Add-On Prostaglandin E1 in Venovenous Extracorporeal Membrane Oxygenation: A Randomized, Double-Blind, Placebo-controlled Pilot Trial.

Rationale: Prostaglandin E1 (alprostadil; PGE1), in addition to low-dose unfractionated heparin, increases the biocompatibility of extracorporeal systems and enhances the efficacy of artificial organs without increasing bleeding risk. Objectives: We investigated the safety and efficacy of PGE1 in adults receiving venovenous extracorporeal membrane oxygenation (ECMO). Methods: This study was a randomized, double-blind, placebo-controlled phase II pilot trial at two medical intensive care units at the Medical University of Vienna, Austria. Adults with venovenous ECMO were randomly assigned to receive an intravenous infusion of 5 ng/kg/min PGE1 or placebo (0.9% saline) in addition to standard anticoagulation with unfractionated heparin. Measurements and Main Results: The primary outcome was the rate of transfused packed red blood cells per ECMO day. Secondary outcomes were the incidence of and time to clinically overt bleeding and thromboembolic events. A post hoc subgroup analysis included only patients with coronavirus disease (COVID-19). Between September 2016 and April 2021, of 133 screened patients, 50 patients were randomized, of whom 48 received the assigned study medication (24 per group). The transfusion rate was similar between groups (0.41 vs. 0.39; P = 0.733). PGE1 was associated with fewer thromboembolic events (7 vs. 16; P = 0.020) and longer thromboembolism-free time (hazard ratio [HR], 0.302; P = 0.01), fewer clinically overt bleeding events (2 vs. 11; P = 0.017), and longer bleeding-free time (HR, 0.213; P = 0.047). In patients with COVID-19 (n = 25), the HRs for clinically overt bleeding and thromboembolism were 0.276 (95% confidence interval, 0.035-2.186) and 0.521 (95% confidence interval, 0.149-1.825), respectively. Conclusions: Add-on treatment with PGE1 was safe but did not meet the primary endpoint of reducing the rate of red blood cell transfusions in patients receiving venovenous ECMO. Larger studies need to evaluate the safety and efficacy of additional PGE1 in ECMO. Clinical trial registered with EudraCT (2015-005014-30) and www.clinicaltrials.gov (NCT02895373).

Comparison of Weaning Strategies in Patients Receiving Venovenous Extracorporeal Membrane Oxygenation: An Exploratory Retrospective Study.

Venovenous extracorporeal membrane oxygenation (VV ECMO) facilitates the reduction of mechanical ventilation (MV) support in acute respiratory failure. Contrary to increasing evidence regarding its initiation, the optimal timing of VV ECMO weaning in interaction with MV weaning is undetermined. In this retrospective study, 47 patients who received VV ECMO between 2013 and 2021 and survived ≥1 day after ECMO cessation were divided according to their MV status before ECMO removal: 28 patients were classified into an "ECMO weaning during assisted MV/spontaneous breathing" group and 19 into an "ECMO weaning during controlled MV" group. Extracorporeal membrane oxygenation duration was longer in the "assisted MV/spontaneous breathing" group (17 [Interquartile range (IQR) = 11-35] vs. 6 [5-11] days, p < 0.001). These patients had a longer intensive care unit (ICU) stay after ECMO start (48 [29-66] vs. 31 [15-40] days, p = 0.01). No significant differences were found for MV duration after ECMO start (30 [19-45] vs. 19 [12-30] days, p = 0.06) and further ICU survival (86% vs. 89%, p ≥ 0.9). There was a trend toward more patients with mechanical ECMO complications in the "assisted MV/spontaneous breathing" group (57% vs. 32%, p = 0.08). Thus, our results suggest a possible benefit of early ECMO weaning during controlled MV.

Incidence of heparin resistance and heparin failure in patients receiving extracorporeal membrane oxygenation: an exploratory retrospective analysis.

BACKGROUND: Unfractionated heparin (UFH) is used in most centers for extracorporeal membrane oxygenation (ECMO) anticoagulation. When standard doses do not achieve desired target values, heparin resistance is reported, most commonly defined as doses of UFH > 35 000 IU/d. OBJECTIVES: To study the incidence of heparin resistance and its association with thromboembolic complications in patients requiring ECMO support. METHODS: In this observational cohort study, we included adults who received venovenous, venoarterial ECMO and extracorporeal carbon dioxide removal between January 2010 and May 2022. Main risk factor was heparin resistance (UFH, > 35 000 IU/d or > 20 IU/kg/h); the outcome was thromboembolism. Multivariable Poisson regression was used to estimate the effects of heparin resistance, adjusted for several clinical variables on the thromboembolism rate per 100 ECMO patient-days. RESULTS: Of the 197 patients included, 33 (16.8%) required UFH > 35 000 IU/d and 14 (7.1%) required UFH > 20 IU/kg/h. Thromboembolic complications occurred at a rate of 5.89/100 ECMO d. Heparin resistance was not associated with thromboembolic events (incidence rate ratio [IRR], 0.93; 95% CI, 0.14-5.82), whereas COVID-19 (IRR, 2.33; 95% CI, 1.4-3.96; P < .001) and ECMO type (venoarterial ECMO: IRR, 2.29; 95% CI, 1.34-3.92; P = .002; extracorporeal carbon dioxide removal: IRR, 2.89; 95% CI, 1.46-5.59; P = .002; reference venovenous ECMO) were significantly associated with the risk of thromboembolic events. CONCLUSION: A significant proportion of patients fulfilled the common definition of heparin resistance. However, this did not influence the occurrence of thromboembolic events.

Anticoagulation with argatroban using hemoclot™ targets is safe and effective in CARDS patients receiving venovenous extracorporeal membrane oxygenation: An exploratory bi-centric cohort study.

Direct thrombin inhibitors, including argatroban, are increasingly used for anticoagulation during venovenous extracorporeal membrane oxygenation (VV ECMO). In many centers activated partial thromboplastin time (aPTT) is used for monitoring, but it can be affected by several confounders. The aim of this study was to evaluate the safety and efficacy of anticoagulation with argatroban titrated according to diluted thrombin time targets (hemoclot™ assay) compared to anti-Xa guided anticoagulation with unfractionated heparin (UFH). METHODS: This cohort study included adults at two tertiary care centers who required VV ECMO for severe COVID-19-related acute respiratory distress syndrome (CARDS). Patients received center-dependent argatroban or UFH for anticoagulation during ECMO. Argatroban was guided following a hemoclot™ target range of 0.4-0.6 µg/ml. UFH was guided by anti-factor Xa (antiXa) levels (0.2-0.3 IU/ml). The primary outcome was safety of argatroban compared to UFH, assessed by time to first clinically relevant bleeding event or death during ECMO. Secondary outcomes included efficacy (time to thromboembolism) and feasibility (proportion of anticoagulation targets within range). RESULTS: From 2019 to 2021 57 patients were included in the study with 27 patients (47 %) receiving argatroban and 30 patients (53 %) receiving UFH. The time to the first clinically relevant bleeding or death during ECMO was similar between groups (HR (argatroban vs. UFH): 1.012, 95 % CI 0.44-2.35, p = 0.978). Argatroban was associated with a decreased risk for thromboembolism compared to UFH (HR 0.494 (95 % CI 0.26-0.95; p = 0.034)). The overall proportion of anticoagulation within target ranges was not different between groups (46 % (23-54 %) vs. 46 % (37 %-57 %), p = 0.45). CONCLUSION: Anticoagulation with argatroban according to hemoclot™ targets (0.4-0.6 µg/ml) compared to antiXa guided UFH (0.2-0.3 IU/ml) is safe and may prolong thromboembolism-free time in patients with severe ARDS requiring VV ECMO.

Prevalence and Impact of Lupus Anticoagulant in Patients Receiving Extracorporeal Membrane Oxygenation.

BACKGROUND: Monitoring of blood coagulation is essential in ECMO patients. We investigated the prevalence of lupus anticoagulant (LA) and its association with coagulation testing and hemostaseologic complications in patients treated with ECMO. METHODS: This is a retrospective analysis including adult patients who received ECMO at a medical intensive care unit at the Medical University of Vienna. The primary outcome was the prevalence of LA. Secondary outcomes included conditions associated with LA positivity, rates of bleeding and thromboembolic events, as well as the proportions of aPTT and antiXa measurements within the target range. RESULTS: Between 2013 and 2021 193 patients received ECMO, in 62 (32%) of whom LA diagnostics were performed. Twenty-two (35%) patients tested positive. LA positive patients had more frequently received VV ECMO (77.3% vs 34.3%; p = 0.002), were more frequently diagnosed with viral respiratory infections (SARS-CoV2: 45.5% vs 20%; p = 0.041, influenza virus: 22.7% vs 0%; p = 0.003), had a longer ECMO treatment duration (25 vs 10 days; p = 0.011) and a longer ICU stay (48 vs 25 days; p = 0.022), but similar rates of bleeding and thromboembolic events.

Comparison of Hemostatic Changes in Pump-driven Extracorporeal Carbon Dioxide Removal and Venovenous Extracorporeal Membrane Oxygenation.

Extracorporeal carbon dioxide removal (ECCO 2 R) has gained widespread use as a supposedly less invasive alternative for hypercapnic respiratory failure besides venovenous extracorporeal membrane oxygenation (VV ECMO). Despite technological advances, coagulation-related adverse events remain a major challenge in both therapies. The overlapping operating areas of VV ECMO and pump-driven ECCO 2 R could allow for a device selection targeted at the lowest risk of such complications. This retrospective analysis of 47 consecutive patients compared hemostatic changes between pump-driven ECCO 2 R (n = 23) and VV ECMO (n = 24) by application of linear mixed effect models. A significant decrease in platelet count, increase in D-dimer levels, and decrease of fibrinogen levels were observed. However, except for fibrinogen, the type of extracorporeal support did not have a significant effect on the time course of these parameters. Our findings suggest that in terms of hemocompatibility, pump-driven ECCO 2 R is not significantly different from VV ECMO.

Long-term Respiratory Extracorporeal Membrane Oxygenation and Prognosis: A Retrospective Analysis.

The duration of extracorporeal membrane oxygenation (ECMO) treatments increases, however, data presented from prolonged support is limited. We retrospectively analyzed all patients during a 4-year period undergoing respiratory ECMO for duration of therapy, demographics, therapy-associated parameters, and outcome according to ECMO duration (<28 days and ≥28 days = long-term ECMO). Out of 55 patients undergoing ECMO for ARDS or during bridging to lung transplantation, 18 were on ECMO for ≥28 days (33%). In the long-term group, median ECMO run time was 40 days (interquartile range 34-54 days). Hospital survival was not significantly different between the groups (54% in short-term and 50% in long-term ECMO patients). There was a significantly higher proportion of patients suffering from malignancy in the group of long-term nonsurvivors. Recovery occurred after more than 40 days on ECMO in 3 patients. The longest ECMO run time in a hospital survivor was 65 days. Duration of ECMO support alone was no prognostic factor and should not represent a basis for decision-making. In patients suffering from malignancy, long-term ECMO support seems to be a factor of adverse prognosis, if not futile.

Incidence and Etiology of System Exchanges in Patients Receiving Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) has established as a cornerstone therapy in severe acute respiratory distress syndrome and refractory hemodynamic failure. As circuit integrity is crucial for adequate organ support, component failure may necessitate a system exchange. In this retrospective study, incidence and etiology of system exchanges during applications of venovenous, venoarterial ECMO, and extracorporeal CO2 removal were examined. Sixty-three (44.4%) of 142 patients were affected by one or more exchanges, totaling 105 replaced circuits. The predominant exchange reason was clotting (n = 20), followed by hemolysis (n = 19), systemic coagulation disorders (n = 13), reconfiguration (n = 13), impaired gas exchange (n = 10), mechanical complications (n = 8), bleeding (n = 6), failed weaning (n = 5), prophylactic exchange (n = 3), and undocumented/other (n = 8). Nineteen (18.1%) events were classified as acute and 70 (66.7%) events as elective exchanges. Patients with circuit exchanges more frequently underwent renal replacement therapy at ECMO initiation (49.2% vs. 29.1%; p = 0.023), had a longer ECMO treatment duration (18 vs. 7.5 days, p < 0.001), and lower hospital survival (29.5% vs. 57.1%; p = 0.002). Considering the high occurrence of coagulation complications, further optimization of coagulation management is deemed necessary.

Propofol-based sedation does not negatively influence oxygenator running time compared to midazolam in patients with extracorporeal membrane oxygenation.

OBJECTIVE: Patients on extracorporeal membrane oxygenation are frequently in need for sedation. Use of propofol has been associated with impaired oxygenator function due to adsorption to the membrane as well as lipid load. The aim of our retrospective analysis was to compare two different sedation regimens containing either propofol or midazolam with respect to oxygenator running time. METHODS: Midazolam was used in 73 patients whereas propofol was used in 49 patients, respectively. In the propofol group, veno-arterial-extracorporeal membrane oxygenation was used predominantly (84%), while veno-venous-extracorporeal membrane oxygenation was used more often in the midazolam group (64%). RESULTS: Oxygenator running time until first exchange was 7 days in both groups ( p = 0.759). No statistically significant differences could be observed between the subgroup of patients receiving lipid-free (n = 24) and lipid-containing (n = 31) parenteral nutrition, respectively. Laboratory parameters like triglycerides, free hemoglobin, fibrinogen, platelets, and activated partial thromboplastin time were not significantly different between both sedation regimens ( p = 0.462, p = 0.489, p = 0.960, p = 0.134, and p = 0.843) and were not associated with oxygenator running time. CONCLUSION: The use of propofol as sedative seems suitable in patients undergoing extracorporeal membrane oxygenation therapy.