PGE1 as Additive Anticoagulant in ECMO-Therapy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Respiratory Distress Syndrome, Adult, Extracorporeal Membrane Oxygenation

Intervention / Treatment
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* Drug: Alprostadil
* Drug: 0.9% sodium chloride solution


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alprostadil<br>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 | Drug: Alprostadil<br>* 5ng/kg/min, continuously, start within 24h of initiation of ECMO therapy and end at the end of ECMO therapy<br>|
| Placebo Comparator: Placebo<br>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 | Drug: 0.9% sodium chloride solution<br>* continuously, start within 24h of initiation of ECMO therapy and end at the end of ECMO therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of bleeding incidences and severity of bleeding (bleeding grades) | 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 | up to six months | 
| Number of Clotting Events | 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. | up to six months | 
| Function of the membrane oxygenator | 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. | up to six months | 
| Number of changes of the membrane oxygenator relative to the duration of ECMO therapy | Membrane oxygenators need to be changed due to loss of function (cause by clotting etc.). | up to six months | 
| Inflammation specific biomarkers (i.e. C-reactive protein, blood counts, reticulated platelets, etc.) | daily routine measurements and frozen plasma | 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 | 
| Global Coagulation assays |  | 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 | 
| Thromboelastometry |  | 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 | 
| platelet function analyzer-100 |  | 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 | 
| Fibrinogen levels |  | 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 | 
| whole blood aggregometry |  | 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 | 
| D-Dimer levels |  | 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 | 
| Catecholamines | need for and dose of catecholamines | 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 | 
| cardiac output |  | 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 | 
| blood pressure |  | 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 | 
| mortality | by chart review or telephone call | 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 | 
| number of platelet transfusions, fresh frozen plamsa, coagulation interventions etc. | by chart review, number relative to the duration of ECMO therapy | up to six months | 
| number of platelet transfusions | by chart review, number relative to the duration of ECMO therapy | up to six months | 
| number of coagulation interventions | by chart review, number relative to the duration of ECMO therapy | up to six months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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platelet inhibition, alprostadil, extracorporeal membrane oxygenation, bleeding, thromboembolic