ZEPLAST- PED: ZEro_PLASma Trial in Small Infants Undergoing Cardiac Surgery

Study Overview
=================
Brief Summary
-----------------
In pediatric patients (newborns and infants weighing less than 10 kg) undergoing cardiac surgery with extracorporeal circulation postoperative bleeding represents a known complication with a significant impact on outcome. Fresh frozen plasma (FFP) for bleeding management is associated, particularly in this kind of patients, to volume overload and a significative increase of Transfusion Related Acute Lung Injury (TRALI), further worsening the postoperative outcome. In the adult patient FFP employment could be almost completely canceled by administration of concentrated hemostatic components - the fibrinogen concentrate and prothrombin complex concentrate (PCC). We designed this phase II pilot study to establish whether an analogous strategy, modified accordingly to pediatric physiology, could be safely and successfully applied in newborns and infants.

Detailed Description
-----------------
The study population will be randomized to two groups: ZEPLAST and control, respectively. The two groups will receive the same priming solution (containing Red Blood Cells and albumin 5%) and heparin/protamine management. In both groups coagulation will be assessed with rotational thromboelastometry (ROTEM - EXTEM, INTEM, HEPTEM and FIBTEM tests) after heparin antagonization. In case of bleeding, coagulopathies will be treated differently: in the ZEPLAST group, fibrinogen deficiency (FIBTEM Maximum Clot Firmness MCF < 8 mm) will be treated with 30 mg/kg of concentrated fibrinogen; low thrombin generation (EXTEM Clotting Time CT > 100 s) will be treated with 20 mg/kg of prothrombin complex concentrate; in the control group, coagulopathies will be treated with 10-20 ml/kg of FFP. In case of refractory bleeding, PCC and fibrinogen can be administered as a rescue treatment. Further ROTEM tests will be performed at 24 and 48 hours post surgery. Outcome parameters will be collected at the same timepoints.

Official Title
-----------------
ZEPLAST- PED: ZEro_PLASma Trial in Small Infants Undergoing Cardiac Surgery Randomized Controlled Pilot Phase II Study

Conditions
-----------------
Bleeding, Cardiac Defect, Surgery--Complications, Fibrinogenopenia; Acquired, Transfusion-Related Acute Lung Injury, Transfusion-Associated Circulatory Overload, Congenital Heart Disease

Intervention / Treatment
-----------------
* Drug: Fibrinogen Concentrate Human
* Drug: Prothrombin Complex Concentrate
* Biological: Fresh Frozen Plasma


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: newborns and infants with weight lower than 10 kg undergoing cardiac surgery with extracorporeal circulation: informed consent signed by both parents or legal guardian. Exclusion Criteria: emergency surgery; known congenital coagulopathy or suspected based on anamnesis; participation to other clinical trials; known hypersensitivity to components and excipients of FFP , prothrombin complex concentrate or fibrinogen concentrate.

Ages Eligible for Study
-----------------
Minimum Age: 1 Day
Maximum Age: 2 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZEPLAST<br>In case of bleeding and: CT INTEM > CT HEPTEM by 25% : give protamine 0.25 mg/kg; MCF FIBTEM < 8 mm : give Fibrinogen Concentrate 30 mg/kg; CT EXTEM > 100 s : give Prothrombin Complex Concentrate 20 mg/kg. | Drug: Fibrinogen Concentrate Human<br>* Treatment of acquired postoperatively fibrinogen deficiency as assessed by ROTEM FIBTEM test.<br>* Other names: Haemocomplettan;Drug: Prothrombin Complex Concentrate<br>* Treatment of acquired postoperatively thrombin generation deficiency as assessed by ROTEM EXTEM test.<br>* Other names: Confidex;|
| Active Comparator: Control<br>In case of bleeding and: CT INTEM > CT HEPTEM by 25% : give protamine 0.25 mg/kg; fibrinogen and/or thrombin generation deficiency : give FFP 10-20 ml/kg. | Biological: Fresh Frozen Plasma<br>* Treatment of acquired postoperative coagulopathy as assessed by ROTEM FIBTEM and INTEM tests.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transfusion of Fresh Frozen Plasma (FFP) | Number of patients transfused with FFP | First 48 hours after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative bleeding | Amount of blood collected by chest drainages | First 12, 24 and 48 hours after surgery | 
| Severe bleeding | Number of patients who experienced severe bleeding (higher than 30 ml/kg in the first 12 hours after surgery) | First 12 hours after surgery | 
| Surgical re-exploration for bleeding | Number of patients requiring surgical re-exploration due to bleeding (bleeding with no coagulopathies detected or refractory to pharmacological treatment) | First 12, 24 and 48 hours after surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
bleeding, pediatric cardiac surgery, fresh frozen plasma, fibrinogen concentrate, prothrombin complex concentrate