Intensive Care Medicine Experimental最新文献

The vascular waterfall phenomenon, rooted in Starling resistor principles, describes how blood flow becomes independent of downstream pressure when intraluminal pressure falls below a critical closing pressure (Pcrit). This review first introduces the classic arterial vascular waterfall, where local Pcrit enables organ-specific autoregulation of blood flow despite varying metabolic demands. Building on this framework, we extend the concept to the venous side, where similar mechanisms govern venous return and protect against congestion. The pulmonary vascular waterfall serves as a prototype, illustrating how alveolar pressures redefine downstream limits, shaping the effects of mechanical ventilation and positive end-expiratory pressure (PEEP). In valveless venous beds such as the hepatic veins, a reverse vascular waterfall may occur when elevated downstream pressure, typically right atrial pressure, causes brief, localized backflow buffered by vessel collapse and the emergence of a new Pcrit. These mechanisms explain organ-specific vulnerabilities to venous congestion: organs with effective venous waterfalls, such as the liver and intestine, can partially buffer overload, whereas the kidney, lacking such protection, is highly susceptible to venous pressure-dependent injury. Clinical implications include refined approaches to PEEP titration, fluid management balancing responsiveness with tolerance, and congestion assessment through Doppler ultrasound. Reframing congestion as a dynamic Starling resistor process explains why similar CVP elevations produce heterogeneous organ effects and provides a mechanistic basis for individualized, physiology-guided critical care.

Sepsis remains a leading cause of death worldwide, characterized by a dysregulated host response to infection that results in organ dysfunction. Extracorporeal blood purification (EBP) therapies traditionally aim to remove circulating mediators involved in this pathological response, although novel technologies that can remove cells and even living pathogens have recently been developed. Despite their growing clinical use, robust evidence supporting EBP in septic shock as an adjuvant therapy is lacking, and several knowledge gaps hinder their effective and safe application. This narrative review critically examines these gaps from both mechanistic and clinical perspectives. Key issues include the dynamic and compartmentalized nature of the immune response, the unclear roles of specific cytokines, and the potential removal of protective anti-inflammatory mediators. Broad-spectrum adsorption may induce unintended immunomodulatory effects, including desorption and altered leukocyte trafficking. Selective approaches, such as endotoxin removal with polymyxin B hemoadsorption, face challenges related to dose, patient stratification, and the limitations of endotoxin activity assays. Therapeutic plasma exchange offers the potential to restore homeostasis but raises questions regarding optimal regimens, replacement fluids, and the risk of unintended drug clearance. The heterogeneity of trial designs, insufficient patient phenotyping, and variability in treatment protocols have led to inconclusive or conflicting clinical outcomes, including some trials suggesting potential harm. This review underscores the need for better mechanistic understanding, real-time immune monitoring, and ideally targeted clinical trial designs to define which patients might benefit from EBP and when. Ultimately, the path to effective application of EBP in sepsis lies in individualized therapy guided by immune profiling, biomarker-driven stratification, and rigorous evaluation in high-quality randomized controlled trials.

Background: The concurrent application of extracorporeal carbon dioxide removal (ECCO₂R) and continuous renal replacement therapy (CRRT) delivers essential respiratory and renal support. However, the use of bicarbonate (HCO₃⁻) in substitution solution increases the external HCO₃⁻ load and affect the carbon dioxide removal rate (VCO₂). This study aims to investigate the influence of low bicarbonate substitution solution on VCO₂ within the combined ECCO₂R-CRRT system.

Methods: This crossover study was conducted with hypercapnic pigs and patients with acute respiratory distress syndrome (ARDS). In pigs, we tested two extracorporeal blood flow rates (200 and 350 mL/min) alongside three continuous veno-venous hemofiltration (CVVH) strategies: a control group receiving ECCO₂R alone without CVVH, a low HCO₃⁻ group receiving ECCO₂R combined with CVVH (HCO₃⁻ concentration of 16 mmol/L at a substitution rate of 30 mL/kg/h), and a normal HCO₃⁻ group (HCO₃⁻ concentration of 25 mmol/L). Respiratory variables, hemodynamic parameters, and VCO₂ were measured 30 min after each intervention. In ARDS patients, we also assessed ECCO₂R combined with these CVVH strategies. The primary endpoint was the comparison of VCO₂ among the three groups in both the pig and patient.

Results: This study involved 12 hypercapnic pigs. At a blood flow rate of 200 mL/min, the VCO₂ were significantly different among groups (P = 0.029). The VCO₂ in the low HCO₃⁻ group (51.7 ± 6.0 mL/min) was significantly higher than that in the normal HCO₃⁻ group (46.1 ± 2.9 mL/min) and comparable to the control group (50.3 ± 5.4 mL/min). However, at a blood flow rate of 350 mL/min, VCO₂ values were similar across all three groups. In 10 ARDS patients with a mean age of 64 ± 8 years, the PaCO₂ was 60.0 ± 4.7 mmHg prior to ECCO₂R. At a blood flow rate of 293 ± 59 mL/min, VCO₂ did not change significantly in the low HCO₃⁻ group (77.0 ± 16.2 mL/min) compared to the control group (75.2 ± 15.9 mL/min), a decrease was noted in the normal HCO₃⁻ group (69.9 ± 16.6 mL/min, P < 0.010).

Conclusion: A low bicarbonate concentration of 16 mmol/L in the substitution solution may optimize CO₂ elimination in the ECCO₂R-CRRT system, especially at lower extracorporeal blood flow rates.

Background: Sepsis is a life-threatening infectious syndrome that lacks targeted pharmacological therapies and poses major challenges in reducing mortality and long-term complications such as disability and frailty. Early and intensive intervention is critical to improving prognosis and preventing multiorgan dysfunction. However, alternative treatment strategies are urgently needed for patients who do not respond to guideline-based resuscitation, such as those outlined in the Surviving Sepsis Campaign. Natural killer (NK) cells are key effectors of the innate immune system, and their balanced activity may be crucial in preventing the progression of sepsis. Given conflicting evidence on whether NK cell activity (NKA) is protective or harmful, we investigated NKA in a murine model of intra-abdominal sepsis, assessing activating and inhibitory NK receptors (NKRs), as well as NK cell subsets in whole blood, bone marrow, lymph nodes, spleen, and liver.

Methods: C57BL/6 mice underwent cecal ligation and puncture (CLP) to induce mid-grade (MGS, 30% 7-day survival) or high-grade sepsis (HGS, 0% 7-day survival), with sham-operated mice as controls. Blood and immune-related organs were collected on days 1, 3, and 7 post-surgery (MGS: days 1, 3, 7; HGS: days 1, 3; Sham: day 7). Flow cytometry was used to analyze CD11b and CD27 expression to define maturation-associated cytolytic and cytokine-producing NK cell phenotypes. CD3⁻NK1.1⁺ NK cells were purified by FACS for RT-PCR of activating (Ly49D, Ly49H) and inhibitory (Ly49C, Ly49G2) NKRs, and ELISA was performed for granzyme B and IFN-γ.

Results: Our experiments consistently showed that in MGS, NKA-initially suppressed-was significantly restored by day 7 after CLP. This recovery was characterized by increased expression of activating NKRs, decreased inhibitory NKRs, expansion of terminally differentiated cytotoxic NK subsets (CD11b⁺/CD27^-), higher total NK cell counts, and elevated granzyme B levels. In contrast, HGS, associated with high lethality, was marked by persistent suppression of NKA.

Conclusions: The sustained impairment of NK cell phenotype is associated with lethal outcomes in sepsis.

Background: Veno-venous (V-V) extracorporeal membrane oxygenation (ECMO) is widely used in critical care but remains associated with high mortality rates (22-68%). In septic shock, increased pulmonary inflammation and impaired intestinal and hepatic microcirculation have been observed during ECMO therapy. To explore the impact of ECMO-induced inflammation, this study used a rat model with varying ECMO blood flows to assess intestinal and hepatic microcirculation and lung inflammation.

Methods: Thirty male Lewis rats were randomised into three groups: sham, low-flow ECMO (60 mL/kg/min), and high-flow ECMO (90 mL/kg/min). V-V ECMO was established via femoral drainage and jugular return. Microcirculation in the intestine and liver was measured using micro-light guide spectrophotometry after laparotomy. Systemic and pulmonary inflammation were evaluated through cytokine levels in plasma and bronchoalveolar lavage (BAL), focusing on tumour necrosis factor-alpha (TNF-α), interleukins 6 (IL6) and 10 (IL10), and C-X-C motif chemokine ligands 2 (CXCL2) and 5 (CXCL5). Hemodynamic data were obtained using a left ventricular pressure-volume catheter.

Results: Intestinal oxygenation was significantly impaired only during low-flow ECMO therapy (65% [62-70%]) compared to sham therapy (76% [72-79%], p = 0.003), while hepatic microcirculation was reduced during both low-flow (21% [14-26%]) and high-flow (19% [16-21%]) ECMO therapy compared to sham therapy (43% [38-48%], all p < 0.001). Serum TNF-α levels were only significantly elevated during high-flow ECMO therapy (1 h: 14 [12-22] pg/mL; 2 h: 18 [15-38] pg/mL) compared to the sham procedure (1 h: 10 [9-11] pg/mL; 2 h: 10 [9-11] pg/mL; p = 0.033). In contrast, BAL IL6 levels were significantly lower during both high- and low-flow ECMO therapy (32 pg/mL) than sham therapy (81 pg/mL, p ≤ 0.001). IL10, CXCL2, and CXCL5 levels did not differ significantly between the low- and high-flow ECMO and sham therapies.

Conclusions: ECMO-induced inflammation is blood flow dependent. In healthy rats, high-flow ECMO did not impair intestinal microcirculation and was associated with reduced pulmonary inflammation, likely due to lung-protective ventilation.

Background: Sepsis is characterized by organ dysfunction due to infection, with increasing evidence of mitochondrial dysfunction assessed preclinically and invasively. Protoporphyrin IX-triplet state lifetime technique (PpIX-TSLT) permits non-invasive determination of cellular oxygen metabolism and may provide deeper pathophysiological insights.

Methods: This analysis is part of a prospective monocentric cohort study. ICU patients with sepsis and septic shock and healthy controls were enrolled between May 2018 and June 2022. Mitochondrial oxygen tension (mitoPO₂), consumption (mitoVO₂) and delivery (mitoDO₂) were assessed in the skin of healthy controls and patients with sepsis in the acute phase (3 ± 1 days after onset) and long-term course of disease (6 ± 2 months after onset) using PpIX-TSLT (CE-certified Cellular Oxygen METabolism system). Primary endpoints were differences in mitoPO₂, mitoVO₂, and mitoDO₂ between patients in the acute phase of sepsis and controls. We tested group differences with t-tests and report Cohen's d (d) as effect size.

Results: In the acute phase, mitochondrial oxygen tension (mitoPO₂) was significantly reduced (n = 133, mean ± standard deviation: 58.4 ± 19.2 mmHg) compared to controls (n = 79, 67.3 ± 17.7 mmHg, p = 0.002, d = - 0.48). We found no significant differences in oxygen tension in the long-term course (n = 43) or in oxygen consumption and delivery between acute and long-term course of sepsis and controls. In the acute phase, lower mitochondrial oxygen delivery was associated with higher Sequential Organ Failure Assessment score (Spearman's ρ = - 0.23, p = 0.009) and higher lactate concentrations (ρ = - 0.21, p = 0.021) and, thus, correlated with disease severity.

Conclusions: Our results suggest that cellular oxygen metabolism in sepsis is characterized by a reversible restriction of oxygen tension without an impairment of mitochondrial oxygen consumption. Additionally, oxygen delivery is dependent on disease severity. These findings should be re-validated in a larger cohort.

Trial registration: NCT03620409 (Ethics vote: 5276-09/17; German Register of Clinical Studies: DRKS00013347), Principal investigator: Sina M. Coldewey, Date of Registration: 11-30-2017 NCT03620409.

Background: Delirium is a serious complication in patients with COVID-19-related acute respiratory distress syndrome (ARDS) admitted to the intensive care unit (ICU). Although numerous clinical risk factors have been identified, the immunologic pathways underlying delirium remain unclear. In this retrospective cohort study, we investigated high-dimensional immune signatures in ICU patients to delineate peripheral immune markers associated with delirium. We also explored machine learning (ML) approaches to enhance biomarker discovery and strengthen predictive modelling through synthetic data generation.

Methods: We studied a cohort of 62 COVID-19 ARDS patients admitted to the ICU at Lausanne University Hospital, Switzerland. The primary analysis compared patients within this cohort who developed delirium (n = 39) to those who remained delirium-free (n = 23). As a baseline for disease severity, we also compared the ICU cohort to 55 non-ICU COVID-19 patients and 450 healthy individuals. We performed high-dimensional immunophenotyping of cytokines, chemokines, and growth factors using multiplex beads assay, along with immune cell profiling via mass cytometry (CyTOF). Ridge regression has been employed to build classification models. We also generated synthetic samples using beta-variational autoencoders to improve sample size and subsequently model stability.

Results: Delirious patients exhibited a distinctive immune signature, including elevated CXCL1, CCL11, CXCL13, HGF, and VEGF-A, coupled with reduced IL-1α, IL-21, and IL-22. Alterations in immune cell populations featured increased exhausted B cells and decreases in CXCR3 + CD4 + T cells, IgM + unswitched memory B cells, and HLA-DR + activated T cells. Leveraging these high-dimensional data, we trained ridge regression models to predict delirium. Incorporating synthetic data helped stabilize the models with a best-performing model achieving an area under the curve (AUC) of 0.95, with high sensitivity (93%) and specificity (86%), based on 12 identified markers.

Conclusion: Our findings demonstrate a distinct immune profile linked to ICU delirium and illustrate how ML can enhance biomarker discovery. Further prospective validation may refine these markers and guide precision-targeted interventions for mitigating delirium in critically ill populations.

Background: Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) seriously threatens the lives of preterm infants. The absence of animal models that can simulate its progression from early hyperoxic lung injury to late hypoxic vascular remodeling has hindered related research.

Objective: To establish a neonatal rat BPD-PH model by simulating exposure to sequential hyperoxic hypoxia experienced by human preterm infants.

Methods: Newborn SD rats were randomized into two control groups (C1 exposed to 21% O₂ for 2 weeks; C2 exposed to 21% O₂ for 3 weeks), and three exposure groups (H1 exposed to 75% O₂ for 2 weeks; H2 exposed to 75% O₂ for 2 weeks and then to 10% O₂ for a week; H3 exposed to 75% O₂ for 2 weeks and then to normoxia for a week). Cardiopulmonary parameters were evaluated by echocardiography, right ventricular systolic pressure measurement, histology, and α-SMA immunofluorescence.

Results: H1 and H2 groups exhibited distinct phenotypes, with those in the H2 group showing more severe phenotypes. The H2 group exhibited a 142% increase in RVSP relative to those in the C2 group. The right-heart index (RI) was 0.43 ± 0.01 in the H2 group, 0.36 ± 0.02 in the H3 group, and 0.22 ± 0.03 in the C2 group. Pulmonary vascular remodeling was significantly increased in the H2 group compared to the control and H3 groups. The H2 group uniquely replicated the disease process, with alveolar simplification preceding hypoxia-induced vascular thickening.

Conclusion: The sequential hyperoxic hypoxia model dynamically mimicked the clinical progression of BPD-PH, which may provide a powerful platform for stage-specific mechanism research and development of novel therapeutic strategies.

Background: Inotropic support is often used to improve hemodynamics and organ perfusion in patients with advanced heart failure-related cardiogenic shock (ADHF-CS). We aimed to evaluate the effect of inotrope timing on patient mortality in patients meeting Society for Cardiovascular Angiography and Interventions (SCAI) stage-C criteria within 24 h of hospital presentation.

Methods: We analyzed a local cardiogenic shock database of patients admitted to our cardiovascular intensive care units at the University of Pennsylvania from five emergency departments between 2021 and 2023. Adult patients with left ventricular ejection fraction ≤40% were eligible for inclusion. Patients with hypoperfusion, who met at least one physical, biochemical, and hemodynamic criterion for SCAI-C shock were included. The primary outcome was 28-day mortality. We also compared SCAI criteria and diagnostic examination timing between early and delayed inotropic support groups.

Results: A total of 138 out of 623 patients (22%) with cardiogenic shock met inclusion criteria for this study. 28-day mortality was higher in patients who received inotropic therapies ≥8 h after cardiogenic shock onset compared to patients who received earlier support (4-h odds ratio of death (OR) 3.19, 95% CI: 1.34-8.03; 8-h OR: 2.4, 95% CI: 1.09-5.26). 28-day mortality was lower in the early inotrope group (<8 h from shock onset) compared to the delayed (≥8 h) group (15/87; 17% vs. 17/51; 32%, p = 0.031). Patients with early inotropic support more often presented with a cool peripheral exam (34% vs. 16%, p = 0.022) and an initial lactate > 2 mmol/dL (71% vs. 49%, p = 0.009). Delayed inotropic support was associated with hypotension at presentation (84% vs. 57%, p = 0.001), longer time to echocardiography (19 [11-36] vs. 15 [3-24] h, p = 0.053) and time to pulmonary artery catheterization (25 [16-45] vs. 16 [2-46] h, p = 0.042).

Conclusion: Our findings suggest that inotropic support initiated within 8 h of acute presentation is associated with decreased 28-day mortality for patients with ADHF-related cardiogenic shock. Peripheral perfusion and cardiac output measurement were less frequently quantified within the first 24 h for patients with delayed inotropic support. Using shock classification tools, such as the SCAI shock criteria, may help identify patients with CS, especially in its early stages.

Background: Breath stacking, particularly double triggering, is a common patient-ventilator asynchrony during strong inspiratory effort. It can cause excessive tidal volumes and high transpulmonary pressures, contributing to ventilator-induced lung injury (VILI). The mode-specific consequences of breath stacking induced by strong inspiratory effort remain unclear.

Methods: In a porcine model of minimal lung injury, 17 animals were randomized to volume-controlled ventilation (VCV, n = 9) or pressure-controlled ventilation (PCV, n = 8). High respiratory drive was induced with continuous CO₂ inhalation, and ventilator settings were dynamically adjusted to maintain a breath stacking ratio of 40-70% of spontaneous efforts. Measurements included airway and transpulmonary pressures, driving pressures, tidal volume, esophageal pressure swings (ΔPes), stress index (SI), respiratory compliance, and histological lung injury. Risk factors for baro/volutrauma were defined by elevated plateau or driving pressures, transpulmonary pressures, or tidal volume >10 mL/kg. Atelectrauma risk was defined by SI < 0.9, negative end-expiratory transpulmonary pressure (PLexp), or vigorous effort (ΔPes > 5 cmH₂O or Pmus > 8 cmH₂O).

Results: VCV animals exhibited higher respiratory rates (44.0 vs. 30.5 breaths/min, p = 0.027), whereas PCV resulted in stronger inspiratory efforts (ΔPes 6.1 vs. 4.2 cmH₂O, p = 0.015). During breath stacking, VCV produced larger tidal volumes and higher plateau pressures, accumulating more baro/volutrauma risk factors (median 4.0 vs. 0.0, p < 0.001). In contrast, PCV animals developed more atelectrauma risk factors (3.0 vs. 1.0, p = 0.004). Histological injury scores were comparable, with a non-significant trend toward greater severity in PCV.

Conclusions: Breath stacking under strong inspiratory drive can promote lung injury through distinct mechanisms depending on ventilation mode. VCV was associated with the risk of overdistension, whereas PCV involved vigorous inspiratory effort and potential atelectrauma. Double triggering should be recognized as a clinical warning sign, prompting careful assessment of respiratory drive, inspiratory effort, and ventilator settings.