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Comparative study of antifibrinolytic drugs in orthotopic liver transplantation
ANESTHESIA; HEMODYNAMIC ALTERATIONS
Comparative Study of Antifibrinolytic Drugs in Orthotopic Liver Transplantation A. Dalmau, A. Sabate´, F. Acosta, L. Garcia-Huete, M. Koo, M. Reche, A. Rafecas, J. Figueras, and E. Jaurrieta
A
ACTIVATION of the fibrinolytic system is one factor that contributes to bleeding during orthotopic liver transplantation (OLT). Antifibrinolytic drugs have been used during OLT to control fibrinolysis and, consequently, to reduce blood loss. Few studies have been done to determine the efficacy of prophylactic use of epsilonaminocaproic acid (EACA)1,2 and tranexamic acid (TA).3–5 The objective of this study was to evaluate the efficacy of prophylactic administration of EACA and TA in reducing blood transfusion requirements in patients undergoing OLT.
PATIENTS AND METHODS After institutional review board approval, a double-blind, prospective, randomized, placebo-controlled study was performed on 153 consecutive adult patients undergoing orthotopic liver transplantation (OLT) from January 1997 and September 1998 in two Spanish liver transplant centers (Murcia and Barcelona). We excluded patients with Budd–Chiari syndrome, acute hepatic failure, retransplantation of less than 1 month, simultaneous kidney and liver transplantation and amyloidosos. Participants were randomly assigned to receive either TA or EACA or placebo (P). Forty-two patients received a continuous-dose infusion of TA (5 g in 450 mL of normal saline) at 10 mg/kg per hour; 42 patients received a continuous-dose infusion of EACA (8 g in 480 mL of normal saline) of 16 mg/kg per hour; 40 patients (control group) received an equal volume infusion of normal saline. Drugs were infused from the anesthesia induction to graft reperfusion. All groups were managed by standard anesthetic techniques and by the same surgical team. Packed red blood cells (RBC) were
administered to maintain hemoglobin level at 100 g/L. Fresh frozen plasma (FFP) was administered only when protrombin time (PT) ratio was ⬎1.8. Platelets were given to maintain values over 5 ⫻ 109/L and cryoprecipitate was added to attain fibrinogen levels of ⬎1.5 g/L. No intraoperative salvage of blood was used. Coagulation tests, thromboelastogram (TEG), and blood requirements were recorded at different phases and during the first 24 hours. Parametric and nonparametric tests were used. P ⬍ .05 was considered significant.
RESULTS
Groups were demographically similar regarding age, gender sex, previous upper abdominal surgery, diagnosis, child value, graft cold ischemia time, and the duration of the anhepatic phase. Table 1 shows the biological data and the total blood product requirements (TBPR). No RBC requirements was observed in 13 patients in the TNXA group (31%), in 6 patients in EACA group (14%), and in 3 patients in the placebo group (75%) (P ⫽ .016). At the end of the operation, hemoglobin, platelet count, coagulation tests, and TEG were comparable between groups (ie, on the first postoperative day). There were no differences in TBPR on postoperative day 1. There were no differences in regard to thrombotic events (TA: 4 of 42, 9.5%; EACA: 2 of 42, 4.7%; P: 2 of 40, 5%; P ⫽ .4), reoperations, or mortality. From the Liver Transplant Unit, C.S.U. Bellvitge, University of Barcelona. Address reprint requests to Dr A. Dalmau, c/Aviadell No 4, 1-2, 08190 Sant Cugat Barcelona, Spain.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/99/$–see front matter PII S0041-1345(99000378-4
Transplantation Proceedings, 31, 2361–2362 (1999)
2361
DALMAU, SABATE´, ACOSTA ET AL
2362 Table 1. TNXA (n ⫽ 42) Mean (SD)
D-hb (g/L) D-hto (%) D-plat (109/L) D-PT (ratio) D-aTTP (ratio) D-Fg (g/L) D-r (min) D-␣ (°) D-MA (mm) D-temp (mm) D-Ca⫹⫹ (mmol/ L) D-pH AH-hb (g/L) AH-hto (%) AH-plat (109/L) AH-PT (ratio) AH-aTTP (ratio AH-Fg (g/L) AH-temp (°C) AH-Ca⫹ (mmol/ L) AH-pH R-hb (g/L) R-hto (%) R-plat (109/L) R-PT (ratio) R-aTTP (ratio) R-Fg (g/L) R-r (min) R-␣ (°) R-MA (mm) R-temp (°C) R-Ca⫹ (mmol/L) R-pH T-RBC (U)* T-FFP (U)* T-cryorp (units)† T-platelet (units)†
Intraoperative Data EACA (n ⫽ 42) Mean (SD)
Placebo (n ⫽ 40) Mean (SD)
ANOVA
105 (16) 31 (5) 81 (67) 1.4 (0.3) 1.3 (0.3) 2.1 (0.7) 15 (11) 47 (18) 52 (19) 35.6 (0.7) 1.07 (0.1)
98 (23) 30 (7) 75 (37) 1.5 (0.5) 1.5 (0.6) 2 (0.9) 14 (8) 48 (15) 48 (12) 35.8 (0.5) 1.11 (0.2)
97 (18) 29 (5) 86 (34) 1.5 (0.3) 1.4 (0.4) 2.3 (1.5) 17 (8) 43 (16) 48(16) 35.7 (06) 1.07 (0.1)
.153 .156 .617 .532 .260 .596 .434 .541 .510 .486 .359
7.42 (0.06) 108 (16) 32 (4) 66 (40) 1.5 (0.3) 1.4 (0.5) 1.9 (0.6) 35.6 (0.7) 1.12 (0.2)
7.42 (0.06) 104 (18) 31 (6) 71 (36) 1.5 (0.3) 1.5 (0.3) 1.9 (0.6) 35.9 (0.7) 1.22 (0.2)
7.41 (0.07) 100 (19) 30 (5) 79 (34) 1.5 (0.4) 1.6 (1) 2.1 (1.4) 35.6 (0.8) 1.15 (0.2)
.737 .141 .088 .318 .814 .267 .422 .109 .117
7.41 (0.06) 98 (15) 30 (4) 71 (35) 1.7 (0.3) 2.8 (1.7) 1.6 (0.5) 25 (23) 34 (19) 39 (14) 34.7 (0.9) 1.18 (0.2) 7.37 (0.07) 4.4 (5.2)/3 3.2 (5.7)/0 2.8 (6.4)/0 8.3 (9.4)/8
7.37 (0.06) 101 (16) 30 (5) 72 (32) 1.7 (0.5) 3.1(2) 1.7 (0.7) 24 (22) 31 (21) 40 (19) 35.1 (0.8) 1.21 (0.2) 7.35 (0.09) 6 (5.6)/4 4.4 (6.1)/2 4.2 (8.8)/0 8.3 (9.1)/8
7.39 (0.08) 93 (17) 28 (5) 68 (27) 1.9 (0.7) 3.1 (1.9) 1.7 (1.1) 31 (23) 22 (15) 31 (19) 34.7 (0.9) 1.18 (0.2) 7.36 (0.1) 6.9 (5.2)/6 5 (5.7)/3 4.3 (8.3)/0 8.4 (8.5)/8
.037 .071 .064 .825 .310 .650 .919 .488 .029 .111 .054 .601 .459 .023† .065† .676† .940†
Abbreviations: TNXA, tranexamic acid; EACA, epsilon-aminocaproic acid; P, placebo; D, dissection; AH, anhepatic; R, Reperfusion; Hb, hemoglobin; Hto, hematocrit; plat, platelet; PT, prothrombin time; aTTP, activated partial tromboplastine time; Fg, fibrinogen; r, reaction time (TEG); ␣, clot formation (TEG); MA, maximum amplitude (TEG); temp, temperature; Ca⫹⫹, ionized calcium. T-RBC, total red blood cells; T-FFP, total fresh frozen plasma; T-cryopr, total cryoprecipitates; ANOVA, analysis of variance. Mean (SD)/median. † Kruskal–Wallis
DISCUSSION AND CONCLUSIONS
REFERENCES
In our study TNXA has been effective in reducing fibrinolysis and transfusion requirements without a higher risk of thrombosis, which is why we think it can be used as a useful and low-cost therapy for patients undergoing OLT, especially for the most difficult cases that have higher transfusion requirements. However, we also believe that we need to observe a greater number of patients to determine if there is an increased risk of thrombosis. EACA has also reduced fibrinolysis and transfusion requirements, but not significantly.
1. Kang YG, Lewis H, Navalgund A, et al: Anesthesiology 66:766, 1987 2. McSorley MW, Taraporewalla D: Transplant Proc 23:1941, 1991 3. Kaspar M, Ramsay MAE, Nguyen A-T, et al: Anesthes Analges 85:281, 285, 1997 4. Yassen K, Bellamy MC, Sadek SA, et al: Clin Transplant 7:453, 1993 5. Boylan JF, Klinck JR, Sandler AN, et al: Anesthesiology 85:1043, 1996
Comparative Study of Antifibrinolytic Drugs in Orthotopic Liver Transplantation A. Dalmau, A. Sabate´, F. Acosta, L. Garcia-Huete, M. Koo, M. Reche, A. Rafecas, J. Figueras, and E. Jaurrieta
A
ACTIVATION of the fibrinolytic system is one factor that contributes to bleeding during orthotopic liver transplantation (OLT). Antifibrinolytic drugs have been used during OLT to control fibrinolysis and, consequently, to reduce blood loss. Few studies have been done to determine the efficacy of prophylactic use of epsilonaminocaproic acid (EACA)1,2 and tranexamic acid (TA).3–5 The objective of this study was to evaluate the efficacy of prophylactic administration of EACA and TA in reducing blood transfusion requirements in patients undergoing OLT.
PATIENTS AND METHODS After institutional review board approval, a double-blind, prospective, randomized, placebo-controlled study was performed on 153 consecutive adult patients undergoing orthotopic liver transplantation (OLT) from January 1997 and September 1998 in two Spanish liver transplant centers (Murcia and Barcelona). We excluded patients with Budd–Chiari syndrome, acute hepatic failure, retransplantation of less than 1 month, simultaneous kidney and liver transplantation and amyloidosos. Participants were randomly assigned to receive either TA or EACA or placebo (P). Forty-two patients received a continuous-dose infusion of TA (5 g in 450 mL of normal saline) at 10 mg/kg per hour; 42 patients received a continuous-dose infusion of EACA (8 g in 480 mL of normal saline) of 16 mg/kg per hour; 40 patients (control group) received an equal volume infusion of normal saline. Drugs were infused from the anesthesia induction to graft reperfusion. All groups were managed by standard anesthetic techniques and by the same surgical team. Packed red blood cells (RBC) were
administered to maintain hemoglobin level at 100 g/L. Fresh frozen plasma (FFP) was administered only when protrombin time (PT) ratio was ⬎1.8. Platelets were given to maintain values over 5 ⫻ 109/L and cryoprecipitate was added to attain fibrinogen levels of ⬎1.5 g/L. No intraoperative salvage of blood was used. Coagulation tests, thromboelastogram (TEG), and blood requirements were recorded at different phases and during the first 24 hours. Parametric and nonparametric tests were used. P ⬍ .05 was considered significant.
RESULTS
Groups were demographically similar regarding age, gender sex, previous upper abdominal surgery, diagnosis, child value, graft cold ischemia time, and the duration of the anhepatic phase. Table 1 shows the biological data and the total blood product requirements (TBPR). No RBC requirements was observed in 13 patients in the TNXA group (31%), in 6 patients in EACA group (14%), and in 3 patients in the placebo group (75%) (P ⫽ .016). At the end of the operation, hemoglobin, platelet count, coagulation tests, and TEG were comparable between groups (ie, on the first postoperative day). There were no differences in TBPR on postoperative day 1. There were no differences in regard to thrombotic events (TA: 4 of 42, 9.5%; EACA: 2 of 42, 4.7%; P: 2 of 40, 5%; P ⫽ .4), reoperations, or mortality. From the Liver Transplant Unit, C.S.U. Bellvitge, University of Barcelona. Address reprint requests to Dr A. Dalmau, c/Aviadell No 4, 1-2, 08190 Sant Cugat Barcelona, Spain.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/99/$–see front matter PII S0041-1345(99000378-4
Transplantation Proceedings, 31, 2361–2362 (1999)
2361
DALMAU, SABATE´, ACOSTA ET AL
2362 Table 1. TNXA (n ⫽ 42) Mean (SD)
D-hb (g/L) D-hto (%) D-plat (109/L) D-PT (ratio) D-aTTP (ratio) D-Fg (g/L) D-r (min) D-␣ (°) D-MA (mm) D-temp (mm) D-Ca⫹⫹ (mmol/ L) D-pH AH-hb (g/L) AH-hto (%) AH-plat (109/L) AH-PT (ratio) AH-aTTP (ratio AH-Fg (g/L) AH-temp (°C) AH-Ca⫹ (mmol/ L) AH-pH R-hb (g/L) R-hto (%) R-plat (109/L) R-PT (ratio) R-aTTP (ratio) R-Fg (g/L) R-r (min) R-␣ (°) R-MA (mm) R-temp (°C) R-Ca⫹ (mmol/L) R-pH T-RBC (U)* T-FFP (U)* T-cryorp (units)† T-platelet (units)†
Intraoperative Data EACA (n ⫽ 42) Mean (SD)
Placebo (n ⫽ 40) Mean (SD)
ANOVA
105 (16) 31 (5) 81 (67) 1.4 (0.3) 1.3 (0.3) 2.1 (0.7) 15 (11) 47 (18) 52 (19) 35.6 (0.7) 1.07 (0.1)
98 (23) 30 (7) 75 (37) 1.5 (0.5) 1.5 (0.6) 2 (0.9) 14 (8) 48 (15) 48 (12) 35.8 (0.5) 1.11 (0.2)
97 (18) 29 (5) 86 (34) 1.5 (0.3) 1.4 (0.4) 2.3 (1.5) 17 (8) 43 (16) 48(16) 35.7 (06) 1.07 (0.1)
.153 .156 .617 .532 .260 .596 .434 .541 .510 .486 .359
7.42 (0.06) 108 (16) 32 (4) 66 (40) 1.5 (0.3) 1.4 (0.5) 1.9 (0.6) 35.6 (0.7) 1.12 (0.2)
7.42 (0.06) 104 (18) 31 (6) 71 (36) 1.5 (0.3) 1.5 (0.3) 1.9 (0.6) 35.9 (0.7) 1.22 (0.2)
7.41 (0.07) 100 (19) 30 (5) 79 (34) 1.5 (0.4) 1.6 (1) 2.1 (1.4) 35.6 (0.8) 1.15 (0.2)
.737 .141 .088 .318 .814 .267 .422 .109 .117
7.41 (0.06) 98 (15) 30 (4) 71 (35) 1.7 (0.3) 2.8 (1.7) 1.6 (0.5) 25 (23) 34 (19) 39 (14) 34.7 (0.9) 1.18 (0.2) 7.37 (0.07) 4.4 (5.2)/3 3.2 (5.7)/0 2.8 (6.4)/0 8.3 (9.4)/8
7.37 (0.06) 101 (16) 30 (5) 72 (32) 1.7 (0.5) 3.1(2) 1.7 (0.7) 24 (22) 31 (21) 40 (19) 35.1 (0.8) 1.21 (0.2) 7.35 (0.09) 6 (5.6)/4 4.4 (6.1)/2 4.2 (8.8)/0 8.3 (9.1)/8
7.39 (0.08) 93 (17) 28 (5) 68 (27) 1.9 (0.7) 3.1 (1.9) 1.7 (1.1) 31 (23) 22 (15) 31 (19) 34.7 (0.9) 1.18 (0.2) 7.36 (0.1) 6.9 (5.2)/6 5 (5.7)/3 4.3 (8.3)/0 8.4 (8.5)/8
.037 .071 .064 .825 .310 .650 .919 .488 .029 .111 .054 .601 .459 .023† .065† .676† .940†
Abbreviations: TNXA, tranexamic acid; EACA, epsilon-aminocaproic acid; P, placebo; D, dissection; AH, anhepatic; R, Reperfusion; Hb, hemoglobin; Hto, hematocrit; plat, platelet; PT, prothrombin time; aTTP, activated partial tromboplastine time; Fg, fibrinogen; r, reaction time (TEG); ␣, clot formation (TEG); MA, maximum amplitude (TEG); temp, temperature; Ca⫹⫹, ionized calcium. T-RBC, total red blood cells; T-FFP, total fresh frozen plasma; T-cryopr, total cryoprecipitates; ANOVA, analysis of variance. Mean (SD)/median. † Kruskal–Wallis
DISCUSSION AND CONCLUSIONS
REFERENCES
In our study TNXA has been effective in reducing fibrinolysis and transfusion requirements without a higher risk of thrombosis, which is why we think it can be used as a useful and low-cost therapy for patients undergoing OLT, especially for the most difficult cases that have higher transfusion requirements. However, we also believe that we need to observe a greater number of patients to determine if there is an increased risk of thrombosis. EACA has also reduced fibrinolysis and transfusion requirements, but not significantly.
1. Kang YG, Lewis H, Navalgund A, et al: Anesthesiology 66:766, 1987 2. McSorley MW, Taraporewalla D: Transplant Proc 23:1941, 1991 3. Kaspar M, Ramsay MAE, Nguyen A-T, et al: Anesthes Analges 85:281, 285, 1997 4. Yassen K, Bellamy MC, Sadek SA, et al: Clin Transplant 7:453, 1993 5. Boylan JF, Klinck JR, Sandler AN, et al: Anesthesiology 85:1043, 1996