Daily Anesthesiology Research Analysis

BACKGROUND: Sepsis is a dysregulated host response to infection resulting in life-threatening organ failure. Although immune dysregulation is central to the sepsis definition, immunomodulation trials enrol participants based on clinical severity, not the extent of dysregulation, which could contribute to treatment heterogeneity. A pragmatic way to quantify immune dysregulation could improve prognostication, help to evaluate treatment responses, and identify individuals most likely to benefit from immunomodulation. We aimed to construct a parsimonious machine-learning tool that defines and quantifies immune dysregulation, thereby supporting biologically informed immunomodulation. METHODS: In this multicohort analysis and reanalysis of a randomised controlled trial, the primary objective was to derive and validate a categorical and continuous immune dysregulation score that is independent of clinical presentation or outcome. We measured 35 plasma biomarkers reflecting key host response domains in individuals with community-acquired pneumonia (CAP) across different care settings (emergency department, general ward, and intensive care unit) and disease severities using data from three independent cohorts. We applied unsupervised trajectory inference analysis to identify an immune dysregulation gradient captured as discrete immune dysregulation stages (Dysregulated Immune Profile [DIP]) and a continuous score (cDIP; 0-1). We developed two parsimonious machine-learning models to predict the DIP stages and cDIP scores based on 35 biomarkers, and validated their ability to capture immune dysregulation and predict clinical outcomes in five independent cohorts. On the basis of our hypothesis that only individuals with severe immune dysregulation benefit from immunomodulation, we carried out a post-hoc analysis of a randomised trial evaluating hydrocortisone in severe CAP (CAPE COD trial, NCT02517489), assessing treatment effects across DIP stages and the cDIP continuum, and how hydrocortisone influenced dysregulation trajectories over time. FINDINGS: We organised 398 participants with CAP along a continuum of immune dysregulation from mild to severe on the basis of 35 plasma biomarkers, yielding three dysregulation stages (DIP1-3) and a continuous score (cDIP). Clinical severity proved to be an inadequate proxy for immune dysregulation. A three-biomarker machine-learning framework (procalcitonin, soluble TREM-1, and IL-6) accurately predicted the degree of dysregulation derived from 35 biomarkers (DIP stage accuracy 91·2%; cDIP root mean square error 0·056). Although the framework was not designed for outcome prediction, increased immune dysregulation-reflected in DIP and cDIP-was associated with a gradual rise in mortality (cDIP odds ratio [OR] 1·26 [95% CI 1·13-1·40] per 10% increase, p<0·0001) and secondary infections (OR 1·50 [1·22-1·93] per 10% increase, p=0·0005), independent of clinical severity. The three-biomarker tool was validated in five external cohorts of varying infections, severities, and care settings (n=1191). Reanalysis of the CAPE COD trial showed that hydrocortisone conferred a survival benefit only in participants classified as severely dysregulated by our model (30-day mortality: DIP3 OR 0·25 [0·05-0·85], p=0·042; cDIP ≥0·63 OR 0·21 [0·10-0·72], p=0·011), accompanied by faster immune recovery (time × treatment interaction, p<0·0001). No such effect modification was observed when stratifying participants by clinical severity. INTERPRETATION: We have provided a publicly available three-biomarker framework to determine the extent of host response dysregulation with potential value for precision-guided immunomodulatory therapy. FUNDING: EU Horizon 2020.

INTRODUCTION: Patients undergoing multiple wound repair surgeries often develop moderate-to-severe anxiety and depression. However, there is a lack of effective rapid emotional intervention strategies during the perioperative period. METHODS: This multi-centre, randomized, double-blind, placebo-controlled trial involved 130 adult patients (65 in the esketamine group and 65 in the placebo group). Participants were randomly assigned to receive either esketamine (0.2-0.3 mg/kg) or saline intravenously during surgery. The primary outcome was the response rate (proportion of patients with ≥50% reduction in MADRS total score from baseline) on postoperative days (PODs) 1-3, evaluated using the Montgomery-Åsberg depression rating scale (MADRS). The secondary outcome was the remission rate (proportion of patients with MADRS total score ≤10) on postoperative days (PODs) 1-3; scores on the Patient Health Questionnaire-9 (PHQ-9), the Hospital Anxiety and Depression Scale-Anxiety subscale (HADS-A); and esketamine-related neuropsychiatric adverse events assessed using the Young Mania Rating Scale (YMRS), Clinician-Administered Dissociative States Scale (CADSS), and Brief Psychiatric Rating Scale (BPRS) within 30 days after surgery. RESULTS: The esketamine group showed a significantly higher response rate than the placebo group on POD 1-3. (POD 1: 53.8% vs. 26.2%, p = 0.001; POD 2: 60.0% vs. 40.0%, p = 0.009; POD 3: 73.8% vs. 53.8%, p = 0.018). The esketamine group also showed a higher remission rate and lower MADRS scores (POD 1: 33.8% vs. 10.8%, p = 0.002; POD 2: 40.0% vs. 23.1%, p = 0.038; POD 3: 56.9% vs. 23.1%, p < 0.001). Esketamine improved HADS-A and PHQ-9 scores by POD 3 without increasing neuropsychiatric adverse events within 30 days postoperatively. CONCLUSIONS: The results demonstrate that the intraoperative use of low-dose esketamine can rapidly and effectively alleviate moderate-to-severe anxiety and depressive symptoms in the early postoperative period (POD 1-3) among patients requiring repeated debridement surgeries without increasing neuropsychiatric or systemic adverse events within 30 days after surgery.

10%, that is, over 32 million patients-suffer from inadequate anesthesia monitoring in surgical procedures yearly, global-results in unwanted intraoperative risks. On-site, precise analysis of anesthesia concentration during patient surgery is highly desired yet has not been achieved owing to the lack of a satisfactory biosensor device: it allows sample collection-and-detection seamlessly and in a timely manner. Here, we introduce a new chiral plasma biosensor, a tandem integrating of one 3D nano-helical silver array with an optofluidic chip that enables real-time depth of anesthesia monitoring during surgery. The patient's blood flows into and is processed through our device's designed channel, where capillary-driven flow enables rapid plasma separation from whole blood. The isolated plasma is then directly delivered to the surface-enhanced Raman scattering (SERS) sensing region, and diverse functional anesthetics in blood are meanwhile recognized by the chiral plasma detector. The cost-effective sensor enables the detection limitation at a level of 0.1 µg/mL, and more importantly, all analyses are completed within a minute level, showing an advance compared to current hour/day suboptimal temporal resolution. We further apply this device in the clinic, monitor the anesthetics, and offer individual drug metabolism profiles in various patients. In addition, this precise, on-site, and real-time biochip features a user-friendly diagnostic system that uses mobile applications and portable accessories to address critical clinical needs, providing an opportunity for personalized anesthesia management based on patient-specific needs.