Intensive Care Medicine Experimental最新文献

Background: ECPELLA, a combination of veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) and Impella, a percutaneous left ventricular (LV) assist device, has emerged as a novel therapeutic option in patients with severe cardiogenic shock (CS). Since multiple cardiovascular and pump factors influence the haemodynamic effects of ECPELLA, optimising ECPELLA management remains challenging. In this study, we conducted a comprehensive simulation study of ECPELLA haemodynamics. We also simulated global oxygen delivery (DO₂) under ECPELLA in severe CS and acute respiratory failure as a first step to incorporate global DO₂ into our developed cardiovascular simulation.

Methods and results: Both the systemic and pulmonary circulations were modelled using a 5-element resistance‒capacitance network. The four ventricles were represented by time-varying elastances with unidirectional valves. In the scenarios of severe LV dysfunction, biventricular dysfunction with normal pulmonary vascular resistance (PVR, 0.8 Wood units), and biventricular dysfunction with high PVR (6.0 Wood units), we compared the changes in haemodynamics, pressure-volume relationship (PV loop), and global DO₂ under different VA-ECMO flows and Impella support levels.

Results: In the simulation, ECPELLA improved total systemic flow with a minimising biventricular pressure-volume loop, indicating biventricular unloading in normal PVR conditions. Meanwhile, increased Impella support level in high PVR conditions rendered the LV-PV loop smaller and induced LV suction in ECPELLA support conditions. The general trend of global DO₂ was followed by the changes in total systemic flow. The addition of veno-venous ECMO (VV-ECMO) augmented the global DO₂ increment under ECPELLA total support conditions.

Conclusions: The optimal ECPELLA support increased total systemic flow and achieved both biventricular unloading. The VV-ECMO effectively improves global DO₂ in total ECPELLA support conditions.

Background: Exhaled volatile organic compounds (VOCs), particularly hydrocarbons from oxidative stress-induced lipid peroxidation, are associated with hyperoxia exposure. However, important heterogeneity amongst identified VOCs and concerns about their precise pathophysiological origins warrant translational studies assessing their validity as a marker of hyperoxia-induced oxidative stress. Therefore, this study sought to examine changes in VOCs previously associated with the oxidative stress response in hyperoxia-exposed lung epithelial cells.

Methods: A549 alveolar epithelial cells were exposed to hyperoxia for 24 h, or to room air as normoxia controls, or hydrogen peroxide as oxidative-stress positive controls. VOCs were sampled from the headspace, analysed by gas chromatography coupled with mass spectrometry and compared by targeted and untargeted analyses. A secondary analysis of breath samples from a large cohort of critically ill adult patients assessed the association of identified VOCs with clinical oxygen exposure.

Results: Following cellular hyperoxia exposure, none of the targeted VOCs, previously proposed as breath markers of oxidative stress, were increased, and decane was significantly decreased. Untargeted analysis did not reveal novel identifiable hyperoxia-associated VOCs. Within the clinical cohort, three previously proposed breath markers of oxidative stress, hexane, octane, and decane had no real diagnostic value in discriminating patients exposed to hyperoxia.

Conclusions: Hyperoxia exposure of alveolar epithelial cells did not result in an increase in identifiable VOCs, whilst VOCs previously linked to oxidative stress were not associated with oxygen exposure in a cohort of critically ill patients. These findings suggest that the pathophysiological origin of previously proposed breath markers of oxidative stress is more complex than just oxidative stress from hyperoxia at the lung epithelial cellular level.

Acute respiratory distress syndrome (ARDS) is the primary cause of respiratory failure in critically ill patients. Despite remarkable therapeutic advances in recent years, ARDS remains a life-threatening clinical complication with high morbidity and mortality, especially during the global spread of the coronavirus disease 2019 (COVID-19) pandemic. Previous studies have demonstrated that mesenchymal stem cell (MSC)-based therapy is a potential alternative strategy for the treatment of refractory respiratory diseases including ARDS, while extracorporeal membrane oxygenation (ECMO) as the last resort treatment to sustain life can help improve the survival of ARDS patients. In recent years, several studies have explored the effects of ECMO combined with MSC-based therapies in the treatment of ARDS, and some of them have demonstrated that this combination can provide better therapeutic effects, while others have argued that some critical issues need to be solved before it can be applied to clinical practice. This review presents an overview of the current status, clinical challenges and future prospects of ECMO combined with MSCs in the treatment of ARDS.

Background: How assisted spontaneous breathing should be used during acute respiratory distress syndrome is questioned. Recent evidence suggests that high positive end-expiratory pressure (PEEP) may limit the risk of patient self-inflicted lung injury (P-SILI). The aim of this study was to assess the effects of PEEP on esophageal pressure swings, inspiratory drive, and the neuromuscular efficiency of ventilation. We hypothesized that high PEEP would reduce esophageal pressure swings, regardless of inspiratory drive changes, by modulating the effort-to-drive ratio (EDR). This was tested retrospectively in an experimental animal crossover study. Anesthetized pigs (n = 15) were subjected to mild to moderate lung injury and different PEEP levels were applied, changing PEEP from 0 to 15 cmH₂O and back to 0 cmH₂O in steps of 3 cmH₂O. Airway pressure, esophageal pressure (Pes), and electric activity of the diaphragm (Edi) were collected. The EDR was calculated as the tidal change in Pes divided by the tidal change in Edi. Statistical differences were tested using the Wilcoxon signed-rank test.

Results: Inspiratory esophageal pressure swings decreased from - 4.2 ± 3.1 cmH₂O to - 1.9 ± 1.5 cmH₂O (p < 0.01), and the mean EDR fell from - 1.12 ± 1.05 cmH₂O/µV to - 0.24 ± 0.20 (p < 0.01) as PEEP was increased from 0 to 15 cmH₂O. The EDR was significantly correlated to the PEEP level (r_s = 0.35, p < 0.01).

Conclusions: Higher PEEP limits inspiratory effort by modulating the EDR of the respiratory system. These findings indicate that PEEP may be used in titration of the spontaneous impact on ventilation and in P-SILI risk reduction, potentially facilitating safe assisted spontaneous breathing. Similarly, ventilation may be shifted from highly spontaneous to predominantly controlled ventilation using PEEP. These findings need to be confirmed in clinical settings.

The models used to investigate the pathophysiological mechanisms of acute critical illness are not limited to mammalian species. The zebrafish (Danio rerio) is a popular model organism for studying diseases due to its transparency and rapid development. The genes and signaling pathways involved in acute critical illness appear highly conserved among zebrafish and humans. Forward genetics such as random mutagenesis by a chemical mutagen or reverse genetics methods represented by CRISPR/Cas9 allowed researchers to reveal multiple novel aspects of pathological processes in areas including infection, immunity, and regeneration. As a model of sepsis, transgenic zebrafish allowed the visualization of lipopolysaccharide (LPS)-induced vascular leakage in vivo and the demonstration of changes in the expression of cellular junction proteins. Other transgenic zebrafish visualizing the extravascular migration of neutrophils and macrophages have demonstrated a decrease in neutrophil numbers and an increased expression of an inflammatory gene, which replicates a phenomenon observed in humans in clinically encountered sepsis. The regenerative potential and the visibility of zebrafish organs also enabled clarification of important mechanisms in wound healing, angiogenesis, and neurogenesis. After spinal cord injury (SCI), a marker gene expressed in glial bridging was discovered. Furthermore, localized epithelial-to-mesenchymal transition (EMT) and molecular mechanisms leading to spinal cord repair were revealed. These translational studies using zebrafish show the potential of the model system for the treatment of acute critical illnesses such as sepsis, organ failure, and trauma.

Background: Rhabdomyolysis is characterized by the destruction and necrosis of skeletal muscle tissue, resulting in acute kidney injury (AKI). Recombinant antithrombin (rAT) has DNA repair and vascular endothelial-protection properties. Herein, we investigated whether rAT therapy has beneficial effects against rhabdomyolysis-induced AKI. Ten-week-old male B6 mice were injected with 5 mL/kg of 50% glycerol intramuscularly in the left thigh after 24 h of fasting to create a rhabdomyolysis mouse model. Further, 750 IU/kg rAT was injected intraperitoneally at 24 and 72 h after the rhabdomyolysis model was established. The mice were euthanized after 96 h for histological analysis. Saline was administered to mice in the control group.

Results: Blood tests show elevated serum creatinine, urea nitrogen, and neutrophil gelatinase-associated lipocalin levels in rhabdomyolysis. Loss of tubular epithelial cell nuclei and destruction of the tubular luminal surface structure was observed in the untreated group, which improved with rAT treatment. Immunostaining for Ki-67 showed increased Ki-67-positive nuclei in the tubular epithelial cells in the rAT group, suggesting that rAT may promote tubular epithelial cell regeneration. The microvilli of the brush border of the renal tubules were shed during rhabdomyolysis, and rAT treatment reduced this injury. The vascular endothelial glycocalyx, which is usually impaired by rhabdomyolysis, became functional following rAT treatment.

Conclusions: Treatment with rAT suppressed rhabdomyolysis-induced AKI, suggesting that rAT therapy may be a novel therapeutic approach.

Introduction: Lung weight is an important study endpoint to assess lung edema in porcine experiments on acute respiratory distress syndrome and ventilatory induced lung injury. Evidence on the relationship between lung-body weight relationship is lacking in the literature. The aim of this work is to provide a reference equation between normal lung and body weight in female domestic piglets.

Materials and methods: 177 healthy female domestic piglets from previous studies were included in the analysis. Lung weight was assessed either via a CT-scan before any experimental injury or with a scale after autopsy. The animals were randomly divided in a training (n = 141) and a validation population (n = 36). The relation between body weight and lung weight index (lung weight/body weight, g/kg) was described by an exponential function on the training population. The equation was tested on the validation population. A Bland-Altman analysis was performed to compare the lung weight index in the validation population and its theoretical value calculated with the reference equation.

Results: A good fit was found between the validation population and the exponential equation extracted from the training population (RMSE = 0.060). The equation to determine lung weight index from body weight was: [Formula: see text] At the Bland and Altman analyses, the mean bias between the real and the expected lung weight index was - 0.26 g/kg (95% CI - 0.96-0.43), upper LOA 3.80 g/kg [95% CI 2.59-5.01], lower LOA - 4.33 g/kg [95% CI = - 5.54-(- 3.12)].

Conclusions: This exponential function might be a valuable tool to assess lung edema in experiments involving 16-50 kg female domestic piglets. The error that can be made due to the 95% confidence intervals of the formula is smaller than the one made considering the lung to body weight as a linear relationship.

Background: Respiratory quotient (RQ) is an important variable when assessing metabolic status in intensive care patients. However, analysis of RQ requires cumbersome technical equipment. The aim of the current study was to examine a simplified blood gas-based method of RQ assessment, using Douglas bag measurement of RQ (Douglas-RQ) as reference in a laboratory porcine model under metabolic steady state. In addition, we aimed at establishing reference values for RQ in the same population, thereby generating data to facilitate further research.

Methods: RQ was measured in 11 mechanically ventilated pigs under metabolic steady state using Douglas-RQ and CO-oximetry blood gas analysis of pulmonary artery and systemic carbon dioxide and oxygen content. The CO-oximetry data were used to calculate RQ (blood gas RQ). Paired recordings with both methods were made once in the morning and once in the afternoon and values obtained were analyzed for potential significant differences.

Results: The average Douglas-RQ, for all data points over the whole day, was 0.97 (95%CI 0.95-0.99). The corresponding blood gas RQ was 0.95 (95%CI 0.87-1.02). There was no statistically significant difference in RQ values obtained using Douglas-RQ or blood gas RQ for all data over the whole day (P = 0.43). Bias was - 0.02 (95% limits of agreement ± 0.3). Douglas-RQ decreased during the day 1.00 (95%CI 0.97-1.03) vs 0.95 (95%CI 0.92-0.98) P < 0.001, whereas the decrease was not significant for blood gas RQ 1.02 (95%CI 0.89-1.16 vs 0.87 (0.80-0.94) P = 0.11.

Conclusion: RQ values obtained with blood gas analysis did not differ statistically, compared to gold standard Douglas bag RQ measurement, showing low bias but relatively large limits of agreement, when analyzed for the whole day. This indicates that a simplified blood gas-based method for RQ estimations may be used as an alternative to gold standard expired gas analysis on a group level, even if individual values may differ. In addition, RQ estimated with Douglas bag analysis of exhaled air, was 0.97 in anesthetized non-fasted pigs and decreased during prolonged anesthesia.