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Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In this context, biomarkers could be considered as indicators of either infection or dysregulated host response or response to treatment and/or aid clinicians to prognosticate patient risk. More than 250 biomarkers have been identified and evaluated over the last few decades, but no biomarker accurately differentiates between sepsis and sepsis-like syndrome. Published data support the use of biomarkers for pathogen identification, clinical diagnosis, and optimization of antibiotic treatment. In this narrative review, we highlight how clinicians could improve the use of pathogen-specific and of the most used host-response biomarkers, procalcitonin and C-reactive protein, to improve the clinical care of patients with sepsis. Biomarker kinetics are more useful than single values in predicting sepsis, when making the diagnosis and assessing the response to antibiotic therapy. Finally, integrated biomarker-guided algorithms may hold promise to improve both the diagnosis and prognosis of sepsis. Herein, we provide current data on the clinical utility of pathogen-specific and host-response biomarkers, offer guidance on how to optimize their use, and propose the needs for future research., ACM is is supported by a Clinician Scientist Fellowship from the Medical Research Council (MR/V006118/1)

Funding This work received an unrestricted grant from GSK Portugal and was supported by Sociedade Portuguesa de Ginecologia (SPG). Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In this context, biomarkers could be considered as indicators of either infection or dysregulated host response or response to treatment and/or aid clinicians to prognosticate patient risk. More than 250 biomarkers have been identified and evaluated over the last few decades, but no biomarker accurately differentiates between sepsis and sepsis-like syndrome. Published data support the use of biomarkers for pathogen identification, clinical diagnosis, and optimization of antibiotic treatment. In this narrative review, we highlight how clinicians could improve the use of pathogen-specific and of the most used host-response biomarkers, procalcitonin and C-reactive protein, to improve the clinical care of patients with sepsis. Biomarker kinetics are more useful than single values in predicting sepsis, when making the diagnosis and assessing the response to antibiotic therapy. Finally, integrated biomarker-guided algorithms may hold promise to improve both the diagnosis and prognosis of sepsis. Herein, we provide current data on the clinical utility of pathogen-specific and host-response biomarkers, offer guidance on how to optimize their use, and propose the needs for future research. publishersversion epub_ahead_of_print

Contains fulltext : 252214.pdf (Publisher’s version ) (Open Access) BACKGROUND: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. METHODS: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. FINDINGS: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H(2)O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p

Funding Information: The Société Française d’Anesthésie et de Réanimation (SFAR), Sociedad Española de Medicina Intensiva, Crítica y Unidades Coronarias (SEMICYUC), Sociedad Argentina de Terapia Intensiva (SATI), Sociedad Chilena de Medicina Intensiva (SOCHIMI), Associação de Medicina Intensiva Brasileira (AMIB-Net) and the Brazilian Research in Intensive Care Network (BricNet) supported this survey. We would also like to thank our friend Tiago Rocha for making the amazing logo for this study. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brazil (CAPES)—Finance Code 001. Publisher Copyright: © 2022, The Author(s). Background: Since the publication of the 2018 Clinical Guidelines about sedation, analgesia, delirium, mobilization, and sleep deprivation in critically ill patients, no evaluation and adequacy assessment of these recommendations were studied in an international context. This survey aimed to investigate these current practices and if the COVID-19 pandemic has changed them. Methods: This study was an open multinational electronic survey directed to physicians working in adult intensive care units (ICUs), which was performed in two steps: before and during the COVID-19 pandemic. Results: We analyzed 1768 questionnaires and 1539 (87%) were complete. Before the COVID-19 pandemic, we received 1476 questionnaires and 292 were submitted later. The following practices were observed before the pandemic: the Visual Analog Scale (VAS) (61.5%), the Behavioral Pain Scale (BPS) (48.2%), the Richmond Agitation Sedation Scale (RASS) (76.6%), and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) (66.6%) were the most frequently tools used to assess pain, sedation level, and delirium, respectively; midazolam and fentanyl were the most frequently used drugs for inducing sedation and analgesia (84.8% and 78.3%, respectively), whereas haloperidol (68.8%) and atypical antipsychotics (69.4%) were the most prescribed drugs for delirium treatment; some physicians regularly prescribed drugs to induce sleep (19.1%) or ordered mechanical restraints as part of their routine (6.2%) for patients on mechanical ventilation; non-pharmacological strategies were frequently applied for pain, delirium, and sleep deprivation management. During the COVID-19 pandemic, the intensive care specialty was independently associated with best practices. Moreover, the mechanical ventilation rate was higher, patients received sedation more often (94% versus 86.1%, p < 0.001) and sedation goals were discussed more frequently in daily rounds. Morphine was the main drug used for analgesia (77.2%), and some sedative drugs, such as midazolam, propofol, ketamine and quetiapine, were used more frequently. Conclusions: Most sedation, analgesia and delirium practices were comparable before and during the COVID-19 pandemic. During the pandemic, the intensive care specialty was a variable that was independently associated with the best practices. Although many findings are in accordance with evidence-based recommendations, some practices still need improvement. publishersversion published

RESUMO Objetivo: Descrever o IMPACTO-MR, um estudo brasileiro de plataforma nacional em unidades de terapia intensiva focado no impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. Métodos: Descrevemos a plataforma IMPACTO-MR, seu desenvolvimento, critérios para seleção das unidades de terapia intensiva, caracterização da coleta de dados, objetivos e projetos de pesquisa futuros a serem realizados na plataforma. Resultados: Os dados principais foram coletados por meio do Epimed Monitor System® e consistiram em dados demográficos, dados de comorbidades, estado funcional, escores clínicos, diagnóstico de internação e diagnósticos secundários, dados laboratoriais, clínicos e microbiológicos e suporte de órgãos durante a internação na unidade de terapia intensiva, entre outros. De outubro de 2019 a dezembro de 2020, 33.983 pacientes de 51 unidades de terapia intensiva foram incluídos no banco de dados principal. Conclusão: A plataforma IMPACTO-MR é um banco de dados clínico brasileiro de unidades de terapia intensiva focado na pesquisa do impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. Essa plataforma fornece dados para o desenvolvimento e pesquisa de unidades de terapia intensiva individuais e ensaios clínicos observacionais e prospectivos multicêntricos. ABSTRACT Objective: To describe the IMPACTO-MR, a Brazilian nationwide intensive care unit platform study focused on the impact of health care-associated infections due to multidrug-resistant bacteria. Methods: We described the IMPACTO-MR platform, its development, criteria for intensive care unit selection, characterization of core data collection, objectives, and future research projects to be held within the platform. Results: The core data were collected using the Epimed Monitor System® and consisted of demographic data, comorbidity data, functional status, clinical scores, admission diagnosis and secondary diagnoses, laboratory, clinical, and microbiological data, and organ support during intensive care unit stay, among others. From October 2019 to December 2020, 33,983 patients from 51 intensive care units were included in the core database. Conclusion: The IMPACTO-MR platform is a nationwide Brazilian intensive care unit clinical database focused on researching the impact of health care-associated infections due to multidrug-resistant bacteria. This platform provides data for individual intensive care unit development and research and multicenter observational and prospective trials.

Additional file 6: Spanish version of the questionnaire���COVID-19. Contains Spanish version of the questionnaire administrated during the COVID-19 pandemic.

Additional file 3: French version of questionnaire. Contains French version of the questionnaire administrated before the COVID-19 pandemic.

Additional file 8: Portuguese version of the questionnaire���COVID-19. Contains Portuguese version of the questionnaire administrated during the COVID-19 pandemic.

Additional file 4: Portuguese version of the questionnaire. Contains the Portuguese version of the questionnaire administrated before the COVID-19 pandemic.

Additional file 5: English version of the questionnaire���COVID-19. Contains English version of the questionnaire administrated during the COVID-19 pandemic.

Additional file 9: CHERRIES Checklist. Contains checklist for Reporting Results of Internet E-Surveys (CHERRIES).

Additional file 10: Supplementary Material. Contains the supplementary results of the study.

Additional file 2: Spanish version of questionnaire. Contains Spanish version of the questionnaire administrated before the COVID-19 pandemic.

Additional file 7: French version of the questionnaire���COVID-19. Contains French version of the questionnaire administrated during the COVID-19 pandemic.

Additional file 1: Supplementary figures.

Schistosomiasis, a neglected tropical disease caused by trematodes of the Schistosoma genus, affects over 250 million people around the world. This disease has been associated with learning and memory deficits in children, whereas reduced attention levels, impaired work capacity, and cognitive deficits have been observed in adults. Strongly correlated with poverty and lack of basic sanitary conditions, this chronic endemic infection is common in Africa, South America, and parts of Asia and contributes to inhibition of social development and low quality of life in affected areas. Nonetheless, studies on the mechanisms involved in the neurological impairment caused by schistosomiasis are scarce. Here, we used a murine model of infection with Schistosoma mansoni in which parasites do not invade the central nervous system to evaluate the consequences of systemic infection on neurologic function. We observed that systemic infection with S. mansoni led to astrocyte and microglia activation, expression of oxidative stress-induced transcription factor Nrf2, oxidative damage, Tau phosphorylation, and amyloid-β peptide accumulation in the prefrontal cortex of infected animals. We also found impairment in spatial learning and memory as evaluated by the Morris water maze task. Administration of anthelmintic (praziquantel) and antioxidant (N-acetylcysteine plus deferoxamine) treatments was effective in inhibiting most of these phenotypes, and the combination of both treatments had a synergistic effect to prevent such changes. These data demonstrate new perspectives toward the understanding of the pathology and possible therapeutic approaches to counteract long-term effects of systemic schistosomiasis on brain function.

To contribute to updating the recommendations for brain-dead potential organ donor management.A group of 27 experts, including intensivists, transplant coordinators, transplant surgeons, and epidemiologists, answered questions related to the following topics were divided into mechanical ventilation, hemodynamics, endocrine-metabolic management, infection, body temperature, blood transfusion, and checklists use. The outcomes considered were cardiac arrests, number of organs removed or transplanted as well as function / survival of transplanted organs. The quality of evidence of the recommendations was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system to classify the recommendations.A total of 19 recommendations were drawn from the expert panel. Of these, 7 were classified as strong, 11 as weak and 1 was considered a good clinical practice.Despite the agreement among panel members on most recommendations, the grade of recommendation was mostly weak.Fornecer recomendações para nortear o manejo clínico do potencial doador em morte encefálica.O presente documento foi formulado em dois painéis compostos por uma força tarefa integrada por 27 especialistas de diferentes áreas que responderam a questões dirigidas aos seguintes temas: ventilação mecânica, hemodinâmica, suporte endócrino-metabólico, infecção, temperatura corporal, transfusão sanguínea, e uso de checklists. Os desfechos considerados foram: parada cardíaca, número de órgãos retirados ou transplantados e função/sobrevida dos órgãos transplantados. A qualidade das evidências das recomendações foi avaliada pelo sistema Grading of Recommendations Assessment, Development, and Evaluation.Foram geradas 19 recomendações a partir do painel de especialistas. Dessas, 7 foram classificadas como fortes, 11 fracas e uma foi considerada boa prática clínica.Apesar da concordância entre os membros do painel em relação à maior parte das recomendações, o grau de recomendação é fraco em sua maioria.

The emergence of the coronavirus SARS-CoV-2 has raised a global issue and a pandemic disease outbreak, COVID-19, was declared by the World Health Organization on March 12th, 2020. The new virus is rapidly spreading in humans and cases of severe acute respiratory syndromes are being reported worldwide. Health authority advisors and governments from small towns to large countries need to quickly manage and deal with growing epidemiological data on a daily basis. In this work, current available data from reported cases and deaths over time were analyzed and treated. Lethality has been calculated by finding linearization of death cases against reported ones, using a time-delayed data transposition. A two-wave statistical model, 2WM, based on the superposition of normal distributions was used to fit current data and to estimate the evolution of infections and deaths, using Microsoft® Excel. The model showed good agreement even for apparent single wave behavior in some countries and can easily be extended to any number of waves. A gamma distribution was used as a risk function to estimate death probability from patient admission to reported death. Evolution of fatality cases over time can then be estimated from the model with reasonable accuracy. Data from South Korea, China, Australia, Germany, Italy and Spain were used to validate the model. Data from The United States, United Kingdom and Brazil were used to study the epidemiology as the pandemic progresses. Additionally, the 2WM was applied to world data and to the Brazilian state of Santa Catarina. The model was implemented in MS-Excel, a popular and easy to use analytical tool. A template spreadsheet is provided as supplementary material. Constant lethality can be determined from the initial stage of the pandemic wave. Values ranged from 1.7% to 15.3%, depending on the degree of possible sub notification cases. Even for places with low testing, a linear relationship can be found. The two-wave model can be fine-tuned to properly adjust the data. The second wave pattern was estimated according to the first wave parameter. The accuracy for estimating COVID-19 evolution was compared to the classic SIR model with good agreement. According to the model, based on current trends, health protocols and policies, approximately 10,000,000 cases and 860,000 deaths will be recorded worldwide. Approximately 99% of that number would be reached by the end of July 2020 given constant conditions.

Additional file 2. Declaration of competing interests.

Additional file 1. Working group and contributions of each participant.

Additional file 3. Checklist for clinical management of brain-dead potential organ donor.

RESUMO Objetivo: Investigar os efeitos da administração de canabidiol em um modelo de isquemia/reperfusão renal em animais. Métodos: Foi induzida uma lesão renal, por meio de 45 minutos de isquemia renal seguida por reperfusão. Administrou-se canabidiol (5mg/kg) imediatamente após a reperfusão. Resultados: A isquemia/reperfusão aumentou os níveis de interleucina 1 e fator de necrose tumoral, o que foi atenuado pelo tratamento com canabidiol. Além disso, o canabidiol foi capaz de diminuir o dano oxidativo de lipídios e proteínas, mas não os níveis de nitrito/nitrato. A lesão renal após isquemia/reperfusão pareceu ser independente da expressão dos receptores canabidiol-1 e canabidiol-2, já que não houve aumento significante desses receptores após a reperfusão. Conclusão: O tratamento com canabidiol teve um efeito protetor contra a inflamação e o dano oxidativo em um modelo de isquemia/reperfusão renal. Esses efeitos parecem não ocorrer via ativação dos receptores canabidiol-1/canabidiol-2. ABSTRACT Objective: This work aimed to investigate the effects of the administration of cannabidiol in a kidney ischemia/reperfusion animal model. Methods: Kidney injury was induced by 45 minutes of renal ischemia followed by reperfusion. Cannabidiol (5mg/kg) was administered immediately after reperfusion. Results: Ischemia/reperfusion increased the IL-1 and TNF levels, and these levels were attenuated by cannabidiol treatment. Additionally, cannabidiol was able to decrease lipid and protein oxidative damage, but not the nitrite/nitrate levels. Kidney injury after ischemia/reperfusion seemed to be independent of the cannabidiol receptor 1 and cannabidiol receptor 2 (CB1 and CB2) expression levels, as there was no significant increase in these receptors after reperfusion. Conclusion: The cannabidiol treatment had a protective effect against inflammation and oxidative damage in the kidney ischemia/reperfusion model. These effects seemed to be independent of CB1/CB2 receptor activation.

Celiac disease is a chronic small intestinal inflammatory condition caused by an inappropriate immune response to gluten of wheat, rye and barley, with a prevalence of about 1: 100 in the Caucasian population when occurs a inflammatory response and seems to involve high levels of interleukins. Objective: Determine the presence of oxidative stress and inflammation in the gut of patients with CD. Methods: Transversal study that included patients undergoing upper gastrointestinal (GI) endoscopy was performed. The study population consisted 24 cases and 26 controls. The duodenal levels of protein carbonyls, thiobarbituric acid reactive species (TBARS), as well as catalase (CAT), superoxide dismutase (SOD) activities were measured. Gut levels of interleukin (IL) 6, 10 and 8 were also determined. The Marsh classification was recorded and used as a parameter of disease severity. Results: Both IL-6 and IL-10, but not IL8, were increased in CD patients when compared to healthy individuals. Oxidative damage parameters were increased while antioxidant defenses were decreased in our sample. Both IL6 levels and SOD activity were related to Marsh score. Conclusions: Different markers of inflammation and oxidative stress are altered in the gut of CD patients, and some of them are related to disease severity.

Objectives: The goal of the present study was to investigate the effects of lithium administration on behavior, oxidative stress parameters and cytokine levels in the periphery and brain of mice subjected to an animal model of mania induced by paradoxical sleep deprivation (PSD). Methods: Male C57 mice were treated with saline or lithium for 7 days. The sleep deprivation protocol started on the 5th day during for the last 36 hours of the treatment period. Immediately after the sleep deprivation protocol, animals locomotor activity was evaluated and serum and brain samples was extracted to evaluation of corticosterone and adrenocorticotropic hormone circulating levels, oxidative stress parameters and citokynes levels. Results: The results showed that PSD induced hyperactivity in mice, which is considered a mania-like behavior. PSD increased lipid peroxidation and oxidative damage to DNA, as well as causing alterations to antioxidant enzymes in the frontal cortex, hippocampus and serum of mice. In addition, PSD increased the levels of cytokines in the brains of mice. Treatment with lithium prevented the mania-like behavior, oxidative damage and cytokine alterations induced by PSD. Conclusions: Improving our understanding of oxidative damage in biomolecules, antioxidant mechanisms and the inflammatory system − alterations presented in the animal models of mania – is important in helping us to improve our knowledge concerning the pathophysiology of BD, and the mechanisms of action employed by mood stabilizers.

OBJECTIVES: The objectives of this study are to compare the sensitivity and specificity of three diagnostic tools for delirium (the Intensive Care Delirium Screening Checklist, the Confusion Assessment Method for Intensive Care Units and the Confusion Assessment Method for Intensive Care Units Flowsheet) in a mixed population of critically ill patients, and to validate the Brazilian Portuguese Confusion Assessment Method for Intensive Care Units. METHODS: The study was conducted in four intensive care units in Brazil. Patients were screened for delirium by a psychiatrist or neurologist using the Diagnostic and Statistical Manual of Mental Disorders. Patients were subsequently screened by an intensivist using Portuguese translations of the three tools. RESULTS: One hundred and nineteen patients were evaluated and 38.6% were diagnosed with delirium by the reference rater. The Confusion Assessment Method for Intensive Care Units had a sensitivity of 72.5% and a specificity of 96.2%; the Confusion Assessment Method for Intensive Care Units Flowsheet had a sensitivity of 72.5% and a specificity of 96.2%; the Intensive Care Delirium Screening Checklist had a sensitivity of 96.0% and a specificity of 72.4%. There was strong agreement between the Confusion Assessment Method for Intensive Care Units and the Confusion Assessment Method for Intensive Care Units Flowsheet (kappa coefficient = 0.96). CONCLUSION: All three instruments are effective diagnostic tools in critically ill intensive care unit patients. In addition, the Brazilian Portuguese version of the Confusion Assessment Method for Intensive Care Units is a valid and reliable instrument for the assessment of delirium among critically ill patients.

New studies suggest that polyunsaturated fatty acids, such as omega-3, may reduce the symptoms of schizophrenia. The present study evaluated the preventive effect of omega-3 on interleukines (IL) and neurotrophin brain-derived neurotrophic factor (BDNF) levels in the brains of young rats subjected to a model of schizophrenia. Treatment was performed over 21 days, starting on the 30th day of rat’s life. After 14 days of treatment with omega-3 or vehicle, a concomitant treatment with saline or ketamine (25 mg/kg) was started and maintained until the last day of the experiment. BDNF levels in the rat’s prefrontal cortex were decreased at 1 h and 24 h after the last administration of ketamine, whereas the group administered with ketamine and omega-3 showed a decrease in BDNF levels only after 24 h. In contrast, both interventions induced similar responses in levels of IL-1β and IL6. These findings suggest that the similarity of IL-1β and IL6 levels in our experimental groups is due to the mechanism of action of ketamine on the immune system. More studies have to be carried out to explain this pathology. In conclusion, according to previous studies and considering the current study, we could suggest a prophylactic role of omega-3 against the outcome of symptoms associated with schizophrenia.

Made available in DSpace on 2021-06-25T10:32:46Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-04-12 Asian Development Bank American Dysautonomia Institute Armed Forces Health Surveillance Branch Health Systems Institute ACG Institute for Clinical Research and Education Ministério da Saúde IMPORTANCE: The effectiveness of checklists, daily goal assessments, and clinician prompts as quality improvement interventions in intensive care units (ICUs) is uncertain. OBJECTIVE: To determine whether a multifaceted quality improvement intervention reduces the mortality of critically ill adults. DESIGN, SETTING, AND PARTICIPANTS: This study had 2 phases. Phase 1 was an observational study to assess baseline data on work climate, care processes, and clinical outcomes, conducted between August 2013 and March 2014 in 118 Brazilian ICUs. Phase 2 was a cluster randomized trial conducted between April and November 2014 with the same ICUs. The first 60 admissions of longer than 48 hours per ICU were enrolled in each phase. INTERVENTIONS: Intensive care units were randomized to a quality improvement intervention, including a daily checklist and goal setting during multidisciplinary rounds with follow-up clinician promptingfor 11 care processes, or to routine care. MAIN OUTCOMES AND MEASURES: In-hospital mortality truncated at 60 days (primary outcome) was analyzed using a random-effects logistic regression model, adjusted for patients' severity and the ICU's baseline standardized mortality ratio. Exploratory secondary outcomes included adherence to care processes, safety climate, and clinical events. RESULTS: A total of 6877 patients (mean age, 59.7 years; 3218 [46.8%] women) were enrolled in the baseline (observational) phase and 6761 (mean age, 59.6 years; 3098 [45.8%] women) in the randomized phase, with 3327 patients enrolled in ICUs (n = 59) assigned to the intervention group and 3434 patients in ICUs (n = 59) assigned to routine care. There was no significant difference in in-hospital mortality between the intervention group and the usual care group, with 1096 deaths (32.9%) and 1196 deaths (34.8%), respectively (odds ratio, 1.02; 95% CI, 0.82-1.26; P =.88). Among 20 prespecified secondary outcomes not adjusted for multiple comparisons, 6 were significantly improved in the intervention group (use of low tidal volumes, avoidance of heavy sedation, use of central venous catheters, use of urinary catheters, perception of team work, and perception of patient safety climate), whereas there were no significant differences between the intervention group and the control group for 14 outcomes (ICU mortality, central line-associated bloodstream infection, ventilator-associated pneumonia, urinary tract infection, mean ventilator-free days, mean ICU length of stay, mean hospital length of stay, bed elevation to ≥30°, venous thromboembolism prophylaxis, diet administration, job satisfaction, stress reduction, perception of management, and perception of working conditions). CONCLUSIONS AND RELEVANCE: Among critically ill patients treated in ICUs in Brazil, implementation of a multifaceted quality improvement intervention with daily checklists, goal setting, and clinician prompting did not reduce in-hospital mortality. Research Institute HCor-Hospital do Coração, Rua Abílio Soares 250, 12th Floor Research Institute HCor-Hospital do Coração D'Or Institute for Research and Education Oswaldo Cruz Foundation Latin American Sepsis Institute Hospital Samaritano Hospital Moinhos de Vento University of Pittsburgh Casa de Saúde Santa Marta Casa de Saúde São Bento Centro Hospitalar Unimed Complexo Hospitalar São Mateus Fundação Hospital de Clinicas Gaspar Vianna Fundação Hospital Getúlio Vargas Hospital Aristides Maltez Hospital Aviccena Hospital Casa de Caridade de Carangola Hospital Casa de Portugal Hospital Copa D'Or Hospital da Sagrada Familia Hospital das Clinicas-FMUSP Hospital das Clinicas da UFPE Hospital das Clínicas Faculdade de Medicina de Botucatu/UNESP Hospital das Clinicas de Goiás Hospital das Clinicas Luzia de Pinho Melo-SPDM Hospital de Base do Distrito Federal Hospital de Clinicas de Porto Alegre Hospital de Messejana Dr Carlos Alberto Studart Gomes Hospital de Urgência e Emergência de Rio Branco Hospital Distrital Dr Evandro Ayres de Moura Hospital do Coração Balneário Camboriú Hospital e Pronto Socorro Dr Aristóteles Platao Bezerra de Araújo Hospital Eduardo de Menezes Hospital Estadual Américo Brasiliense Hospital Estadual Getúlio Vargas-Secretaria de Estado de Saúde Hospital Estadual Monsenhor Walfredo Gurgel Hospital Evangélico de Cachoeira de Itapemirim Hospital Federal da Lagoa Hospital Federal Servidores do Estado Hospital Fernandes Tavora Hospital Geral de Camaçari Hospital Geral de Fortaleza Hospital Geral de Nova Iguaçu Hospital Geral de Palmas Hospital Guilherme Álvaro Hospital Instituto Dr Jose Frota Hospital Joari Hospital Maternidade e Pronto Socorro Santa Lucia Hospital Maternidade Municipal Dr Odelmo Leão Carneiro Hospital Municipal Dr Carmino Caricchio Hospital Municipal de Paracatu Hospital Municipal Dr Mario Gatti Hospital Municipal Padre Germano Lauck de Foz do Iguaçu Hospital Municipal Pedro II Hospital Municipal Souza Aguiar Hospital Naval Marcilio Dias Hospital Nereu Ramos Hospital Nossa Senhora Auxiliadora Hospital Nossa Senhora dos Prazeres Hospital 9 de Julho Hospital Primavera Hospital Procordis Hospital Pronto Socorro 28 de Agosto Hospital Regional da Unimed Fortaleza Hospital Regional de Juazeiro Hospital Universitário Regional dos Campos Gerais Hospital Regional de Presidente Prudente Hospital Regional Deputado Manoel Gonçalves Abrantes Hospital Regional Público do Araguaia Hospital Regional João Penido Hospital Santa Casa de Campo Mourão Hospital Municipal Santa Isabel-Joao Pessoa Hospital Santa Lucia de Divinópolis Hospital Santa Rosa Hospital Municipal São Francisco de Assis Hospital São Joao de Deus Hospital São Jose-Criciúma Hospital São Jose de Doenças Infecciosas Hospital São Jose de Teresópolis Hospital São Jose do Avaí Hospital São Paulo Hospital São Vicente de Paula-Cruz Alta Hospital São Vicente de Paulo-Vitória da Conquista Hospital São Vicente de Paulo-Passo Fundo Hospital Unimed Bebedouro Hospital Unimed Costa do Sol Hospital Unimed Maceió Hospital Unimed Natal Hospital Unimed Rio Hospital Universitário-Universidade Estadual de Londrina Hospital Universitário Cassiano Antonio Moraes-Universidade Federal do Espirito Santo Hospital Universitário Lauro Wanderley Hospital Universitário Onofre Lopes Hospital Universitário Polydoro Ernani de São Thiago-Universidade Federal de Santa Catarina Hospital Universitário Prof. Edgar Santos-Universidade Federal da Bahia Hospital Universitário Regional de Maringá Hospital Universitário São Francisco de Paula-Pelotas Hospital Vila da Serra-Instituto Materno Infantil de Minas Gerais Hospital Vivalle Instituto Nacional de Infectologia Evandro Chagas/Fiocruz Irmandade da Santa Casa de Misericórdia de São Paulo Irmandade do Hospital Nossa Senhora das Dores Irmandade Santa Casa de Misericórdia de Maringá Santa Casa de Belo Horizonte Santa Casa de Caridade de Diamantina Santa Casa de Misericórdia de Anapolis Santa Casa de Misericórdia de Feira de Santana Santa Casa de Misericórdia de Guaxupé Santa Casa de Misericórdia de Pelotas Santa Casa de Misericórdia de Porto Alegre Santa Casa de Misericórdia de São Joao Del Rei Sociedade Beneficente Hospitalar Maravilha Unidade de Emergência Hospital das Clinicas de Ribeirão Preto-FMRP-USP Hospital de Clinicas-Universidade Estadual de Campinas Vila Velha Hospital Vitoria Apart Hospital Hospital das Clínicas Faculdade de Medicina de Botucatu/UNESP

OBJETIVO: Determinar a associação entre a administração pré-operatória de estatina e o delírium pós-operatório em uma corte prospectiva de pacientes submetidos à cirurgia cardíaca. MÉTODOS: Foram analisados pacientes adultos internados na unidade de terapia intensiva após cirurgia cardíaca entre janeiro e junho de 2011. A triagem para delirium foi realizada utilizando o Confusion Assessment Method para analisar delirium em uma unidade de terapia intensiva (CAM-ICU) e Delirium Screening Checklist para terapia intensiva (ICDSC) durante a internação na terapia intensiva RESULTADOS: Cento e sessenta e nove pacientes foram submetidos à cirurgia cardíaca eletiva, dos quais 40,2% estavam utilizando estatina no pré-operatório. Delirium foi identificado em 14,9% dos pacientes que não utilizavam estatina comparado com 11,8% dos que utilizavam (p=0,817) quando avaliados pelo CAM-ICU. Utilizando o ICDSC 18,8% dos pacientes que não usam estatina comparado com 10.3% dos que usam (p=0,191). CONCLUSÃO: Não há relação entre uso de estatinas com a ocorrência de delirium em pacientes submetidos a cirurgia cardíaca. OBJECTIVE: To determine the association between the preoperative administration of statins and postoperative delirium in a prospective cohort of patients undergoing cardiac surgery. METHODS: All adult patients who were admitted to the intensive care unit following cardiac surgery between January and June 2011 were included. Delirium was screened during the postoperative period using the Confusion Assessment Method for Intensive Care Unit (CAM-ICU) and Intensive Care Delirium Screening Checklist (ICDSC). RESULTS: A total of 169 patients underwent elective cardiac surgery, and 40.2% of the patients were treated preoperatively with statins. Delirium was identified using the CAM-ICU in 14.9% of patients not taking preoperative statins in comparison with 11.8% of the patients taking statins (p = 0.817). Using the ICDSC, delirium was identified in 18.8% of patients not taking statins in comparison with 10.3% of the patients taking statins (p = 0.191). CONCLUSION: The use of preoperative statins is not correlated with postoperative delirium in patients undergoing cardiac surgery.

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A atuação do intensivista durante a manutenção do potencial doador falecido na busca da redução de perdas de doadores e do aumento da efetivação de transplantes não se restringe aos aspectos hemodinâmicos. O adequado controle endócrino-metabólico é essencial para a manutenção do aporte energético aos tecidos e do controle hidro-eletrolítico, favorecendo inclusive a estabilidade hemodinâmica. A abordagem das alterações hematológicas é igualmente importante considerando as implicações da prática transfusional inapropriada. Ressalta-se ainda o papel da ventilação protetora na modulação inflamatória e conseqüente aumento do aproveitamento de pulmões para transplante. Por fim, assinala-se a relevância da avaliação criteriosa das evidências de atividade infecciosa e da antibioticoterapia na busca do maior utilização de órgãos de potenciais doadores falecidos The role of intensive care specialists in the maintenance of deceased potential donors is not restricted to hemodynamics. Appropriate endocrine-metabolic management is fundamental to maintaining energy support and hydroelectrolytic control, which cooperate for hemodynamic stability. Hematological changes are also important, especially considering the issues caused by inappropriate transfusions. In addition, this article discusses the role of appropriate protective ventilation to prevent inflammatory responses and to provide more transplantable lungs. Finally, judicious assessment of infections and antibiotic therapy is discussed

Sepsis and its complications are the leading causes of mortality in intensive care units, accounting for 10-50% of deaths. Intensive care unit survivors present long-term cognitive impairment, including alterations in memory, attention, concentration, and/or global loss of cognitive function. In the present study, we investigated behavioral alterations in sepsis-surviving rats. One hundred and ten male Wistar rats (3-4 months, 250-300 g) were submitted to cecal ligation and puncture (CLP), and 44 were submitted to sham operation. Forty-four rats (40%) survived after CLP, and all sham-operated animals survived and were used as control. Twenty animals of each group were used in the object recognition task (10 in short-term memory and 10 in long-term memory), 12 in the plus-maze test and 12 in the forced swimming test. Ten days after surgery, the animals were submitted individually to an object recognition task, plus-maze and forced swimming tests. A significant impairment of short- and long-term recognition memory was observed in the sepsis group (recognition index 0.75 vs 0.55 and 0.74 vs 0.51 for short- and long-term memory, respectively (P < 0.05). In the elevated plus-maze test no difference was observed between groups in any of the parameters assessed. In addition, sepsis survivors presented an increase in immobility time in the forced swimming test (180 vs 233 s, P < 0.05), suggesting the presence of depressive-like symptoms in these animals after recovery from sepsis. The present results demonstrated that rats surviving exposure to CLP, a classical sepsis model, presented recognition memory impairment and depressive-like symptoms but not anxietylike behavior.

As propagandas de medicamentos veiculadas nas principais rádios do Rio Grande do Sul, Brasil, foram analisadas no período de agosto de 1995 a janeiro de 1996. Durante o período de observação foram documentadas 250 peças publicitárias referentes a 28 produtos. A maioria destas propagandas (>80%) não apresenta declarações quanto ao nome genérico, à composição, à posologia e ao laboratório fabricante do produto, infringindo, dessa forma, a legislação vigente no país. Além disso, um número significativo das peças publicitárias (39%) enfatizam a ausência de quaisquer riscos, mediante declarações como "Não tem contra-indicações", caracterizando a indução ao uso indiscriminado. A análise mostra que os medicamentos são promovidos como produtos quaisquer, omitindo-se informações fundamentais a respeito de cuidados, reações adversas e contra-indicações. Drug advertisements for non-prescription (over-the-counter) drugs on the main radio stations in the State of Rio Grande do Sul, Brazil, were analyzed as to the information provided about generic names, pharmaceutical company, composition, and dosage. From August 1995 to January 1996, 250 advertisements for 28 products were recorded. More than 80% of these advertisements provided no information on these topics and thus failed to comply with Brazilian legislation. On the contrary, a large number of advertisements (39%) emphasize absence of risks, with claims such as "no contraindications", inducing consumers to use such drugs indiscriminately. The study showed that drugs were advertised like any other merchandise, with no concern over fundamental information such as product identification, precautions, and possible side effects.

The purpose of this study determined if oral supplementation of Protandim® (a nutraceutical) for 90 days improved 5-km running performance and reduced serum thiobarbituric acid-reacting substances (TBARS) at rest, an indicator of oxidative stress. Secondary objectives were to measure whole blood superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPX), at rest and 10 minutes after completion of the race before and after supplementation as well as quality of life. In a double-blind, randomized, placebo controlled trial, 38 runners [mean (SD) = 34 (7) yrs; BMI = 22 (2) kg/m2] received either 90 days of Protandim® [1 pill a day, n = 19)] or placebo (n = 19). Randomization was done in blocks of two controlling for sex and 5-km baseline performance. A 5-km race was performed at baseline and after 90 days of supplementation, with blood samples taken before and 10-min after each race. Fasting blood samples were acquired at baseline, after 30, 60, and 90 days of supplementation. TBARS, SOD, GPX, and GSH were assayed in an out-of-state accredited lab. Running performance was not altered by Protandim® or placebo [20.3 (2.1) minutes, with an -8 (33) seconds change in 5-km time regardless of group]. There was no change in TBARS, SOD, or GPX (at rest) after three months of Protandim® supplementation compared to placebo. However, in a subgroup ≥ 35 years of age, there was a 2-fold higher increase in SOD in those taking Protandim® for three months compared to those on placebo (p = 0.038). The mean post-race change in TBARS (compared to pre-race) increased by about 20% in half of the subjects, but was not altered between groups, even after three months of supplementation. Quality of life was also not different between the two conditions. In conclusion, Protandim® did not (1) alter 5-km running time, (2) lower TBARS at rest (3) raise antioxidant enzyme concentrations compared to placebo (with exception of SOD in those ≥ 35 years old) or, (4) affect quality of life compared to placebo. Trial Registration: ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02172625","term_id":"NCT02172625"}}NCT02172625

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Ciências Médicas, Florianópolis, 2015. Justificativa: Traumatismo cranioencefálico é um grave problema de saúde pública, devido sua alta incidência, mortalidade e morbidade. No Brasil, cerca de 341 casos por 100.000 habitantes são registrados anualmente. Aproximadamente 50% dos sobreviventes de TCE grave apresentam sequelas de longo prazo e o aumento do risco da depressão é bem estabelecido, podendo estar relacionado com o processo inflamatório no sistema nervoso central (SNC). Objetivos: Identificar a associação dos níveis de marcadores inflamatórios (NPT e IL-10) com a incidência de depressão e alteração de personalidade após TCE grave. Resultados: Indivíduos do sexo masculino constituíam 78,4% da amostra e a idade média das vítimas de TCE grave foi de 31 anos. Dentre as variáveis sócio-demográficas, psiquiátricas e de hospitalização analisadas, apenas níveis séricos elevados de IL-10 (p=0,03) e a razão entre citocinas pró e anti-inflamatórias (TNF-a/IL-10, p=0,01) estiveram independentemente associados ao aparecimento da depressão pós TCE. A incidência de alteração de personalidade foi de 24,3%. Não houve associação dos níveis séricos de neopterina (TCE agudo) com a gravidade do TCE, tempo de coleta ou com a taxa de mortalidade (p=0,82). Conclusões e implicações: Nossos resultados sugerem que o aumento sérico dos níveis de IL-10 podem ser usados como um biomarcador de mau prognóstico em pacientes vítimas de TCE grave tanto na fase aguda (mortalidade hospitalar) como na fase crônica (depressão) do TCE. Os mecanismos envolvidos nas associações observadas continuam desconhecidos e precisam ser investigados em mais estudos. Abstract : Justification: traumatic brain injury (TBI) is a serious public health problem due to its high incidence, mortality and morbitidy. In Brazil, the annual incidence of traumatic brain injury (TBI) is approximately 341 cases per 100,000 inhabitants. Approximately 50% of severe TBI survivors have long-term sequelae that impair their functionality and social reintegration. The cause of the incresead risk of depression after TBI is unclear but may be inflammatory-related with incresead brain sensitivity to secondary inflammatory challenges. Objectives: Identify the association of levels of inflammatory markers (NPT and IL-10) with the incidence of depression and personality disorders after severe TBI. Results: The sample was comprised primarily for male gender (78,4%) and the mean age of the victims was 31 years old. Among all the socio demographics, psychiatric and hospitalization variables, only the serum levels of IL-10 (p = 0.03) and the ratio between pro- and antiinflammatory cytokines (TNF-a / IL-10, p = 0.01) were independently associated with depression after TBI. The incidence of personality change was 24.3%. There was no association of serum neopterin (acute TBI) with the severity of TBI, time of collection of blood samples or the mortality rate (p = 0.82). Conclusions: our results suggests that enhanced levels o IL-10 are a biomarker of worse prognosis of severe TBI patients evaluated in the acute (hospital mortality) and chronic (depression) phases of TBI. The mechanism involved in the observed associations remain to be investigated.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Ciências Médicas, FLorianópolis, 2015. Objetivo: avaliar a validade global e a utilidade para rastreio de depressão da Escala de Depressão de Hamilton (HRSD), do Inventário de Depressão de Beck (BDI), da Escala Hospitalar de Ansiedade e Depressão (HADS) total e da subescala Depressão (HADS-D) em pacientes com epilepsia mesial temporal com esclerose do hipocampo (EMT-EH) refratária. Método: Cento e vinte e três pacientes com EMT-EH refratária foram arrolados consecutivamente. Todos os pacientes tiveram exame neurológico, análise interictal e ictal de vídeo-EEG e imagem de ressonância magnética (IRM) do crânio como exame complementar. A avaliação psiquiátrica foi baseada na quarta edição do Manual Diagnóstico e Estatístico de Transtornos Mentais (DSM-IV-TR) como ?padrão-ouro? diagnóstico. HRSD, Beck, HADS e HADS-D foram as escalas psicométricas utilizadas como instrumento de rastreio para depressão. Resultado: Na análise de característica de operação do receptor (ROC) todas as escalas apresentaram áreas sob a curva (AUC) próximas a 0,8, sem diferença significativa entre elas. O ponto de corte = 9 na HRSD e = 8 na HADS-D mostraram sensibilidades maiores que 70% e especificidades próximas a 80%, com valores preditivos positivos (VPP) na faixa de 50% e valores preditivos negativos (VPN) próximos a 90%. O ponto de corte = 19 em ambas as escalas, Beck e HADS, apresentou cerca de 55% de sensibilidade e cerca de 90% de especificidade, com VPP maiores que 60% e VPN na faixa de 80%. Conclusões: Todos os instrumentos demonstraram capacidade discriminativa e boa validade global na avaliação da depressão na ELTM-EH refratária. HRSD e HADS-D tiveram pontos de corte ótimos próximos aos pontos de corte padrão na depressão geral, com um bom balanço entre sensibilidade e especificidade, e assim parecem úteis para uso clínico sem maiores ajustes. BDI e HADS foram pouco sensíveis nos pontos de corte ótimos. Para todas as escalas, o VPP foi moderado e o VPN alto nos pontos de corte ótimos, indicando maior utilidade para descartar depressão em um contexto de rastreio. Abstract : Objective: To evaluate the global validity and utility for screening of depression of the Hamilton Rating Scale for Depression (HRSD), Beck Depression Inventory (BDI), Hospital Anxiety and Depression Scale (HADS) and Hospital Anxiety and Depression Scale Depression subscale (HADS-D) in patients with refractory mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS).Methods: One hundred and three consecutive patients with refractory MTLE-HS were enrolled. All patients had neurological examination, interictal and ictal video-EEG analyses and MRI as complementary exams. Psychiatric evaluation was based on 4th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria and ILAE Commission of Psychobiology as gold standard diagnosis. HRSD, BDI, HADS and HADS-D were utilized as psychometric screening tools to be evaluated.Results: All the area under the curve (AUC) were approximately 0.8, there were no statistically significant differences among them. A cutoff point = 9 on the HRSD and a cutoff point = 8 on the HADS-D showed sensitivity greater than 70% and specificity of around 80% with positive predictive values (PPV) in the range of 50% and negative predictive values (NPV) near 90%. A cutoff point = 19 on the BDI and HADS total showed a sensitivity of around 55% and a specificity of 90% with PPV greater than 60% and NPV around of 80% .Significance: all instruments showed discriminative capacity and good global validity in assessing depression in refractory TLE-HS. HRSD and HADS-D had optimal cutoffs close to the standard cutoff points for the general depression, with a good balance between sensitivity and specificity, and thus appear useful for clinical use without major adjustments. BDI and HADS had low sensitivity in optimal cutoffs. For all scales, the PPV was moderate and the NPV was high in optimal cutoffs, indicating more useful to rule out depression in a screening context.

A vitamina A apresenta importantes papéis no sistema cardiovascular, desde a fase embrionária até a vida adulta. Além disso, propriedades antioxidantes são atribuídas a essa vitamina; Contudo, propriedades pró-oxidantes lhe são atribuídas. Portanto, nosso objetivo foi comparar parâmetros energéticos/redox (no sistema cardiovascular) entre animais submetidos a uma suplementação com vitamina A e animais não submetidos a essa suplementação. Ratos adultos Wistar machos foram tratados com 4 diferentes doses (1000-9000 UI.Kg-1.dia-1) de palmitato de retinol ou com salina (controle) ao longo de 3 diferentes períodos (3, 7 e 28 dias). Após o tratamento, a artéria aorta e o coração foram retirados para as análises. Foram avaliados parâmetros de estresse oxidativo em ambas as estruturas, e parâmetros de estresse nitrosativo e energéticos no coração dos animais tratados por 28 dias. A análise estatística foi realizada por Anova de uma via, seguida do pos hoc de Dunnet, com significância de ρ ≤ 0,05. Na artéria aorta, foi observada uma diminuição na lipoperoxidação após 7 e 28 dias, bem como aumento de sulfidril em 3 dias e alterações enzimáticas em todos períodos. No coração, foi detectado um aumento de lipoperoxidação e de carbonilação após 7 e 28 dias e uma dimuição na reatividade não enzimática nos 3 períodos. Alterações enzimáticas foram vistas nos 3 períodos. No período mais longo, foi observado aumento de nitração na fração mitocondrial e diminuição da atividade dos complexos da cadeia transferidora de elétrons. Concluímos que ocorre uma adaptação oposta entre coração e artéria, onde há um aumento de estresse oxidativo no coração e uma diminuição na aorta, no entanto, uma futura análise fisiológica ainda é necessária para se sugerir um ou outro como positivo ou negativo. Além disso, o estresse cardíaco crônico está associado com um possível bloqueio energético e um estado de estresse nitrosativo mitocondrial. Vitamin A plays important roles on cardiovascular system, since development until adult life. Besides physiological roles, antioxidants properties are also attributed to its. However, pro-oxidants properties have been associated to vitamin A. Therefore, our aim was to compare redox parameters among animals supplemented with vitamin A and one not. Adult male Wistar rats were treated with different doses (1000-9000 IU.Kg-1.day-1) of retinyl palmitate or saline (control) for 3 different periods (3, 7 and 28 days). Thereafter, the aorta artery and the heart were removed to follow analysis. Oxidative stress parameters were assessed in both organs, while nitrosative stress and energetic parameters were evaluated only at heart from animals treated for 28 days. Statistics were conducted with Anova one way, followed by Dunnet’s pos hoc, and significance of ρ ≤ 0.05. On arterial level it was observed a decrease in lipoperoxidation after 7 and 28 days, as well as an increase in sulfhydryl after 3 days and changed enzymatic activity for all periods. In the heart, it was detected an increased lipoperoxidation and carbonyl levels after 7 and 28 days, and a decreased non-enzimatic reactivity for all periods. Additionally, enzymatic changes were also seen. For the chronic treatment we could observe an increase in mitochondrial nitration and a decrease in respiratory chain complexes activities. Thus, we concluded that happens an opposite adaptation between heart and aorta, since there is an increased oxidative stress status in the heart, while in the aorta there is a decreased status. However, a physiological evaluation is needed to suggest what is positive or negative. Furthermore, the cardiac oxidative stress is associated to an energetic impairment and a mitochondrial nitrosative stress.

Pacientes diabéticos tipo 2 apresentam risco de 3 à 5 vezes maior de sofrer infarto do miocárdio do que indivíduos não diabéticos, sendo que 75% desses pacientes morrem de complicações aterotrombóticas. Os mecanismos que levam o indivíduo a apresentar esse perfil pró-trombótico incluem danos ao endotélio, liberação de citocinas pró-inflamatórias, estresse oxidativo, ativação da cascata de coagulação e das plaquetas. As proteínas da cascata de coagulação e as plaquetas são os principais atores do controle do balanço anti/pró-coagulante. A cascata de coagulação pode ser ativada por dano ao endotélio ou por liberação de fatores, como o Fator Tecidual. Essa cascata culmina com a ativação da enzima trombina, que cliva o fibrinogênio e permite sua polimerização e deposição na forma de fibrina. A trombina também participa da ativação das plaquetas. Outros mecanismos têm sido propostos na tentativa de entender as causas do perfil pró-trombótico apresentado por indivíduos diabéticos. A geração Produtos Finais de Glicação Avançada (do inglês Advanced Glycation End-Products – AGE) nesses indivíduos tem sido frequentemente relatada como importante fator. Os AGE são modificações póstraducionais encontradas em proteínas e têm origem em uma reação nãoenzimática entre uma proteína e um açúcar redutor, ou com um aldeído reativo. Durante o diabetes a hiperglicemia é considerada a principal fonte de geração de AGE, mas a participação de outros aldeídos reativos, como o metilglioxal e o glicolaldeído (GA) também são de grande importância. O processo de glicação pode levar a duas situações no organismo: a) alteração na estrutura da proteína com consequente alteração da sua função; b) a geração de moléculas sinalizadoras (AGE) com potencial pró-inflamatório e pró-trombótico. Estudos recentes demonstraram que os AGE podem causar a ativação de plaquetas e promover a liberação de Fator Tecidual por monócitos e células endoteliais. Muitos estudos têm sido realizados com a intenção de entender o papel dos AGE sobre a coagulação, no entanto, faltam dados sobre os efeitos dos seus precursores (açucares e aldeídos reativos) na modulação da hemostasia. Nesta tese, demonstramos que o GA é capaz de reagir com proteínas plasmáticas in vitro, levando a um aumento nos níveis de carbonil. Os coágulos formados a partir de plasma incubado com GA apresentaram-se resistentes à ação proteolítica. O GA teve os mesmos efeitos quando incubado com o fibrinogênio purificado, indicando que essa proteína é um alvo importante no desequilíbrio hemostático causado pelo aldeído. Para avaliar se o aumento dos níveis do GA é relevante in vivo, ratos Wistar adultos foram injetados com esse aldeído. Verificou-se aumento na oxidação de proteínas (carbonil e sulfidril) e um encurtamento no tempo necessário para a coagulação do plasma, indicando um perfil pró-trombótico. Após o isolamento do fibrinogênio desses ratos, foi identificada a formação de CML e um atraso no tempo necessário para a fibrina polimerizar. Os nossos resultados indicam que o GA pode danificar diretamente o fibrinogênio e contribuir para os efeitos prótrombóticos vistos em algumas enfermidades. Ainda, os efeitos do GA in vivo não se restringem apenas às proteínas da cascata de coagulação sendo necessária a avaliação dos efeitos do GA sobre as células envolvidas com os processos de coagulação (plaquetas e células endoteliais). The risk of myocardial infarction is 3-5 folds higher in type 2 diabetic patients than in healthy subjects. Seventy five percent of these patients die with atherothrombotic complications. The mechanisms behind this prothrombotic profile include endothelial damage, cytokine release, oxidative stress, coagulation and platelet activation. The balance between anti/pro-coagulant is controlled mainly by proteins of coagulation cascade and platelets. Coagulation can be triggered by endothelial damage or by factors release, such as Tissue Factor. This cascade ends with thrombin activation, which act upon fibrinogen and allows its polymerization in the insoluble form fibrin. Moreover, thrombin also may activate platelets. Several mechanisms have been proposed in order to explain the underlying factor responsible for prothrombotic profile seen in diabetes. The generation of Advanced Glycation End-products (AGE) in these patients has been often described as an important factor. AGE are posttranslational modifications found in proteins that have origin in a non-enzymatic reaction between a protein and a sugar (or reactive aldehydes). During the diabetes, the hyperglycaemia is believed to be the main agent of protein glycation. The role of reactive aldehydes, such as methylglyoxal and glycolaldehyde (GA) are important too. Glycation can lead to a two main events in organism: a) alteration in protein configuration, with change of function; b) generation of a class of signaling molecules (AGE), which may trigger the proinflammatory and pro-thrombotic events. Recent studies have revealed that AGE can cause platelet activation and induce Tissue Factor release from monocytes and endothelial cells. A lot of studies have been developed to understand the role of AGE in coagulation, although few have studied the glycation precursors on hemostasis. Here we show that GA is able in reacting with plasma proteins in vitro leading to generation of protein carbonyl. The clots generated from GA-incubated plasma were resistant to proteolysis. The incubation of purified fibrinogen in presence of GA revealed the same profile than we saw in whole plasma, suggesting the importance of this protein in the hemostatic dysfunction induced by GA. To evaluate if the increased levels of GA is relevant in vivo, Wistar rats were injected with the aldehyde and plasma was evaluated. Plasma proteins showed increase in oxidative damage (carbonyl and sulfhydryl) whereas the time necessary to plasma to clot shortened, suggesting a prothrombotic profile. The purification of fibrinogen from GA-injected rats revealed that there was an increase in generation of CML, evaluated by western blot. Moreover, there was a delay in the time necessary to fibrin polymerization in a system containing isolated fibrinogen. Our results suggest that GA can directly damage fibrinogen and thus, contribute to prothrombotic effects seen in some diseases. Moreover, the in vivo effects of GA are not only restricted to the coagulation cascade proteins. More studies are necessary to evaluate the effects of GA on cell that participate in coagulation regulation (e.g. platelets and endothelial cells).

É bem estabelecido que respostas imunes possam ser influenciadas pelo sistema nervoso. O neuropeptídeo, peptídeo liberador de gastrina (GRP) tem sido detectado na produção e liberação de citocinas, em modelo animal e em humanos com doenças inflamatórias e sabe-se que o antagonista do receptor de GRP, RC-3095 modula a resposta de citocinas pro-inflamatórias em macrófagos ativados por lipopolissacarídeo (LPS) molhando a sobrevivência em modelo animal de sepse induzida por ligação e perfuração cecal (CLP). Neste contexto, neste estudo avaliamos o efeito modulatório de GRP em modelos animais de doenças inflamatórias agudas: injúria pulmonar associada à pleurisia induzida por carragenina e sepse induzida por CLP e adicionalmente, em pacientes sépticos através da correlação dos seus níveis com o desfecho clínico. Para esta proposta, no Capítulo 1 avaliamos em pleurisia induzida por carragenina os seguintes parâmetros: migração celular, atividade da lactato desidrogenase, conteúdo de proteínas totais, concentração de nitrito/nitrato e níveis de TNF-α e IL- β no exsudato pleural e atividade da mieloperoxidade e marcadores de dano oxidativo em lipídios e proteínas no tecido pulmonar. Assim, o RC-3095 exibiu significante ação anti-inflamatória através da inibição do influxo de leucócitos e bloqueio da mieloperoxidade, conteúdo de nitrito/nitrato e níveis de citocinas. Além disso, os resultados mostraram que RC-3095 exerce ação contra o dano oxidativo em lipídios e proteínas, bem como o aumento na viabilidade celular. Isto sugere que RC- 3095 tem propriedades anti-inflamatórias que podem estar relacionadas com a redução do dano oxidativo. No Capítulo 2, entretanto, nós seguimos no modelo animal de sepse onde buscamos o entendimento do papel protetor que exerce o RC-3095. Vários estudos sugerem o envolvimento de TLR-4 como um importante elemento de defesa do hospedeiro durante a infecção, e importantes eviências indicam que esses receptores também possuem um papel na patofisiologia da sepse, onde camundongos deficientes de TLR-4 não apresentam falência na migração de neutrófilos para a cavidade peritoneal durante a sepse polimicrobiana induzida por CLP letal, e como conseqüência, foram mais resistentes para sepse que controles. Nossos resultados indicam que este efeito protetor pode ser atribuído para uma atenuação de sinalização de TLR-4 em cultura de células RAW 264.7 estimuladas por LPS e tecido pulmonar em ratos CLP, levando a uma diminuição de citocinas proinflamatórias as quais a via de ativação de GRPR mostra seletividade como verificado no Capítulo 3, possibilitando a explicação dos baixos níveis de citocinas pro-inflamatórias em pacientes sépticos tratados com RC-3095. Esta atenuação favorece a infiltração de neutrófilos, resultando na diminuição de bacteremia preservando o controle da infecção no local melhorando o desfecho da sepse. Nossos resultados ainda mostram que níveis plasmáticos de GRP podem predizer o desfecho na sepse, mas não em pacientes SIRS sugerindo que GRP exerce funções diferenciais nas duas condições e sugere que o antagonismo de GRPR modula a inflamação incontrolada por agir em respostas mediadas por TLR-4 e funcionalidade imunoregulatória. Em conclusão, os presentes resultados indicam que o antagonista de GRPR exerce um papel na inflamação aguda e pode ser utilizado como uma nova terapia alternativa para sepse bacteriana Gram-negativa. It is well established that immune responses may be influenced by the nervous system. The neuropeptide gastrin-releasing peptide (GRP) has been detected on the production and release of cytokines, both in animal models and humans with inflammatory diseases and reported that the GRP receptor antagonist RC-3095 modulates the response of proinflammatory cytokines in activated macrophages by lipopolysaccharide and improved the survival in an animal model of sepsis induced by cecal ligation and puncture (CLP). Within this context, in this work we evaluate the GRP modulatory effect in animal models of acute inflammatory illnesses: lung injury associated with carrageenan-induced pleurisy, and in CLP-induced sepsis and additionally in septic patients through the correlations of its levels with the clinical outcome. For this purpose, in Chapter 1 we evaluated in carrageenan-induced pleurisy the following parameters: cell migration, lactate dehydrogenase activity, total protein content, nitrite/nitrate concentration, TNF-α and interleukin-1β (IL-1β) levels in pleural exudates; myeloperoxidase activity and lipid and protein oxidative damage markers in lung tissue. Thus, RC-3095 exhibited pronounced anti-inflammatory actions by inhibition of leukocyte influx and blockade of myeloperoxidase, nitrite/nitrate content and cytokine levels. Moreover, the results showed that RC-3095 elicits action against oxidative damage in lipids and proteins, as well as increases cell viability. These suggest that RC-3095 has anti-inflammatory properties that can be related with the reduction of oxidative damage. In Chapter 2, however, we follow the animal model of sepsis where we search the agreement of the protective role that RC-3095 exerts. Increasing evidences suggest the evolvement of TLR-4 as an important element of host defense during an infection, a growing body of evidence indicates that these receptors also may play a role in the pathophysiology of sepsis where TLR-4 defective mice did not present failure of neutrophil migration to the peritoneal cavity during polymicrobial sepsis induced by lethal CLP, and as consequence, they were more resistant to sepsis than controls Our results further indicate that this protective effect can be attributed to an attenuation of TLR-4 signaling in RAW 264.7 cell culture stimulated by LPS and lung tissue in CLP rats, leading to a decrease of release of proinflammatory cytokines which the pathway of activation of GRPR shows selectivity as verified in Chapter 3, and can additionally explain the lower levels of the proinflammatory cytokine in RC-3095-treated septic patients. This attenuation favors neutrophil infiltration, resulting in decreased bacteremia preserving the control of infection in situ improving sepsis outcome. Our finding still show that plasma GRP levels could predict outcome in sepsis but not SIRS patients suggesting that GRP plays different roles in the two conditions and suggest that GRPR antagonism modulates uncontrolled inflammation by targeting TLR-4-mediated responses and immunoregulatory functionality. Taken together, the present results indicate that a GRPR antagonist plays a role in acute inflammation and could be developed as a new alternative therapy for Gram-negative bacterial sepsis.

Este trabalho apresenta a compilação de 5 experimentos carreados ao longo de 2004-2007. Na parte 1 apresenta sucintamente o marco teórico dos quatro trabalhos. Inicialmente são discutidos aspectos gerais da sepse. Após, são descritos alguns mecanismos conhecidos do envolvimento do sistema nervoso central com a sepse, como a permeabilidade diminuída da barreira sanguínea cerebral, alteração de alguns neurotransmissores, apoptose neuronal, ativação de algumas cascatas imunológicas, enfim, o processo inflamatório no sistema nervoso central. Os danos cognitivos ocasionados pela encefalopatia séptica também foram relatados, e por fim o estresse oxidativo e as defesas antioxidantes como um mecanismo que possa estar mediando os danos cognitivos observados em pacientes sobreviventes as sepse. Os experimentos (Parte II) comportamentais realizados 10 dias após a indução da sepse em ratos ocupam os Capítulos 1 e 2. No capítulo 1 é apresentado um corpo de resultados que permite observar os déficits cognitivos nos testes de Habituação ao Campo Aberto, Esquiva Inibitória e Esquiva Inibitória de Múltiplos Treinos em ratos sobreviventes a sepse após 10 dias da indução pelo modelo animal de CLP. Estes dados demonstram uma incapacidade cognitiva no aprendizado e na memória dos animais sépticos. O Capítulo 2 apresenta os resultados dos testes comportamentais de Reconhecimento de Objeto, Labirinto de Cruz Elevada e Teste de Natação Forçada, onde foi possível demonstrar que os ratos sépticos apresentaram uma incapacidade na memória e comportamento compatível com “depressão”, mas não com ansiedade. O Capítulo 3 estende os achados comportamentais observados no Capítulo 1, realizando os testes comportamentais de Habituação ao Campo Aberto, Esquiva Inibitória e Esquiva Inibitória de Múltiplos Treinos após 30 dias da indução de sepse em ratos pelo procedimento CLP. Os dados obtidos confirmam que a incapacidade de aprendizado e memória demonstrados no Capítulo 1 persiste após 30 dias da cirurgia de CLP. A mensuração do estresse oxidativo no hipocampo, cerebelo, estriado e córtex de ratos submetidos à sepse foram descrito no Capítulo 4. Neste experimento foi observado que nas horas iniciais após a indução de sepse em ratos, houve danos oxidativos, avaliados pelo TBARS e carbonil em diversas regiões do cérebro. Entretanto, a exceção do estriado, foi demonstrado um aumento na atividade de SOD sem um proporcional aumento na atividade de CAT, com aumento conseqüente na relação de SOD e CAT, também nos períodos iniciais após a indução de sepse nos ratos (6 horas). O Capítulo 6 aborda os resultados do experimento realizado com administração de antioxidantes NAC e DFX antes do Teste de Esquiva Inibitória, Esquiva Inibitória de Múltiplos Treinos após 10 e 30 dias da indução da sepse e Habituação ao Campo Aberto após 10 dias da cirurgia de CLP, onde foi demonstrando que, DFX e NAC associado, porém não isoladamente, revertem os danos cognitivos observados em ratos submetidos aos testes acima. A discussão geral (parte III) busca integrar esses achados descritos nos capítulos anteriores dentro de uma nova perspectiva para esclarecer os mecanismos neurobiológicos do dano cognitivo em sobreviventes a sepse. Além disso, abre discussões acerca de possíveis novas possibilidades de pesquisas. This work presents the compilation of 5 experiments enters throughout 2004-2007. The part I presents lightly the theoretical landmark of the four works. Initially general aspects of sepsis are argued. After, some known mechanisms of the involvement of the central nervous system with sepsis are described, as the diminished permeability of the brain blood barrier, alteration of some neurotransmitters, neuronal apoptosis, activation of some inflammatory cascades, at last, the inflammatory process in the central nervous system. The cognitive damage caused by the septic encephalopathy had been also discussed, and finally it stress oxidative and the antioxidants defenses as a mechanism that can be causing the cognitive deficit in sepsis survivors patients. The main experiments (part II) carried through 10 days after the induction of sepsis in rats occupy chapters 1 and 2. In chapter 1 a body of results is presented that allows observing the cognitive incapacities to the tests of Habituation to the Open Field, Inhibitory Avoidance and Continuous Multiple Trials Step-down Inhibitory Avoidance in rats surviving sepsis after 10 days of the induction for the animal model of CLP. These data demonstrate a cognitive incapacity in the memory and the learning of the septic animals. chapter 2 presents the results of the complementary behavioural tests: Object Recognition, Elevated Plus-maze and Forced Swimming Test, where it was possible to demonstrate that the septic rats had presented incapacity in the memory and symptoms of depression, but not of anxiety. chapter 3 extends the observed findings in chapter 1, carrying through the tests of Habituation to the Open Field, Continuous Multiple Trials Step-down Inhibitory Avoidance after 30 days of the induction of sepsis in rats for procedure CLP. The gotten data confirm that the incapacity of demonstrated learning and memory in chapter 1 after persists 30 days of the surgery of CLP. The measure of it stress oxidative in hippocampus, cerebellum, striatum and cortex of rats submitted to sepsis was described in chapter 4. In this experiment it was observed that in the initial hours after the induction of sepsis in rats, had oxidative damages, evaluated for the TBARS and carbonyl in diverse regions of the brain. However, the exception of the striatum, was demonstrated an increase in the activity of SOD without a proportional increase in the activity of CAT, with consequent increase in the relation of SOD and CAT, also in the initials periods after induction of sepsis in the rats (6 hours). chapter 5 approaches the results of the experiment carried through with antioxidants substance administration NAC and DFX before the Test of Inhibitory Avoidance and Continuous Multiple Trials Step-down Inhibitory Avoidance after 10 and 30 days of the induction of sepsis and Habituation to the Open Field after 10 days of the surgery of CLP, where it was demonstrating that, DFX and NAC associated, but not separately, above revert the observed cognitive damages in rats submitted to the tests. The general quarrel (part III) searches to integrate these described findings in the previous chapters inside of a new perspective to clarify the neurobiological mechanisms underlying brain damage in sepsis survivors. Moreover, it opens possible quarrels concerning new possibilities of research.

Diabetes mellitus (DM) é um grupo de anomalias metabólicas caracterizadas principalmente pela hiperglicemia. Componentes macro- e microvasculares, além de neuropáticos inter-relacionados com a elevação da glicemia são fatores freqüentemente envolvidos em acidentes cérebro-vasculares, infartos miocárdicos, doença vascular periférica, retinopatia e nefropatia diabética. Na literatura científica atual pode-se obter um grande número de trabalhos onde o uso de plantas medicinais, extratos ou substâncias vegetais isoladas é positivamente relacionado ao tratamento do DM e/ou seus efeitos diretos e indiretos. Bauhinia microstachya (RADDI) MACBR. (Caesalpinaceae) é uma planta que ocorre naturalmente na região sul do Brasil onde é conhecida popularmente como “escada-de-macaco”. Algumas populações fazem uso de preparações das folhas no tratamento do DM e suas complicações. Neste trabalho propomos que os extratos aquoso e hidro-etanólico, obtidos das folhas de B. microstachya possuem ação antioxidante in vitro e que o extrato hidro-etanólico apresenta poder antioxidante in vivo, além de efeito hipoglicemiante, apesar de ser potencialmente hepatotóxico. Diabetes mellitus (DM) is a heterogeneous group of metabolic disorders characterized by chronic hyperglycemia. Both DM types share aspects that are related to uncontrolled hyperglycaemia: alterations in the carbohydrate, fat, and protein metabolism. In addition, increased cardiovascular disease risk, retinopathy, nephropathy, and neuropathy are vascular complications associated to diabetes. In scientific literature there are several reports where the use of folk medicine is positively related to DM treatment and/or their direct and indirect effects. Bauhinia microstachya (RADDI) MACBR. (Caesalpinaceae) is a creeper plant that occurs naturally in southern Brazil where is popularly known as “escada-de-macaco” (monkey’s ladder) and often used as herbal antidiabetic medicine. In the present work, we propose that the extracts obtained from B. microstachya leaves have in vitro and in vivo antioxidant action, hypoglycemic effect, despite their hepatotoxic potential.

OBJETIVOS: determinar a relação entre parâmetros de estresse oxidativo, gravidade de sepse e resposta ao tratamento com antioxidantes. MATERIAL E MÉTODOS: foram incluídos pacientes consecutivos admitidos na UTI de um hospital terciário com o diagnóstico de sepse, sepse grave ou choque séptico. Os pacientes foram avaliados diariamente e foi coletado sangue imediatamente após a inclusão no estudo (máximo de 12h após diagnóstico de sepse). Avaliou-se os níveis séricos de substâncias reativas ao ácido tiobarbitúrico (TBARS), carbonilação de proteínas, atividade de superóxido dismutase (SOD) e catalase. Estas variáveis foram correlacionadas com desfecho e variáveis clínicas. Para determinar a relação dos parâmetros oxidativos na resposta ao tratamento, utilizamos o modelo de ligação cecal e perfuração (CLP) empregando ou não tratamento antioxidante (N-acetilcisteína mais deferoxamina). Coletou-se sangue da veia caudal 3h após a indução de sepse e correlacionou-se os parâmetros com resposta ao tratamento antibiótico e antioxidante. Para determinar se o tratamento antioxidante poderia ser retardado por 12h, em uma segunda amostra de animais coletou-se sangue da veia caudal e administrou-se ou não tratamento após 12h da indução de sepse. RESULTADOS: níveis elevados de proteínas carboniladas e de SOD no diagnóstico de sepse são relacionados com óbito por sepse nesta amostra. Estes parâmetros são correlacionados com a gravidade da doença avaliada pelos escores APACHE II e MODS. Níveis de atividade da SOD podem prever resposta ao tratamento com antioxidantes no modelo CLP, tanto 3 como 12h após a indução de sepse. CONCLUSÃO: Parâmetros oxidativos são associados com gravidade e desfecho de sepse em UTI geral, e podem prever resposta ao tratamento antioxidante em animas. OBJECTIVE: determine the relationship between oxidative stress parameters, sepsis severity and treatment response to antioxidants. MATERIALS AND METHODS: were included consecutive patients admited on ICU at a tertiary care Hospital with sepsis, severe sepsis or septic shock. The patients were evaluated, blood samples were colected immediately after study inclusion (12h maximum after sepsis diagnosis). We determined plasma levels of thiobarbituric acid reactive species (TBARS), protein carbonyls, superoxide dismutase (SOD) and catalase activities and correlate it to clinical parameters. To determine the relation between oxidative parameters and response to antioxidant treatment we used the cecal ligation and perforation (CLP) model of sepsis, using or not antioxidants (n-acetyilcysteine plus deferoxamine) 3 or 12 hours after CLP. RESULTS: non-survivor septic patients presented higher protein carbonyls and SOD activity when compared to survivor patients. These parameters were correlated to APACHE II and MODS in our sample. In addition, plasma SOD levels predicted response to antioxidant treatment in the CLP model, both 3 and 12 houras after sepsis induction. CONCLUSION: Oxidative parameters are correlated to severity and outcome in septic patients and could predict response to antioxidant treatment in the CLP model.

O presente estudo investigou as atividades antioxidantes in vitro, ex vivo e in vivo dos extratos de folhas Passiflora alata e Passiflora edulis, plantas usadas na medicina popular e ricas em polifenóis, compostos com reconhecida atividade antioxidante. No modelo experimental in vitro, ambos os extratos demonstraram atividade antioxidante e proteção contra dano protéico induzido por glicose. Fatias de fígado de ratos foram utilizadas como modelo ex vivo. Tanto o extrato de P. alata quanto o extrato de P. edulis protegeram de forma significativa o dano protéico e a morte celular induzidos por FeSO4. Como a P. alata é uma droga oficial da Farmacopéia Brasileira, os efeitos antioxidantes deste extrato foram investigados in vivo. Ratos machos Wistar receberam tratamento intragástrico de extrato de folhas de P. alata (1 e 5 mg/kg), trolox (0,18 mg/kg) ou água (controle) durante 30 dias, seguido de uma dose de CCl4 (3 ml/kg, i.p.) no 30º dia. O dano hepático e os efeitos antioxidantes do pré-tratamento com extrato de P. alata foram avaliados em vários órgãos. Quando comparados ao grupo controle, os ratos pré-tratados com o extrato demonstraram dano hepático menor, evidenciado por um grau menor de necrose, níveis menores de lipoperoxidação e maior atividade das enzimas superóxido dismutase e catalase. Adicionalmente, níveis menores de lipoperoxidação cardíaca foram observados com o pré-tratamento de P. alata (5mg/kg). Os resultados obtidos neste estudo indicam que os extratos de Passiflora são fontes potenciais de antioxidantes naturais. Estudos adicionais investigando o papel de compostos isolados destes extratos em patologias humanas onde o estresse oxidativo está envolvido são necessários.

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O estresse oxidativo tem um papel importante no desenvolvimento da falência orgânica múltipla e choque séptico. O presente estudo foi realizado para determinar diferentes parâmetros de dano oxidativo a biomoléculas, produção de superóxido mitocondrial, atividades da superóxido dismutase e catalase e suas relações com a mortalidade por sepse em um modelo animal. Além disso, nós avaliamos os efeitos da combinação de antioxidantes (N-acetilcisteína e deferoxamina) em um modelo murino de sepse polimicrobiana induzida por ligação cecal e punção (CLP). Ratos Wistar machos (250-300 g) foram randomicamente divididos em quatro grupos: sham-operated, CLP ressuscitado com solução salina (50 ml/Kg imediatamente e 12h após CLP), CLP ressuscitado com solução salina e antibioticoterapia (solução salina 50 ml/ Kg imediatamente e 12h após CLP + ceftriaxone 30 mg/Kg e clindamicina 25 mg/Kg de 6/6h), e CLP com N-acetilcisteína (20 mg/kg subcutâneo, 3h, 6h, 12h, 18h e 24h após CLP) + deferoxamina (20mg/kg, subcutâneo, 3h e 24h após CLP). A peroxidação lipídica, a carbonilação protéica e a atividade da superóxido dismutase se apresentaram significativamente aumentadas nos animais não-sobreviventes podendo predizer a mortalidade. Nós demonstramos que existe uma modulação diferente da superóxido dismutase e da catalase nos animais não-sobreviventes. Existe um grande aumento da atividade da superóxido dismutase sem um aumento proporcional da atividade da catalase nos não-sobreviventes. Os ratos tratados com antioxidantes apresentaram uma redução significante da atividade da mieloperoxidase e da peroxidação lipídica em todos os órgãos estudados. A produção de superóxido mitocondrial apresentou uma redução significante nos animais tratados com antioxidantes. Além disto, o tratamento com antioxidantes melhorou o equilíbrio entre a atividade da catalase e superóxido dismutase. A sobrevivências nos ratos sépticos não tratados foi de 10%. A sobrevivência aumentou para 40% com a ressuscitação volêmica e antibióticos. Ratos tratados apenas con N-acetilcisteína e desferoxamina apresentaram uma sobrevivência de 47%, similar aos ratos que receberam suporte básico. Este estudo demonstrou pela primeira vez que a atividade da superóxido dismutase deve ser um marcador precoce de mortalidade em sepse. Nossos resultados auxiliam o entendimento de aspectos importantes da resposta oxidativa na sepse; um aumento na atividade da superóxido dismutase sem um aumento proporcional na atividade da catalase. Além disto, nossos resultados demonstraram que o tratamento combinado com N-acetilcisteína e desferoxamina reduzem as conseqüências da sepse, reduzindo o estresse oxidativo, limitando a ativação de neutrófilos e a disfunçào mitocondrial, levando a uma melhor sobrevida.