Intensive Care Medicine Experimental最新文献

Background: Histones released in response to cellular injury are important mediators of organ failure and death in sepsis. Preclinical studies demonstrate that neutralization of histones in sepsis is associated with improved outcome. M6229 is a low-anticoagulant heparin able to neutralize histones. We aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of M6229 in critically ill patients with sepsis.

Methods: This was a first-in-human, phase I, monocenter trial in patients with sepsis admitted to the intensive care unit (ICU). Patients received a single 6 h intravenous infusion of M6229. A modified continual reassessment method (mCRM) with escalation overdose control was used for dose-escalation. The model was based on the probability of activated partial thromboplastin time (aPTT) being above 90 s (i.e., dose limiting pharmacologic event, DLPE). Three cohorts were studied (1: 0.15 mg/kg/h; 2: 0.45 mg/kg/h; 3: 0.90 mg/kg/h).

Results: Ten patients were included. The aPTT increased proportionally with increasing dosages of M6229 and decreased rapidly after infusion cessation. One DLPE occurred (aPTT of 100 s). Based on the mCRM model and data safety monitoring board recommendations, the maximum tolerated dose was defined as 0.9 mg/kg/h for a 6 h infusion of M6229. No serious adverse events were related to study drug infusion. An increase in QTc was probably related to infusion in one patient. M6229 showed close to dose-proportional pharmacokinetics. Total histone H3 and H2b plasma levels increased during and/or in the hours after M6229 infusion in all patients. In four out of five patients with plasma samples positive for histone H3, proteolytic cleavage was observed after infusion start. A decrease in sequential organ failure assessment score was observed in the days after infusion in 70% of patients.

Conclusions: M6229 was deemed safe to use in critically ill sepsis patients. Our results suggest intravascular neutralization of histones by M6229. Future clinical studies need to confirm our findings and the efficacy of M6229.

Background: Artificial intelligence (AI) has emerged as a promising tool for decision support in managing acute respiratory failure, yet its real-world clinical impact remains unclear. This scoping review identifies clinically validated AI-driven tools in this domain, focusing on the reporting of key evaluation quality measures that are a prerequisite for broader deployment.

Eligibility criteria: Studies were included if they compared a clinical, human factors, or health systems-related outcome of an AI-driven intervention to a control group in adult patients with acute respiratory failure. Studies were excluded if they lacked a machine learning model, compared models trained on the same dataset, assessed only model performance, or evaluated models in simulated settings. A systematic literature search was conducted in PubMed, CINAHL, and EmBase, from inception until January 2025. Each abstract was independently screened by two reviewers. One reviewer extracted data and performed quality assessment, following the DECIDE-AI framework for early-stage clinical evaluation of AI-based decision support systems.

Results: Of 5,987 citations, six studies met eligibility. The studies, conducted between 2012 and 2024 in Taiwan, Italy, and the U.S., included 40-2,536 patients. Four studies (67%) focused on predicting weaning from mechanical ventilation. Three (50%) of the studies demonstrated a statistically significant and clinically meaningful outcome. Studies met a median of 3.5 (IQR: 2.25-6.25) of the 17 DECIDE-AI criteria. None reported AI-related errors, malfunctions, or algorithmic fairness considerations. Only one study (17%) described user characteristics and adherence, while two (33%) assessed human-computer agreement and usability.

Conclusions: Our review identified six studies evaluating AI-driven decision support tools for acute respiratory failure, with most focusing on predicting weaning from mechanical ventilation. However, methodological rigor for early clinical evaluation was inconsistent, with studies meeting few of the DECIDE-AI criteria. Notably, critical aspects such as error reporting, algorithmic fairness, and user adherence were largely unaddressed. Further high-quality assessments of reliability, usability, and real-world implementation are essential to realize the potential of these tools to transform patient care.

Background: Acute respiratory distress syndrome (ARDS) is characterised by significant morphological heterogeneity. Morphological sub-phenotyping can potentially be used to personalise mechanical ventilation. Current methods to classify lung injury as focal or diffuse rely on subjective image interpretation, which risks misclassification and suboptimal treatment. This study aimed to investigate the morphological appearance features of lung injury objectively. The focal index, an objective quantitative tool, was introduced to assess focality in lung injury.

Methods: In this single-centre retrospective study, we included lung computed tomography (CT) scans from COVID-19 ARDS patients on invasive mechanical ventilation, classified as diffuse lung injury. CT data were analysed to extract regional Hounsfield Unit (HU) profiles across nine predefined lung areas. The focal index was derived by quantifying the non-overlapping area under HU distribution curves between the apical ventral and diaphragmatic dorsal regions. Correlations with lung weight, gas volume, and ventilatory settings were assessed. For validation, at least two experienced ICU consultants assessed the same images and determined whether ARDS was of a diffuse or focal type. The experts classified 36 out of 37 patients as diffuse ARDS, with substantial interobserver agreement (k = 0.65, 95% CI 0.02-1.00).

Results: The focal index demonstrated a wide range (25-175; mean 95.5 ± standard deviation 42.8), correlating significantly with the dorsal diaphragmatic non-aerated area (r = 0.67, p < 0.01) and with total gas volume (r = - 0.36, p = 0.03). There was no significant influence of ventilatory settings on the focal index.

Conclusions: The analysis suggested diffuse lung injury includes a spectrum of focality rather than a binary classification. The focal index provides an objective method to quantify the focality of lung injury in ARDS. Further studies are needed to validate the focal index across diverse ARDS aetiologies and establish its clinical application threshold for guiding personalised ventilation strategies.

Background: In murine models, controversial data have been reported on the effect of hydrogen sulfide (H₂S) administration during resuscitation from trauma-and-hemorrhage. The H₂S donor sodium thiosulfate (Na₂S₂O₃) is a recognized drug devoid of major side effects, and, hence, we determined its effects in our full scale ICU-model of resuscitated murine trauma-and-hemorrhage. We hypothesized that Na₂S₂O₃ might improve energy metabolism and thereby exert organ-protective effects as previously demonstrated in animals with genetic cystathionine-γ-lyase (CSE) deletion (CSE^-/-).

Methods: 30 mice underwent combined blast wave-induced blunt chest trauma followed by 1 h of hemorrhagic shock (mean arterial pressure MAP = 35 ± 5 mmHg). Thereafter, resuscitation was initiated comprising re-transfusion of shed blood, lung-protective mechanical ventilation, fluid resuscitation and continuous i.v. noradrenaline infusion to maintain MAP > 55 mmHg over 6 h, and randomized administration of either i.v. 0.45 mg/g_bodyweight Na₂S₂O₃ or vehicle (NaCl 0.9%). Hemodynamics, lung mechanics, gas exchange, acid-base-status and organ function parameters were recorded. Metabolic pathways were quantified based on gas chromatography/mass spectrometry assessment of plasma isotope enrichment during primed-continuous infusion of stable, non-radioactive, isotope labeled substrates. Mitochondrial function was determined using high-resolution respirometry, and tissue target proteins (nitrotyrosine formation, extravascular albumin accumulation, CSE expression) were analyzed using immunohistochemistry.

Results: Data originate from 23 mice (Na₂S₂O₃ n = 12; vehicle n = 11)_. Na₂S₂O₃ affected neither survival nor noradrenaline requirements. While minute ventilation had to be increased over time in both groups to maintain arterial PCO₂ without intergroup difference, arterial PO₂ decreased over time in Na₂S₂O₃-treated mice (p = 0.006). Although arterial pH decreased in both groups (vehicle p = 0.049; Na₂S₂O₃ p < 0.001), metabolic acidosis was more pronounced in the Na₂S₂O₃ group. Neither metabolic pathways nor tissue mitochondrial respiratory activity or tissue target proteins showed any intergroup differences.

Discussion: In this model of resuscitated trauma-and-hemorrhage, Na₂S₂O₃ did not exert any beneficial metabolic or organ-protective effect and was even associated with impaired pulmonary function. These results are in contrast to our previous findings in CSE^-/- mice, but in line with more recent findings in CSE^-/-<

Background: Spontaneous breathing trials (SBT) are crucial for determining when mechanically ventilated patients are ready for extubation. While pressure support (PS) and T-piece trials are commonly used, humidified high-flow (HHF) is increasingly considered, but its physiological effects remain unclear. This bench study compares T-piece, PS, and HHF modalities, evaluating their impact on work of breathing (WOB), tidal volume (Vt), total positive end-expiratory pressure (PEEPtot) and CO₂ clearance.

Methods: A 3D-printed manikin head connected to an artificial lung was used. Four SBT modalities were tested: T-piece with and without supplemental oxygen, PS at 7 cmH₂O (PEEP 0 cmH₂O), and HHF at 50 L/min. The tests were performed under three lung conditions (normal, obstructive, restrictive) and two respiratory drive and effort settings (normal and intense), resulting in 24 scenarios. Measurements included WOB, CO₂ clearance, PEEPtot, and Vt.

Results: T-piece and HHF50 SBTs exhibited similar effects on WOB, irrespective of the effort pattern associated with the underlying respiratory mechanics. For intense effort patterns, the CO₂ concentration was lower with HHF than with PS, regardless of respiratory mechanics. The HHF50 SBT increased PEEPtot more than T-piece SBTs, but less than PS SBT, for all scenarios. HHF50 SBT generated lower tidal volume than T-piece and PS SBTs.

Conclusions: Humidified high-flow at 50 L/min, while preserving WOB and not increasing tidal volume, may offer specific advantages, such as improved CO₂ clearance and PEEP effect, and could be considered as a trade-off for T-piece or PS SBTs.

Background: Despite advanced and early treatment in the intensive care unit (ICU), mortality in patients with sepsis remains high. Sepsis is often associated with hemolysis. In the clinical routine, hemolysis is often overlooked, as markers of hemolysis are often not routinely measured. Aim of this scoping literature review is to quantify the incidence and extent of hemolysis in patients with sepsis and the association with mortality.

Methods: Systematic literature search in bibliographic databases MEDLINE, EMBASE and Web of Science for sepsis and hemolysis.

Results: A total of 3382 studies underwent title-abstract screening and 169 studies were reviewed in full. There were 34 studies with a total of 27,702 patients with sepsis and reported hemolysis or hemolytic markers and clinical outcomes included in the final analyses. Mortality ranged from 5.4 to 78.6% with a mean mortality of 20.1% across all studies. A significant association between hemolysis or hemolytic markers with increased mortality was observed in nine studies.

Conclusions: Although significant associations between hemolysis and outcome in patients with sepsis were observed, hemolytic markers are not yet routinely and regularly monitored in clinical routine on the ICU. Hemolytic markers can provide information about disease severity and outcome on ICU admission and during the course of the disease. Future work should focus on identification of reliable markers of hemolysis with a potential for easy and timely measurements ideally at the patients' bedside. With an additional definition of monitoring standards, the potential of hemolysis monitoring for prognostication and therapeutic approaches will emerge.

Background: In congenital heart disease (CHD), the evaluation of pulmonary perfusion remains challenging, particularly in pediatric critically ill patients, where anatomical anomalies significantly impact pulmonary blood flow. We aim at demonstrating the reliability and the accuracy to investigate pulmonary perfusion in the presence of CHD by using electrical impedance tomography (EIT), a non-invasive, bedside, real-time, radiation-free imaging technique that assesses lung ventilation and perfusion.

Results: This methodologies series explores the application of EIT in three pediatric critically ill patients with CHD admitted to the Pediatric Intensive Care Unit at Papa Giovanni XXIII Hospital, Bergamo, Italy: (1) a newborn post-corrective surgery for transposition of the great arteries; (2) an infant post-repair of tetralogy of Fallot with bilateral pulmonary branch stenosis; and (3) an infant with severe hypoxemia following Stage I Norwood-Sano repair. EIT perfusion was performed by injecting a bolus of 0.5 ml/kg of 5% saline through a central venous catheter during an inspiratory hold and was compared to standard imaging techniques that assess pulmonary perfusion. EIT findings were consistent with conventional imaging modalities that are not available at bedside (i.e., computed tomography, magnetic resonance imaging, angiography) or that do not allow regional assessment of lung perfusion and are operator dependent (i.e., ultrasound), demonstrating the reliability and the accuracy of EIT assessment. EIT provided critical insights into ventilation-perfusion dynamics, allowing to identify perfusion defects and guiding clinical decisions.

Conclusions: This clinical investigation highlights the potential of EIT to improve pulmonary perfusion monitoring and clinical management of complex CHD cases in pediatric critically ill patients. Further research is needed to establish standardized protocols and validate the EIT clinical utility in larger cohorts.