Fibrinogen Concentrate as an Alternative to Cryoprecipitate in a Postcardiopulmonary Transfusion Algorithm in Infants Undergoing Cardiac Surgery: A Prospective Randomized Controlled Trial

Abstract

BACKGROUND: 

Infants undergoing cardiac surgery are at risk for bleeding and massive transfusion due to an immature coagulation system, complex surgeries, and cardiopulmonary bypass (CPB) effects. Hemodilution from CPB promotes an acquired hypofibrinogenemia that results in impaired fibrin formation, inadequate clot formation, and increased bleeding. In North America, the current standard of care to supplement fibrinogen is cryoprecipitate. An alternative option is the off-label use of fibrinogen concentrate (FC; RiaSTAP; CSL Behring, Marburg, Germany), a purified fibrinogen. Because perioperative allogenic transfusions are associated with increased morbidity and mortality, we sought to determine whether FC would be an acceptable alternative to cryoprecipitate in a post-CPB transfusion algorithm in infants undergoing open-heart surgery.

METHODS: 

We randomized 60 infants (<12 months) undergoing nonemergent cardiac surgery with CPB at 2 tertiary care children’s hospitals to receive either cryoprecipitate or FC in a post-CPB transfusion algorithm. Infants underwent a stratified randomization based on institution and surgical complexity. The primary outcome was the difference in number of intraoperative allogenic blood product transfusions. Secondary outcomes included 24-hour chest tube output (CTO), mechanical ventilation time, adverse events (AEs), intensive care unit (ICU) length of stay (LOS), hospital LOS, postoperative thrombosis, and death within 30 days of surgery. The primary analysis followed the intent-to-treat (ITT) principle and was performed using linear regression adjusted for institution and complexity of surgery. A per-protocol (PP) analysis was also performed.

RESULTS: 

Between June 2016 and January 2018, we enrolled 60 patients with complete data available for 25 patients who received cryoprecipitate and 29 patients who received FC. Patients in the cryoprecipitate group (median age: 4 months [2–6 months]) received 5.5 (4.0–7.0) allogeneic blood units in the ITT analysis and 6.0 units (5.0–7.0 units) in the PP analysis. Patients in the FC group (median age: 4 months [2–5]) received 4 units (3.0–5.0 units) in the ITT analysis and 4.0 units (3.0–5.0 units) in the PP analysis. In the adjusted ITT analysis, the FC group received 1.79 units (95% confidence interval [CI], 0.64–2.93; P = .003) less than the cryoprecipitate group. In the adjusted PP analysis, the FC group received 2.67 units (95% CI, 1.75–3.59; P < .001) less than the cryoprecipitate group. There were no significant differences in secondary outcomes or AEs.

CONCLUSIONS: 

Our findings suggest that FC may be considered as an alternative to cryoprecipitate for the treatment of hypofibrinogenemia in infants with bleeding after CPB. Although we found no significant differences between secondary outcomes or AEs, further studies are needed to assess safety.

KEY POINTS

• Questions: Can fibrinogen concentrate (FC) reduce intraoperative transfusions in infants undergoing heart surgery with cardiopulmonary bypass (CPB)?
• Findings: When compared to cryoprecipitate, FC may reduce intraoperative allogenic blood exposures in infants when used as part of a post-CPB transfusion protocol without evidence of increased adverse events (AEs).
• Meanings: Blood product alternatives, such as FC, may reduce allogenic blood transfusions in neonates and infants undergoing open-heart surgery without a risk of increased AEs.

Neonates and infants undergoing cardiac surgery are at risk for excessive bleeding and massive transfusion due to an immature coagulation system, complex surgeries, and cardiopulmonary bypass (CPB) effects.^1–3 Transfusion of adult blood products is often needed to restore post-CPB hemostasis. However, excessive postoperative bleeding and perioperative transfusions are independent predictors for morbidity and mortality.^4–7 Given the risks associated with bleeding and blood product transfusion, these children would benefit from efforts to reduce their exposure to allogenic blood products. Unfortunately, the data regarding safe and effective alternatives to blood products to manage post-CPB coagulopathy in neonates and infants are lacking.

A growing body of literature suggests that fibrinogen is the first coagulation factor to decrease during massive bleeding and that critically low levels contribute to significant post-CPB bleeding.^8–10 The hemodilutional effects of CPB in neonates and infants result in low fibrinogen levels that lead to impaired fibrin formation, inadequate clot formation, and increased risk of post-CPB bleeding. In addition, neonates and infants have an immature hemostatic system and demonstrate qualitative deficiencies in fibrinogen function even before CPB.^11–15 Traditionally, cryoprecipitate has been the source for fibrinogen replacement in the United States. However, cryoprecipitate is an allogenic blood product that requires cross-matching and thawing before administration and is associated with immunologic reactions and possible pathogen transmission. An alternative to cryoprecipitate is fibrinogen concentrate (FC; RiaSTAP; CSL Behring), a purified form of fibrinogen derived from pooled human plasma, which undergoes a pasteurization process to minimize the risk of immunologic and allergic reactions. Currently, FC is being used off-label to replace low fibrinogen levels associated with bleeding in adult and pediatric surgical patients.^16–21 In pediatric patients, FC may have several advantages over cryoprecipitate: (1) small volume, (2) accurate dosing, (3) immediate availability, (4) lower infectious risk, and (5) decreased allergic or immunologic reactions.

As more perioperative allogenic transfusions are associated with increased morbidity and mortality, we designed a prospective randomized control trial (RCT) comparing the use of FC to cryoprecipitate as part of a post-CPB transfusion algorithm for infants undergoing cardiac surgery with CPB. Our primary outcome was the difference in overall intraoperative allogenic blood transfusions between the 2 groups. We hypothesized that FC would reduce intraoperative allogenic donor exposures without affecting postoperative outcomes.

METHODS

This study was a 2-center, prospective, RCT comparing FC to cryoprecipitate for the treatment of post-CPB bleeding in infants undergoing cardiac surgery (Figure 1A). The trial was completed at 2 tertiary children’s hospitals over 2 consecutive years. An Investigational New Drug (IND) exemption was obtained from the Federal Drug Administration (FDA) for the off-label use of FC. This study was approved by the institutional review board (IRB) at both institutions (IRB #36374 and IRB #93671), and written informed consent was obtained from parents or legal guardians of subjects participating in the trial. The trial was registered at clinicaltrials.gov (NCT030314700, principal investigator: G.D.W., MD, date of registration: December 02, 2016). The IRB approved the study at institution 1 without requiring CT.gov registration, and several patients at institution 1 were enrolled before registration. No patients were enrolled at institution 2 before registration.

Figure 1.: Study Overview. A, Study design. Patients eligible for the study will be randomized after informed consent to receive either cryoprecipitate or fibrinogen concentrates as part of a post-bypass transfusion algorithm. *A fibrinogen level drawn on bypass will be used to calculate the FC dose to reach target level of 300 mg/dL posttransfusion of FC. **Two units of cryoprecipitate will be transfused as part of the post-CPB transfusion algorithm for patients in the control arm. B, Trial profile. *Consent withdrawn before surgery; no data collected. CPB indicates cardiopulmonary bypass; CTO, chest tube output; ECMO, extracorporeal membrane oxygenation; FC, fibrinogen concentrate; ICU, intensive care unit; LOS, length of stay; PP, per protocol; TEG, thromboelastogram.

Patients under 12 months of age presenting for elective cardiac surgery with CPB were screened for eligibility. Exclusion criteria included a gestational age (GA) of <32 weeks at birth and/or <36 weeks GA on the day of surgery (DOS), weight <3 kg on the DOS, emergency surgery, patient or family history of coagulopathy or thrombosis, and active infection. After enrollment, patients were randomized using a 24-hour web-based Data Management Website (REDCap; Vanderbilt University, Nashville, TN) managed by Stanford University, Palo Alto, CA. Patients were randomly assigned (1:1) to receive either cryoprecipitate or FC as part of a post-CPB transfusion algorithm. Randomization was stratified by institution and complexity of surgery, that is, high versus low likelihood of bleeding post-CPB. While the anesthesiologist caring for the patient was aware of the group allocation, parents, surgeons, and critical care physicians were not.

Anesthesia Management and CPB Management

Composition of the anesthesiology, perfusion, and surgery teams remained constant at each institution throughout the study. Anesthesia techniques followed institutional protocol, which included a balanced anesthesia technique and necessary invasive monitoring. CPB management followed institutional protocols as described below.

Institution 1.

Nonpulsatile CPB was performed using a nonheparin-coated system, a Terumo FX-05 hollow-fiber membrane oxygenator (Terumo Cardiovascular Systems, Ann Arbor, MI), and Medtronic balance coated neonatal circuits (Medtronic Inc, Minneapolis, MN). Circuits contained a 250–300 mL priming volume: 60 mL fresh-frozen plasma (FFP), 50 mL 25% albumin (Grifols Biologicals Inc, Los Angeles, CA), Normosol-R (Hospira Inc, Lake Forest, IL), mannitol, calcium chloride, heparin, and 8.4% sodium bicarbonate. Washed red blood cells (RBCs) were added to achieve and maintain a hematocrit (Hct) of 30% throughout the duration of CPB. Conventional or zero-balance ultrafiltration was performed throughout CPB. pH-stat blood gas management was used during bypass.

Before heparin administration, a Heparin Dose Response (HDR) test was performed on a patient blood sample using the Hemostasis Management System (HMS) PLUS (Medtronic Inc). The HDR included the patient’s baseline activated clotting time (ACT) and the projected heparin concentration required to maintain an ACT of 480 seconds. Anticoagulation was established with an initial dose of 400 units/kg of heparin for a target ACT of 480 seconds and the heparin concentration as predicted by the HDR test. Heparin was redosed to maintain the projected heparin concentration and ACT >480 seconds. The calculated dose of protamine was administered to neutralize heparin. Additional protamine was administered if residual heparin was noted on thromboelastography (TEG^R; Haemonetics Corporation, Braintree, MA), or ACT levels were above baseline.

All neonates (<30 days of age) and patients undergoing redo sternotomy received ε-aminocaproic acid: neonates received a bolus of 40 mg/kg, 100 mg/L to the CPB prime, and an infusion of 30 mg/kg/h until intensive care unit (ICU) arrival; infants received a bolus 75 mg/kg, a dose of 250 mg/L to the CPB prime, and an infusion of 75 mg/kg/h infusion until ICU arrival.

Institution 2.

Nonpulsatile CPB was performed using a nonheparin-coated system, a Terumo FX-05 hollow-fiber membrane oxygenator (Terumo Cardiovascular Systems, Ann Arbor, MI), and Livanova SMArt-coated neonatal circuits (LIVANOVA USA; Sorin Group USA, Arvada, CO). Circuits contained a 250–300 mL priming volume: 50 ml 25% albumin (Grifols Biologicals Inc, Los Angeles, CA), Plasmalyte, mannitol, calcium gluconate, heparin, and 8.4% sodium bicarbonate. Packed RBCs (pRBCs), <14 days old, were added to achieve and maintain an Hct of 30% throughout the duration of CPB. In neonates and cyanotic infants, 50 mL FFP was added to the CPB prime and an additional 50 mL FFP was added on rewarming. Conventional or zero-balance ultrafiltration was performed throughout CPB. pH-stat blood gas management was used during bypass.

Anticoagulation was established with 500 units/kg of heparin. ACT values >480 seconds were confirmed before the initiation of CPB (i-STAT1 Analyzer; Abbot Point of Care Inc, Abbott Park, IL) and maintained >480 seconds throughout CPB. Protamine (5 mg/kg) was used for heparin reversal. Additional protamine was administered if residual heparin was noted on TEG^R or ACT levels were above baseline.

All neonates (<30 days of age) and patients undergoing redo sternotomy received tranexamic acid: a bolus dose of 100 mg/kg, a dose of 100 mg/kg to the CPB prime, and an infusion of 10 mg/kg/h until ICU arrival.

Coagulation Tests

Preoperative laboratory data included Hct, hemoglobin (Hgb), platelet count, Clauss fibrinogen level, prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT). Intraoperatively, arterial blood gases (ABGs), TEG^Rs, and fibrinogen levels were performed at set time points: (1) after induction of anesthesia and before surgical incision (T1); (2) 10 minutes after the initiation of CPB (T2); and (3) after termination of CPB, protamine reversal and completion of fibrinogen/cryoprecipitate administration (T3). These test results were immediately available and used to guide intraoperative transfusions. On arrival to the ICU, coagulation laboratory tests for Hct, Hgb, platelet count, fibrinogen level, PT, PTT, and TEG^R were performed (T4).

Transfusion Protocol

Intraoperative transfusion practice was standardized at each institution. RBCs were transfused for an Hct <32% in acyanotic patients, while cyanotic patients were transfused for an Hct >35%–45%.

All patients received platelets and either cryoprecipitate or FC depending on their randomization group after protamine administration (Figure 1A). At both institutions, historical data showed that 2 units of cryoprecipitate resulted in a mean postoperative fibrinogen level of 345 mg/dL (range: 258–469). Thus, 2 units was the amount administered to patients in the control group. Taking into consideration that cryoprecipitate contains a variable degree of fibrinogen, we targeted a fibrinogen level of 300 mg/dL for patients in the FC group using the equation from the package insert: dose = (target level − measured level)/1.7 × weight (kg).²² If a patient continued to have post-CPB bleeding in either arm, the anesthesiologist used point-of-care testing, TEG^R, or clinical judgment to determine appropriate products for transfusion. If further fibrinogen replacement was deemed necessary, cryoprecipitate was used in both groups. At institution 1, a 4-factor prothrombin complex concentration (PCC), Factor Eight Inhibitor Bypass Activity (FEIBA; Takeda Pharmaceutical Company Limited, Lexington, MA), was routinely used at a dose of 10 units/kg for patients at high risk of post-CPB bleeding. Postoperative transfusion therapy was not protocolized and at the discretion of the ICU physicians.

Data Collection

Demographic and other surgical data were recorded for each patient. The primary outcome was the total number of allogenic blood transfusions during the intraoperative period, that is, the sum of cryoprecipitate, pRBCs, FFP, and platelet units. Secondary outcomes included 24-hour chest tube output (CTO), mechanical ventilation time, adverse events (AEs), ICU length of stay (LOS), hospital LOS, and death within 30 days of surgery. Standard coagulation tests were also collected and compared. All outcomes were specified a priori.

A data safety monitoring committee reviewed all serious AEs. AEs were reported from the time of enrollment through postoperative day 7 or hospital discharge. Predetermined AEs included thrombotic events, infection, need for extracorporeal membrane oxygenation (ECMO) support within 24 hours of surgery, tamponade, chest reexploration, stroke, repeat surgery, arrhythmia requiring treatment, and death within 30 days of surgery.

Statistical Analysis

Baseline characteristics are presented according to the study arm. Study arms are displayed according to the randomized intervention, intent to treat (ITT) and, for a subset of patients who completed the study, per protocol (PP).²³

The primary analysis followed the ITT principle and was performed using a linear regression adjusted for the randomization strata of institution and complexity of surgery. A PP analysis was also performed for the primary outcome using a linear regression adjusted for the randomization strata. In addition, for the PP patients, a sensitivity analysis adjusted for weight and CPB time was performed. For the ITT analyses, we assumed that our randomization balanced all covariates. However, in the PP analyses, we adjusted for the additional covariates of weight and CPB time to exclude any selection bias that may have been introduced. We performed a post hoc exploratory analysis in which additional linear models were fit to compare post-bypass allogeneic blood transfusions. In all analyses, assumptions for linear regression were assessed by visual examination including reviewing residual plots.

For secondary analyses, we used a Mann-Whitney U test for continuous outcomes and a χ² test for categorical outcomes when the expected count in each cell was >5. Otherwise we used a Fisher exact test. All secondary analyses were conducted on the subset of PP patients. Sensitivity analyses were performed for the secondary outcomes adjusting for site, complexity, weight, and CPB time. For continuous secondary outcomes, we log-transformed the outcome then fit a linear regression model, and for the outcome of any AE, we fit a logistic regression model. Comparisons of coagulation tests between arms were performed separately within each time point and are exploratory.

For patients who did not complete the study PP and were missing their primary outcome, we took a conservative approach of imputing their missing outcome using a worst-case approach. Patients in the control group were assigned 0, and patients in the intervention arm were assigned the maximum number of total units of allogenic blood transfusions observed²⁴ in the ITT analyses. All statistical tests were 2-sided and performed at the α = .05 level. Analyses were performed in R version 3.5.0 (R Core Team, Vienna, Austria).²⁵

Sample Size Justification

We designed our study to have 90% power to detect a reduction of 2 allogenic blood product transfusions when assuming that the mean number of units in patients receiving cryoprecipitate was 7 with a standard deviation of 2.2 units in both arms. These assumptions are based on historical data obtained from both institutions. Using a 2-sample t test and performing a 2-sided test with an α = .05, we found that 27 patients per arm were needed. We assumed approximately 10% of patients would be missing their primary outcome and therefore enrolled 30 patients per arm.

RESULTS

Table 1. - Baseline and Postintervention Characteristics Displayed According to Assigned Study Arm (ITT) and for the Subset of Patients Who Completed the Study PP

	ITT Cryo	ITT FC	ITT D	ITT P Value	PP Cryo	PP FC	PP D	PP P Value
n	29	30			25	29
Baseline characteristics
Male	14 (48.3)	21 (70.0)	0.453		13 (52.0)	21 (72.4)	0.431
Age, mo	4.0 (2.0–5.0)	4.0 (2.0–7.0)	0.170		4.0 (2.0–5.0)	4.0 (2.0–7.0)	0.289
Weight, kg	5.3 (4.2–6.1)	6.2 (5.1–7.2)	0.565		5.2 (4.1–5.9)	6.2 (5.1–7.2)	0.668
Height, cm	59.0 (55.8–63.0)	62.3 (57.6–66.0)	0.428		59.0 (55.0–62.5)	63.0 (58.0–66.0)	0.532
Prematurity	2 (6.9)	2 (6.7)	0.009		1 (4.0)	2 (6.9)	0.128
Single ventricle	2 (6.9)	4 (13.3)	0.215		2 (8.0)	4 (13.8)	0.187
Prior surgery	7 (24.1)	6 (20.0)	0.100		4 (16.0)	6 (20.7)	0.121
Preoperative anticoagulants	8 (26.7)	5 (16.7)	0.245		7 (28.0)	5 (17.2)	0.259
Postintervention characteristics
Anesthesia time, min	379.5 (349.8–509.8)	443.5 (353.5–514.5)	0.028	.401	381.0 (353.0–508.0)	433.0 (353.0–507.0)	0.094	.609
Surgery time, min	229.0 (206.5–366.5)	248.5 (205.5–366.0)	0.171	.669	229.0 (211.0–366.0)	241.0 (205.0–351.0)	0.196	.890
CPB time, min	121.0 (113.0–161.0)	140.5 (120.8–184.0)	0.102	.335	121.0 (113.0–161.0)	140.0 (119.0–181.0)	0.126	.400
Aortic cross-clamp, min	71.0 (35.5–97.0)	74.0 (60.5–98.5)	0.099	.497	71.0 (35.5–97.0)	75.0 (59.8–98.8)	0.099	.561
Antifibrinolytics	15 (53.6)	19 (63.3)	0.199	.626	15 (60.0)	19 (65.5)	0.114	.892
Low complexity	19 (63.3)	18 (60.0)	0.069	>.999	17 (68.0)	18 (62.1)	0.125	.866
Surgical category			0.722	.675			0.727	.727
Aortic arch reconstruction	1 (3.7)	0 (0.0)			1 (4.0)	0 (0.0)
ASO	1 (3.7)	4 (13.8)			1 (4.0)	4 (13.8)
AVC repair	6 (22.2)	5 (17.2)			6 (24.0)	5 (17.2)
Rastelli	3 (11.1)	1 (3.4)			3 (12.0)	1 (3.4)
Septal defect	4 (14.8)	6 (20.7)			4 (16.0)	6 (20.7)
TOF repair	6 (22.2)	5 (17.2)			6 (24.0)	5 (17.2)
Unifocalization/ PA plasty	5 (18.5)	4 (13.8)			3 (12.0)	4 (13.8)
BDG	1 (3.7)	3 (10.3)			1 (4.0)	3 (10.3)
BT shunt	0 (0.0)	1 (3.4)			0 (0.0)	1 (3.4)

Abbreviations: ASO, arterial switch operation; AVC, atrioventricular canal; BDG, bidirectional Glenn; BT, Blalock Taussig; CPB, cardiopulmonary bypass; Cryo, cryoprecipitate arm; D, standardized difference (a measure of the difference between the distribution of the characteristic in the 2 arms expressed in units of standard deviations); FC, fibrinogen concentrate arm; IQR, interquartile range; ITT, intent-to-treat; PA, pulmonary artery; PP, per protocol; TOF, tetralogy of Fallot.

^aNumber (%); P values were obtained from a χ² test except where noted.

^bMedian (IQR) = (25th–75th percentile); P values were obtained from a Mann-Whitney U test.

^cP values were obtained from a Fisher exact test.

Between 2 tertiary pediatric hospitals, a total of 157 patients were screened for eligibility and 98 patients met inclusion criteria (Figure 1B). Sixty patients were enrolled and randomized to participate in the study. Thirty patients were randomized to receive cryoprecipitate and 30 to receive FC. In the control group, there were 5 protocol violations: 3 patients did not require CPB, 1 patient’s surgery was canceled, and 1 patient’s consent was withdrawn after randomization. In the study group, there was 1 protocol violation: 1 patient was unable to wean from bypass and transitioned directly to ECMO without fibrinogen replacement. There were no differences between groups in baseline demographics and intraoperative characteristics (Table 1; Supplemental Digital Content, Table 1A–D, https://links.lww.com/AA/C922).

Blood Transfusion Requirements.

Table 2 (Supplemental Digital Content, Table 2A–C, https://links.lww.com/AA/C922) shows the total number of intraoperative allogenic blood components received by each group. In the ITT analysis, patients in the FC group received significantly fewer total intraoperative allogenic blood transfusions when compared to patients in the cryoprecipitate group, 4 units (interquartile range [IQR]: 3.0–5.0) vs 5.5 units (IQR: 4.0–7.0), respectively. Overall, the FC group received a mean of 1.79 (95% confidence interval [CI], 0.64–2.93; P = .003) less allogenic donor exposures than the cryoprecipitate group when adjusted for institution and complexity. In the adjusted PP analysis, the FC group received a mean of 2.67 (95% CI, 1.75–3.59; P value < .001) less allogenic donor exposures than the cryoprecipitate group. When adjusted for weight and CPB time, the results were similar to the primary analyses. In a post hoc ITT analysis of post-bypass transfusions, the FC group received a mean of 1.66 (95% CI, 0.77–2.54; P = .001) less allogenic donor exposures than the cryoprecipitate group. In a similar PP analysis, the FC group received a mean of 2.47 (95% CI, 1.76–3.18; P < .001) less allogenic donor exposures than the cryoprecipitate group.

Table 2. - Intraoperative Product Usage Displayed According to Assigned Study Arm (ITT) and for the Subset of Patients Who Completed the Study PP

	ITT Cryo	ITT FC	ITT D	ITT P Value	PP Cryo	PP FC	PP D	PP P Value
n	29	30			25	29
pRBC
Total, units	2.0 (1.0–2.0)	2.0 (1.0–2.8)	0.084	.383	2.0 (1.0–3.0)	2.0 (1.0–3.0)	0.100	.920
Total, mL/kg	49.7 (37.1–77.5)	45.4 (36.8–75.5)	0.113	.906	56.1 (38.1–81.8)	44.2 (36.1–73.4)	0.398	.344
Post-bypass, units	0.0 (0.0–0.0)	0.0 (0.0–0.8)	0.225	.483	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.053	.944
Post-bypass, mL/kg	0.0 (0.0–2.6)	0.0 (0.0–5.6)	0.061	.702	0.0 (0.0–10.0)	0.0 (0.0–3.9)	0.269	.728
FFP
Total, units	1.0 (0.0–1.0)	1.0 (1.0–1.0)	0.246	.263	1.0 (0.0–1.0)	1.0 (1.0–1.0)	0.083	.703
Total, mL/kg	19.2 (0.0–36.1)	15.3 (0.0–47.2)	0.024	.868	31.2 (0.0–36.4)	15.2 (0.0–49.1)	0.174	.568
Post-bypass, units	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.372	.154	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.263	.353
Post-bypass ml/kg	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.143	.557	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.204	.895
Platelet
Total, units	1.0 (1.0–1.0)	1.0 (1.0–1.0)	0.297	.257	1.0 (1.0–1.0)	1.0 (1.0–1.0)	0.053	.846
Total, mL/kg	14.8 (9.2–24.8)	16.0 (9.3–22.2)	0.065	.888	15.7 (11.9–27.2)	16.6 (10.0–22.3)	0.315	.456
Post-bypass, units	1.0 (1.0–1.0)	1.0 (1.0–1.0)	0.512	.057	1.0 (1.0–1.0)	1.0 (1.0–1.0)	0.053	.846
Post-bypass, mL/kg	14.8 (9.2–24.8)	17.6 (10.3–23.4)	0.306	.304	15.7 (11.9–27.2)	16.8 (10.2–22.8)	0.029	.755
Cryo
Total, units	2.0 (2.0–2.0)	0.0 (0.0–0.0)	1.933	<.001	2.0 (2.0–2.0)	0.0 (0.0–0.0)	2.505	<.001
Total, mL/kg	8.0 (6.2–11.2)	0.0 (0.0–0.0)	1.974	<.001	9.1 (6.6–13.1)	0.0 (0.0–0.0)	2.574	<.001
Post-bypass, units	2.0 (2.0–2.0)	0.0 (0.0–0.0)	1.813	<.001	2.0 (2.0–2.0)	0.0 (0.0–0.0)	2.505	<.001
Post-bypass, mL/kg	7.6 (5.9–11.2)	0.0 (0.0–0.0)	1.846	<.001	9.1 (6.6–13.1)	0.0 (0.0–0.0)	2.574	<.001
All products
Total units of product	5.5 (4.0–7.0)	4.0 (3.0–5.0)	0.638	.007	6.0 (5.0–7.0)	4.0 (3.0–5.0)	1.036	<.001
Post–bypass units of product	3.0 (3.0–3.8)	1.0 (1.0–2.0)	0.920	.001	3.0 (3.0–4.0)	1.0 (1.0–2.0)	1.645	<.001

Abbreviations: Cryo, cryoprecipitate arm; D, standardized difference (a measure of the difference between the distribution of the characteristic in the 2 arms expressed in units of standard deviations); FC, fibrinogen concentrate arm; FFP, fresh-frozen plasma; IQR, interquartile range; ITT, intent-to-treat; PP, per protocol; pRBCs, products of red blood cells.

^aCells contain median (IQR) = (25th–75th percentile); P values were obtained from a Mann-Whitney U test.

^bRandomized patients may not have received products if they did not complete the study per protocol or had data collected if consent was withdrawn. We have imputed values for these patients using a worst-case imputation approach in the ITT columns.

We did not observe a difference in the volumes of RBCs, FFP, and platelets received intraoperatively by patients in the cryoprecipitate group and FC group (post hoc ITT analysis: P = .906, .868, and .888), while patients in the FC group received significantly less transfusion of cryoprecipitate (P < .001). Only 1 patient in the FC group required a rescue dose of cryoprecipitate. In patients who were categorized as “high risk of bleeding,” a PP analysis demonstrated that the cryoprecipitate group received a median of 9.5 total units (IQR: 6.5–10.8), while the FC group received a median of 5 units (IQR: 4.0–6.0; Table 3). In low-complexity patients, the cryoprecipitate group received a median of 5 total units (IQR: 4.0–6.0) compared to 3.5 units (IQR: 3.0–4.8) in the FC group (Supplemental Digital Content, Table 2A, https://links.lww.com/AA/C922). The average dose of FC was 107.8 mg/kg (IQR: 86.5–118.1).

Table 3. - Intraoperative Product Usage Displayed for the Subset of Patients Undergoing High-Complexity Surgery Who Completed the Study PP

	PP Cryo	PP FC	PP D
n	8	11
pRBC
Total, units	2.5 (1.8–4.0)	2.0 (2.0–3.0)	0.336
Total, mL/kg	94.1 (77.2–161.4)	66.7 (41.1–78.1)	1.011
Post-bypass, units	0.5 (0.0–1.0)	0.0 (0.0–0.5)	0.368
Post-bypass, mL/kg	11.4 (0.0–24.7)	0.0 (0.0–3.1)	0.883
FFP
Total, units	1.0 (1.0–1.3)	1.0 (1.0–1.5)	0.016
Total, mL/kg	35.5 (33.6–57.0)	30.3 (15.3–61.5)	0.202
Post-bypass, units	0.0 (0.0–0.0)	0.0 (0.0–0.0)	<0.001
Post-bypass, mL/kg	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.500
Platelet
Total, units	1.0 (1.0–2.0)	1.0 (1.0–1.0)	0.416
Total, mL/kg	23.5 (13.3–37.3)	18.3 (11.6–24.7)	0.558
Post-bypass, units	1.0 (1.0–2.0)	1.0 (1.0–1.0)	0.416
Post-bypass, mL/kg	23.5 (13.3–37.3)	18.3 (11.6–24.7)	0.558
Cryo
Total, units	3.5 (2.0–5.0)	0.0 (0.0–0.0)	2.676
Total, mL/kg	13.8 (9.0–15.2)	0.0 (0.0–0.0)	2.392
Post-bypass, units	3.5 (2.0–5.0)	0.0 (0.0–0.0)	2.676
Post-bypass, mL/kg	13.8 (9.0–15.2)	0.0 (0.0–0.0)	2.392
All products
Total units of product	9.5 (6.5–10.8)	5.0 (4.0–6.0)	1.453
Post-bypass units of product	5.5 (3.8–8.0)	1.0 (1.0–2.0)	2.234

Abbreviations: Cryo, cryoprecipitate arm; D, standardized difference (a measure of the difference between the distribution of the characteristic in the 2 arms expressed in units of standard deviations); FC, fibrinogen concentrate arm; FFP, fresh-frozen plasma; IQR, interquartile range; PP, per protocol; pRBCs, products of red blood cells.

^aCells contain median (IQR) = (25th–75th percentile).

^bRandomized patients may not have received products if they did not complete the study per protocol or had data collected if consent was withdrawn.

Six patients in the FC group received RBCs postoperatively, while only 1 patient in the cryoprecipitate group received RBCs. One patient in each group received FFP postoperatively. Two patients in the cryoprecipitate group received platelets, while none did in the FC group. No patients received cryoprecipitate. At institution 1, 7 of the 11 high-risk patients (3 in the cryoprecipitate group and 4 in the FC group) received FEIBA intraoperatively. No patients at institution 2 received a PCC.

Coagulation Tests.

Figure 2.: Summary of fibrinogen levels. A, Fibrinogen levels at different time points in each study group. B, Box plot with distribution of fibrinogen levels in each study group at different time points. ^aMedian (IQR) = (25th–75th percentile). Cryo indicates cryoprecipitate arm; D, standardized difference (a measure of the difference between the distribution of the characteristic in the 2 arms expressed in units of standard deviations); FC, fibrinogen concentrate arm; IQR, interquartile range; INR, international normalized ratio; PP, per protocol.

The fibrinogen levels at each time point are shown in Figure 2A, B. The results of all coagulation tests are shown in Supplemental Digital Content, Table 3A–C, https://links.lww.com/AA/C922. At all times points, test results showed no evidence of a difference between the FC and cryoprecipitate patients.

Clinical Outcomes and AEs.

Table 4. - Secondary Outcomes and Adverse Events Displayed According to Assigned Study Arm for the Subset of Patients Who Completed the Study PP

	Cryo	FC	P Value	Adjusted P Value
n	25	29
Secondary outcomes
Chest tube output, mL/kg	18.1 (10.9–26.0)	16.1 (12.6–25.0)	.671	.538
Hours of intubation	30.3 (18.7–98.7)	27.1 (20.4–51.6)	.510	.408
LOS ICU, d	4.5 (2.0–6.0)	3.0 (2.0–7.0)	.487	.392
LOS hospital, d	8.0 (5.0–19.0)	7.0 (4.0–11.0)	.342	.904
Death within 30 days	0 (0.0)	1 (3.4)	>.999	…
Adverse events
Any adverse event	10 (40.0)	9 (31.0)	.688	.455
Arrhythmia requiring treatment	6 (24.0)	5 (17.2)
Thrombosis requiring intervention	0 (0.0)	1 (3.4)
Requiring ECMO within 24 hours	0 (0.0)	0 (0.0)
Infection within 14 days	1 (4.2)	0 (0.0)
Repeat surgery within 7 days	2 (8.3)	0 (0.0)
Tamponade	0 (0.0)	1 (3.4)
Chest exploration	1 (4.0)	2 (6.9)
Stroke	1 (4.0)	0 (0.0)
Death	0 (0.0)	1 (3.4)

Abbreviations: CPB, cardiopulmonary bypass; Cryo, cryoprecipitate arm; ECMO, extracorporeal membrane oxygenation; FC, fibrinogen concentrate arm; ICU, intensive care unit; IQR, interquartile range (25th–75th percentile); LOS, length of stay; PP, per protocol.

^aP values were obtained from a Mann-Whitney U test unless otherwise noted.

^bP values were obtained from a linear regression with a log-transformed dependent variable adjusted for site, complexity, weight, and CPB time unless otherwise noted.

^cMedian (IQR).

^dNumber (%).

^eP value obtained from a Fisher exact test.

^fModel not fit due to small number of deaths observed.

^gP value obtained from a χ² test.

^hP value obtained from a logistic regression adjusted for site, complexity, weight, and CPB time.

There were no statistically significant differences between the FC or cryoprecipitate groups in secondary outcomes or AEs (Table 4; Supplemental Digital Content, Table 4A, B, https://links.lww.com/AA/C922). There was 1 hemorrhagic stroke in the control group. The thrombosis requiring intervention in the FC group was at the site of a femoral arterial line placed after multiple attempts. There was 1 death on postoperative day 26 in the FC group secondary to a respiratory arrest at home in a patient with known tracheomalacia.

DISCUSSION

The results of this 2-center prospective RCT demonstrate that FC reduced intraoperative allogenic blood transfusions when compared to cryoprecipitate in infants requiring cardiac surgery. The reduction was 1.79 (95% CI, 0.64–2.93) donor exposures in the ITT analysis and 2.67 (95% CI, 1.75–3.59) in the PP analysis. We found no statistically significant difference between the 2 groups in secondary outcomes or AEs including CTO, length of mechanical ventilation, ICU or hospital LOS, postoperative thrombosis, or death. These findings suggest that FC may be an acceptable alternative to cryoprecipitate as part of a post-CPB transfusion algorithm for the treatment of hypofibrinogenemia in infants with bleeding after CPB.

Critically low fibrinogen levels are associated with increased postoperative blood loss in both adult and pediatric cardiac surgery patients.^10,26 Given this and in an attempt to reduce blood product transfusions, FC is increasingly being used as an alternative to cryoprecipitate. Prospective trials in adult cardiovascular surgery have shown mixed results.^18,19,27 The Randomized Evaluation of Fibrinogen Versus Placebo in Complex Cardiovascular Surgery (REPLACE) trial, a multicenter trial of adults undergoing elective aortic surgery, showed that patients randomized to FC received more allogenic blood transfusions in the first 24 hours postoperatively when compared to placebo.²⁸ A recent meta-analysis comparing FC versus inactive control found that FC significantly decreased the number of patients receiving allogenic RBCs but did not decrease the total number of allogenic transfusions.²¹ Despite the lack of strong evidence in adult patients, FC is an attractive alternative for infants. Hemodilution of coagulation factors by large CPB circuits and the presence of fetal fibrinogen, which forms weaker clots with faster degradation times,¹⁴ increase their risk of post-CPB bleeding and exposure to allogenic blood transfusions.^1,3,28 Increased donor exposures are independently associated with worse outcomes²⁹ and, in children requiring multiple procedures throughout their lifetime, make it hard to find suitable blood products for future surgeries or heart transplantation if necessary.^30–32 FC has other clinical benefits: small volume, accurate dosing, immediate availability, and decreased infectious or immunologic risk. However, cryoprecipitate contains additional coagulation proteins that may be critical to restoring hemostasis in infants so its substitution by FC is not intuitive.

To date, this is the second RCT comparing FC directly to cryoprecipitate as a fibrinogen replacement in pediatric cardiac patients undergoing CPB and is the only trial specifically performed in infants. In 2014, Galas et al¹⁷ examined the use of FC compared to cryoprecipitate in reducing blood loss in children undergoing cardiac surgery. Although there was no difference in intraoperative blood loss between the 2 groups, over half of the patients in the FC group also received cryoprecipitate making it difficult to draw conclusions. In contrast, our study was performed across 2 institutions and focused specifically on neonates and infants. We utilized a stratified randomization strategy to account for differences in institutional practices and surgical complexity in this heterogeneous population. In both the ITT and PP analyses, FC patients received less allogenic blood transfusions than patients in the cryoprecipitate group (1.79 and 2.67 units, respectively). While this difference is likely due to the fact that FC replaced 2 units of cryoprecipitate within the transfusion algorithm, the narrow CI around the mean difference suggests that FC patients did not require more products than the cryoprecipitate patients. In our post hoc analysis examining post-bypass transfusions only, FC patients also received less allogeneic transfusions that those in the cryoprecipitate group (1.66 for ITT and 2.47 for PP) suggesting yet again that FC is a suitable alternative to cryoprecipitate. In addition, our data imply that FC may be more effective in infants at higher risk for post-CPB bleeding. In the high-complexity group, infants randomized to the cryoprecipitate arm received a median of 9.5 total allogenic units (IQR: 6.50–10.75), while those randomized to the FC group received a median of 5 units (IQR: 4.00–6.00), approximately half the number of allogenic transfusions. Patients in the high-risk cryoprecipitate arm received more pRBCs, platelets, and cryoprecipitate than those in the FC arm. In light of these findings, future studies should focus on the use of FC in patients at high risk for bleeding complications.

This study has several limitations. First, the study was completed at 2 different centers. Despite each institutions use of similar transfusion goals and CPB strategies, there were differences in patient management. One institution included FFP in all infant CPB primes, while the other only used FFP in neonates and cyanotic infants. Although this did not affect fibrinogen levels, it may have contributed to differences in hemostasis not measured by standard laboratory tests. The first institution also had an established practice of using FEIBA for high-risk bleeding cases, which may have decreased the number of allogenic blood transfusions unrelated to fibrinogen replacement.³³ Second, the median fibrinogen level after the transfusion of 2 units of cryoprecipitate was lower (276.5 mg/dL [IQR: 192.3–323.5 mg/dL]) than the median fibrinogen level after treatment with FC (314.5 mg/dL [IQR: 296.5–342.5 mg/dL]) in our patient sample. This is likely due to the fact that each unit of cryoprecipitate has variable amounts of fibrinogen. However, this difference was not statistically significant. Third, our post-CPB transfusion algorithm was followed intraoperatively only making it difficult to assess the differences in postoperative transfusion between the 2 groups. Fourth, our study did not involve patients >30 days postoperatively or >30 days following hospital discharge, so we could not assess long-term risks or benefits between the 2 groups. Finally, we do not know the true thrombotic rate. We only screened for clinically significant thrombosis and did not seek to detect nonclinically significant thrombosis. While postoperative thrombotic complications are reported to occur in 10%–30% of pediatric patients undergoing cardiac surgery,^34,35 our thrombosis rate was much lower at 1.5%. Of note, this study was not properly powered to assess differences in thrombosis.

Given the safety concerns and increased mortality associated with allogenic blood product transfusions, we evaluated FC as an alternative to cryoprecipitate as part of a post-CPB transfusion algorithm in infants having cardiac surgery. Our findings demonstrate that FC may be an effective replacement for cryoprecipitate. We did not detect any significant differences in clinical outcomes or AEs.

DISCLOSURES

Name: Laura A. Downey, MD.

Contribution: This author helped design the study, collect the data, write the manuscript, and approve the final version of the manuscript. L. A. Downey oversaw the clinical trial at both institutions and was the primary investigator at Emory University.

Name: Jennifer Andrews, MD.

Contribution: This author helped consult on study design, manage the clinical trial at Stanford University, write the manuscript, and approve the final version of the manuscript.

Name: Haley Hedlin, PhD.

Contribution: This author helped manage the data collection and data analysis, write the manuscript, and approve the final version of the manuscript.

Name: Komal Kamra, MD.

Contribution: This author helped with patient recruitment and data collection, and approved the final version of the manuscript.

Name: E. Dean McKenzie, MD.

Contribution: This author helped with patient recruitment and approved the final version of the manuscript.

Name: Frank L. Hanley, MD.

Contribution: This author helped with patient recruitment and approved the final version of the manuscript.

Name: Glyn D. Williams, MD.

Contribution: This author helped with study design, patient recruitment, data collection and clinical trial logistics at Stanford University, and writing of the manuscript and approved the final version of the manuscript. G. D. Williams was the PI at Stanford University.

Name: Nina A. Guzzetta, MD, FAAP.

Contribution: This author helped with patient recruitment, data collection, and the writing of the manuscript and approved the final version of the manuscript.

This manuscript was handled by: James A. DiNardo, MD, FAAP.