Purpose: This scoping review aims to identify and describe knowledge gaps and research priorities in veno-arterial extracorporeal membrane oxygenation (VA-ECMO).Methods: An expert panel was recruited consisting of eight international experts from different backgrounds. First, a list of priority topics was made. Second, the panel developed structured questions using population, intervention, comparison and outcomes (PICO) format. All PICOs were scored and prioritized. For every selected PICO, a structured literature search was performed.Results: After an initial list of 49 topics, eight were scored as high-priority. For most of these selected topics, current literature is limited to observational studies, mainly consisting of retrospective cohorts. Only for ECPR and anticoagulation, randomized controlled trials (RCTs) have been performed or are ongoing. Per topic, a summary of the literature is stated including recommendations for further research.Conclusions: This scoping review identifies and presents an overview of knowledge gaps and research priorities in VA-ECMO. Current literature is mostly limited to observational studies, although with increasing attention for this patient population, more RCTs are finishing or ongoing. Translational research, from preclinical trials to high-quality or randomized controlled trials, is important to improve the standard practices in this critically ill patient population.Take-home messageThis scoping review identifies and presents an overview of research gaps and priorities in VA-ECMO. Translational research, from preclinical trials to high-quality or randomized controlled trials, is important to improve the standard practices in this critically ill patient population.

Veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO) is used in case of potentially reversible cardiac failure and restores systemic hemodynamics. However, whether this is followed by improvement of microcirculatory perfusion is unknown. Moreover, critically ill patients have possible pre‐existing microcirculatory perfusion disturbances. Therefore, this review provides an overview of alterations in sublingual microcirculatory perfusion in critically ill adult patients receiving VA‐ECMO support. Pubmed, Embase (Ovid), Cochrane Central Register of Controlled Trials, and Web of Science were systematically searched according to PRISMA guidelines. Studies reporting sublingual microcirculatory perfusion measurements in adult patients supported by VA‐ECMO were included. Outcome parameters included small vessel density (SVD), perfused vessel density (PVD), perfused small vessel density (PSVD), proportion of perfused vessels (PPV), microvascular flow index (MFI) and the heterogeneity index (HI). The protocol was registered at PROSPERO (CRD42021243930). The search identified 1215 studies of which 11 were included. Cardiogenic shock was the most common indication for VA‐ECMO (n=8). Three studies report increased PSVD, PPV, and MFI 24 hours after initiation of ECMO compared to pre‐ECMO. Nonetheless, microcirculatory perfusion stabilized thereafter. Four out of four studies showed higher PSVD and PPV in survivors compared to non‐survivors. Over time, survivors showed recovery of microcirculatory perfusion within hours of initiation of ECMO, whereas this was absent in non‐survivors. Notwithstanding the limited sample, VA‐ECMO seems to improve microcirculatory perfusion shortly after initiation of ECMO, especially in survivors. Further research in larger cohorts is needed to clarify the longitudinal effects of ECMO on microcirculatory perfusion.

Alterations in platelet function have been implicated in the pathophysiology of COVID-19 since the beginning of the pandemic. While early reports linked hyperactivated platelets to thromboembolic events in COVID-19, subsequent investigations demonstrated hyporeactive platelets with a procoagulant phenotype. Mitochondria are important for energy metabolism and the function of platelets. Here, we sought to map the energy metabolism of platelets in a cohort of noncritically ill COVID-19 patients and assess platelet mitochondrial function, activation status, and responsiveness to external stimuli. We enrolled hospitalized COVID-19 patients and controls between October 2020 and December 2021. Platelets function and metabolism was analyzed by flow cytometry, metabolomics, glucose fluxomics, electron and fluorescence microscopy and western blot. Platelets from COVID-19 patients showed increased phosphatidylserine externalization indicating a procoagulant phenotype and hyporeactivity to ex vivo stimuli, associated with profound mitochondrial dysfunction characterized by mitochondrial depolarization, lower mitochondrial DNA–encoded transcript levels, an altered mitochondrial morphology consistent with increased mitochondrial fission, and increased pyruvate/lactate ratios in platelet supernatants. Metabolic profiling by untargeted metabolomics revealed NADH, NAD⁺, and ATP among the top decreased metabolites in patients’ platelets, suggestive of energy metabolism failure. Consistently, platelet fluxomics analyses showed a strongly reduced utilization of ¹³C-glucose in all major energy pathways together with a rerouting of glucose to de novo generation of purine metabolites. Patients’ platelets further showed evidence of oxidative stress, together with increased glutathione oxidation and synthesis. Addition of plasma from COVID-19 patients to normal platelets partially reproduced the phenotype of patients’ platelets and disclosed a temporal relationship between mitochondrial decay and (subsequent) phosphatidylserine exposure and hyporeactivity. These data link energy metabolism failure in platelets from COVID-19 patients with a prothrombotic platelet phenotype with features matching cell death.

Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for patients with circulatory and/or pulmonary failure; however, the rate of complications remains high. ECMO induces systemic inflammation, which may activate and damage the endothelium, thereby causing edema and organ dysfunction. Advancing our understanding in this area is crucial for improving patient outcomes during ECMO. The goal of this review is to summarize the current evidence of the effects of ECMO on endothelial activation and damage in both animals and patients. PubMed and Embase databases were systematically searched for both clinical and animal studies including ECMO support. The outcome parameters were markers of endothelial activation and damage or (in)direct measurements of endothelial permeability, fluid leakage and edema. In total, 26 studies (patient n = 16, animal n = 10) fulfilled all eligibility criteria, and used VA-ECMO (n = 13) or VV-ECMO (n = 6), or remained undefined (n = 7). The most frequently studied endothelial activation markers were adhesion molecules (ICAM-1) and selectins (E- and P-selectin). The levels of endothelial activation markers were comparable to or higher than in healthy controls. Compared to pre-ECMO or non-ECMO, the majority of studies showed stable or decreased levels. Angiopoietin-2, von Willebrand Factor and extracellular vesicles were the most widely studied circulating markers of endothelial damage. More than half of the included studies showed increased levels when compared to normal ranges, and pre-ECMO or non-ECMO values. In healthy animals, ECMO itself leads to vascular leakage and edema. The effect of ECMO support in critically ill animals showed contradicting results. ECMO support (further) induces endothelial damage, but endothelial activation does not, in the critically ill. Further research is necessary to conclude on the effect of the underlying comorbidity and type of ECMO support applied on endothelial dysfunction.

Endotheliopathy plays a role in the development of acute kidney and lung injury in COVID-19, probably due to inflammation, endothelial permeability, vascular leakage and edema formation. This study examined alterations in the circulation of patients with mild and severe COVID-19 on in vitro endothelial permeability and its relation to the endothelial angiopoietin/Tie2 system, which is involved in the regulation of endothelial permeability. Plasma was obtained from COVID-19 patients admitted to the ward (n = 14) or ICU (n = 20) at admission and after 1 and 2 weeks and healthy controls (n = 5). Human kidney and lung endothelial cells were exposed to patient plasma and treated with recombinant angiopoietin-1. In vitro endothelial barrier function was assessed using electric cell-substrate impedance sensing. Circulating markers of the angiopoietin/Tie2 system, endothelial dysfunction and glycocalyx degradation were measured by ELISA. Plasma from COVID-19 patients reduced endothelial resistance compared to healthy controls, but COVID-19 plasma-induced drop in endothelial resistance did not differ between ward and ICU patients. Circulating angiopoietin-2, soluble Tie2 and soluble Tie1 levels increased over time in ICU patients, whereas levels remained stable in ward patients. The increase in angiopoietin-2 was able to predict 90-day mortality (AUC = 0.914, p < 0.001). Treatment with recombinant angiopoietin-1 did not restore COVID-19 plasma-induced hyperpermeability. In conclusion, these results suggest that indirect effects of the virus represented in the circulation of COVID-19 patients induced endothelial hyperpermeability irrespective of disease severity and changes in the endothelial angiopoietin/Tie2 system. Nonetheless, angiopoietin-2 might be of interest in the context of organ injury and patient outcome in COVID-19.

Acute kidney injury (AKI) is a common complication following cardiac surgery with cardiopulmonary bypass (CPB). This study investigated whether cell-free hemoglobin (CFHb) levels after CPB are associated with endothelial damage and postoperative AKI in patients with preexisting renal dysfunction. A substudy of a randomized controlled trial. Secondary referral and tertiary hospital. Adult patients undergoing cardiac surgery with CPB and an estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m² or diabetes mellitus with an eGFR of <60 mL/min/1.73 m². Clinical data and plasma samples were collected after induction of anesthesia, within 1 hour at the intensive care unit, and 24 and 48 hours postoperatively. Of the 89 patients included, 21% developed AKI. CFHb peaked at 1 hour postoperatively (22.5 v 5.4 mg/dL, p < 0.001), and lactate dehydrogenase rose until 48 hours postoperatively (119 v 339 U/L, p < 0.001). Tumor necrosis factor α and intercellular adhesion molecule 1 increased following surgery (7.06 v 9.21 ng/mL, p = 0.020; 247 v 388 ng/mL, p < 0.001). Angiopoietin-2 rose until 48 hours postoperatively and was higher in patients with AKI at 24 hours (4,162 v 3,374 pg/mL, p = 0.027). Similarly, neutrophil gelatinase-associated lipocalin increased in patients with AKI (43.1 v 88.0 ng/mL, p < 0.001). CFHb at 1 hour postoperatively was not associated with angiopoietin-2 at 24 or 48 hours. Adding CFHb to a prediction model of AKI did not improve model fit (p = 0.28) or discrimination (p = 0.32). This study demonstrates that CPB induces hemolysis and endothelial activation and damage in patients with preexisting renal dysfunction. Although CFHb concentrations were higher in those developing AKI, CFHb did not predict AKI or correlate with markers of endothelial damage.