Intensive Care Medicine Experimental最新文献

Introduction: CO₂-derived variables, veno-arterial CO₂ content gradient (ΔCCO₂) and the ratio of ΔCCO₂ with arterio-venous oxygen difference (AV-DO₂) (ΔCCO2/AV-DO₂), may have a potential role as indicators of low cardiac output and anaerobic metabolism, respectively. We sought to describe and evaluate the association of CO₂-derived variables with patients' outcomes in the post cardiopulmonary bypass (CPB) period in children.

Methods: Prospective, single-center, study enrolling children post-CPB with paired arterial and venous blood gases for determination of lactate, O₂ extraction, ΔCCO₂, and ΔCCO₂/AV-DO₂ at admission (H0), and at 6 (H6), 12 (H12) and 24 (H24) hours. Different clinical patterns were defined based on the presence of an anaerobic context or a hypoperfusion context, using both O₂ and CO₂-derived variables. The presence of anaerobic metabolism was defined with a lactate > 2 mmol/l and ΔCCO₂/AV-DO₂ > 1.8; the presence of hypoperfusion was defined with an O₂ extraction > 30% and ΔCCO₂ > 6 mL. The potential association of duration of amine support and mechanical ventilation was tested with CO₂-derived variables and specific clinical patterns.

Results: A total of 51 patients with a median age of 36 (IQR 11-85) months were included. Median admission ΔCCO₂ was 9.3 mL (IQR 5.6-11.4) with 72% above 6 mL. Median ΔCCO₂/AV-DO₂ was 2.1 (IQR 1.5-2.4) with 58% above 1.8. Admission ΔCCO₂ showed a significant association with the duration of mechanical ventilation (R2 21.6, p value = 0.001) but not with the duration of vasoactive support. Neither H0 ΔCCO₂ nor H0 ΔCCO₂/AV-DO₂ improved outcome prediction by a model including lactate and O₂ extraction. Anaerobic metabolism context showed a significant association with prolonged vasoactive support [28.4 (CI 95% 12.2-44.6) p = 0.001] and mechanical ventilation duration [1.4 (95% CI 0.62-2.3) p = 0.003]. In hypoperfusion context, neither duration of vasoactive support nor mechanical ventilation appeared different in the subgroups analysis.

Conclusion: CO₂-derived variables may improve outcome prediction after cardiac surgery in pediatric patients. Further evaluation in larger multicentered trials is necessary to improve its validation.

Background: Critically ill patients frequently experience profound skeletal muscle (SM) wasting, to which early detection and effective clinical management remain significant challenges. Ultrasonography (US) provides early objective information about SM compared with usual functional tests. The characteristics of the optimal nutritional support are controversial. This observational study aimed to characterize the SM changes through US in the first week after Intensive Care Unit (ICU) admission and to evaluate the potential interference factors with a focus on nutritional support.

Results: A total of 95 patients (age 55.7 ± 16.01 years, 70.5% male) were included. All the ultrasound SM measures tendentially reduced after admission: quadriceps muscle layer thickness (QMLT) 10.03% (0.38 ± 0.73 cm), rectus femoris cross-sectional area (RF-CSA) 10.48% (0.50 ± 1.38 cm²), RF pennation angle (RF-PA) 0.94 ± 4.14 º, RF echogenicity (RF-EG) 1.05 ± 22.33 in echo-intensity gray scale and RF shear wave elastography (RF-SWE) 0.13 ± 1.25 m/s and 3.96 ± 28.10 kPa. A significant association between nutritional risk at baseline and SM changes (QMLT 0.194, p = 0.079 and RF-CSA 0.25, p = 0.027) was observed and confirmed in a linear regression model (1.257 and p = 0.011). No significant associations were found between SM changes and nutritional support.

Conclusion: Present findings demonstrate a marked reduction in the SM ultrasound measures evaluated in the first week after ICU admission, mainly in patients at nutritional risk. More evidence on optimal nutritional strategies to attenuate SM wasting is warranted.

Background: Despite advances in treatment, critically ill COVID-19 patients requiring intensive care unit (ICU) admission continue to comprise a substantial proportion of cases. However, the factors influencing poor prognosis in this population remain poorly understood. To address this knowledge gap, we conducted a prospective analysis of serum neutralizing activity against SARS-CoV-2 in 49 non-selected, critically ill COVID-19 patients enrolled in the multicenter SEVARVIR cohort between October 2022 and May 2024.

Methods: This a substudy of the SEVARVIR prospective multicenter observational cohort study (NCT05162508). We included 49 critically ill COVID-19 patients hospitalized in four French intensive care units between October 2022 and May 2024 from the 827 patients enrolled in the multicenter, prospective SEVARVIR study. Serum neutralizing titers of authentic SARS-CoV-2 isolates were measured using the S-Fuse assay and patients categorized as neutralizers if they had an anti-spike serum neutralization titer against the infecting variant > 15 and non-neutralizers if ≤ 15. Full-length SARS-CoV-2 genomes from all included patients were sequenced by means of next-generation sequencing.

Results: Median age was 73 years (59-75) and 34.7% of patients (n = 17/49) were female. Half of the patients (53.1%, n = 26/49) had immunosuppressive comorbidities. A large proportion of individuals lacked the capacity to neutralize their infecting variant (57.1%, n = 28/49). Neutralizing titers were significantly higher in 28-day survivors than in deceased patients (p = 0.0212) and neutralizers had a significantly lower 28-day mortality than non-neutralizers (5.0%, n = 1/21 vs. 32.1%, n = 9/28; p = 0.0312). Nine out of the ten patients who succumbed to the disease within 28 days of admission had undetectable serum neutralizing capacity, which was significantly more prevalent than in survivors (p = 0.03), irrespective of immunosuppression status. The sole patient who died despite having detectable neutralizing antibodies against SARS-CoV-2, was found to have anti-interferon auto-antibodies.

Conclusion: These findings underscore the potential benefits of early therapeutic interventions aimed at enhancing neutralization, which may improve survival outcomes in both immunocompetent and immunocompromised critically ill COVID-19 patients.

Background: Fluid overload in critically ill patients has been associated with muscle edema, decreased tissue quality, and the development of intensive care unit-acquired weakness (ICU-AW). Continuous renal replacement therapy (CRRT) with ultrafiltration (UF) contributes to removing excess extracellular fluid. This study aimed to evaluate whether UF is associated with changes in muscle ultrasound parameters and strength in critically ill patients.

Methods: Critically ill patients with resolved hypoperfusion undergoing CRRT with fluid removal via UF were prospectively enrolled and compared with a control group without UF. Muscle ultrasound assessments included rectus femoris and vastus intermedius thickness, echogenicity, and subcutaneous tissue. Global muscle strength was assessed using the Medical Research Council Sum Score (MRC-SS). Assessments were performed at CRRT initiation (T1) and again 36 h later (T2).

Results: Twenty-eight patients were enrolled, 18 in the UF group and 10 patients in the control group. All ultrasonographic variables measured were different between the UF and control groups. In the UF group, median rectus femoris thickness decreased from 1.74 to 1.57 cm (p = 0.03), vastus intermedius from 1.14 to 0.95 cm (p < 0.01), echogenicity from 91.7 to 78.3 grayscale units (p < 0.01), and subcutaneous tissue thickness from 1.98 to 1.79 cm (p < 0.01). MRC-SS increased from 45.0 to 49.0 points (p = 0.05). A positive correlation was found between UF volume (mL/kg) and MRC-SS at T2 (ρ = 0.71, p < 0.01), and a negative correlation between UF volume and change in muscle echogenicity (ρ = - 0.49, p = 0.039). ROC curve analysis identified that a UF volume ≥ 82 mL/kg was associated with MRC-SS > 48 points obtaining an AUC of 0.982 (95% CI: 0.928-1.000), sensitivity 92.9%, and specificity 100%.

Conclusion: Ultrafiltration was associated with changes in muscle echogenicity and subcutaneous tissue as well as an increase in MRC scoring at follow-up. These results suggest a potential relationship between fluid balance and muscle ultrasound parameters. No causal inferences can be drawn; therefore, further studies are needed.

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.