Adequate hemostasis remains an important issue in

Fresh Frozen Plasma in the Pediatric Pump Prime: A Prospective, Randomized Trial Mary M. McCall, MSN, Mindy M. Blackwell, MS, Jonathan T. Smyre, MS, Joseph J. Sistino, MPA, Jeffrey R. Acsell, BS, B. Hugh Dorman, MD, PhD, and Scott M. Bradley, MD Cardiovascular Perfusion Program, Department of Anesthesia, and Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina Background. The aim of this study was to determine whether the use of fresh frozen plasma (FFP) in the infant pump prime can avoid dilution of fibrinogen, decrease the need for blood product transfusion after bypass, and decrease exposure to donor blood products. Methods. Twenty infants weighing less than 8 kg were prospectively randomized to receive either 1UofFFP(10 patients) or no FFP (10 patients) in the pump prime. Mean age (4.2 2.8 months), weight (4.3 1.1 kg), total prime volume (641 96 ml), cardiopulmonary bypass time, cross-clamp time, lowest temperature on bypass, and preoperative coagulation parameters did not differ between the two groups. Results. At the end of bypass, the mean fibrinogen level was significantly higher in the FFP than the no FFP group (123 20 versus 58 17 mg/dl; p < 0.0001), whereas the mean platelet count did not differ (60 25 versus 52 26 K/mm 3 ; p 0.5). Patients in the FFP group received significantly fewer units of cryoprecipitate (0.4 0.8 versus 2.0 0.9 U/patient; p < 0.001), and had a mean total donor exposure of 4.1 1.5 U/patient versus 5.4 1.4 U/patient in the no FFP group (p 0.06). The mean chest tube output over the first 24 hours did not differ between groups. Conclusions. The use of FFP in the pump prime significantly limited dilutional hypofibrinogenemia, decreased the transfusion of cryoprecipitate after bypass, and tended to decrease the overall mean patient exposure to blood products. (Ann Thorac Surg 2004;77:983 7) 2004 by The Society of Thoracic Surgeons Adequate hemostasis remains an important issue in infants who have undergone cardiopulmonary bypass [1 3]. Compared with older patients, neonates and infants are at increased risk for impaired hemostasis, bleeding, and transfusion requirements after open-heart surgery [4, 5]. Patients weighing less than 8 kg have also been found to have increased rates of bleeding and blood product transfusion after cardiopulmonary bypass [6]. A major factor affecting the coagulation system during infant cardiopulmonary bypass is hemodilution. The proportionally large volume of the bypass pump prime compared with the patient s blood volume results in a significant decrease in platelet count and dilution of coagulation factors including fibrinogen [2, 6, 7]. The fibrinogen level at the end of bypass has, in turn, been shown to correlate with 24-hour chest tube drainage in children weighing less than 8 kg [6]. One approach to coagulation management in children undergoing cardiopulmonary bypass is the use of fresh whole blood [3]. However fresh whole blood is not readily available in all institutions. An alternative is the use of fresh frozen plasma (FFP) in the pump prime. We Presented at the Forty-ninth Annual Meeting of the Southern Thoracic Surgical Association, Miami Beach, FL, Nov 7 9, 2002. Address reprint requests to Dr Bradley, Division of Cardiothoracic Surgery, Medical University of South Carolina, 96 Jonathan Lucas St, Charleston, SC 29425; e-mail: bradlesm@musc.edu. hypothesized that FFP might avoid dilution of coagulation factors, such as fibrinogen, and, in turn, decrease transfusion requirements. The aim of this study was to determine the effects of including FFP in the pump prime on fibrinogen levels and transfusion requirements in infants undergoing cardiopulmonary bypass. Material and Methods This study was approved by the Institutional Review Board of the Medical University of South Carolina. Informed consent was obtained from the parents or guardians of each patient. Twenty patients scheduled to undergo heart surgery were prospectively enrolled in the study. Inclusion criteria were a primary operation (nonreoperation) using cardiopulmonary bypass and weight less than 8 kg. Exclusion criteria included a preexisting coagulopathy documented either by history or an abnormal prothrombin time, partial thromboplastin time, or platelet count. Patients receiving a medication known to alter coagulation (such as aspirin) were also excluded. On the day before surgery, each patient was randomized, using a series of sealed envelopes, to receive either1uof FFP or no FFP in the cardiopulmonary bypass pump prime. No study patient received whole blood or any antifibrinolytic agent including aprotinin. Aprotinin has been shown to reduce bleeding in complex operations 2004 by The Society of Thoracic Surgeons 0003-4975/04/$30.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2003.09.030

984 MCCALL ET AL Ann Thorac Surg FRESH FROZEN PLASMA IN THE PEDIATRIC PUMP PRIME 2004;77:983 7 Table 1. Bypass Pump Prime Constituents Total volume (ml) 646 103 636 93 0.8 Packed red blood cells (ml) 175 89 188 57 0.7 FFP (ml) 252 46 0 0.01 a 25% Albumin (ml) 40 29 100 9 0.01 a such as the arterial switch procedure [8]. As it is our policy, as well as that of others [9, 10] to administer aprotinin to all patients undergoing a Norwood or arterial switch procedure, none were included in this study. Operative Management The cardiopulmonary pump prime included Plasmalyte A (Baxter Healthcare Corp, Deerfield, IL), and packed red blood cells to achieve a postdilutional patient hematocrit roughly equal to the target cooling temperature (Table 1). One unit of FFP was added to the pump prime of the patients randomized to the FFP group. Additionally, 25% salt poor albumin (ZL:B Bioplasma AG, Bern, Switzerland) was added to achieve a colloid osmotic pressure of 16 mm Hg for each patient. Due to the colloid osmotic pressure of FFP the patients in the FFP group received less albumin in the prime than those in the no FFP group (Table 1). Prime medications included: heparin (1400 2000 U), sodium bicarbonate (to achieve a ph of 7.35 7.45), mannitol (250 mg/kg), cefazolin (25 mg/kg), and regitine (0.25 mg/kg) for a target cooling temperature less than 25 C. Anesthesia was induced and maintained with intravenous midazolam and fentanyl. Pancuronium was utilized for muscle relaxation. Systemic heparinization was achieved with a heparin dose of 400 U/kg. Activated clotting time (ACT) was measured every twenty minutes with a Hemochron 6000 system (International Technidyne Corp, Edison, NJ). All patients underwent ultrafiltration during bypass, as well as arteriovenous modified ultrafiltration immediately after bypass. Modified ultrafiltration was carried out to filter a volume equal to the prime volume, which generally took a period of 12 minutes. The protamine dose was calculated based on 60% of the total heparin given. Heparin reversal was verified by return of ACT to base line ten minutes after protamine administration. Study Protocol Laboratory tests (fibrinogen level, platelet count, prothrombin time, partial thromboplastin time, hematocrit) were determined before skin incision. The fibrinogen level and platelet count were repeated during the rewarming phase of bypass. After protamine administration blood products were administered according to a predetermined protocol: platelets (0.5 U/kg) were given for a platelet count less than 60 K/mm 3, and cryoprecipitate (0.5 U/kg) for a fibrinogen level less than 80 mg/dl. Table 2. Demographics and Operative Data Patients 10 10 Cyanotic 3 2 Age (months) 4.0 3.9 4.4 1.2 0.7 Weight (kg) 4.0 1.3 4.6 0.9 0.2 Cardiopulmonary bypass 105 32 110 35 0.7 time (min) Cross-clamp time (min) 42 18 46 22 0.6 Lowest temperature ( C) 24 3 26 2 0.2 Operation 0.6 Ventricular septal defect 2 5 Tetralogy of Fallot 3 1 TAPVR 3 0 Left atrial aneurysm 1 0 Secundum ASD 1 0 Cor triatriatum 0 1 Partial AVSD 0 1 Division main PA, 0 1 modified BT shunt Bidirectional Glenn shunt 0 1 ASD atrial septal defect; AVSD atrioventricular septal defect; BSA body surface area; BT Blalock-Taussig; FFP fresh frozen plasma; PA pulmonary artery; TAPVR total anomalous pulmonary venous return. If bleeding continued subsequently, laboratory tests were repeated and additional blood products administered at the discretion of the surgeon and anesthesiologist. These additional blood products were platelets (1 patient in each group), cryoprecipitate (2 patients in the FFP group), and FFP (3 patients in the no FFP group). Upon arrival in the intensive care unit, laboratory tests were repeated. The volume of chest tube output over the first 24 hours in the intensive care unit and the units of blood products administered in the operating room and over the first 24 hours in the intensive care unit were recorded. Statistics Data from the FFP and no FFP groups were compared by the unpaired Student t test, the Fischer exact test, or 2 test, as appropriate. Data are shown as mean SD. Statistical significance was defined as p 0.05. Results Patients There was no significant difference in the age or weight of the patients in the FFP and no FFP groups (Table 2). Three patients in the FFP group and 2 patients in the no FFP group were cyanotic (baseline systemic oxygen saturation 90%) before operation. The mean cardiopulmonary bypass time, cross-clamp time, and lowest temperature on bypass did not differ between the two groups (Table 2). The operative procedures in the two groups are detailed in Table 2.

Ann Thorac Surg MCCALL ET AL 2004;77:983 7 FRESH FROZEN PLASMA IN THE PEDIATRIC PUMP PRIME Table 3. Laboratory Tests Preoperative Fibrinogen (mg/dl) 234 84 188 34 0.1 Platelet count (K/mm 3 ) 381 149 418 122 0.5 Prothrombin time (s) 13 2 13 2 0.8 Partial thromboplastin time (s) 34 6 38 8 0.3 Hematocrit (%) 41 9 34 8 0.06 End of bypass Fibrinogen (mg/dl) 123 20 58 17 0.0001 a Platelet count (K/mm 3 ) 60 25 52 26 0.5 ICU admission Fibrinogen (mg/dl) 195 20 215 42 0.4 Platelet count (K/mm 3 ) 178 71 140 37 0.5 Prothrombin time (s) 16 2 19 8 0.3 Partial thromboplastin time (s) 49 18 50 24 0.9 Hematocrit (%) 39 6 38 4 0.7 Coagulation Parameters and Bleeding The preoperative mean fibrinogen level, platelet count, prothrombin time, and partial thromboplastin time did not differ between the FFP and no FFP patients (Table 3). However before the end of bypass, the mean fibrinogen level in the no FFP group had fallen to 58 mg/dl, whereas the mean fibrinogen level in the FFP group was significantly higher, 123 mg/dl (Table 3). The mean platelet count was low in both groups, 60 K/mm 3 in the FFP patients versus 52 K/mm 3 in the no FFP patients which was not a significant difference (Table 3). By the time of admission to the intensive care unit, there were again no differences between the two groups in mean fibrinogen level, platelet count, prothrombin time, or partial thromboplastin time (Table 3). The mean chest tube output over the first 24 hours in the intensive care unit was 10 7 ml/kg in the FFP group versus 10 5 ml/kg in the no FFP group (p 0.9). Donor Exposures The FFP and no FFP groups had a similar mean number of donor exposures from packed red blood cells (1.8 versus 2.1 U/patient) and from platelets (0.9 versus 1.0 U/patient; Table 4). As expected donor exposures from FFP were higher in the FFP group but this was offset by a Table 4. Donor Exposures Per Patient Packed red blood cells 1.8 0.4 2.1 0.3 0.09 Platelets 0.9 0.7 1.0 0.7 0.8 FFP 1.0 0.0 0.3 0.5 0.001 a Cryoprecipitate 0.4 0.8 2.0 0.9 0.001 a Total 4.1 1.5 5.4 1.4 0.06 significantly lower number of donor exposures from cryoprecipitate (0.4 versus 2.0 U/patient; Table 4). Overall, the patients in the FFP group had a mean total donor exposure of 4.1 U/patient compared with 5.4 U/patient in the no FFP group (Table 4). This difference approached statistical significance (p 0.06). Comment 985 This study examined the effects of including FFP in the cardiopulmonary bypass pump prime of patients weighing less than 8 kg. We found that the use of FFP led to a significantly higher fibrinogen level at the end of bypass. This, in turn, led to less transfusion of cryoprecipitate and a trend toward less overall exposure to donor blood products. A major factor affecting the coagulation system in an infant undergoing cardiopulmonary bypass is the dilution of plasma proteins and platelets that results from the relatively large priming volume of the bypass pump [1, 11, 12]. Whereas an average-size adult s blood volume is diluted 25% 35% during cardiopulmonary bypass, dilution may be 200 400% in a neonate [11 13]. As a result, factor levels and platelet counts decrease markedly as soon as the patient is placed on bypass. Kern and associates observed that coagulation factors decreased 50% and platelet counts decreased 70% in neonates within 1 minute of being placed on bypass [2]. Chan and associates also showed that among 22 pediatric patients aged 1 15 years, plasma concentrations of hemostatic proteins decreased by an average of 56% immediately after the initiation of bypass [13]. Our findings support this as at the end of bypass, both the FFP and no FFP patients had fibrinogen levels and platelet counts well below their preoperative values. However the use of FFP in the prime did significantly offset the decrease in fibrinogen levels at the end of bypass. Bleeding and transfusion requirements remain important issues in pediatric patients undergoing cardiopulmonary bypass. Neonates and infants have been shown to be at particularly high risk for exposure to blood products after bypass [2 4, 6, 14]. Miller and associates reported that children weighing less that 8 kg have more severe coagulopathy, bleed more, and require more coagulation product transfusion than children weighing more than 8 kg [6]. Williams and associates found that both postoperative blood loss and blood product transfusion were higher in younger patients; among 414 consecutive children undergoing open heart procedures, the median number of blood products received was 2 U in children 1 5 years old, 6 U in children 1 12 months old, and8uinchildren less than 1 month old [4]. A subsequent prospective multivariate analysis by the same group showed that younger patient age was the most significant single risk factor for bleeding and transfusions in children undergoing open-heart surgery [5]. Chambers and associates reported that infants undergoing primary operations received a mean of 2.1 donor unit exposures for routine procedures and 6.1 exposures for complex procedures [15]. Our findings are in agreement

986 MCCALL ET AL Ann Thorac Surg FRESH FROZEN PLASMA IN THE PEDIATRIC PUMP PRIME 2004;77:983 7 with these studies: the mean total donor exposure in our study group was 4.8 U/patient. Decreasing the need for blood product transfusion in children after bypass is a desirable goal. The potential risks of blood product transfusion include transfusion reactions, immunosuppression, and transfusionassociated infection [16, 17]. Administration of blood products to a child after cardiopulmonary bypass carries additional risks: rapid infusion can cause volume overload, whereas inadequate infusion can result in ongoing bleeding. Postbypass correction of dilutional coagulopathy also entails the cost of the blood products as well as the cost of operating room time if chest closure is delayed. On average the patients in our FFP group received 1.3 fewer donor exposures per patient than the no FFP patients, a difference which approached statistical significance. The FFP patients tended to receive fewer packed red blood cell transfusions (1.8 versus 2.1 U/patient). However this may reflect the slightly higher preoperative mean hematocrit in the FFP patients as the two groups had no difference in mean hematocrit at ICU arrival or in 24-hour chest tube drainage. The lower donor exposure of the FFP group was primarily due to significantly fewer transfusions of cryoprecipitate (0.4 versus 2 U/patient). This was a direct result of the FFP group s higher mean fibrinogen level at the end of bypass along with the study protocol for cryoprecipitate transfusion. This protocol was designed before the study to provide a systematic approach to transfusion rather than relying solely on the discretion of the surgeon and anesthesiologist. The specific guidelines selected for transfusion of cryoprecipitate and platelets were selected because the fibrinogen level and platelet count at the end of bypass have been shown to be predictive of chest tube drainage over the first 24 hours in children weighing less than 8 kg [6]. The transfusion protocol is also in line with recommendations in the literature [1, 12, 16]. Another recent study examined the effects of FFP versus 5% albumin in the pump prime for pediatric cardiopulmonary bypass [7]. As in our study there was no difference in blood loss between the two groups although a subgroup analysis suggested that the use of FFP decreased blood loss in cyanotic patients and those having complex operations. In contrast to our results the FFP group had a greater total transfusion requirement although once adjustment was made for cyanotic patients there was no significant difference between the two groups [7]. The differing results of these two studies may be due to different approaches concerning the use of cryoprecipitate, which was used infrequently in their study and fibrin glue, which was used more frequently in their FFP group but not in any of our patients. Administration of FFP to pediatric patients after bypass, rather than in the pump prime, has been reported to be detrimental being associated with worsened coagulation parameters, greater chest tube drainage, and more coagulation product transfusion in the intensive care unit [6]. Both the current study and that of Oliver and associates [7] found that FFP could be added to the pump prime without compromising coagulation parameters or bleeding. It is possible that adding FFP to the pump before bypass may be more efficient than administering it after bypass-induced dilution has already occurred. Another approach to coagulation management in children undergoing cardiopulmonary bypass is the use of fresh whole blood. Manno and associates prospectively compared the relative effects of whole blood to those of blood reconstituted from packed red blood cells, platelets, and fresh frozen plasma [3]. Either whole blood or reconstituted blood was used both in the pump prime and for postbypass transfusion. They found that whole blood was more effective in decreasing postoperative bleeding in patients less than 2 years old undergoing complex operations. Whether the whole blood was less than 6 hours old or 24 48 hours old did not make a significant difference. The authors suggested that improved platelet function accounted for the salutary effects of whole blood. They also pointed out that the platelets in the 24 48 hour old blood presumably had decreased function due to storage at 4 C for at least 24 hours [3]. Further studies of the effects of fresh whole blood in pediatric open-heart surgery would help to clarify its role. Currently not all institutions have fresh whole blood routinely available. The use of FFP in the pump prime may provide a useful alternative. A limitation of this study was the small number of patients that did not allow delineation of any potential differences between cyanotic and acyanotic patients or those undergoing simple versus complex operations. Another limitation was the use of a transfusion protocol for cryoprecipitate and platelets. This directly affected the number of donor exposures in many of the study patients. In summary this prospective randomized study examined the inclusion of FFP in the pump prime of infants weighing less than 8 kg. Our findings suggest that the use of FFP may limit dilutional hypofibrinogenemia and decrease the need for postbypass transfusion of blood products. Further study is warranted in a larger number of patients, particularly cyanotic patients undergoing complex operations. The authors would like to thank Martha R. Stroud, MS, for statistical assistance. References 1. Guay J, Rivard G. Mediastinal bleeding after cardiopulmonary bypass in pediatric patients. Ann Thorac Surg 1996;62: 1955 60. 2. Kern FH, Morana NJ, Sears JJ, Hickey PR. Coagulation defects in neonates during cardiopulmonary bypass. Ann Thorac Surg 1992;54:541 6. 3. Manno CS, Hedberg KW, Kim HC, Bunjin GR, Nicolson S, Jobes D, Schwartz E, Norwood WI. Comparison of the hemostatic effects of fresh whole blood, stored whole blood, and components after open heart surgery in children. Blood 1991;77:930 6. 4. Williams GD, Bratton SL, Riley EC, Ramamoorthy C. Asso-

Ann Thorac Surg MCCALL ET AL 2004;77:983 7 FRESH FROZEN PLASMA IN THE PEDIATRIC PUMP PRIME ciation between age and blood loss in children undergoing open heart operations. Ann Thorac Surg 1998;66:870 6. 5. Williams GD, Bratton SL, Ramamoorthy C. Factors associated with blood loss and blood product transfusions: a multivariate analysis in children after open-heart surgery. Anesth Analg 1999;89:57 64. 6. Miller BE, Mochizuki T, Levy JH, Bailey JM, Tosone SR, Tam VK, Kanter KR. Predicting and treating coagulopathies after cardiopulmonary bypass in children. Anesth Analg 1997;85: 1196 202. 7. Oliver WC, Beynen FM, Nuttall GA, Schroeder DR, Ereth MH, Dearani JA, Puga FJ. Blood loss in infants and children for open heart operations: albumin 5% versus fresh-frozen plasma in the prime. Ann Thorac Surg 2003;75:1506 12. 8. Carrel TP, Schwanda M, Vogt PR, Turina MI. Aprotinin in pediatric cardiac operations: a benefit in complex malformations and with high-dose regimen only. Ann Thorac Surg 1998;66:153 8. 9. Jaquiss RDB, Ghanayem NS, Zacharisen MC, Mussatto KA, Tweddell JS, Litwin SB. Safety of aprotinin use and re-use in pediatric cardiothoracic surgery. Circulation 2002;106(suppl I):I-90 4. 10. Tweddell JS, Hoffman GM, Mussatto KA, Fedderly RT, Berger S, Jaquiss RDB, Ghanayem NS, Frisbee SJ, Litwin SB. 987 Improved survival of patients undergoing palliation of hypoplastic left heart syndrome: lessons learned from 115 consecutive patients. Circulation 2002;106(suppl I):I-82 9. 11. Pouard P. Review of efficacy parameters. Ann Thorac Surg 1998;65:S40 4. 12. Rinder CS. Hematologic effects of cardiopulmonary bypass. In: Gravlee GP, Davis RF, Kurusz M, Utley JR, eds. Cardiopulmonary bypass. Lippincott, Williams, & Wilkins: Philadelphia, PA, 2000:498. 13. Chan AKC, Leaker M, Burrows FA, Williams WG, Gruenwald CE, Whyte L, et al. Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass. Thromb Haemostasis 1997;77:270 7. 14. Petaja J, Lundstrom U, Lleijala M, Peltola K, Siimes MA. Bleeding and use of blood products after heart operations in infants. J Thorac Cardiovasc Surg 1995;109:524 9. 15. Chambers LA, Cohen DM, Davis JT. Transfusion patterns in pediatric open-heart surgery. Transfusion 1996;36:150 4. 16. Barcelona SL, Cote CJ. Pediatric resuscitation in the operating room. Anesth Clin North Am 2001;19:339 65. 17. American Society of Anesthesiologists Task Force on Blood Component Therapy. Practice guidelines for blood component therapy. Anesthesiology 1996;84:732 47. DISCUSSION DR JAMES A. QUINTESSENZA (St. Petersburg, FL): I think it is a good idea to put FFP in the pump. The question I have is at what point in time do you put the FFP in? Is it at the beginning of the pump run or as you are rewarming right before you are going to come off and try to reverse your anticoagulants? DR MCCALL: In order to avoid the initial dilution, we put it in up front before we go on bypass. DR LYNN H. HARRISON (New Orleans, LA): Could you tell us a little bit about your modified ultrafiltration techniques and whether you go for a specified period of time or to a set volume, and was there any significant difference in the free water eluted by those techniques? DR MCCALL: There wasn t any difference in the amount of volume that we took off, and we standardized the amount of time that we MUF at 12 minutes, so all patients received the ultrafiltration for 12 minutes. We all used the same amount of vacuum on the suction, so similar volume amounts were removed. We pull blood from the aorta and reinfuse back through the venous side.