Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) requiring invasive mechanical ventilation (IMV) are associated with high mortality and long-term disability. Extracorporeal CO₂ removal (ECCO₂R) using modern high-capacity devices may facilitate early endotracheal extubation and reduce IMV-related complications. To evaluate whether ECCO2R-facilitated early extubation improves clinical outcomes compared with standard IMV in patients with severe AE-COPD requiring IMV. Adults with acute hypercapnic respiratory failure due to AE-COPD requiring IMV who failed or were ineligible for extubation within 24 hours of intubation were randomized to ECCO2R or no ECCO2R. The primary endpoint was a composite of death or severe disability at day 60. 18 patients were randomized before the trial was terminated early by the sponsor for financial reasons (planned enrollment: 192). The primary composite endpoint occurred in 0/8 ECCO2R-treated patients versus 3/9 evaluable IMV-treated patients (33
There is a notorious difficulty in judging micronutrient stores and requirements in critically ill patients and deficiency states will be rarely associated with clinical symptoms. A fundamental exception is vitamin B1, thiamine, a micronutrient of crucial importance in mitochondrial energy production. With thiamine deficiency ”the energy plug is out”, resulting in multiple organ dysfunctions, such as of brain, heart, kidney or respiratory system, lactate formation is increased, lactate clearance reduced, all fundamentally affecting the course of disease and prognosis of a patient. Several patient groups, such as malnourished subjects or patients with liver or kidney disease are already deficient prior to hospital or ICU admission, but there is also a high risk of developing deficiency during ICU stay. There are several well defined patient groups at risk, however, there is no need to measure plasma concentrations, as assays are mostly not available, costly and actually do not reflect the cellular status. There is quite solid evidence that thiamine may preserve / improve organ function (brain, heart, kidney), reduce blood lactate concentration and reduce mortality in various groups of critically ill patient. An extra thiamine supplementation should be given in high-risk patient groups, which bears no risk of inducing toxicity and is cheap, so we advocate to administer thiamine whenever a deficiency state is suspected.
Continuous monitoring of inspiratory effort during assisted mechanical ventilation remains challenging, yet it is vital as the transition from controlled to assisted mechanical ventilation requires careful titration of inspiratory effort to ensure patient safety. The Mixed Integer Multi-Effort (MIME) method is a physiological modeling approach that uses standard ventilator signals to non-invasively estimate inspiratory muscle pressure (Pmus). We evaluated the accuracy of MIME during pressure support ventilation (PSV) in patients with acute hypoxemic respiratory failure (AHRF). We conducted a prospective physiological validation study in adult patients with AHRF within 48 h of their first transition from controlled mechanical ventilation to PSV. Airway and esophageal pressure, flow, and volume, were recorded and analyzed offline with the MIME algorithm, which estimates Pmus by reconstructing airway pressure and separating ventilator-delivered from patient-generated pressure using a respiratory mechanics-based model. MIME-derived Pmus estimates were compared with esophageal pressure-derived Pmus using Bland–Altman analysis with mixed-effects modeling to account for repeated measurements within patients. Receiver operating characteristic analysis was used to evaluate MIME’s ability to detect high and low inspiratory effort and to compare its performance with end-expiratory occlusion pressure (ΔPocc). Sixty-two independent model-fitting windows (1240 breaths) from 18 patients were analyzed. Median inspiratory Pmus was 7.5 (IQR 6.0–9.1) cmH₂O for MIME-derived estimates and 6.9 (5.9–8.9) cmH₂O for esophageal pressure-derived measurements. Breath-by-breath analysis demonstrated a mean difference of 0.4 cmH₂O with limits of agreement ranging from − 3.4 to 4.2 cmH₂O. Agreement between methods improved when inspiratory effort was averaged over multiple breaths. Averaged values within each analyzed recording set showed a mean difference of 0.4 cmH₂O with limits of agreement ranging from − 2.2 to 3.0 cmH₂O. MIME demonstrated good discriminative performance in detecting both high and low inspiratory effort (AUROC 0.83 and 0.88, respectively). Compared with ΔPocc, MIME showed similar performance for detecting low inspiratory effort, whereas ΔPocc performed better for detecting high inspiratory effort. The MIME method provided non-invasive estimates of inspiratory effort during pressure support ventilation and may complement established physiological tools such as ΔPocc by supporting longitudinal assessment. Validation in broader populations and physiological settings, together with dedicated assessment of convergence and computational performance, is required before real-time bedside implementation.
The capillary refill test is a widely used bedside marker of tissue perfusion, but its reliability during acute inflammation is not well characterised. The guiding 3-s threshold rests on limited physiological validation and on visual assessment with high observer variability. How finger capillary refill time (CRT) behaves during acute inflammation remains unclear. Using quantitative capillary refill time (qCRT), which removes observer variability, we determined how finger qCRT behaves over an acute inflammatory episode in a controlled human endotoxemia model. In a double-blind, randomized, crossover study, 25 healthy volunteers received an intravenous bolus of Escherichia coli lipopolysaccharide (0.8 ng/kg) or saline placebo. Finger qCRT was measured by polarized reflectance imaging at baseline and 1.5, 3.5, and 5 h, and analysed with censored (Tobit) mixed-effects models adjusting for physiological covariates. Finger qCRT followed a biphasic course that crossed the 3-s clinical threshold in both directions within a single inflammatory episode. From a baseline near 3.5 s, it was prolonged to 8.31 s at 1.5 h, with 14 of 25 reaching the 10-s ceiling, then shortened to 1.27 s at 5 h during persisting systemic inflammation. Estimated marginal contrasts against placebo were 4.13 s and − 3.10 s at these time points (both p < 0.0001). The early prolongation persisted after adjustment for physiological covariates, whereas the late shortening was attenuated after adjustment for concurrent thermoregulatory and haemodynamic covariates. Skin temperature was the strongest qCRT covariate, with each standard-deviation increase associated with a 1.62 s decreased qCRT. No formal mediation analysis was performed. Resting values were highly variable, with between-subject differences explaining a minority of total variance (intraclass correlation 0.30). Finger qCRT tracks the course of acute systemic inflammation but crosses the 3-s clinical threshold in both directions within a single episode. Because between-subject differences account for a minority of total variance and resting values depend strongly on skin temperature, a single value against a fixed threshold is unreliable, whereas change over time within a participant is informative. These findings in healthy participants are not directly generalizable to septic shock and require confirmation in prospective patient studies before informing clinical practice. ClinicalTrials.gov NCT06618716. Registered September 27, 2024.
The effect of positive end-expiratory pressure (PEEP) on the injured brain is uncertain, and existing evidence is usually reduced to a single high-versus-low contrast. We quantified the dose–response relationship between PEEP and intracranial pressure (ICP), cerebral perfusion pressure (CPP) and brain-tissue oxygenation (PbtO₂) in adults with acute brain injury (ABI). We systematically searched MEDLINE, Embase, Scopus, Cochrane CENTRAL and Web of Science to 5 July 2026 (PRISMA 2020). Within-patient PEEP-titration studies formed a primary layer; between-patient and observational studies formed a separate secondary layer. Overlapping cohorts were resolved by a pre-specified anti-duplication rule. Study-clustered multilevel meta-regression with cluster-robust (CR2) variance estimated the slope of each outcome per cmH₂O of PEEP; restricted cubic splines tested non-linearity. Robustness was examined with a one-stage dose–response model reconstructing the within-study covariance, prediction intervals, leave-one-out, leave-cluster-out analyses, publication-bias tests and pre-specified effect modifiers. Certainty was rated with GRADE against pre-anchored minimal important differences (MID; ICP 2 mmHg, CPP 5 mmHg). Of 4471 records, 37 studies were included. In the primary layer (410 patients), ICP rose + 0.118 mmHg per cmH₂O (95
Mitochondrial dysfunction has been implicated in sepsis-related organ failure. We investigated whether plasma profiles of mitochondrial-associated proteins are associated with illness severity and short-term outcomes and explored whether they reveal distinct mitochondrial subphenotypes. In this post hoc analysis of the Acutelines data-biobank, we included 213 adult patients presenting to the emergency department with a suspicion of sepsis, with infection confirmed by independent adjudication. Blood plasma proteins of patients were quantified with the Olink Explore HT platform; of 5,416 proteins, 232 mitochondrial-associated proteins (MitoCarta3.0) were z-standardized and averaged per patient to derive a continuous mitochondrial-protein score. To explore whether operationally distinct patient groups could be identified along this gradient, we additionally performed principal component analysis with K-means clustering on the same protein set. Differential abundance analysis, pathway enrichment, and least absolute shrinkage and selection operator regression were performed as exploratory analyses. The continuous mitochondrial-associated protein score increased with illness severity (Spearman ρ 0.18–0.29; p < 0.01) and worse 72-hour outcomes (odds ratio per standard deviation: organ failure-free survival 0.57; intensive care unit admission 1.66; mortality 2.36). Exploratory clustering identified two groups differing mainly in overall mitochondrial-associated protein abundance. Considerable overlap and limited support for a discrete two-cluster structure suggested variation along a continuum rather than clearly distinct mitochondrial subphenotypes. Exploratory pathway analyses implicated mitochondrial metabolism, cellular stress, and injury-related processes. Higher plasma mitochondrial-associated protein abundance was associated with greater illness severity and worse short-term outcomes in suspected sepsis. These associations are hypothesis-generating, providing a first step toward understanding the role of mitochondrial dysfunction in sepsis severity.
To determine whether indirect calorimetry (IC)-guided nutritional prescriptions improve weaning success and time to liberation from prolonged mechanical ventilation (PMV) compared with predictive-equation-guided feeding. In this double-blind randomized controlled trial conducted at Reuth Tel-Aviv Rehabilitation Hospital (Nov 2019-Apr 2023), with 1-year follow-up, adults ventilated ≥ 21 days were randomized to receive IC-guided energy targets or predictive-equation-guided feeding. Primary outcomes were successful weaning (≥ 7 consecutive days of spontaneous breathing) and time to successful weaning. Secondary outcomes included number of weaning cycles and 1-year mortality. Metabolic/nutritional safety parameters were recorded. Analyses followed the intention-to-treat principle, with additional per-protocol analyses. Time-to-event outcomes were evaluated using Kaplan–Meier estimates and Cox proportional hazards models. Among 211 randomized patients (111 IC; 100 control), successful weaning was achieved in 58
In clinical practice, death determination—a core responsibility of critical care clinicians—is commonly taught as the technical application of standardized medical and legal criteria. However, contemporary practices, including resuscitation, death determination by neurological criteria, withdrawal of life-sustaining treatment, and controlled donation after circulatory determination of death, show that determining death also requires interpretative and performative, context-dependent clinical judgement operating within persistent scientific limits and implicit assumptions about human life and its end. Using a single illustrative clinical scenario followed across four trajectories—obvious death, cardiac arrest and resuscitation, death determined by neurological criteria, and circulatory death following withdrawal of life-sustaining treatment—we examine how death determination operates at the intersection of medical criteria, clinical judgement, scientific limits, and implicit assumptions. Particular uncertainties concern the relationships between circulation, cerebral perfusion, and brain function; the distinction between complete and partial loss of brain function; the distinction between permanent and irreversible loss; and the prediction of neurological recovery, acceptable functional outcome, and meaningful life. These uncertainties are managed differently across clinical contexts. Across these contexts, clinicians do not simply observe a discrete biological event: they interpret an evolving process of dying within established medical and legal frameworks. The declaration of death is therefore also performative, transforming the patient’s medical, legal, and social status. Death determination should not be understood or taught solely as the application of criteria and protocols. Making explicit in critical care education the scientific limits, implicit assumptions, and context-dependent clinical judgement involved in determining and declaring death may help clinicians better assume this responsibility, improve communication with families, and sustain public trust in end-of-life care and organ donation.
Sepsis remains a leading cause of morbidity and mortality in neonatal and pediatric intensive care units (NICU/PICU). Given the rapid clinical deterioration of these vulnerable populations, shifting from reactive diagnosis to proactive prediction of sepsis onset is crucial. Multidimensional hematological parameters may provide new insights for risk stratification. While routine complete blood count (CBC) is widely used, the predictive potential of high-dimensional hematological cell morphology features that extend beyond traditional CBC remains under-investigated in large-scale pediatric cohorts. This multicenter study utilized a large-scale dataset from the CALM2302 project, encompassing 17,066 critically ill neonates and children across 30 Chinese hospitals between October 2020 and October 2023. We developed population-specific CatBoost models for NICU and PICU to predict sepsis onset. To mitigate class imbalance, random undersampling was applied to the training sets. From a candidate pool of 1,924 parameters (37 routine CBC and 1,887 research features), optimized signatures of approximately 200 features were selected for each population. Model performance was evaluated by the area under the ROC curve (AUC) across internal and dual external validation cohorts. Furthermore, SHAP (SHapley Additive exPlanations) analysis was performed to ensure model interpretability and identify key biological predictors. Among the total cohort, 10,347 infants were categorized into the NICU cohort (sepsis incidence: 7.48
Open access intensive care unit (ICU) databases, including MIMIC-III, MIMIC-IV, the eICU Collaborative Research Database (eICU-CRD), AmsterdamUMCdb, HiRID-high time resolution ICU data set, and the Salzburg Intensive Care Database (SICdb), have fundamentally transformed critical care research over the past decade. Despite their widespread use, no comprehensive bibliometric analysis has systematically mapped the scientific output generated by studies relying on these resources. A structured search was conducted in PubMed and Web of Science covering 2018 to 2025, retrieving original articles citing at least one of six defined open access ICU databases in title or abstract. Database selection followed the methodology of two prior systematic reviews of publicly available adult ICU datasets. Structured fields covering database used, machine learning (ML) methods, study design, clinical outcomes, AUROC values and patient counts were extracted via a semi-automated AI pipeline (DeepSeek API, multi-label JSON schema). The extraction pipeline was validated against a manually coded reference sample of 110 publications. Bibliometric analyses used R (bibliometrix v4.0.1) and Python. Citation counts, open-access status and SCImago journal quartile were retrieved via OpenAlex and SCImago to characterise the visibility and venue quality of the corpus. Four network analyses were performed: database-to-ML-method co-occurrence, country-to-database, international collaboration, and clinical topic co-occurrence networks. A total of 4,648 publications were included. Annual publication counts increased 45-fold from 42 (2018) to 1,907 (2025), accelerating markedly after 2021 following the release of MIMIC-IV. MIMIC-IV dominated database attributions (54.6
Lung protective ventilation is crucial for preventing ventilator-induced lung injury in cardiac surgery. The protective role of a low tidal volume (VT) has been established, whereas the added protection afforded by lung recruitment remains uncertain. We investigated whether sigh breaths could provide additional lung protection, when added to protective ventilation with low VT. This randomized, assessor-blinded, phase 2 proof-of-concept trial enrolled 192 patients undergoing elective on-pump cardiac surgery from February to August 2024. Patients were randomly allocated in a 1:1 ratio to receive sigh ventilation (sigh breaths plus protective ventilation with low VT; 96 patients) or conventional ventilation (protective ventilation with low VT; 96 patients). Sigh breaths targeting a plateau pressure of 35 cmH2O (or 40 cmH2O for BMI >35 kg/m2) were delivered once every 6 min. Perioperative respiratory mechanics and gas exchange were monitored. The primary outcome was postoperative oxygenation, a marker of lung injury, as measured by the time-weighted average SpO2/FiO2 ratio during the first postextubation hour. There were 9 predefined secondary outcomes, including the severity of respiratory failure within postextubation day 7. All 192 patients completed the trial (53
Sepsis is associated with immunosuppression, predisposing patients to secondary infections. Many treatments routinely used for infections have immunomodulatory effects, including antibiotics. We therefore assessed the immunomodulatory effects of beta-lactam antibiotics on monocyte and lymphocyte immunophenotype. Peripheral blood mononuclear cells isolated from Emergency Department patients with bacterial infection were incubated with narrow-spectrum (amoxicillin and cefuroxime) or broad-spectrum (piperacillin-Tazobactam and meropenem) beta-lactam antibiotics at low and high concentrations. We compared the effects of antibiotics with and without an additional stimulus, LPS for 24 h or anti-CD3/CD28 beads for 72 h to evaluate the effect on monocyte and lymphocyte phenotype respectively. Using spectral flow cytometry, we evaluated functional markers associated with immune activation and reproducible phenotypes consistent with sepsis-induced immunosuppression. Beta-lactams, at higher-dose, were associated with increased monocyte CCR2 and decreased CD14 expression. Cefuroxime, meropenem and piperacillin had additional effects, causing a reduced monocyte HLA-DR, NOX-2, CLIP, and NF-κB expression with increased CD80. Beta-lactam exposure was associated with increased CD4+ lymphocyte viability, whilst amoxicillin had additional effects including reduced PD-1 expression and proliferation, and increased IL-7R expression. Changes to immune cell phenotype were minimal in CD8+ lymphocytes, at lower antibiotic doses, or in unstimulated cells. Beta-lactam antibiotics have immunomodulatory effects in vitro, including changes consistent with sepsis-induced immunosuppression at clinically relevant doses. Further work is required to determine the mechanisms underpinning these observations and clinical implications, which may have significant clinical implications on the type and duration of antibiotics administered, and highlight the need for therapeutic antibiotic monitoring.
Hypoalbuminemia is highly prevalent in critically ill children and is an established independent risk factor for mortality. Whether albumin supplementation is associated with improved survival remains unclear, particularly in pediatric populations where causal evidence is sparse. This retrospective cohort study used data from the Pediatric Intensive Care (PIC) database, a single-center pediatric-specific critical care database in China, and adopted a target trial emulation (TTE) framework. Children whose first albumin measurement within 24 h of ICU admission was below 30 g/L were included (N = 1,649). Time zero was defined as the first detection of albumin below 30 g/L. The exposure was receipt of at least one dose of human albumin within 24 h after time zero. Primary outcomes were 7-day and 28-day all-cause mortality, estimated using IPTW-weighted Cox proportional hazards models with doubly robust adjustment. Sensitivity to unmeasured confounding was assessed by E-value. Among 1,649 children, 374 (22.7
