Effects of IV fluid restriction according to site-specific intensity of standard fluid treatment-protocol.

BACKGROUND: Variation in usual practice in fluid trials assessing lower versus higher volumes may affect overall comparisons. To address this, we will evaluate the effects of heterogeneity in treatment intensity in the Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care trial. This will reflect the effects of differences in site-specific intensities of standard fluid treatment due to local practice preferences while considering participant characteristics. METHODS: We will assess the effects of heterogeneity in treatment intensity across one primary (all-cause mortality) and three secondary outcomes (serious adverse events or reactions, days alive without life support and days alive out of hospital) after 90 days. We will classify sites based on the site-specific intensity of standard fluid treatment, defined as the mean differences in observed versus predicted intravenous fluid volumes in the first 24 h in the standard-fluid group while accounting for differences in participant characteristics. Predictions will be made using a machine learning model including 22 baseline predictors using the extreme gradient boosting algorithm. Subsequently, sites will be grouped into fluid treatment intensity subgroups containing at least 100 participants each. Subgroups differences will be assessed using hierarchical Bayesian regression models with weakly informative priors. We will present the full posterior distributions of relative (risk ratios and ratios of means) and absolute differences (risk differences and mean differences) in each subgroup. DISCUSSION: This study will provide data on the effects of heterogeneity in treatment intensity while accounting for patient characteristics in critically ill adult patients with septic shock. REGISTRATIONS: The European Clinical Trials Database (EudraCT): 2018-000404-42, ClinicalTrials. gov: NCT03668236.

Effects of restrictive fluid therapy on the time to resolution of hyperlactatemia in ICU patients with septic shock. A secondary post hoc analysis of the CLASSIC randomized trial.

PURPOSE: The aim of this study was to examine the effects of intravenous (IV) fluid restriction on time to resolution of hyperlactatemia in septic shock. Hyperlactatemia in sepsis is associated with worse outcome. Sepsis guidelines suggest targeting lactate clearance to guide fluid therapy despite the complexity of hyperlactatemia and the potential harm of fluid overload. METHODS: We conducted a post hoc analysis of serial plasma lactate concentrations in a sub-cohort of 777 patients from the international multicenter clinical CLASSIC trial (restriction of intravenous fluids in intensive care unit (ICU) patients with septic shock). Adult ICU patients with septic shock had been randomized to restrictive (n = 385) or standard (n = 392) intravenous fluid therapy. The primary outcome, time to resolution of hyperlactatemia, was analyzed with a competing-risks regression model. Death and discharge were competing outcomes, and administrative censoring was imposed 72 h after randomization if hyperlactatemia persisted. The regression analysis was adjusted for the same stratification variables and covariates as in the original CLASSIC trial analysis. RESULTS: The hazard ratios (HRs) for the cumulative probability of resolution of hyperlactatemia, in the restrictive vs the standard group, in the unadjusted analysis, with time split, were 0.94 (confidence interval (CI) 0.78-1.14) at day 1 and 1.21 (0.89-1.65) at day 2-3. The adjusted analyses were consistent with the unadjusted results. CONCLUSION: In this post hoc retrospective analysis of a multicenter randomized controlled trial (RCT), a restrictive intravenous fluid strategy did not seem to affect the time to resolution of hyperlactatemia in adult ICU patients with septic shock.

Albumin use in patients with septic shock-Post-hoc analyses of an international randomised fluid trial.

BACKGROUND: Albumin administration is suggested in patients with sepsis and septic shock who have received large volumes of crystalloids. Given lack of firm evidence, clinical practice variation may exist. To address this, we investigated if patient characteristics or trial site were associated with albumin use in septic shock. METHODS: We conducted a post-hoc study of the CLASSIC international, randomised clinical trial of fluid volumes in septic shock. Associations between selected baseline variables and trial site with albumin use during ICU stay were assessed in Cox models considering death, ICU discharge, and loss-to-follow-up as competing events. Baseline variables were first assessed individually, adjusted for treatment allocation (restrictive vs. standard IV fluid), and then adjusted for allocation and the other baseline variables. Site was assessed in a model adjusted for allocation and baseline variables. RESULTS: We analysed 1541 of 1554 patients randomised in CLASSIC (99.2%). During ICU stay, 36.3% of patients in the restrictive-fluid group and 52.6% in the standard-fluid group received albumin. Gastrointestinal focus of infection and higher doses of norepinephrine were most strongly associated with albumin use (subgroup with highest quartile of norepinephrine doses, hazard ratio (HR) 2.58, 95% CI 1.89 to 3.53). HRs for associations between site and albumin use ranged from 0.11 (95% CI 0.05 to 0.26) to 1.70 (95% CI 1.06 to 2.74); test for overall effect of site: p < .001. CONCLUSIONS: In adults with septic shock, gastrointestinal focus of infection and higher doses of norepinephrine at baseline were associated with albumin use, which also varied substantially between sites.

Restrictive versus standard IV fluid therapy in adult ICU patients with septic shock-Bayesian analyses of the CLASSIC trial.

BACKGROUND: The CLASSIC trial assessed the effects of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock. This pre-planned study provides a probabilistic interpretation and evaluates heterogeneity in treatment effects (HTE). METHODS: We analysed mortality, serious adverse events (SAEs), serious adverse reactions (SARs) and days alive without life-support within 90 days using Bayesian models with weakly informative priors. HTE on mortality was assessed according to five baseline variables: disease severity, vasopressor dose, lactate levels, creatinine values and IV fluid volumes given before randomisation. RESULTS: The absolute difference in mortality was 0.2%-points (95% credible interval: -5.0 to 5.4; 47% posterior probability of benefit [risk difference <0.0%-points]) with restrictive IV fluid. The posterior probabilities of benefits with restrictive IV fluid were 72% for SAEs, 52% for SARs and 61% for days alive without life-support. The posterior probabilities of no clinically important differences (absolute risk difference ≤2%-points) between the groups were 56% for mortality, 49% for SAEs, 90% for SARs and 38% for days alive without life-support. There was 97% probability of HTE for previous IV fluid volumes analysed continuously, that is, potentially relatively lower mortality of restrictive IV fluids with higher previous IV fluids. No substantial evidence of HTE was found in the other analyses. CONCLUSION: We could not rule out clinically important effects of restrictive IV fluid therapy on mortality, SAEs or days alive without life-support, but substantial effects on SARs were unlikely. IV fluids given before randomisation might interact with IV fluid strategy.

The Computational Acid-Base Chemistry of Hepatic Ketoacidosis.

Opposing evidence exists for the source of the hydrogen ions (H+) during ketoacidosis. Organic and computational chemistry using dissociation constants and alpha equations for all pertinent ionizable metabolites were used to (1) document the atomic changes in the chemical reactions of ketogenesis and ketolysis and (2) identify the sources and quantify added fractional (~) H+ exchange (~H+e). All computations were performed for pH conditions spanning from 6.0 to 7.6. Summation of the ~H+e for given pH conditions for all substrates and products of each reaction of ketogenesis and ketolysis resulted in net reaction and pathway ~H+e coefficients, where negative revealed ~H+ release and positive revealed ~H+ uptake. Results revealed that for the liver (pH = 7.0), the net ~H+e for the reactions of ketogenesis ending in each of acetoacetate (AcAc), ß-hydroxybutyrate (ß-HB), and acetone were -0.9990, 0.0026, and 0.0000, respectively. During ketogenesis, ~H+ release was only evident for HMG CoA production, which is caused by hydrolysis and not ~H+ dissociation. Nevertheless, there is a net ~H+ release during ketogenesis, though this diminishes with greater proportionality of acetone production. For reactions of ketolysis in muscle (pH = 7.1) and brain (pH = 7.2), net ~H+ coefficients for ß-HB and AcAc oxidation were -0.9649 and 0.0363 (muscle), and -0.9719 and 0.0291 (brain), respectively. The larger ~H+ release values for ß-HB oxidation result from covalent ~H+ release during the oxidation-reduction. For combined ketogenesis and ketolysis, which would be the metabolic condition in vivo, the net ~H+ coefficient depends once again on the proportionality of the final ketone body product. For ketone body production in the liver, transference to blood, and oxidation in the brain and muscle for a ratio of 0.6:0.2:0.2 for ß-HB:AcAc:acetone, the net ~H+e coefficients for liver ketogenesis, blood transfer, brain ketolysis, and net total (ketosis) equate to -0.1983, -0.0003, -0.2872, and -0.4858, respectively. The traditional theory of ketone bodies being metabolic acids causing systemic acidosis is incorrect. Summation of ketogenesis and ketolysis yield H+ coefficients that differ depending on the proportionality of ketone body production, though, in general, there is a small net H+ release during ketosis. Products formed during ketogenesis (HMG-CoA, acetoacetate, ß-hydroxybutyrate) are created as negatively charged bases, not acids, and the final ketone body, acetone, does not have pH-dependent ionizable groups. Proton release or uptake during ketogenesis and ketolysis are predominantly caused by covalent modification, not acid dissociation/association. Ketosis (ketogenesis and ketolysis) results in a net fractional H+ release. The extent of this release is dependent on the final proportionality between acetoacetate, ß-hydroxybutyrate, and acetone.

Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock.

PURPOSE: To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock included in the European Conservative versus Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care (CLASSIC) trial. METHODS: We conducted the pre-planned analyses of mortality, health-related quality of life (HRQoL) using EuroQol (EQ)-5D-5L index values and EQ visual analogue scale (VAS), and cognitive function using Mini Montreal Cognitive Assessment (Mini MoCA) test at 1 year. Deceased patients were assigned numerical zero for HRQoL as a state equal to death and zero for cognitive function outcomes as worst possible score, and we used multiple imputation for missing data on HRQoL and cognitive function. RESULTS: Among 1554 randomized patients, we obtained 1-year data on mortality in 97.9% of patients, HRQoL in 91.3%, and cognitive function in 86.3%. One-year mortality was 385/746 (51.3%) in the restrictive-fluid group versus 383/767 (49.9%) in the standard-fluid group, absolute risk difference 1.5%-points [99% confidence interval (CI) - 4.8 to 7.8]. Mean differences were 0.00 (99% CI - 0.06 to 0.05) for EQ-5D-5L index values, - 0.65 for EQ VAS (- 5.40 to 4.08), and - 0.14 for Mini MoCA (- 1.59 to 1.14) for the restrictive-fluid group versus the standard-fluid group. The results for survivors only were similar in both groups. CONCLUSIONS: Among adult ICU patients with septic shock, restrictive versus standard IV fluid therapy resulted in similar survival, HRQoL, and cognitive function at 1 year, but clinically important differences could not be ruled out.

Albumin administration in septic shock-Protocol for post-hoc analyses of data from a multicentre RCT.

BACKGROUND: Intravenous (IV) albumin is suggested for patients with septic shock who have received large amounts of IV crystalloids; a conditional recommendation based on moderate certainty of evidence. Clinical variation in the administration of IV albumin in septic shock may exist according to patient characteristics and location. METHODS: This is a protocol and statistical analysis plan for a post-hoc secondary study of the Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) RCT of 1554 adult ICU patients with septic shock. We will assess if specific baseline characteristics or trial site are associated with the administration of IV albumin during ICU stay using Cox models with competing events. All models will be adjusted for the treatment allocation in CLASSIC (restrictive vs. standard IV fluid), and all analyses will consider competing events (death, ICU discharge and loss-to-follow-up). We will present results as hazard ratios with 95% confidence intervals and p-values for the associations of baseline characteristics or site with IV albumin administration. Between-group differences (interactions) will be assessed using p-values from likelihood ratio tests. All results will be considered exploratory only. DISCUSSION: This secondary study of the CLASSIC RCT may yield important insight into potential practice variation in the administration of albumin in septic shock.

Blood urea nitrogen - independent marker of mortality in sepsis.

BACKGROUND: This retrospective study examines the relationship between admission Blood Urea Nitrogen (BUN) levels and clinical outcomes in patients with sepsis from two separate cohorts in the Czech Republic and the United States. METHODS: The study included 9126 patients with sepsis between January 2014 and December 2018. Kaplan-Meier survival curves and Cox regression were used to analyse the data. An optimal cut-off was calculated by means of the Youden-Index. RESULTS: BUN at ICU admission was categorized as 10-20, 20-40 and >40 mg/dL. Comparing the group with the highest BUN levels to the one with lowest levels, we found HR for 28 days mortality 2.764 (CI 95% 2.37-3.20; P<0.001). We derived an optimal cut-off for prediction of 28 days mortality of 23 mg/dL. The association between BUN and 28 days mortality remained significant after adjusting for potential confounders - for APACHE IV (HR 1.374; 95%CI 1.20-1.58; P<0.001), SAPS2 (HR 1.545; 95%CI 1.35-1.77; P<0.001), eGFR (HR 1.851; 95%CI 1.59-2.16; P<0.001) and several other variables in an integrative model. CONCLUSIONS: Our findings support the BUN level as an independent and easily available predictor of 28 days mortality in septic critically ill patients admitted to an ICU.

Restriction of Intravenous Fluid in ICU Patients with Septic Shock.

BACKGROUND: Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU). METHODS: In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization. RESULTS: We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], -4.7 to 4.9; P = 0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, -1.7 percentage points; 99% CI, -7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups. CONCLUSIONS: Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, NCT03668236.).

IFI27 transcription is an early predictor for COVID-19 outcomes, a multi-cohort observational study.

Purpose: Robust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness. Methods: We conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients. Results: We show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression in the lower respiratory tract is associated with the presence of a high viral load. We further demonstrate that the systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 infection. For clinical outcome prediction (e.g., respiratory failure), IFI27 expression displays a high sensitivity (0.95) and specificity (0.83), outperforming other known predictors of COVID-19 outcomes. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients. Conclusion: These data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus.

Association Between Premorbid Beta-Blocker Exposure and Sepsis Outcomes-The Beta-Blockers in European and Australian/American Septic Patients (BEAST) Study.

OBJECTIVES: To examine the effect of premorbid ß-blocker exposure on mortality and organ dysfunction in sepsis. DESIGN: Retrospective observational study. SETTING: ICUs in Australia, the Czech Republic, and the United States. PATIENTS: Total of 4,086 critical care patients above 18 years old with sepsis between January 2014 and December 2018. INTERVENTION: Premorbid beta-blocker exposure. MEASUREMENTS AND MAIN RESULTS: One thousand five hundred fifty-six patients (38%) with premorbid ß-blocker exposure were identified. Overall ICU mortality rate was 15.1%. In adjusted models, premorbid ß-blocker exposure was associated with decreased ICU (adjusted odds ratio, 0.80; 95% CI, 0.66-0.97; p = 0.025) and hospital (adjusted odds ratio, 0.83; 95% CI, 0.71-0.99; p = 0.033) mortality. The risk reduction in ICU mortality of 16% was significant (hazard ratio, 0.84, 95% CI, 0.71-0.99; p = 0.037). In particular, exposure to noncardioselective ß-blocker before septic episode was associated with decreased mortality. Sequential Organ Failure Assessment score analysis showed that premorbid ß-blocker exposure had potential benefits in reducing respiratory and neurologic dysfunction. CONCLUSIONS: This study suggests that ß-blocker exposure prior to sepsis, especially to noncardioselective ß blockers, may be associated with better outcome. The findings suggest prospective evaluation of ß-blocker use in the management of sepsis.

Immunophenotyping of Peripheral Blood Mononuclear Cells in Septic Shock Patients With High-Dimensional Flow Cytometry Analysis Reveals Two Subgroups With Differential Responses to Immunostimulant Drugs.

Sepsis is associated with a dysregulated inflammatory response to infection. Despite the activation of inflammation, an immune suppression is often observed, predisposing patients to secondary infections. Therapies directed at restoration of immunity may be considered but should be guided by the immune status of the patients. In this paper, we described the use of a high-dimensional flow cytometry (HDCyto) panel to assess the immunophenotype of patients with sepsis. We then isolated peripheral blood mononuclear cells (PBMCs) from patients with septic shock and mimicked a secondary infection by stimulating PBMCs for 4 h in vitro with lipopolysaccharide (LPS) with or without prior exposure to either IFN-γ, or LAG-3Ig. We evaluated the response by means of flow cytometry and high-resolution clustering cum differential analysis and compared the results to PBMCs from healthy donors. We observed a heterogeneous immune response in septic patients and identified two major subgroups: one characterized by hypo-responsiveness (Hypo) and another one by hyper-responsiveness (Hyper). Hypo and Hyper groups showed significant differences in the production of cytokines/chemokine and surface human leukocyte antigen-DR (HLA-DR) expression in response to LPS stimulation, which were observed across all cell types. When pre-treated with either interferon gamma (IFN-γ) or lymphocyte-activation gene 3 (LAG)-3 recombinant fusion protein (LAG-3Ig) prior to LPS stimulation, cells from the Hypo group were shown to be more responsive to both immunostimulants than cells from the Hyper group. Our results demonstrate the importance of patient stratification based on their immune status prior to any immune therapies. Once sufficiently scaled, this approach may be useful for prescribing the right immune therapy for the right patient at the right time, the key to the success of any therapy.

Blood transcriptome analysis of patients with uncomplicated bacterial infection and sepsis.

OBJECTIVES: Hospitalized patients who presented within the last 24 h with a bacterial infection were recruited. Participants were assigned into sepsis and uncomplicated infection groups. In addition, healthy volunteers were recruited as controls. RNA was prepared from whole blood, depleted from beta-globin mRNA and sequenced. This dataset represents a highly valuable resource to better understand the biology of sepsis and to identify biomarkers for severe sepsis in humans. DATA DESCRIPTION: The data presented here consists of raw and processed transcriptome data obtained by next generation RNA sequencing from 105 peripheral blood samples from patients with uncomplicated infections, patients who developed sepsis, septic shock patients, and healthy controls. It is provided as raw sequenced reads and as normalized log2 transformed relative expression levels. This data will allow performing detailed analyses of gene expression changes between uncomplicated infections and sepsis patients, such as identification of differentially expressed genes, co-regulated modules as well as pathway activation studies.

Prospective validation study of prognostic biomarkers to predict adverse outcomes in patients with COVID-19: a study protocol.

INTRODUCTION: Accurate triage is an important first step to effectively manage the clinical treatment of severe cases in a pandemic outbreak. In the current COVID-19 global pandemic, there is a lack of reliable clinical tools to assist clinicians to perform accurate triage. Host response biomarkers have recently shown promise in risk stratification of disease progression; however, the role of these biomarkers in predicting disease progression in patients with COVID-19 is unknown. Here, we present a protocol outlining a prospective validation study to evaluate the biomarkers' performance in predicting clinical outcomes of patients with COVID-19. METHODS AND ANALYSIS: This prospective validation study assesses patients infected with COVID-19, in whom blood samples are prospectively collected. Recruited patients include a range of infection severity from asymptomatic to critically ill patients, recruited from the community, outpatient clinics, emergency departments and hospitals. Study samples consist of peripheral blood samples collected into RNA-preserving (PAXgene/Tempus) tubes on patient presentation or immediately on study enrolment. Real-time PCR (RT-PCR) will be performed on total RNA extracted from collected blood samples using primers specific to host response gene expression biomarkers that have been previously identified in studies of respiratory viral infections. The RT-PCR data will be analysed to assess the diagnostic performance of individual biomarkers in predicting COVID-19-related outcomes, such as viral pneumonia, acute respiratory distress syndrome or bacterial pneumonia. Biomarker performance will be evaluated using sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operating characteristic curve. ETHICS AND DISSEMINATION: This research protocol aims to study the host response gene expression biomarkers in severe respiratory viral infections with a pandemic potential (COVID-19). It has been approved by the local ethics committee with approval number 2020/ETH00886. The results of this project will be disseminated in international peer-reviewed scientific journals.

COVID-US: A simplified approach to cardiopulmonary ultrasound in suspected and confirmed COVID-19 patients in surge crisis.

The severe acute respiratory syndrome coronavirus 2 (COVID-19) pandemic has placed an unprecedented challenge on healthcare systems across the globe. Rapid assessment of the cardiorespiratory function to monitor disease progression and guide treatment is essential. Therefore, we have designed the COVID-US: a simplified cardiopulmonary ultrasound approach to use in suspected and confirmed COVID-19 patients, to aid front-line health workers in their decision-making in a surge crisis.

Pathway mapping of leukocyte transcriptome in influenza patients reveals distinct pathogenic mechanisms associated with progression to severe infection.

BACKGROUND: Influenza infections produce a spectrum of disease severity, ranging from a mild respiratory illness to respiratory failure and death. The host-response pathways associated with the progression to severe influenza disease are not well understood. METHODS: To gain insight into the disease mechanisms associated with progression to severe infection, we analyzed the leukocyte transcriptome in severe and moderate influenza patients and healthy control subjects. Pathway analysis on differentially expressed genes was performed using a topology-based pathway analysis tool that takes into account the interaction between multiple cellular pathways. The pathway profiles between moderate and severe influenza were then compared to delineate the biological mechanisms underpinning the progression from moderate to severe influenza. RESULTS: 107 patients (44 severe and 63 moderate influenza patients) and 52 healthy control subjects were included in the study. Severe influenza was associated with upregulation in several neutrophil-related pathways, including pathways involved in neutrophil differentiation, migration, degranulation and neutrophil extracellular trap (NET) formation. The degree of upregulation in neutrophil-related pathways were significantly higher in severely infected patients compared to moderately infected patients. Severe influenza was also associated with downregulation in immune response pathways, including pathways involved in antigen presentation such as CD4+ T-cell co-stimulation, CD8+ T cell and Natural Killer (NK) cells effector functions. Apoptosis pathways were also downregulated in severe influenza patients compare to moderate and healthy controls. CONCLUSIONS: These findings showed that there are changes in gene expression profile that may highlight distinct pathogenic mechanisms associated with progression from moderate to severe influenza infection.

Correction to: The association between premorbid beta blocker exposure and mortality in sepsis-a systematic review.

In the publication of this article [1], there was an error in the cited reference 23 [2] within the Family Name. This has now been updated in the original article.

Long-term patient-important outcomes after septic shock: A protocol for 1-year follow-up of the CLASSIC trial.

BACKGROUND: In patients with septic shock, mortality is high, and survivors experience long-term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive vs standard-care intravenous (IV) fluid therapy. The hypothesis is that IV fluid restriction improves patient-important long-term outcomes. AIM: To assess the predefined patient-important long-term outcomes in patients randomised into the CLASSIC trial. METHODS: In this pre-planned follow-up study of the CLASSIC trial, we will assess all-cause mortality, health-related quality of life (HRQoL) and cognitive function 1 year after randomisation in the two intervention groups. The 1-year mortality will be collected from electronic patient records or central national registries in most participating countries. We will contact survivors and assess EuroQol 5-Dimension, -5-Level (EQ-5D-5L) and EuroQol-Visual Analogue Scale and Montreal Cognitive Assessment 5-minute protocol score. We will analyse mortality by logistic regression and use general linear models to assess HRQoL and cognitive function. DISCUSSION: With this pre-planned follow-up study of the CLASSIC trial, we will provide patient-important data on long-term survival, HRQoL and cognitive function of restrictive vs standard-care IV fluid therapy in patients with septic shock.

The association between premorbid beta blocker exposure and mortality in sepsis-a systematic review.

BACKGROUND: The effect of premorbid ß-blocker exposure on clinical outcomes in patients with sepsis is not well characterized. We aimed to examine the association between premorbid ß-blocker exposure and mortality in sepsis. METHODS: EMBase, MEDLINE, and Cochrane databases were searched for all studies of premorbid ß-blocker and sepsis. The search was last updated on 22 June 2019. Two reviewers independently assessed, selected, and abstracted data from studies reporting chronic ß-blocker use prior to sepsis and mortality. Main data extracted were premorbid ß-blocker exposure, mortality, study design, and patient data. Two reviewers independently assessed the risk of bias and quality of evidence. RESULTS: In total, nine studies comprising 56,414 patients with sepsis including 6576 patients with premorbid exposure to ß-blockers were eligible. For the primary outcome of mortality, two retrospective studies reported adjusted odds ratios showing a reduction in mortality with premorbid ß-blocker exposure. One study showed that premorbid ß-blocker exposure decreases mortality in patients with septic shock. Another study showed that continued ß-blockade during sepsis is associated with decreased mortality. CONCLUSION: This systematic review suggests that ß-blocker exposure prior to sepsis is associated with reduced mortality. There was insufficient data to conduct a bona fide meta-analysis. Whether the apparent reduction in mortality may be attributed to the mitigation of catecholamine excess is unclear. TRIAL REGISTRATION: PROSPERO, CRD42019130558 registered June 12, 2019.

Neutrophils-related host factors associated with severe disease and fatality in patients with influenza infection.

Severe influenza infection has no effective treatment available. One of the key barriers to developing host-directed therapy is a lack of reliable prognostic factors needed to guide such therapy. Here, we use a network analysis approach to identify host factors associated with severe influenza and fatal outcome. In influenza patients with moderate-to-severe diseases, we uncover a complex landscape of immunological pathways, with the main changes occurring in pathways related to circulating neutrophils. Patients with severe disease display excessive neutrophil extracellular traps formation, neutrophil-inflammation and delayed apoptosis, all of which have been associated with fatal outcome in animal models. Excessive neutrophil activation correlates with worsening oxygenation impairment and predicted fatal outcome (AUROC 0.817-0.898). These findings provide new evidence that neutrophil-dominated host response is associated with poor outcomes. Measuring neutrophil-related changes may improve risk stratification and patient selection, a critical first step in developing host-directed immune therapy.