Epsilon-Aminocaproic Acid Has No Association With Thromboembolic Complications, Renal Failure, or Mortality After Liver Transplantation

Epsilon-Aminocaproic Acid Has No Association With Thromboembolic Complications, Renal Failure, or Mortality after Liver Transplantation Ramona Nicolau-Raducu, MD, PhD,* Timothy C. Ku, MD,† Donald R. Ganier, MD,* Brian M. Evans, MD,* Joseph Koveleskie, MD,* William J. Daly Jr, MD,* Brian Fish, MD,* Ari J. Cohen, MD, MSc, FRCSC, FACS,‡ Trevor W. Reichman, MD, PhD,‡ Humberto E. Bohorquez, MD, FACS,‡ David S. Bruce, MD,‡ Ian C. Carmody, MD,‡ George E. Loss, MD, FACS, PhD,‡ Marina Gitman, MD,§ Thomas Marshall, MD,* and Bobby D. Nossaman, MD* Objectives: To examine the role of epsilon-aminocaproic acid (EACA) administered after reperfusion of the donor liver in the incidences of thromboembolic events and acute kidney injury within 30 days after orthotopic liver transplantation. One-year survival rates between the EACAtreated and EACA-nontreated groups also were examined. Design: Retrospective, observational, cohort study design. Setting: Single-center, university hospital. Participants: The study included 708 adult liver transplantations performed from 2008 to 2013. Interventions: None. Measurements and Main Results: EACA administration was not associated with incidences of intracardiac thrombosis/pulmonary embolism (1.3%) or intraoperative death (0.6%). Logistic regression (n ¼ 708) revealed 2 independent risk factors associated with myocardial ischemia (age and pre-transplant vasopressor use) and 8 risk factors associated

with the need for post-transplant dialysis (age, female sex, redo orthotopic liver transplantation, preoperative sodium level, pre-transplant acute kidney injury or dialysis, platelet transfusion, and re-exploration within the first week after transplant); EACA was not identified as a risk factor for either outcome. One-year survival rates were similar between groups: 92% in EACA-treated group versus 93% in the EACA-nontreated group. Conclusions: The antifibrinolytic, EACA, was not associated with an increased incidence of thromboembolic complications or postoperative acute kidney injury, and it did not alter 1-year survival after liver transplantation. & 2016 Elsevier Inc. All rights reserved.

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administration during the neo-hepatic phase of OLT. All patients, including patients with antecedents of thrombotic events/thrombophilia, were included. All recipients received deep venous thrombosis (DVT) prophylaxis with both mechanical compression stockings and 5,000 U of subcutaneous heparin every 8 hours once platelet counts were 470  103/mL. Combined organ transplants were excluded. The standard surgical technique was OLT with caval replacement, with the exception of 9 piggy-back cases. None of the cases included veno-venous bypass. All patients received a tacrolimus-based immunosuppressant protocol. Of the 708 transplants, 702 liver grafts originated from deceased donors (626 brain dead and 76 donations after cardiac death), and 6 liver grafts (right lobe graft) were from living donors. The quality of donor organs was assessed using the donor risk index: demographic characteristics (age, race, and height), causes of death (cerebral vascular accident, trauma, anoxia, other), type of death (donations after cardiac death), split/partial graft, cold ischemia time, and donor location (local, regional, national).10

IBRINOLYSIS AND ITS role in coagulopathy in patients undergoing orthotopic liver transplantation (OLT) have been reported for decades.1-3 A meta-analysis by Molenaar et al reported decreases in surgical blood loss and transfusion requirements without an associated increased risk of thromboembolic events during OLT when prophylactic antifibrinolytics were used.4 However, case reports of thromboembolic risks associated with antifibrinolytics cautioned against acceptance of this class of agents during OLT.5,6 Excessive activation of coagulation secondary to the dissection, massive bleeding, venous stasis secondary to clamping of the cava and portal vein, and the use of veno-venous bypass have been shown to be the leading factors associated with increased risk for thromboembolic complications during OLT.4 Past OLT studies have focused on the use of aprotinin,4 now removed from the US market because of increased incidences of renal failure or mortality in patients undergoing cardiac surgery.79 Subsequently, only 2 synthetic lysine derivative antifibrinolytics now are available in the United States: epsilon-aminocaproic acid (EACA) (Amicar; Akorn, Marietta, GA) and tranexamic acid. Considering the substantial cost difference and the comparable efficacy and safety reported in non-OLT studies, EACA is used widely in liver transplant programs in the United States.4 However, the safety of EACA in OLT is not well-studied. The purpose of this study was to investigate the effect of EACA administered during the neo-hepatic phase of OLT on the incidences of thromboembolic events, acute postoperative renal failure within 30 days after OLT, and 1-year survival rates. METHODS

After institutional review board approval, data from 708 adult OLT performed from 2008 to 2013 were abstracted. Endpoints of the study were risks associated with EACA

KEY WORDS: epsilon-aminocaproic acid, antifibrinolytics, thromboembolic complications, acute kidney injury, intracardiac thrombosis/pulmonary embolism, liver transplantation

From the *Department of Anesthesiology, Ochsner Clinic Foundation, New Orleans, LA, †Department of Anesthesiology, Tulane Medical Center, New Orleans, LA, ‡Department of Surgery/ Transplantation, Ochsner Clinic Foundation, New Orleans, LA; and §Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL. Address reprint requests to Ramona Nicolau-Raducu, MD, PhD, Department of Anesthesiology, Ochsner Medical Center, 1514 Jefferson Highway, New Orleans, LA 70121. E-mail: rnicolauraducu@ ochsner.org © 2016 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2015.12.003

Journal of Cardiothoracic and Vascular Anesthesia, Vol ], No ] (Month), 2016: pp ]]]–]]]

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NICOLAU-RADUCU ET AL

This study analyzed the role of EACA administration on the incidences of thromboembolic complications, renal failure within the first month after transplant, and 1-year survival rates. The decision to administer EACA during the neo-hepatic phase was based on the presence of fibrinolysis, analyzed using thromboelastography (TEG; Haemonetics, Braintree, MA) at 5 and/or 30 minutes after reperfusion and on clinical observation of the surgical field by the surgeons. Presence of fibrinolysis using TEG analysis was defined as Z8% reduction in the postmaximum amplitude signals up to 30 minutes from the start of the test.11 Bolus intravenous (IV) dosing and/or continuous infusion of EACA were based on clinical conditions. Continuous infusion of EACA (total of 5 g) was discontinued either in the operating room or intensive care unit. Since 2012, thromboprophylaxis has been initiated routinely with IV heparin (average dose of 2000 U) administered before caval cross-clamping in 39% (275/708) of patients (Fig 1). Protamine, average of 57 ⫾ 30 mg IV, was administered after hepatic artery reperfusion in 54% (381/708) of the patients. A heparin effect was documented with paired TEG tracings (kaolin v heparinase), with a correction of more than 30% to 50% of the rþk time interval after addition of heparinase12,13 or activated partial thromboplastin time 450 seconds (reference range: 21.0-32.0 seconds). Intraoperative blood product administrations were recorded from the induction of general anesthesia until transport to the intensive care unit. Transfusion targets with packed red blood

cells (pRBC) and cell-saver and blood products (fresh frozen plasma [FFP], platelets [PLTS], or cryoprecipitate [CRYO]) were based on the amount of bleeding, hourly TEG analysis, and laboratory results. In surgical situations with massive bleeding, an optimal FFP:pRBC ratio of at least 1:2 was used. Control of surgical and medical bleeding at the end of surgery was required with target hematocrit values of 28% to 30% (reference range: 37.0%-48.5%), hemoglobin values of 8 to 9 g/dL (reference range: 12.0-16.0 g/dL), platelet values 450,000 K/uL (reference range:150-350 K/uL), international normalized ratio o2 (reference range: 0.8-1.2), fibrinogen 4180 mg (reference range:182-366 mg/dL), and/ or TEG values within normal limits (r time 4-9 min; k time 1-3 min; alpha angle 59-74 degrees; maximum amplitude 5574 mm). Acute kidney injury (AKI), both before transplant (pre-TX) and/or after transplant (post-TX) was defined as an increase in serum creatinine (sCr) of Z0.3 mg/dL over 48 hours or an increase in sCr Z1.5 times the baseline sCr value within 7 days before or after OLT.14 Pre-TX and post-TX renal replacement therapy (RRT) were defined as any form of renal dialysis before and within 1 month after OLT, respectively. The following thromboembolic complications within 1 month of transplantation were recorded: myocardial ischemia (MI), defined as an increase in cardiac biomarkers in the presence of electrocardiographic changes suggesting ischemia

708 paents

Heparin-treated (16%) 45 paents

EACA-treated (39%)

EACA-nontreated (61%)

275 paents

433 paents

Heparin-nontreated (84%) 230 paents

Heparin-treated (53%)

Heparin-nontreated (47%)

229 paents

204 paents

Myocardial Infracon 1 paent

Myocardial Infarcon 10 paents

Myocardial Infarcon none

Myocardial Infarcon 6 paents

Ischemic Stroke 1 paent

Ischemic stroke 2 paents

Ischemic Stroke 1 paent

Ischemic Stroke none

Early Hepac Artery Thrombosis none

Early Hepac Artery Thrombosis 1 paent

Early Hepac Artery Thrombosis 7 paents

Early Hepac Artery Thrombosis 7 paents

Hepac Venous Thrombosis none

Hepac Venous Thrombosis 5 paents

Hepac Venous thrombosis 2 paents

Hepac Venous Thrombosis 4 paents

Extra hepac Venous Thrombosis 4 paents

Extra hepac Venous Thrombosis 5 paents

Extra hepac Venous Thrombosis 8 paents

Extra hepac Venous Thrombosis 4 paents

Fig 1.

The incidence of thrombotic events with or without epsilon-aminocaproic acid (EACA) and with or without heparin.

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AMICAR AND LIVER TRANSPLANTATION

and/or new wall motion abnormalities on echocardiogram15; ischemic stroke diagnosed using computed tomography/magnetic resonance imaging of the head in the presence of mental status changes; and venous thrombotic complications—hepatic (portal or hepatic vein thrombosis), extrahepatic (upper or lower DVT), or early (o1 month) hepatic artery thrombosis (HAT) as documented on Doppler ultrasound, computed tomography, or magnetic resonance imaging results. The authors recorded and analyzed the incidence of intraoperative cardiac thrombosis or pulmonary embolism, defined as presence of clot in the heart chambers observed using transesophageal echocardiography or by sudden increases in central venous and pulmonary artery pressures with or without cardiovascular instability or arrest requiring cardiopulmonary resuscitation.

stopping rule p value threshold of 0.25 for probability to enter and a more stringent p value of 0.25 for probability to leave, conducted in a mixed direction, to identify which predictor variables were associated statistically with increased incidence of post-TX RRT or MI o1 month and for adjustments for the potential influence of cofounders, such as EACA. Odds ratios (OR) with 95% confidence intervals were calculated. Misclassification rates calculated the proportion of observations allocated to the incorrect group or the false positive rate. C statistic for both models was calculated as a measure of diagnostic accuracy. Linear regression was performed between EACA dosing groups (none, 1 to r5 g, 5 to r10 g, or 410 g) and total pRBCs, FFP, PLTS, and CRYO transfused to identify the relationship between the EACA dose and overall blood and blood product transfused. The statistical software program used in this study was JMP 9.01 (SAS Institute, Cary, NC).

Statistics Categoric variables were presented as percentages, and differences between the groups were assessed using χ2 tests. Continuous variables with skewed distributions were presented as median and 25% to 75% interquartile range, with differences between groups assessed using 2-sided Wilcoxon rank sum test. One-year survival rates were assessed using Kaplan Meier survival log-rank test. Nominal logistic regression analysis (n ¼ 708) was performed using a stepwise personality with a

RESULTS

Demographics, pre-TX clinical variables, intraoperative data, and postoperative outcomes are presented in Tables 1 to 3. Administration of EACA after OLT reperfusion was observed in 39% (275/708) of the patients. In that subgroup, 96% (264/275) of the patients received an average IV bolus dose of 6.6 ⫾ 2.7 g, followed by a continuous infusion of 1g/h of EACA in 55% (146/264) of the patients. EACA was

Table 1. Demographic and Pre-Transplant Clinical Characteristics of Patients With and Without Epsilon-Aminocaproic Acid EACA-Treated (n ¼ 275)

Age, years Caucasian, n (%) Male, n (%) BMI, kg/m2 MELD (medical score) Redo transplantation, n (%) Portal vein thrombosis, n (%) Liver etiology Chronic, n (%) Acute on chronic, n (%) Fulminate, n (%) Pre-TX AKI (no RRT), n (%) Pre-TX RRT, n (%) Pre-TX, days on dialysis, n (%) Creatinine DOS, mg (%) Sodium DOS, mEq/L Bilirubin DOS, mg (%) INR DOS Baseline TEG DOS r time k time Alpha angle Maximum amplitude History of CAD, n (%) History of diabetes, n (%) History of DVT, n (%) Pre-TX ICU, n (%) Pre-TX vasopressor, n (%)

EACA-Nontreated (n ¼ 433)

p Value

55 181 185 29 22 22 37

(50-60) (66%) (67%) (26-34) (17-30) (8%) (13%)

56 274 283 28 19 29 48

(51-62) (63%) (65%) (25-32) (13-26) (7%) (11%)

0.2098 0.5556 0.5999 0.0451* o0.0001* 0.5135 0.2710 0.0662

261 13 1 65 31 7 1 135 6 1.8

(95%) (5%) (0%) (24%) (11%) (4-11) (0.8-1.4) (132-138) (3-13) (1.4-2.2)

400 21 12 62 32 6 0.9 137 4 1.6

(92%) (5%) (3%) (14%) (7%) (2-17) (0.7-1.3) (133-139) (2-9) (1.3-2)

0.0016* 0.0770 0.6592 0.0310* 0.0041* o0.0001* o0.0001*

7.2 3 53.2 46.5 19 83 9 55 28

(5.9-8.7) (2.2-4.5) (43.2-60.8) (38.3-53.2) (7%) (30%) (3%) (20%) (10%)

6.2 2.4 57.6 52.3 31 133 12 50 13

(5-7.6) (1.8-3.5) (49.4-64.3) (43.7-60.7) (7%) (31%) (3%) (12%) (3%)

o0.0001* o0.0001* o0.0001* o0.0001* 0.8992 0.8804 0.7015 0.0020* o0.0001*

NOTE. The values are presented as median (25th and 75th percentiles) or as numbers and percentages. Abbreviations: AKI, acute kidney injury; BMI, body mass index; CAD, coronary artery disease; DOS, day of surgery; DVT, deep vein thrombosis; EACA, epsilon-aminocaproic acid; ICU, intensive care unit; INR, International Normalized Ratio; MELD, medical model for end-stage liver disease; pre-TX, pre-transplant; RRT, renal replacement therapy; TEG, thromboelastogram. *p o 0.05 is statistically significant

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NICOLAU-RADUCU ET AL

Table 2. Intraoperative Data for Patients With and Without Epsilon-Aminocaproic Acid EACA-Treated (n ¼ 275)

Intraoperative RRT, n (%) Surgery time (h) CIT (h) pRBC (U) FFP (U) Platelets (U) Cryoprecipitate (U) Cell saver (mL) End surgery temperature (ºC) DRI DCD, n (%)

56 4.5 4.7 5 6 3 2 433 36.6 1.481 31

EACA-Nontreated (n ¼ 433)

(20%) (4.2-5.4) (4-5.5) (3-8) (3-11) (2-4) (1-3) (109-1,164) (36.1-37) (1.329-1.640) (11%)

70 4.3 4.7 2 2 1 1 142 36.9 1.513 45

(16%) (4-5) (4-5.4) (0-4) (0-4) (0-2) (0-2) (0-481) (36.4-37.3) (1.326-1.646) (10%)

p Value

0.1953 o0.0001* 0.9370 o0.0001* o0.0001* o0.0001* o0.0001* o0.0001* o0.0001* 0.4228 0.7123

NOTE. The values are presented as median (25th and 75th percentiles) or as numbers and percentages. Abbreviations: CIT, cold ischemia time; DCD, deceased cardiac death; DRI, donor risk index; EACA, epsilon-aminocaproic acid; FFP, fresh frozen plasma; pRBC, packed red blood cells; R RT, renal replacement therapy. *p o 0.05 is statistically significant.

patients experienced 41 thrombotic event within 30 days, with 3 of those 6 patients receiving EACA. The incidence of thrombotic events with or without EACA and with or without heparin is presented in Fig 1. The overall incidence of thromboembolic complications was similar between groups, with the exception of early HAT and MI incidence. The overall incidence of early HAT in this study was 2% (15/708) and appeared to be increased significantly (OR 9.2 [1.8-166.3]) in the EACA-nontreated group (χ2 ¼ 8.5, p ¼ 0.0036). Logistic regression (n ¼ 708) identified 2 risk factors associated with MI events: age and pre-TX vasopressor requirement (Table 5). The whole model (χ2 ¼ 21, p o 0.0001) was statistically significant. A C statistic of 0.80 was calculated for this group of risk factors, with a misclassification rate of 0.02. Heparin administration was associated with a statistically significant (χ2 ¼ 10, p ¼ 0.0014) protective effect (OR 0.09 [0.005-0.473]) on the incidence of postoperative MI. A 1.3% (9/708) incidence of intraoperative cardiac thrombosis/pulmonary embolism (4 preanhepatic cases, 2 anhepatic cases, 3 neohepatic cases), with a 0.6% (4/708) incidence of intraoperative deaths, was observed; however, none of these events occurred in the presence of

administered as a continuous infusion of 1 g/h without a bolus in 4% (11/275) of the patients. The average total EACA dose administered (bolus plus infusion) was 9.2 ⫾ 4 g and varied from 1 to 15 g. Post-reperfusion fibrinolysis demonstrated on TEG was significantly higher (26% [72/275]) in patients receiving EACA compared with 14% (61/433) of patients who did not receive EACA (χ2 = 15.8, p o 0.0001), given that no clinical bleeding was observed. When the blood product data were analyzed between groups, the group that received EACA had statistically higher administrations of blood products (pRBC, FFP, PLTS, CRYO) compared with the EACA-nontreated group (Table 4). There was a statistical association between the total EACA dose administered (none, 1 to r5 g, 5 to r10 g, or 410 g) and the presence of coagulopathy as reflected in units of pRBC, FFP, PLTS, and CRYO transfused (see Table 4). When the EACA doses of 45 to r10 g versus 410 g were compared, there were no statistically significant differences in the pRBC, FFP, PLTS, and CRYO transfused (see Table 4). A 9% (62/708) incidence of any thromboembolic complications was observed (see Table 3). Ten percent (6/62) of OLT

Table 3. Postoperative Outcomes for Patients With and Without Epsilon-Aminocaproic Acid EACA-Treated (n ¼ 275)

All patients with thrombotic events o1 month, n (%) Hepatic thrombotic events, n (%) Extrahepatic thrombotic events, n (%) Myocardial infarction o1 month, n (%) Stroke ischemic o1 month, n (%) Early HAT o1 month, n (%) Post-TX bleeding o1 week, n (%) Post-TX AKI first week, n (%) Post-TX RRT o 1 month, n (%) Dialysis dependent at 90 days, n (%) Post-TX ventilator, days Reintubation, n (%) Post-TX ICU, days Post-TX hospital stay, days

26 5 9 11 3 1 19 114 52 5 1 32 3 8

(9%) (2%) (3%) (4%) (1%) (0.4%) (7%) (42%) (19%) (2%) (1-1) (12%) (2-4) (6-17)

EACA-Nontreated (n ¼ 433)

36 6 12 6 1 14 35 164 47 11 1 28 2 8

(8%) (1%) (3%) (1%) (0.2%) (3%) (8%) (39%) (11%) (3%) (0-1) (6%) (1-3) (6-12)

p Value

0.6008 0.6502 0.7015 0.0268* 0.1368 0.0098* 0.5662 0.3902 0.0026* 0.5286 o0.0001* 0.0161* o0.0001* 0.0042*

NOTE. The values are presented as median (25th and 75th percentiles) or as numbers and percentages. Abbreviations: AKI, acute kidney injury; EACA, epsilon-aminocaproic acid; HAT, hepatic artery thrombosis; ICU, intensive care unit; post-TX, post-transplant; RRT, renal replacement therapy. *p o 0.05 is statistically significant.

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AMICAR AND LIVER TRANSPLANTATION

Table 4. EACA Dose and the Role on Blood Product Use in 708 Patients Undergoing Liver Transplantation EACA Total Dose

pRBCs (units)

None (n ¼ 433) 1 to r5 g (n ¼ 101) 5 to r10 g (n ¼ 103) 410 (n ¼ 70) Non-parametric 5 to r10 g v none 410 g v none 1 to r5 g v none 5 to r10 g v 1 r5 g 410 g v 1 to r5 g 410 g v 5 to r10 g

2 4 5 6

FFP (units)

(0-4) (2-6) (4-9) (4-9)

PLTS (units)

2 (0-4) 3 (2-7) 6 (4-12) 8 (4-13)

z Scores

p Values

9.1 7.6 4.1 4.1 3.5 –0.2

o0.0001 o0.0001* o0.0001* o0.0001* 0.0004* 0.8704 *

1 2 3 3

z Scores

p Values

10.5 8.6 4.5 5.3 4.7 0.2

o0.0001 o0.0001* o0.0001* o0.0001* o0.0001* 0.8719 *

CRYO (units)

(0-2) (1-3) (2-4) (2-4)

1 2 2 2

(0-2) (1-2) (1-3) (1-3)

z Scores

p Values

z Scores

p Values

9.5 8.0 6.3 3.1 2.6 –0.3

o0.0001 o0.0001* o0.0001* 0.0017* 0.0091* 0.7436

7.1 6.0 4.4 2.5 2.1 –0.2

o0.0001* o0.0001* o0.0001* 0.0121* 0.0376* 0.8333

*

NOTE. The values are presented as median (25th and 75th percentiles). Abbreviations: CRYO, cryoprecipitate; EACA, epsilon aminocaproic acid; FFP, fresh frozen plasma; PLTS, platelet packs; pRBC, packed red blood cells. *p o 0.05 is statistically significant.

EACA administration. Specific for this group of patients, heparin administration during the preanhepatic stage appeared to have a protective effect (OR 0.2 [0.01-1.07]) regarding the incidence of intraoperative thrombosis (χ2 ¼ 3.5, p ¼ 0.0618); however, the χ2 statistic did not reach significance. An associated increase in the incidence of AKI during the first week post-TX compared with patients who did not receive EACA was not observed (see Table 3). The incidence of postTX RRT o1 month was higher in the EACA-treated group (see Table 3). However, multivariable analysis (n ¼ 708) identified 8 statistically significant risk factors associated with post-TX RRT within the first month after OLT: age, female sex, redo OLT, pre-TX serum sodium levels, pre-TX AKI, preTX RRT, intraoperative platelet transfusion, and surgical reexploration for postoperative bleeding within the first week after OLT (Table 5). The whole model (χ2 ¼ 202, p o 0.0001) was statistically significant. A C statistic of 0.88 was calculated

Table 5. Predictors for Postoperative Renal Replacement Therapy and Myocardial Ischemia o1 Month Odds Ratio

Postoperative RRT o1 month Age (per unit change) Pre-TX sodium (per unit change) Platelets transfusion (per unit change) Sex: Female v male Redo transplantation Pre-TX AKI (no RRT) Pre-TX RRT Post-TX bleeding o1 week Postoperative MI o1 month Age (per unit change) Pre-TX vasopressors

95% CI

p Value

1.04 0.94

1.014-1.077 0.887-0.989

0.0033* 0.0194*

1.54

1.319-1.823

o0.0001*

2.48 5.02 2.88 34.3 3.28

1.408-4.411 0.0016* 2.065-11.963 0.0005* 1.531-5.356 0.0012* 16.598-74.650 o0.0001* 1.434-7.322 0.0055*

1.10 8.5

1.039-1.187 2.500-25.720

0.0008* 0.0014*

Abbreviations: AKI, acute kidney injury; MI, myocardial ischemia; post-TX, post-transplant; pre-TX, pre-transplant; RRT, renal replacement therapy. *p o 0.05 is statistically significant.

for this group of risk factors associated with post-TX RRT, with a misclassification rate of 0.10. A 2.5% (18/708) incidence of redo OLT within 1 year was observed, in which 0.3% (2/708) of cases were a result of primary hepatic non-function, and none was attributed to EACA administration. No significant difference in the 1-year survival rates was observed between groups: 92% versus 93% (χ2 ¼ 0.05, p ¼ 0.8188). DISCUSSION

The diversity of the OLT population with a potential risk for life-threatening thromboembolic complications5,6,16,17 led to the observation of no consensus regarding antifibrinolytics usage and dosage guidelines in OLT. Antifibrinolytic agents have been used during OLT either “therapeutically” (to treat fibrinolysis when it occurs during OLT) or “prophylactically” (bolus and/or infusion after induction of general anesthesia) in an attempt to minimize blood loss and transfusion requirement. Of the 2 antifibrinolytic agents available on the US market, EACA is used consistently in the authors’ institution to treat fibrinolysis/coagulopathy when it occurs after reperfusion because of its low cost. The authors’ data showed that, based on the magnitude and persistence of post-reperfusion coagulopathy, higher doses of EACA (Z5 g IV bolus followed by 1 g/h IV infusion) are acceptable in OLT patients with no difference in the amount of blood products transfused with doses 410 g. Regarding the “therapeutic” dose to treat fibrinolysis when it occurs during OLT, there are published reports of smaller doses of EACA (0.25-2 g) being effective in treating fibrinolysis in OLT patients.1,2,16,17 Other authors18,19 advocated a regimen of a 5-g IV bolus followed by a 1-g/h IV infusion or a single dose of 10 g IV in an attempt to maintain adequate blood levels of the drug in the setting of cardiac surgery. Because EACA was not used as “prophylaxis” from the beginning of OLT, but rather as a “therapeutic” regimen, the authors could not conclude whether a reduction in blood transfusion requirements had occurred. In fact, the EACAtreated group required significantly more blood products during

6

transplantation than the EACA-nontreated group. In addition, the OLT patients who received EACA were more coagulopathic, as reflected by baseline TEG analysis, and had significantly higher body mass index and medical model for end-stage liver disease (MELD) scores (mean 24), higher incidences of pre-TX AKI, and longer hospitalization times. Nevertheless, 1-year survival rates were similar between groups. A similar survival rate of 92% was reported by Mangus et al when a single small bolus of 25 mg/kg of EACA was “prophylactically” administered before incision in 216 patients (mean MELD, 18) without a significant difference in pRBC requirements, but with significantly less FFP administration and blood loss compared with the control group.20 In the Dalmau et al study, 42 patients received a prophylactic EACA dose of 16 mg/kg/h continuously administered from induction of general anesthesia until organ reperfusion to reduce fibrinolysis and blood product usage, but it was not as effective as tranexamic acid, and this was attributed to the small dose used.21 Recent evidence confirmed that “prophylactic” EACA administered in 31 patients with a mean MELD score of 18 (150 mg/kg IV before to incision followed by 15 mg/kg/h IV infusion until 2 hours after the graft reperfusion) appeared to decrease blood loss without an increase in thrombotic complications.22 AKI is a common preoperative and postoperative complication in patients with end-stage liver disease.23-26 In this study the reported incidence of AKI within the first week post-TX was similar between the EACA-treated and EACA-nontreated groups. As reported in other studies, EACA when administered “prophylactically” did not significantly affect postoperative renal function.20,22 However, significant increases in the incidence of post-TX RRT o1 month, duration of mechanical ventilation, and ICU and hospital lengths of stay were observed in the EACA-treated group, perhaps as a reflection of the complexity in the cases related to pre-TX conditions. However, logistic regression (n = 708) did not identify EACA to be associated statistically with the incidence of post-TX RRT o1 month after OLT. The low misclassification rates for post-TX RRT o1 month suggest low false positive rates (10 of 100 patients). In this study, the reported overall incidence of venous thromboembolic (hepatic and extrahepatic) complications within 1-year after OLT was 6.9% (49/708), with the majority occurring during the first month (4.5% [32/708]). Salami et al reported a 1-year post-OLT incidence of extrahepatic thromboembolic complications of 4.6% (45/917), which was similar to the incidence after other major abdominal procedures (5%10%).27 The reported incidence of extrahepatic thrombotic complications within the first month of transplantation in this study was 3% (9/275) in the EACA-treated group, which was higher than the 0% incidence reported in the “prophylactic” EACA studies.21,22 However, in the Mangus et al “prophylactic” EACA study, the 5% incidence of DVT was significantly higher than the 2% observed in the control group.20 Early HAT incidence in this study’s EACA-treated group was 0.4% (1/275), which was lower than the 4.8% (2/42) incidence reported in the Dalmau et al study.21 The incidence of postoperative MI was higher significantly in the EACAtreated group; however, logistic regression (n ¼ 708) identified 2 independent risk factors (age and pre-TX vasopressor use) that were associated statistically with the incidence of

NICOLAU-RADUCU ET AL

postoperative MI. The antifibrinolytic EACA was not associated as a risk factor. The misclassification rates for MI o1 month accurately predicted (true positive) the associated risk factors in 98 of 100 patients. The 1% to 4% incidence of devastating intraoperative cardiac thrombosis/pulmonary embolism previously reported in the literature was consistent with the 1.3% reported in this study.5,28,29 However, the intraoperative thrombotic episodes in this study predominant occurred during the dissection and anhepatic phases (6 cases), with only 3 cases occurring after reperfusion and none associated with EACA administration. Specific to this study, of the 39% (275/708) of patients who received IV heparin before caval cross-clamping, only 1 patient developed intraoperative cardiac thrombosis/pulmonary embolism (30 minutes after reperfusion); this patient died with a flat-line TEG after reperfusion (kaolin and heparinase). The flat-line TEG, as previously reported by Sakai et al, is a significant risk factor and predictor for the development of intraoperative cardiac thrombosis/pulmonary embolism after reperfusion.29 Ischemia/reperfusion injury with release of cellular debris from the liver graft and activation of hyperacute disseminated intravascular coagulation previously was suggested as a mechanism for this phenomenon,28,29 which was observed in this study in the presence of heparin. This study was limited because it was a retrospective study. Because EACA was not used as “prophylaxis” therapy from the beginning of OLT but rather as a “therapeutic” regimen for postreperfusion fibrinolysis/coagulopathy, the authors could not conclude whether a reduction in blood transfusion requirements occurred because there was no comparable control group. Another limitation was the possibility of additional missed intraoperative cardiac thrombosis/pulmonary embolism events because transesophageal echocardiography was used largely as a diagnostic tool rather than for continuous monitoring. Even though no relationship with thromboembolic events was observed in this study, the thrombotic risk with the use of antifibrinolytic drugs can be associated in specific subsets of patients, which needs to be studied further. The clinical relevance of independent predictors for MI o1 month and postoperative RRT may require meta-analysis to obtain sufficient subgroup populations to clarify EACA risk. In conclusion, EACA administration for the treatment of postreperfusion fibrinolysis and/or clinical bleeding appeared to be safe with standard EACA dosing. EACA was not associated with an increased risk of the development of thromboembolic complications or AKI and did not increase mortality rates. Therefore, changing the practice to a “prophylaxis” regimen does not look appealing at this time. The occurrence of intraoperative cardiac thrombosis/pulmonary embolism appeared to be multifactorial and could occur during all phases of OLT; therefore, a small dose of heparin given during the preanhepatic stage appeared to be beneficial in preventing perioperative thrombotic events. ACKNOWLEDGMENTS

The authors thank Qingyang Luo, PhD, Department of Biostatistics, Ochsner Medical Center, New Orleans, LA, for statistical advice.

7

AMICAR AND LIVER TRANSPLANTATION

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