Reduced anticoagulation strategy is associated with a lower incidence of intracerebral hemorrhage in COVID-19 patients on extracorporeal membrane oxygenation.

BACKGROUND: Optimal anticoagulation strategies for COVID-19 patients with the acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) remain uncertain. A higher incidence of intracerebral hemorrhage (ICH) during VV ECMO support compared to non-COVID-19 viral ARDS patients has been reported, with increased bleeding rates in COVID-19 attributed to both intensified anticoagulation and a disease-specific endotheliopathy. We hypothesized that lower intensity of anticoagulation during VV ECMO would be associated with a lower risk of ICH. In a retrospective, multicenter study from three academic tertiary intensive care units, we included patients with confirmed COVID-19 ARDS requiring VV ECMO support from March 2020 to January 2022. Patients were grouped by anticoagulation exposure into higher intensity, targeting anti-factor Xa activity (anti-Xa) of 0.3-0.4 U/mL, versus lower intensity, targeting anti-Xa 0.15-0.3 U/mL, cohorts. Mean daily doses of unfractionated heparin (UFH) per kg bodyweight and effectively measured daily anti-factor Xa activities were compared between the groups over the first 7 days on ECMO support. The primary outcome was the rate of ICH during VV ECMO support. RESULTS: 141 critically ill COVID-19 patients were included in the study. Patients with lower anticoagulation targets had consistently lower anti-Xa activity values over the first 7 ECMO days (p < 0.001). ICH incidence was lower in patients in the lower anti-Xa group: 4 (8%) vs 32 (34%) events. Accounting for death as a competing event, the adjusted subhazard ratio for the occurrence of ICH was 0.295 (97.5% CI 0.1-0.9, p = 0.044) for the lower anti-Xa compared to the higher anti-Xa group. 90-day ICU survival was higher in patients in the lower anti-Xa group, and ICH was the strongest risk factor associated with mortality (odds ratio [OR] 6.8 [CI 2.1-22.1], p = 0.001). CONCLUSIONS: For COVID-19 patients on VV ECMO support anticoagulated with heparin, a lower anticoagulation target was associated with a significant reduction in ICH incidence and increased survival.

Outcomes of patients with acute respiratory failure on veno-venous extracorporeal membrane oxygenation requiring additional circulatory support by veno-venoarterial extracorporeal membrane oxygenation.

Objective: Veno-venous (V-V) extracorporeal membrane oxygenation (ECMO) is increasingly used to support patients with severe acute respiratory distress syndrome (ARDS). In case of additional cardio-circulatory failure, some experienced centers upgrade the V-V ECMO with an additional arterial return cannula (termed V-VA ECMO). Here we analyzed short- and long-term outcome together with potential predictors of mortality. Design: Multicenter, retrospective analysis between January 2008 and September 2021. Setting: Three tertiary care ECMO centers in Germany (Hannover, Bonn) and Switzerland (Zurich). Patients: Seventy-three V-V ECMO patients with ARDS and additional acute cardio-circulatory deterioration required an upgrade to V-VA ECMO were included in this study. Measurements and main results: Fifty-three patients required an upgrade from V-V to V-VA and 20 patients were directly triple cannulated. Median (Interquartile Range) age was 49 (28-57) years and SOFA score was 14 (12-17) at V-VA ECMO upgrade. Vasoactive-inotropic score decreased from 53 (12-123) at V-VA ECMO upgrade to 9 (3-37) after 24 h of V-VA ECMO support. Weaning from V-VA and V-V ECMO was successful in 47 (64%) and 40 (55%) patients, respectively. Duration of ECMO support was 12 (6-22) days and ICU length of stay was 32 (16-46) days. Overall ICU mortality was 48% and hospital mortality 51%. Two additional patients died after hospital discharge while the remaining patients survived up to two years (with six patients being lost to follow-up). The vast majority of patients was free from higher degree persistent organ dysfunction at follow-up. A SOFA score > 14 and higher lactate concentrations at the day of V-VA upgrade were independent predictors of mortality in the multivariate regression analysis. Conclusion: In this analysis, the use of V-VA ECMO in patients with ARDS and concomitant cardiocirculatory failure was associated with a hospital survival of about 50%, and most of these patients survived up to 2 years. A SOFA score > 14 and elevated lactate levels at the day of V-VA upgrade predict unfavorable outcome.

Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome.

BACKGROUND: A higher-than-usual resistance to standard sedation regimens in COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) has led to the frequent use of the second-line anaesthetic agent ketamine. Simultaneously, an increased incidence of cholangiopathies in mechanically ventilated patients receiving prolonged infusion of high-dose ketamine has been noted. Therefore, the objective of this study was to investigate a potential dose-response relationship between ketamine and bilirubin levels. METHODS: Post hoc analysis of a prospective observational cohort of patients suffering from COVID-19-associated ARDS between March 2020 and August 2021. A time-varying, multivariable adjusted, cumulative weighted exposure mixed-effects model was employed to analyse the exposure-effect relationship between ketamine infusion and total bilirubin levels. RESULTS: Two-hundred forty-three critically ill patients were included into the analysis. Ketamine was infused to 170 (70%) patients at a rate of 1.4 [0.9-2.0] mg/kg/h for 9 [4-18] days. The mixed-effects model revealed a positively correlated infusion duration-effect as well as dose-effect relationship between ketamine infusion and rising bilirubin levels (p < 0.0001). In comparison, long-term infusion of propofol and sufentanil, even at high doses, was not associated with increasing bilirubin levels (p = 0.421, p = 0.258). Patients having received ketamine infusion had a multivariable adjusted competing risk hazard of developing a cholestatic liver injury during their ICU stay of 3.2 [95% confidence interval, 1.3-7.8] (p = 0.01). CONCLUSIONS: A causally plausible, dose-effect relationship between long-term infusion of ketamine and rising total bilirubin levels, as well as an augmented, ketamine-associated, hazard of cholestatic liver injury in critically ill COVID-19 patients could be shown. High-dose ketamine should be refrained from whenever possible for the long-term analgosedation of mechanically ventilated COVID-19 patients.