Pediatric HD, Bleeding
Conditions
Brief summary
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.
Detailed description
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)
Interventions
DRUGFibrinogen
Fibrinogen Concentrate (Human) Injection \[Fibryga\] (dose: 70 mg/kg; intervention group). 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).
DRUGCryoprecipitate
Cryoprecipitate group (dose: 10 ml/kg; active control group) 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).
Sponsors
University of Virginia
Octapharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 24 Months
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| A Composite of the Number of Any Allogeneic Blood Products (RBCs, Plasma, Platelets, Cryoprecipitate) Transfused From Administration of the Study Medication Until 48 Hours After Surgery | from immediately after the administration of the fibrinogen concentrate or cryoprecipitate through the first 48 hours after admission to the ICU/post anesthesia care unit | comparison between study groups of the number of allogeneic blood products transfused (RBC, plasma, platelets, cryoprecipitate) from immediately after the administration of the study drug (fibrinogen concentrate or cryoprecipitate) until 48 hours since admission to the ICU |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Post CPB Bleeding (in ml) Between the Study Groups | from administration of fibrinogen concentrate or cryoprecipitate until 48 hours after primary postoperative admission to the ICU | (intraoperatively = cell saver volume in ml; postoperatively = chest drain output in ml) |
| Comparison of the Number RBC Units Transfused Immediately After Administration of the Study Medication and Until Postoperative Day 7 | From immediately after study medication administration through postoperative day 7 | Comparison between the study groups of the number of RBC units transfused immediately after administration of the study medication (fibrinogen concentrate or cryoprecipitate) until postoperative day 7 |
| Comparison of the Number Platelets Units Transfused Immediately After Administration of the Study Medication and Until Postoperative Day 7 | From immediately after study medication administration through postoperative day 7 | Comparison between the study groups of the number of platelets units transfused immediately after administration of the study medication (fibrinogen concentrate or cryoprecipitate) until postoperative day 7 |
| Comparison of the Number Plasma Units Transfused Immediately After Administration of the Study Medication and Until Postoperative Day 7 | From immediately after study medication administration through postoperative day 7 | Comparison between the study groups of the number of plasma units transfused immediately after administration of the study medication (fibrinogen concentrate or cryoprecipitate) until postoperative day 7 |
| Comparison of Additional Number Cryoprecipitate Units Transfused Immediately After Administration of the Study Medication and Until Postoperative Day 7 | From immediately after study medication administration through postoperative day 7 | Comparison between the study groups of the number of additional cryoprecipitate units transfused immediately after administration of the study medication (fibrinogen concentrate or cryoprecipitate) until postoperative day 7 |
| Number of Participants With Postoperative Surgical Chest Re-exploration for Excessive Bleeding/Cardiac Tamponade | from admission to the ICU until postoperative day 7 | Comparison between study groups of the number of participants with postoperative surgical chest re-exploration in the ICU/OR for excessive bleeding or cardiac tamponade |
| Incidence of the Use of Factor VIIa for Bleeding | from separation from CPB until 48 hours after surgery | comparison of percent of patients requiring factor VIIa for bleeding (intraoperatively or postoperatively in the ICU between the study groups |
| In-hospital Mortality | from admission to the ICU until 30 days after the operation/discharge from the hospital (whichever is earlier) | comparison of the incidence of in-hospital mortality between the study groups |
| Post Operative Acute Kidney Injury (AKI) | from admission to the ICU until postoperative day 7 | comparison of the incidence of postoperative AKI between study groups. AKI will be assessed based on the Acute Kidney Injury Network (AKIN) classification (stages 0-3, with higher stage reflecting worse outcome) |
| Postoperative Infection | rom admission to the ICU until 30 days after the operation/discharge from the hospital (whichever is earlier) | comparison of the incidence of pneumonia, sternal wound infection, mediastinitis, sepsis between study groups |
| Percent of Patients With Postoperative Neurological Injury | from admission to the ICU until POD 7 | Comparison between study groups of the percent of patients with seizures/stroke that occur after surgery |
| Intubation Time | from admission to the ICU until 30 days after surgery or discharge from the ICU (whichever is earlier) | comparison of the time to intubation from the completion of surgery until extubation in the ICU between the study groups |
| Postoperative Thromboembolic Event | from admission to the ICU until 7 days postoperatively | comparison of the incidence of DVT/PE/shunt thrombosis between the study groups |
| ICU Length of Stay | from admission to the ICU after surgery until 90 days after surgery or discharge from the ICU (whichever occurs earlier) | comparison of the postoperative time period spent in the ICU |
| Hospital Length of Stay | from admission to the ICU postoperatively until postoperative day 90 or discharge from the hospital (whichever occurs earlier) | comparison between the study groups of the time in the hospital from admission to the ICU postoperatively until discharge from the hospital |
Countries
United States
Contacts
STUDY_DIRECTORKeita Ikeda, MD
UVA Anesthesiology
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 15 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 4.9 months STANDARD_DEVIATION 4.39 |
| Race and Ethnicity Not Collected | 0 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 12 Participants |
| Weight | 5.55 kg STANDARD_DEVIATION 1.89 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 15 |
| other Total, other adverse events | 0 / 11 | 3 / 15 |
| serious Total, serious adverse events | 1 / 11 | 0 / 15 |
Outcome results
None listed