Acute respiratory distress syndrome (ARDS) is a common condition associated with critically ill patients, characterized by bilateral chest radiographical opacities with refractory hypoxemia due to noncardiogenic pulmonary edema. Despite significant advances, the mortality of ARDS remains unacceptably high, and there are still no effective targeted pharmacotherapeutic agents. With the outbreak of coronavirus disease 19 worldwide, the mortality of ARDS has increased correspondingly. Comprehending the pathophysiology and the underlying molecular mechanisms of ARDS may thus be essential to developing effective therapeutic strategies and reducing mortality. To facilitate further understanding of its pathogenesis and exploring novel therapeutics, this review provides comprehensive information of ARDS from pathophysiology to molecular mechanisms and presents targeted therapeutics. We first describe the pathogenesis and pathophysiology of ARDS that involve dysregulated inflammation, alveolar-capillary barrier dysfunction, impaired alveolar fluid clearance and oxidative stress. Next, we summarize the molecular mechanisms and signaling pathways related to the above four aspects of ARDS pathophysiology, along with the latest research progress. Finally, we discuss the emerging therapeutic strategies that show exciting promise in ARDS, including several pharmacologic therapies, microRNA-based therapies and mesenchymal stromal cell therapies, highlighting the pathophysiological basis and the influences on signal transduction pathways for their use. 

Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS)

Management of acute respiratory distress syndrome (ARDS) represents one of the greatest challenges in intensive care and despite all efforts mortality remains high. One common phenotype of ARDS is that of a secondary injury to a dysregulated inflammatory host response resulting in increased capillary congestion, interstitial lung edema, atelectasis, pulmonary embolism, muscle wasting, recurring infectious episodes, and multiple organ failure. In cases of hyperinflammation, immunomodulation by extracorporeal cytokine removal such as the CytoSorb hemoadsorption cartridge could conceptually enhance lung recovery during the early course of the disease. The aim of this narrative review is to summarize the currently available data in this field and to provide an overview of pathophysiology and rationale for the use of CytoSorb hemoadsorption in patients with hyperinflammatory ARDS. 

The potential role of extracorporeal cytokine removal with CytoSorb® as an adjuvant therapy in Acute Respiratory Distress Syndrome

ABSTRACT Background: The COVID-19 pandemic has posed a disproportionately high threat to the global health system and social stability. COVID-19 damage can lead to hyperinflammation and tissue damage due to a “cytokine storm,” which in turn contributes to an increase in the mortality rate. Extracorporeal hemoadsorption therapy (HAT) in patients with severe COVID-19 may improve organ function and stabilize hemodynamic status; however, the effects of supplemental HAT remain controversial. Methods: The Cochrane Library, Embase, and PubMed databases were comprehensively searched from inception to August 20, 2022, for potential studies. Results: A total of 648 patients with severe COVID-19 in three randomized controlled trials and 11 observational studies met the inclusion criteria. A meta-analysis indicated that supplemental HAT significantly improved the mortality rate of patients with severe COVID-19 compared with conventional therapy (relative risk [RR] = 0.74, 95% confidence interval [CI] = 0.56 to 0.96, P = 0.026). In subgroup analyses, supplemental HAT significantly decreased mortality rates in patients without extracorporeal membrane oxygenation (ECMO) support (RR = 0.59, 95% CI = 0.44–0.79, P &lt; 0.0001), while a significant difference was not observed in patients requiring ECMO support (RR = 1.61, 95% CI = 0.63–4.09, P = 0.316). Standardized mean difference (SMD) meta-analysis showed that IL-6 removal was more significant in HAT group than conventional therapy group (SMD = 0.46, 95% CI = 0.01 to 0.91, P = 0.043), followed by C-reactive protein (SMD = 0.70, 95% CI = −0.04 to 1.44, P = 0.065) and IL-8 (SMD = 0.36, 95% CI = −0.34 to 1.07, P = 0.311). No evidence of substantial publication bias concerning mortality was observed. Conclusion: Given the better mortality outcomes, HAT confers clinical benefits to patients with severe COVID-19, which correlated with cytokine removal by HAT. Cytokine adsorption may not provide clinical benefits for patients with severe COVID-19 requiring ECMO and should be used with caution. However, because of the very low quality of evidence, multicenter randomized trials with large sample sizes are required to verify these findings. 

Efficacy of supplemental hemoadsorption therapy on severe and critical patients with covid-19: an evidence-based analysis

The survival rate of extracorporeal life support (ECLS) remains overall at 60 %. Research and development is slow, partly due to the lack of sophisticated experimental models. This publication introduces a dedicated rodent oxygenator (“RatOx”) and shows preliminary in vitro classification tests. The RatOx has an adaptable fiber module size for various rodent models. Gas transfer performance over the fiber module for different blood flows and fiber module sizes were tested according to DIN EN ISO 7199.At the maximum possible amount of effective fiber surface and a blood flow of 100 ml/min, the oxygenator performance has been tested to a maximum of 6.27 ml O2/min and 8.2 ml CO2/min, respectively. The priming volume for this the largest fiber module is 5.4 ml, while the smallest possible configuration with a single fiber mat layer has 1.1 ml of priming volume. The novel RatOx ECLS system has been evaluated in-vitro to comply to a high degree with all predefined functionality criteria for rodent sized animal models. We intend for the RatOx to become a standard testing platform for scientific studies on ECLS therapy and technology. 

Novel Size-Variable Dedicated Rodent Oxygenator for ECLS Animal Models: Introduction of the “Ratox” Oxygenator and Preliminary In-Vitro Results

Impact between the favorable and unfavorable criteria for initiating extracorporeal cardiopulmonary resuscitation and clinical outcomes.

Background After its approval by the European Union in 2011, CytoSorb therapy has been applied to control cytokine storm and lower the increased levels of cytokines and other inflammatory mediators in blood. However, the efficiency of this CytoSorb treatment in patients with coronavirus disease (COVID-19) still remains unclear. To elucidate the Cytosorb efficiency, we conducted a systematic review and single-arm proportion meta-analysis to combine all evidence available in the published literature to date, so that this comprehensive knowledge can guide clinical decision-making and future research. Methods The literature published within the period 1 December 2019 to 31 December 2021 and stored in the Cochrane Library, Embase, PubMed, and International Clinical Trials Registry Platform (ICTRP) was searched for all relevant studies including the cases where COVID-19 patients were treated with CytoSorb. We performed random-effects meta-analyses by R software (3.6.1) and used the Joanna Briggs Institute checklist to assess the risk of bias. Both categorical and continuous variables were presented with 95% confidence intervals (CIs) as pooled proportions for categorical variables and pooled means for continuous outcomes. Results We included 14 studies with 241 COVID-19 patients treated with CytoSorb hemadsorption. Our findings reveal that for COVID-19 patients receiving CytoSorb treatment, the combined in-hospital mortality was 42.1% (95% CI 29.5–54.6%, I2 = 74%). The pooled incidence of adjunctive extracorporeal membrane oxygenation (ECMO) support was 73.2%. Both the C-reactive protein (CRP) and interleukin-6 (IL-6) levels decreased after CytoSorb treatment. The pooled mean of the CRP level decreased from 147.55 (95% CI 91.14–203.96) to 92.36 mg/L (95% CI 46.74–137.98), while that of IL-6 decreased from 339.49 (95% CI 164.35–514.63) to 168.83 pg/mL (95% CI 82.22–255.45). Conclusions The majority of the COVID-19 patients treated with CytoSorb received ECMO support. In-hospital mortality was 42.1% for the COVID-19 patients who had CytoSorb treatment. Both CRP and IL-6 levels decreased after Cytosorb treatment.

/pdf/cytosorb-in-patients-with-coronavirus-disease-2019-a-rapid-78u4y1sn.pdf

CytoSorb in patients with coronavirus disease 2019: A rapid evidence review and meta-analysis

BACKGROUND
Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been widely used in high-risk acute myocardial infarction (AMI) patients with promising outcomes. However, the underlying molecular mechanisms remain unknown and a VA-ECMO animal model has not yet been established. The purpose of this study was to establish a VA-ECMO model in AMI rats and evaluate long-term cardiac function.


METHODS
We first established AMI in 20 Sprague-Dawley (SD) rats by ligating the left anterior descending coronary artery, while 5 rats underwent a thoracotomy to form the sham group. VA-ECMO was established after 30mins of AMI in 10 rats through the right jugular vein for venous drainage and right femoral artery for arterial infusion. Arterial blood pressure was monitored using a catheter in the left femoral artery, blood gas parameters were measured using a blood gas analyzer, while myocardial enzymes were detected using an ELISA Kit. Cardiac function was assessed through echocardiography on day 15. Masson staining and Western Blot were used for evaluating myocardial fibrosis, while histological injury was evaluated using hematoxylin and eosin staining.


RESULTS
VA-ECMO support stabilized blood pressure, decreased the levels of myocardial enzymes including cTnI, cTnT, CK-MB, and was associated with a higher survival rate. In the long-term, the VA-ECMO group showed improved cardiac function, significantly increased EF and FS but significantly decreased EDV and ESV compared to the AMI group. Furthermore, VA-ECMO significantly alleviated pathological damage and myocardial fibrosis.


CONCLUSION
We established an economical, reliable, and reproducible VA-ECMO animal model in AMI rats, and demonstrated that VA-ECMO support prevents deteriorated cardiac function.

Venoarterial extracorporeal membrane oxygenation improves survival in a rat model of acute myocardial infarction.

Background: In lung transplantation surgery, extracorporeal life support (ECLS) is essential for safety. Various support methods, including cardiopulmonary bypass (CPB) and off-pump techniques, are used, with extracorporeal membrane oxygenation (ECMO) gaining prominence. However, consensus on the best support strategy is lacking.Purpose: This article reviews risks, benefits, and outcomes of different support strategies in lung transplantation. By consolidating knowledge, it aims to clarify selecting the most appropriate ECLS modality.Research Design: A comprehensive literature review examined CPB, off-pump techniques, and ECMO outcomes in lung transplantation, including surgical results and complications.Study Sample: Studies, including clinical trials and observational research, focused on ECLS in lung transplantation, both retrospective and prospective, providing a broad evidence base.Data Collection and/or Analysis: Selected studies were analyzed for surgical outcomes, complications, and survival rates associated with CPB, off-pump techniques, and ECMO to assess safety and effectiveness.Results: Off-pump techniques are preferred, with ECMO increasingly vital as a bridge to transplant, overshadowing CPB. However, ECMO entails hidden risks and higher costs. While safer than CPB, optimizing ECMO postoperative use and monitoring is crucial for success.Conclusions: Off-pump techniques are standard, but ECMO's role is expanding. Despite advantages, careful ECMO management is crucial due to hidden risks and costs. Future research should focus on refining ECMO use and monitoring to improve outcomes, emphasizing individualized approaches for LT recipients.

Which strategy is better for lung transplantation: Cardiopulmonary bypass or extracorporeal membrane oxygenation?

We have read the excellent article written by Schurink et al1 with great interest and much appreciation. The authors show that abdominal normothermic regional perfusion is powerful in protecting extended criteria controlled donation after circulatory death (DCD) liver grafts that could be eventually transplanted with results comparable to donation after brain death liver graft transplantation. The conclusions drawn from this study are of great importance for improving the utilization rate of DCD livers. However, there are still some considerations needing further clarification. First, because each country has different standards for the use of DCD donor livers, whether the authors collect the specific reasons for the declined extended criteria DCD livers and the liver biochemical indicators at the time of decline, and if this part is included in the study, we can also see the liver protective potential of NRP more specifically. This will serve as a reference for other countries and may save a part of the liver that should be declined. Second, because of the powerful effect of abdominal normothermic regional perfusion, it can be seen that a large amount of the donor’s liver is wasted; it is time to unify the standard to reduce the declined rate of extended criteria DCD livers. It is possible to appropriately expand the criteria for liver selection during perfusion; however, this procedure must be performed with great caution to prevent severe postoperative complications. Furthermore, increasing evidence has shown that Hypothermic Oxygenated Machine Perfusion (HOPE) plays an excellent role in protecting the donor liver.2 We also suggest that the authors should actively include HOPE in the study to observe whether HOPE can protect the DCD liver and whether NRP + HOPE has a more positive effect, which will significantly improve the utilization rate of the DCD liver and minimize postoperative complications. 

Comment on “Salvage of Declined Extended Criteria DCD Livers Using In-Situ Normothermic Regional Perfusion”

Extracorporeal membrane oxygenation in pregnancy and the postpartum period：A Systematic Review andMeta Analysis

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