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Ann Thorac Surg 2006;82:1779-1783
© 2006 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, Mount Sinai Hospital, New York, New York
b Department of Anesthesiology, Mount Sinai Hospital, New York, New York
Accepted for publication May 16, 2006.
* Address correspondence to Dr Filsoufi, Department of Cardiothoracic Surgery, Mount Sinai Medical Center, 1190 Fifth Ave, Box 1028, New York, NY 10029 (Email: farzan.filsoufi{at}mountsinai.org).
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Abstract |
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 Top Abstract IntroductionMaterial and MethodsResultsCommentReferences |
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METHODS: From June 2003 to December 2005, 17 patients (mean age, 65 ± 18 years) received rFVIIa for refractory bleeding after cardiac surgery. Preoperative risk factors for bleeding included reoperation (n = 7), emergency surgery (n = 7), and renal or hepatic failure (n = 3). Surgical procedures were aortic surgery (n = 7), complex valve operations (n = 7), coronary artery bypass grafting (n = 2), and cardiac tumor resection (n = 1).
RESULTS: The average dose of rFVIIa was 103.1 ± 30.2 µg/kg. After the administration of rFVIIa the blood loss was reduced and chest tube output decreased from an average of 300 mL/h to 60 mL/h (p = 0.024). Coagulation variables normalized (mean prothrombin time, 18 ± 7 versus 14 ± 3 seconds; p = 0.03; mean partial thromboplastin time, 94 ± 50 versus 49 ± 14 seconds; p = 0.02), and the need for blood products was significantly reduced. Only 1 patient required mediastinal reexploration. No thromboembolic complications occurred during hospitalization.
CONCLUSIONS: This study suggests that rFVIIa is safe and efficacious in the management of refractory postcardiotomy bleeding. The use of rFVIIa is associated with reduced blood loss, rapid improvement of coagulation variables, and decreased need for blood products. Further studies are necessary to determine the safety and efficacy of this new hemostatic agent and its precise role in the treatment of severe postoperative coagulopathy.
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Introduction |
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TopAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Recombinant activated factor VII (rFVIIa; NovoSeven, NovoNordisk, Copenhagen, Denmark) is a hemostatic agent that was initially developed for the treatment of bleeding in patients with hemophilia A or B with inhibitors to factor VIII and IX [3, 4]. More recently, the off-label use of this agent was reported in patients with life-threatening bleeding after trauma or major abdominal surgery [5, 6]. The use of rFVIIa is not well-known in cardiac surgery, and only a few case reports [7, 8] or series [9–13] have reported its use and safety in this patient population. Herein we report our clinical experience in patients who were treated with rFVIIa for intractable bleeding after cardiac surgery at our institution.
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Material and Methods |
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TopAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Patient Characteristics
The demographics and clinical characteristics of the 17 patients are reported in Table 1. Mean age in this population was 65 ± 18 years. Eleven (65%) patients were male. Mean ejection fraction was 0.46 ± 0.17. Mean body weight and body surface area were 90 ± 44.1 kg and 1.4 ± 0.5 m2, respectively.
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Additional preoperative risk factors included recent stroke (n = 3, 18%), respiratory failure requiring intubation (n = 2, 12%), and acute myocardial infarction (n = 2, 12%). Finally, 2 patients required preoperative cardiopulmonary resuscitation.
Intraoperative Hemostatic and Anticoagulation Management
After induction of general anesthesia, a loading dose of 
-aminocaproic acid (150 mg/kg) was administered for 30 minutes, followed by a continuous infusion of 15 mg · kg–1
· min–1. No -aminocaproic acid was added to the cardiopulmonary bypass circuit prime. The infusion was continued until the end of surgery. Seven (41%) patients in this study were given -aminocaproic acid.
Aprotinin was administered at a loading dose of 2,000,000 KIU intravenously for a 30-minute period. After completion of the loading dose, a maintenance dose of 500,000 KIU was started and continued until the surgical procedure was finished. In addition 2,000,000 KIU was added to the cardiopulmonary bypass circuit prime. Ten (59%) patients received aprotinin intraoperatively.
Before establishment of cardiopulmonary bypass heparin was given to achieve an activated clotting time of at least 480 seconds with a heparin level at or greater than 200 U/kg, or more specifically 2.7 U/mL circulating volume. After the completion of cardiopulmonary bypass, protamine was given on the basis of the heparin level.
After the administration of protamine, blood products (packed red blood cells, fresh-frozen plasma, platelets, and cryoprecipitate) were given to correct the coagulopathy. In the absence of response to transfusion, rFVIIa was administered as a "last resort" therapy to control the bleeding. The timing of administration was determined on an individual basis by the surgical and intensive care unit team.
Complete coagulation profile was obtained in all patients at the following time points: preoperatively, before the administration of rFVIIa, and within 6 hours after its delivery. Information with respect to blood product transfusion was also obtained in all patients before and after the administration of rFVIIa.
Surgical Procedures
Seven (41%) patients had aortic operations (2 ascending aorta and arch replacement, 1 extensive thoracoabdominal aneurysm repair, and 4 type A dissection repair). Two patients presented with Marfan's syndrome. The surgical repair required deep hypothermic circulatory arrest in 5 of these patients.
Two (12%) patients underwent emergent coronary artery bypass grafting after failed percutaneous transluminal coronary angioplasty. These 2 patients presented with tamponade and extensive epicardial hematoma as a result of coronary artery dissection or perforation. Seven (41%) patients underwent multiple valve operations. Three of these patients had extensive aortic root calcification. Finally, 1 patient underwent the resection of a large right ventricle and pulmonary artery tumor necessitating an extensive right ventricular outflow tract reconstruction. The cardiac procedures and intraoperative findings are reported in Table 2. The mean cross-clamp time and bypass time were 196 ± 87 minutes and 282 ± 156 minutes, respectively.
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2 test as appropriate. Statistical significance was considered when a probability value was less than 0.05. |
Results |
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TopAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Twelve (70%) patients received rFVIIa in the operating room, whereas 5 (30%) patients had rFVIIa in the intensive care unit. Before the administration of rFVIIa, the average transfusion was 5.8 ± 4.9 units of packed red blood cells, 6.9± 4.3 units of fresh-frozen plasma, 17.1 ± 7 units of platelets, and 22.3 ± 18 units of cryoprecipitate (Table 3). Despite the administration of blood products, the coagulation profile remained abnormal in all patients (Table 4).
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No thromboembolic events occurred in this series after rFVIIa delivery. The in-hospital mortality was 29% (n = 5). The causes of death were myocardial failure (n = 1, patient 2), extensive cerebrovascular accident (n = 2, patients 3 and 5), and multisystem organ failure (n = 2, patients 8 and 11). The 2 patients with postoperative stroke suffered from an intimal flap occluding the left carotid artery after acute type A aortic dissection. This diagnosis was made after a postmortem autopsy in both patients, which also ruled out any intracerebral thrombus formation. The patient with myocardial failure was an 84-year-old woman who underwent a complex valve procedure with prolonged cardiopulmonary bypass and cross-clamp time. She had intractable right ventricular myocardial failure despite inotropic support and intraaortic balloon pump insertion. Finally, the 2 patients who died of multisystem organ failure had a prolonged postoperative low cardiac output syndrome.
Postoperative morbidities included respiratory failure (n = 1), low cardiac output requiring intraaortic balloon pump insertion (n = 1), and sternal wound infection (n = 1).
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Comment |
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TopAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Taking into consideration the hemostatic effect of this agent, rFVIIa has been recently used in the management of postoperative bleeding. The data with respect to the use of this agent in adult cardiac surgery are scarce and include often small observational case series [9–12]. Hyllner and colleagues [10] reported the use of rFVIIa in a series of 24 cardiac surgery patients with refractory bleeding. In this series, after the administration of a median bolus dose of 60 µg/kg, blood loss significantly decreased and coagulation variables were effectively corrected. In a case series of 9 patients, Halkos and coworkers [9] reported the use of rFVIIa as a rescue therapy for the control of postoperative bleeding. These authors also reported that the use of rFVIIa was associated with improved hemostasis and rapid reduction of blood loss, no need for surgical reexploration, and reduction of transfusion requirements. Our results confirm the findings of these two studies using rFVIIa in adult cardiac surgery patients. The administration of rFVIIa was associated with rapid normalization of coagulation variables and decreased blood loss. In this life-threatening condition, the use of rFVIIa was a very useful adjunct to control refractory postcardiotomy bleeding. No patients in our series died of this complication. Furthermore, despite the risk of hypercoagulable state induced by rFVIIa, no thromboembolic complications occurred in these 17 patients.
Similarly in a propensity score-matched case control study of 51 patients, Karkouti and associates [13] reported a markedly decreased blood loss and a reduced need for blood products after rFVIIa administration. These authors reported a similar rate of adverse events between the group of patients treated with rFVIIa and the matched control group, except for a higher rate of renal dysfunction in the rFVIIa group. It should be emphasized that the sample size was not large enough to detect significant differences between the two groups.
Our series presents several limitations similar to the studies reported by Hyllner and colleagues [10] and Halkos and associates [9]. First, this was a retrospective study; therefore, any conclusions should be limited in their implications. Second, the lack of a control group makes difficult any definite conclusions because the administration of rFVIIa did not occur in a random manner. Third, the lack of a precise and standardized protocol in terms of indications, timing, and dosage in the administration of rFVIIa as a rescue therapy for life-threatening bleeding render impossible any specific recommendations at the present time. Despite all these limitations, the accumulation of information through these retrospective studies is crucial in the future design of appropriate prospective studies.
In summary, these early promising results should be confirmed by additional studies to further determine the safety and efficacy of rFVIIa as a hemostatic agent in this particular indication. In addition, these studies should also address the questions of timing, dosage, and cost-effectiveness associated with the usage of this drug.
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References |
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