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Recombinant Activated Factor VII in Critical Bleeding After Orthotopic Liver Transplantation
Recombinant Activated Factor VII in Critical Bleeding After Orthotopic Liver Transplantation S. Busani, G. Semeraro, C. Cantaroni, M. Masetti, M. Marietta, and M. Girardis ABSTRACT Critical bleeding throughout the intraoperative phase of orthotopic liver transplantation (OLT) strongly increases patient mortality and intensive care unit (ICU) stay. The aim of this study was to report our experience on the use of recombinant activated factor VII (rFVIIa) in postoperative critical bleeding after OLT. In 7 patients with persistent severe bleeding after application of a standard transfusion protocol, we administered a 90 g/kg bolus of rFVIIa and if necessary eventually repeated it after 3 hours. We recorded the blood loss and the need for transfusions before and after the rFVIIa therapy. Blood losses and need for platelets significantly decreased after rFVIIa administration; a nonsignificant decrease in red blood cells and fresh frozen plasma transfusions also occurred. In 6 patients treatment with rFVIIa was effective; only 1 patient died because of hemorrhagic shock and no thromboses were detected among the treated patients. Awaiting stronger evidence from randomized controlled trials, we suggest that in some challenging cases of massive bleeding rFVIIa should be considered a useful option to control bleeding.
C
RITICAL BLEEDING throughout the intraoperative phase of orthotopic liver transplantation (OLT) strongly increases patient mortality and intensive care unit (ICU) stay.1 Recombinant activated factor VII (rFVIIa) prophylactic or therapeutic administration in this scenario has been heavily debated in the last few years without conclusive evidence.2,3 Only a few studies have reported rFVIIa use for bleeding control in the postoperative period.4 The aim of this paper was to report our experience on the use of rFVIIa in postoperative critical bleeding after OLT. MATERIALS AND METHODS Our study was performed from January 2003 to December 2006 in the setting of a university surgical ICU. Patient inclusion criteria were: critical bleeding (defined as blood loss of more than 200 –500 mL/h for at least 2 consecutive hours) within 15 days after OLT refractory to standard transfusion protocol, no surgical or radiological indications for the hemorrhage treatment, no congenital coagulation disorders, no preoperative anticoagulants or antiplatelet therapy. The following standard transfusion protocol was applied during hemorrhage: red blood cells (RBC) if hematocrit ⬍24%; fresh frozen plasma (FFP; 15–20 mL/kg) if prothrombin time international normalized ratio (INR) ⬎1.5; platelet concentrates (PC; 1–2 U/10 kg) if platelet counts ⬍50,000 units/L; calcium correction if ionized serum calcium below normal ranges; acidosis correction if pH ⬍7.2; and hypothermia correction if core temperature ⬍35°C.
In a patient with persistent critical bleeding despite application of the protocol, and without any surgical or radiological indication for bleeding source control, an rFVIIa bolus of 90 y/kg was administered and eventually a second bolus (90 y/kg) after 3 hours. We recorded hourly blood loss in the 6 hours before and after the administration of the first bolus of rFVIIa and the need for transfusions in the same period of time. Results are reported as mean values ⫾ standard deviations and for time comparison we used paired Student t tests with P ⬍ .05 considered statistically significant.
RESULTS
During the study period, 135 OLTs were performed at our institution with 7 patients (5 males, 2 females) of mean age 53.2 ⫾ 13.9 years satisfying the inclusion criteria. The etiologies of critical bleeding were: 4 graft primary nonfunction, 1 fulminant liver failure, 1 gastric hemorrhage, and 1 hemothorax after thoracic drain placement. Blood losses and need for transfusion products (normalized per hour) From the Cattedra e Servizio di Anestesia e Rianimazione (S.B., G.S., C.C., M.G.), Centro Trapianti di Fegato e Multiviscerale (M.M.), and Divisione di Oncologia ed Ematologia (M.M.), Policlinico di Modena, Modena, Italy. Address reprint requests to Stefano Busani, Cattedra di Anestesia e Rianimazione, Università di Modena e Reggio Emilia, Policlinico di Modena, L.go del Pozzo 71, 41100 Modena, Italy. E-mail: [email protected]
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.05.021
Transplantation Proceedings, 40, 1989 –1990 (2008)
1989
1990
BUSANI, SEMERARO, CANTARONI ET AL
before and after rFVIIa administration are shown in Table 1. Two patients needed a second bolus of rFVIIa because of persistent bleeding. After rFVIIa, the bleeding was controlled in all patients apart from 1 who died due to hemorrhagic shock. Another patient died in the ICU because of septic shock not related to the hemorrhagic shock 17 days after the bleeding episode. No thrombotic events related to rFVIIa administration were recorded during the hospital stay of these patients. DISCUSSION
rFVIIa provided a marked decrease in blood loss and platelets transfusion. Similarly, we observed a 50% decrease in RBC and FFP transfusions, but this difference was not significant. The rFVIIa treatment was effective in 85% of patients, while the hospital survival of the treated patients was 71%. Both these results are interesting because of the complexity of these patients and the challenging clinical setting of massive hemorrhage. Seven patients is too small Table 1. Blood Loss and Need for Transfusion Products Before and After rFVIIa Administration
Blood loss (mL/h) RBC (U) FFP (U) Platelets (U)
Before rFVIIa
After rFVIIa
P
400.0 ⫾ 97.2 8.7 ⫾ 6.2 6.1 ⫾ 3.1 11.4 ⫾ 6.0
198.5 ⫾ 201.6 4.5 ⫾ 3.9 3.8 ⫾ 3.7 4.2 ⫾ 4.2
.04 NS NS .02
a sample to draw any conclusion on the effects of rFVIIa on persistent critical bleeding after OLT; nevertheless, awaiting stronger evidence from a randomized controlled trial, our experience suggested that in some patients with challenging cases of massive bleeding who do not respond to standard treatments, rFVIIa can be considered a powerful option for bleeding control. However, in the immediate postoperative period after OLT a higher tissue factor exposure is present in the hepatic sinusoids5 and along the vascular anastomosis with an increased risk for thrombosis. For these reasons and considering the prothrombotic effect of rFVIIa, we believe that in postoperative OLT patients: this drug should be used only to control life-threatening hemorrhage. REFERENCES 1. Mor E, Jennings L, Gonwa TA, et al: The impact of operative bleeding on outcome in transplantation of the liver. Surg Gynecol Obstet 176:219, 1993 2. Pugliese F, Ruberto F, Summonti D, et al: Activated recombinant factor VII in orthotopic liver transplantation. Transplant Proc 39:1883, 2007 3. Porte RJ, Caldwell SH: The role of recombinant factor VIIa in liver transplantation. Liver Transpl 11:872, 2005 4. Lodge JP, Jonas S, Jones RM, et al: Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation. Liver Transpl 11:973, 2005 5. Clavien PA: Sinusoidal endothelial cell injury during hepatic preservation and reperfusion. Hepatology 28:281, 1998
C
RITICAL BLEEDING throughout the intraoperative phase of orthotopic liver transplantation (OLT) strongly increases patient mortality and intensive care unit (ICU) stay.1 Recombinant activated factor VII (rFVIIa) prophylactic or therapeutic administration in this scenario has been heavily debated in the last few years without conclusive evidence.2,3 Only a few studies have reported rFVIIa use for bleeding control in the postoperative period.4 The aim of this paper was to report our experience on the use of rFVIIa in postoperative critical bleeding after OLT. MATERIALS AND METHODS Our study was performed from January 2003 to December 2006 in the setting of a university surgical ICU. Patient inclusion criteria were: critical bleeding (defined as blood loss of more than 200 –500 mL/h for at least 2 consecutive hours) within 15 days after OLT refractory to standard transfusion protocol, no surgical or radiological indications for the hemorrhage treatment, no congenital coagulation disorders, no preoperative anticoagulants or antiplatelet therapy. The following standard transfusion protocol was applied during hemorrhage: red blood cells (RBC) if hematocrit ⬍24%; fresh frozen plasma (FFP; 15–20 mL/kg) if prothrombin time international normalized ratio (INR) ⬎1.5; platelet concentrates (PC; 1–2 U/10 kg) if platelet counts ⬍50,000 units/L; calcium correction if ionized serum calcium below normal ranges; acidosis correction if pH ⬍7.2; and hypothermia correction if core temperature ⬍35°C.
In a patient with persistent critical bleeding despite application of the protocol, and without any surgical or radiological indication for bleeding source control, an rFVIIa bolus of 90 y/kg was administered and eventually a second bolus (90 y/kg) after 3 hours. We recorded hourly blood loss in the 6 hours before and after the administration of the first bolus of rFVIIa and the need for transfusions in the same period of time. Results are reported as mean values ⫾ standard deviations and for time comparison we used paired Student t tests with P ⬍ .05 considered statistically significant.
RESULTS
During the study period, 135 OLTs were performed at our institution with 7 patients (5 males, 2 females) of mean age 53.2 ⫾ 13.9 years satisfying the inclusion criteria. The etiologies of critical bleeding were: 4 graft primary nonfunction, 1 fulminant liver failure, 1 gastric hemorrhage, and 1 hemothorax after thoracic drain placement. Blood losses and need for transfusion products (normalized per hour) From the Cattedra e Servizio di Anestesia e Rianimazione (S.B., G.S., C.C., M.G.), Centro Trapianti di Fegato e Multiviscerale (M.M.), and Divisione di Oncologia ed Ematologia (M.M.), Policlinico di Modena, Modena, Italy. Address reprint requests to Stefano Busani, Cattedra di Anestesia e Rianimazione, Università di Modena e Reggio Emilia, Policlinico di Modena, L.go del Pozzo 71, 41100 Modena, Italy. E-mail: [email protected]
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.05.021
Transplantation Proceedings, 40, 1989 –1990 (2008)
1989
1990
BUSANI, SEMERARO, CANTARONI ET AL
before and after rFVIIa administration are shown in Table 1. Two patients needed a second bolus of rFVIIa because of persistent bleeding. After rFVIIa, the bleeding was controlled in all patients apart from 1 who died due to hemorrhagic shock. Another patient died in the ICU because of septic shock not related to the hemorrhagic shock 17 days after the bleeding episode. No thrombotic events related to rFVIIa administration were recorded during the hospital stay of these patients. DISCUSSION
rFVIIa provided a marked decrease in blood loss and platelets transfusion. Similarly, we observed a 50% decrease in RBC and FFP transfusions, but this difference was not significant. The rFVIIa treatment was effective in 85% of patients, while the hospital survival of the treated patients was 71%. Both these results are interesting because of the complexity of these patients and the challenging clinical setting of massive hemorrhage. Seven patients is too small Table 1. Blood Loss and Need for Transfusion Products Before and After rFVIIa Administration
Blood loss (mL/h) RBC (U) FFP (U) Platelets (U)
Before rFVIIa
After rFVIIa
P
400.0 ⫾ 97.2 8.7 ⫾ 6.2 6.1 ⫾ 3.1 11.4 ⫾ 6.0
198.5 ⫾ 201.6 4.5 ⫾ 3.9 3.8 ⫾ 3.7 4.2 ⫾ 4.2
.04 NS NS .02
a sample to draw any conclusion on the effects of rFVIIa on persistent critical bleeding after OLT; nevertheless, awaiting stronger evidence from a randomized controlled trial, our experience suggested that in some patients with challenging cases of massive bleeding who do not respond to standard treatments, rFVIIa can be considered a powerful option for bleeding control. However, in the immediate postoperative period after OLT a higher tissue factor exposure is present in the hepatic sinusoids5 and along the vascular anastomosis with an increased risk for thrombosis. For these reasons and considering the prothrombotic effect of rFVIIa, we believe that in postoperative OLT patients: this drug should be used only to control life-threatening hemorrhage. REFERENCES 1. Mor E, Jennings L, Gonwa TA, et al: The impact of operative bleeding on outcome in transplantation of the liver. Surg Gynecol Obstet 176:219, 1993 2. Pugliese F, Ruberto F, Summonti D, et al: Activated recombinant factor VII in orthotopic liver transplantation. Transplant Proc 39:1883, 2007 3. Porte RJ, Caldwell SH: The role of recombinant factor VIIa in liver transplantation. Liver Transpl 11:872, 2005 4. Lodge JP, Jonas S, Jones RM, et al: Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation. Liver Transpl 11:973, 2005 5. Clavien PA: Sinusoidal endothelial cell injury during hepatic preservation and reperfusion. Hepatology 28:281, 1998