Intensive Care Medicine Experimental最新文献

Background: Liposomes coated with fibrinogen γ-chain (HHLGGAKQAGDV, H12) peptide and encapsulating adenosine-diphosphate (ADP) [H12-(ADP)-liposomes] can augment platelet aggregation via glycoprotein IIb/IIIa receptors displayed on activated platelets. H12-(ADP)-liposomes release ADP, which is metabolized into adenosine that has tissue-protective effects. This study evaluated the life-saving efficacy of post-treatment with H12-(ADP)-liposomes in rats with LPS-induced coagulopathy and critical organ injuries.

Methods: LPS (10 mg/kg) was administered intraperitoneally to rats. The rats were then treated with an intravenous injection of either H12-(ADP)-liposomes or normal saline (vehicle control) 4 h later.

Results: Post-treatment with H12-(ADP)-liposomes significantly shortened the coagulation time compared to the vehicle treatment at 8 h after LPS challenge and reduced expression of CD62P, a marker of platelet activation, on CD61⁺ platelets at 12 h. H12-(ADP)-liposome post-treatment also normalized the elevated levels of neutrophil elastase (complex) at 6-24 h and citrullinated histone H3 in bronchoalveolar lavage fluid at 24 h. H12-(ADP)-liposome-treated rats showed reductions in the pathological injury score for the lungs and kidneys at 8 h. The survival rates of rats given H12-(ADP)-liposomes were markedly improved 24 h after LPS challenge relative to vehicle-treated rats (50% vs. 21%, p = 0.038).

Conclusions: These findings suggest that post-treatment with H12-(ADP)-liposomes ameliorates LPS-induced coagulopathy and neutrophil activation, thereby improving critical organ injuries and survival in LPS-challenged rats.

Acute respiratory failure and the acute respiratory distress syndrome (ARDS) are characterized by profound spatial and temporal heterogeneity in lung aeration, mechanics, and inflammation. While mechanical ventilation is often vital to ensure gas exchange, it can also cause or worsen lung injury as a result of the superimposed mechanical stress due to the application of positive pressure on a heterogeneous parenchyma. Characterizing the lung microstructure and function at small length scales is essential for understanding the pathogenesis of ventilator-induced lung injury. This is a challenging task due to the complex architecture of the lung, to its constant motion and deformation with breathing and pulsatile blood flow, and its multiscale organization. Indeed, mechanical forces act on the components of the extracellular matrix and cells, acini, airways and blood vessels at the microscale to impact numerous biological processes. Beyond these effects, the global mechanical behavior and function of the lung emerge from this complex dynamic system. Because synchrotron radiation imaging techniques such as phase-contrast computed tomography (PC-CT), and K-edge subtraction CT (KES-CT), have a high spatial resolution, are quantitative, and are fast, they offer unique insights into the multiscale, dynamic behavior of the lung. These modalities enable mapping of regional ventilation, blood distribution, within-breath alveolar recruitment/derecruitment, airway closure, and tissue strain. This review explains synchrotron radiation imaging modalities, and discusses the findings in models of acute respiratory failure, their translational implications, as well as future areas of investigation.

Background: Retrospective studies frequently use single-time-point Berlin physiologic criteria (PaO₂/FiO₂ < 300 mm Hg plus positive end-expiratory pressure ≥ 5 cm H₂O) to identify acute respiratory distress syndrome (ARDS). However, transient hypoxaemia is common among critically ill patients and often does not represent ARDS. Using these screens may overestimate ARDS prevalence and yield a cohort inconsistent with those seen in clinical trials. We sought to determine whether a 72-h persistence criterion for hypoxaemia improves the accuracy of ARDS case identification and evaluate the additional case-finding value of radiology keyword searches and ICD-codes.

Methods: We conducted a retrospective cohort study using the MIMIC-IV database (2008-2019) for derivation and a UK ICU dataset (Imperial College Healthcare National Health Service Trust, 2009-2024) for external validation. All patients meeting Berlin physiologic criteria for at least 72 h were identified. From MIMIC-IV, we randomly selected 2000 patients who met 72-h persistence criteria for expert adjudication based on detailed review of clinical notes, imaging, and echocardiography, classifying them as ARDS, non-ARDS acute hypoxaemic respiratory failure, or possible ARDS. Sensitivity analyses with shorter durations (≥ 24 and ≥ 48 h) were performed. Diagnostic performance of radiology keyword searches and ARDS-specific ICD-9/10 codes were compared to expert adjudication.

Results: Of 18,621 patients who ever met physiologic criteria, 3940 met the 72-h persistence threshold. In a random sample of 2000 from this 72-h MIMIC-IV cohort, expert adjudication identified ARDS in 49.7% (95% CI, 48-52%); in the external UK validation cohort, 56% (95% CI, 46-66%) were adjudicated as ARDS. ARDS prevalence significantly declined with shorter persistence requirements: 21% after 48 h, 8% after 24 h, and 6% with single isolated measurements. Within the 72-h persistence criterion enriched sample, the highest performing radiology keyword search set provided limited sensitivity (49%) and moderate specificity (76%), whereas ICD codes had higher sensitivity (76%) but low specificity (47%).

Conclusions: Berlin physiologic criteria alone were inadequate for retrospective ARDS identification. A ≥ 72-h persistence rule improved cohort enrichment but did not define ARDS, with substantial residual misclassification remaining after physiologic screening. Persistence should therefore be viewed as a pragmatic enrichment strategy rather than a definitive retrospective ARDS label.

Background: Systemic thrombolysis is recommended for high-risk pulmonary embolism, but is associated with a substantial bleeding risk due to thrombolysis-induced coagulopathy. However, recent advances in precision and personalised care offer the potential to reduce mortality as well as the incidence of chronic thromboembolic pulmonary hypertension and post-pulmonary embolism impairment, thereby improving long-term outcomes. Our primary objective was to evaluate the feasibility of a viscoelastic testing-guided, low-dose, prolonged systemic thrombolysis protocol in acute pulmonary embolism. Exploratory secondary objectives included assessment of the safety and efficacy of the protocol using an individualised approach tailored to each patient's coagulation profile.

Methods: This single-centre, prospective, randomised interventional feasibility trial was conducted at Semmelweis University (Budapest, Hungary). Adult pulmonary embolism patients were randomly assigned to a control group (CG) receiving the ESC-recommended 100 mg/2 h dose of rtPA or a viscoelastometry-guided group (VGG), in which the rtPA dose and duration were adjusted based on viscoelastic tests. Transthoracic echocardiography (TTE) was performed every two hours to monitor right ventricular (RV) function and determine cessation of systemic thrombolysis in VGG. The primary outcome was feasibility; the secondary outcome was safety and efficacy.

Results: Among 33 enrolled patients, 19 were included in the analysis (CG: 7; VGG: 12). Patients in the VGG received significantly lower doses of rtPA (median 32.00 mg [IQR 20.95-42.75 mg]) despite longer infusion duration (median 8.5 h [IQR 6.6-10.0]) and showed no coagulopathy. RV dysfunction persisted in two CG patients, whereas in the VGG it resolved in all patients. Major bleeding occurred in two patients in the CG and in one patient in the VGG.

Conclusions: Viscoelastometry-guided, individualised, low-dose systemic thrombolysis is feasible and supports a personalised approach to thrombolysis in the management of pulmonary embolism.

Background: Plasma extracellular vesicles (EV) play an inflammatory role in bacterial pneumonia. This study aimed to determine if plasma EVs could be manipulated to reduce lung injury. We hypothesized that inhibition of multidrug resistance-associated protein (MRP) 1 on EVs would increase total leukotriene (LT) B₄ and lipoxin (LX) A₄ levels and, when incubated with immune cells, would increase bacterial phagocytosis and decrease cytokines secreted by the cells.

Results: Plasma EVs released from ex vivo perfused human lungs injured with E.coli bacteria (E.coli EV) or from control lungs (nEV) were incubated with LPS and Reversan, a MRP1 inhibitor, and the effect of EVs on bacterial phagocytosis and inflammation was studied using a macrophage cell line. In addition, the therapeutic effects of Reversan were studied in perfused human lungs injured with E.coli pneumonia. Levels of LTB₄ and LXA₄ were lower in E.coli EVs compared to nEVs. E.coli EVs were less capable than nEVs to stimulate bacterial phagocytosis by macrophages in vitro. Pretreatment of E.coli EVs with LPS and Reversan increased both total LTB₄ and LXA₄ levels, and, when incubated with Raw264.7 cells, bacterial phagocytosis was increased and TNFα levels secretion was decreased by the cells. Intravenous administration of Reversan to human lungs injured with E.coli bacterial pneumonia significantly restored alveolar fluid clearance rate and reduced bacterial levels in the injured alveolus at 6 h.

Conclusion: Administration of a MRP1 inhibitor to plasma EVs increased its LTB₄ content, which, when incubated with macrophages, further increased phagocytosis of bacteria by the cells.

Haematological malignancies (HMs) are characterized by profound immune dysregulation, which increases susceptibility to sepsis. This dysregulation arises from the underlying disease and may be exacerbated by treatments. Sepsis itself induces a biphasic immune response, with an initial hyperinflammatory phase followed by prolonged immunosuppression that can persist for months or years, potentially impacting the course of HMs. This review examines the reciprocal interactions between HMs and sepsis, focusing on innate and adaptive immune alterations, the influence of malignancy-associated dysbiosis, and insights gained from experimental models. In addition, we discuss how sepsis-induced systemic inflammation may influence the progression of the underlying malignancy, through pro-inflammatory cytokine signaling and alterations in the bone marrow microenvironment. Understanding these complex interactions may provide a framework for mitigating infection-related complications and for exploring their influence on the natural history and progression of HM.

Background: Volatile anesthetics are widely used for sedation in intensive care. Being potent greenhouse gases, their efficient utilization is imperative. We investigated whether the efficiency of anesthetic reflection devices, such as Sedaconda ACD-S (ACD), can be improved by thermocycling, i.e., cooling the reflector during expiration and warming it during inspiration, and aimed to identify the optimal temperatures required.

Methods: A test lung connected to the ACD was ventilated under body temperature pressure saturated and normocapnic conditions. Isoflurane and sevoflurane were infused at rates of 0.5, 1, 2, and 5 mL/h, with sevoflurane additionally administered at 10 mL/h. For thermocycling, inspired air was heated to 37 °C by an active humidifier without water. Cooling in steps of 26, 21, 16, 11, 6, and 1 °C was achieved by passing air from the test lung through a freezer before reaching the ACD.

Results: Thermocycling significantly increased concentrations of isoflurane and sevoflurane in the test lung compared with control conditions. Cooling of the expired air led to substantial increases down to a cooling temperature of 16 °C; below 16 °C, further increases in concentrations were much smaller. Interpolation of our data shows that at clinically used concentrations (isoflurane: 0.4-0.6 Vol%; sevoflurane: 0.9-1.1 Vol%), consumption could be reduced by 70% (isoflurane from 2.46 to 0.74 mL/h) and 72% (sevoflurane from 5.73 to 1.60 mL/h). Reflection efficiencies-the ratio of re-inspired from exhaled anesthetic molecules in one breath-increased from around 70% to 90%.

Conclusions: Thermocycling significantly enhances the efficiency of volatile anesthetic reflection, offering a promising strategy to reduce the impact of intensive care sedation on climate change.

Introduction: Post-cardiac arrest syndrome (PCAS) under veno-arterial ECMO (VA-ECMO) is frequently complicated by severe vasoplegia and microcirculation failure. Conventional resuscitation relies heavily on catecholamines and crystalloids loading, which may exacerbate endothelial dysfunction and oxidative stress. We evaluated whether a multimodal non-catecholaminergic strategy (vasopressin, methylene blue, albumin, and hypothermia) could improve hemodynamics and microcirculation compared to standard therapy with norepinephrine.

Methods: Twenty pigs underwent surgically induced ischemic cardiac arrest and were resuscitated with VA-ECMO after 30 min of CPR. Animals were randomized (1:1) to receive either standard care (norepinephrine and crystalloids) or optimized treatment combining vasopressin, methylene blue, 20% albumin, and moderate hypothermia (34 °C). Hemodynamic, metabolic, and microcirculatory parameters were monitored for 6 h. Sublingual microcirculation was assessed using sidestream dark field (SDF) imaging.

Results: Eighteen animals completed the protocol (9 per group). The optimized group required significantly less norepinephrine (7 mg [0-20] vs 78 mg [58-126], p = 0.0046) and fluid loading (4.5 L [4-5] vs. 14 L [13-18.5], p = 0.0007). Microcirculatory perfusion was markedly improved in the optimized group (PPV 88% vs. 28%, p < 0.001; MFI 2.25 vs. 0.25, p < 0.01). Lactate clearance did not differ significantly. Histological analysis showed less intestinal ischemic injury (Chiu/Park score 1 [0-1] vs. 4 [3-4], p = 0.003).

Conclusion: In a porcine model of refractory cardiac arrest resuscitated with VA-ECMO, a multimodal non-catecholaminergic resuscitation strategy reduced vasopressor and fluid requirements and preserved microcirculation. These findings support multimodal, catecholamine-sparing approaches to limit endothelial dysfunction in ECMO-treated PCAS.

Background: It is unclear whether the rate of intravenous fluid (IVF) administration in sepsis influences glycocalyx breakdown. This study aimed to measure the effect of rapid versus slow fluid bolus in a septic pig model on the integrity of the glycocalyx by measuring the serum levels of heparan sulfate and syndecan-1, breakdown products of the glycocalyx. Because endothelial glycocalyx is composed of apical cell membrane-bound proteoglycans such as syndecan-1, covalently bound with long linear glycosaminoglycans such as heparan sulfate, shedding of these different glycocalyx components is closely related. Additionally, we measured central blood volume (blood volume in the heart and lungs) to determine the effect of fluid administration rate on intravascular volume. Plasma membrane type-1 matrix metalloproteinase (MT1-MMP) levels (indicating vascular shear stress) were compared between groups to assess whether fast IVF boluses generate greater endothelial shearing forces than slow boluses.

Methods: A porcine septic shock model using lipopolysaccharide-induced endotoxemia was used. We randomized 22 piglets to receive two fluid boluses of 20 mL/kg each 30 min apart; 11 received the fluid bolus over 5 min and 11 over 20 min. We monitored the central blood volume index (CBVI) using ultrasound dilution. Measurements of glycocalyx degradation markers, heparan sulfate and syndecan-1, MT1-MMP, and CBVI were obtained at the onset of septic shock and every 30 min for four measurements. Study variables were summarized as mean (standard deviation) by fast versus slow IVF groups across measurement time points. To assess the mean trends in outcomes (syndecan-1, heparan sulfate, MT1-MMP, CBVI) between the two speeds of IVF administration over time, a linear mixed-effects model with a first-order autoregressive within-subject correlation structure was applied.

Results: Serum heparan sulfate and syndecan-1 levels showed no significant differences (P = 0.405 and 0.571, respectively). Baseline-adjusted mean central blood volumes over the four measurements were greater in the slow IVF versus fast group; however, the difference fell short of statistical significance (P = 0.073), indicating a nonsignificant trend toward greater central blood volume with slower infusion. Although MT1-MMP levels increased with time, there was no between-group difference in the MT1-MMP levels.

Conclusions: There was no difference in glycocalyx degradation or vascular shear stress between an IVF bolus given over 5 min compared with 20 min. Central blood volumes trended greater in the slow IVF group compared with the fast IVF group.