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Abstract Background Sepsis is a life-threatening condition which may arise from infection in any organ system and requires early recognition and management. Healthcare professionals working in any specialty may need to manage patients with sepsis. Educating medical students about this condition may be an effective way to ensure all future doctors have sufficient ability to diagnose and treat septic patients. However, there is currently no consensus on what competencies medical students should achieve regarding sepsis recognition and treatment. This study aims to outline what sepsis-related competencies medical students should achieve by the end of their medical student training in both high or upper-middle incomes countries/regions and in low or lower-middle income countries/regions. Methods Two separate panels from high or upper-middle income and low or lower-middle income countries/regions participated in a Delphi method to suggest and rank sepsis competencies for medical students. Each panel consisted of 13–18 key stakeholders of medical education and doctors in specialties where sepsis is a common problem (both specialists and trainees). Panelists came from all continents, except Antarctica. Results The panels reached consensus on 38 essential sepsis competencies in low or lower-middle income countries/regions and 33 in high or upper-middle incomes countries/regions. These include competencies such as definition of sepsis and septic shock and urgency of antibiotic treatment. In the low or lower-middle income countries/regions group, consensus was also achieved for competencies ranked as very important, and was achieved in 4/5 competencies rated as moderately important. In the high or upper-middle incomes countries/regions group, consensus was achieved in 41/57 competencies rated as very important but only 6/11 competencies rated as moderately important. Conclusion Medical schools should consider developing curricula to address essential competencies, as a minimum, but also consider addressing competencies rated as very or moderately important.

RESUMO Introdução: Há diversas terapias sendo utilizadas, consideradas ou propostas para o tratamento da COVID-19, muitas carecendo de apropriada avaliação de efetividade e segurança. O propósito deste documento é fornecer recomendações baseadas nas evidências científicas disponíveis e em sua interpretação transparente, para subsidiar decisões sobre o tratamento farmacológico da COVID-19 no Brasil. Métodos: Um grupo de 27 especialistas e metodologistas integraram a força-tarefa formada pela Associação de Medicina Intensiva Brasileira (AMIB), pela Sociedade Brasileira de Infectologia (SBI) e pela Sociedade Brasileira de Pneumologia e Tisiologia (SBPT). Foram realizadas revisões sistemáticas rápidas, atualizadas até 28 de abril de 2020. A qualidade das evidências e a elaboração das recomendações seguiram o sistema GRADE. As recomendações foram elaboradas nos dias 5, 8 e 13 de maio de 2020. Resultados: Foram geradas 11 recomendações, embasadas em evidência de nível baixo ou muito baixo. Não há indicação para uso de rotina de hidroxicloroquina, cloroquina, azitromicina, lopinavir/ritonavir, corticosteroides ou tocilizumabe no tratamento da COVID-19. Heparina deve ser utilizada em doses profiláticas no paciente hospitalizado, mas não deve ser realizada anticoagulação na ausência de indicação clínica específica. Antibacterianos e oseltamivir devem ser considerados somente nos pacientes em suspeita de coinfecção bacteriana ou por influenza, respectivamente. Conclusão: Até o momento, não há intervenções farmacológicas com efetividade e segurança comprovada que justifiquem seu uso de rotina no tratamento da COVID-19, devendo os pacientes serem tratados preferencialmente no contexto de pesquisa clínica. As recomendações serão revisadas continuamente, de forma a capturar a geração de novas evidências.

Abstract Background The quality of clinical care of brain-dead potential organ donors may help reduce donor losses caused by irreversible or unreversed cardiac arrest and increase the number of organs donated. We sought to determine whether an evidence-based, goal-directed checklist for donor management in intensive care units (ICUs) can reduce donor losses to cardiac arrest. Methods/design The DONORS study is a multicentre, cluster-randomised controlled trial with a 1:1 allocation ratio designed to compare an intervention group (goal-directed checklist for brain-dead potential organ donor management) with a control group (standard ICU care). The primary outcome is loss of potential donors due to cardiac arrest. Secondary outcomes are the number of actual organ donors and the number of solid organs recovered per actual donor. Exploratory outcomes include the achievement of relevant clinical goals during the management of brain-dead potential organ donors. The present statistical analysis plan (SAP) describes all primary statistical procedures that will be used to evaluate the results and perform exploratory and sensitivity analyses of the trial. Discussion The SAP of the DONORS study aims to describe its analytic procedures, enhancing the transparency of the study. At the moment of SAP subsmission, 63 institutions have been randomised and were enrolling study participants. Thus, the analyses reported herein have been defined before the end of the study recruitment and database locking. Trial registration ClinicalTrials.gov, NCT03179020 . Registered on 7 June 2017.

Sepsis is a global health emergency, which is caused by various sources of infection that lead to changes in gene expression, protein-coding, and metabolism. Advancements in “omics” technologies have provided valuable tools to unravel the mechanisms involved in the pathogenesis of this disease. In this study, we performed shotgun mass spectrometry in peripheral blood mononuclear cells (PBMC) from septic patients (N=24) and healthy controls (N=9) and combined these results with two public microarray leukocytes datasets. Through combination of transcriptome and proteome profiling, we identified 170 co‐differentially expressed genes/proteins. Among these, 122 genes/proteins displayed the same expression trend. Ingenuity Pathway Analysis revealed pathways related to lymphocyte functions with decreased status, and defense processes that were predicted to be strongly increased. Protein-protein interaction network analyses revealed two densely connected regions, which mainly included down‐regulated genes/proteins that were related to the transcription of RNA, translation of proteins, and mitochondrial translation. Additionally, we identified one module comprising of up‐regulated genes/proteins, which were mainly related to low-density neutrophils (LDNs). LDNs were reported in sepsis and in COVID-19. Changes in gene expression level were validated using quantitative real-time PCR in PBMCs from patients with sepsis. To further support that the source of the upregulated module of genes/proteins found in our results were derived from LDNs, we identified an increase of this population by flow cytometry in PBMC samples obtained from the same cohort of septic patients included in the proteomic analysis. This study provides new insights into a reprioritization of biological functions in response to sepsis that involved a transcriptional and translational shutdown of genes/proteins, with exception of a set of genes/proteins related to LDNs and host‐defense system.

Introduction Daily multidisciplinary rounds (DMRs) consist of systematic patient-centred discussions aiming to establish joint therapeutic goals for the next 24 hours of intensive care unit (ICU) care. The aim of the present study protocol is to evaluate whether an intervention consisting of guided DMRs, supported by a remote specialist and audit/feedback on care performance will reduce ICU length of stay compared with a control group.Methods and analysis A multicentre, controlled, cluster-randomised superiority trial including 30 ICUs in Brazil (15 intervention and 15 control), from August 2019 to June 2021. In a parallel assignment, ICUs are randomised to a complex-intervention composed by daily rounds carried out through Tele-ICU by a remote ICU physician; development of local quality indicators dashboards coupled with monthly meetings with local leadership; and dissemination of evidence-based clinical protocols versus usual care. Primary outcome is ICU length of stay. Secondary outcomes include classification of the unit according to the profiles defined by the standardised resource use and the standardised mortality rate, hospital mortality, incidence of healthcare-associated infections, ventilator-free days at 28 days, patient-days receiving oral or enteral feeding, patient-days under light sedation or alert and calm, rate of patients under normoxaemia. All adult patients admitted after the beginning of the study in each participant ICU will be enrolled. Inclusion criteria (clusters): public Brazilian ICUs with a minimum of 8 ICU beds interested/committed to participating in the study. Exclusion criteria (clusters): units with fully established DMRs by an intensivist, specialised or step-down units.Ethics and dissemination The study protocol was approved by the institutional review board (IRB) of the coordinator centre, and by IRBs of each enrolled hospital/ICU. Statistical analysis protocol is being prepared for submission before the end of patient’s enrolment. Results will be disseminated through conferences, peer-reviewed journals and to each participating unit.Trial registration number NCT03920501; Pre-results.

Abstract Objectives Primary objective: To estimate the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization. Secondary objectives: To examine whether the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization varies between subgroups related to treatment characteristics, disease severity at the time of randomization, patient characteristics, or risk of bias. To examine the effect of corticosteroids compared with usual care or placebo on serious adverse events. Study design Prospective meta-analysis of randomized controlled trials. Both placebo-controlled and open-label trials are eligible. Participants Hospitalised, critically ill patients with suspected or confirmed COVID-19. Intervention and comparator Intervention groups will have received therapeutic doses of a steroid (dexamethasone, hydrocortisone or methylprednisolone) with IV or oral administration immediately after randomization. The comparator groups will have received standard of care or usual care or placebo. Main outcome All-cause mortality up to 28 days after randomization. Search methods Systematic searching of clinicaltrials.gov , EudraCT, the WHO ISRCTN registry, and the Chinese clinical trials registry. Additionally, research and WHO networks will be asked for relevant trials. Risk of bias assessments These will be based on the Cochrane RoB 2 tool, and will use structured information provided by the trial investigators on a form designed for this prospective meta-analysis. Summary of findings We will use GRADE to assess the certainty of the evidence. Statistical analyses Trial investigators will provide data on the numbers of participants who did and did not experience each outcome according to intervention group, overall and in specified subgroups. We will conduct fixed-effect (primary analysis) and random-effects (Paule-Mandel estimate of heterogeneity and Hartung-Knapp adjustment) meta-analyses. We will quantify inconsistency in effects between trials using I2 statistics. Evidence for subgroup effects will be quantified by ratios of odds ratios comparing effects in the subgroups, and corresponding interaction p-values. Comparisons between subgroups defined by trial characteristics will be made using random-effects meta-regression. Comparisons between subgroups defined by patient characteristics will be made by estimating trial-specific ratios of odds ratios comparing intervention effects between subgroups then combining these using random-effects meta-analysis. Steroid interventions will be classified as high or low dose according to whether the dose is greater or less than or equal to 400 mg hydrocortisone per day or equivalent. We will use network meta-analysis methods to make comparisons between the effects of high and low dose steroid interventions (because one trial randomized participants to both low and high dose steroid arms). PROSPERO registration number CRD42020197242 Full protocol The full protocol for this prospective meta-analysis is attached as an additional file, accessible from the Trials website (Additional file 1). To expedite dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol for the systematic review.

Abstract Background Most adult intensive care units (ICUs) worldwide adopt restrictive family visitation models (RFVMs). However, evidence, mostly from non-randomized studies, suggests that flexible adult ICU visiting hours are safe policies that can result in benefits such as prevention of delirium and increase in satisfaction with care. Accordingly, the ICU Visits Study was designed to compare the effectiveness and safety of a flexible family visitation model (FFVM) vs. an RFVM on delirium prevention among ICU patients, and also to analyze its potential effects on family members and ICU professionals. Methods/design The ICU Visits Study is a cluster-randomized crossover trial which compares an FFVM (12 consecutive ICU visiting hours per day) with an RFVM (

Abstract 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.

Abstract 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.

Abstract Background Controlling blood pH during acute ventilatory failure and hypercapnia in individuals suffering from severe acute kidney injury (AKI) and undergoing continuous renal replacement therapy (CRRT) is of paramount importance in critical care settings. In this situation, the optimal concentration of sodium bicarbonate in the dialysate is still an unsolved question in critical care since high concentrations may worsen carbon dioxide levels and low concentrations may not be as effective in controlling pH. Methods We performed a randomized, non-blinded, experimental study. AKI was induced in 12 female pigs via renal hilum ligation and hypoventilation by reducing the tidal volume during mechanical ventilation with the goal of achieving a pH between 7.10–7.15. After achieving the target pH, animals were randomized to undergo isovolemic hemodialysis with one of two bicarbonate concentrations in the dialysate (40 mEq/L [group 40] vs. 20 mEq/L [group 20]). Results Hemodynamic, respiratory, and laboratory data were collected. The median pH value at CRRT initiation was 7.14 [7.12, 7.15] in group 20 and 7.13 [7.09, 7.14] in group 40 (P = ns). The median baseline PaCO2 was 74 [72, 81] mmHg in group 20 vs. 79 [63, 85] mmHg in group 40 (P = ns). After 3 h of CRRT, the pH value was 7.05 [6.95, 7.09] in group 20 and 7.12 [7.1, 7.14] in group 40 (P

RESUMO Objetivo: Explorar os fatores associados aos níveis sanguíneos da pressão parcial de oxigênio e da pressão parcial de gás carbônico. Métodos: Os fatores associados com a regulação do oxigênio e de gás carbônico foram investigados em um modelo com porcos em apneia com suporte de oxigenação por membrana extracorpórea venovenosa. Foi testada uma sequência predefinida de fluxos de sangue e gás. Resultados: A oxigenação associou-se principalmente com o fluxo da oxigenação por membrana extracorpórea (coeficiente beta = 0,036mmHg/mL/minuto), débito cardíaco (coeficiente beta = -11,970mmHg/L/minuto) e shunt pulmonar (coeficiente beta = -0,232mmHg/%). As mensurações iniciais da pressão parcial de oxigênio e da pressão parcial de gás carbônico também se associaram com oxigenação, com coeficientes beta de 0,160 e 0,442mmHg/mmHg, respectivamente. A pressão parcial de gás carbônico se associou com débito cardíaco (coeficiente beta = 3,578mmHg/L/minuto), fluxo de gás (coeficiente beta = -2,635mmHg/L/minuto), temperatura (coeficiente beta = 4,514mmHg/°C), pH inicial (coeficiente beta = -66,065mmHg/0,01 unidade) e hemoglobina (coeficiente beta = 6,635mmHg/g/dL). Conclusão: Elevações nos fluxos de sangue de gás em um modelo de oxigenação por membrana extracorpórea venovenosa durante apneia resultaram em aumento da pressão parcial de oxigênio e redução da pressão parcial de gás carbônico, respectivamente. Ainda, sem a possibilidade de uma inferência causal, a pressão parcial de oxigênio associou-se negativamente com o shunt pulmonar e o débito cardíaco, e a pressão parcial de gás carbônico teve associação positiva com o débito cardíaco, temperatura central e hemoglobina inicial.

RESUMO Objetivo: Avaliar as concentrações séricas e a variação de vitamina D em pacientes com sepse grave ou choque séptico e indivíduos controles na admissão e após 7 dias de internação na unidade de terapia intensiva, correlacionando-os com a gravidade da disfunção orgânica. Métodos: Estudo caso-controle, prospectivo e observacional em pacientes com mais de 18 anos com sepse grave ou choque séptico pareados com grupo controle. Foi realizada dosagem sérica de vitamina D na inclusão (D0) e no sétimo dia (D7). Definiu-se deficiência grave se vitamina D < 10ng/mL, deficiência se entre 10 e 20ng/mL, insuficiência se entre 20 e 30ng/mL e suficiência se ≥ 30ng/mL. Consideramos melhora a modificação para qualquer classificação mais elevada, associada ao incremento de 50% dos valores absolutos. Resultados: Incluímos 51 pacientes (26 sépticos e 25 controles). A prevalência de concentrações de vitamina D ≤ 30ng/mL foi de 98%. Não houve correlação entre a concentração sérica de vitamina D no D0 e o escore SOFA no D0 ou com sua variação após 7 dias, tanto na população geral quanto nos sépticos. Pacientes com melhora da deficiência tiveram melhora no escore SOFA no D7 (p = 0,013). Conclusão: Na população estudada, os pacientes sépticos apresentaram melhora das concentrações séricas de vitamina D no sétimo dia em comparação com controles. Encontramos associação entre a melhora das concentrações de vitamina D e a maior redução da intensidade de disfunção orgânica.

RESUMO Objetivo: Analisar as correlações da taxa de fluxo sanguíneo e rotação da bomba com a pressão transmembrana e a transferência de CO2 e O2 durante o suporte respiratório extracorpóreo. Métodos: Cinco animais foram instrumentalizados e submetidos à oxigenação extracorpórea de membrana em um protocolo de cinco fases, as quais incluíam sepse abdominal e lesão pulmonar. Resultados: Este estudo demonstrou que as variações da taxa de fluxo sanguíneo e rotação da bomba dependem, de forma logarítmica positiva, do fluxo sanguíneo na membrana extracorpórea de oxigenação. As variações da taxa de fluxo sanguíneo e rotação da bomba têm associação negativa com a pressão transmembrana (R2 = 0,5 para o fluxo sanguíneo = 1.500mL/minuto e R2 = 0,4 para o fluxo sanguíneo = 3.500mL/minuto, ambos com p < 0,001) e associação positiva com as variações de transferência de CO2 (R2 = 0,2 para o fluxo do gás de varredura ≤ 6L/minuto, p < 0,001, e R2 = 0,1 para o fluxo de gás de varredura > 6L/minuto, p = 0,006). A taxa de fluxo sanguíneo com a rotação da bomba não se associa às variações na transferência de O2 (R2 = 0,01 para o fluxo sanguíneo = 1.500mL/minuto, p = 0,19, e R2 = -0,01 ao fluxo sanguíneo = 3.500mL/minuto, p = 0,46). Conclusão: Neste modelo em animais, a variação da taxa de fluxo sanguíneo e rotação da bomba se associa negativamente com a pressão transmembrana e positivamente com a transferência de CO2. Conforme a situação clínica, uma diminuição na taxa do fluxo sanguíneo e rotação da bomba pode, na ausência de hipoxemia, indicar uma disfunção do pulmão artificial.

Objetivo: Avaliar os efeitos imediatos da transfusão de hemácias nos níveis de saturação venosa central de oxigênio e de lactato em pacientes com choque séptico usando diferentes níveis gatilho de hemoglobina para indicar transfusão. Métodos: Incluímos pacientes com diagnóstico de choque séptico nas últimas 48 horas e níveis de hemoglobina abaixo de 9,0g/dL. Os pacientes foram randomizados para receber imediatamente transfusão se as concentrações se mantivessem acima de 9,0g/dL (Grupo Hb9) ou adiar a transfusão até que a hemoglobina caísse abaixo de 7,0g/dL (Grupo Hb7). Os níveis de hemoglobina, lactato e saturação venosa central de oxigênio foram determinados antes e 1 hora após cada transfusão. Resultados: Incluímos 46 pacientes, totalizando 74 transfusões. Os pacientes do Grupo Hb7 tiveram uma redução significante nos níveis medianos de lactato de 2,44 (2,00 - 3,22) mMol/L para 2,21 (1,80 - 2,79) mMol/L; p = 0,005. Isto não foi observado no Grupo Hb9 [1,90 (1,80 - 2,65) mMol/L para 2,00 (1,70 - 2,41) mMol/L; p = 0,23]. A saturação venosa central de oxigênio aumentou no Grupo Hb7 [68,0 (64,0 - 72,0)% para 72,0 (69,0 - 75,0)%; p < 0,0001], mas não no Grupo Hb9 [72,0 (69,0 - 74,0)% para 72,0 (71,0 - 73,0)%; p = 0,98]. Pacientes com elevados níveis de lactato ou saturação venosa central de oxigênio menor que 70% na avaliação basal tiveram um aumento significante nessas variáveis, independentemente dos níveis basais de hemoglobina. Pacientes com valores normais não demonstraram diminuição em quaisquer dos grupos. Conclusão: A transfusão de hemácias aumentou a saturação venosa central de oxigênio e diminuiu os níveis de lactato em pacientes com hipoperfusão, independentemente de seus níveis basais de hemoglobina. A transfusão não pareceu influenciar essas variáveis em pacientes sem hipoperfusão. ClinicalTrials.gov NCT01611753

To investigate whether performing alveolar recruitment or adding inspiratory pauses could promote physiologic benefits (VT) during moderately-high-frequency positive pressure ventilation (MHFPPV) delivered by a conventional ventilator in a porcine model of severe acute respiratory distress syndrome (ARDS).Prospective experimental laboratory study with eight pigs. Induction of acute lung injury with sequential pulmonary lavages and injurious ventilation was initially performed. Then, animals were ventilated on a conventional mechanical ventilator with a respiratory rate (RR) = 60 breaths/minute and PEEP titrated according to ARDS Network table. The first two steps consisted of a randomized order of inspiratory pauses of 10 and 30% of inspiratory time. In final step, we removed the inspiratory pause and titrated PEEP, after lung recruitment, with the aid of electrical impedance tomography. At each step, PaCO2 was allowed to stabilize between 57-63 mmHg for 30 minutes.The step with RR of 60 after lung recruitment had the highest PEEP when compared with all other steps (17 [16,19] vs 14 [10, 17]cmH2O), but had lower driving pressures (13 [13,11] vs 16 [14, 17]cmH2O), higher P/F ratios (212 [191,243] vs 141 [105, 184] mmHg), lower shunt (23 [20, 23] vs 32 [27, 49]%), lower dead space ventilation (10 [0, 15] vs 30 [20, 37]%), and a more homogeneous alveolar ventilation distribution. There were no detrimental effects in terms of lung mechanics, hemodynamics, or gas exchange. Neither the addition of inspiratory pauses or the alveolar recruitment maneuver followed by decremental PEEP titration resulted in further reductions in VT.During MHFPPV set with RR of 60 bpm delivered by a conventional ventilator in severe ARDS swine model, neither the inspiratory pauses or PEEP titration after recruitment maneuver allowed reduction of VT significantly, however the last strategy decreased driving pressures and improved both shunt and dead space.

Background and objectives: anemia is a common clinical finding in intensive care units. The red blood cell transfusion is the main form of treatment, despite the associated risks. Thus, we proposed to evaluate the profile of transfusional patients in different intensive care units. Methods: prospective analysis of patients admitted in the intensive care units of a tertiary university hospital with an indication for transfusion of packed red blood cells. Demographic profile and transfusional profile were collected, a univariate analysis was done, and the results were considered significant at p = 0.05. Results: 408 transfusions were analyzed in 71 patients. The mean hemoglobin concentration on admission was 9.7 ± 2.3 g/dL and the pre-transfusional concentration was 6.9 ± 1.1 g/dL. The main indications for transfusion were hemoglobin concentration (49%) and active bleeding (32%). The median number of units transfused per episode was 2 (1-2) and the median storage time was 14 (7-21) days. The number of patients transfused with hemoglobin levels greater than 7 g/dL and the number of bags transfused per episode were significantly different among intensive care units. Patients who received three or more transfusions had longer mechanical ventilation time and intensive care unit stay and higher mortality after 60 days. There was an association of mortality with disease severity but not with transfusional characteristics. Conclusions: the practice of blood products transfusion was partially in agreement with the guidelines recommended, although there are differences in behavior between the different profiles of intensive care units. Transfused patients evolved with unfavorable outcomes. Despite the scarcity of blood in blood banks, the mean storage time of the bags was high.

OBJECTIVE: Veno-venous extracorporeal oxygenation for respiratory support has emerged as a rescue alternative for patients with hypoxemia. However, in some patients with more severe lung injury, extracorporeal support fails to restore arterial oxygenation. Based on four clinical vignettes, the aims of this article were to describe the pathophysiology of this concerning problem and to discuss possibilities for hypoxemia resolution. METHODS: Considering the main reasons and rationale for hypoxemia during veno-venous extracorporeal membrane oxygenation, some possible bedside solutions must be considered: 1) optimization of extracorporeal membrane oxygenation blood flow; 2) identification of recirculation and cannula repositioning if necessary; 3) optimization of residual lung function and consideration of blood transfusion; 4) diagnosis of oxygenator dysfunction and consideration of its replacement; and finally 5) optimization of the ratio of extracorporeal membrane oxygenation blood flow to cardiac output, based on the reduction of cardiac output. CONCLUSION: Therefore, based on the pathophysiology of hypoxemia during veno-venous extracorporeal oxygenation support, we propose a stepwise approach to help guide specific interventions.

OBJECTIVES: The aim of this manuscript is to describe the first year of our experience using extracorporeal membrane oxygenation support. METHODS: Ten patients with severe refractory hypoxemia, two with associated severe cardiovascular failure, were supported using venous-venous extracorporeal membrane oxygenation (eight patients) or veno-arterial extracorporeal membrane oxygenation (two patients). RESULTS: The median age of the patients was 31 yr (range 14-71 yr). Their median simplified acute physiological score three (SAPS3) was 94 (range 84-118), and they had a median expected mortality of 95% (range 87-99%). Community-acquired pneumonia was the most common diagnosis (50%), followed by P. jiroveci pneumonia in two patients with AIDS (20%). Six patients were transferred from other ICUs during extracorporeal membrane oxygenation support, three of whom were transferred between ICUs within the hospital (30%), two by ambulance (20%) and one by helicopter (10%). Only one patient (10%) was anticoagulated with heparin throughout extracorporeal membrane oxygenation support. Eighty percent of patients required continuous venous-venous hemofiltration. Three patients (30%) developed persistent hypoxemia, which was corrected using higher positive end-expiratory pressure, higher inspired oxygen fractions, recruitment maneuvers, and nitric oxide. The median time on extracorporeal membrane oxygenation support was five (range 3-32) days. The median length of the hospital stay was 31 (range 3-97) days. Four patients (40%) survived to 60 days, and they were free from renal replacement therapy and oxygen support. CONCLUSIONS: The use of extracorporeal membrane oxygenation support in severely ill patients is possible in the presence of a structured team. Efforts must be made to recognize the necessity of extracorporeal respiratory support at an early stage and to prompt activation of the extracorporeal membrane oxygenation team.

OBJETIVO: Investigar o impacto hemodinâmico, respiratório e metabólico do contato do sangue suíno com o volume do primming e com o circuito extracorpóreo da oxigenação por membrana extracorpórea, antes do início da ventilação e da oxigenação da membrana. MÉTODOS: Cinco animais foram instrumentados e submetidos a oxigenação por membrana extracorpórea. Os dados foram coletados no basal e 30 minutos depois do início da circulação extracorpórea, ainda sem o fluxo de ventilação da membrana. RESULTADOS: Depois do início da circulação pela membrana, houve elevação não significativa da resistência vascular pulmonar de 235 (178,303) para 379 (353,508) dyn.seg.(cm5)-1 (p=0,065), associada a uma elevação no gradiente alveolo arterial de oxigênio de 235 (178,303) para 379 (353,508) mmHg (p=0,063). Foi observada também uma queda no trabalho sistólico do ventrículo esquerdo de 102 (94,105) para 78 (71,87) (mL.mmHg)/batimento (p=0,064), em paralelo a uma redução do débito cardíaco de 7,2 (6,8-7,6) para 5,9 (5,8-6,3) L/min (p=0,188). O trabalho sistólico do ventrículo direito foi contrabalanceado entre o aumento da resistência vascular pulmonar e a queda do débito cardíaco, mantendo-se estável. CONCLUSÕES: O modelo é seguro e factível. O contato do sangue dos animais com o primming e o circuito extracorpóreo resultou em alterações sistêmicas e metabólicas não significativas.

Em 2009, muitos casos de infecção pulmonar com hipoxemia grave refratária às estratégias ventilatórias habitualmente utilizadas e às manobras de resgate para a síndrome do desconforto respiratório agudo foram relatados durante a epidemia por influenza A (H1N1). Em muitos desses pacientes, o uso de extracorporeal membrane oxygenation (ECMO, oxigenação extracorpórea por membrana) foi necessário, fato que fez reacender o interesse na ECMO globalmente. O Grupo De Estudos em Suporte Extracorpóreo foi criado visando a aprender a técnica e a utilizar ECMO no tratamento de pacientes com hipoxemia grave. Neste artigo, são discutidas as indicações de ECMO e é relatado o caso de uma paciente com hipoxemia refratária que foi tratada através de ECMO de forma bem sucedida.In 2009, during the influenza A (H1N1) epidemic, there were many reported cases of pulmonary infection with severe hypoxemia that was refractory to the ventilatory strategies and rescue therapies commonly used to treat patients with severe acute respiratory distress syndrome. Many of those cases were treated with extracorporeal membrane oxygenation (ECMO), which renewed international interest in the technique. The Extracorporeal Support Study Group was created in order to practice ECMO and to employ it in the treatment of patients with severe hypoxemia. In this article, we discuss the indications for using ECMO and report the case of a patient with refractory hypoxemia who was successfully treated with ECMO.

OBJETIVO: Avaliar o efeito de alterações hemodinâmicas, respiratórias e metabólicas sobre a pressão intracraniana em um modelo de lesão pulmonar aguda e síndrome compartimental abdominal. MÉTODOS: Oito porcos Agroceres foram submetidos, após a instrumentação, a cinco cenários clínicos: 1) estado basal com baixa pressão intra-abdominal e pulmão sadio; 2) pneumoperitôneo, com pressão intra-abdominal de 20 mm Hg; 3) lesão pulmonar aguda induzida por lavagem pulmonar e desativação de surfactante; 4) pneumoperitôneo com pressão intra-abdominal de 20 mm Hg na vigência de lesão pulmonar aguda e com PEEP baixo; e 5) PEEP ajustado a 27 cm H2O na vigência de pneumoperitôneo e lesão pulmonar aguda. Variáveis respiratórias e hemodinâmicas foram coletadas. Análise multivariada foi realizada buscando as variáveis associadas com elevação da pressão intracraniana nos cinco cenários estudados. RESULTADOS: Após a análise multivariada, nas situações não associadas com lesão pulmonar aguda apenas a pressão de platô das vias aéreas se correlacionou positivamente com a pressão intracraniana. Nos modelos associados com lesão pulmonar aguda, a pressão de platô de vias aéreas, a pressão arterial de CO2, o CO2 no final da expiração e a pressão venosa central se correlacionaram positivamente com incrementos da pressão intracraniana. CONCLUSÃO: Em um modelo de disfunção orgânica múltipla com situações clínicas associadas com aumento da pressão torácica e abdominal, o incremento da pressão intracraniana desencadeado pela elevação da pressão abdominal parece ser decorrente da piora da complacência do sistema respiratório e da redução do gradiente para drenagem venosa cerebral ocasionado pela elevação da pressão venosa central.OBJECTIVE: To evaluate the effects of hemodynamic, respiratory and metabolic changes on intracranial pressure in a model of acute lung injury and abdominal compartment syndrome. METHODS: Eight Agroceres pigs were submitted to five different clinical scenarios after instrumentation: 1) a baseline condition with low intra-abdominal pressure and healthy lungs; 2) pneumoperitoneum with 20 mmHg intra-abdominal pressure; 3) acute lung injury induced by pulmonary lavage with surfactant deactivation; 4) pneumoperitoneum with 20 mmHg intra-abdominal pressure with lung pulmonary injury and low positive end-expiratory pressure; and 5) 27 cmH2O positive end-expiratory pressure with pneumoperitoneum and acute lung injury. Respiratory and hemodynamic variables were collected. A multivariate analysis was conducted to search for variables associated with increased intracranial pressure in the five scenarios. RESULTS: Only plateau airway pressure showed a positive correlation with intracranial pressure in the multivariate analysis. In the models with acute lung injury, plateau airway pressure, CO2 arterial pressure, end tidal CO2 and central venous pressure were positively correlated with increased intracranial pressure. CONCLUSION: In a model of multiple organ dysfunction with associated clinical conditions causing increased intra-thoracic and abdominal pressure, increased intracranial pressure triggered by elevated intra-abdominal pressure is apparently caused by worsened respiratory system compliance and a reduced brain venous drainage gradient due to increased central venous pressure.

Sepsis is a major cause of mortality and morbidity in intensive care units. Organ dysfunction is triggered by inflammatory insults and tissue hypoperfusion. The brain plays a pivotal role in sepsis, acting as both a mediator of the immune response and a target for the pathologic process. The measurement of brain dysfunction is difficult because there are no specific biomarkers of neuronal injury, and bedside evaluation of cognitive performance is difficult in an intensive care unit. Although sepsis-associated encephalopathy was described decades ago, it has only recently been subjected to scientific scrutiny and is not yet completely understood. The pathophysiology of sepsis-associated encephalopathy involves direct cellular damage to the brain, mitochondrial and endothelial dysfunction and disturbances in neurotransmission. This review describes the most recent findings in the pathophysiology, diagnosis, and management of sepsis-associated encephalopathy and focuses on its many presentations.

PURPOSE: To compare the evolution of standard base excess and serum lactate level between surviving and non surviving patients with severe sepsis and septic shock resuscitated with early goal-directed therapy. METHODS: This is a retrospective study in an intensive care unit of a university tertiary hospital where 65 consecutive severe sepsis and septic shock patients were observed without any intervention in the treatment by the authors of this report. RESULTS: In our study, the mortality of severe sepsis and septic shock patients was 38%. The central venous oxygen saturation of both groups was above 70% after the resuscitative period, excluding the second day of the non survivors group (69.8%). After the second day, the central venous oxygen saturation was significantly higher in the survivors group (P < .001). Standard base excess was initially low in both groups, but from the second day on, the correction of standard base excess was significantly more successful and linear in the survivor group (P < .001). Lactate levels were similar during the evolution of both groups. CONCLUSIONS: Although evolutive standard base excess and serum lactate level are still outcome markers in severe sepsis and septic shock patients resuscitated with early goal-directed therapy, other studies must be performed to clarify if hemodynamic interventions based on standard base excess and serum lactate level could be reliable to improve clinical outcomes in severe sepsis and septic shock patients.

IntroductionResidual inflammation at ICU discharge may have impact upon long-term mortality. However, the significance of ongoing inflammation on mortality after ICU discharge is poorly described. C-reactive protein (CRP) and albumin are measured frequently in the ICU and exhibit opposing patterns during inflammation. Since infection is a potent trigger of inflammation, we hypothesized that CRP levels at discharge would correlate with long-term mortality in septic patients and that the CRP/albumin ratio would be a better marker of prognosis than CRP alone.MethodsWe evaluated 334 patients admitted to the ICU as a result of severe sepsis or septic shock who were discharged alive after a minimum of 72 hours in the ICU. We evaluated the performance of both CRP and CRP/albumin to predict mortality at 90 days after ICU discharge. Two multivariate logistic models were generated based on measurements at discharge: one model included CRP (Model-CRP), and the other included the CRP/albumin ratio (Model-CRP/albumin).ResultsThere were 229 (67%) and 111 (33%) patients with severe sepsis and septic shock, respectively. During the 90 days of follow-up, 73 (22%) patients died. CRP/albumin ratios at admission and at discharge were associated with a poor outcome and showed greater accuracy than CRP alone at these time points (p = 0.0455 and p = 0.0438, respectively). CRP levels and the CRP/albumin ratio were independent predictors of mortality at 90 days (Model-CRP: adjusted OR 2.34, 95% CI 1.14-4.83, p = 0.021; Model-CRP/albumin: adjusted OR 2.18, 95% CI 1.10-4.67, p = 0.035). Both models showed similar accuracy (p = 0.2483). However, Model-CRP was not calibrated.ConclusionsResidual inflammation at ICU discharge assessed using the CRP/albumin ratio is an independent risk factor for mortality at 90 days in septic patients. The use of the CRP/albumin ratio as a long-term marker of prognosis provides more consistent results than standard CRP values alone.

BackgroundPrevious studies showed higher sepsis mortality rates in Brazil compared to other developed or developing countries. Moreover, another trial demonstrated an increased mortality rate in public hospitals compared to private hospitals in Brazil. The reasons for these findings may include delayed recognition and inadequate treatment of sepsis in public facilities. We designed this study to evaluate the factors associated with mortality in septic patients admitted to intensive care units in a network of public and private institutions.Materials and methodsThis study is a retrospective analysis of a prospective cohort of sepsis patients in 19 private and public institutions in Brazil. We analyzed data from the original database and collected additional data to assess compliance to the treatment guidelines and to determine the time from the onset of organ dysfunction and the sepsis diagnosis by the healthcare team.ResultsA total of 396 patients were analyzed. Patients in public hospitals were younger, had a greater number of dysfunctional organs at baseline and a lower chance to have sepsis diagnosed within two hours of the onset of organ dysfunction. Private hospitals had a better compliance to lactate and blood culture sampling and maintenance of glycemic control. The multivariate analysis showed that age, disease severity at baseline and being treated at a public hospital were independent risk factors for mortality. A delay in the sepsis diagnosis of longer than two hours was associated with mortality only in the public setting.ConclusionsWe confirmed a lower sepsis mortality rate in the private hospitals of this network. Being treated in a public hospital was an independent factor for mortality. Delayed recognition of sepsis was more frequent in public institutions and this might have been associated with a higher mortality. Improving sepsis recognition and early diagnosis may be important targets in public institutions.

Bacterial meningitis is associated with significant burden in Brazil. In 2010, both 10-valent pneumococcal conjugate vaccine and meningococcal capsular group C conjugate vaccine were introduced into the routine vaccination schedule. Haemophilus influenzae type b vaccine was previously introduced in 1999. This study presents trends in demographics, microbiological characteristics and seasonality patterns of bacterial meningitis cases in Brazil from 2000 to 2010.All meningitis cases confirmed by clinical and/or laboratory criteria notified to the national information system for notifiable diseases between 2000 and 2010 were analyzed. Proportions of bacterial meningitis cases by demographic characteristics, criteria used for confirmation and etiology were calculated. We estimated disease rates per 100,000 population and trends for the study period, with emphasis on H. influenzae, N. meningitidis and S. pneumoniae cases. In the decade, 341,805 cases of meningitis were notified in Brazil. Of the 251,853 cases with defined etiology, 110,264 (43.8%) were due to bacterial meningitis (excluding tuberculosis). Of these, 34,997 (31.7%) were due to meningococcal disease. The incidence of bacterial meningitis significantly decreased from 3.1/100,000 population in 2000-2002 to 2.14/100,000 in 2009-2010 (p

There is no consensual definition of refractory shock. The use of more than 0.5 mcg/kg/min of norepinephrine or epinephrine to maintain target blood pressure is often used in clinical trials as a threshold. Nearly 6% of critically ill patients will develop refractory shock, which accounts for 18% of deaths in intensive care unit. Mortality rates are usually greater than 50%. The assessment of fluid responsiveness and cardiac function can help to guide therapy, and inotropes may be used if hypoperfusion signs persist after initial resuscitation. Arginine vasopressin is frequently used in refractory shock, although definite evidence to support this practice is still missing. Its associations with corticosteroids improved outcome in observational studies and are therefore promising alternatives. Other rescue therapies such as terlipressin, methylene blue, and high-volume isovolemic hemofiltration await more evidence before use in routine practice.

Extracorporeal membrane oxygenation (ECMO) has gained renewed interest in the treatment of respiratory failure since the advent of the modern polymethylpentene membranes. Limited information exists, however, on the performance of these membranes in terms of gas transfers during multiple organ failure (MOF). We investigated determinants of oxygen and carbon dioxide transfer as well as biochemical alterations after the circulation of blood through the circuit in a pig model under ECMO support before and after induction of MOF. A predefined sequence of blood and sweep flows was tested before and after the induction of MOF with fecal peritonitis and saline lavage lung injury. In the multivariate analysis, oxygen transfer had a positive association with blood flow (slope = 66, P

OBJECTIVES: To assess the impact of vasopressin on the microcirculation and to develop a predictive model to estimate the probability of microcirculatory recruitment in patients with septic shock. METHODS: This prospective interventional study included patients with septic shock receiving noradrenaline for less than 48 hours. We infused vasopressin at 0.04 U/min for one hour. Hemodynamic measurements, including sidestream dark-field imaging, were obtained immediately before vasopressin infusion, 1 hour after vasopressin infusion and 1 hour after vasopressin withdrawal. We defined patients with more than a 10% increase in total vascular density and perfused vascular density as responders. ClinicalTrials.gov: NCT02053675. RESULTS: Eighteen patients were included, and nine (50%) showed improved microcirculation after infusion of vasopressin. The noradrenaline dose was significantly reduced after vasopressin (p=0.001) and was higher both at baseline and during vasopressin infusion in the responders than in the non-responders. The strongest predictor for a favorable microcirculatory response was the dose of noradrenaline at baseline (OR=4.5; 95% CI: 1.2-17.0; p=0.027). For patients using a noradrenaline dose higher than 0.38 mcg/kg/min, the probability that microcirculatory perfusion would be improved with vasopressin was 53% (sensitivity 78%, specificity 77%). CONCLUSIONS: In patients with septic shock for no longer than 48 h, administration of vasopressin is likely to result in an improvement in microcirculation when the baseline noradrenaline dose is higher than 0.38 mcg/kg/min.

RESUMO Objetivo: Caracterizar pacientes graves transportados em suporte respiratório ou cardiovascular extracorpóreo. Métodos: Descrição de uma série de 18 casos registrados no Estado de São Paulo. Todos os pacientes foram consecutivamente avaliados por uma equipe multidisciplinar no hospital de origem. Os pacientes foram resgatados, sendo a oxigenação por membrana extracorpórea instalada in loco. Os pacientes foram, então, transportados para os hospitais referenciados já em oxigenação por membrana extracorpórea. Os dados foram recuperados de um banco de dados prospectivamente coletado. Resultados: De 2011 até 2017, 18 pacientes com 29 (25 - 31) anos, SAPS3 de 84 (68 - 92), com principais diagnósticos de leptospirose e influenza A (H1N1) foram transportados no Estado de São Paulo para três hospitais referenciados. Uma distância mediana de 39 (15 - 82) km foi percorrida em cada missão, em um tempo de 360 (308 - 431) minutos. As medianas de um (0 - 2) enfermeiro, três (2 - 3) médicos e um (0 - 1) fisioterapeuta foram necessárias por missão. Dezessete transportes foram realizados por ambulância e um por helicóptero. Existiram intercorrências: em duas ocasiões (11%), houve falha de fornecimento de energia para a bomba e, em duas ocasiões, queda da saturação de oxigênio < 70%. Treze pacientes (72%) sobreviveram para a alta hospitalar. Dos pacientes não sobreviventes, dois tiveram morte encefálica; dois, disfunção de múltiplos órgãos; e um, fibrose pulmonar considerada irreversível. Conclusões: O transporte com suporte extracorpóreo ocorreu sem intercorrências maiores, com uma sobrevida hospitalar alta dos pacientes.