Comparison of Fibrinogen Concentrate and Cryoprecipitate in Pediatric Cardiac Surgery Patients

Comparison of Fibrinogen Concentrate and Cryoprecipitate in Pediatric Cardiac Surgery Patients

The aim of the current pilot study proposal is to compare the use of the purified human fibrinogen concentrate (Fibryga®, Octapharma USA) to cryoprecipitate for the treatment of cardiopulmonary bypass (CPB)-associated bleeding in pediatric cardiac patients in whom fibrinogen supplementation is indicated.

The investigators' hypothesis is that fibrinogen concentrate will be as effective as cryoprecipitate in achieving adequate hemostasis after separation from CPB in pediatric cardiac surgery patients.

Study Design: this will be a single-center, prospective, randomized, active-control study in pediatric (24 months of age or younger) patients undergoing elective cardiac surgery with CPB (n=30) in-whom fibrinogen supplementation after separation from CPB is indicated, based on the presence of clinically-significant bleeding and documentation of low fibrinogen level on viscoelastic point-of-care testing (MCF < 10 mm on the FIBTEM assay of ROTEM). Informed consent will be obtained from a parent or a legal guardian prior to surgery and anesthesia. Once the need for fibrinogen supplementation is confirmed, study participants will be randomized into one of two treatment groups (n=15 in each group):

1. Cryoprecipitate group (dose: 10 ml/kg; active control group) or
2. Fibrinogen Concentrate group (dose: 70 mg/kg; intervention group). There will be no placebo group since withholding treatment is neither consistent with standard of care nor acceptable ethically. No other aspects of care will be modified. In the event that an additional dose of fibrinogen supplementation is required (bleeding with documented hypofibrinogenemia) cryoprecipitate will be administered to all study subjects (including those who received FC).

The results of this study will be used for publication as well as the first stage towards a significantly larger randomized multi-center trial (see below).

Based on the results of this pilot study the investigators plan to conduct a large multi-center, randomized active-control non-inferiority trial in the future, comparing the use of FC to cryoprecipitate in a much larger cohort of pediatric patients undergoing cardiac surgery with CPB. Ultimately, the results of this trial are likely to improve the care of pediatric cardiac surgical patients experiencing post-CPB bleeding, an under-studied yet high-risk patient population.

Once the need for fibrinogen supplementation is confirmed, study participants will be randomized into one of two treatment groups (n=15 in each group):

1. Cryoprecipitate group (dose: 10 ml/kg; active control group) or
2. Fibrinogen Concentrate group (dose: 70 mg/kg; intervention group). There will be no placebo group since withholding treatment is neither consistent with standard of care nor acceptable ethically. No other aspects of care will be modified. In the event that an additional dose of fibrinogen supplementation is required (bleeding with documented hypofibrinogenemia) cryoprecipitate will be administered to all study subjects (including those who initially received FC).

Data to be obtained:

1. Demographic/preoperative data: collected from the medical record

   • age in days/months (all patients to be younger than 24 months)
   • gender
   • weight
   • preoperative diagnosis
   • surgery type & date (Norwood, arterial switch, truncus arteriosus, Glenn, Fontan, TAPVR, AV canal, tetralogy of Fallot, etc)
   • preoperative standard of care labs PT/aPTT/INR/hgb level/ hematocrit/ platelet count/ fibrinogen level (if exists)/ creatinine

2. Intra-operative Data:

   • CPB time & aortic cross clamp time
   • use of hypothermic circulatory arrest (ice packs placed on the head)
   • was post-CPB ultrafiltration performed?
   • Platelet count prior to separation from CPB
   • was ATIII administered? (thrombate)
   • Transfusion requirements: PRBC/Cell Saver/FFP/PLT/ cryo - to be collected as number of units per each product, not volume. (for PLT - was it pooled PLT or single donor apheresis, if possible)
   • was rFVIIa given (factor seven, novoseven). Please pay attention - the fact that rFVIIa was ordered DOES NOT mean that was actually administered as we order factor VII for ALL big cases (to have available in the OR) but not necessarily administer it
   • Need for ECMO
   • Was the chest left open? (always in ECMO, but open chest does not necessarily mean ECMO)

3. Postoperative Data

   • admission PT/aPTT/INR/platelet count/ fibrinogen level/ hgb level/HCT level (could be obtained from initial ABG)
   • Bleeding (Chest drain/s output)
   • Need for additional transfusion (PRBC/cell saver/FFP/platelets/cryoprecipitate). Will need to know, if possible, whether transfused from same unit that was already exposed to in the OR or new unit (= new exposure)
   • Factor VIIa administration
   • re-exploration? (= starting ECMO in the PICU)
   • delayed chest closure? (will answer whether went to PICU with chest open)

Inclusion Criteria:

• pediatric (age 24 months or younger) patients undergoing elective cardiac surgery with CPB (n=30) in-whom fibrinogen supplementation after separation from CPB is indicated, based on the presence of clinically-significant bleeding and documentation of low fibrinogen level on viscoelastic point-of-care testing (MCF < 10 mm on the FIBTEM assay of ROTEM).

Exclusion Criteria:

• gestational age < 33 weeks at birth
• gestational age < 35 weeks on the day of surgery
• emergency surgery
• patient or parent history of coagulopathy/clotting abnormalities
• patient history of thrombophilia
• refusal to participate in the study,
• known severe allergic reaction/anaphylaxis to fibrinogen concentrate,
• administration of fibrinogen concentrate or cryoprecipitate in the 24 hours prior to surgery
• baseline fibrinogen level higher than 300 mg/dL (to avoid the risk of increasing the fibrinogen level above the normal upper level of 400 mg/dL)