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Ann Thorac Surg 2006;81:875-879
© 2006 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Recombinant Activated Factor VII: Treating Postoperative Hemorrhage in Cardiac Surgery

^a Department of Cardiothoracic Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
^b Department of Hematology, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia

Accepted for publication September 1, 2005.

^_* Address correspondence to Professor Tatoulis, Suite 28, Private Medical Centre, Royal Melbourne Hospital, Victoria 3050, Australia (Email: james.tatoulis{at}mh.org.au).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
BACKGROUND: The purpose of this study is to review the effect of recombinant activated factor VII (rFVIIa) as rescue therapy in continuing severe postoperative hemorrhage, despite conventional measures in a series of cardiac patients at our institution.

METHODS: A series of all patients who received rFVIIa as rescue therapy for uncontrollable postoperative hemorrhage after cardiac surgery over a 2-year period was analyzed. We assessed and compared the use of blood products, coagulation indicators (international normalized ratio [INR], activated partial thromboplastin [APTT], and fibrinogen), and platelet levels immediately before and after the rFVIIa was given.

RESULTS: Twelve patients received rFVIIa. Eight patients (75%) had thoracic aortic surgery. Bleeding stopped in all cases. Prior to the administration of rFVIIa, mean blood product usage was the following: fresh frozen plasma (FFP) 18.7 units (range, 10–40); packed cells 7.7U (range, 0–18); cryoprecipitate 19.5U (range, 8–32); and platelets 22.5U (range, 10–40). The mean coagulation results immediately prior to rFVIIa were the following: INR 2.0 (range, 1.3–8.5); APTT 60 seconds (range, 30–220); fibrinogen 3.2 gm/L (range, 1.6–6.4), and platelet count was 174,000 (range, 78,000–257,000). After rFVIIa administration the mean blood product usage was the following: FFP 0U (range, 0–2); red cells 0U (range, 0–1); cryoprecipitate 0 (range, 0); and platelets 0 (range, 0); p less than 0.0005. The mean INR was 0.9 (range, 0.7–1.5), p less than 0.001; mean APTT was 42 seconds (range, 30–87), mean fibrinogen was 3.1 (range, 1.7–4.5), and the mean platelet count was 170,000 (range, 93,000–289,000); p values not significant. There were no thrombotic complications, no cardiac ischemic events, and no deaths.

CONCLUSIONS: Our results support the use of rFVIIa as rescue therapy in severe, uncontrollable, nonsurgical, postoperative hemorrhage after cardiac surgery as efficacious and safe.

	Introduction

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Postoperative hemorrhage is a relatively common occurrence in cardiac surgery when compared with other surgical specialties [1–8]. Bleeding is also a significant cause of morbidity and mortality, prolonged hospital stay, and increased cost [3, 4]. The management of postoperative hemorrhage in this setting may require massive transfusion of blood and blood products, which in itself has inherent risks [5–7]. Within the cardiac surgery population, those with increasing age and long cardiopulmonary bypass (CPB) times are especially at risk of postoperative bleeding [7–9]. The use of recombinant activated factor VII (rFVIIa) has been shown to induce hemostasis in patients with severe hemophilia A or B with factor specific inhibitors [10]. The first such use of rFVIIa was in 1987 in a patient with severe hemophilia A undergoing an open synovectomy in a knee joint [11]. The efficacy of rFVIIa in this situation has led to its increased use in both treatment of acute hemorrhage and prophylaxis for surgical procedures in hemophiliac patients with inhibitors, and this is the accepted indication. Recombinant activated factor VII has also been used in patients with platelet function disorders such as Glanzmann's thrombasthenia [12, 13]. All other uses, including those in trauma and postcardiac surgery, are "off label." The rFVIIa promotes hemostasis by enhancing the generation of thrombin on platelets. Recombinant activated factor VII complexes with all available tissue factor (TF/FVIIa) to activate factorX directly and induce thrombin generation. This results in the formation of a tight and stable fibrin plug that is resistant to premature fibrinolysis [14]. Recently, rFVIIa has been reported in the management of life-threatening hemorrhage in patients with previously normal coagulation. In particular, it may now have a role in hemostasis in multitrauma, liver transplantation, major orthopedic surgery, hemorrhagic pancreatitis, gastrointestinal bleeding, and cardiac surgery [15]. Our aim is to review the experience of our center in the use of rFVIIa in cardiac surgery, with a secondary aim of identifying a subset of cardiac surgery patients who are most likely to require rFVIIa postoperatively.

	Material and Methods

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Patients
All cardiac surgery patients who received rFVIIa over a 23-month period (January 2003 to November 2004) were identified by the Cardiac Surgery and the Royal Melbourne Hospital Blood Bank database. Our institution approved the use of rFVIIa in the setting of life-threatening postcardiac surgery hemorrhage. Authorization for use in each specific instance was by the Director of Cardiac Surgery after consultation with the cardiac surgeon, anesthetist, and hematologist. Specific patient or patient family consent for this off label use was not obtained because of the emergency nature of the circumstances, although all patients had given informed consent to the procedures and were aware that hemorrhage was a possible and significant complication. Demographic, procedural, and hematologic data were collected from the medical records. Demographic data included the age and sex of the patient. Procedural data included the type of procedure, the duration of the procedure, cardiopulmonary bypass (CPB) time, and the need for reexploration for bleeding. Intraoperative use of the antifibrinolytic aprotinin and desmopressin (DDAVP) was also noted. Hematologic data included coagulation parameters, international normalized ratio (INR), activated partial thromboplastin time (APTT), and fibrinogen levels, and platelet counts immediately prior to rFVIIa infusion and within 4 hours post dose. The number of blood products used (fresh frozen plasma [FFP], platelets, cryoprecipitate [CPP], red cell concentrates both pre-rFVIIa and after it was given) was also identified. Postoperative chest drainage and cardiovascular complications were noted.

Conduct of Cardiopulmonary Bypass
Cardiopulmonary bypass (CPB) was by standard (noncoated) tubing, a membrane oxygenator, centrifugal arterial pump, and a 40 micron arterial filter. The CPB was conducted at 33°C for the valve cases. For major ascending aortic surgery, which involved transverse arch reconstruction, the patient was cooled to 18°C–20°C for a period of circulatory arrest of less than 30 minutes. Cerebral protection was supplemented by right axillary artery cannulation and antegrade carotid perfusion. Patient temperature was 36°C or greater before CPB was discontinued. Care was taken to ensure small temperature gradients during the rewarming phase.

A loading dose of 3 mg (300 units) of heparin/kg was given pre-bypass with a target activated clotting time (ACT) greater than 500 seconds. Further heparin was given if required to maintain the ACT greater than 500 seconds. Heparin was reversed with protamine 1 mg/1 mg of heparin and checked by standard and heparinase-treated ACT (normal < 150 seconds). In general, triggers for transfusion were hemoglobin of less than 80 gm/L for red blood cells, INR greater than 1.5 for FFP, fibrinogen less than 2.0 gm/L for cryoprecipitate, and platelets less than 100,000 for platelets or bypass time greater than 3 hours.

Definitions
Bleeding of some degree from mediastinal and chest drains after cardiac surgery is expected and there is currently no standard definition for excessive postoperative hemorrhage [3]. In this series, we defined postoperative hemorrhage as the need for non-red cell blood product support (FFP, platelets, CPP) or the need for surgical reexploration, or not being able to close the sternotomy greater than 2 hours after completion of CPB and heparin reversal because of continuing blood loss. We defined cessation of hemorrhage as no further need of blood products or surgical reexploration.

Usage of rFVIIa
The decision to use rFVIIa was at the discretion of the treating surgical team in consultation with a hematologist as per hospital protocol, after exhausting extensive conventional hemostatic measures and ensuring there was no site of surgical bleeding. These included non-red cell blood product support, (FFP, platelets, CPP), desmopressin and antifibrinolytics. A prospective management protocol (guidelines), for excessive nonsurgical bleeding immediately postoperatively was developed to incorporate the potential use of rFVIIa (Table 1). When these failed to secure hemostasis the rFVIIa was given at a dose of 100 µg/kg body weight. The rFVIIa was administered after transfusion of platelets, FFP, and cryoprecipitate to ensure adequate hemostatic constituents were present to maximize the effect of rFVIIa. In all but one instance, the patient was still in the operating room after the cardiac procedure, when the rFVIIa was administered.

Data Analysis
Demographic, procedural, and hematologic data are tabulated. The differences between the paired mean values for blood product usage and coagulation profile were analyzed statistically by way of the paired sample, exact permutation, test for equality of means (StatXact v. 6, Cytel Software Corporation, Cambridge, MA). A two-sided p value 0.05 or less was regarded as statistically significant.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Demographic and Procedural Data
A total of 1,393 cardiac surgery cases were performed over the 23 month period from January 2003 to November 2004. During this time, 12 patients (less than 1%) received rFVIIa after 13 operations. One patient had two separate operations where rFVIIa was used postoperatively on both occasions. One patient (redo Bentalls/ aortic valve replacement [AVR]) who had bled at the first operation, had rFVIIa administered prophylactically immediately after cessation of CPB and reversal of heparin with protamine.

Eight patients had thoracic aortic aneurysm surgery (5 of which were acute aortic dissections with additional hemiarch replacement under circulatory arrest at 18°C–20°C). Three patients had multiple valve surgery (one reoperation). No patient had isolated coronary bypass surgery or primary isolated cardiac valve surgery. The CPB times for this complex surgery group averaged almost 5 hours (288 minutes). Demographic and operative details are presented in Table 2.

Chest Drainage
Chest drainage was a mean of 472 mL (range, 190–1,220 mL), (39 mL/hour) in the first 12 hours and a mean of 743 mL (range, 245–1,550), (31 mL/hour) in the first 24 hours after sternotomy closure.

Complications
There were no complications in the patient group that could be attributed to the use of rFVIIa. In particular, there were no thromboembolic events, no cardiac ischemic events, and no allergic reactions. All patients were alive at 30 days after their operation.

	Comment

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Although originally conceived as a treatment for hemorrhage in hemophiliacs, rFVIIa could be seen as a panacea in an area such as cardiac surgery where hemorrhage associated with coagulopathy is a relatively common event. In our series, hemorrhage ceased in all 13 cases with normalization of the coagulation profile. This occurred without adverse event. As age and long CPB times are important risk factors for postoperative bleeding in cardiac surgery, the cases where rFVIIa are most appropriate make up a specific subset of the cardiac surgery population. This is notable in our series where ascending aorta and arch replacement and double valve surgeries are most prominent, reflecting long CPB times. This would only make a small proportion of cases in most cardiac surgery units where the majority of cases involve isolated coronary artery bypass graft surgery (CABGS) or single valve repair-replacement. Interestingly, the mean age of patents in this series is actually younger than many who undergo cardiac surgery in this unit. An explanation for this could be that younger patients are more likely deemed suitable for bigger operations with longer CPB times, thus making them more likely to be complicated by postoperative hemorrhage.

The efficacy of rFVIIa in controlling life-threatening hemorrhage after cardiac surgery has been previously reported by other groups [16, 17], who have also used it in rescue situations after massive blood product and coagulation factor replacement has failed—salvaging patients who most probably would have died.

With postoperative hemorrhage, the main question, which needs addressing, is at what stage should administration of rFVIIa be given. With 12 of 13 cases in our study rFVIIa was only given after extensive initial treatment with non-red cell blood products, as a last resort. In one isolated case, rFVIIa was given preemptively at the first sign of bleeding to good effect. Given that we can identify a subset of patients who are more likely to be complicated by severe nonsurgical postoperative hemorrhage, a strong argument could be made that rFVIIa should be used early in high risk patients when bleeding occurs in order to minimize exposure to blood products and minimize blood loss. One could even argue that in this group of patients rFVIIa could be given as prophylaxis when coming off CPB rather than waiting for the inevitable coagulopathy to cause bleeding. These principles are used in hemophilia patients who are to undergo elective surgery or who have suffered trauma [10–12]. While this study shows there is a role for rFVIIa in cardiac surgery, more research including randomized trials would be of benefit to categorically determine any benefits and the optimal timing of administration of rFVIIa [(18).

Compounding the question of timing is the issue of cost. The high price of rFVIIa limits its use, particularly if use is intended at an early stage or for prophylaxis. Although blood products are also expensive the costs are not passed on to the individual surgical units of a public hospital and thus are essentially "free," making them financially a more attractive first and second line treatment for postoperative hemorrhage. As the Australian Red Cross Blood Service, who are the blood product providers in Australia, are continually running at very low supply levels, a fastidious approach to restrict blood product usage would be beneficial to all stakeholders in the long term. The high cost of rFVIIa (approximately US $7,000 per patient) also needs to be offset by the costs involved with opening and staffing an operating theatre for a reexploration for blood products as well as for increased patient stay and morbidity.

Concern was raised by the participating surgeons about the safety of using rFVIIa, particularly with the theoretical risk of thrombosis causing graft occlusion where CABGS are involved. There have been more than 400,000 standard doses of rFVIIa administered before November 2002 with a serious adverse event rate of less than 1%. In particular there were only seven acute myocardial infarctions reported [19]. In the population of patients involved in our study, only two patients had CABGS, both in combination with other procedures. Neither patient had evidence of cardiac ischemia postoperatively.

Enhanced thrombin generation after ceased CPB and elevated circulating tissue factor and myocardial tissue factor expression are theoretical possibilities. However, there were no clinical episodes of vascular thrombosis in this series, nor are we are aware of any de novo arterial thrombotic events in the literature in post CPB patients. This theoretical adverse effect must be balanced by the real benefit of rFVIIa in salvaging those few cardiac surgery patients who continue to exsanguinate due to profound coagulopathy despite attempted correction with continued hemostatic agents and massive coagulation product transfusion.

Aggarwal and colleagues [16] reported only one case of subclavian vein thrombosis in a cohort of 23 who received rFVIIa, which was related to a previously placed central venous line. Similarly, Karkouti and colleagues [17] found no difference in the serious adverse event rates between rFVIIa patients and matched controls. The use of rFVIIa in a randomized double blind placebo-controlled, dose escalation trial in the setting of intracranial hemorrhage, raised no safety concerns with events in placebo and treatment groups being similar [20].

In conclusion, our experience suggests that rFVIIa is a safe and dramatically effective treatment for coagulopathic postoperative hemorrhage in cardiac surgery. The exact role of rFVIIa in cardiac surgery, particularly its timing of administration, is yet to be determined. A randomized trial as performed by Herbertson and colleagues [21] is needed to clarify these issues.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The authors wish to thank Professor John Ludbrook, MD, DSc, ChM, BmedSc, FRCS, FRACS, AStat, Director, Biomedical Statistical Consulting Service, for his help with the statistical analyses.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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