Duration of antibiotic therapy in critically ill patients: a randomized controlled trial of a clinical and C-reactive protein-based protocol versus an evidence-based best practice strategy without biomarkers.

BACKGROUND: The rational use of antibiotics is one of the main strategies to limit the development of bacterial resistance. We therefore sought to evaluate the effectiveness of a C-reactive protein-based protocol in reducing antibiotic treatment time in critically ill patients. METHODS: A randomized, open-label, controlled clinical trial conducted in two intensive care units of a university hospital in Brazil. Critically ill infected adult patients were randomly allocated to (i) intervention to receive antibiotics guided by daily monitoring of CRP levels and (ii) control to receive antibiotics according to the best practices for rational use of antibiotics. RESULTS: One hundred thirty patients were included in the CRP (n = 64) and control (n = 66) groups. In the intention-to-treat analysis, the median duration of antibiotic therapy for the index infectious episode was 7.0 (5.0-8.8) days in the CRP and 7.0 (7.0-11.3) days in the control (p = 0.011) groups. A significant difference in the treatment time between the two groups was identified in the curve of cumulative suspension of antibiotics, with less exposure in the CRP group only for the index infection episode (p = 0.007). In the per protocol analysis, involving 59 patients in each group, the median duration of antibiotic treatment was 6.0 (5.0-8.0) days for the CRP and 7.0 (7.0-10.0) days for the control (p = 0.011) groups. There was no between-group difference regarding the total days of antibiotic exposure and antibiotic-free days. CONCLUSIONS: Daily monitoring of CRP levels may allow early interruption of antibiotic therapy in a higher proportion of patients, without an effect on total antibiotic consumption. The clinical and microbiological relevance of this finding remains to be demonstrated. TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT02987790. Registered 09 December 2016.

Goal-directed therapy guided by the FloTrac sensor in major surgery: a systematic review and meta-analysis.

OBJECTIVE: To provide insights into the potential benefits of goal-directed therapy guided by FloTrac in reducing postoperative complications and improving outcomes. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials to evaluate goal-directed therapy guided by FloTrac in major surgery, comparing goal-directed therapy with usual care or invasive monitoring in cardiac and noncardiac surgery subgroups. The quality of the articles and evidence were evaluated with a risk of bias tool and GRADE. RESULTS: We included 29 randomized controlled trials with 3,468 patients. Goal-directed therapy significantly reduced the duration of hospital stay (mean difference -1.43 days; 95%CI 2.07 to -0.79; I2 81%), intensive care unit stay (mean difference -0.77 days; 95%CI -1.18 to -0.36; I2 93%), and mechanical ventilation (mean difference -2.48 hours, 95%CI -4.10 to -0.86, I2 63%). There was no statistically significant difference in mortality, myocardial infarction, acute kidney injury or hypotension, but goal-directed therapy significantly reduced the risk of heart failure or pulmonary edema (RR 0.46; 95%CI 0.23 - 0.92; I2 0%). CONCLUSION: Goal-directed therapy guided by the FloTrac sensor improved clinical outcomes and shortened the length of stay in the hospital and intensive care unit in patients undergoing major surgery. Further research can validate these results using specific protocols and better understand the potential benefits of FloTrac beyond these outcomes.

Early identification of ICU patients at risk of complications: Regularization based on robustness and stability of explanations.

The aim of this study is to build machine learning models to predict severe complications using administrative and clinical elements that are collected immediately after patient admission to the intensive care unit (ICU). Risk models are of increasing importance in the ICU setting. However, they generally present the black-box issue because they do not provide meaningful information about the logic involved in patient-specific predictions. Fortunately, effective algorithms exist for explaining black-box models, and in practice, they offer valuable explanations for model predictions. These explanations are becoming essential to engender trust and accreditation to the model. However, once the model is implemented, a major issue is whether it will continue to employ the same prediction logic as originally intended to. To build our models, features are obtained from patient administrative data, laboratory results and vital signs available within the first hour after ICU admission. This enables our models to provide great anticipation because complications can occur at any moment during ICU stay. To build models that continue to work as originally designed we first propose to measure (i) how the provided explanations vary for different inputs (that is, robustness), and (ii) how the provided explanations change with models built from different patient sub-populations (that is, stability). Second, we employ these measures as regularization terms that are coupled with a feature selection procedure such that the final model provides predictions with more robust and stable explanations. Experiments were conducted on a dataset containing 6000 ICU admissions of 5474 patients. Results obtained on an external validation cohort of 1069 patients with 1086 ICU admissions showed that selecting features based on robustness led to gains in terms of predictive power that varied from 6.8% to 9.4%, whereas selecting features based on stability led to gains that varied from 7.2% to 11.5%, depending on the target complication. Our results are of practical importance as our models predict complications with great anticipation, thus facilitating timely and protective interventions.

Performance of High Mobility Protein Group 1 and Interleukin-6 as Predictors of Outcomes Resulting from Variceal Bleeding in Patients with Advanced Chronic Liver Disease.

Variceal bleeding is a serious complication in cirrhotic patients and is related to increased expression of inflammatory mediators that accentuate circulatory dysfunction. The study aims to evaluate the performance of high mobility protein group 1 (HMG1) and interleukin-6 (IL-6) as predictors of acute kidney injury (AKI), infection and death in these patients. Fifty patients who were diagnosed with advanced chronic liver disease with variceal bleeding were included. The mean age was 52.8 ± 10.8 years, and 33 (66%) were male. Twenty-one (42%) patients were classified as Child-Pugh C, 21 (42%) Child-Pugh B and 8 (16%) Child-Pugh A. The mean HMG1 serum level was 2872.36 pg/mL ± 2491.94, and the median IL-6 serum level was 47.26 pg/mL (0-1102.4). In AKI, the serum level of HMG1 that performed best on the ROC curve was 3317.9 pg/mL. The IL-6 serum level was not associated with AKI. HMG1 and IL-6 cut-off values that better predicted infection were 3317.9 pg/mL and 72.9 pg/mL, and for mortality, the values were 2668 pg/mL and 84.5 pg/mL, respectively. In multivariate analysis, the variables that were associated with AKI and infection outcomes were model for end-stage liver disease and HMG1. Infections were related to the risk of death. Clinical and laboratory variables related to the outcomes were identified. Serum levels of HMG1 were associated with AKI and infection and had good performance in the ROC curve. IL-6 levels were not maintained in logistic regression outcomes but had good performance in infection and death outcomes. Such data will be useful for comparisons and possible future validations.

Clinical Characteristics and In-Hospital Mortality of Cardiac Arrest Survivors in Brazil: A Large Retrospective Multicenter Cohort Study.

OBJECTIVES: Data on cardiac arrest survivors from developing countries are scarce. This study investigated clinical characteristics associated with in-hospital mortality in resuscitated patients following cardiac arrest in Brazil. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Ninety-two general ICUs from 55 hospitals in Brazil between 2014 and 2015. PATIENTS: Adult patients with cardiac arrest admitted to the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 2,296 patients (53% men; median 67 yr (interquartile range, 54-79 yr]). Eight-hundred patients (35%) had a primary admission diagnosis of cardiac arrest suggesting an out-of-hospital cardiac arrest; the remainder occurred after admission, comprising an in-hospital cardiac arrest cohort. Overall, in-hospital mortality was 83%, with only 6% undergoing withholding/withdrawal-of-life support. Random-effects multivariable Cox regression was used to assess associations with survival. After adjusting for age, sex, and severity scores, mortality was associated with shock (adjusted odds ratio, 1.25 [95% CI, 1.11-1.39]; p < 0.001), temperature dysregulation (adjusted odds ratio for normothermia, 0.85 [95% CI, 0.76-0.95]; p = 0.007), increased lactate levels above 4 mmol/L (adjusted odds ratio, 1.33 [95% CI, 1.1-1.6; p = 0.009), and surgical or cardiac cases (adjusted odds ratio, 0.72 [95% CI, 0.6-0.86]; p = 0.002). In addition, survival was better in patients with probable out-of-hospital cardiac arrest, unless ICU admission was delayed (adjusted odds ratio for interaction, 1.63 [95% CI, 1.21-2.21]; p = 004). CONCLUSIONS: In a large multicenter cardiac arrest cohort from Brazil, we found a high mortality rate and infrequent withholding/withdrawal of life support. We also identified patient profiles associated with worse survival, such as those with shock/hypoperfusion and arrest secondary to nonsurgical admission diagnoses. Our findings unveil opportunities to improve postarrest care in developing countries, such as prompt ICU admission, expansion of the use of targeted temperature management, and implementation of shock reversal strategies (i.e., early coronary angiography), according to modern guidelines recommendations.

Endotoxin tolerance and cross-tolerance in mast cells involves TLR4, TLR2 and FcepsilonR1 interactions and SOCS expression: perspectives on immunomodulation in infectious and allergic diseases.

BACKGROUND: The study of the endotoxin tolerance phenomenon in light of the recently defined roles of mast cells and toll-like receptors as essential components of the innate immune response and as orchestrators of acquired immunity may reveal potentially useful mechanisms of immunomodulation of infectious and allergic inflammatory responses, such as sepsis or asthma. Here we evaluated the phenomenon of direct tolerance of endotoxins, as well as the induction of cross-tolerance and synergism by stimulation with toll-like receptor-2 (TLR2) and FcepsilonR1 agonists, in murine mast cells prestimulated with lipopolysaccharide (LPS). Additionally, we evaluated some stimulatory and inhibitory signaling molecules potentially involved in these phenomena. METHODS: MC/9 cells and primary bone marrow-derived mast cells obtained from C57BL/6 and TLR4-/- knock-out mice were sensitized to DNP-HSA (antigen) by incubation with DNP-IgE and were prestimulated with LPS for 18 hr prior to stimulation. Cultures were stimulated with LPS or Pam3Cys-Ser-(Lys)4 3HCl (P3C), a TLR2 agonist, individually or in combination with antigen. The production of IL-6 and TNFalpha, the phosphorylation of NFkappaB and p38 MAPK, and the expression of TLR4 and SOCS-1 and -3 were analyzed. RESULTS: We found that production of TNFalpha and IL-6 in murine mast cells that have been pretreated with LPS and challenged with TLR4 (LPS) or -2 (P3C) agonists was reduced, phenomena described as endotoxin tolerance (LPS) and cross-tolerance (P3C), respectively. The expression of TLR4 was not affected by LPS pretreatment. Our results show that the FcepsilonR1 agonist DNP-HSA (antigen) interacts synergistically with LPS or P3C to markedly enhance production of cytokines (TNFalpha and IL-6). This synergistic effect with LPS and P3C was also attenuated by LPS pretreatment and was mediated by TLR4. These results may be attributed to the reduction in phosphorylation of the mitogen-activated protein kinase (MAPK), p38, and the transcription factor NFkappaB, as well as to an increase in the expression of the suppressors of cytokine signaling (SOCS)-1 and -3 proteins in LPS-pretreated mast cells. CONCLUSIONS: These findings can be explored with respect to the modulation of inflammatory responses associated with infectious and allergic processes in future studies.

Goal-directed therapy guided by the FloTrac sensor in major surgery: a systematic review and meta-analysis / Terapia guiada por metas utilizando o sensor FloTrac em cirurgia de grande porte: revisão sistemática e metanálise

ABSTRACT Objective To provide insights into the potential benefits of goal-directed therapy guided by FloTrac in reducing postoperative complications and improving outcomes. Methods We performed a systematic review and meta-analysis of randomized controlled trials to evaluate goal-directed therapy guided by FloTrac in major surgery, comparing goal-directed therapy with usual care or invasive monitoring in cardiac and noncardiac surgery subgroups. The quality of the articles and evidence were evaluated with a risk of bias tool and GRADE. Results We included 29 randomized controlled trials with 3,468 patients. Goal-directed therapy significantly reduced the duration of hospital stay (mean difference -1.43 days; 95%CI 2.07 to -0.79; I2 81%), intensive care unit stay (mean difference -0.77 days; 95%CI -1.18 to -0.36; I2 93%), and mechanical ventilation (mean difference -2.48 hours, 95%CI -4.10 to -0.86, I2 63%). There was no statistically significant difference in mortality, myocardial infarction, acute kidney injury or hypotension, but goal-directed therapy significantly reduced the risk of heart failure or pulmonary edema (RR 0.46; 95%CI 0.23 - 0.92; I2 0%). Conclusion Goal-directed therapy guided by the FloTrac sensor improved clinical outcomes and shortened the length of stay in the hospital and intensive care unit in patients undergoing major surgery. Further research can validate these results using specific protocols and better understand the potential benefits of FloTrac beyond these outcomes.

RESUMO Objetivo Fornecer informações sobre os possíveis benefícios da terapia guiada por metas utilizando o sensor FloTrac na redução de complicações pós-operatórias e na melhoria dos desfechos. Métodos Realizamos uma revisão sistemática e uma metanálise de estudos controlados e randomizados para avaliar a terapia guiada por metas utilizando o sensor FloTrac em cirurgias de grande porte, comparando a terapia guiada por metas com os cuidados habituais ou o monitoramento invasivo em subgrupos de cirurgias cardíacas e não cardíacas. A qualidade dos artigos e das evidências foi avaliada com uma ferramenta de risco de viés e o GRADE. Resultados Incluímos 29 estudos controlados e randomizados com 3.468 pacientes. A terapia guiada por metas reduziu significativamente a duração da internação hospitalar (diferença média de -1,43 dia; IC95% 2,07 - -0,79; I2 81%), a internação na unidade de terapia intensiva (diferença média de -0,77 dia; IC95% -1,18 - -0,36; I2 93%) e a ventilação mecânica (diferença média de -2,48 horas, IC95% -4,10 - -0,86; I2 63%). Não houve diferença estatisticamente significativa na mortalidade, no infarto do miocárdio, na lesão renal aguda e nem na hipotensão, mas a terapia guiada por metas reduziu significativamente o risco de insuficiência cardíaca ou edema pulmonar (risco relativo de 0,46; IC95% 0,23 - 0,92; I2 0%). Conclusão A terapia guiada por metas utilizando o sensor FloTrac melhorou os desfechos clínicos e reduziu o tempo de internação no hospital e na unidade de terapia intensiva em pacientes submetidos a cirurgias de grande porte. Outras pesquisas podem validar esses resultados usando protocolos específicos e entender melhor os possíveis benefícios do FloTrac além desses desfechos.

Toll-like receptors, new horizons in sepsis.

Sepsis and septic shock, its more severe form, have shown alarming increases in incidence and a persistently high mortality rate, despite technological advancement allowing adequate support of vital functions in intensive care units. Progress in understanding of physiopathology has directed the therapeutic approach, until recently limited to sustaining failing organ systems and combating infectious agents, towards the alterations provoked by an unbalanced systemic inflammatory response and its deleterious effects on cellular function. Less than 10 years ago, the discovery of Toll-Like Receptor proteins, which allow the detection of pathogen molecular patterns, initiate and modulate the immune response, opened up new and exciting possibilities in approaches to sepsis. The elucidation of the transduction pathways triggered by Toll-Like Receptors activation signals exposes promising therapeutic targets. Currently, mechanisms associated within the context of Toll-Like Receptor signalization are identified in the tolerance phenomena described in the past. The description of genetic polymorphisms associated with Toll-Like Receptors, and the different patterns of response to infectious insults have defined high-risk subgroups of imbalanced immune response with greater specificity. A better understanding of the molecular structures involved in the process and the negative-regulation of some of them have opened up possibilities in antagonizing and modulating the response to the inflammatory activation mediated by Toll-Like Receptors. Having understood how the immune system recognizes pathogens and organizes the inflammatory response upon the discovery of Toll-Like Receptors and their signaling pathways, we gained an insight into the possibilities of specific treatment instead of supportive measures for sepsis.

EVALUATION OF THE BEHAVIOR OF LEVELS OF HMGB1 AND IL6 AS PREDICTORS OF INFECTION, ACUTE KIDNEY INJURY AND MORTALITY IN CIRRHOTIC PATIENTS WITH VARICEAL BLEEDING.

BACKGROUND: Gastroesophageal varices and associated bleeding are a major cause of morbidity and mortality in cirrhotic patients. OBJECTIVE: To evaluate the potential role of the biomarkers HMGB1 (High Mobility Group Box 1) and IL-6 (Interleukin-6) as predictors of infection, acute kidney injury and mortality in these patients. METHODS: It is a prospective, observational study that included 32 cirrhotic patients with variceal bleeding. RESULTS: The subjects'mean age was 52±5 years and 20 (62.5%) were male. The average MELD was 17.53±5 and the average MELD-Na was 20.63±6.06. Thirty patients (93.3%) patients were Child-Pugh class B or C. Infection was present in 9 subjects (28.1%), acute kidney injury was present in 6 (18.1%) and 4 (12.5%) patients died. The median serum levels of HMGB1 were 1487 pg/mL (0.1 to 8593.1) and the median serum level of IL-6 was 62.1 pg/mL (0.1 to 1102.4). The serum levels of HMGB1 and IL-6 were significantly higher in patients who developed infection, acute kidney injury and death (P<0.05). The Spearman's correlations for HMGB1 and IL-6 were 0.794 and 0.374 for infection, 0.53 and 0.374 for acute kidney injury and 0.467 and 0.404 for death, respectively. CONCLUSION: Serum levels of HMGB1 and IL-6 were higher in patients with the three studied outcomes. HMGB1 serum levels showed a high correlation with infection and a moderate correlation with acute kidney injury and death, while IL-6 showed a moderate correlation with infection and death and a low correlation with acute kidney injury.

Avaliação do comportamento dos níveis séricos de HMGB1 e IL-6 como preditores de infecção, injúria renal aguda e mortalidade em pacientes cirróticos com varizes sangrantes / Evaluation of the behavior of levels of hmgb1 and il6 as predictors of infection, acute kidney injury and mortality in cirrhotic patients with variceal bleeding

ABSTRACT BACKGROUND: Gastroesophageal varices and associated bleeding are a major cause of morbidity and mortality in cirrhotic patients. OBJECTIVE: To evaluate the potential role of the biomarkers HMGB1 (High Mobility Group Box 1) and IL-6 (Interleukin-6) as predictors of infection, acute kidney injury and mortality in these patients. METHODS: It is a prospective, observational study that included 32 cirrhotic patients with variceal bleeding. RESULTS: The subjects'mean age was 52±5 years and 20 (62.5%) were male. The average MELD was 17.53±5 and the average MELD-Na was 20.63±6.06. Thirty patients (93.3%) patients were Child-Pugh class B or C. Infection was present in 9 subjects (28.1%), acute kidney injury was present in 6 (18.1%) and 4 (12.5%) patients died. The median serum levels of HMGB1 were 1487 pg/mL (0.1 to 8593.1) and the median serum level of IL-6 was 62.1 pg/mL (0.1 to 1102.4). The serum levels of HMGB1 and IL-6 were significantly higher in patients who developed infection, acute kidney injury and death (P<0.05). The Spearman's correlations for HMGB1 and IL-6 were 0.794 and 0.374 for infection, 0.53 and 0.374 for acute kidney injury and 0.467 and 0.404 for death, respectively. CONCLUSION: Serum levels of HMGB1 and IL-6 were higher in patients with the three studied outcomes. HMGB1 serum levels showed a high correlation with infection and a moderate correlation with acute kidney injury and death, while IL-6 showed a moderate correlation with infection and death and a low correlation with acute kidney injury.

RESUMO CONTEXTO: Varizes esofagogástricas são a maior causa de morbimortalidade em pacientes cirróticos. OBJETIVO: Avaliar o papel de biomarcadores, High Mobility Group Box 1 (HMGB 1) e interleucina-6 (IL-6) como preditores de infecção, injúria renal aguda e mortalidade nestes pacientes. MÉTODOS: Estudo prospectivo, observacional que incluiu 32 pacientes com cirrose hepática na fase aguda do sangramento. RESULTADOS: A média de idade dos pacientes foi de 52±5 anos sendo 20 (62,5%) do gênero masculino. A média do MELD foi de 17,53±5 e a média do MELD-Na 20,63±6,06. Trinta (93,3%) pacientes foram classificados como Child B ou C. Complicação infecciosa esteve presente em 9 (28,1%) pacientes, injúria renal aguda em 6 (18,1%) e 4 (12,5%) evoluíram para o óbito. A mediana do nível sérico de HMGB 1 foi de 1487 pg/mL (0,1- 8593,1) e da IL-6 foi de 62,1pg/mL (0,1-1102,4). Os níveis séricos de HMGB 1 e IL-6 foram significativamente maiores nos pacientes que evoluíram com infecção, injúria renal aguda e óbito (P<0,05). Os valores da correlação de Spearman para os níveis séricos de HMGB 1 e IL-6 foram de 0,794 e 0,374 para infecção, 0,53 e 0,374 para injuria renal aguda e 0,467 e 0,404 para óbito, respectivamente. CONCLUSÃO: Níveis séricos de HMGB 1 e IL-6 foram maiores nos três desfechos estudados. Níveis séricos de HMGB 1 apresentaram alta correlação para com o desfecho infecção e moderada correlação para com injúria renal aguda e óbito, enquanto os níveis séricos de IL-6 apresentaram moderada correlação para com infecção e óbito e baixa correlação para com injúria renal aguda.