Three-month outcomes and cost-effectiveness of interferon gamma-1b in critically ill patients: a secondary analysis of the PREV-HAP trial.

BACKGROUND: Interferon gamma­1b has been proposed to treat critical illness-induced immunosuppression. We aimed to determine the effects on 90-day outcomes and the cost-effectiveness of interferon gamma­1b compared to placebo in mechanically ventilated critically ill patients. METHODS: A cost-effectiveness analysis (CEA) was embedded in the "PREV-HAP trial", a multicenter, placebo­controlled, randomized trial, which randomly assigned critically ill adults under mechanical ventilation to receive interferon gamma or placebo. The CEA compared interferon-gamma with placebo using a collective perspective at a 90-day time horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER) expressed in terms of adjusted cost per adjusted Quality-Adjusted Life-Years (QALYs) gained. QALYs were estimated from the responses of patients and proxy respondents to the health-related quality of life questionnaire EQ-5D-3L. RESULTS: The 109 patients in the PREV-HAP trial were included in the CEA. At day 90, all-cause mortality rates were 23.6% in the interferon group and 25% in the placebo group (Odds Ratio (OR) = 0.88 (0.40 -1.93) p = 0.67). The difference in the mean adjusted costs per patient at 90 days was €-1.638 (95%CI €-17.534 to €11.968) in favor of interferon gamma-1b. The mean difference in adjusted QALYs between interferon gamma-1b and the placebo group was + 0.019 (95%CI -0.005 to 0.043). The probability that interferon gamma-1b was cost-effective ranged from 0.60 to 0.71 for a willingness to pay a QALY between €20k and €150k for the base case analysis. CONCLUSION: Early administration of interferon gamma might be cost-effective in critically ill patients supporting the realization of other studies on this treatment. However, the generalization of the findings should be considered cautiously, given the small sample size due to the premature end of PREV-HAP. Trial registration ClinicalTrials.gov Identifier: NCT04793568, Registration date: 2021-02-24.

Tranexamic acid: a narrative review of its current role in perioperative medicine and acute medical bleeding.

Purpose: Tranexamic acid (TXA) is the most widely prescribed antifibrinolytic for active bleeding or to prevent surgical bleeding. Despite numerous large multi-center randomized trials involving thousands of patients being conducted, TXA remains underutilized in indications where it has demonstrated efficacy and a lack of harmful effects. This narrative review aims to provide basic concepts about fibrinolysis and TXA's mode of action and is focused on the most recent and important trials evaluating this drug in different hemorrhagic situations. Methods: We selected every low bias RCT, and we highlighted their strengths and limitations throughout this review. Principal findings: While TXA appears to have a favorable benefit-risk ratio in most situations (trauma, obstetrics, at-risk for bleeding surgeries) evidence of benefit is lacking in certain medical settings (SAH, digestive bleeding). Conclusion: Although in some situations the drug's effect on significant outcomes is modest, its favorable safety profile allows it to be recommended for trauma patients, in obstetrics, and in scheduled surgeries at risk of bleeding. However, it cannot be recommended in cases of spontaneous intracranial bleeding, subarachnoid hemorrhage (SAH), or gastrointestinal bleeding.

Predictive Models of Long-Term Outcome in Patients with Moderate to Severe Traumatic Brain Injury are Biased Toward Mortality Prediction.

BACKGROUND: The prognostication of long-term functional outcomes remains challenging in patients with traumatic brain injury (TBI). Our aim was to demonstrate that intensive care unit (ICU) variables are not efficient to predict 6-month functional outcome in survivors with moderate to severe TBI (msTBI) but are mostly associated with mortality, which leads to a mortality bias for models predicting a composite outcome of mortality and severe disability. METHODS: We analyzed the data from the multicenter randomized controlled Continuous Hyperosmolar Therapy in Traumatic Brain-Injured Patients trial and developed predictive models using machine learning methods and baseline characteristics and predictors collected during ICU stay. We compared our models' predictions of 6-month binary Glasgow Outcome Scale extended (GOS-E) score in all patients with msTBI (unfavorable GOS-E 1-4 vs. favorable GOS-E 5-8) with mortality (GOS-E 1 vs. GOS-E 2-8) and binary functional outcome in survivors with msTBI (severe disability GOS-E 2-4 vs. moderate to no disability GOS-E 5-8). We investigated the link between ICU variables and long-term functional outcomes in survivors with msTBI using predictive modeling and factor analysis of mixed data and validated our hypotheses on the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model. RESULTS: Based on data from 370 patients with msTBI and classically used ICU variables, the prediction of the 6-month outcome in survivors was inefficient (mean area under the receiver operating characteristic 0.52). Using factor analysis of mixed data graph, we demonstrated that high-variance ICU variables were not associated with outcome in survivors with msTBI (p = 0.15 for dimension 1, p = 0.53 for dimension 2) but mostly with mortality (p < 0.001 for dimension 1), leading to a mortality bias for models predicting a composite outcome of mortality and severe disability. We finally identified this mortality bias in the IMPACT model. CONCLUSIONS: We demonstrated using machine learning-based predictive models that classically used ICU variables are strongly associated with mortality but not with 6-month outcome in survivors with msTBI, leading to a mortality bias when predicting a composite outcome of mortality and severe disability.

Value of a secretomic approach for distinguishing patients with COVID-19 viral pneumonia among patients with respiratory distress admitted to intensive care unit.

In intensive care units, COVID-19 viral pneumonia patients (VPP) present symptoms similar to those of other patients with Nonviral infection (NV-ICU). To better manage VPP, it is therefore interesting to better understand the molecular pathophysiology of viral pneumonia and to search for biomarkers that may clarify the diagnosis. The secretome being a set of proteins secreted by cells in response to stimuli represents an opportunity to discover new biomarkers. The objective of this study is to identify the secretomic signatures of VPP with those of NV-ICU. Plasma samples and clinical data from NV-ICU (n = 104), VPP (n = 30) or healthy donors (HD, n = 20) were collected at Nantes Hospital (France) upon admission. Samples were enriched for the low-abundant proteins and analyzed using nontarget mass spectrometry. Specifically deregulated proteins (DEP) in VPP versus NV-ICU were selected. Combinations of 2 to 4 DEPs were established. The differences in secretome profiles of the VPP and NV-ICU groups were highlighted. Forty-one DEPs were specifically identified in VPP compared to NV-ICU. We describe five of the best combinations of 3 proteins (complement component C9, Ficolin-3, Galectin-3-binding protein, Fibrinogen alpha, gamma and beta chain, Proteoglycan 4, Coagulation factor IX and Cdc42 effector protein 4) that show a characteristic receptor function curve with an area under the curve of 95.0%. This study identifies five combinations of candidate biomarkers in VPP compared to NV-ICU that may help distinguish the underlying causal molecular alterations.

Sepsis-trained macrophages promote antitumoral tissue-resident T cells.

Sepsis induces immune alterations, which last for months after the resolution of illness. The effect of this immunological reprogramming on the risk of developing cancer is unclear. Here we use a national claims database to show that sepsis survivors had a lower cumulative incidence of cancers than matched nonsevere infection survivors. We identify a chemokine network released from sepsis-trained resident macrophages that triggers tissue residency of T cells via CCR2 and CXCR6 stimulations as the immune mechanism responsible for this decreased risk of de novo tumor development after sepsis cure. While nonseptic inflammation does not provoke this network, laminarin injection could therapeutically reproduce the protective sepsis effect. This chemokine network and CXCR6 tissue-resident T cell accumulation were detected in humans with sepsis and were associated with prolonged survival in humans with cancer. These findings identify a therapeutically relevant antitumor consequence of sepsis-induced trained immunity.

Clinical evaluation of the BioFire Respiratory Pathogen Panel for the guidance of empirical antimicrobial therapy in critically ill patients with hospital-acquired pneumonia: A multicenter, quality improvement project.

BACKGROUND: We aimed to determine whether implementing antimicrobial stewardship based on multiplex bacterial PCR examination of respiratory fluid can enhance outcomes of critically ill patients with hospital-acquired pneumonia (HAP). METHODS: We conducted a quality improvement study in two hospitals in France. Adult patients requiring invasive mechanical ventilation with a diagnosis of HAP were included. In the pre-intervention period (August 2019 to April 2020), antimicrobial therapy followed European guidelines. In the «intervention¼ phase (June 2020 to October 2021), treatment followed a multiplex PCR-guided protocol. The primary endpoint was a composite endpoint made of mortality on day 28, clinical cure between days 7 and 10, and duration of invasive mechanical ventilation on day 28. The primary outcome was analyzed with a DOOR strategy. RESULTS: A total of 443 patients were included in 3 ICUs from 2 hospitals (220 pre-intervention; 223 intervention). No difference in the ranking of the primary composite outcome was found (DOOR: 50.3%; 95%CI, 49.9%-50.8%). The number of invasive mechanical ventilation-free days at day 28 was 10.0 [0.0; 19.0] in the baseline period and 9.0 [0.0; 20.0] days during the intervention period (p = 0.95). The time-to-efficient antimicrobial treatment was 0.43 ± 1.29 days before versus 0.55 ± 1.13 days after the intervention (p = 0.56). CONCLUSION: Implementation of Rapid Multiplex PCR to guide empirical antimicrobial therapy for critically ill patients with HAP was not associated with better outcomes. However, adherence to stewardship was low, and the study may have had limited power to detect a clinically important difference.

Systemic inflammatory response syndrome triggered by blood-borne pathogens induces prolonged dendritic cell paralysis and immunosuppression.

Blood-borne pathogens can cause systemic inflammatory response syndrome (SIRS) followed by protracted, potentially lethal immunosuppression. The mechanisms responsible for impaired immunity post-SIRS remain unclear. We show that SIRS triggered by pathogen mimics or malaria infection leads to functional paralysis of conventional dendritic cells (cDCs). Paralysis affects several generations of cDCs and impairs immunity for 3-4 weeks. Paralyzed cDCs display distinct transcriptomic and phenotypic signatures and show impaired capacity to capture and present antigens in vivo. They also display altered cytokine production patterns upon stimulation. The paralysis program is not initiated in the bone marrow but during final cDC differentiation in peripheral tissues under the influence of local secondary signals that persist after resolution of SIRS. Vaccination with monoclonal antibodies that target cDC receptors or blockade of transforming growth factor ß partially overcomes paralysis and immunosuppression. This work provides insights into the mechanisms of paralysis and describes strategies to restore immunocompetence post-SIRS.

Robust airway microbiome signatures in acute respiratory failure and hospital-acquired pneumonia.

Respiratory microbial dysbiosis is associated with acute respiratory distress syndrome (ARDS) and hospital-acquired pneumonia (HAP) in critically ill patients. However, we lack reproducible respiratory microbiome signatures that can increase our understanding of these conditions and potential treatments. Here, we analyze 16S rRNA sequencing data from 2,177 respiratory samples collected from 1,029 critically ill patients (21.7% with ARDS and 26.3% with HAP) and 327 healthy controls, sourced from 17 published studies. After data harmonization and pooling of individual patient data, we identified microbiota signatures associated with ARDS, HAP and prolonged mechanical ventilation. Microbiota signatures for HAP and prolonged mechanical ventilation were characterized by depletion of a core group of microbes typical of healthy respiratory samples, and the ARDS microbiota signature was distinguished by enrichment of potentially pathogenic respiratory microbes, including Pseudomonas and Staphylococcus. Using machine learning models, we identified clinically informative, three- and four-factor signatures that predicted ARDS, HAP and prolonged mechanical ventilation with relatively high accuracy (area under the curve of 0.751, 0.72 and 0.727, respectively). We validated the signatures in an independent prospective cohort of 136 patients on mechanical ventillation and found that patients with microbiome signatures associated with ARDS, HAP or prolonged mechanical ventilation had longer times to successful extubation than patients lacking these signatures (hazard ratios of 1.56 (95% confidence interval (CI) 1.07-2.27), 1.51 (95% CI 1.02-2.23) and 1.50 (95% CI 1.03-2.18), respectively). Thus, we defined and validated robust respiratory microbiome signatures associated with ARDS and HAP that may help to identify promising targets for microbiome therapeutic modulation in critically ill patients.

RUFY3 regulates endolysosomes perinuclear positioning, antigen presentation and migration in activated phagocytes.

Endo-lysosomes transport along microtubules and clustering in the perinuclear area are two necessary steps for microbes to activate specialized phagocyte functions. We report that RUN and FYVE domain-containing protein 3 (RUFY3) exists as two alternative isoforms distinguishable by the presence of a C-terminal FYVE domain and by their affinity for phosphatidylinositol 3-phosphate on endosomal membranes. The FYVE domain-bearing isoform (iRUFY3) is preferentially expressed in primary immune cells and up-regulated upon activation by microbes and Interferons. iRUFY3 is necessary for ARL8b + /LAMP1+ endo-lysosomes positioning in the pericentriolar organelles cloud of LPS-activated macrophages. We show that iRUFY3 controls macrophages migration, MHC II presentation and responses to Interferon-γ, while being important for intracellular Salmonella replication. Specific inactivation of rufy3 in phagocytes leads to aggravated pathologies in mouse upon LPS injection or bacterial pneumonia. This study highlights the role of iRUFY3 in controlling endo-lysosomal dynamics, which contributes to phagocyte activation and immune response regulation.

Cost effectiveness and long-term outcomes of dexamethasone administration in major non-cardiac surgery.

STUDY OBJECTIVES: Postoperative administration of dexamethasone has been proposed to reduce morbidity and mortality in patients undergoing major non-cardiac surgery. In this ancillary study of the PACMAN trial, we aimed to evaluate the cost effectiveness of dexamethasone in patients undergoing major non-cardiac surgery. METHODS: Patients included in the multicentric randomized double-blind, placebo-controlled PACMAN trial were followed up for 12 months after their surgical procedure. Patients were randomized to receive either dexamethasone (0.2 mg/kg immediately after the surgical procedure, and on day 1) or placebo. Cost effectiveness between the dexamethasone and placebo groups was assessed for the 12-month postoperative period from a health payer perspective. RESULTS: Of 1222 randomized patients in PACMAN, 137 patients (11%) were followed up until 12 months after major surgery (71 in the DXM group and 66 in the placebo group). Postoperative dexamethasone administration reduced costs per patient at 1 year by €358.06 (95%CI -€1519.99 to €803.87). The probability of dexamethasone being cost effective was between 12% and 22% for a willingness to pay of €100,000 to €150,000 per life-year, which is the threshold that is usually used in France and was 52% for willingness to pay of €50,000 per life-year (threshold in USA). At 12 months, 9 patients (13.2%) in the DXM group and 10 patients (16.1%) in the placebo group had died. In conclusion, our study does not demonstrate the cost effectiveness of perioperative administration of DXM in major non-cardiac surgery.

Mechanical ventilation in patients with acute brain injury: a systematic review with meta-analysis.

OBJECTIVE: To describe the potential effects of ventilatory strategies on the outcome of acute brain-injured patients undergoing invasive mechanical ventilation. DESIGN: Systematic review with an individual data meta-analysis. SETTING: Observational and interventional (before/after) studies published up to August 22nd, 2022, were considered for inclusion. We investigated the effects of low tidal volume Vt < 8 ml/Kg of IBW versus Vt > = 8 ml/Kg of IBW, positive end-expiratory pressure (PEEP) < or > = 5 cmH2O and protective ventilation (association of both) on relevant clinical outcomes. POPULATION: Patients with acute brain injury (trauma or haemorrhagic stroke) with invasive mechanical ventilation for ≥ 24 h. MAIN OUTCOME MEASURES: The primary outcome was mortality at 28 days or in-hospital mortality. Secondary outcomes were the incidence of acute respiratory distress syndrome (ARDS), the duration of mechanical ventilation and the partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio. RESULTS: The meta-analysis included eight studies with a total of 5639 patients. There was no difference in mortality between low and high tidal volume [Odds Ratio, OR 0.88 (95%Confidence Interval, CI 0.74 to 1.05), p = 0.16, I2 = 20%], low and moderate to high PEEP [OR 0.8 (95% CI 0.59 to 1.07), p = 0.13, I2 = 80%] or protective and non-protective ventilation [OR 1.03 (95% CI 0.93 to 1.15), p = 0.6, I2 = 11]. Low tidal volume [OR 0.74 (95% CI 0.45 to 1.21, p = 0.23, I2 = 88%], moderate PEEP [OR 0.98 (95% CI 0.76 to 1.26), p = 0.9, I2 = 21%] or protective ventilation [OR 1.22 (95% CI 0.94 to 1.58), p = 0.13, I2 = 22%] did not affect the incidence of acute respiratory distress syndrome. Protective ventilation improved the PaO2/FiO2 ratio in the first five days of mechanical ventilation (p < 0.01). CONCLUSIONS: Low tidal volume, moderate to high PEEP, or protective ventilation were not associated with mortality and lower incidence of ARDS in patients with acute brain injury undergoing invasive mechanical ventilation. However, protective ventilation improved oxygenation and could be safely considered in this setting. The exact role of ventilatory management on the outcome of patients with a severe brain injury needs to be more accurately delineated.

High-flow oxygen therapy versus facemask preoxygenation in anticipated difficult airway management (PREOPTI-DAM): an open-label, single-centre, randomised controlled phase 3 trial.

Background: Difficult airway management remains a critical procedure with life-threatening adverse events. Current guidelines suggest high-flow therapy by nasal cannulae (HFNC) as a preoxygenation device in this setting. However, there is an evidence gap to support this recommendation. Methods: The PREOPTI-DAM study is an open-label, single-centre, randomised controlled phase 3 trial done at Nantes University Hospital, France. Patients were aged 18-90 years with one major or two minor criteria of anticipated difficult airway management, and requiring intubation for scheduled surgery, were eligible. Patients with body mass index >35 kg/m2 were excluded. Patients were randomly allocated (1:1) to receive 4-min preoxygenation by HFNC or facemask. Randomisation was stratified according to the intubation strategy (laryngoscopic versus fiberoptic intubation). The primary outcome was the incidence of oxygen desaturation ≤94% or of bag-mask ventilation during intubation. The primary and safety analyses included the intention to treat population. This trial is registered with ClinicalTrials.gov (NCT03604120) and EudraCT (2018-A00434-51). Findings: From September 4 2018 to March 31 2021, 186 patients were enrolled and randomly assigned. One participant withdrew consent and 185 (99.5%) were included in the primary analysis (HFNC, N = 95; Facemask, N = 90). The incidence of the primary outcome was not significantly different between the HFNC and the facemask groups, respectively 2 (2%) versus 7 (8%); adjusted difference, -5.6 [95% confidence interval (CI), -11.8 to 0.6], P = 0.10. In the HFNC group, 76 patients (80%) versus 53 (59%) in the facemask group, reported good or excellent intubation experiences; adjusted difference 20.5 [95% CI, 8.3-32.8], P = 0.016. Comparing HFNC with facemask, severe complication occurred in 22 (23%) versus 27 (30%) patients (P = 0.29), and moderate complication in 14 (15%) versus 18 (20%) patients (P = 0.35). No death or cardiac arrest occurred during the study. Interpretation: Compared with facemask, HFNC did not significantly reduce the incidence of desaturation ≤94% or bag-mask ventilation during anticipated difficult intubation but the trial was underpowered to rule out a clinically significant benefit. Patient satisfaction was improved with HFNC. Funding: Nantes University Hospital and Fisher & Paykel Healthcare.