Critical Care

Background: Many patients in the ICU receive oxygen to secure blood and tissue oxygenation. Increasing evidence shows exposure to high fractions of inhaled oxygen (FiO2) being associated with adverse effects. In patients with severe ARDS, veno-venous Extracorporeal Membrane Oxygenation (VV-ECMO) can be implemented as a rescue therapy and PaO2 levels can be controlled by the blood flow of the VV-ECMO. Yet, optimal oxygenation targets in ARDS patients treated with VV-ECMO are unknown. Methods: Retrospective analysis of 443 patients with severe ARDS treated with VV-ECMO. Regression analyses were performed for mortality and time-weighted averages of PaO2 and FiO2. Furthermore, considering a possible non-linear relationship, a restricted cubic spline (RCS) model was performed for PaO2. Results: A simple logistic regression for mean PaO2 and ICU mortality showed a significant positive association (per mmHg OR 0.99 [95%CI 0.98-1.00], p=0.002). RCS analysis showed a U-shaped association of mortality and mean paO2 (paO2 69.70-90.24mmHg: OR 0.92 [95%CI 0.89-0.94], p<0.001; paO2 90.24-123.40mmHg: OR 1.09 [95%CI 1.06-1.13], p<0.001). A model including PaO2 as RCS variable and FiO2 showed significant associations of mortality with both variables (PaO2 69.70-90.24mmHg: OR 0.94 [95%CI 0.91-0.97], p<0.001; paO2 90.24-123.40 mmHg: OR 1.07 [95%CI 1.04-1.11], p<0.001; FiO2: OR 35.98 [95%CI 8.67-158.60], p<0.001, VIF<1.11). Conclusions: PaO2-levels in patients with ARDS and VV-ECMO have a U-shaped association with mortality. Optimal outcomes are observed in the 90-123 mmHg range, which is higher compared to non-ECMO settings. Whether this is explainable by increased tissue oxygenation with concurrent avoidance of pulmonary hypoxia should be subject of future research.

Rationale: Sepsis is a life-threatening syndrome causing significant morbidity and mortality especially in the aging population. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition of clonal expansion of hematopoietic stem cells harboring somatic mutations associated with increased incidence of chronic illness and all-cause mortality. Objective: Evaluate the association of pre-illness CHIP with mortality and morbidity in patients admitted to the ICU with sepsis. Methods: We performed a retrospective study using a de-identified electronic health record linked with a DNA biorepository. We identified adult patients with sepsis who had DNA collected prior to ICU admission. We tested the association between CHIP status, determined from whole-genome sequencing, and ICU mortality, organ support-free days, and long-term survival adjusting for age, sex, race and Sequential Organ Failure Assessment (SOFA) score on ICU admission. Measurements and Main Results: Pre-illness CHIP was associated with increased sepsis mortality (OR = 1.54, 95% CI 1.13 to 2.07, P = 0.005) and fewer days alive and free of organ support (-1.7 days, 95% CI -3.2 to -0.2, P = 0.028) after adjusting for age, sex, race, and SOFA score. In sepsis survivors, CHIP was also associated with increased long-term mortality after discharge (HR 1.40, 95% CI 1.01 to 1.93, P = 0.041). Conclusions: Pre-illness CHIP was independently associated with increased mortality and morbidity in critically-ill adults with sepsis. These findings suggest that CHIP is a risk factor for sepsis severity. Elucidating the mechanism underlying this association could uncover new therapeutic interventions for sepsis.

BackgroundThe role of arterial blood gas (ABG) testing in the intensive care unit (ICU) remains debated within the "less is more" paradigm. While unnecessary testing may pose risks without benefit, timely ABGs provide critical information in unstable patients. Institutional variation in early ABG utilization and its association with outcomes remains unclear. MethodsWe conducted a multicenter retrospective cohort study using the Japanese Intensive Care PAtient Database (JIPAD) between April 2015 and March 2023. Adult ICU patients with a stay [&ge;]24 h and arterial line placement were included. The standardized number of ABGs (SNABGs) within the first 24 h was calculated as the ratio of observed to expected values, where expectations were derived from a multivariable model adjusting for patient covariates. ICUs were categorized into tertiles according to SNABG utilization. The primary outcome was in-hospital mortality, analyzed using multilevel logistic regression with ICU-level random intercepts. Restricted cubic splines were used to explore non-linear associations. ResultsAmong 117,546 patients from 87 ICUs, the mean number of ABGs varied widely. After standardization, SNABGs ranged from 0.73-0.90 in the low tertile to 1.09-1.15 in the high tertile. In the multilevel model, SNABG was not significantly associated with in-hospital mortality (adjusted OR 0.942 [95% CI 0.807-1.100] for tertile 2; 0.874 [95% CI 0.751-1.017] for tertile 3). Flexible modeling suggested a non-linear trend toward better outcomes with higher utilization, but confidence intervals included unity. ConclusionEarly ABG utilization varied across ICUs, yet was not significantly associated with mortality. Sensitivity analysis suggested a non-linear relationship, with a tendency toward better outcomes at higher utilization. These findings warrant further investigation to clarify the role of early ABG utilization in critical care.

Rationale: Fibrinolysis resistance in sepsis associates with thrombotic burden, multi-organ failure and death. The degrees and dynamics of resistance that associate with mortality in acute sepsis are unknown, and a simple tool to aid clinician interpretation of fibrinolysis measurements is lacking. Objectives: To establish a point of care grading tool of fibrinolysis resistance that aligns with scoring systems for disease acuity, is substantiated by plasma fibrinolysis markers and enables rapid investigation of the fibrinolysis state at the point of care. Methods: Prospective observational study of 116 adult sepsis/septic shock patients with sequential measurements of fibrinolysis resistance during Intensive Care Unit (ICU) admission using tissue plasminogen activator (tPA) enhanced viscoelastic testing (VET). The clot lysis time (TPA-LT) adjusted for fibrin clot amplitude (TPA-LT/FIBA10, sec/mm) underwent cluster analysis and was evaluated against disease severity scores, standard pathology, clinical outcomes and fibrinolysis markers. Measurements and Main Results: Three clusters of progressively increasing fibrinolysis resistance were identified (Grades 1-3). At admission, Grade 3 associated with the highest disease severity, organ failure, haematological and biochemical perturbations, fibrinolysis marker inhibitory profile and mortality (42% versus 24% and 15% in Grade 2 and Grade 1, respectively) with a 3.9-fold [95% CI 1.4-11] increased hazard ratio for death at 28 days compared to Grade 1. Transitions between grades were frequent over 7 days with a reduced Grade associated with decreased risk of death. Conclusions: Grading of fibrinolysis resistance in sepsis enables rapid identification of patients at greatest mortality risk with any dynamic improvement corresponding to favourable clinical outcomes.

BackgroundSepsis is a major public health challenge, and reliable biomarkers are essential for distinguishing sepsis from other conditions. Neutrophil Gelatinase-Associated Lipocalin (Neutrophil gelatinase-associated lipocalin (NGAL)) has shown promise as a diagnostic marker due to its role in the immune response. This study evaluates plasma NGAL as a diagnostic tool at the time of ICU admission. MethodsWe analysed plasma NGAL and C-reactive protein (CRP) levels in 4732 adult patients admitted to four ICUs between 2015 and 2018. All patients were retrospectively screened for Sepsis-3 criteria at ICU admission. The discriminative performance of NGAL and CRP for sepsis was assessed using receiver operating characteristic (ROC) analysis, with NGAL levels adjusted for Chronic kidney disease (CKD) and age. Patients were stratified by renal function. ResultsPlasma NGAL levels were significantly higher in septic patients (p<0.001). For the whole cohort, NGAL alone yielded an Area under the curve (AUC) of 0.67 (Confidence interval (CI) 0.66-0.69), CRP yielded an AUC of 0.72 (CI 0.71-0.73, p<0.001), and combining NGAL with CRP nominally improved discriminative performance (AUC 0.74 vs 0.72, p<0.001). Stratified analyses indicated that NGAL, together with CRP, significantly outperformed CRP alone in patients with no kidney injury and those with Acute Kidney Injury (AKI) only. In contrast, differences were not significant in patients with CKD only or CKD and AKI. ConclusionIn this large cohort, NGAL showed modest discrimination for sepsis, with a nominal improvement when combined with CRP. These findings do not indicate that NGAL meaningfully improves sepsis diagnosis in the ICU.

The Sequential Organ Failure Assessment (SOFA)-2 score was recently validated for ICU mortality prediction across more than 3 million admissions but was not evaluated across demographic subgroups. We assessed the discrimination and calibration of the SOFA-2 score for ICU mortality across subgroups defined by age, sex, race and ethnicity, primary language, and insurance status. We conducted a retrospective cohort study of adult patients (aged 18 years or older) admitted to ICUs at Beth Israel Deaconess Medical Center between 2008 and 2022 (MIMIC-IV, version 3.1), selecting the first ICU admission per patient. First-day SOFA-2 scores (range, 0-24) were calculated using worst recorded values across 6 organ systems. Discrimination was assessed using AUROC, calibration using intercepts and slopes, and subgroup differences using bootstrap resampling. Among 64,015 ICU admissions (median age, 66 years [IQR, 54-78]; 56.1% male; 66.1% White), overall ICU mortality was 7.2% (n=4,596). Overall AUROC was acceptable at 0.77 (95% CI, 0.76-0.77). Notably, discrimination declined significantly with age: AUROC was 0.85 (95% CI, 0.83-0.87) for ages 18-44 and 0.72 (95% CI, 0.70-0.73) for ages 75 and older (difference in AUROC, -0.14; 95% CI, -0.16 to -0.11), with systematic underprediction of mortality in older patients (calibration intercept, 0.39). Discrimination was also significantly lower among non-English speakers (difference in AUROC, -0.04; 95% CI, -0.07 to -0.01) but did not differ significantly across documented racial and ethnic groups. Patients with unknown race/ethnicity (14.3% of the cohort) had nearly double the overall mortality rate and poor calibration. SOFA-2 demonstrated good overall performance for ICU mortality prediction but with clinically meaningful variation across demographic subgroups, particularly a substantial decline in discrimination with advancing age. These findings underscore the need for routine equity evaluation of clinical prediction tools before widespread implementation.

Sepsis is defined as a dysregulated response to infection, leading to life-threatening organ dysfunction that particularly affects parenchymal organs. Clinical studies remain inconclusive regarding the impact of biological sex on sepsis, and preclinical studies are predominantly performed in male animals. We examined early (8 h) septic responses in male and female mice using a fecal-induced peritonitis (FIP) model. Blood biochemical parameters, body temperature, and murine sepsis scores provided evidence of a septic response in animals randomized to FIP compared to controls, but showed no physiological differences between male and female mice. Transcriptomic analysis of the liver, kidney, and lung showed consistent inflammatory activation in response to sepsis as compared to controls. Notably, in the kidney and lung, female mice exhibited stronger immune activation and a heightened inflammatory response compared to males. Thus, biological sex differences in the septic response can be detected in early acute sepsis without apparent physiological differences.

Class B scavenger receptors BI (SR-BI) and BII (SR-BII) internalize lipoproteins but also bind and internalize bacteria. Their roles in sepsis are unknown. We overexpressed human SR-BI and BII in the liver and kidney as well as bone marrow-derived macrophages, and then performed cecal ligation and puncture (CLP) surgery. SR-BI and BII transgenic mice had significantly worse survival compared to WT mice. 24 h after CLP, liver injury markers and histological damage were prominent in both SR-BI and BII transgenic mice, whereas kidney damage was similar. Systemic inflammatory cytokines were markedly increased in SR-BI and BII transgenic mice; parallel increases were seen in liver mRNA expression, not in the kidney. The highest degree of neutrophil infiltration was observed in the liver of SR-BI. Human SR-BI and BII dramatically decreased bacterial accumulation in the liver. Green fluorescence protein-labeled E. coli were efficiently phagocytosed in hepatic macrophages of SR-BI and BII transgenic mice; phagocytosis was more prominent in SR-BII transgenic mice. Finally, human SR-BI overexpression reduced systemic HDL-C level, eliminated adrenal cortex lipid droplets, and dampened the systemic increase of corticosterone after CLP. Supplementation with glucocorticoid and mineralocorticoid improved survival in SR-BI, but not SR-BII, transgenic mice after CLP. In summary, our findings suggest human SR-BI and BII overexpression contributes to higher mortality after CLP by excessive inflammatory response due to adrenal insufficiency (SR-BI) or hyperactive phagocytosis (SR-BII) in the liver.

Functional capacity, muscle strength, and patient-reported outcome measures are important indicators of health. In chronic obstructive pulmonary disease (COPD), these traits are often impaired beyond normal age-related decline. Substantial variability exists in both COPD and healthy populations, the biological basis of which remains poorly understood. Given the known contribution of genetics to complex traits, genetic factors may partly explain this variability. This study aimed to identify genetic variants associated with measures used to characterise extrapulmonary traits in COPD. Genome-wide association studies were conducted on the Lab3R-ESSUA cohort for the 6-minute walk test (6MWT), the 1-minute sit-to-stand test (1-min STS), the quadriceps maximal voluntary contraction (QMVC), the handgrip muscle strength, and the chronic airways assessment test (CAAT), adjusting for age, sex, body mass index, pack-years and ancestry. Variants with P<1E-05 were selected for replication in the EARLYCOPD cohort, and effects compared between COPD and healthy populations (two-way ANOVA). A total of 639 participants (364 people with COPD, 275 healthy; 75% male, median age 67 years; BMI of 27 Kg/m2; 10 pack-years) were included. Significant variants were identified for the 6MWT (rs1108983:G, {beta}=-186.5m, P=4.8E-08), the 1-min STS (rs5889103:GTT, {beta}=4.2reps, P=4.8E-08), the Handgrip (rs67352743:A, {beta}=-4.4Kg, P=2.8E-08), and for the CAAT (rs11747040:C, {beta}=4.4points, P=4.0E-09; rs11041680:A, {beta}=-2.6points, P=2.5E-08). Effects were independent of COPD diagnosis. Replication in EARLYCOPD (n=282) confirmed one SNP for 6MWT and three for CAAT. These findings highlight genetic contributions to functional capacity, muscle strength, and disease burden. COPD-related impairments appear to build on pre-existing genetic predisposition, contributing to disease heterogeneity.

Background Acute respiratory distress syndrome (ARDS) is characterised by substantial physiological heterogeneity, which contribute to a very variable clinical outcomes and therefore inconsistent responses to ventilatory strategies. We aimed to externally validate physiological ARDS subphenotypes previously identified using routine ventilatory and gas-exchange variables, assess their prognostic relevance across independent cohorts, and examine heterogeneity of treatment effect according to PEEP strategy. Methods Unsupervised Gaussian Mixture Modelling was used to identify physiological subphenotypes based on ventilatory mechanics and gas-exchange parameters. Labels were subsequently used to train and validate supervised classifiers using XGBoost. Prognostic relevance was assessed across three independent cohorts, including two randomised controlled trials (ALVEOLI and LOVS). Predictive enrichment for PEEP strategy was evaluated using individual patient data from ALVEOLI and LOVS (n = 1,532) using intention-to-treat analyses, applying both one-stage and two-stage fixed-effects IPD meta-analytic approaches to test for interaction between physiological subphenotype and PEEP strategy. Results Two distinct physiological subphenotypes, termed Efficient and Restrictive, were replicated across independent cohorts. Across each cohort, patients classified as Restrictive consistently exhibited higher all-cause 28-day mortality compared to Efficient patients. When pooled across studies, the Restrictive subphenotype was associated with a significantly increased risk of death (pooled odds ratio 1.75, 95% CI 1.36-2.24), with no evidence of between-study heterogeneity. Predictive analyses showed a statistically significant interaction between physiological subphenotype and PEEP strategy in the one-stage IPD model (p for interaction = 0.037), with concordant findings in the two-stage fixed-effects IPD meta-analysis (interaction OR 1.91, 95% CI 1.00-3.66; I2 = 0%). Higher PEEP was associated with increased mortality in Efficient patients and reduced mortality in Restrictive patients, indicating effect modification by physiological subphenotype. Interpretation Physiological ARDS subphenotypes derived from routinely collected bedside data provide robust and externally validated prognostic stratification across observational and randomised trial cohorts. The observed interaction with PEEP strategy suggests that underlying physiological profiles may influence treatment response, supporting the concept that physiology-based be a starting point for personalized medicine and therefore better ventilatory strategies in future clinical trials.

ObjectiveTo develop and validate a predictive model incorporating behavioral telemetry signals--documentation pattern anomalies derived from routine EHR charting--alongside clinical variables for ICU mortality prediction in patients with low acute physiologic derangement. Materials and MethodsRetrospective cohort study of 46,002 adult ICU stays from MIMIC-IV v3.1 (2008-2022) with SOFA scores 0-2, excluding neurological units. We extracted 66 variables spanning demographics, acuity, behavioral telemetry, clinical enrichment, and temporal factors. Progressive logistic regression models (M1-M7) were compared using cross-validation, DeLong tests, net reclassification improvement, and calibration analysis. ResultsOverall mortality was 9.34% (4,295 deaths). The clinical model (M5) achieved cross-validated AUROC 0.691 versus 0.639 for demographics alone (M2; {Delta}AUROC = 0.052, DeLong p = 4.41x10-47). NRI was 24.3%. Discordant care patients received 30.5% more chart events than concordant patients, with the sole deficit in neurological assessments (-15.4%), refuting the neglect hypothesis. Kaplan-Meier analysis confirmed survival separation (log-rank {chi}2 = 138.6, p = 5.32x10-32). In the most conservative subgroup (SOFA 0, no sedation, no ventilation, N = 11,158), orientation omission remained associated with mortality (adjusted OR 1.52, p = 0.027). DiscussionDeep sedation and mechanical ventilation function as mediators on the causal pathway rather than traditional confounders; the discordant care signal retains significance after full sedation adjustment. ConclusionDocumentation pattern analysis adds measurable predictive value for ICU mortality risk stratification and represents a novel signal for real-time EHR-based clinical decision support.

PurposeSepsis-associated immunothrombosis significantly contributes to high mortality, yet the role of N-glycosylation in this process remains poorly understood. This study aimed to comprehensively profile the plasma N-glycosylation landscape in sepsis and elucidate how its specific reprogramming in the complement and coagulation cascades influences immunothrombotic balance and patient outcomes. MethodsWe performed in-depth 4D-DIA proteomic and N-glycomic analyses on plasma from 43 sepsis patients and 9 healthy controls. Differential expression, weighted gene co-expression network analysis (WGCNA), and protein-glycosylation correlation analyses were used to characterize molecular features. Clinical relevance was assessed via correlation and survival analyses. ResultsExtensive N-glycosylation reprogramming was observed in sepsis plasma,with marked enrichment in complement and coagulation pathways(KEGG p=7.76x10- {superscript 2}{superscript 1}).Pro-coagulant proteins(eg,vWF,fibrinogen)showed increased abundance together with enhanced site-specific glycosylation,potentially amplifying their activity.In contrast,key anticoagulant proteins(eg,SERPINC1)displayed unchanged glycosylation at critical sites despite abundance changes,which may impair function.Survival analysis revealed distinct prognostic values of glycoproteins and specific glycosylation sites.For instance,high vWF protein levels predicted mortality(HR=2.83),whereas elevated glycosylation at vWF N211 was associated with improved survival(HR=0.135),suggesting a negative regulatory role.These glycosylation markers correlated closely with disease severity and prognosis,representing potential early-warning biomarkers independent of current clinical coagulation indicators. ConclusionOur study demonstrates widespread reprogramming of the plasma proteome and N-glycome in sepsis.We propose that decoupling of protein function from abundance through N-glycosylation in the complement-coagulation network contributes to immunothrombotic imbalance.Specific N-glycosylation sites may serve as novel prognostic biomarkers,offering new perspectives for early risk stratification and glycosylation-targeted therapies in sepsis. Key PointsO_LISepsis plasma exhibits specific N-glycosylation reprogramming overwhelmingly focused on the complement and coagulation cascade. C_LIO_LIA dominant "glycosylation-dominated co-upregulation" mode in procoagulant factors, coupled with a "silent" glycosylation state in key anticoagulants, drives prothrombotic imbalance. C_LIO_LISite-specific N-glycosylation levels provide prognostic information distinct from, and often superior to, their carrier protein abundance, offering novel early-risk biomarkers. C_LI

RationaleSevere SARS-CoV-2 infection induces disrupted oropharyngeal and gut microbiota during acute disease which may persist and contribute to the development of post-acute pulmonary sequelae. To date, it is unclear whether dysbiosis following severe disease is linked to long-term pulmonary function impairment. ObjectivesTo determine associations between oropharyngeal and gut microbiota composition with lung function after severe COVID-19. Methods16S and internal transcribed spacer (ITS) rRNA amplicon sequencing were performed on oropharyngeal (16S and ITS) and rectal (16S) swabs at 3-, 6- and 12-months post-hospitalisation from 83 subjects previously admitted to the ICU with severe COVID-19 (Swiss COVIDlung study, NCT04581135). Subjects underwent 1-3 follow-up visits during which lung function testing was performed to investigate associations with microbiota composition. Measurements and Main ResultsThe oropharyngeal microbiota of subjects having suffered from COVID-19-related-severe acute non-cardiogenic hypoxemic respiratory failure with bilateral lung infiltrates (AHRF-BLI) was characterized by decreased -diversity and the presence of differentially abundant taxa. Subjects who recovered in lung function (TLC, FVC, FEV1 and DLCO >Lower Limit of Normal) had a distinct oropharyngeal and gut microbiota composition compared to those whose lung function never recovered. Fungal analysis of oropharyngeal samples revealed the presence of three distinct clusters which were characterized by distinct lung-function associated bacterial-fungal co-occurrence. ConclusionsThis study provide first insights into the role of the airway and gut microbiota in the development of long-term pulmonary sequelae after severe SARS-CoV-2 infection, shedding the light on the potential of the microbiota for preventive and therapeutic strategies in severe COVID-19.

BackgroundPatients with acute respiratory failure requiring non-invasive respiratory support are at high risk of deterioration. Different advanced monitoring instruments are available that can provide objective measurements. However, there is currently no evidence synthesis on these instruments. The aim of this project is to systematically synthetise data identifying the advanced monitoring instruments used and their effectiveness. MethodsWe conducted a systematic search of MEDLINE (via Pubmed), EMBASE, Web of Science, Cochrane Library and CINAHL (PROSPERO registration: CRD42024597047). We included studies with acute respiratory failure patients requiring non-invasive respiratory support where the investigators used advanced monitoring instrument during hospital stay. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. ResultsSeventy-eight studies including 3709 patients fulfilled the selection criteria. The monitoring instruments used were respiratory muscle ultrasound in 32% (n= 25/78), oesophageal manometry in 32% (n= 25/78), electrical impedance tomography in 24% (n= 19/78), electrical activity of the diaphragm (Eadi) catheter in 18% (n= 14/78) and surface EMG of parasternal muscle in 6% (n= 5/78). Thirteen studies (17%) used a multi-modal monitoring approach. Patients failing non-invasive respiratory support showed higher oesophageal pressure ({Delta}Pes) [MD 12.60 (95% CI 4.03;21.16), p=0.004], lung ultrasound score (LUS) [MD 3.93 (95% CI 1.29,6.570), p=0.003] and parasternal intercostal thickening fraction (PIC-TF%) [MD 12.58 (95% CI 8.02,17.13), p<0.001] but lower diaphragmatic thickening fraction (DTF%) [MD - 17.20 (95% CI -20.97,-13.42); p<0.001] and lower diaphragmatic excursion (DE) [MD - 0.95 (95% CI -1.08,-0.82); p<0.001. ConclusionAdvanced monitoring instruments may detect patient failing non-invasive respiratory support. Take home messageAdvanced bedside monitoring during non-invasive respiratory support can provide unique physiological insights into respiratory muscle workload and treatment response in acute respiratory failure. Our meta-analysis shows that five measurements: i) oesophageal pressure changes ({Delta}Pes), ii) lung ultrasound score (LUS), iii) parasternal intercostal thickening fraction (PIC-TF%), iv) diaphragmatic thickening fraction (DTF%) and v) diaphragmatic excursion (DE) may discriminate patients who are responders from non-responders to non-invasive respiratory support.

BackgroundEarly lactate is widely used to risk-stratify septic shock, yet clinically actionable cut-offs for 28-day mortality remain uncertain. MethodsIn a single-centre study conducted across two intensive care units, we analysed 84 adults with septic shock identified within 24 hours of intensive care unit admission. The primary endpoint was 28-day mortality. Four lactate metrics obtained during the first 24 hours were evaluated: first (admission) lactate, last lactate, peak lactate, and lactate clearance from first to last. Associations were tested using logistic regression with and without adjustment for the Simplified Acute Physiology Score 3; discrimination was assessed by area under the receiver-operating characteristic curve (AUROC), and optimal cut-offs were defined by the Youden index. ResultsThirty-nine of 84 patients (46.4%) died by day 28. Higher absolute lactate values were independently associated with death (adjusted odds ratio (OR) per 1 mmol/L increase: First 1.47, p<0.001; Last 1.41, p=0.002; Peak 1.39, p<0.001), whereas Lactate clearance was not (OR 0.65, p=0.202). Discrimination was moderate to good for peak (AUROC 0.817), first (0.791), and last (0.757) lactate, and poor for clearance (0.577). Youden-derived thresholds provided pragmatic trade-offs: First 3.55 mmol/L (sensitivity 0.821, specificity 0.689), Last 3.15 mmol/L (0.567, 0.864), and Peak 3.55 mmol/L (0.973, 0.556). Kaplan-Meier curves using these cut-offs showed early and sustained separation. ConclusionsIn adults with septic shock, simple early lactate thresholds around 3.3- 3.6 mmol/L (first/peak) and approximately 3.15 mmol/L (last) identify 28-day mortality risk and outperform lactate clearance.

IntroductionCardiopulmonary exercise testing (CPET) quantifies exercise limitation and helps differentiate cardiovascular dysfunction from deconditioning in patients with exertional dyspnoea. In mild pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), traditional CPET oxygen delivery parameters may not adequately distinguish cardiac limitation. We evaluated whether oxygen pulse (O2 pulse) kinetics and the ratio of ventilation-carbon dioxide slope to peak oxygen uptake (VEVCO2/peakVO2) improve identification of cardiovascular limitation and prognostication. MethodsWe retrospectively analysed 289 consecutive patients referred for CPET. Patients were categorised into pre-capillary PH, no PH, or "unclassified" PH based on haemodynamics. O2 pulse slopes were calculated across exercise phases, and qualitative curve patterns were classified. VEVCO2/peakVO2 was derived from standard CPET parameters. Logistic regression assessed predictors of cardiac dysfunction (peak O2 pulse <65% predicted). Survival was evaluated using Kaplan-Meier and Cox regression analyses. ResultsPre-capillary PH patients demonstrated more impaired aerobic capacity and ventilatory efficiency than those without PH. Abnormal O2 pulse patterns (early plateauing or down-sloping) were associated with shallower slopes, lower peak O2 pulse, and greater chronotropic index. A work-phase O2 pulse slope < 0.40 identified impaired oxygen delivery but was not independently predictive in multivariable analysis. VEVCO2/peakVO2 independently predicted cardiac dysfunction (OR 3.9 [2.6-6.2], p < 0.001) and showed strong discrimination (AUC 0.83). VEVCO2/peakVO2 [&ge;] 2.7 independently predicted mortality (HR 13.6, 95% CI 3.8-48.5, p<0.001) outperforming peak O2 pulse and VE/VCO2 slope. ConclusionO2 pulse kinetics, particularly a work-phase slope < 0.40 and plateauing or decreasing trajectories, are associated with cardiac dysfunction in patients with pre-capillary PH. VEVCO2/peakVO2 appears to be a marker of cardiovascular limitation and mortality and may aid differentiation between cardiac dysfunction and deconditioning in this population when conventional CPET parameters are inconclusive.

BackgroundPatent ductus arteriosus (PDA) is a common and potentially serious cardiovascular condition in preterm infants, particularly those with low gestational age and birth weight. Its management remains controversial due to variability in screening, diagnostic criteria, and treatment strategies. This study aimed to evaluate risk factors, outcomes, and management strategies for PDA in preterm infants, and to identify predictors of clinical and echocardiographic response to therapy. MethodsWe conducted a retrospective cohort study over a 4-year period (2016-2019) in the neonatal intensive care unit (NICU) of a tertiary care center. All consecutive preterm infants admitted during the study period were eligible. Infants with echocardiographically confirmed PDA who received pharmacological treatment with intravenous paracetamol or ibuprofen were included in the analysis. Missing data were minimal and handled using available-case analysis. Statistical analyses included descriptive statistics, Pearsons chi-square test, and multivariable logistic regression. ResultsAmong 2154 preterm infants admitted to the NICU, 60 were diagnosed with PDA (incidence : 2.8%). The mean gestational age was 29 {+/-} 2.6 weeks, and the median birth weight was 1200 g. Respiratory distress occurred in 95% of cases, mainly due to hyaline membrane disease (86.7%). PDA was symptomatic in 80% of infants. First-line treatment resulted in clinical improvement in 77% and ductal closure in 83.3% of cases, most within 3 days. Predictors of successful closure included gestational age [&ge;] 28 weeks (OR = 5.9; 95% CI : 1.7-20.2) and antenatal corticosteroid exposure (OR = 1.2; 95% CI : 1.0-1.6). Overall mortality was 35% and was significantly higher in infants < 28 weeks (OR = 5.0; 95% CI : 2.4-10.3). Clinical improvement (OR = 3.7) and echocardiographic closure (OR = 4.5) after first-line treatment were associated with reduced mortality. ConclusionsPDA in preterm infants is associated with substantial morbidity and mortality, particularly in those born before 28 weeks of gestation. Early diagnosis, antenatal corticosteroid exposure, and timely pharmacological treatment may improve outcomes. Systematic echocardiographic screening in high-risk neonates should be considered.

RationaleAutonomic dysfunction is a hallmark of sepsis pathophysiology, yet its quantification remains challenging. Multiscale entropy (MSE) derived from heart rate variability (HRV) offers a dynamic measure of physiological complexity and may serve as a biomarker of early deterioration associated with subsequent organ failure, vasopressor escalation, or mortality. ObjectiveTo determine whether MSE computed across multiple temporal scales during the first 24 hours of Intensive Care Unit (ICU) admission is associated with short-term mortality and longer-term organ dysfunction in patients with sepsis, and whether these relationships vary across vasopressor exposure. Unlike prior studies that focused on short-term HRV metrics, we applied MSE across multiple temporal scales and incorporated these features into machine learning models to evaluate their prognostic utility in septic shock. MethodsThis retrospective cohort study included adult ICU sepsis patients at Emory University Hospital from January 2016 to December 2019. Of 2,076 eligible patients, 958 were propensity matched into two cohorts: fluids-only and fluids-plus-vasopressor, with norepinephrine as the primary vasopressor. High-resolution electrocardiogram (ECG) waveforms were analyzed to compute MSE across 20 temporal scales. Machine learning models using (1) MSE features alone and (2) MSE combined with demographic and vital sign data (MSE-DV) were compared against traditional HRV measures based model and severity of illness scores for predicting outcomes. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC), with a primary outcome of mortality at day 7 and secondary outcome of persistent organ dysfunction at day 28. ResultsIn the fluids-plus-vasopressor cohort, MSE-based models demonstrated superior predictive performance for 7-day mortality (AUROC 0.84) compared to severity of illness scores (AUROC 0.64). MSE-DV models also predicted organ dysfunction including 28-day renal (AUROC 0.75), neurological (AUROC 0.79), and respiratory (AUROC 0.71) dysfunction. Patients receiving second-line and third-line vasopressors and corticosteroids exhibited progressively lower MSE values, particularly at mid-range and long-range scales. ConclusionMSE features in the first 24 hours of ICU stay predict mortality and organ dysfunction with higher discrimination than traditional severity of illness scores. Future work should validate these findings, assess longitudinal MSE trends, and race-specific autonomic patterns to refine predictive models.

ObjectiveTo systematically review and characterize methodological heterogeneity in sepsis case detection using the MIMIC-III and eICU-CRD databases. Materials and MethodsWe conducted a PRISMA-guided systematic review of PubMed and Web of Science (publication years 2016-2024). We extracted methodological details on sepsis case detection across six domains: parameter coverage, temporal windows, aggregation methods, missing-data handling, SOFA calculation, and infection detection methods. For studies with available source code, we additionally examined code structure and repository dependencies to identify methodological decisions across these domains. ResultsOf 396 publications screened, 64 met the inclusion criteria and 12 provided available source code. Sepsis detection rates ranged from 3.4% to 65.2% in MIMIC-III and from 9.8% to 47.9% in eICU-CRD. Substantial variability persisted among studies using identical cohort definitions within both databases (MIMIC-III: 16.9%-42.2%; eICU-CRD: 13.9%-31.4%). The overall proportion of studies reporting methodological details varied by domain: SOFA calculation (53.1%), infection detection methods (42.2%), temporal windows (37.5%), aggregation methods (26.6%) and missing-data handling (17.2%). Source code analysis identified 321 implementation decisions, revealing heterogeneity in baseline SOFA definitions (SOFA=0 vs dynamic baseline), temporal windows (infection-centered vs ICU-admission-centered) and infection detection methods (antibiotic-culture matching vs APACHE-based diagnosis). Dependencies among several MIMIC-III repositories suggested propagation of implementation decisions across studies. DiscussionClinically validated sepsis definitions yield substantially different detection rates across studies using identical datasets, indicating heterogeneity in computational implementation. ConclusionTo improve reproducibility in sepsis research and the robustness of sepsis prediction models, we recommend standardized reporting of sepsis case detection methodology and the publication of version-controlled source code.

BackgroundThe cardiovascular (CV) benefit of CPAP in OSA remains debated and its effects on new OSA-related CV risk markers are unclear. We aimed to quantify short-term CPAP effects on these markers along with vascular and autonomic phenotypes. MethodsIn a 2-week withdrawal study, patients on long-standing effective CPAP took part in three visits (V1-V3: on/off/back-on CPAP) with overnight polygraphy followed by vascular and autonomic phenotyping. Co-primary endpoints included endothelial function assessed by flow-mediated dilation (FMD) and baroreflex sensitivity (BRS), hypoxic burden (HB), pulse wave amplitude drop index (PWADi) and spontaneous-PWADi (excl. apnoea-triggered drops), and event-related heart-rate response ({Delta}HR). Between-visit differences were tested in adjusted mixed models, with visit or within-participant changes in AHI/HB as fixed effects. ResultsIn 42 participants (61{+/-}10 years, 83% male), CPAP withdrawal reinstated OSA (medians [IQR] V1 to V3: AHI 3.9[1.5, 8.8] to 33.4[19.5, 42.1] to 4.0[2.0, 8.8] events/h, HB 4.3[1.1, 8.7] to 51.3[19.7, 83.7] to 2.0[1.2, 6.5] %{middle dot}min/h, p<0.001) and increased total PWADi (mean{+/-}SD 42.25{+/-}18.73 to 50.22{+/-}17.77 to 41.29{+/-}17.14 drops/h, p<0.001), while spontaneous PWADi decreased as respiratory-events recurred (-1.17 drops/h per 10 events/h, p=0.015) along with FMD (3.7{+/-}1.9% to 3.2{+/-}2.5% to 4.2{+/-}2.7%, V2 vs V3 p=0.047). {Delta}HR and BRS were stable across visits. ConclusionShort-term CPAP re-initiation improved endothelial function (FMD), with no significant effects on autonomic measures (BRS, {Delta}HR) or structural vascular indices. This supports a temporal dissociation between rapidly reversible exposure metrics (AHI, HB) and slower dynamics of autonomic markers. Changes in spontaneous PWADi suggests that it may track physiological CPAP benefits beyond indices driven primarily by respiratory-event frequency.