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Orosomucoid, or alpha-1 acid glycoprotein (AGP), is a major acute-phase protein expressed in response to systemic injury and inflammation. AGP has been described as an inhibitor of neutrophil migration on sepsis, particularly its immunomodulation effects. AGP's biological functions in coronavirus disease 2019 (COVID-19) are not understood. We sought to investigate the role of AGP in severe COVID-19 infection patients and neutrophils infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Epidemiological data, AGP levels, and other laboratory parameters were measured in blood samples from 56 subjects hospitalized in the ICU with SARS-CoV-2 infection. To evaluate the role of AGP in NETosis in neutrophils, blood samples from health patients were collected, and neutrophils were separated and infected with SARS-CoV-2. Those neutrophils were treated with AGP or vehicle, and NETosis was analyzed by flow cytometry. AGP was upregulated in severe COVID-19 patients (p<0.05). AGP level was positively correlated with IL-6 and C-reactive protein (respectively, p=0.005, p=0.002) and negatively correlated with lactate (p=0.004). AGP treatment downregulated early and late NETosis (respectively, 35.7% and 43.5%) in neutrophils infected with SARS-CoV-2 and up-regulated IL-6 supernatant culture expression (p<0.0001). Our data showed increased AGP in COVID-19 infection and contributed to NETosis regulation and increased IL-6 production, possibly related to the Cytokine storm in COVID-19.

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BACKGROUND & AIM: Among critical patients, there is an early onset of changes in both the quantity and quality of muscle mass. It is essential to find tools that promptly identify this muscle mass loss. The aim of this study was to compare the ultrasonography of the quadriceps femoris to the gold standard, thigh computed tomography (CT) for assessing the musculature of critically ill patients with different body mass index who have suffered traumatic brain injury. METHODS: This is a prospective validation study in an Intensive Care Unit (ICU) specialized in trauma care, located at a tertiary teaching hospital. Our study involved a convenience sample of patients. Sequential ultrasound and CT scans were performed at three distinct time intervals: upon admission, between 24 and 96 h' post-admission, and finally, between 96 and 168 h' post-admission. For all ultrasound measurements, we conducted simultaneous quadriceps CT measurements. The correlation between measurements obtained by ultrasound and computed tomography at three different times and in three BMI ranges was analyzed, in individuals with normal weight, overweight and obese. RESULTS: Results: We analyzed 252 images in 49 patients in time 1, 40 patients in time 2, and 37 in time 3 to compare the thickness quadriceps muscle using US and CT. Of these, 18 patients had a BMI ≤ 24.9 kg/m2 (normal weight), 18 patients from 25 to 29.9 kg/m2 (overweight), and 8 patients had a BMI ≥ 30 kg/m2 (obese). The mean age was 37 years, the majority (94%) were male and the main comorbidities were: hypertension 12%, diabetes 4% and 14% smoking. The results revealed minor discrepancies between measurements obtained through the two methods, these changes were not influenced by the body mass index, with these variations being practically insignificant in the context of clinical application. Thus, the correlation and concordance between the values obtained found a strong positive correlation with good limits of agreement. The Spearman's correlation coefficients obtained were r = 0.89, 0.91 and 0.88, p < 0.01 at T1, T2 and T3 respectively for normal weight, r = 0.91, 0.80 and 0.81, p < 0.01 at T1, T2 and T3 respectively for overweight and r = 0.89, 0.94 and 0.84, p < 0.01 at T1, T2 and T3 respectively for obesity. In addition to a positive correlation, we observed a high agreement between the methods. The Bland & Altman analysis at time 1 showed, respectively, the bias of 1.46, 2.03 and 0.76. At time 2, the bias was 0.42, 3.11 and 2.12. At time 3, the bias was 2.26, 3.38 and 2.11 mm. CONCLUSION: Our findings suggest that measure femoral quadriceps muscle thickness ultrasound-based exhibits a comparable performance to thigh CT. This conclusion stems from the excellent correlation and good agreement observed between ultrasound and CT, which is considered the gold standard for muscle assessment in critically ill patients. TRIAL REGISTRATION: This clinical trial is registered at REBEC https://ensaiosclinicos.gov.br/ identifier: RBR-2bzspnz. The protocol was approved, on July 30, 2019, by the Research Ethics Committee of the Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto - Trial Registration Number: 3,475,851.

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Airway epithelial cells (AEC) infected with SARS-CoV-2 may drive the dysfunction of macrophages during COVID-19. We hypothesized that the direct interaction of AEC with macrophages mediated by CD95/CD95L or indirect interaction mediated by IL-6 signaling are key steps for the COVID-19 severe acute inflammation. The interaction of macrophages with apoptotic and infected AEC increased CD95 and CD163 expression, and induced macrophage death. Macrophages exposed to tracheal aspirate with high IL-6 levels from intubated patients with COVID-19 or to recombinant human IL-6 exhibited decreased HLA-DR expression, increased CD95 and CD163 expression and IL-1ß production. IL-6 effects on macrophages were prevented by both CD95/CD95L antagonist and by IL-6 receptor antagonist and IL-6 or CD95 deficient mice showed significant reduction of acute pulmonary inflammation post-infection. Our findings show a non-canonical CD95L-CD95 pathway that simultaneously drives both macrophage activation and dysfunction and point to CD95/CD95L axis as therapeutic target.

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The cytokine storm in SARS-CoV-2 infection contributes to the onset of inflammation and target-organ damage. The endothelium is a key player in COVID-19 pathophysiology and it is an important target for cytokines. Considering that cytokines trigger oxidative stress and negatively impact endothelial cell function, we sought to determine whether serum from individuals with severe COVID-19 decreases endothelial cells' main antioxidant defense, i.e., the antioxidant transcriptional factor Nrf2. Human umbilical vein endothelial cells (HUVECs) were incubated with serum from patients with severe COVID-19 at different time points and the effects on redox balance and Nrf2 activity were determined. Serum from individuals with COVID-19 increased oxidant species, as indicated by higher DHE (dihydroethydine) oxidation, increased protein carbonylation, and induced mitochondrial reactive oxygen species (ROS) generation and dysfunction. Serum from patients with COVID-19, but not serum from healthy individuals, induced cell death and diminished nitric oxide (NO) bioavailability. In parallel, Nrf2 nuclear accumulation and the expression of Nrf2-targeted genes were decreased in endothelial cells exposed to serum from individuals with COVID-19. In addition, these cells exhibited higher expression of Bach-1, a negative regulator of Nrf2 that competes for DNA binding. All events were prevented by tocilizumab, an IL-6 receptor blocker, indicating that IL-6 is key to the impairment of endothelial antioxidant defense. In conclusion, endothelial dysfunction related to SARS-CoV-2 infection is linked to decreased endothelial antioxidant defense via IL-6-dependent mechanisms. Pharmacological activation of Nrf2 may decrease endothelial cell damage in individuals with severe COVID-19.NEW & NOTEWORTHY We demonstrate that endothelial cell dysfunction in SARS-CoV-2-infected individuals is linked to decreased activity of the major antioxidant system regulator, the Nrf2 transcription factor. We provide evidence that this phenomenon relies on IL-6, an important cytokine involved in the pathophysiology of COVID-19. Our data support the view that Nrf2 activation is a potential therapeutical strategy to prevent oxidative stress and vascular inflammation in severe cases of COVID-19.

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Critical patients have conditions that may favor the occurrence of hospital-acquired pressure injury (HAPI). The objective of this study was to identify the incidence and factors associated with the occurrence of HAPI in patients with coronavirus disease 2019 admitted to the intensive care unit (ICU) who used the prone position. Retrospective cohort study carried out in an ICU of a tertiary university hospital. Two hundred four patients with positive real-time polymerase chain reactions were evaluated, of which 84 were placed in the prone position. All patients were sedated and submitted to invasive mechanical ventilation. Of the prone patients, 52 (62%) developed some type of HAPI during hospitalization. The main place of occurrence of HAPI was the sacral region, followed by the gluteus and thorax. Of the patients who developed HAPI, 26 (50%) had this event in places possibly associated with the prone position. The factors associated with the occurrence of HAPI in patients prone to coronavirus disease 2019 were the Braden Scale and the length of stay in the ICU. The incidence of HAPI in prone patients was extremely high (62%), which denotes the need to implement protocols in order to prevent the occurrence of these events.

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Coronavirus disease 2019 (COVID-19) infection has a negative impact on the cytokine profile of pregnant women. Increased levels of proinflammatory cytokines seem to be correlated with the severity of the disease, in addition to predisposing to miscarriage or premature birth. Proinflammatory cytokines increase the generation of reactive oxygen species (ROS). It is unclear how interleukin-6 (IL-6) found in the circulation of patients with severe COVID-19 might affect gestational health, particularly concerning umbilical cord function. This study tested the hypothesis that IL-6 present in the circulation of women with severe COVID-19 causes umbilical cord artery dysfunction by increasing ROS generation and activating redox-sensitive proteins. Umbilical cord arteries were incubated with serum from healthy women and women with severe COVID-19. Vascular function was assessed using concentration-effect curves to serotonin in the presence or absence of pharmacological agents, such as tocilizumab (antibody against the IL-6 receptor), tiron (ROS scavenger), ML171 (Nox1 inhibitor), and Y27632 (Rho kinase inhibitor). ROS generation was assessed by the dihydroethidine probe and Rho kinase activity by an enzymatic assay. Umbilical arteries exposed to serum from women with severe COVID-19 were hyperreactive to serotonin. This effect was abolished in the presence of tocilizumab, tiron, ML171, and Y27632. In addition, serum from women with severe COVID-19 increased Nox1-dependent ROS generation and Rho kinase activity. Increased Rho kinase activity was abolished by tocilizumab and tiron. Serum cytokines in women with severe COVID-19 promote umbilical artery dysfunction. IL-6 is key to Nox-linked vascular oxidative stress and activation of the Rho kinase pathway.

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RATIONALE: Methylene blue (MB) has been used to increase blood pressure in septic shock, acting on the activity of guanylate cyclase and nitric oxide synthase. PATIENCE CONCERNS: The aim of this study is to demonstrate the benefit of MB in early phase of septic shock.Diagnoses: We report 6 cases of patients with septic shock with up to 72 hours of evolution. INTERVENTIONS: We used MB after fluid replacement, use of norepinephrine and vasopressin. Patients received a loading dose of MB and maintenance for 48 hours. OUTCOMES: All patients presented a reduction in the dose of vasopressors and lactate levels soon after the administration of the loading dose of MB, an effect that was maintained with the maintenance dose for 48 hours. Interleukin 6 and interleukin 8 were elevated at the beginning of the septic condition, with a progressive and marked reduction after the beginning of MB infusion, demonstrating a role of MB in reducing the inflammatory activity. LESSONS: This case series suggests that MB used early in the treatment of septic shock may be useful in reducing vasopressor dose and lactate levels. Further studies are still required to further validate these findings.

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INTRODUCTION: Therapy and nutritional status directly interfere in the clinical evolution of critically ill patients, in reducing morbidity and mortality, by maintaining the functional integrity of the gastrointestinal tract, decreasing the catabolic response, besides contributing to the reduction of hospitalization time resulting in less treatment cost. Critical patients and trauma victims suffer early changes in the quantity and quality of muscle mass. Tools to identify the groups most susceptible to these complications are necessary so that interventions can minimize the deleterious effects of malnutrition in critically ill patients. METHODS AND ANALYSIS: The aim of the present study is to measure muscle mass loss by measuring the thickness of the rectus femoris muscle by bedside ultrasound in critically ill patients admitted to the Intensive Care Unit (ICU) of a university hospital. Information will be collected regarding the length of hospital and ICU stay, the reason for admission, anthropometric data at admission and during hospitalization, energy needs, nutritional therapy used, and fasting time. This is a prospective, observational study that will be carried out in a single center in an ICU of a tertiary university hospital. The study population will undergo 3 tomographic images and 3 ultrasounds of the rectus femoris of each patient at different times. We propose, unprecedentedly, performing a validation study of ultrasound with the gold standard Computed tomography to evaluate the musculature of critically ill patients victims of traumatic brain injury. The results got will texto be fundamental for the development of new fields of investigation and certainly contribute to the discovery of a new approach to treat sarcopenia in critically ill patients. The Research Ethics Committee approved the study and all patients included will sign an informed consent form. (Clinical Record: RBR-2bzspnz).

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Precocity and assertiveness when diagnosing brain death are essential for identifying potential donors. To assess the knowledge of physicians about brain death and organ donation, cross-sectional web-based survey was carried out with physicians from different specialties. The knowledge about brain death and organ donation was assessed by a questionnaire with 12 multiple-choice or multiple-answer questions (possible range from 0 to 12). The nonparametric Mann-Whitney and Kruskal-Wallis tests were performed to verify the association between the physicians' knowledge and others variables. The project was approved by the Research Ethics Committee of the Hospital das Clínicas, Faculty of Medicine of Ribeirão Preto, University of São Paulo, under number 4.022.657, and all patients agreed to participate and provided free prior-informed consent. Three hundred sixty physicians were included in this study, most of them have postgraduate (55%) and 59.2% were intensive care physicians. The median of responses was 5 (obtained range from 0 to 10). The participants were classified in 2 groups: with satisfactory knowledge (scores above 5) or without satisfactory knowledge (scores equal/below 5). There was better performance among participants who: completed graduation between 6 and 10 years (P < .012); were intensive care physicians (P < .002); had participated in training courses (P < .001); and those who had worked in intensive care unit (ICU) from 6 to 10 years (P < .023); had performed over 10 brain death protocols (P < .001), and felt safe to talk to family members about brain death (P < .001). The results showed that the participants had low knowledge about diagnosis of brain death and organ donation protocols despite the majority working in ICUs. Be an intensive care physician, had large time experience in ICU, and had performed brain death protocols were associated with unsatisfactory knowledge concerning the subject.

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We correlated clinical, epidemiological, microbiological, and genomic data of an outbreak with polymyxin B (PB)- and carbapenem-resistant Klebsiella pneumoniae during the COVID-19 pandemic. Twenty-six PB- and carbapenem-resistant K. pneumoniae were isolated from patients in the COVID-19 ICU (Intensive Care Unit), non-COVID-19 ICU (Intensive Care Unit), clinical, or surgical ward. Bacterial identification, drug susceptibility tests, and DNA sequencing were performed, followed by in silico resistance genes identification. All isolates showed extensively drug-resistant (XDR) phenotypes. Four different sequence types (ST) were detected: ST16, ST11, ST258, and ST437. Nineteen isolates were responsible for an outbreak in the ICU in September 2020. They belong to ST258 and harbored the 42Kb IncX3plasmid (pKP98M3N42) with the same genomic pattern of two K. pneumoniae identified in 2018. Twenty-four isolates carried bla-KPC-2 gene. No plasmid-mediated colistin (mcr) resistance genes were found. Eight isolates presented mgrB gene mutation. The clonal isolates responsible for the outbreak came from patients submitted to pronation, with high mortality rates in one month. XDR-K. pneumoniae detected during the outbreak presented chromosomal resistance to PB and plasmid-acquired carbapenem resistance due to KPC production in most isolates and 42Kb IncX3(pKP98M3N42) plasmid carrying blaKPC-2 was associated with ST258 isolates. The outbreak followed the collapse of the local healthcare system with high mortality rates.

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In the present study, the levels of serum and airway soluble chemokines, pro-inflammatory/regulatory cytokines, and growth factors were quantified in critically ill COVID-19 patients (total n=286) at distinct time points (D0, D2-6, D7, D8-13 and D>14-36) upon Intensive Care Unit (ICU) admission. Augmented levels of soluble mediators were observed in serum from COVID-19 patients who progress to death. An opposite profile was observed in tracheal aspirate samples, indicating that systemic and airway microenvironment diverge in their inflammatory milieu. While a bimodal distribution was observed in the serum samples, a unimodal peak around D7 was found for most soluble mediators in tracheal aspirate samples. Systems biology tools further demonstrated that COVID-19 display distinct eccentric soluble mediator networks as compared to controls, with opposite profiles in serum and tracheal aspirates. Regardless the systemic-compartmentalized microenvironment, networks from patients progressing to death were linked to a pro-inflammatory/growth factor-rich, highly integrated center. Conversely, patients evolving to discharge exhibited networks of weak central architecture, with lower number of neighborhood connections and clusters of pro-inflammatory and regulatory cytokines. All in all, this investigation with robust sample size landed a comprehensive snapshot of the systemic and local divergencies composed of distinct immune responses driven by SARS-CoV-2 early on severe COVID-19.

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a hyperinflammatory state and lymphocytopenia, a hallmark that appears as both signature and prognosis of disease severity outcome. Although cytokine storm and a sustained inflammatory state are commonly associated with immune cell depletion, it is still unclear whether direct SARS-CoV-2 infection of immune cells could also play a role in this scenario by harboring viral replication. We found that monocytes, as well as both B and T lymphocytes, were susceptible to SARS-CoV-2 infection in vitro, accumulating double-stranded RNA consistent with viral RNA replication and ultimately leading to expressive T cell apoptosis. In addition, flow cytometry and immunofluorescence analysis revealed that SARS-CoV-2 was frequently detected in monocytes and B lymphocytes from coronavirus disease 2019 (COVID-19) patients. The rates of SARS-CoV-2-infected monocytes in peripheral blood mononuclear cells from COVID-19 patients increased over time from symptom onset, with SARS-CoV-2-positive monocytes, B cells, and CD4+ T lymphocytes also detected in postmortem lung tissue. These results indicated that SARS-CoV-2 infection of blood-circulating leukocytes in COVID-19 patients might have important implications for disease pathogenesis and progression, immune dysfunction, and virus spread within the host.

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BACKGROUND: We aimed to evaluate the impact of providing dental care to critically ill patients on their risk of death and ventilator-associated pneumonia (VAP). METHODS: A quasi-experimental study was conducted in 2 intensive care units (ICU) from 2016 to 2019. The intervention consisted of implementing routine dental care, focusing on oral hygiene and periodontal treatment, at least 3 times a week, for patients admitted to the study units. In the pre-intervention period, routine oral hygiene was provided by the ICU nursing staff. The primary and secondary study outcomes were mortality, evaluated at the end of the ICU stay, and VAP incidence density, respectively. Data were analyzed using the ARIMA (autoregressive integrated moving average) time series model in R software. RESULTS: During the intervention period, 5,147 dental procedures were performed among 355 patients. The time series showed that ICU mortality was 36.11%, 32.71%, and 32.30% within the 3 years before the intervention, and 28.71% during the intervention period (P = .015). VAP incidence density did not significantly change during the study period (P = .716). CONCLUSION: A dental care intervention focused on oral hygiene and periodontal treatment regularly provided by dentists to critically ill patients may decrease their risk of dying in the ICU. Randomized clinical trials should be performed to confirm these findings. TRIAL REGISTRATION: WHO-affiliated Brazilian Clinical Trials Registry. RBR-4jmz36. Registered 7 October 2018, before first patient enrollment.

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INTRODUCTION: Septic shock is a lethal disease responsible for a large proportion of deaths in the Intensive Care Unit (ICU), even with therapy centered on fluid resuscitation, use of vasopressors and empirical antibiotic therapy applied within the first hour of diagnosis. Considering the multifactorial pathophysiology of septic shock and the mechanism of action of vasopressors, some patients may not respond adequately, which can lead to the maintenance of vasodilatation, hypotension and increased morbidity, and mortality. This protocol aims to verify whether the use of methylene blue in septic patients with an early diagnosis can contribute to an earlier resolution of a shock compared to standard treatment. METHODS AND ANALYSIS: This is a study protocol for a single-center randomized clinical trial design in an ICU of a tertiary university hospital. In this study, we intend to include 64 patients aged between 18 and 80 years with a diagnosis of septic shock, of any etiology, with up to 72 hours of evolution after volume restoration, using norepinephrine at a dose ≥0.2 µg/kg/min and vasopressin at a dose of 0.04 IU/min. After the initial approach, we will randomize patients into two groups, standard care, and standard care plus methylene blue. The sample size was calculated in order to show 30% differences in septic shock resolution between groups. The Research Ethics Committee approved the study, and all patients included will sign an informed consent form (Clinical registration: RBR-96584w4).

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OBJECTIVES: Evaluate the impact of ABO histo-blood group type on COVID-19 severity. BACKGROUND: ABO histo-blood type has been associated with different outcomes in infectious diseases. It has also shown a higher proportion of type A patients with SARS-CoV-2. In this observational study, extracted from an ongoing clinical trial on the efficacy of convalescent plasma transfused in COVID-19 patients, we describe the impact of ABO blood type on the risk of developing severe COVID-19. MATERIALS AND METHODS: Seventy-two consecutive patients (37 type A, 23 type O, 11 type B, 1 type AB) with severe (respiratory failure) COVID-19 were included. Control group was composed of 160 individuals randomly selected from the same populational basis. RESULTS: Blood group A was overrepresented (51.39%) in the patient group in relation to the control group (30%), whereas blood group O was less represented (31.94%) in patient than in control group (48%). Odds ratio (A vs. O) was 2.581 (1.381-4.817), CI 95%; p = 0.004. Also, blood group A patients appeared to have more severe disease, given by the scores of the Sequential Organ Failure Assessment and Simplified Acute Physiologic Score 3 (p = 0.036 and p = 0.058, respectively). CONCLUSION: Histo-blood type A is associated with a higher risk of developing severe COVID-19 in relation to blood type O.

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Sepsis remains one of the main causes of death in intensive care unit (ICU) worldwide, despite all technological and scientific advances. Microvesicles (MV) have become promising biomarkers for quick and accurate monitoring of several illnesses. The aim of this pilot study was to characterize and evaluate the performance of MV as biomarker of clinical outcome in septic and trauma patients. For this purpose, 39 subjects, both genders, aging from 18 to 85 years were included in three groups referred as Sepsis, Trauma and Healthy Control. Kinetic analysis of MV was carried out at four consecutive time points: admission (baseline)/T1, 24 h/T2, 72 h/T3 and outcome/T4 of discharge or death. At admission, an overall increase in total MV (Annexin V+) was observed in Sepsis.MV CD14+ (monocytes) was a putative biomarker to identify trauma patients, while MV CD3+ (T-cells) and CD41+ (platelets) were qualified to discriminated Trauma from Sepsis. Sepsis (Death) presented an increase in MV Annexin V+, CD45+, CD16+, CD14+, and CD41+ in comparison to Sepsis (Discharge). Moreover, Trauma (Death) presented an increase of MV CD3+ and CD235+ as compared to Trauma (Discharge). Analysing the ROC curve of specific MV evaluated according to performance, an accuracy of 100% was found to segregate the outcome in sepsis, and 95% in trauma. Our findings suggest that MV might be useful as a potential role in discriminating outcome in patients with sepsis/septic shock and trauma with high accuracy. However, further studies with a larger number of participants will be necessary to validate our findings.

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OBJECTIVE: to assess the demand for Intensive Care Unit beds as well as the classification of the patients for admission, according to the priority system. METHOD: a retrospective and cross-sectional study, developed from January2014 to December2018 in two Intensive Care Units for adults of a university hospital. The sample consisted of the requests for vacancies according to the priority system(scale from 1 to 4, where 1 is the highest priority and 4 is no priority), registered in the institution's electronic system. RESULTS: a total of 8,483 vacancies were requested, of which 4,389(51.7%) were from unitB. The highest percentage in unitA was of Priority2 patients(32.6%); and Priority1 was prevalent in unitB(45.4%). The median lead time between request and admission to unitA presented a lower value for priority1 patients(2h57) and a higher value for priority4 patients(11h24); in unitB, priority4 patients presented shorter time(5h54) and priority3 had longer time(11h54). 40.5% of the requests made to unitA and 48.5% of those made to unitB were fulfilled, with 50.7% and 48.5% of these patients being discharged from the units, respectively. CONCLUSION: it is concluded that the demand for intensive care beds was greater than their availability. Most of the patients assisted were priorities1 and2, although a considerable percentage of those classified as priorities3 and4 is observed.

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