BACKGROUND: The efficacy objective was to determine whether a novel nasopharyngeal catheter could be used to cool the human brain after traumatic brain injury, and the safety objective was to assess the local and systemic effects of this therapeutic strategy. METHODS: This was a prospective, non-randomized, interventional clinical trial that involved five patients with severe traumatic brain injury. The intervention consisted of inducing and maintaining selective brain cooling for 24 h by positioning a catheter in the nasopharynx and circulating cold water inside the catheter in a closed-loop arrangement. Core temperature was maintained at ≥ 35 °C using counter-warming. RESULTS: In all study participants, a brain temperature reduction of ≥ 2 °C was achieved. The mean brain temperature reduction from baseline was 2.5 ± 0.9 °C (P = .04, 95% confidence interval). The mean systemic temperature was 37.3 ± 1.1 °C at baseline and 36.0 ± 0.8 °C during the intervention. The mean difference between the brain temperature and the systemic temperature during intervention was - 1.2 ± 0.8 °C (P = .04). The intervention was well tolerated with no significant changes observed in the hemodynamic parameters. No relevant variations in intracranial pressure and transcranial Doppler were observed. The laboratory results underwent no major changes, aside from the K+ levels and blood counts. The K+ levels significantly varied (P = .04); however, the variation was within the normal range. Only one patient experienced an event of mild localized and superficial nasal discoloration, which was re-evaluated on the seventh day and indicated complete recovery. CONCLUSION: The results suggest that our noninvasive method for selective brain cooling, using a novel nasopharyngeal catheter, was effective and safe for use in humans.

Effect of Increasing Blood Pressure With Noradrenaline on the Microcirculation of Patients With Septic Shock and Previous Arterial Hypertension.

OBJECTIVES: To assess whether an increase in mean arterial pressure in patients with septic shock and previous systemic arterial hypertension changes microcirculatory and systemic hemodynamic variables compared with patients without arterial hypertension (control). DESIGN: Prospective, nonblinded, interventional study. SETTING: Three ICUs in two teaching hospitals. PATIENTS: After informed consent, we included patients older than 18 years with septic shock for at least 6 hours, sedated, and under mechanical ventilation. We paired patients with and without arterial hypertension by age. INTERVENTIONS: After obtaining systemic and microcirculation baseline hemodynamic variables (time 0), we increased noradrenaline dose to elevate mean arterial pressure up to 85-90 mm Hg before collecting a new set of measurements (time 1). MEASUREMENTS AND MAIN RESULTS: We included 40 patients (20 in each group). There was no significant difference in age between the groups. After the rise in mean arterial pressure, there was a significant increase in cardiac index and a slight but significant reduction in lactate in both groups. We observed a significant improvement in the proportion of perfused vessels (control: 57.2 ± 14% to 66 ± 14.8%; arterial hypertension: 61.4 ± 12.3% to 70.8 ± 7.1%; groups: p = 0.29; T0 and T1: p < 0.001; group and time interaction: p = 0.85); perfused vessels density (control: 15.6 ± 4 mm/mm to 18.6 ± 4.5 mm/mm; arterial hypertension: 16.4 ± 3.5 mm/mm to 19.1 ± 3 mm/mm; groups: p = 0.51; T0 and T1: p < 0.001; group and time interaction: p = 0.70), and microcirculatory flow index (control: 2.1 ± 0.6 to 2.4 ± 0.6; arterial hypertension: 2.1 ± 0.5 to 2.6 ± 0.2; groups: p = 0.71; T0 and T1: p = 0.002; group and time interaction: p = 0.45) in both groups. CONCLUSIONS: Increasing mean arterial pressure with noradrenaline in septic shock patients improves density and flow in small vessels of sublingual microcirculation. However, this improvement occurs both in patients with previous arterial hypertension and in those without arterial hypertension.

Organizational factors associated with target sedation on the first 48 h of mechanical ventilation: an analysis of checklist-ICU database.

BACKGROUND: Although light sedation levels are associated with several beneficial outcomes for critically ill patients on mechanical ventilation, the majority of patients are still deeply sedated. Organizational factors may play a role on adherence to light sedation levels. We aimed to identify organizational factors associated with a moderate to light sedation target on the first 48 h of mechanical ventilation, as well as the association between early achievement of within-target sedation and mortality. METHODS: This study is a secondary analysis of a multicenter two-phase study (prospective cohort followed by a cluster-randomized controlled trial) performed in 118 Brazilian ICUs. We included all critically ill patients who were on mechanical ventilation 48 h after ICU admission. A moderate to light level of sedation or being alert and calm (i.e., the Richmond Agitation-Sedation Scale of - 3 to 0) was the target for all patients on mechanical ventilation during the study period. We collected data on the type of hospital (public, private, profit and private, nonprofit), hospital teaching status, nursing and physician staffing, and presence of sedation, analgesia, and weaning protocols. We used multivariate random-effects regression with ICU and study phase as random-effects and correction for patients' Simplified Acute Physiology Score 3 and Sequential Organ Failure Assessment. We also performed a mediation analysis to explore whether sedation level was just a mediator of the association between organizational factors and mortality. RESULTS: We included 5719 patients. Only 1710 (29.9%) were on target sedation levels on day 2. Board-certified intensivists on the morning and afternoon shifts were associated with an adequate sedation level on day 2 (OR = 2.43; CI 95%, 1.09-5.38). Target sedation levels were associated with reduced hospital mortality (OR = 0.63; CI 95%, 0.55-0.72). Mediation analysis also suggested such an association, but did not suggest a relationship between the physician staffing model and hospital mortality. CONCLUSIONS: Board-certified intensivists on morning and afternoon shifts were associated with an increased number of patients achieving lighter sedation goals. These findings reinforce the importance of organizational factors, such as intensivists' presence, as a modifiable quality improvement target.

Effect of Flexible Family Visitation on Delirium Among Patients in the Intensive Care Unit: The ICU Visits Randomized Clinical Trial.

Importance: The effects of intensive care unit (ICU) visiting hours remain uncertain. Objective: To determine whether a flexible family visitation policy in the ICU reduces the incidence of delirium. Design, Setting and Participants: Cluster-crossover randomized clinical trial involving patients, family members, and clinicians from 36 adult ICUs with restricted visiting hours (<4.5 hours per day) in Brazil. Participants were recruited from April 2017 to June 2018, with follow-up until July 2018. Interventions: Flexible visitation (up to 12 hours per day) supported by family education (n = 837 patients, 652 family members, and 435 clinicians) or usual restricted visitation (median, 1.5 hours per day; n = 848 patients, 643 family members, and 391 clinicians). Nineteen ICUs started with flexible visitation, and 17 started with restricted visitation. Main Outcomes and Measures: Primary outcome was incidence of delirium during ICU stay, assessed using the CAM-ICU. Secondary outcomes included ICU-acquired infections for patients; symptoms of anxiety and depression assessed using the HADS (range, 0 [best] to 21 [worst]) for family members; and burnout for ICU staff (Maslach Burnout Inventory). Results: Among 1685 patients, 1295 family members, and 826 clinicians enrolled, 1685 patients (100%) (mean age, 58.5 years; 47.2% women), 1060 family members (81.8%) (mean age, 45.2 years; 70.3% women), and 737 clinicians (89.2%) (mean age, 35.5 years; 72.9% women) completed the trial. The mean daily duration of visits was significantly higher with flexible visitation (4.8 vs 1.4 hours; adjusted difference, 3.4 hours [95% CI, 2.8 to 3.9]; P < .001). The incidence of delirium during ICU stay was not significantly different between flexible and restricted visitation (18.9% vs 20.1%; adjusted difference, -1.7% [95% CI, -6.1% to 2.7%]; P = .44). Among 9 prespecified secondary outcomes, 6 did not differ significantly between flexible and restricted visitation, including ICU-acquired infections (3.7% vs 4.5%; adjusted difference, -0.8% [95% CI, -2.1% to 1.0%]; P = .38) and staff burnout (22.0% vs 24.8%; adjusted difference, -3.8% [95% CI, -4.8% to 12.5%]; P = .36). For family members, median anxiety (6.0 vs 7.0; adjusted difference, -1.6 [95% CI, -2.3 to -0.9]; P < .001) and depression scores (4.0 vs 5.0; adjusted difference, -1.2 [95% CI, -2.0 to -0.4]; P = .003) were significantly better with flexible visitation. Conclusions and Relevance: Among patients in the ICU, a flexible family visitation policy, vs standard restricted visiting hours, did not significantly reduce the incidence of delirium. Trial Registration: ClinicalTrials.gov Identifier: NCT02932358.

Exosomes from patients with septic shock convey miRNAs related to inflammation and cell cycle regulation: new signaling pathways in sepsis?

BACKGROUND: Exosomes isolated from plasma of patients with sepsis may induce vascular apoptosis and myocardial dysfunction by mechanisms related to inflammation and oxidative stress. Despite previous studies demonstrating that these vesicles contain genetic material related to cellular communication, their molecular cargo during sepsis is relatively unknown. In this study, we evaluated the presence of microRNAs (miRNAs) and messenger RNAs (mRNAs) related to inflammatory response and redox metabolism in exosomes of patients with septic shock. METHODS: Blood samples were collected from 24 patients with septic shock at ICU admission and after 7 days of treatment. Twelve healthy volunteers were used as control subjects. Exosomes were isolated by ultracentrifugation, and their miRNA and mRNA content was evaluated by qRT-PCR array. RESULTS: As compared with healthy volunteers, exosomes from patients with sepsis had significant changes in 65 exosomal miRNAs. Twenty-eight miRNAs were differentially expressed, both at enrollment and after 7 days, with similar kinetics (18 miRNAs upregulated and 10 downregulated). At enrollment, 35 differentially expressed miRNAs clustered patients with sepsis according to survival. The pathways enriched by the miRNAs of patients with sepsis compared with control subjects were related mostly to inflammatory response. The comparison of miRNAs from patients with sepsis according to hospital survival demonstrated pathways related mostly to cell cycle regulation. At enrollment, sepsis was associated with significant increases in the expression of mRNAs related to redox metabolism (myeloperoxidase, 64-fold; PRDX3, 2.6-fold; SOD2, 2.2-fold) and redox-responsive genes (FOXM1, 21-fold; SELS, 16-fold; GLRX2, 3.4-fold). The expression of myeloperoxidase mRNA remained elevated after 7 days (65-fold). CONCLUSIONS: Exosomes from patients with septic shock convey miRNAs and mRNAs related to pathogenic pathways, including inflammatory response, oxidative stress, and cell cycle regulation. Exosomes may represent a novel mechanism for intercellular communication during sepsis.

Clinical Features of Kidney Transplant Recipients Admitted to the Intensive Care Unit.

INTRODUCTION: There is a paucity of data regarding the complications in kidney transplant patients who may require intensive care unit (ICU) management, despite being the most common solid organ transplant worldwide. OBJECTIVE: To identify the main reasons for ICU admission and to determine the factors associated with hospital mortality in kidney transplant recipients. DESIGN: This single-center retrospective cohort study was conducted between September 2013 and June 2014, including all consecutive kidney transplant patients requiring ICU admission. We collected data on patient demographics, transplant characteristics, clinical data, and prognostic scores. The independent determinants of hospital mortality were identified by multiple logistic regression analysis. We also assessed the performance of Simplified Acute Physiology Score 3 (SAPS 3) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. RESULTS: We analyzed data from 413 patients, the majority of whom were admitted late after renal transplantation (1169 days; 63-3003 days). The main reason for admission was sepsis (33.2%), followed by cardiovascular disease (16%). Age (odds ratio [OR] 1.05, confidence interval [CI], 1.01-1.09), SAPS 3 score (OR 1.04, CI, 1.01-1.08), the need for mechanical ventilation (OR 26.47, CI, 10.30-68.08), and vasopressor use (OR 3.34, CI, 1.37-8.13) were independently associated with hospital mortality. The performance of SAPS 3 and APACHE II scores was poor in this population and overestimated the mortality rates. CONCLUSION: Sepsis was the main reason for ICU admission in kidney transplant recipients, followed by cardiovascular disease. Age and disease severity were associated with hospital mortality.

Implementation of sepsis bundles in public hospitals in Brazil: a prospective study with heterogeneous results.

BACKGROUND: Public hospitals in emerging countries pose a challenge to quality improvement initiatives in sepsis. Our objective was to evaluate the results of a quality improvement initiative in sepsis in a network of public institutions and to assess potential differences between institutions that did or did not achieve a reduction in mortality. METHODS: We conducted a prospective study of patients with sepsis or septic shock. We collected baseline data on compliance with the Surviving Sepsis Campaign 6-h bundles and mortality. Afterward, we initiated a multifaceted quality improvement initiative for patients with sepsis or septic shock in all hospital sectors. The primary outcome was hospital mortality over time. The secondary outcomes were the time to sepsis diagnosis and compliance with the entire 6-h bundles throughout the intervention. We defined successful institutions as those where the mortality rates decreased significantly over time, using a logistic regression model. We analyzed differences over time in the secondary outcomes by comparing the successful institutions with the nonsuccessful ones. We assessed the predictors of in-hospital mortality using logistic regression models. All tests were two-sided, and a p value less than 0.05 indicated statistical significance. RESULTS: We included 3435 patients from the emergency departments (50.7%), wards (34.1%), and intensive care units (15.2%) of 9 institutions. Throughout the intervention, there was an overall reduction in the risk of death, in the proportion of septic shock, and the time to sepsis diagnosis, as well as an improvement in compliance with the 6-h bundle. The time to sepsis diagnosis, but not the compliance with bundles, was associated with a reduction in the risk of death. However, there was a significant reduction in mortality in only two institutions. The reduction in the time to sepsis diagnosis was greater in the successful institutions. By contrast, the nonsuccessful sites had a greater increase in compliance with the 6-h bundle. CONCLUSIONS: Quality improvement initiatives reduced sepsis mortality in public Brazilian institutions, although not in all of them. Early recognition seems to be a more relevant factor than compliance with the 6-h bundle.

Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Importance: The effects of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remain uncertain. Objective: To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate to severe ARDS compared with a conventional low-PEEP strategy. Design, Setting, and Participants: Multicenter, randomized trial conducted at 120 intensive care units (ICUs) from 9 countries from November 17, 2011, through April 25, 2017, enrolling adults with moderate to severe ARDS. Interventions: An experimental strategy with a lung recruitment maneuver and PEEP titration according to the best respiratory-system compliance (n = 501; experimental group) or a control strategy of low PEEP (n = 509). All patients received volume-assist control mode until weaning. Main Outcomes and Measures: The primary outcome was all-cause mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days through day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality. Results: A total of 1010 patients (37.5% female; mean [SD] age, 50.9 [17.4] years) were enrolled and followed up. At 28 days, 277 of 501 patients (55.3%) in the experimental group and 251 of 509 patients (49.3%) in the control group had died (hazard ratio [HR], 1.20; 95% CI, 1.01 to 1.42; P = .041). Compared with the control group, the experimental group strategy increased 6-month mortality (65.3% vs 59.9%; HR, 1.18; 95% CI, 1.01 to 1.38; P = .04), decreased the number of mean ventilator-free days (5.3 vs 6.4; difference, -1.1; 95% CI, -2.1 to -0.1; P = .03), increased the risk of pneumothorax requiring drainage (3.2% vs 1.2%; difference, 2.0%; 95% CI, 0.0% to 4.0%; P = .03), and the risk of barotrauma (5.6% vs 1.6%; difference, 4.0%; 95% CI, 1.5% to 6.5%; P = .001). There were no significant differences in the length of ICU stay, length of hospital stay, ICU mortality, and in-hospital mortality. Conclusions and Relevance: In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients. Trial Registration: clinicaltrials.gov Identifier: NCT01374022.

Daily laxative therapy reduces organ dysfunction in mechanically ventilated patients: a phase II randomized controlled trial.

INTRODUCTION: Constipation is a common problem in intensive care units. We assessed the efficacy and safety of laxative therapy aiming to promote daily defecation in reducing organ dysfunction in mechanically ventilated patients. METHODS: We conducted a prospective, randomized, controlled, nonblinded phase II clinical trial at two general intensive care units. Patients expected to remain ventilated for over 3 days were randomly assigned to daily defecation or control groups. The intervention group received lactulose and enemas to produce 1-2 defecations per day. In the control group, absence of defecation was tolerated up to 5 days. Primary outcome was the change in Sequential Organ Failure Assessment (SOFA) score between the date of enrollment and intensive care unit discharge, death or day 14. RESULTS: We included 88 patients. Patients in the treatment group had a higher number of defecations per day (1.3 ± 0.42 versus 0.7 ± 0.56, p < 0.0001) and lower percentage of days without defecation (33.1 ± 15.7% versus 62.3 ± 24.5%, p < 0.0001). Patients in the intervention group had a greater reduction in SOFA score (-4.0 (-6.0 to 0) versus -1.0 (-4.0 to 1.0), p = 0.036) with no difference in mortality rates or in survival time. Adverse events were more frequent in the treatment group (4.5 (3.0-8.0) versus 3.0 (1.0-5.7), p = 0.016), including more days with diarrhea (2.0 (1.0-4.0) versus 1.0 (0-2.0) days, p < 0.0001). Serious adverse events were rare and did not significantly differ between groups. CONCLUSIONS: Laxative therapy improved daily defecation in ventilated patients and was associated with a greater reduction in SOFA score. TRIAL REGISTRATION: Clinical Trials.gov NCT01607060, registered 24 May 2012.

Early sedation and clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study.

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.

Prevalence and risk factors of Burnout syndrome among intensive care unit members during the second wave of COVID-19: a single-center study.

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.

Assessment of the components of fluid balance in patients with septic shock: a prospective observational study.

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.

VATICAN (Ventilator-Associated Tracheobronchitis Initiative to Conduct Antibiotic Evaluation): protocol for a multicenter randomized open-label trial of watchful waiting versus antimicrobial therapy for ventilator-associated tracheobronchitis.

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.

Adherence to low tidal volume in the transition to spontaneous ventilation in patients with acute respiratory failure in intensive care units in Latin America (SPIRAL): a study protocol.

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.

High-touch surfaces disinfection compliance in a COVID-19 intensive care unit.

Environmental cleaning and disinfection are fundamental health care-associated infection prevention measures. This study aimed to evaluate the disinfection compliance of high-touch surfaces in a COVID-19-only intensive care unit, using a fluorescent marker. It was divided into 3 phases, baseline assessment, educational feedback, and post feedback. Disinfection compliance improved significantly from the first to the third phase, 14.3% to 51.4% (P < .001), respectively.