Human Fibrinogen Concentrate in Pediatric Cardiac Surgery (RiaSTAP)

The Role of Human Fibrinogen Concentrate (RiaSTAP) in Decreasing Blood Loss and the Need for Component Blood Therapy in Infants Undergoing Cardiopulmonary Bypass.

The goal of the study is to determine whether the use of Human Fibrinogen Concentrate (RiaSTAP) will decrease blood loss and the need for component blood therapy in neonates and infants undergoing cardiopulmonary bypass.

Study Overview

• Status: Completed
• Conditions: Afibrinogenemia; Hypofibrinogenemia; Bleeding Disorders
• Intervention / Treatment: Drug: RiaStAP; Drug: Saline

Detailed Description

The goal of the study is to determine whether the use of Human Fibrinogen Concentrate (RiaSTAP) will decrease blood loss and the need for component blood therapy in neonates and infants undergoing cardiopulmonary bypass. RiaSTAP will be administered after termination of Cardiopulmonary Bypass (CPB) at a dose of 70 mg/kg, in a prospective, randomized, controlled study. We hypothesize that the administration of RiaSTAP in this manner will reduce peri-operative bleeding and transfusion requirements.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33155
      • Nicklaus Children's Hospital
    • Miami, Florida, United States, 33155
      • Nickalus Children's Hospital f/k/a Miami Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Neonatal and infant cardiac patients presenting for open-heart surgery at Nicklaus Children's Hospital will be eligible for enrollment in the study.

Exclusion Criteria:

• Patients who fall outside of the age range for the study will be excluded. Patients known to have had an anaphylactic or severe reaction to the drug or its components will not be enrolled. At the time of the rewarming ROTEM, any patient with a FIBTEM MCF > 15mm, will be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: RiaSTAP; Group 1 will receive an infusion of RiaSTAP after termination of CPB at a dose of 70 mg/kg after randomization to this group.	Drug: RiaStAP; To decrease post-operative bleeding volume.; Other Names: Fibrinogen Concentrate Human
Placebo Comparator: Saline; Group 2 will receive a placebo consisting of Normal Saline 0.9% (NS) after randomization to this group.	Drug: Saline; Placebo consisting of normal saline 0.9%; Other Names: Normal Saline 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative Blood Loss After Surgery (Estimated Blood Loss (EBL))	Primary outcome efficacy: Estimated blood loss (EBL); median; A transfusion algorithm was developed based on three previous studies, modified for pediatrics. Clinically significant bleeding requiring treatment was defined as a rate >10 cc kg-1 hr-1 calculated every 15 minutes while in the OR, measured by blood in the suction canister. In cases of continued bleeding following randomization to HFC or placebo, cryoprecipitate was considered for fibrinogen <200 mg/dL or FIBTEM MCF <7 mm. Thereafter, as per routine care, ROTEM analysis was performed at least every 30 minutes while in the OR, or sooner, at the discretion of the OR team. Once the patient left the OR, ROTEM was performed at least every 60 minutes for the first 6 hours or until clinically significant bleeding had stopped. Blood products transfused after CPB separation were based on a pre-defined protocol. Recommended volumes of each therapy were based on pre-defined formulae and a ROTEM analysis algorithm.	Within 24 hours of surgery
Post-operative 2 hr Hemoglobin (Hg) mg/dL Measure	Post-operative 2 hr hemoglobin (Hg) between the treatment and placebo group. A transfusion algorithm was developed based on three previous studies, modified for pediatrics. Clinically significant bleeding requiring treatment was defined as a rate >10 cc kg-1 hr-1 calculated every 15 minutes while in the OR, measured by blood in the suction canister. In cases of continued bleeding following randomization to HFC or placebo, cryoprecipitate was considered for fibrinogen <200 mg/dL or FIBTEM MCF <7 mm. Thereafter, as per routine care, ROTEM analysis was performed at least every 30 minutes while in the OR, or sooner, at the discretion of the OR team. Once the patient left the OR, ROTEM was performed at least every 60 minutes for the first 6 hours or until clinically significant bleeding had stopped. Blood products transfused after CPB separation were based on a pre-defined protocol. Recommended volumes of each therapy were based on pre-defined formulae and a ROTEM analysis algorithm.	2 hour
Post-operative 24-hr Hemoglobin (Hg) mg/dL	Post-operative 24-hr hemoglobin (Hg) between treatment and placebo. A transfusion algorithm was developed based on three previous studies, modified for pediatrics. Clinically significant bleeding requiring treatment was defined as a rate >10 cc kg-1 hr-1 calculated every 15 minutes while in the OR, measured by blood in the suction canister. In cases of continued bleeding following randomization to HFC or placebo, cryoprecipitate was considered for fibrinogen <200 mg/dL or FIBTEM MCF <7 mm. Thereafter, as per routine care, ROTEM analysis was performed at least every 30 minutes while in the OR, or sooner, at the discretion of the OR team. Once the patient left the OR, ROTEM was performed at least every 60 minutes for the first 6 hours or until clinically significant bleeding had stopped. Blood products transfused after CPB separation were based on a pre-defined protocol. Recommended volumes of each therapy were based on pre-defined formulae and a ROTEM analysis algorithm.	24 hr
Post-operative 2 hr Hematocrit (HCT) Measure	Post-operative 2 hr Hematocrit (HCT) between the treatment and placebo group.	2 hour
Post-operative 24 hr Hematocrit (HCT) Measure	Post-operative 24 hr Hematocrit (HCT) between the treatment and placebo group	24 hour
Post-operative 2 hr Platelets Count Test (PLT) 10K/uL	Post-operative 2 hr Platelets Count Test (PLT) between the treatment and placebo group. A transfusion algorithm was developed based on three previous studies, modified for pediatrics. Clinically significant bleeding requiring treatment was defined as a rate >10 cc kg-1 hr-1 calculated every 15 minutes while in the OR, measured by blood in the suction canister. In cases of continued bleeding following randomization to HFC or placebo, cryoprecipitate was considered for fibrinogen <200 mg/dL or FIBTEM MCF <7 mm. Once the patient left the OR, ROTEM was performed at least every 60 minutes for the first 6 hours or until clinically significant bleeding had stopped. Blood products transfused after CPB separation were based on a pre-defined protocol. Recommended volumes of each therapy were based on pre-defined formulae and a ROTEM analysis algor	2 hour
Post-operative 24 hr Platelets Count Test (PLT) 10K/uL	Post-operative 24 hr Platelets Count Test (PLT) between the treatment and placebo group. A transfusion algorithm was developed based on three previous studies, modified for pediatrics. Clinically significant bleeding requiring treatment was defined as a rate >10 cc kg-1 hr-1 calculated every 15 minutes while in the OR, measured by blood in the suction canister. In cases of continued bleeding following randomization to HFC or placebo, cryoprecipitate was considered for fibrinogen <200 mg/dL or FIBTEM MCF <7 mm. Once the patient left the OR, ROTEM was performed at least every 60 minutes for the first 6 hours or until clinically significant bleeding had stopped. Blood products transfused after CPB separation were based on a pre-defined protocol. Recommended volumes of each therapy were based on pre-defined formulae and a ROTEM analysis algo	24 hour
Post-operative 2 hr Prothrombin (PT) Seconds	Post-operative 2 hr Prothrombin (PT) between the treatment and placebo group. A transfusion algorithm was developed based on three previous studies, modified for pediatrics. Clinically significant bleeding requiring treatment was defined as a rate >10 cc kg-1 hr-1 calculated every 15 minutes while in the OR, measured by blood in the suction canister. In cases of continued bleeding following randomization to HFC or placebo, cryoprecipitate was considered for fibrinogen <200 mg/dL or FIBTEM MCF <7 mm. Thereafter, as per routine care, ROTEM analysis was performed at least every 30 minutes while in the OR, or sooner, at the discretion of the OR team. Once the patient left the OR, ROTEM was performed at least every 60 minutes for the first 6 hours or until clinically significant bleeding had stopped. Blood products transfused after CPB separation were based on a pre-defined protocol. Recommended volumes of each therapy were based on pre-defined formulae and a ROTEM analysis algorithm.	2 hour
Post-operative 24 hr Prothrombin (PT) Seconds	Post-operative 24 hr Prothrombin (PT) between the treatment and placebo group. A transfusion algorithm was developed based on three previous studies, modified for pediatrics. Clinically significant bleeding requiring treatment was defined as a rate >10 cc kg-1 hr-1 calculated every 15 minutes while in the OR, measured by blood in the suction canister. In cases of continued bleeding following randomization to HFC or placebo, cryoprecipitate was considered for fibrinogen <200 mg/dL or FIBTEM MCF <7 mm. Thereafter, as per routine care, ROTEM analysis was performed at least every 30 minutes while in the OR, or sooner, at the discretion of the OR team. Once the patient left the OR, ROTEM was performed at least every 60 minutes for the first 6 hours or until clinically significant bleeding had stopped. Blood products transfused after CPB separation were based on a pre-defined protocol. Recommended volumes of each therapy were based on pre-defined formulae and a ROTEM analysis algorithm.	24 hour
Post-operative 2 hr International Normalize Ratio (INR)	Post-operative 2 hr International Normalize Ratio (INR) between the treatment and placebo group	2 hour
Post-operative 24 hr International Normalize Ratio (INR)	Post-operative 24 hr International Normalize Ratio (INR) between the treatment and placebo group. A transfusion algorithm was developed based on three previous studies, modified for pediatrics. Clinically significant bleeding requiring treatment was defined as a rate >10 cc kg-1 hr-1 calculated every 15 minutes while in the OR, measured by blood in the suction canister. In cases of continued bleeding following randomization to HFC or placebo, cryoprecipitate was considered for fibrinogen <200 mg/dL or FIBTEM MCF <7 mm. Once the patient left the OR, ROTEM was performed at least every 60 minutes for the first 6 hours or until clinically significant bleeding had stopped. Blood products transfused after CPB separation were based on a pre-defined protocol. Recommended volumes of each therapy were based on pre-defined formulae and a ROTEM ana	24 hour
Post-operative 2 hr Partial Thromboplastin Time (PTT) Seconds	Post-operative 2 hr Partial Thromboplastin Time (PTT) between the treatment and placebo group	2 hour
Post-operative 24 hr Partial Thromboplastin Time (PTT) Seconds	Post-operative 24 hr Partial Thromboplastin Time (PTT) between the treatment and placebo group. A transfusion algorithm was developed based on three previous studies, modified for pediatrics. Clinically significant bleeding requiring treatment was defined as a rate >10 cc kg-1 hr-1 calculated every 15 minutes while in the OR, measured by blood in the suction canister. In cases of continued bleeding following randomization to HFC or placebo, cryoprecipitate was considered for fibrinogen <200 mg/dL or FIBTEM MCF <7 mm. Once the patient left the OR, ROTEM was performed at least every 60 minutes for the first 6 hours or until clinically significant bleeding had stopped. Blood products transfused after CPB separation were based on a pre-defined protocol. Recommended volumes of each therapy were based on pre-defined formulae and a ROTEM analys	24 hour
Post-operative 2 hr Fibrinogen mg/dL	Post-operative 2 hr Fibrinogen between the treatment and placebo group. A transfusion algorithm was developed based on three previous studies, modified for pediatrics. Clinically significant bleeding requiring treatment was defined as a rate >10 cc kg-1 hr-1 calculated every 15 minutes while in the OR, measured by blood in the suction canister. In cases of continued bleeding following randomization to HFC or placebo, cryoprecipitate was considered for fibrinogen <200 mg/dL or FIBTEM MCF <7 mm. Thereafter, as per routine care, ROTEM analysis was performed at least every 30 minutes while in the OR, or sooner, at the discretion of the OR team. Once the patient left the OR, ROTEM was performed at least every 60 minutes for the first 6 hours or until clinically significant bleeding had stopped. Blood products transfused after CPB separation were based on a pre-defined protocol. Recommended volumes of each therapy were based on pre-defined formulae and a ROTEM analysis algorithm.	2 hour
Post-operative 24 hr Fibrinogen mg/dL	Post-operative 24 hr Fibrinogen between the treatment and placebo group	24 hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-Operative Respiratory Failure Adverse Events	Patients who suffered from respiratory failure post operatively.	24 hours after surgery
Post-operative Thrombus Adverse Events	Patient who suffered from Thrombus events post-operatively.	within 24 hours of surgery

Collaborators and Investigators

• Sponsor: Nicklaus Children's Hospital f/k/a Miami Children's Hospital
• Investigators: Principal Investigator: Christopher Tirotta, MD, Director Cardiac Anesthesia

Publications and helpful links

General Publications

• Kern FH, Morana NJ, Sears JJ, Hickey PR. Coagulation defects in neonates during cardiopulmonary bypass. Ann Thorac Surg. 1992 Sep;54(3):541-6. doi: 10.1016/0003-4975(92)90451-9.
• Paparella D, Brister SJ, Buchanan MR. Coagulation disorders of cardiopulmonary bypass: a review. Intensive Care Med. 2004 Oct;30(10):1873-81. doi: 10.1007/s00134-004-2388-0. Epub 2004 Jul 24.
• Moulton MJ, Creswell LL, Mackey ME, Cox JL, Rosenbloom M. Reexploration for bleeding is a risk factor for adverse outcomes after cardiac operations. J Thorac Cardiovasc Surg. 1996 May;111(5):1037-46. doi: 10.1016/s0022-5223(96)70380-x.
• Dacey LJ, Munoz JJ, Baribeau YR, Johnson ER, Lahey SJ, Leavitt BJ, Quinn RD, Nugent WC, Birkmeyer JD, O'Connor GT. Reexploration for hemorrhage following coronary artery bypass grafting: incidence and risk factors. Northern New England Cardiovascular Disease Study Group. Arch Surg. 1998 Apr;133(4):442-7. doi: 10.1001/archsurg.133.4.442.
• Miller BE, Tosone SR, Guzzetta NA, Miller JL, Brosius KK. Fibrinogen in children undergoing cardiac surgery: is it effective? Anesth Analg. 2004 Nov;99(5):1341-1346. doi: 10.1213/01.ANE.0000134811.27812.F0.
• Chan AK, Leaker M, Burrows FA, Williams WG, Gruenwald CE, Whyte L, Adams M, Brooker LA, Adams H, Mitchell L, Andrew M. Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass. Thromb Haemost. 1997 Feb;77(2):270-7. Erratum In: Thromb Haemost 1997 May;77(5):1047.
• Karlsson M, Ternstrom L, Hyllner M, Baghaei F, Nilsson S, Jeppsson A. Plasma fibrinogen level, bleeding, and transfusion after on-pump coronary artery bypass grafting surgery: a prospective observational study. Transfusion. 2008 Oct;48(10):2152-8. doi: 10.1111/j.1537-2995.2008.01827.x. Epub 2008 Jul 24.
• Karlsson M, Ternstrom L, Hyllner M, Baghaei F, Flinck A, Skrtic S, Jeppsson A. Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised pilot study. Thromb Haemost. 2009 Jul;102(1):137-44. doi: 10.1160/TH08-09-0587.
• Rahe-Meyer N, Pichlmaier M, Haverich A, Solomon C, Winterhalter M, Piepenbrock S, Tanaka KA. Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study. Br J Anaesth. 2009 Jun;102(6):785-92. doi: 10.1093/bja/aep089. Epub 2009 May 2.
• Tirotta CF, Lagueruela RG, Gupta A, Salyakina D, Aguero D, Ojito J, Kubes K, Hannan R, Burke RP. A Randomized Pilot Trial Assessing the Role of Human Fibrinogen Concentrate in Decreasing Cryoprecipitate Use and Blood Loss in Infants Undergoing Cardiopulmonary Bypass. Pediatr Cardiol. 2022 Oct;43(7):1444-1454. doi: 10.1007/s00246-022-02866-4. Epub 2022 Mar 19.

Helpful Links

• Nicklaus Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2017
• Primary Completion (Actual): August 26, 2019
• Study Completion (Actual): December 24, 2020

Study Registration Dates

• First Submitted: June 30, 2016
• First Submitted That Met QC Criteria: July 1, 2016
• First Posted (Estimate): July 4, 2016

Study Record Updates

• Last Update Posted (Actual): September 16, 2021
• Last Update Submitted That Met QC Criteria: August 20, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: CBP, congenital heart defects, cardiopulmonary bypass
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Hemostatic Disorders; Blood Coagulation Disorders; Afibrinogenemia
• Other Study ID Numbers: NCH0000201496

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No