PACE: Prostacyclin AntiCoagulation in ECMO

Safety and Maximum Tolerated Dose

The primary outcome is to determine the MTD of continuous infusion epoprostenol, defined as a DLT rate ≥ 33.3% after a cohort has enrolled and study drug received. There are 3 DLTs defined for this study and will be followed for 24 hours after end of infusion: 1. Adverse Hemodynamic Effects - in the first 4 hours following target dose, sustained decreases in mean arterial pressure, increases in vasopressor/inotropic support, or administration of 40 mL/kg or \>2 L of fluid to treat hypotension; between 4-72h if any of the above hemodynamic changes occur, the independent medical monitor (IMM) will adjudicate 2. Clinically Significant Bleeding - adapted from ECMO-CENTRAL definitions for the duration of epoprostenol infusion 3. Clinically Significant Pulmonary Edema - in the first 4 hours following target dose and defined through combination of changes in lung ultrasound score and changes in oxygenation; between 4-72h if any of the above hemodynamic changes occur, the IMM will adjudicate

Determination of the Steady State Concentration of Epoprostenol Metabolites

We will determine the steady-state concentration (Css) of epoprostenol metabolites in each patient. In a standard patient receiving drug by continuous infusion, Css is defined as: Css = R0/CL, where R0 is the rate of infusion and CL is the patient's clearance of the drug. In a patient on ECMO, clearance will include patient clearance (CLp) and sequestration of drug by the circuit (CLs). The half-life of epoprostenol metabolites is \~15 minutes, so our first PK sampling time point (4 hours) will allow evaluation of ongoing sequestration across the ECMO circuit, since the patient should be at steady state at this time. We will compare metabolite concentrations at the 3 sampling sites - pre-membrane, post-membrane, and patient (arterial) - to determine sequestration at this time point. It is expected that sequestration is saturable and will not be ongoing at 24 hours.

Population Pharmacokinetic Analysis

As an exploratory analysis, we will perform population PK (popPK) analysis using all available concentration data from enrolled patients. The objective of the popPK analysis is to develop metabolite-only models for each metabolite. Since parent drug concentrations will not be available, we will assume a two-compartment structure where drug is administered into the first (latent) compartment and only the 2nd compartment is observed. In this setup, k12 will represent formation of the metabolite. Because the fraction of parent drug converted to each metabolite will not be known, all PK parameters (CL, V) will be apparent parameters. As the data allows, more complex model structures will be explored. Covariate analysis will be used to statistically evaluate how factors relating to ECMO (flow rate, circuit age, etc.) and the patient (age, renal function, etc.) influence epoprostenol metabolite PK.

Thromboelastography (TEG) with platelet mapping

To evaluate the effect of epoprostenol on platelet function within the ECMO circuit environment and patient, thromboelastography (TEG) with platelet mapping, focusing on the Maximum Amplitude (MA) parameter, will be measured at various timepoints during epoprostenol infusion.

Light-transmission aggregometry

To evaluate the effect of epoprostenol on platelet function within the ECMO circuit environment and patient, light-transmission aggregometry against ADP, thrombin, TRAP, and CRP-A agonists will be utilized at various timepoints during epoprostenol infusion.

Exploratory Efficacy

To observe circuit integrity (development and/or progression of circuit thrombosis and fibrin deposition) via visual inspection and qualitative descriptions by ECMO specialists. Due to the infusion period being 48 hours, longer term assessments of ECMO circuit efficacy outside of infusion period will be confounded by short epoprostenol exposure in relation to total ECMO duration.

Platelet transfusion Requirements

A surrogate marker for platelet consumption, platelet transfusion requirements, before, during, and after study drug infusion for the duration of ECMO will be determined using amount of daily platelet transfusion (in ml/kg recieved by subject). Differences in platelet requirements in the three phases in relation to study drug will be compared both within subject and across subjects in a study groups.

Platelet Count Trend

A surrogate marker for platelet consumption, platelet count (10³/µL) will be followed before, during, and after study drug infusion for the duration of ECMO. Platelelt count trajectories, in coordination with transfusion requirements, will be compared both within subject and across subjects within a study groups.

Anticoagulation Dose

Heparin (units/kg/hr) or Bivalirudin (mg/kg/hr) continuous infusion dosing regiments and their corresponding laboratory evaluations PTT (seconds), unfractionated heparin anti-Xa (IU/ml), and DTI (microgram/ml) will be followed prior to, during, and after study drug infusion while subject is on ECMO. Dose changes and laboratory data will be compared per patient before and after study drug infusion.