Discussion
’, inflammation, post-resuscitation syndrome, pulmonary edema, ARDS, hypertensive
DISEASE COURSE, ADVERSE EVENTS, INFLAMMATION, DISEASE, SEVERE SARS-COV-2 INFECTION, PULMONARY EDEMA, PRESSURE AREA, LEAKAGE, ARDS, EXTRAVASATION, VENTILATOR-ASSOCIATED PNEUMONIA
In this multicenter, double-blinded, randomized trial, FX06 did not alter the thermodilution-measured EVLWi evolution during SARS-CoV-2-induced ARDS. Other markers of pulmonary vascular leakage, e.g., patients’ functional outcomes reflecting pulmonary function and 60-day survival, were also not affected. Although elevated at baseline, circulating markers of inflammation and endothelial lesions were comparable for the 2 groups. Despite their similar rates of serious adverse events, FX06 was associated with higher rates of ventilator-associated pneumonia.Inflammation-induced pulmonary vascular leakage is widely diffused during severe SARS-CoV-2 infection. Autopsies of COVID-19 patients revealed markedly elevated lung weights [However, several factors limit the interpretation of our results. SARS-CoV-2 is responsible for a particular form of ARDS, in which several mechanisms other than VE-cadherin-mediated endothelial barrier disruption could account for vascular leakage that might have masked the FX06 effect. Results of autopsy series previously showed disruption of endothelial tight junctions [Our population had other limitations hampering treatment evaluation. With a median of 13 days between first symptoms and treatment initiation, it is likely that we missed the initial exudative phase of ARDS. That supposition is supported by the elevated EVLWi in our population at baseline. Notably, pulmonary edema remains a dynamic balance between fluid extravasation and resorption. Likewise, VE-cadherin-dependent interendothelial cell-junction stability relies on a dynamic balance between its internalization and recycling to the membrane [Better characterization of vascular leakage kinetics during ARDS in humans and drug evaluation earlier during disease evolution are needed to determine the optimal window for its administration during ARDS. FX06 assessment in other entities with inflammation-induced vascular leakage, that would allow its prompt administration earlier during the disease course, might also be highly contributive. In this setting, post-resuscitation syndrome, in which the drug was highly effective in pre-clinical studies [The dosing regimen used is also open to debate. At a median of 4.2 mg/kg/d, our FX06 dose was close to the optimal one described for animals [Beyond PK, evaluating FX06 biological activity is complex. Although thermodilution-measured EVLWi accurately reflects the level of pulmonary edema [Other techniques might also be more sensitive in detecting vascular leakage and serve as better surrogate markers for FX06 development. Among markers implicated in endothelial physiology, several have been associated with patients’ outcomes after various causes of critical illnesses [VV-ECMO, implanted in one-third of our patients, may have also interfered with the evaluation of an FX06 effect, with the device influencing drug PK. However, considering the low lipophilic properties of FX06, significant adsorption onto the membrane is unlikely. EVLWi evaluation itself is also affected by VV-ECMO blood flow [Our observations on FX06 effect on arterial pressure are noteworthy. After 4 days of treatment, FX06 recipients were indeed less hypertensive than patients given the placebo. Although that finding remains exploratory, it might indicate an FX06 effect on the vasculature to be investigated in future studies.With comparable rates of serious adverse events reported for both trial groups, our results confirm the good safety profile of FX06. Although exploratory, the higher rates of ventilator-associated pneumonia episodes developing in FX06 recipients warrant attention. Fibrin fragment Bβ15-42 was shown to inhibit leukocyte transendothelial migration in vitro [