PGE1 as Additive Anticoagulant in ECMO-Therapy (ECMO_PGE1)

A Prospective Randomized, Double Blind Study on Safety and Efficacy of Alprostadil as Additional Anticoagulant in Patients With Veno- Venous Extracorporeal Membrane Oxygenation (ECMO)

After completion of pilot study (n=50) no effect on primary outcome and limited feasibility of recruitment and study procedures

Bleeding complications and thromboembolic complications are frequent during extracorporeal membrane oxygenation (ECMO). Retrospective data suggest that platelet inhibition using prostaglandins, in this case PGE1, may reduce thromboembolic complications without increasing the bleeding risk. This randomized, double-blind trial aims to investigate the effects of PGE1 on bleeding risk, thromboembolic complications and the function of the ECMO.

Prostaglandins may inhibit platelet activation via the P2Y1 ADP receptor. Platelets may contribute to thromboembolic complications and coagulation activation during ECMO therapy. Retrospective data suggest that treatment with PGE1 may serve beneficial by reducing the amount of heparin needed for inhibition of coagulation activation, and by reducing the thromboembolic risk without increasing the risk of bleeding. Inhibition of platelets via PGE1 (Alprostadil) may be interesting in this setting, because, in contrast to other platelet inhibitors, it has a very short half-life and platelets remain susceptible for activation by more potent agonists (i.e. thrombin, ADP). Thus, although reducing the contribution of platelets to coagulation activation, it may not affect safety of participating subjects. This randomized, double-blind, placebo controlled trial will investigate whether treatment of patients with ECMO therapy proves beneficial.

heparin (dose adjusted to aptt 50-60s) + Alprostadil (=PGE1) 5ng/kg/min, continuously, start within 24h of initiation of ECMO therapy and end at the end of ECMO therapy

heparin (dose adjusted to aptt 50-60s) + 0.9% sodium chloride infusion, continuously, start within 24h of initiation of ECMO therapy and end at the end of ECMO therapy

5ng/kg/min, continuously, start within 24h of initiation of ECMO therapy and end at the end of ECMO therapy

Bleeding rate (quantified by the number of packed red blood cells transfused in relation to the duration of ECMO therapy)

The bleeding rate will be quantified by the number of packed red blood cells in relation to the duration of ECMO therapy. This duration may vary and cannot be predicted. Thus, we will calculate the required number of packed red blood cells i.e. per week.

type 0: no bleeding type1: bleeding that is not actionable type 2: any overt actionable sign of hemorrhage type3: a) overt bleeding plut hb drop of 3-5g/dl b) >5g/dl, cardiac tamponade, requiring surgical intervention, bleeding requiring vasoactive agents c)intracranial bleeding, type 5: fatal bleeding number and severity of bleeding relative to the duration of ECMO therapy

clinically noticeable thromboembolic events cannulized veins (Duplex 24h after canula removal) need of Membrane- changes,, macroscopic thrombus, discoloration Global clotting tests (prothrombin time, activated partial thromboplastin time, Fibrinogen, D-Dimer) number of Clotting events in relation to the duration of ECMO therapy.

The function of the membrane oxygenator will be assessed on a daily basis as part of clinical routine.This includes the capacity of oxygen transfer and carbon-dioxide (CO2) transfer.

Inflammation specific biomarkers (i.e. C-reactive protein, blood counts, reticulated platelets, etc.)

Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months

Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months

Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months

Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months

Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months

Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months

Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months

Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months

Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months

Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months

Day 28/90, ICU mortality assessed at the discharge from the Intensive Care unit, this will be up to 12 months after inclusion into the study

Inclusion Criteria: minimum age 18 years Veno-Venous- ECMO Minimum of 24h planned ECMO- therapy Exclusion Criteria: • Long- term therapy with other antiplatelet drugs including Acetyl Salicylic Acid known Heparin induced thrombocytopenia Bleeding diathesis = contraindication for heparin (e.g. GI-bleeding, Intracerebral bleeding) Platelets < 50 G/L Thromboplastin time < 50% Pregnancy Patient < 18 years prothrombin time <50% Drop out criteria: Major bleeding (from Type 3 bleeding; see "primary objective") Occurrence of HIT (4 T- Score: Number of platelets, development over time, manifestation of thrombosis, other reasons for thrombocytopenia [10]) Plt < 50 G/l

Data will be published in a peer-reviewed journal, individual data will not be made publicly available except by a direct request to the PI (in an anonymized fashion)

Buchtele N, Schorgenhofer C, Schwameis M, Jilma B, Schellongowski P, Herkner H, Riss K, Schmid M, Hermann A, Robak O, Nagler B, Traby L, Bojic A, Staudinger T. Add-On Prostaglandin E1 in Venovenous Extracorporeal Membrane Oxygenation: A Randomized, Double-Blind, Placebo-controlled Pilot Trial. Am J Respir Crit Care Med. 2022 Jul 15;206(2):170-177. doi: 10.1164/rccm.202110-2359OC.