Search

Objective: To predict exhaled air in patients undergoing mechanical ventilation during bedside diagnosis of ventilator-associated pneumonia., Methods: Air samples were collected through the expiratory branch of the mechanical ventilation circuit during the hospitalization of patients at the intensive care unit of Hospital São José in Criciúma (SC), Brazil. In this study, 83 participants were divided into two groups, namely, the group with and the group without ventilator-associated pneumonia., Results: The analysis of three air patterns revealed a predictive value for the diagnosis of ventilator-associated pneumonia. The analyses of samples from the first 12 hours of invasive mechanical ventilation were able to predict ventilator-associated pneumonia (p = 0.018). However, none of the other air samples collected during hospitalization were useful in identifying the severity or predicting early or late ventilator-associated pneumonia., Conclusion: The use of a gas analyzer may be helpful for the early identification of patients admitted to intensive care who will develop ventilator-associated pneumonia.

Objective: To investigate the relationship between the levels of adipokines and other endocrine biomarkers and patient outcomes in hospitalized patients with COVID-19., Methods: In a prospective study that included 213 subjects with COVID-19 admitted to the intensive care unit, we measured the levels of cortisol, C-peptide, glucagon-like peptide-1, insulin, peptide YY, ghrelin, leptin, and resistin.; their contributions to patient clustering, disease severity, and predicting in-hospital mortality were analyzed., Results: Cortisol, resistin, leptin, insulin, and ghrelin levels significantly differed between severity groups, as defined by the World Health Organization severity scale. Additionally, lower ghrelin and higher cortisol levels were associated with mortality. Adding biomarkers to the clinical predictors of mortality significantly improved accuracy in determining prognosis. Phenotyping of subjects based on plasma biomarker levels yielded two different phenotypes that were associated with disease severity, but not mortality., Conclusion: As a single biomarker, only cortisol was independently associated with mortality; however, metabolic biomarkers could improve mortality prediction when added to clinical parameters. Metabolic biomarker phenotypes were differentially distributed according to COVID-19 severity but were not associated with mortality.

Background: Delirium is a potentially severe form of acute encephalopathy. Minocycline has neuroprotective effects in animal models of neurologic diseases; however, data from human studies remain scarce., Research Question: Does the neuroprotective effect of minocycline prevent delirium occurrence in critically ill patients?, Study Design and Methods: This study was a randomized, placebo-controlled, double-anonymized trial conducted in four ICUs. Patients aged 18 years or older were eligible and randomized to receive minocycline (100 mg, twice daily) or placebo. The primary outcome was delirium incidence within 28 days or before ICU discharge. Secondary outcomes included days in delirium during ICU stay, delirium/coma-free days, length of mechanical ventilation, ICU length of stay, ICU mortality, and hospital mortality. The kinetics of various inflammatory (IL-1β, IL-6, IL-10, and C-reactive protein) and brain-related biomarkers (brain-derived neurotrophic factor and S100B) were used as exploratory outcomes., Results: A total of 160 patients were randomized, but one patient in the placebo group died before treatment; thus the data from 159 patients were analyzed (minocycline, n = 84; placebo, n = 75). After the COVID-19 pandemic it was decided to stop patient inclusion early. There was a small but significant decrease in delirium incidence: 17 patients (20%) in the minocycline arm compared with 26 patients (35%) in the placebo arm (P = .043). No other delirium-related outcomes were modified by minocycline treatment. Unexpectedly, there was a significant decrease in hospital mortality (39% vs. 23%; P = .029). Among all analyzed biomarkers, only plasma levels of C-reactive protein decreased significantly after minocycline treatment (F = 0.75, P = .78, within time; F = 4.09, P = .045, group × time)., Interpretation: Our findings in this rather small study signal a possible positive effect of minocycline on delirium incidence. Further studies are needed to confirm the benefits of this drug as a preventive measure in critically ill patients., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT04219735; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Because severe acute respiratory syndrome coronarivus 2 (SARS-CoV-2) leads to severe conditions and thrombus formation, evaluation of the coagulation markers is important in determining the prognosis and phenotyping of patients with COVID-19., Methods: In a prospective study that included 213 COVID-19 patients admitted to the intensive care unit (ICU) the levels of antithrombin, C-reactive protein (CRP); factors XI, XII, XIII; prothrombin and D-dimer were measured. Spearman's correlation coefficient was used to assess the pairwise correlations between the biomarkers. Hierarchical and non-hierarchical cluster analysis was performed using the levels of biomarkers to identify patients´ phenotypes. Multivariate binary regression was used to determine the association of the patient´s outcome with clinical variables and biomarker levels., Results: The levels of factors XI and XIII were significantly higher in patients with less severe COVID-19, while factor XIII and antithrombin levels were significantly associated with mortality. These coagulation biomarkers were associated with the in-hospital survival of COVID-19 patients over and above the core clinical factors on admission. Hierarchical cluster analysis showed a cluster between factor XIII and antithrombin, and this hierarchical cluster was extended to CRP in the next step. Furthermore, a non-hierarchical K-means cluster analysis was performed, and two phenotypes were identified based on the CRP and antithrombin levels independently of clinical variables and were associated with mortality., Conclusion: Coagulation biomarkers were associated with in-hospital survival of COVID-19 patients. Lower levels of factors XI, XII and XIII and prothrombin were associated with disease severity, while higher levels of both CRP and antithrombin clustered with worse prognosis. These results suggest the role of coagulation abnormalities in the development of COVID-19 and open the perspective of identifying subgroups of patients who would benefit more from interventions focused on regulating coagulation., (© 2023. The Author(s).)

Objective: To assess factors associated with long-term neuropsychiatric outcomes, including biomarkers measured after discharge from the intensive care unit., Methods: A prospective cohort study was performed with 65 intensive care unit survivors. The cognitive evaluation was performed through the Mini-Mental State Examination, the symptoms of anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale, and posttraumatic stress disorder was evaluated using the Impact of Event Scale-6. Plasma levels of amyloid-beta (1-42) [Aβ (1-42)], Aβ (1-40), interleukin (IL)-10, IL-6, IL-33, IL-4, IL-5, tumor necrosis factor alpha, C-reactive protein, and brain-derived neurotrophic factor were measured at intensive care unit discharge., Results: Of the variables associated with intensive care, only delirium was independently related to the occurrence of long-term cognitive impairment. In addition, higher levels of IL-10 and IL-6 were associated with cognitive dysfunction. Only IL-6 was independently associated with depression. Mechanical ventilation, IL-33 levels, and C-reactive protein levels were independently associated with anxiety. No variables were independently associated with posttraumatic stress disorder., Conclusion: Cognitive dysfunction, as well as symptoms of depression, anxiety, and posttraumatic stress disorder, are present in patients who survive a critical illness, and some of these outcomes are associated with the levels of inflammatory biomarkers measured at discharge from the intensive care unit.

Sepsis is a life-threatening organ dysfunction triggered by a dysregulated host immune response to eliminate an infection. After the host immune response is activated, a complex, dynamic, and time-dependent process is triggered. This process promotes the production of inflammatory mediators, including acute-phase proteins, complement system proteins, cytokines, chemokines, and antimicrobial peptides, which are required to initiate an inflammatory environment for eliminating the invading pathogen. The physiological response of this sepsis-induced systemic inflammation can affect blood-brain barrier (BBB) function; subsequently, endothelial cells produce inflammatory mediators, including cytokines, chemokines, and matrix metalloproteinases (MMPs) that degrade tight junction (TJ) proteins and decrease BBB function. The resulting BBB permeability allows peripheral immune cells from the bloodstream to enter the brain, which then release a range of inflammatory mediators and activate glial cells. The activated microglia and astrocytes release reactive oxygen species (ROS), cytokines, chemokines, and neurochemicals, initiate mitochondrial dysfunction and neuronal damage, and exacerbate the inflammatory milieu in the brain. These changes trigger sepsis-associated encephalopathy (SAE), which has the potential to increase cognitive deterioration and susceptibility to cognitive decline later in life., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Introduction: Necrotizing Enterocolitis (NEC) is a serious intestinal disease that affects premature neonates, causing high mortality, despite the technological development in neonatal intensive care, with antibiotics, parenteral nutrition, surgery, and advanced life support. The correction of dysbiosis with fecal microbiome transplantation (FMT) has shown beneficial effects in experimental models of the disease. The different forms of administration and conservation of FMT and mixed results depending on several factors lead to questions about the mechanism of action of FMT. This study aimed to compare the effectiveness of fresh, sterile FMT and probiotic treatment under parameters of inflammation, oxidative stress, and tissue damage in a neonatal model of NEC., Methods: One-day-old Wistar rats were used to induce NEC model. Animals were divided in five groups: Control + saline; NEC + saline; NEC + fresh FMT; NEC + sterile FMT and NEC+ probiotics. Parameters of inflammatory response and oxidative damage were measured in the gut, brain, and serum. It was also determined gut histopathological alterations., Results: Proinflammatory cytokines were increased in the NEC group, and IL-10 levels decreased in the gut, brain, and serum. Fresh and sterile FMT decreased inflammation when compared to the use of probiotics. Oxidative and histological damage to the intestine was apparent in the NEC group, and both FMT treatments had a protective effect., Conclusion: Fresh and sterile FMT effectively reduced the inflammatory response, oxidative damage, and histological alterations in the gut and brain compared to an experimental NEC model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Background: Considering millions of people affected by Coronavirus disease 2019 (COVID-19), long-lasting sequelae can significantly impact health worldwide. Data from prospective studies in lower-middle-income countries on persistent lung dysfunction secondary to COVID-19 are lacking. This work aims to determine risk factors and the impact of persistent lung dysfunctions in COVID-19 survivors., Methods: Observational and prospective cohort of patients admitted to a tertiary hospital from June 2020 to November 2020. Persistence of chest CT scan alterations, desaturation in the six-minute walk test (6MWT), forced expiratory volume in one second (FEV1), lung carbon monoxide diffusion (DLCO), and maximum inspiratory pressure (MIP) were measured 6 months after hospital discharge. Additionally, the Barthel index (BI) and the Modified Medical Research Council (mMRC) Dyspnea Scale were used to determine the impact of lung dysfunction in activities of daily living (ADL)., Results: It was included 44 patients. Sixty percent had persistent lung CT scan abnormalities. From 18 to 43% of patients had at least one pulmonary function dysfunction, a decrease in FEV1 was the least prevalent (18%), and a reduction in DLCO and MIP was the most frequent (43%). In general, female gender, comorbidity index, and age were associated with worse lung function. Additionally, the presence of lung dysfunction could predict worse BI (r-square 0.28) and mMRC (r-square 0.32)., Conclusion: Long-term lung dysfunction is relatively common in survivors from severe COVID-19 and impacts negatively on ADL and the intensity of dyspnea, similar to studies in high-income countries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Prestes, Simon, Walz, Ritter and Dal-Pizzol.)

Objectives: Sepsis is a life-threatening organ dysfunction caused by a host's unregulated immune response to eliminate the infection. After hospitalization, sepsis survivors often suffer from long-term impairments in memory, attention, verbal fluency, and executive functioning. To understand the effects of sepsis and the exacerbated peripheral inflammatory response in the brain, we asked the question: What are the findings and inflammatory markers in the brains of deceased sepsis patients? To answer this question, we conducted this systematic review by the recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses., Data Sources: Relevant studies were identified by searching the PubMed/National Library of Medicine, PsycINFO, EMBASE, Bibliographical Index in Spanish in Health Sciences, Latin American and Caribbean Health Sciences Literature, and Web of Science databases for peer-reviewed journal articles published on April 05, 2021., Study Selection: A total of 3,745 articles were included in the primary screening; after omitting duplicate articles, animal models, and reviews, 2,896 articles were selected for the study. These studies were selected based on the title and abstract, and 2,772 articles were still omitted based on the exclusion criteria., Data Extraction: The complete texts of the remaining 124 articles were obtained and thoroughly evaluated for the final screening, and 104 articles were included., Data Synthesis: The postmortem brain had edema, abscess, hemorrhagic and ischemic injuries, infarction, hypoxia, atrophy, hypoplasia, neuronal loss, axonal injuries, demyelination, and necrosis., Conclusions: The mechanisms by which sepsis induces brain dysfunction are likely to include vascular and neuronal lesions, followed by the activation of glial cells and the presence of peripheral immune cells in the brain., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Ethnopharmacological Relevance: Bauhinia forficata Link, is a Brazilian native plant and popularly known as pata-de-vaca ("paw-of-cow"). The tea prepared with their leaves has been extensively used in the Brazilian traditional practices for the diabetes treatment. The aim of the present study was to investigate the effect of capsules containing granules of a standardized extract of B. forficata leaves as adjuvant treatment on the glycemic control of patients with type-2 diabetes melitus., Materials and Methods: A double-blind, randomized clinical trial using capsules containing granules prepared by wet granulation of a standardized extract from B. forficata leaves as adjuvant treatment, was conducted. 92 patients aged 18-75 years from an outpatient clinic with type-2 diabetes were randomly assigned by a simple randomization scheme, in a 1:1 ratio to receive capsules of B. forficata or placebo for four months. The capsules used contain 300 mg of standardized extract from B. forficata leaves, yielding 2% of total flavonoid content per capsule. Primary outcome was glycated hemoglobin levels and fasting plasma glucose at 4 months. Possible harms were also determined., Results: The findings showed that at 4 months, the mean fasting plasma glucose levels and glycated hemoglobin were both significantly lower in the B. forficata group than in the placebo group., Conclusion: The present study suggests that the adjunctive use of capsules containing standardized extract of B. forficata can add to regular oral anti-diabetics in the metabolic and inflammatory control of type-2 diabetes patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Microglia are involved in many dynamic processes in the central nervous system (CNS) including the development of inflammatory processes and neuromodulation. Several sedative, analgesic or anaesthetic drugs, such as opioids, ∝ 2 -adrenergic agonists, ketamine, benzodiazepines and propofol can cause both neuroprotective and harmful effects on the brain. The purpose of this review is to present the main findings on the use of these drugs and the mechanisms involved in microglial activation. Alpha 2-adrenergic agonists, propofol and benzodiazepines have several pro- or anti-inflammatory effects on microglia. Long-term use of benzodiazepines and propofol causes neuroapoptotic effects and α 2 -adrenergic agonists may attenuate these effects. Conversely, morphine and fentanyl may have proinflammatory effects, causing behavioural changes in patients and changes in cell viability in vitro. Conversely, chronic administration of morphine induces CCL5 chemokine expression in microglial cells that promotes their survival., (Copyright © 2021. Published by Elsevier Ltd.)

Survivors of sepsis often develop long-term cognitive impairments. This review aimed at exploring the results of the behavioral tools and tests which have been used to evaluate cognitive dysfunction in different animal models of sepsis. Two independent investigators searched for sepsis- and cognition-related keywords. 6323 publications were found, of which 355 were selected based on their title, and 226 of these were chosen based on manuscript review. LPS was used to induce sepsis in 171 studies, while CLP was used in 55 studies. Inhibitory avoidance was the most widely used method for assessing aversive memory, followed by fear conditioning and continuous multi-trial inhibitory avoidance. With regard to non-aversive memory, most studies used the water maze, open-field, object recognition, Y-maze, plus maze, and radial maze tests. Both CLP and LPS models of sepsis were effective in inducing short- and long-term behavioral impairment. Our findings help elucidate the mechanisms involved in the pathophysiology of sepsis-induced cognitive changes, as well as the available methods and tests used to study this in animal models., (Copyright © 2020. Published by Elsevier Ltd.)

Lower sepsis mortality rates imply that more patients are discharged from the hospital, but sepsis survivors often experience sequelae, such as functional disability, cognitive impairment, and psychiatric morbidity. Nevertheless, the mechanisms underlying these long-term disabilities are not fully understood. Considering the extensive use of animal models in the study of the pathogenesis of neuropsychiatric disorders, it seems adopting this approach to improve our knowledge of postseptic psychiatric symptoms is a logical approach. With the purpose of gathering and summarizing the main findings of studies using animal models of sepsis-induced psychiatric symptoms, we performed a systematic review of the literature on this topic. Thus, 140 references were reviewed, and most of the published studies suggested a time-dependent recovery from behavior alterations, despite the fact that some molecular alterations persist in the brain. This review reveals that animal models can be used to understand the mechanisms that underlie anxiety and depression in animals recovering from sepsis., (© 2021. The American Society for Experimental NeuroTherapeutics, Inc.)

Objective: To evaluate serum uteroglobin-related protein 1 expression early after smoke inhalation injuries and its association with the severity of inhalation injury in burned patients., Methods: Smoke or chemical inhalation injury is associated with morbidity and mortality. The consequences of inhalation result from an inflammatory response. Uteroglobin-related protein 1 is an anti-inflammatory protein and may improve lung inflammation. We hypothesized that uteroglobin-related protein 1 levels could reflect disease severity and predict outcome in patients with inhalation injury. Sixteen patients diagnosed with acute respiratory distress syndrome secondary to smoke inhalation injury were prospectively included in the study. Plasma was collected upon intensive care unit admission and within 24 hours of the inhalation injury. Bronchoscopies were carried out in all patients to assess the severity of inhalation injury within 72 hours. Uteroglobin-related protein 1 plasma levels were determined in duplicate with enzyme-linked immunosorbent assay., Results: The mean age was 23 ± 5 years, and the inhalation injury distribution was as follows: three of grade 1, four of grade 2, and nine of grade 3. The level of uteroglobin-related protein 1 was related to inhalation severity (grade 1: 0.389 ± 0.053 arbitrary units versus grade 2: 0.474 ± 0.0423 arbitrary units versus grade 3: 0.580 ± 0.094 arbitrary units; p = 0.007)., Conclusion: Plasma levels of uteroglobin-related protein 1 are associated with the degree of lung inhalation injury.

The nervous system is one of the first systems to be affected during sepsis. Sepsis not only has a high risk of mortality, but could also lead to cerebral dysfunction and cognitive impairment in long-term survival patients. The receptor for advanced glycation end products (RAGE) can interact with several ligands, and its activation triggers a series of cell signaling events, resulting in the hyperinflammatory condition related to sepsis. Recent studies show that elevated levels of S100B (RAGE ligand) are associated with the pathophysiology of neurodegenerative disorders. They also participate in inflammatory brain diseases and may lead to an increased activation of microglia and astrocytes, leading to neuronal death. This study aimed to determine the effect of S100B inhibition on the neuroinflammatory response in sepsis. Sepsis was induced in Wistar rats by cecal ligation and perforation (CLP). There were three groups: Sham, CLP, and CLP +10 μg/kg of monoclonal antibody (Anti-S100B) administered intracerebroventricularly. The animals were killed 30 days after sepsis following behavioral evaluation by open field, novel object recognition, and splash test. The hippocampus, prefrontal cortex, and amydgala were used for the determination of S100B and RAGE proteins by western blotting and for the evaluation of cytokine levels and verification of the number of microglial cells by immunohistochemistry. On day 30, both the Sham and CLP + anti-S100B groups were capable of recovering the habitual memory in the open field task. Regarding novel object recognition, Sham and CLP + anti-S100B groups increased the recognition index during the test session in comparison to the training session. There was a significant increase in the time of grooming in CLP + anti-S100B in comparison to the CLP group. There was a modulation of cytokine levels and immunohistochemistry showed that the CLP + anti-S100B group had a decrease in the number of microglial cells only in the hippocampus. These results helped to understand the role of S100B protein in the pathophysiology of sepsis-associated encephalopathy and could be helpful to further experimental studies regarding this subject., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Ammonia is involved in the pathogenesis of neurological conditions associated with hyperammonemia, including hepatic encephalopathy. Few is known about the effects of gestational exposition to ammonia in the developing brain, and the possible long-term consequences of such exposure. We aimed to evaluate the effects of ammonia exposure during the gestation and the possible long-term cognitive alterations on pups. Eight female rats were divided into two groups: (1) control (saline solution); (2) ammonia (ammonium acetate, 2,5mmol/Kg). Each rat received a single subcutaneous injection during all gestational period. The brains from 1-day-old rats were obtained to the determination of thiobarbituric acid reactive species (TBARS), protein carbonyl and nitrite/nitrate levels. Some animals were followed 30 days after delivery and were subjected to the step-down inhibitory avoidance task. It was observed a significant increase in protein carbonyl, but not TBARS or nitrite/nitrate levels, in pups exposed to ammonia. Rats exposed to ammonia presented long-term cognitive impairment. Gestational exposition to ammonia induces protein oxidative damage in the neonatal rat brain, and long-term cognitive impairment.

Background: Neurogranin (Ng) concentrates at dendritic spines. In patients with Alzheimer disease Ng levels are elevated. The role of Ng in delirium development has not been assessed, therefore we hypothesized that Ng levels are associated with delirium in critically ill patients. Materials & methods: From 94 critically ill patients, 47 developed delirium and 47 controls were included. Blood was collected during the first 24 h of intensive care unit (ICU) admission, and on the day of delirium diagnoses. Ng and IL-1β were determined. Results: Ng and IL-1β levels were higher in the delirium group at ICU admission and on the day of delirium diagnoses. IL-1β and Ng were independently associated with delirium occurrence. Conclusion: Ng levels are associated with delirium development in ICU patients.

Introduction: Currently, there is a growing emphasis on the study of intestinal signaling as an influencer in the pathophysiology of neuropsychiatric diseases, and the gut-brain axis is recognized as a communication route through endocrine, immune, and neural pathways (vagus nerve). Studies have shown that diets that modify the microbiota can reduce stress-related behavior and hypothalamic-pituitary-adrenal axis activation. Investigators have used fecal microbiota transplantation (FMT) approaches to demonstrate that stress-related microbiota composition plays a causal role in behavioral changes., Aim: We hypothesized that FMT may present immunomodulatory, biochemical, endocrine, cognitive, and behavioral benefits in stress situations and that these changes can be mediated via the vagus nerve., Methods: Animals were subjected to a chronic mild stress (CMS) protocol. In one experiment, animals were divided into five groups: control, control + FMT, control + FMT + CMS, CMS + saline, and CMS + FMT. The animals received FMT, and behavioral tests were performed; cytokine and carbonyl levels were measured. In a second experiment, animals were submitted to vagotomy and divided into two groups: CMS + FMT and CMS + vagotomy + FMT., Results: Animals submitted to the CMS protocol or that received FMT from stressed animals showed behavioral changes and changes in neuroactive substances (increased IL-6 and TNF-α levels and carbonyl proteins). The FMT of healthy donors improved the analyzed parameters. In addition, vagotomy influenced beneficial FMT results, confirmed by behavioral testing and protein carbonyl in the hippocampus., Conclusion: Manipulation of the microbiota reversed the behavioral and biochemical changes induced by the CMS protocol, and the vagus nerve influenced the gut-brain axis response., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To examine the effectiveness of stratification to identify and target antioxidant therapy for animal models of lethal sepsis and in patients who develop sustained hypotension., Methods: Rats were subjected to sepsis induced by cecal ligation and puncture. Animals were divided into two groups: those with high and low plasma levels of interleukin-6. Following stratification, N-acetylcysteine plus deferoxamine or saline was administered to animals starting 3 and 12 hours after surgery. N-Acetylcysteine plus deferoxamine or placebo was administered within 12 hours of meeting the inclusion criteria in hypotensive patients., Results: N-Acetylcysteine plus deferoxamine increased survival in the cecal ligation and puncture model when administered 3 and 12 hours after sepsis induction. When dividing animals that received antioxidants using plasma interleukin-6 levels, the protective effect was observed only in those animals with high IL-6 levels. The antioxidant effect of N-acetylcysteine + deferoxamine was similar in the two groups, but a significant decrease in plasma interleukin-6 levels was observed in the high-interleukin-6-level group. Compared with patients treated with antioxidants in the low-interleukin-6 subgroup, those in the high-interleukin-6 subgroup had a lower incidence of acute kidney injury but were not different in terms of acute kidney injury severity or intensive care unit mortality., Conclusion: Targeting antioxidant therapy to a high inflammatory phenotype would select a responsive population.

Background: Several different mechanisms have been proposed to explain long-term cognitive impairment in sepsis survivors. The role of persisting mitochondrial dysfunction is not known. We thus sought to determine whether stimulation of mitochondrial dynamics improves mitochondrial function and long-term cognitive impairment in an experimental model of sepsis. Methods: Sepsis was induced in adult Wistar rats by cecal ligation and perforation (CLP). Animals received intracerebroventricular injections of either rosiglitazone (biogenesis activator), rilmenidine, rapamycin (autophagy activators), or n-saline (sham control) once a day on days 7-9 after the septic insult. Cognitive impairment was assessed by inhibitory avoidance and object recognition tests. Animals were killed 24 h, 3 and 10 days after sepsis with the hippocampus and prefrontal cortex removed to determine mitochondrial function . Results: Sepsis was associated with both acute (24 h) and late (10 days) brain mitochondrial dysfunction. Markers of mitochondrial biogenesis, autophagy and mitophagy were not up-regulated during these time points. Activation of biogenesis (rosiglitazone) or autophagy (rapamycin and rilmenidine) improved brain ATP levels and ex vivo oxygen consumption and the long-term cognitive impairment observed in sepsis survivors. Conclusion: Long-term impairment of brain function is temporally related to mitochondrial dysfunction. Activators of autophagy and mitochondrial biogenesis could rescue animals from cognitive impairment., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

This study aimed to evaluate behavioral and neurochemical parameters in adult (180-day-old) and young (60-day-old) rats subjected to sepsis. Sepsis was induced by cecal ligation and perforation (CLP). Thirty days after surgery, behavioral tests were performed, and the β-amyloid content, oxidative damage, and cytokine levels were measured in the hippocampus and prefrontal cortex. In both adult and young rats, sepsis impaired the inhibitory avoidance task performance and increased immobility time in the forced swimming test. However, the adult septic rats had a higher immobility time compared to the young rats. Both sepsis and aging induced brain inflammation and oxidative damage and increased Aβ content. Sepsis along with aging had additive effects on hippocampal interleukin-1 levels and prefrontal carbonyl levels. Taken together, our results suggest that age has a minor influence on brain inflammation and behavioral alterations observed in septic rats., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Delirium is a serious and common disorder that affects up to 80% of acutely ill patients, mainly the aged. In recent years, several studies pointed out possible biomarkers that could be used alone or in combination with other resources in the diagnosis and follow-up of critically ill patients who develop delirium. In this context, a systematic review was conducted to determine the predictive value of several biomarkers in acutely (critically and noncritically) ill adult patients with delirium. Studies that used the confusion assessment method (CAM) and CAM-intensive care unit as the diagnostic method were considered. The most recent search was performed in November 2017. There was no language restriction. Initially, 626 articles were screened and 39 were included in the study. A comprehensive evaluation of the abstracts resulted in the exclusion of 202 studies, leaving 39 articles as potentially relevant. Inflammatory markers, S100β and cortisol, could predict delirium occurrence in a specific subgroup population of critically ill patients.

Traumatic brain injury (TBI) is a worldwide social, economic, and health problem related to premature death and long-term disabilities. There were no prospective and multicentric studies analyzing the predictors of TBI related mortality and estimating the burden of TBI in Brazil. To address this gap, we investigated prospectively: (1) the hospital mortality and its determinants in patients admitted with severe TBI we analyzed in three reference centers; (2) the burden of TBI estimated by the years of life lost (YLLs) due to premature death based on the hospital mortality considering the hospital mortality. Between April 2014 and January 2016 (22 months), all the 266 patients admitted with Glasgow coma scale (GCS), ≤ 8 admitted in three TBI reference centers were included in the study. These centers cover a population of 1,527,378 population of the Santa Catarina state, Southern Brazil. Most patients were male ( n = 230, 86.5%), with a mean (SD) age of 38 (17) years. Hospital mortality was 31.1% ( n = 83) and independently associated with older age, worse cranial CT injury by the Marshall classification, the presence of subarachnoid hemorrhage in the CT, lower GCS scores and abnormal pupils at admission. The final multiple logistic regression model including these variables showed an overall accuracy for hospital mortality of 77.9% (specificity 88.6%, sensitivity 53.8%, PPV 67.7%, and NPV 81.1%). The estimated annual incidence of hospitalizations and mortality due to severe TBI were 9.5 cases and 5.43 per 100,000 inhabitants, respectively. The estimated YLLs in 22 months, in the 2 metropolitan areas were 2,841, corresponding to 1,550 YLLs per year and 101.5 YLLs per 100,000 people every year. The hospital mortality did not change significantly since the end of the 1990s and was similar to other centers in Brazil and Latin America. Significant predictors of hospital mortality were the same as those of studies worldwide, but their strength of association seemed to differ according to countries income. Present study results question the extrapolation of TBI hospital mortality models for high income to lower- and middle-income countries and therefore have implications for TBI multicentric trials including countries with different income levels.

The presence of autoantibodies against neuronal cell surface or synaptic proteins and their relationship to autoimmune encephalitis have recently been characterized. These autoantibodies have been also reported in other pathologic conditions; however, their role during sepsis is not known. This study detected the presence of autoantibodies against neuronal cell surface or synaptic proteins in the serum of septic patients and determined their relationship to the occurrence of brain dysfunction and mortality. This prospective, observational cohort study was performed in four Brazilian intensive care units (ICUs). Sixty patients with community-acquired severe sepsis or septic shock admitted to the ICU were included. Blood samples were collected from patients within 24 h of ICU admission. Antibodies to six neuronal proteins were assessed, including glutamate receptors (types NMDA, AMPA1, and AMPA2); voltage-gated potassium channel complex (VGKC) proteins, leucine-rich glioma-inactivated protein 1 (LGI1), and contactin-associated protein-2 (Caspr2), as well as the GABAB1 receptor. There was no independent association between any of the measured autoantibodies and the occurrence of brain dysfunction (delirium or coma). However, there was an independent and significant relationship between anti-NMDAR fluorescence intensity and hospital mortality. In conclusion, anti-NMDAR was independently associated with hospital mortality but none of the measured antibodies were associated with brain dysfunction in septic patients.

Persistent inflammation in intensive care unit (ICU) survivors is associated with higher long-term mortality and poorer mobility. However, it is unknown if inflammatory markers are associated with other dysfunctions observed in survivors of critical illness. Thus, it was investigated if plasma levels of interleukin (IL)-6 and IL-10 at hospital discharge were associated with long-term functional and cognitive performance after ICU discharge. Adult patients admitted for > 48 h to a 20-bed mixed ICU in a University Hospital had blood collected within 48 h before hospital discharge to measure IL-6 and IL-10 levels. After a median time of 48 months, cognitive status was determined by the Mini-Mental State Examination (MMSE), and functional status was determined by the Barthel Index. Patients at the higher 25th percentile of both IL-6 and IL-10 had a worse long-term cognitive performance, but not worse functional status, even when adjusted for confounders after long-term follow-up. In conclusion, elevated circulating IL-6 and IL-10 concentrations at hospital discharge were associated with long-term cognitive dysfunction in ICU survivors.

During chronic limb ischemia, oxidative damage and inflammation are described. Besides oxidative damage, the decrease of tissue oxygen levels is followed by several adaptive responses. The purpose of this study was to determine whether supplementation with N-acetylcysteine (NAC) is effective in an animal model of chronic limb ischemia. Chronic limb ischemia was induced and animals were treated once a day for 30 consecutive days with NAC (30mg/kg). After this time clinical scores were recorded and soleus muscle was isolated and lactate levels, oxidative damage and inflammatory parameters were determined. In addition, several mechanisms associated with hypoxia adaptation were measured (vascular endothelial growth factor - VEGF and hypoxia inducible factor - HIF levels, ex vivo oxygen consumption, markers of autophagy/mitophagy, and mitochondrial biogenesis). The adaptation to chronic ischemia in this model included an increase in muscle VEGF and HIF levels, and NAC was able to decrease VEGF, but not HIF levels. In addition, ex vivo oxygen consumption under hypoxia was increased in muscle from ischemic animals, and NAC was able to decrease this parameter. This effect was not mediated by a direct effect of NAC on oxygen consumption. Ischemia was followed by a significant increase in muscle myeloperoxidase activity, as well as interleukin-6 and thiobarbituric acid reactive substances species levels. Supplementation with NAC was able to attenuate inflammatory and oxidative damage parameters, and improve clinical scores. In conclusion, NAC treatment decreases oxidative damage and inflammation, and modulates oxygen consumption under hypoxic conditions in a model of chronic limb ischemia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Extracellular superoxide dismutase (ECSOD) protects nitric oxide (NO) bioavailability by decreasing superoxide levels and preventing peroxynitrite generation, which is important in maintaining renal blood flow and in preventing acute kidney injury. However, the profile of ECSOD expression after sepsis is not fully understood. Therefore, we intended to evaluate the content and gene expression of superoxide dismutase (SOD) isoforms in the renal artery and their relation to renal blood flow., Methods: Sepsis was induced in Wistar rats by caecal ligation and perforation. Several times after sepsis induction, renal blood flow (12, 24 and 48 h); the renal arterial content of SOD isoforms, nitrotyrosine, endothelial and inducible nitric oxide synthase (e-NOS and i-NOS), and phosphorylated vasodilator-stimulated phosphoprotein (pVASP); and SOD activity (3, 6 and 12 h) were measured. The influence of a SOD inhibitor was also evaluated., Results: An increase in ECSOD content was associated with decreased 3-nitrotyrosine levels. These events were associated with an increase in pVASP content and maintenance of renal blood flow. Moreover, previous treatment with a SOD inhibitor increased nitrotyrosine content and reduced renal blood flow., Conclusions: ECSOD appears to have a major role in decreasing peroxynitrite formation in the renal artery during the early stages of sepsis development, and its application can be important in renal blood flow control and maintenance during septic insult.

Objectives: To investigate the relationship between prognosis, changes in mitochondrial calcium uptake, and bioenergetic status in the heart during sepsis., Design: In vivo and ex vivo controlled experimental studies., Setting: University research laboratory., Subjects: Male adult Wistar rats., Interventions: Sepsis was induced by intraperitoneal injection of fecal slurry. Sham-operated animals served as controls. Confocal microscopy was used to study functional and bioenergetic parameters in cardiomyocytes isolated after 24-hour sepsis. Electron microscopy was used to characterize structural changes in mitochondria and sarcoplasmic reticulum. The functional response to dobutamine was assessed in vivo by echocardiography., Measurements and Main Results: Peak aortic blood flow velocity measured at 24 hours was a good discriminator for 72-hour survival (area under the receiver operator characteristic, 0.84 ± 0.1; p = 0.03) and was used in ex vivo experiments at 24 hours to identify septic animals with good prognosis. Measurements from animals with good prognostic showed 1) a smaller increase in mitochondrial calcium content and in nicotinamide adenine dinucleotide fluorescence following pacing and 2) increased distance between mitochondria and sarcoplasmic reticulum on electron microscopy, and 3) nicotinamide adenine dinucleotide redox potential and adenosine triphosphate/adenosine diphosphate failed to reach a new steady state following pacing, suggesting impaired matching of energy supply and demand. In vivo, good prognosis animals had a blunted response to dobutamine with respect to stroke volume and kinetic energy., Conclusions: In situations of higher energetic demand decreased mitochondrial calcium uptake may constitute an adaptive cellular response that confers a survival advantage in response to sepsis at a cost of decreased oxidative capacity.

Loss of heart rate variability (HRV) and autonomic dysfunction are associated with poor outcomes in critically ill patients. Neuronal networks comprising brainstem and hypothalamus are involved in the "flight-or-fight" response via control over the autonomic nervous system and circulation. We hypothesized that sepsis-induced inflammation in brain regions responsible for autonomic control is associated with sympathovagal imbalance and depressed contractility. Sepsis was induced by fecal slurry injection in fluid-resuscitated rats. Sham-operated animals served as controls. Echocardiography-derived peak velocity (PV) was used to separate septic animals into good (PV ≥0.93 m/s, low 72-h mortality) and bad (PV <0.93, high 72-h mortality) prognosis. Cytokine protein levels were assessed by ELISA. All experiments were performed at 24 h post-insult. Increased levels of inflammation and oxidative injury were observed in the hypothalamus (TNF-α, IL-10, nitrite and nitrate and carbonyl groups) and brainstem (IL-1, IL-6, IL-10, nitrite and nitrate and carbonyl groups) of the septic animals (p < 0.05 vs. sham), but not in the pre-frontal cortex, an area not directly implicated in control of the autonomic nervous system. Good prognosis septic animals had increased sympathetic output and increased left ventricular contractility (p < 0.05 vs. sham). There was a significant inverse correlation between high frequency power (a marker of parasympathetic outflow) and contractility (r = -0.73, p < 0.05). We found no correlation between the degree of inflammation or injury to autonomic centers and cardiovascular function. In conclusion, control of autonomic centers and cardiac function in our long-term rodent model of sepsis was related to clinical severity but not directly to the degree of inflammation.

There are different theories about the pathophysiology of sepsis-associated encephalopathy (SAE), and the majority of our knowledge was derived from critically ill patients. 7In less severe sepsis, it is probable that neuroinflammation can be a major aspect of SAE development. We hypothesized that in non-severe septic patients, blood biomarkers of inflammation, endothelial activation, coagulation, and brain function would be different when compared to patients with and without brain dysfunction. A total of 30 patients presenting with community-acquired pneumonia (CAP)-induced sepsis were included of which 10 (33 %) developed SAE. Eight medical patients admitted to the general ward, except due to sepsis or infection, which developed delirium were included as delirium, non-sepsis group. From all measured biomarkers, only brain-derived neurotrophic factor (BDNF), regulated upon activation normal T cell expressed, and presumably secreted (RANTES), and interleukin (IL)-10 where significantly different when compared to SAE and sepsis groups. In addition, SAE patients presented higher levels of BDNF, vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), platelet-derived growth factor (PDGF)-AB/BB and RANTES when compared to delirium patients. In conclusion, the profile of biomarkers differs between SAE, sepsis, and delirium patients, suggesting that pathways related to SAE are different from delirium and from sepsis itself.

Background: The aim was to test the primary hypothesis that in patients suffering from shock, treatment with N-acetylcysteine (NAC) plus deferoxamine (DFX) decreases the incidence of acute kidney injury (AKI)., Methods: A double-blind, randomized, placebo-controlled trial was conducted in a general intensive care unit in an academic hospital. Patients were included if they had new-onset hypotension, defined as mean arterial blood pressure <60 mmHg or requirement for vasopressor medication. A loading dose of NAC or placebo of 50 mg/kg in 4 h was administered intravenously. After the loading dose, patients received 100 mg/kg/day for the next 48 h. DFX or placebo was administered once at 1000 mg at a rate of 15/mg/kg/h. The primary outcome was the incidence of AKI., Results: A total of 80 patients were enrolled in the study. The incidence of AKI was 67 % in the placebo arm and 65 % in the treatment group (relative risk (RR) 0.89 (0.35-2.2)). Furthermore, NAC plus DFX was effective in decreasing the severity and duration of AKI, and patients in the treatment group had lower serum creatinine levels at discharge. No severe adverse event associated with treatment was reported. The effects of NAC plus DFX could be secondary to the attenuation of early inflammatory response and oxidative damage., Conclusion: The administration of NAC plus DFX to critically ill patients who had a new episode of hypotension did not decrease the incidence of AKI., Trial Registration: Clinicaltrials.gov NCT00870883 (Registered 25 March 2009.).

Objective: The aim of this study was to investigate whether plasma serotonin levels or acetylcholinesterase activities determined upon intensive care unit admission could predict the occurrence of acute brain dysfunction in intensive care unit patients., Methods: A prospective cohort study was conducted with a sample of 77 non-consecutive patients observed between May 2009 and September 2010. Delirium was determined using the Confusion Assessment Method for the Intensive Care Unit tool, and the acetylcholinesterase and serotonin measurements were determined from blood samples collected up to a maximum of 24 h after the admission of the patient to the intensive care unit., Results: In the present study, 38 (49.6%) patients developed delirium during their intensive care unit stays. Neither serum acetylcholinesterase activity nor serotonin level was independently associated with delirium. No significant correlations of acetylcholinesterase activity or serotonin level with delirium/coma-free days were observed, but in the patients who developed delirium, there was a strong negative correlation between the acetylcholinesterase level and the number of delirium/coma-free days, indicating that higher acetylcholinesterase levels are associated with fewer days alive without delirium or coma. No associations were found between the biomarkers and mortality., Conclusions: Neither serum acetylcholinesterase activity nor serotonin level was associated with delirium or acute brain dysfunction in critically ill patients. Sepsis did not modify these relationships.

The aim of this study was to determine parameters of NO metabolism in plasma and placenta of preeclamptic (PE) patients. It was conducted a case-control study at São José Hospital, Brazil. Thirty-three PE and 33 normotensive pregnant were included in the study. The diagnosis of PE was established in accordance with the definitions of American College of Obstetricians and Gynecologists. Peripheral venous blood and placenta samples were obtained at postpartum period. Plasma NO levels and SOD activity were significantly lower and endothelin-1 levels and arginase activity were significantly higher in PE women when compared to controls. None of the analyzed parameters were different in the placenta between groups. Our findings suggest that parameters associated with NO metabolism are altered only at the systemic level, but not in placenta of PE patients.

Asthma represents a public health problem and traditionally is classified as an atopic disease, where the allergen can induce clinical airway inflammation, bronchial hyperresponsiveness, and reversible obstruction of airways. Studies have demonstrated the presence of T-helper 2 lymphocytes in the lung of patients with asthma. These cells are involved in cytokine production that regulates immunoglobulin synthesis. Recognizing that T cell interaction with antigens/allergens is key to the development of inflammatory diseases, the aim of this study is to evaluate the anti-inflammatory potential of cannabidiol (CBD) in this setting. Asthma was induced in 8-week-old Wistar rats by ovalbumin (OVA). In the last 2 days of OVA challenge animals received CBD (5 mg/kg, i.p.) and were killed 24 hours after. The levels of IL-4, IL-5, IL-13, IL-6, IL-10, and TNF-α were determinate in the serum. CBD treatment was able to decrease the serum levels of all analyzed cytokines except for IL-10 levels. CBD seems to be a potential new drug to modulate inflammatory response in asthma.

Background: The purpose of this research is to study the relationship between superoxide dismutase (SOD) and lung redox state in an animal model of sepsis., Methods: Sepsis was induced in rats by the cecal ligation and perforation model (CLP). After 3, 6, and 12 h, CLP protein content and expression of SOD1, SOD2, and SOD3 were evaluated, and SOD activity was assessed. Oxidative damage was determined by quantifying nitrotyrosine content. Lung localization of SOD3 was performed by immunohistochemistry. The protective effect of a SOD mimetic on oxidative damage, inflammation, and lung permeability was assessed 12 and 24 h after sepsis induction., Results: Lung levels of SOD1 decreased 3 and 12 h after sepsis, but SOD2 and SOD3 increased, as well as SOD activity. These alterations were not associated with changes in sod gene expression. Nitrotyrosine levels increased 3 and 12 h after sepsis. The administration of a SOD mimetic decreased nitrotyrosine and proinflammatory cytokine levels and improved lung permeability., Conclusions: SOD2 and SOD3 increased after sepsis induction, but this was insufficient to protect the lung. Treatments based on SOD mimetics could have a role in lung injury associated with sepsis.

Sepsis and the multiorgan dysfunction syndrome are among the most common reasons for admission to an intensive care unit, and are a leading cause of death. During sepsis, the central nervous system (CNS) is one of the first organs affected, and this is clinically manifested as sepsis-associated encephalopathy (SAE). It is postulated that the common final pathway that leads to SAE symptoms is the deregulation of neurotransmitters, mainly acetylcholine. Thus, it is supposed that inflammation can affect neurotransmitters, which is associated with SAE development. In this review, we will cover the current evidence (or lack thereof) for the mechanisms by which systemic inflammation interferes with the metabolism of major CNS neurotransmitters, trying to explain how systemic inflammation drives the brain crazy.

Introduction: Delirium is a common occurrence in critically ill patients and is associated with an increase in morbidity and mortality. Septic patients with delirium may differ from a general critically ill population. The aim of this investigation was to study the relationship between systemic inflammation and the development of delirium in septic and non-septic critically ill patients., Methods: We performed a prospective cohort study in a 20-bed mixed intensive care unit (ICU) including 78 (delirium = 31; non-delirium = 47) consecutive patients admitted for more than 24 hours. At enrollment, patients were allocated to septic or non-septic groups according to internationally agreed criteria. Delirium was diagnosed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) during the first 72 hours of ICU admission. Blood samples were collected within 12 hours of enrollment for determination of tumor necrosis factor (TNF)-α, soluble TNF Receptor (STNFR)-1 and -2, interleukin (IL)-1β, IL-6, IL-10 and adiponectin., Results: Out of all analyzed biomarkers, only STNFR1 (P = 0.003), STNFR2 (P = 0.005), adiponectin (P = 0.005) and IL-1β (P < 0.001) levels were higher in delirium patients. Adjusting for sepsis and sedation, these biomarkers were also independently associated with delirium occurrence. However, none of them were significant influenced by sepsis., Conclusions: STNFR1, STNFR2, adiponectin and IL-1β were associated with delirium. Sepsis did not modify the relationship between the biomarkers and delirium occurrence.

Survivors from sepsis present long-term cognitive deficits and some of these alterations resemble the pathophysiological mechanisms of neurodegenerative diseases. For this reason, we analyzed beta-amyloid peptide (Aβ) and synaptophysin levels in the brain of rats that survived from sepsis and their relation to cognitive dysfunction and to acute brain inflammation. Sepsis was induced in rats by cecal ligation and puncture, and 30 days after surgery, the hippocampus and prefrontal cortex were isolated just after cognitive evaluation by the inhibitory avoidance test. The immunocontent of Aβ and synaptophysin were analyzed by Western blot analysis. Aβ increased and synaptophysin decreased in septic animals both in the hippocampus and prefrontal cortex concurrent with the presence of cognitive deficits. Prefrontal levels of synaptophysin correlated to the performance in the inhibitory avoidance. Two different treatments known to decrease brain inflammation and oxidative stress when administered at the acute phase of sepsis decreased Aβ levels both in the prefrontal cortex and hippocampus, increased synaptophysin levels only in the prefrontal cortex, and improved cognitive deficit in sepsis-survivor animals. In conclusion, we demonstrated that brain from sepsis-survivor animals presented an increase in Aβ content and a decrease in synaptophysin levels and cognitive impairment. These alterations can be prevented by treatments aimed to decrease acute brain inflammation and oxidative stress.

There is no description on the mechanisms associated with blood-brain barrier (BBB) disruption during sepsis development. Thus, we here determined changes in permeability of the BBB in an animal model of severe sepsis and the role of matrix metalloproteinase (MMP)-2 and MMP-9 in the dysfunction of the BBB. Sepsis was induced in Wistar rats by cecal ligation and perforation. BBB permeability was assessed using the Evans blue dye method. The content of MMP-2 and MMP-9 in the cerebral microvessels was determined by western blot. The activity of MMP-2 and MMP-9 was determined using zymography. An inhibitor of MMP-2 and MMP-9 or specific inhibitors of MMP-2 or MMP-9 were administered to define the role of MMPs on BBB permeability, brain inflammatory response, and sepsis-induced cognitive alterations. The increase of BBB permeability is time-related to the increase of MMP-9 and MMP-2 in the microvessels, both in cortex and hippocampus. Using an MMP-2 and MMP-9 inhibitor, or specific MMP-2 or MMP-9 inhibitors, the increase in the permeability of the BBB was reversed. This was associated with lower brain levels of interleukin (IL)-6 and lower oxidative damage. In contrast, only the inhibition of both MMP-9 and MMP-2 was able to improve acute cognitive alterations associated with sepsis. In conclusion, MMP-2 and MMP-9 activation seems to be a major step in BBB dysfunction, but BBB dysfunction seems not to be associated with acute cognitive dysfunction during sepsis development.

Objective: To evaluate the relationship between brain damage biomarkers and mortality in the intensive care unit (ICU)., Methods: The sample comprised 70 patients admitted to an ICU. Blood samples were collected from all patients on ICU admission, and levels of S100β and neuron-specific enolase (NSE) were determined by ELISA., Results: Acute Physiologic and Chronic Health Evaluation (APACHE II) score was associated with mortality, but NSE and S100β were not associated with this outcome. In contrast, S100β levels were significantly higher in delirious and non-delirious patients who required mechanical ventilation during ICU stay., Conclusion: Levels of brain biomarkers at the time of ICU admission did not predict mortality in critically ill patients.

Sepsis is a major cause of mortality and morbidity in intensive care units. Acute and long-term brain dysfunctions have been demonstrated both in experimental models and septic patients. Sepsis-associated encephalopathy is an early and frequent manifestation but is underdiagnosed, because of the absence of specific biomarkers and of confounding factors such as sedatives used in the intensive care unit. Sepsis-associated encephalopathy may have acute and long-term consequences including development of autonomic dysfunction, delirium, and cognitive impairment. The mechanisms of sepsis-associated encephalopathy involve mitochondrial and vascular dysfunctions, oxidative stress, neurotransmission disturbances, inflammation, and cell death. Here we review specific evidence that links bioenergetics, mitochondrial dysfunction, and oxidative stress in the setting of brain dysfunctions associated to sepsis.

Background: The aim of this study was to evaluate the role of hypomagnesemia as a risk factor for the development of acute kidney injury (AKI) and non-recovery of renal function in critically ill patients., Methods: A cohort study was conducted by collecting data from March to June 2011 in 232 patients who were admitted into an intensive care unit (ICU). Magnesium serum levels were measured daily during ICU stay. Hypomagnesemia was defined as an episode of serum magnesium concentration of <0.70 mmol/L during ICU stay. The Risk, Injury, Failure, Loss and End-stage kidney disease (RIFLE) criteria were used to define AKI. Renal function recovery was defined as an absence of AKI by the RIFLE criteria over a 48-h period, or at ICU discharge, in the patients who developed AKI during ICU stay., Results: The presence of hypomagnesemia was similar in patients with or without AKI (47 and 62%, respectively, P = 0.36). The presence of hypomagnesemia was higher in patients who did not recover renal function when compared with patients who recovered renal function (70 versus 31%, P = 0.003). A multivariate analysis identified hypomagnesemia as an independent risk factor for non-recovery of renal function (P = 0.005). Patients with and without hypomagnesemia had similar mortality rates (P = 0.63)., Conclusions: Hypomagnesemia was an independent risk factor for non-recovery of renal function in a cohort of critically ill AKI patients.

Objective: To determine the relationship between enteral nutrition discontinuation and outcome in general critically ill patients., Materials and Methods: All patients admitted to a mixed intensive care unit in a tertiary care hospital from May-August 2009 were screened for an indication for enteral nutrition. Patients were followed up until leaving the intensive care unit or a maximum of 28 days. The gastrointestinal failure score was calculated daily by adding values of 0 if the enteral nutrition received was identical to the nutrition prescribed, 1 if the enteral nutrition received was at least 75% of that prescribed, 2 if the enteral nutrition received was between 50-75% of that prescribed, 3 if the enteral nutrition received was between 50-25% of that prescribed, and 4 if the enteral nutrition received was less than 25% of that prescribed., Results: The mean, worst, and categorical gastrointestinal failure scores were associated with lower survival in these patients. Age, categorical gastrointestinal failure score, type of admission, need for mechanical ventilation, sequential organ failure assessment, and Acute Physiologic and Chronic Health Evaluation II scores were selected for analysis with binary regression. In both models, the categorical gastrointestinal failure score was related to mortality., Conclusion: The determination of the difference between prescribed and received enteral nutrition seemed to be a useful prognostic marker and is feasible to be incorporated into a gastrointestinal failure score.

Introduction: Because of its relevance to the functioning of the central nervous system, brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of different neuropsychiatric diseases. Whether the BDNF level can be a marker of brain dysfunction and thus predict mortality in critically ill patients is not known. Thus we aimed to determine whether the plasma levels of BDNF are associated with morbidity and mortality in critically ill patients., Methods: Healthy volunteers (n = 40) and consecutive patients older than 18 years (n = 76) admitted for more than 24 hours in an Intensive Care Unit (ICU) in a University hospital between July and October 2010 were included in the present study. First blood samples were collected within 12 hours of enrollment (D0), and a second sample, 48 hours after (D2) for determination of plasma BDNF levels. The relation between BDNF levels and mortality was the primary outcome. The secondary outcomes were the relation between BDNF levels and delirium and coma-free days (DCFD) and ICU and hospital length of stay (LOS)., Results: Admission plasma levels of BDNF were higher in ICU patients when compared with healthy volunteers (1,536 (962) versus 6,565 (2,838) pg/ml). The mean BDNF D2 was significantly lower in nonsurvivor patients (5,865 (2,662) versus 6,741 (2,356) pg/ml). After adjusting for covariates, BDNF levels, the need for mechanical ventilation, and sepsis were associated with mortality. Even in patients without clinically detectable brain dysfunction, lower BDNF D2 levels were associated with mortality. BDNF D2 had a mild correlation to DCFD (r = 0.44), but not to ICU and hospital LOS. In addition, plasma BDNF did not correlate to different plasma cytokines and platelets levels., Conclusions: The plasma levels of BDNF were independently associated with mortality, even in the absence of clinically detectable brain dysfunction.

In sepsis, toll-like receptor (TLR)-4 modulates the migration of neutrophils to infectious foci, favoring bacteremia and mortality. In experimental sepsis, organ dysfunction and cytokines released by activated macrophages can be reduced by gastrin-releasing peptide (GRP) receptor (GRPR) antagonist RC-3095. Here we report a link between GRPR and TLR-4 in experimental models and in sepsis patients. RAW 264.7 culture cells were exposed to lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α and RC-3095 (10 ng/mL). Male Wistar rats were subjected to cecal ligation and puncture (CLP), and RC-3095 was administered (3 mg/kg, subcutaneously); after 6 h, we removed the blood, bronchoalveolar lavage, peritoneal lavage and lung. Human patients with a clinical diagnosis of sepsis received a continuous infusion with RC-3095 (3 mg/kg, intravenous) over a period of 12 h, and plasma was collected before and after RC-3095 administration and, in a different set of patients with systemic inflammatory response syndrome (SIRS) or sepsis, GRP plasma levels were determined. RC-3095 inhibited TLR-4, extracellular-signal-related kinase (ERK)-1/2, Jun NH(2)-terminal kinase (JNK) and Akt and decreased activation of activator protein 1 (AP-1), nuclear factor (NF)-κB and interleukin (IL)-6 in macrophages stimulated by LPS. It also decreased IL-6 release from macrophages stimulated by TNF-α. RC-3095 treatment in CLP rats decreased lung TLR-4, reduced the migration of cells to the lung and reduced systemic cytokines and bacterial dissemination. Patients with sepsis and systemic inflammatory response syndrome have elevated plasma levels of GRP, which associates with clinical outcome in the sepsis patients. These findings highlight the role of GRPR signaling in sepsis outcome and the beneficial action of GRPR antagonists in controlling the inflammatory response in sepsis through a mechanism involving at least inhibition of TLR-4 signaling.

Background: Advanced glycation end-products (AGE) have been involved in inflammatory diseases and may have an important role in the progression of symptoms. However, few studies have analysed the levels of glycated proteins in sepsis. In this study, we evaluated the levels of the well-known AGE (N(ε) -(carboxymethyl)lysine (CML) and N(ε) -(carboxyethyl)lysine (CEL)) in the plasma of septic patients., Material and Methods: Plasma from 36 patients admitted to an adult intensive care unit and 6 healthy controls had the levels of CML/CEL measured by ELISA., Results: The level of AGE in plasma decreased with the increase of severity (1·40±0·46 nmol/mg of protein in sepsis, 0·58±0·23 nmol/mg of protein in severe sepsis and 0·31±0·12 nmol/mg of protein in septic shock). Control plasma presented low AGE concentration (0·06±0·01 nmol/mg protein). Also, we found a decrease in plasma AGE in those patients that died at the end of 28 days follow-up (0·80±0·50 nmol/mg of protein in survivors vs. 0·31±0·10 nmol/mg of protein in nonsurvivors), being associated with the renal component of sequential organ failure assessment (SOFA) score. In the same line, there was a decrease in plasma AGE with the increase in SOFA., Conclusions: Our data demonstrate that plasma AGE levels are inversely associated with the severity of sepsis and may be associated with kidney dysfunction., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.)

Reactive oxygen species and inflammation have been implicated in renal tubule cell injury. However, there is some controversy concerning whether antioxidants might attenuate oxidative damage and inflammation in humans after hypotension in the setting of critical illness. This study was a prospective, randomized, double-blinded, placebo-controlled study that included patients with hypotension. Patients were randomized to receive either N-acetylcysteine (NAC; 50 mg/kg by 4 hours followed by 100 mg/kg/d for 48 hours diluted in 5% glucose) and deferoxamine (DFX; at a single dose of 1000 mg diluted in 5% glucose) or placebo. The primary study outcome was the serum levels of markers of oxidative damage and inflammatory response. Secondary outcomes included the incidence of acute renal failure, serum creatinine at hospital discharge, intensive care unit length of stay, and length of hospital stay. Thirty patients were enrolled in the study. The use of NAC plus DFX decreased the oxidative damage parameters but not plasma interleukin-6 levels. In contrast, plasma nitrite levels increased 24 hours after NAC plus DFX administration. On analysis of secondary outcomes, it was observed that creatinine levels at hospital discharge were lower in patients receiving NAC plus DFX when compared with placebo. NAC plus DFX administration was able to decrease plasma markers of oxidative damage and creatinine levels at hospital discharge.