Recombinant activated factor VII for hemorrhage after pediatric cardiac surgery Sarvesh Pal Singh, Sandeep Chauhan,

Minati Choudhary, Sumit Vasdev and Sachin Talwar Asian Cardiovasc Thorac Ann 2012;20:19-23 DOI: 10.1177/0218492311432584

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Original Article
Asian Cardiovascular & Thoracic Annals 20(1) 1923 The Author(s) 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492311432584 aan.sagepub.com

Recombinant activated factor VII for hemorrhage after pediatric cardiac surgery
Sarvesh Pal Singh1, Sandeep Chauhan1, Minati Choudhary1, Sumit Vasdev1 and Sachin Talwar2

Abstract Postoperative bleeding is a common complication after pediatric cardiac surgery. Use of recombinant activated factor VII for intractable hemorrhage after cardiac, pediatric, and neurosurgery has been shown to decrease postoperative bleeding, but data in children are limited. This retrospective study analyzed 20 children <15 years-old who underwent cardiac surgery and received recombinant activated factor VII for refractory postoperative hemorrhage. All patients underwent mediastinal reexploration before recombinant activated factor VII was administered as a bolus dose over 23 min as rescue therapy. If no significant decrease in chest tube drainage was observed, the dose was repeated after an interval of at least 2 h. The median dose of recombinant activated factor VII administered per bleeding episode was 83.33 mgkg1 (range, 72.4787.50 mgkg1), and the dose per patient was 154.16 mgkg1 (range, 93.06180.52 mgkg1). The median number of doses found to be effective in these children was 1.76. There were significant decreases in mediastinal chest tube drainage and the volume of packed red blood cells, platelet concentrates, and cryoprecipitate administered after recombinant activated factor VII. No complications were observed during the therapy.

Keywords pediatric cardiac surgery, recombinant factor VII, postoperative hemorrhage

Introduction
Postoperative bleeding is a common complication after pediatric cardiac surgery. In rare circumstances, postoperative blood loss may become uncontrollable in spite of prophylactic antibrinolytics and administration of additional blood products. The blood loss may vary from 15 to 110 mLkg1, and the amount of allogenic blood transfused may reach 155 mLkg1 within the rst 24 h.1,2 Surgical reexploration for bleeding has been identied as a strong independent risk factor for operative mortality, renal failure, prolonged mechanical ventilation, respiratory distress syndrome, sepsis, and atrial arrhythmias.3 Also, a surgically manageable cause of postoperative blood loss is only identied in approximately 50% of children.4 These factors have led to the use of desperate measures to treat intractable postoperative blood loss. Withdrawal of aprotinin from the market, after the BART study (Blood Conservation Using Antibrinolytics in a Randomized Trial), led to

an extensive search for a drug to control bleeding in the immediate postoperative period.5 Recent research has shown that recombinant factor VIIa (rFVIIa), a 50-kilodalton molecule produced in baby hamster kidney cells by recombinant DNA technology, decreases postoperative bleeding after various procedures. The US Food and Drug Administration has approved the use of rFVIIa in patients with congenital FVII deciency and hemophilia A or B with inhibitors to coagulation factors VIII and IX. Because of its frequent o-license use for intractable hemorrhage in cardiac, pediatric, and
1 Department of Cardiac Anesthesia, Cardio-Thoracic Sciences Center, All India Institute of Medical Sciences, New Delhi, India. 2 Department of Cardio-Thoracic and Vascular Surgery, Cardio-Thoracic Sciences Center, All India Institute of Medical Sciences, New Delhi, India.

Corresponding author: Sarvesh Pal Singh, MD, Room no. 112 Doctors Hostel, Trauma Center, All India Institute of Medical Sciences, New Delhi 110029, India Email: sarveshpal.singh@gmail.com

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20 neurosurgery, the Food and Drug Administration included a warning against the use of rFVIIa outside the approved indications, because it may lead to serious thrombotic adverse events.69 There is limited data on the use of rFVIIa in children. Most reports on rFVIIa usage in pediatric cardiac surgery are case studies or small case series. Therefore, this retrospective analysis focused on children who underwent corrective surgery for complex congenital heart defects and were given rFVIIa to control severe intractable hemorrhage in the postoperative period.

Asian Cardiovascular & Thoracic Annals 20(1) Administration of rFVIIa as rescue therapy was considered after discussion between the surgeon, anesthesiologist, and ICU physician. It was administered as a bolus dose over a period of 23 min. If no signicant decrease in MCTD was observed, the drug was repeated in the same dose at least 2 h after the rst dose. Subsequent administration was at the discretion of the ICU physician, but not within 2 h of the previous dose. Doses were tailored to round-o the number and match the specication of the supplied vial (1-mg vial). If there was no signicant eect after 3 doses, the drug was discontinued. Coagulation proles were obtained, and additional blood products were administered to bring the parameters within normal ranges in such patients. For analysis, patient characteristics (age, weight, sex, cardiac lesion, and surgery) were noted. Dose of rFVIIa per administration, number of doses per patient, total dose of the drug per patient, and intervals between doses were also taken into account. Mediastinal bleeding after surgical reexploration and units of PRBC, platelet concentrate, cryoprecipitate, and FFP transfused before and after rFVIIa administration were recorded. Results were analyzed using SPSS version 17.0 (SPSS Inc., Chicago, Ill, USA) software. The median of dose of rFVIIa per administration, number of doses per bleeding episode, total amount of drug per bleed, and time intervals between doses were calculated. Volumes of MCTD, PRBC, platelet concentrate, FFP and cryoprecipitate are expressed as mean standard deviation. The paired Student t test (2-tailed) was used to compare values before and after rFVIIa administration.

Patients and Methods

After institutional ethics committee approval, the medical records of children less than 15 years-old, who underwent cardiac surgery and received rFVIIa for refractory postoperative hemorrhage, were reviewed retrospectively. There were 20 such children identied, who were treated over a period of 9 months from December 2010. Descriptive data of all 20 children, the cardiac defects, and type of surgery are listed in Table 1. The median age was 608.33 days (range, 802,007.5 days) and median weight was 8.75 kg (range, 3.7514.3 kg). The male-to-female ratio was 9 : 11. None of these patients had preoperative coagulation abnormalities. All children received the same standardized anesthetic management and conduct of cardiopulmonary bypass (CPB). All received epsilon amino caproic acid 100 mgkg1 before going on CPB, in the pump prime, and after weaning from CPB. Heparin 400 Ukg1 was used to maintain an activated coagulation time of 480600 sec before instituting CPB, and it was reversed with protamine in a ratio of 1.5:1 after weaning from CPB. On completion of surgery, all patients were transferred to the intensive care unit (ICU) and monitored hourly for mediastinal chest tube drainage (MCTD). Postoperative bleeding was controlled by maintaining activated coagulation time within 10% of baseline values and administration of blood and blood products as follows: platelets, 1 unit/10 kg; fresh frozen plasma (FFP), 1015 mLkg1; cryoprecipitate, 1 unit/5 kg, and packed red blood cells (PRBC), 1015 mLkg1. A target hematocrit of 30% was maintained in the postoperative period. Any MCTD > 5% of estimated blood volume for >3 consecutive hours or >10% of estimated blood volume at least for 1 h was taken as a criterion for mediastinal exploration.10 Estimated blood volume was based on body weight: <10 kg, 85 mLkg1; 1020 kg, 80 mLkg1; 2030 kg, 75 mLkg1, and 3040 kg, 70 mLkg1.11 The decision for reexploration was taken by the attending ICU physician in consultation with the surgeon. If the bleeding did not stop after surgical exploration, additional blood and blood products were given.

Results
The dosage, number of doses, and dosing intervals of rFVIIa are given in Table 2. The median number of doses found eective in these children was 1.76. The median interval between the 1st and 2nd dose was 143.75 min (range, 160.0206.67 min), whereas between the 2nd and 3 rd dose, it was 240 min (range, 195600 min). There was a signicant decrease in MCTD and units of PRBC, platelet concentrate, and cryoprecipitate administered after rFVIIa. However, there was no dierence in FFP use before and after rFVIIa (Table 3). No complications that could be assigned to the use of rFVIIa were observed.

Discussion
Children, especially neonates and infants, have a greater tendency for postoperative bleeding after cardiac surgery because of their immature coagulation system, less reactive platelets, CPB-associated dilution of coagulation factors, malabsorption of vitamin K, and delayed hepatic maturation in cyanotic children,

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Singh et al.

Table 1. Descriptive data of 20 children who received rFVIIa for refractory hemorrhage Age 140 180 160 150 240 150 240 200 120 Weight (kg) Sex rFVIIa (mgkg1) No. of Doses Dose 12(min) Total Dose (mgkg1) Dose 23 (min) Response

No.

Diagnosis/Surgery

1 2 3 4 5 6 7 8 9 10 11 12 13 14 240 4.5 years 5 years 6 years 12 years 12 years 14 years 15 years 40.0 F 34.0 M 59.82 100.00 20.0 F 50.00 30.0 F 66.66 2 1 1 1 13.6 F 73.52 2 12.0 15.0 M M 83.33 66.67 3 3 249.99 200.00 147.05 133.32 50.00 58.82 100.00 180 120 150 480 180 720

14 days 24 days 1.5 months 2 months 2.5 months 3 months 3 months 6 months 6 months 1 year 3 years 3 years 4 years

2.3 3.1 3.1 3.4 3.5 4.0 4.2 6.0 4.3 7.0 10.5 12.0 11.0

F F M F F F M F M M F M M

86.95 80.64 80.64 88.23 85.71 87.50 95.23 83.33 93.30 71.42 95.23 83.33 90.90

2 1 2 1 2 2 1 2 2 2 2 3 1

173.90 80.64 161.28 88.23 171.42 175.00 95.23 166.66 186.04 142.84 190.46 249.99 90.90

Effective Effective Effective Effective Effective Effective Effective Effective Effective Effective Effective Ineffective Effective Ineffective Ineffective Effective Effective Effective Effective Effective

15 16

17

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18

19

20

TGA/ASO ASD closure TGA/ASO ASD closure TGA/ASO VSD closure TAPVC repair TGA/ASO VSD closure TGA/ASO VSD closure TGA/ASO VSD closure AVSD/AVSD repair ALCAPA/ALCAPA repair VSD/VSD closure TOF/Intracardiac repair TOF/Intracardiac repair VSD/VSD closure Post-intracardiac repair Redo intracardiac repair TOF/intracardiac repair VSD with IE of TV/ VSD closure TV repair VSD, pulmonary atresia/ conduit repair Tricuspid atresia, post-BD Glenn/Fontan operation DORV, VSD, PS/ intracardiac repair P/conduit repair for VSD PS stenosis/conduit revision

ALCAPA = anomalous left coronary artery from pulmonary artery, ASD = atrial septal defect, AVSD = atrioventricular septal defect, ASO = arterial switch operation, BD Glenn = bidirectional Glenn shunt, DORV = double-outlet right ventricle, IE = infective endocarditis, TAPVC = total anomalous pulmonary venous connection, PS = pulmonary stenosis, rFVIIa = recombinant factor VII, TGA = transposition of great arteries, TOF = tetralogy of Fallot, TV = tricuspid valve, VSD = ventricular septal defect.

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22 causing inappropriate production of coagulation factors, especially brinogen. A drug that can act independently of the levels of coagulation factors, and directly activate thrombin to generate brin, may prove benecial to treat postoperative hemorrhage in the pediatric age group. First used in 1983 as a plasmaderived factor for the treatment of hemophilia A, factor VII has come a long way.12 It is now produced by recombinant DNA technology, and is available for commercial use. Although recommended for specic conditions, the o-label use of rFVIIa is quite common because of its potent hemostatic eect in various clinical situations. Recombinant FVIIa acts by combining with tissue factor released from blood vessels after injury.13 This interaction generates factor Xa that subsequently converts prothrombin to thrombin. A small initial burst of thrombin creates a second thrombin burst of greater magnitude, and converts brinogen to brin that strengthens the blood clot. Two major problems with the use of rFVIIa are its high cost ($1,000 for a 1-mg vial) and the potential risk of thrombosis.14 After reconstitution, chemical and physical stability of rFVIIa has been demonstrated for 6 h at 25 C and 24 h at 5 C. Hence, the feasibility of administration is better in infants because 1 vial may suce for 23 patients or doses. Dose calculation also suers from cost constraint, and is usually tailored to the amount in 1 vial, so as to approximate the dose. Compared to children, infants are at greater risk of bleeding because they undergo more complex operations.4

Asian Cardiovascular & Thoracic Annals 20(1) The half-life of rFVIIa in children is 50% of that in adults (1.2 vs. 2.72 h);15,16 therefore, higher dosages are required in the pediatric age group. In this study, we found that a median dose of 83.33 mgkg1 was eective in reducing MCTD, blood, and blood product requirements. FFP requirements were not signicantly dierent before and after rFVIIa administration, which may be due to the use of FFP for volume replacement in the absence of colloids. As recommended in a meta-analysis, the 2nd dose of rFVIIa was given at least 2 h after the 1st dose.17 A 2-h interval was stipulated because of the high risk of thrombosis, and it is the most common interval chosen by various groups.17 If no benecial eect was detected after the 3rd dose, the drug was discontinued. Thirty-ve percent of patients responded to the 1st dose, and 50% to the 2nd dose. Administration of rFVIIa was ineective in reducing postoperative bleeding in 3 (15%) patients, even after a 3rd dose. In this group of patients treated with rFVIIa, 4 (26.67%) died. Causes of death were low cardiac output in 3 children and intractable arrhythmias in one. Thrombosis was not evident in any major organ in the 4 children who died. Although these patients were not evaluated for thrombotic complications, there is a theoretical possibility of such an occurrence. There is an additional tissue-factor independent mechanism of action of rFVIIa through activated platelets, as demonstrated in healthy volunteers given high doses.18,19 The high dose, acting in a tissue-factor independent manner,

Table 2. Doses and dosing intervals of recombinant activated factor VII in 20 children Variable No. of administrations Dose per administration (mgkg1) Total dose per bleed (mgkg1) No. of doses per bleed Interval between first 2 doses (h) Interval between subsequent doses (h) n 36 83.33 154.16 1.76 143.75 240 72.4787.50 93.06180.52 1.172.46 160.0206.67 195600 Median Interquartile Range

13 3

Table 3. Mediastinal drainage, blood and blood products usage before and after rFVIIa Variable Mediastinal drainage (mLkg ) Packed red blood cells (mLkg1) Fresh frozen plasma (mLkg1) Platelet concentrate (mLkg1) Cryoprecipitate (mLkg1)
rFVIIa = recombinant activated factor VII.
1

Before rFVIIa 19.84 9.43 22.28 9.92 21.78 10.20 11.16 3.71 5.80 1.03

After rFVIIa 10.09 7.80 12.98 6.85 12.09 8.85 6.75 1.90 2.44 3.18

p Value 0.001 0.014 0.133 0.041 0.044

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Singh et al. produces a brin burst that is more resistant to brinolysis.20 This analysis revealed a median dose of 83.33 mgkg1 that may act by both tissue-factor dependent and independent mechanisms. Activated monocytes and platelets, in certain conditions such as diuse intravascular coagulation, may express tissue factor, and increase the risk of thrombosis at remote locations.17 Therefore, we think that the empirical or preemptive use of rFVIIa in pediatric cardiac surgery should not be encouraged. The major limitation of this study is that the safety prole of rFVIIa could not be evaluated. There was no repetition of the drug after 3 doses. In patients who bleed from other sites, mediastinal bleeding may not serve as good index of the amount of postoperative bleeding. In such a situation, the amount of blood and blood products administered may be not in accordance with the MCTD. Also, dierent surgeons may have dierent hemostatic strategies, so the amount of postoperative bleeding and blood product usage may dier. However, we concluded that in children undergoing complex cardiac surgery, use of high doses of rFVIIa reduced postoperative bleeding as well as blood and blood product requirement, without any obvious complications. Funding
This research received no specic grant from any funding agency in the public, commercial, or not-for-prot sectors.

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6. Herbertson M. Recombinant activated factor VII in cardiac surgery [Review]. Blood Coagul Fibrinolysis 2004; 15(Suppl 1): S312. 7. Blatt J, Gold SH, Wiley JM, Monahan PE, Cooper HC and Harvey D. Off-label use of recombinant factor VIIa in patients following bone marrow transplantation. Bone Marrow Transplant 2001; 28: 4057. 8. Sorensen B, Johansen P, Nielsen GL, Srensen JC and Ingerslev J. Reversal of the international normalized ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coagul Fibrinolysis 2003; 14: 46977. 9. Highlights of Prescribing Information. Available from: http://www.fda.gov/downloads/biologicsbloodvaccines/ bloodbloodproducts/ approvedproducts/licensedproductsblas/fractionatedplasmaproducts/ucm056954pd. Accessed November 17, 2011. 10. Guay J and Rivard GE. Mediastinal bleeding after cardiopulmonary bypass in pediatric patients. Ann Thorac Surg 1996; 62: 195560. 11. Dinardo JA. Physiology and techniques of extracorporeal circulation in the pediatric patient. In: Lake CL, Booker PD (eds) Pediatric Cardiac Anesthesia, 4th ed. Philadelphia: Lippincott Williams and Wilkins, 2005, p.240. 12. Hedner U and Kisiel W. Use of human factor VIIa in the treatment of two hemophilia A patients with high-titer inhibitors. J Clin Invest 1983; 71: 183641. 13. Enomoto TM and Thorborg P. Emerging off-label uses for recombinant activated factor VII: grading the evidence. Crit Care Clin 2005; 21: 61132. 14. Matthew P. The use of rFVIIa in non-haemophilia bleeding conditions in pediatrics. Thromb Haemost 2004; 92: 73846. 15. Villar A, Arsonis S, Morfini M, Santagostino E, Auerswald G, Thomsen HF, et al. Pharmacokinetics of activated recombinant coagulation factor VII (Novoseven) in children vs adults with haemophilia A. Haemophilia 2004; 10: 3529. 16. Shapiro AD. Recombinant factor VIIa in the treatment of bleeding in hemophilic children with inhibitors [Review]. Semin Thromb Hemost 2000; 26: 4139. 17. Warren OJ, Rogers PL, Watret AL, de Wit KL, Darzi AW, Gill R, et al. Defining the role of recombinant activated factor VII in pediatric cardiac surgery: where should we go from here? Pediatr Crit Care Med 2009; 10: 57282. 18. Holffman M, Monroe 3rd DM and Roberts HR. Activated factor VII activates factor IX and X on the surface of activated platelets. Blood Coagul Fibrinolysis 1998; 9: S615. 19. Friederich PW, Levi M, Bauer KA, Vlasuk GP, Rote WE, Breederveld D, et al. Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects. Circulation 2001; 103: 25559. 20. He S, Blomback M, Jacobsson Ekman G and Hedner U. The role of recombinant factor VIIa (FVIIa) in fibrin structure in the absence of FVIII/FIX. J Thromb Haemost 2003; 1: 12159.

Conflicts of interest statement

None declared.

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Recombinant activated factor VII for hemorrhage after pediatric cardiac surgery Sarvesh Pal Singh, Sandeep Chauhan, Minati Choudhary, Sumit Vasdev and Sachin Talwar Asian Cardiovasc Thorac Ann 2012;20:19-23 DOI: 10.1177/0218492311432584 This information is current as of March 31, 2012
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