SHORT-TERM INFLAMMATORY BIOMARKER PROFILES ARE ASSOCIATED WITH DEFICIENT MITOCHONDRIAL BIOENERGETICS IN LYMPHOCYTES OF SEPTIC SHOCK PATIENTS-A PROSPECTIVE COHORT STUDY.

ABSTRACT: Introduction: A biomarker strategy based on the quantification of an immune profile could provide a clinical understanding of the inflammatory state in patients with sepsis and its potential implications for the bioenergetic state of lymphocytes, whose metabolism is associated with altered outcomes in sepsis. The objective of this study is to investigate the association between mitochondrial respiratory states and inflammatory biomarkers in patients with septic shock. Methods: This prospective cohort study included patients with septic shock. Routine, complex I, complex II respiration, and biochemical coupling efficiency were measured to evaluate mitochondrial activity. We measured IL-1ß, IL-6, IL-10, total lymphocyte count, and C-reactive protein levels on days 1 and 3 of septic shock management as well as mitochondrial variables. The variability of these measurements was evaluated using delta counts (days 3-1 counts). Results: Sixty-four patients were included in this analysis. There was a negative correlation between complex II respiration and IL-1ß (Spearman ρ, -0.275; P = 0.028). Biochemical coupling efficiency at day 1 was negative correlated with IL-6: Spearman ρ, -0.247; P = 0.05. Delta complex II respiration was negatively correlated with delta IL-6 (Spearman ρ, -0.261; P = 0.042). Delta complex I respiration was negatively correlated with delta IL-6 (Spearman ρ, -0.346; P = 0.006), and delta routine respiration was also negatively correlated with both delta IL-10 (Spearman ρ, -0.257; P = 0.046) and delta IL-6 (Spearman ρ, -0.32; P = 0.012). Conclusions: The metabolic change observed in mitochondrial complex I and complex II of lymphocytes is associated with a decrease in IL-6 levels, which can signal a decrease in global inflammatory activity.

Association between neuromuscular blocking agents and the development of intensive care unit-acquired weakness (ICU-AW): A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: The present study aims to review the literature and synthesize evidence concerning the effects of the use of neuromuscular blocking agents (NMBA) regarding the development of intensive care unit-acquired weakness (ICU-AW). METHODS: This study was registered in the PROSPERO database CRD42020142916. Systematic review in PubMed, Embase, and the Cochrane Central, Randomized clinical trials (RCTs), and cohort studies with adults that reported the use of NMBA and the development of ICU-AW were included. Pre-specified subgroup analyses were performed for presence of sepsis and type of NMBA used. The quality of evidence for intervention effects was summarized. The certainty of evidence was assessed using the GRADE approach. RESULTS: We included 30 studies, four RCTs, 21 prospective and 5 retrospective cohorts, enrolling a total of 3839 patients. Most of the included studies were observational with high heterogeneity, whereas the RCTs had a high risk of bias. The use of NMBA increased the odds of developing ICU-AW (OR = 2.77 [95% CI 1.98-3.88], I2 = 62%), with low-quality of evidence. A trial sequential analysis showed the need to include 22,330 patients in order to provide evidence for either beneficial or harmful intervention effects. CONCLUSIONS: This meta-analysis suggests that the use of NMBA might be implicated in the development of ICU-AW. However, there is not enough evidence to definitively conclude about the association between the use of NMBA and the development of ICU-AW, as these results are based mostly on observational studies with high heterogeneity.

Influence of radiologic pattern and the presence of diffuse parenchymal lung disease on outcome in ventilated patients with COVID-19 pneumonia: impact on prognosis.

BACKGROUND: Suspected organising pneumonia (OP) is a common finding in patients with severe coronavirus disease 2019 (COVID-19), but the impact on outcomes of the radiological patterns of diffuse parenchymal lung disease on outcome of these patients is still uncertain. AIMS: Investigate the presence of radiological images compatible with OP and its association with clinical outcomes in patients with COVID-19 submitted to invasive mechanical ventilation (IMV). METHODS: Retrospective, unicentric cohort study composed of patients who required IMV and underwent chest computerized tomography to investigate secondary complications of COVID-19. We compared patients with radiological findings characteristic of suspected OP with those without this condition. The main outcome was hospital mortality. RESULTS: Two hundred and ten patients were included, and 65 had signals compatible with OP. All patients with suspected OP were treated with corticosteroids. There was no difference in IVM-free days until day 28 between the groups (median, 0 days; interquartile range [IQR], 0-14.8) in the group with suspected OP vs 0 days (IQR, 0-11) in the group without suspected OP (P = 0.14). In univariate analysis, the presence of suspected OP was associated with lower hospital mortality; however, after correction for potential confounding variables, it was not associated with the outcome, even after matching by propensity score in patients without this condition. CONCLUSION: OP radiologic pattern in patients with severe COVID-19 is not associated with worse outcomes.

Antibiotic therapy does not alter mitochondrial bioenergetics in lymphocytes of patients with septic shock - A prospective cohort study.

Antibiotics may trigger alterations in mitochondrial function, which has been explored in cells culture, and in animal model of sepsis. This study sought to evaluate whether antibiotic therapy affects mitochondrial bioenergetics in a 68-patients clinical study. We studied mitochondrial respiratory rates at two time points: the first day of antibiotic administration and three days after. The Δbasal, ΔCI, ΔCII respiration, and ΔBCE respiratory rates were not different between patients administered with polymyxin, vancomycin, amoxicillin-clavulanate, and azithromycin compared to those who were not administered. Specific beta-lactams are associated with specific modifications in mitochondrial respiratory endpoints - patients who used meropenem had higher delta C2 values compared to those who did not (p = 0.03). Patients who used piperacillin-tazobactam had lower delta C1 (p = 0.03) values than those who did not, but higher delta C2 values (p = 0.02). These mitochondrial metabolic signatures in isolated lymphocytes challenges the proposed effects of antibiotics in mitochondrial bioenergetics of cell cultures, but at current status have an uncertain clinical significance.

Assessing the prognosis of cirrhotic patients in the intensive care unit: What we know and what we need to know better.

Critically ill cirrhotic patients have high in-hospital mortality and utilize significant health care resources as a consequence of the need for multiorgan support. Despite this fact, their mortality has decreased in recent decades due to improved care of critically ill patients. Acute-on-chronic liver failure (ACLF), sepsis and elevated hepatic scores are associated with increased mortality in this population, especially among those not eligible for liver transplantation. No score is superior to another in the prognostic assessment of these patients, and both liver-specific and intensive care unit-specific scores have satisfactory predictive accuracy. The sequential assessment of the scores, especially the Sequential Organ Failure Assessment (SOFA) and Chronic Liver Failure Consortium (CLIF)-SOFA scores, may be useful as an auxiliary tool in the decision-making process regarding the benefits of maintaining supportive therapies in this population. A CLIF-ACLF > 70 at admission or at day 3 was associated with a poor prognosis, as well as SOFA score > 19 at baseline or increasing SOFA score > 72. Additional studies addressing the prognostic assessment of these patients are necessary.

Impact of cytomegalovirus reactivation just before liver transplantation: A prospective cohort study.

BACKGROUND: Cytomegalovirus (CMV) is the most common viral pathogen after liver transplantation (LT). Although reactivation of CMV infection is generally described in the context of immunosuppression, it has also been described in critically ill immunocompetent patients including cirrhotic patients. AIM: To determine the incidence of reactivated CMV prior to LT. METHODS: This was a prospective cohort study evaluating adult patients who underwent LT between 2014 and 2016. A plasma sample was obtained from all patients for CMV quantitative real-time PCR testing right before transplantation. Patients were followed for at least 1 year to assess the following outcomes: Incidence of CMV infection, organ rejection and overall mortality. RESULTS: A total of 72 patients were enrolled. Four patients died before transplantation, thus 68 patients were followed up for a median of 44 mo (20-50 mo). In 23/72 patients (31.9%) CMV was reactivated before transplantation. Post-transplantation, 16/68 (23.5%) patients had CMV infection and that was significantly associated with the recipient being CMV negative and a CMV-positive donor. Pre-transplant CMV reactivation was not associated with overall mortality (log rank: 0.9). CONCLUSION: This study shows that CMV infection is common in patients with chronic liver disease just before LT, but the clinical impact of this infection seems to be negligible.

HIV treatment non-adherence is associated with ICU mortality in HIV-positive critically ill patients.

INTRODUCTION: Combined antiretroviral therapy has led to significant decreases in morbidity and mortality in acquired immunodeficiency syndrome patients. Survival among these patients admitted to intensive care units has also improved in the last years. However, the prognostic predictors of human immunodeficiency vírus patients in intensive care units have not been adequately studied. The main objective of this study was to evaluate if non-adherence to antiretroviral therapy is a predictor of hospital mortality. METHODS: A unicentric, retrospective, cohort study composed of patients admitted to a 59-bed mixed intensive care unit including all patients with human immunodeficiency vírus infection. Patients were excluded if exclusive palliative care was established before completing 48 h of intensive care unit admission. Clinical and treatment data were obtained, including demographic records, underlying diseases, Simplified Acute Physiology III score at the time of intensive care unit admission, CD4 lymphocyte count, antiretroviral therapy adherence, admission diagnosis, human immunodeficiency vírus-related diseases, sepsis and use of mechanical ventilation and hemodialysis. The outcome analyzed was hospital mortality. RESULTS: Overall, 167 patients were included in the study, and intensive care unit mortality was 34.7%. Multivariate analysis indicated that antiretroviral therapy adherence and the Simplified Acute Physiology 3 score were independently related to hospital mortality. antiretroviral therapy adherence was a protective factor (OR 0.2; 95% CI 0.05-0.71; P = 0.01), and Simplified Acute Physiology 3 (OR 1.04; 95% CI 1.01-1.08; P < 0.01) was associated with increased hospital mortality. CONCLUSION: Non-adherence to antiretroviral therapy is associated with hospital mortality in this population. Highly active antiretroviral therapy non-adherence may be associated with other comorbidities that may be associated with a worst prognosis in this scenario.

Renal Outcomes of Vasopressin and Its Analogs in Distributive Shock: A Systematic Review and Meta-Analysis of Randomized Trials.

OBJECTIVES: To systematically review the literature and synthesize evidence concerning the effects of vasopressin and its analogs compared with other vasopressors in distributive shock, focusing on renal outcomes. DATA SOURCES: We performed a systematic review in MEDLINE, Embase, Cochrane Central, and Clinicaltrials.gov databases. STUDY SELECTION: Randomized clinical trials that compared vasopressin and its analogs with other vasopressors and reported renal outcomes in adult patients with distributive shock. DATA EXTRACTION: Paired reviewers independently screened citations, conducted data extraction and assessed risk of bias. Three prespecified subgroup analyses were conducted. Three main outcomes related to acute renal failure were analyzed: the need for renal replacement therapy, acute kidney injury incidence, and acute kidney injury-free days. I test was used to evaluate heterogeneity between studies. Substantial heterogeneity was defined as I greater than 50%. A random-effects model with Mantel-Haenszel weighting was used for all analyses. Heterogeneity was explored using subgroup analysis. The quality of evidence for intervention effects was summarized using Grading of Recommendations Assessment, Development, and Evaluation methodology. This study was registered in the PROSPERO database (CRD42017054324). DATA SYNTHESIS: Three-thousand twenty-six potentially relevant studies were identified, and 30 articles were reviewed in full. Seventeen studies met the inclusion criteria, including a total of 2,833 individuals. Of these, 11 studies (2,691 individuals) were suitable for quantitative meta-analysis. Overall, the evidence was of low to moderate quality. Patients who received vasopressin and its analogs had a reduced need for renal replacement therapy (odds ratio, 0.59 [0.37-0.92]; p = 0.02; I = 49%) and a lower acute kidney injury incidence (odds ratio, 0.58 [0.37-0.92]; p = 0.02; I = 63%). These results should be interpreted with caution, due to excessive heterogeneity. Acute kidney injury-free data was not pooled, since the small number of studies and extreme heterogeneity. CONCLUSIONS: In patients with distributive shock, vasopressin and its analogs use is associated with a reduced need for renal replacement therapy and lower acute kidney injury incidence. These results are supported by high risk of bias evidence.

Treatment of infections by cryptic Aspergillus species.

The best treatment for patients with invasive aspergillosis caused by cryptic Aspergillus species remains uncertain, mainly due to the limited clinical data that have been published so far. In face of this limitation, patients should be treated with standard first-line therapy for invasive aspergillosis, with therapy being modified according to in vitro susceptibility testing. In this review, we summarize the importance of cryptic Aspergillus species in modern medicine, including their prevalence, methods for detection and response to antifungal drugs.

Aspergillosis in patients treated with monoclonal antibodies.

Invasive aspergillosis is a disease typically related with prolonged neutropenia or the use of corticosteroids. However, the increased use of new therapeutic modalities such as biologic agents that act by blocking specific immune pathways have put more patients at risk for invasive aspergillosis. Most cases of aspergillosis in patients taking monoclonal antibodies have been associated with the use of tumour necrosis factor (TNF)-alpha blockers. However, many more drugs have been implicated, including interleukin-2 inhibitors, and CD52 and CD20 blockers. In this manuscript we review the pathophysiology associated with an increased risk for aspergillosis in these patients, in addition to diagnostic and therapeutic considerations.