Laurent Papazian

Background/Objectives: Coronavirus disease 2019 (COVID-19) is associated with immunothrombosis involving endothelial dysfunction and coagulation activation. We aimed to compare biomarkers spanning multiple immunothrombotic pathways between patients with moderate and severe COVID-19 at baseline and according to clinical outcome. Secondary analyses compared biomarker levels at days 3 and 7. Methods: This prospective observational study included 42 hospitalized patients with COVID-19 enrolled between April 2020 and January 2021, comprising 21 with moderate and 21 with severe disease. Biomarkers of coagulation, endothelial dysfunction, endogenous anticoagulant pathways, fibrinolysis, and extracellular vesicle-mediated activity were measured at baseline and on days 3 and 7. The prespecified ventilation/death composite included invasive mechanical ventilation already ongoing at baseline or initiated subsequently and/or death by day 28. Results: Seventeen patients (40.5%) met the composite criterion, including 12 patients already receiving invasive mechanical ventilation at baseline. At baseline, severe disease was associated with higher D-dimer (1.74 [0.87–3.67] vs. 0.68 [0.46–0.94] µg/mL FEU), free tissue factor pathway inhibitor (TFPI; 55.00 [38.00–109.00] vs. 16.00 [14.00–29.00] ng/mL), extracellular vesicle-associated tissue factor activity (EV-TF; 28.86 [13.61–48.72] vs. 5.00 [5.00–5.70] fM), and extracellular vesicle-associated plasmin generation capacity (EV-PGC; 93.36 [41.60–303.10] vs. 24.50 [16.14–35.74] fM; all p < 0.01). Exploratory ROC analyses further illustrated the separation of these biomarker distributions between the predefined clinical groups. Conclusions: Severe COVID-19 and unfavorable outcomes were associated with baseline differences in biomarkers spanning several immunothrombotic pathways, some of which remained detectable at days 3 and 7. Interpretation of the marked TFPI elevation is limited by differences in heparin exposure between severity groups. These exploratory findings require confirmation in larger cohorts, and their incremental value beyond routine clinical assessment remains untested. Outcome analyses largely reflected baseline severity, with only five subsequent events.

Purpose The beneficial effects of systematic cisatracurium administration observed in the ACURASYS randomized, multicenter, double-blinded trial may depend on patient-specific factors. This post hoc analysis aimed to explore whether the impact of cisatracurium on mortality varies with baseline characteristics. Methods A Markov chain analysis was conducted using daily clinical states from inclusion to day 90: death (state 0), under mechanical ventilation (state 1), or weaned and alive at day 90 (state 2). Patient trajectories were modeled accordingly. Results Among the 321 included patients, subgroup analysis following univariate analysis focused on 130 individuals under 60 years with non-fatal McCabe scores. Within this subgroup, cisatracurium administration and absence of vasopressor use significantly reduced the probability of remaining ventilated. Estimated survival increased therefore from 0.63 (placebo group, N = 62) to 0.93 (cisatracurium group, N = 68). In contrast, among patients with a rapidly or ultimately fatal prognosis according to McCabe score, the probability of survival did not differ substantially between the placebo and cisatracurium groups. Among patients with a PaO₂:FiO₂ ratio ≤ 100 mmHg at inclusion (N = 65), the estimated survival rate at day 90 was 0.93 in the cisatracurium arm compared with 0.63 in the placebo arm. For patients with a PaO₂:FiO₂ ratio > 100 mmHg at inclusion (N = 98), the corresponding survival rates were 0.92 and 0.63, respectively. In patients aged ≥ 60 years (N = 158), the daily probability of remaining mechanically ventilated was not influenced by any covariate, including the administration of cisatracurium. These results were confirmed by the performed simulations. Conclusion The systematic and short-term administration of cisatracurium in patients with moderate-to-severe ARDS appears to confer greater survival benefit in those with a higher baseline life expectancy. Further validation through retrospective and prospective studies is warranted.

Background: Few data are available concerning the outcome of patients denied venovenous extracorporeal membrane oxygenation (VV-ECMO) relative to severe acute respiratory distress syndrome (ARDS) due to COVID-19. Methods: We compared the 90-day survival rate of consecutive adult patients for whom our center was contacted to discuss VV-ECMO indication. Three groups of patients were created: patients for whom VV-ECMO was immediately indicated (ECMO-indicated group), patients for whom VV-ECMO was not indicated at the time of the call (ECMO-not-indicated group), and patients for whom ECMO was definitely contraindicated (ECMO-contraindicated group). Results: In total, 104 patients were referred for VV-ECMO support due to severe COVID-19 ARDS. Among them, 32 patients had immediate VV-ECMO implantation, 28 patients had no VV-ECMO indication, but 1 was assisted thereafter, and 44 patients were denied VV-ECMO for contraindication. Among the 44 patients denied, 30 were denied for advanced age, 24 for excessive prior duration of mechanical ventilation, and 16 for SOFA score >8. The 90-day survival rate was similar for the ECMO-indicated group and the ECMO-not-indicated group at 62.1 and 61.9%, respectively, whereas it was significantly lower (20.5%) for the ECMO-contraindicated group. Conclusions: Despite a low survival rate, 50% of patients were at home 3 months after being denied for VV-ECMO for severe ARDS due to COVID-19.

Background: This document updates previously published Clinical Practice Guidelines for the management of patients with acute respiratory distress syndrome (ARDS), incorporating new evidence addressing the use of corticosteroids, venovenous extracorporeal membrane oxygenation, neuromuscular blocking agents, and positive end-expiratory pressure (PEEP). Methods: We summarized evidence addressing four “PICO questions” (patient, intervention, comparison, and outcome). A multidisciplinary panel with expertise in ARDS used the Grading of Recommendations, Assessment, Development, and Evaluation framework to develop clinical recommendations. Results: We suggest the use of: 1) corticosteroids for patients with ARDS (conditional recommendation, moderate certainty of evidence), 2) venovenous extracorporeal membrane oxygenation in selected patients with severe ARDS (conditional recommendation, low certainty of evidence), 3) neuromuscular blockers in patients with early severe ARDS (conditional recommendation, low certainty of evidence), and 4) higher PEEP without lung recruitment maneuvers as opposed to lower PEEP in patients with moderate to severe ARDS (conditional recommendation, low to moderate certainty), and 5) we recommend against using prolonged lung recruitment maneuvers in patients with moderate to severe ARDS (strong recommendation, moderate certainty). Conclusions: We provide updated evidence-based recommendations for the management of ARDS. Individual patient and illness characteristics should be factored into clinical decision making and implementation of these recommendations while additional evidence is generated from much-needed clinical trials.