p

f

c

w

(

c

u

h

c

f

a

c

t

a

Datbpdh(lotpasgD

tidfbtnbsistcactD

J

Changing from Aprotinin to Tranexamic Acid Results in Increased Use ofBlood Products and Recombinant Factor VIIa for Aortic Surgery Requiring

Hypothermic Arrest

Roman M. Sniecinski, MD,* Edward P. Chen, MD,† Sunal S. Makadia, BS,* Mutsuhito Kikura, MD,‡

Daniel Bolliger, MD,* and Kenichi A. Tanaka, MD, MSc*

a

d

d

d

a

s

t

u

c

r

p

q

i

©

K

Objective: Aprotinin, once used to reduce allogeneic blood

roduct transfusion during cardiac surgery, was withdrawn

rom the market in late 2007 over concerns of causing in-

reased mortality. This study was undertaken to determine

hat, if any, the impact of changing antifibrinolytic agents

from aprotinin to tranexamic acid) for deep hypothermic

irculatory arrest cases would have on blood bank resource

tilization.

Design: This a retrospective review.

Setting: All cases were performed at a single university

ospital.

Participants: All patients underwent cardiac surgical pro-

edures requiring deep hypothermic circulatory arrest per-

ormed by a single cardiac surgeon between January 2006

nd November 2008.

Intervention: All patients prior to November 15, 2007 re-

eived aprotinin as antifibrinolytic therapy, while those after

hat date received tranexamic acid for antifibrinolytic ther-

HCA cases.

r(cblcpt(tpctsr

h4Fa(bF

rm

a

AA

ournal of Cardiothoracic and Vascular Anesthesia, Vol 24, No 6 (Decemb

Measurements and Main Results: Blood transfusion data

nd recombinant factor VIIa use during the pre- and imme-

iate postoperative period was collected for all patients

uring the study time period. There were no significant

ifferences between the aprotinin (n � 82) and tranexamic

cid (n � 78) groups with regard to baseline coagulation

tatus or operative characteristics. Patients treated with

ranexamic acid required more fresh frozen plasma (2.5

nits, p < 0.001), platelets (0.5 units, p < 0.01), and cryopre-

ipitate (25 units, p < 0.001), and had a higher incidence of

ecombinant factor VIIa use (34.6% v 12.2%, p < 0.01) com-

ared with patients in the aprotinin group.

Conclusions: Patients treated with tranexamic acid re-

uired more clotting factors than the control group receiv-

ng aprotinin.

2010 Elsevier Inc. All rights reserved.

EY WORDS: aortic surgery, blood conservation, hypother-

py. mia/circulatory arrest, antifibrinolytics

EEP HYPOTHERMIC CIRCULATORY ARREST (DHCA)commonly is used for operations involving the thoracic

orta that require interruption of cerebral blood flow.1,2 Whilehe technique provides vital neuroprotection and allows for aloodless surgical field,3 it places considerable stress on theatient’s coagulation system.4 Extensive surgical dissection,rastic temperature changes, periods of blood stasis, and severeemodilution due to prolonged use of cardiopulmonary bypassCPB) result in severe postoperative coagulopathy. Antifibrino-ytic agents, mainly aprotinin and the lysine analogs, �-amin-caproic acid and tranexamic acid (TXA), frequently are usedo reduce systemic activation of fibrinolytic enzymes, and aremature breakdown of hemostatic clot.5,6 When adequatenticoagulation with heparin was ensured, aprotinin had beenhown to be safe and effective at reducing the need for allo-eneic blood products following cardiac surgery requiringHCA.4,7

Prior to November 15, 2007, the use of aprotinin was part ofhe standard institutional practice in high-risk cardiac surgery,ncluding all DHCA cases. Aprotinin was voluntarily with-rawn from the market following the release of clinical datarom the Canadian BART (Blood conservation using Antifi-rinolytics in a Randomized Trial) study that demonstrated arend of increased 30-day morbidity and mortality with aproti-in relative to the lysine analogs.8 As a result, the institutionegan using TXA as antifibrinolytic therapy for all cardiacurgery involving CPB. Several months following the change,t was believed that the use of blood products for cardiacurgery requiring DHCA had significantly increased. The au-hors hypothesized that TXA would be associated with in-reased hemostatic product usage and transfusion cost; thus, theuthors conducted a retrospective review of DHCA cases re-eiving aprotinin or TXA. The goal was also to help quantifyhe impact, if any, of changing antifibrinolytic therapies for

METHODS

Following IRB approval, the authors conducted a retrospective charteview for all DHCA cases performed by a single cardiac surgeonE.P.C.) from January 2006 through November 2008. All reviewedharts involved aortic surgery (ascending, descending, and/or arch)oth with and without combined coronary or valve procedures. Col-ected data were the patient demographics (age, sex, weight), operativeharacteristics (reoperation, emergency, CPB time, and DHCA time),re- and postoperative (1st lab values drawn in the ICU) hematologyest results: hematocrit (%), platelet count (�103/�L), fibrinogen levelmg/dL), international normalized ratio (INR), and activated partialhromboplastin time (aPTT [s]). Additionally, use of blood products,acked red blood cells (RBCs), platelets, fresh frozen plasma (FFP),ryoprecipitate, and recombinant factor VIIa (mg) in the OR and duringhe first 24 hours in the ICU were recorded. Clinically important eventsuch as the need for re-exploration, acute (new-onset) renal failureequiring dialysis, stroke, seizure, and death also were noted.

The institutional CPB anticoagulation protocol (400 units/kg ofeparin initial dose, with additional doses to maintain kaolin ACT �80 s) was used in all cases and did not change during the study period.or antifibrinolytic therapy, patients prior to November 15, 2007 weredministered full-dose aprotinin: 50,000 kallikrein inhibitory unitsKIU) test dose after sternotomy (all were negative), 2 � 106 KIUolus, followed by 0.5� 106 KIU/h infusion until the end of surgery.ollowing the withdrawal of aprotinin, tranexamic acid was adminis-

From the *Departments of Anesthesiology and †Surgery (cardiotho-acic), Emory University School of Medicine, Atlanta, GA and ‡Hama-atsu Medical Center, Hamamatsu, Shizuoka, Japan.Supported in part by Emory University Department of Anesthesiology,

nd the Foundation for Anesthesia Education and Research (S.S.M.).Address reprint requests to Roman Sniecinski, MD, Department of

nesthesiology, Emory University Hospital, 1364 Clifton Road, NE,tlanta, GA 30322. E-mail: roman.sniecinski@emory.edu© 2010 Elsevier Inc. All rights reserved.1053-0770/2406-0009$36.00/0

doi:10.1053/j.jvca.2010.02.018

959er), 2010: pp 959-963

te

arc(pgpuhae

fvaapdwVotcclfimo

Rcsoosdgo(2l

eatocd

tuawppmsaacm

euc

psdianicm

Cammpti

Ftipwu

w

dmum

960 SNIECINSKI ET AL

ered at the dose of a 2-g bolus followed by a 0.5-g/h infusion until thend of surgery.

The surgical conduct of DHCA for all cases included right axillaryrterial cannulation and either atrial or femoral cannulation for venouseturn. Following institution of full CPB, patients were aggressivelyooled for 25 minutes and reached nadir temperatures of 18-20°Cnasopharyngeal). Sodium pentothal (250-500 mg) was administeredrior to circulatory arrest to obtain an isoelectric EEG pattern. Ante-rade cerebral perfusion was used during the DHCA time period at aressure of 60-70 mmHg. Intraoperative red-cell salvage (“cell saver”)se was standard in all cases. RBCs were transfused to maintainematocrit above 21% while in the OR. Crystalloid salt solutions andlbumin, but not hetastarch derivatives, also were used for volumexpansion when necessary.

At the conclusion of CPB, 250 mg of protamine were administeredor heparin neutralization. If the ACT remained above the baselinealue or if heparinized blood from the CPB machine was administered,n additional 25-50 mg of protamine were given. If bleeding continuedt 200 mL/h without any obvious surgical cause, hemostatic bloodroducts (FFP, platelets, and cryoprecipitate) were administered at theiscretion of the attending anesthesiologist. Following consultationith an attending hematologist, the use of recombinant activated factorII (NovoSeven, Bagsbaerd, NovoNordisk) was permitted at the dosef 2.4 mg-4.8 mg when microvascular bleeding continued despiteransfusion of 4 units of FFP, 2 plateletpheresis units, and 20 units ofryoprecipitate. Postoperative care was directed by a separate intensiveare staff who administered blood products according to abnormalaboratory results (platelet count �100 � 103/�L, INR �1.5, and/orbrinogen �150 mg/dL) in the presence of clinical bleeding (�200L/h blood loss). Transfusion of RBCs in the ICU was at the discretion

f the attending intensivist and tailored to the clinical situation.The primary endpoint was the usage of blood products including

BC, FFP, platelets, and cryoprecipitate. Secondary endpoints werelinical events including rFVIIa use, re-exploration rate, renal failure,troke, seizure, in-hospital death, and total hospital stay in days. Basedn the usage of approximately 2 units of FFP (520 � 360 mL) in theperating room in the aprotinin-treated DHCA cases, group sampleizes of 82 (aprotinin) and 78 (TXA) would achieve 80% power toetect a difference of �156 (mL) between the null hypothesis that bothroup means are 520 (mL) and the alternative hypothesis that the meanf group 2 is 676 (mL) with estimated group standard deviations of 360mL) and 360 (mL) and with a significance level (�) of 0.05 using a-sided Mann-Whitney test assuming that the actual distribution isogistic.

Potential predictors of bleeding in the entire cohort (n � 160) werexamined using multiple linear regression analysis. The influence ofge, gender, body weight, type of antifibrinolytic, CPB time, DHCAime, preoperative hematocrit, INR, and platelet count were evaluatedn the 24-hour transfusion (mL) of RBC, FFP, platelets, and cryopre-ipitate. The results of the final reduced model using best fit wereetermined by the R2 value.Statistical analysis comparing aprotinin-treated and TXA-treated pa-

ients initially was carried out using t-test for continuous variables, andsing Fisher’s exact test for categoric valuables. Effects of differentntifibrinolytic therapies on potential increases in blood product usageere assessed using a multiple logistic regression. The increased bloodroduct usage was defined as follows: RBC � 5 units, FFP � 5 units,lateletpheresis � 3 units, cryoprecipitate � 15 units, or rFVIIa ad-inistration. All analyses were controlled for baseline covariates (age,

ex, weight, hematocrit, platelet count, INR) and differences in oper-tive procedure (cell-saver usage, CPB time, circulatory arrest time)mong patients. Using a forward stepwise procedure, weight, plateletount, cell saver (in units), and CPB time were included in the final

odel as significant covariates, and the odds ratio was calculated for r

ach product if applicable. All statistical analyses were performedsing SPSS 11.5 (SPSS Inc., Chicago, IL); a p value of �0.05 wasonsidered significant.

RESULTS

The demographic and clinical data from 160 consecutiveatients were included (Table 1). There was no statisticallyignificant difference between aprotinin and TXA groups in theemographic data. Preoperative laboratory and surgical datandicated statistically significant differences in preoperative PTnd DHCA time. The difference in PT seemed clinically insig-ificant, but DHCA time was approximately 7 minutes longern the TXA group. These 2 parameters and other potentialovariates were controlled in a multivariate logistic regressionodel as described below.There was no significant influence of age, sex, body weight,

PB/circulatory arrest durations, hematocrit, and INR on themount of transfusion in the entire cohort (n � 160). The finalodel of multiple linear regression presented as the best-fitodel demonstrated that only the type of antifibrinolytic and

reoperative platelet count were significantly associated withhe amount of transfused RBC, FFP, platelets, and cryoprecip-tate (Table 2).

Blood-product usage was significantly increased for RBC,FP, plateletpheresis, cryoprecipitate, and rFVIIa (Table 3) in

he TXA group. In particular, the use of FFP and cryoprecip-tate was increased for both intraoperative and postoperativeeriods. For RBC and plateletpheresis, the intraoperative usageas not different between the 2 groups, but the postoperativesage was significantly higher in the TXA group. The use of

Table 1. Demographic and Surgical Data

Aprotinin (n � 82) TXA (n � 78) p Value

Male sex 55 (67.1%) 50 (64.1%) 0.74Age 57.9 � 14.1 56.9 � 14.4 0.67Weight 87.9 � 22.0 85.8 � 22.2 0.54Laboratory data

Hematocrit (%) 38.4 � 5.2 37.3 � 5.3 0.21Platelet (�103/�L) 227 � 69.9 225 � 62.1 0.85INR 1.1 � 0.17 1.0 � 0.13 �0.05PTT (s) 39.2 � 26.8 32.4 � 3.8 0.07ACT (s) 130 � 19.1 136 � 18.6 0.06Serum creatinine 1.13 � 0.28 1.11 � 0.30 0.74

Surgical site 0.16Aortic root 26 (31.7%) 20 (25.6%)Arch involvement 50 (61.0%) 48 (61.5%)DTAA 6 (7.3%) 10 (12.8%)

Redo surgery 21 (25.6%) 21 (26.9%) 0.86Emergency 7 (8.5%) 10 (12.8%) 0.45CPB time (min) 198 � 62.7 195 � 59.1 0.72DHCA time (min) 28.4 � 13.9 35.9 � 15.9 �0.01

NOTE. Surgical site analysis done for different categories as ahole.Abbreviations: DTAA, descending thoracoabdominal aneurysm (ie,

escending aorta only); TXA, tranexamic acid; INR, international nor-alized ratio; PTT, partial thromboplastin time; ACT, activated coag-

lation time; CPB, cardiopulmonary bypass; DHCA, deep hypother-ic circulatory arrest.

FVIIa was significantly increased in the TXA group compared

wat

tprgTcss

icctRii

wa

auatr

fvoDswclaawrdotcTRspb

m

c

961CHANGING FROM APROTININ TO TRANEXAMIC ACID

ith the aprotinin group (34.6% v 12.2%, p � 0.003). Themount of blood processed by the cell salvage was not statis-ically different between the groups (8.6 v 9.6 units, p � 0.23).

The hematologic data drawn immediately postoperatively inhe ICU (Table 4) were similar between the 2 groups, althoughlatelet count was statistically lower in the TXA group. Theate of re-exploration was significantly higher in the TXAroup (Table 4). There was also a trend for more seizures in theXA group, but it did not reach statistical significance. Otherlinically pertinent parameters including renal insufficiency,troke, in-hospital death, and length of hospital stay were theame between the 2 groups.

In the multivariate logistic regression analysis to evaluatencreased blood-product usage (Table 5), weight, platelet count,ell saver (in units), and CPB time were included as significantovariates as described in the methods. Relative to aprotininreatment, the use of TXA did not increase the odds ratio forBC transfusion. However, TXA was associated with 4-fold

ncreases in FFP and plateletpheresis transfusion, and 50-foldncrease in cryoprecipitate transfusion. The use of rFVIIa also

Table 2. Best-Fit Model for Potential Predictors of Blood Product

Use for Entire Cohort

RBC FFP Platelets Cryoprecipitate

Final model, R2 0.194 0.182 0.119 0.202Weight 0.541 0.132 0.869 0.450CPB time 0.054 0.261 0.323 0.649DHCA time 0.693 0.216 0.717 0.271Preop INR 0.344 0.323 0.944 0.335Antifibrinolytic 0.0001 0.003 0.022 0.0001Preop platelet count 0.040 0.004 0.006 0.016

Table 3. Transfusion Requirements–Total and Breakdown Between

OR and ICU

Aprotinin (n � 82) TXA (n � 78) p Value

RBC (mL)Total 2651 (2153-3034) 3558 (3056-4059) �0.05Intraoperative 1410 (1157-1662) 1217 (976-1458) 0.21Postoperative 1144 (799-1490) 2340 (1986-2695) �0.001

FFP (mL)Total 790 (620-959) 1424 (1251-1599) �0.001Intraoperative 521 (442-601) 819 (723-915) �0.001Postoperative 268 (139-397) 605 (474-738) �0.001

Platelet (mL)Total 498 (426-570) 693 (609-778) �0.01Intraoperative 368 (327-410) 392 (351-434) 0.14Postoperative 134 (86.2-183) 301 (212-390) �0.01

Cryo (mL)Total 336 (283-389) 748 (637-860) �0.001Intraoperative 251 (202-299) 446 (396-495) �0.001Postoperative 86.3 (23.1-150) 303 (215-390) �0.001

Cell saver (U) 8.6 (7.6-9.7) 9.6 (8.5-10.6) 0.23Use of rFVIIa 10 (12.2%) 27 (34.6%) �0.01

NOTE. pRBC�350 mL/unit, FFP�250 mL/unit, plateletpheresis�350L/unit, cryoprecipitate�15 mL/unitAbbreviations: RBC, red blood cells; FFP, fresh frozen plasma; Cryo,

ryoprecipitate; rFVIIa, recombinant factor VIIa.

as increased by 10-fold in TXA therapy compared withprotinin therapy.

The drug cost of TXA was about $1,000 less than that ofprotinin (Table 6). However, the increased use of blood prod-cts costs approximately $3,000 more in TXA treatment than inprotinin treatment. This increase does not include blood bankechnicians’ time for preparations, and the additional use ofFVIIa.

DISCUSSION

The use of antifibrinolytics to reduce postoperative bleedingollowing cardiac surgery has become routine at most high-olume centers.5 For high-risk cases (combined valve/CABGperations, redo sternotomies, and aortic procedures requiringHCA) at the institution, aprotinin was used almost exclu-

ively. This practice abruptly ended on November 15, 2007,hen the drug was withdrawn from the U.S. market following

oncerns over increased morbidity/mortality compared with theysine analogs.8 The institution then switched to tranexamiccid as the sole antifibrinolytic agent in high-risk cases. Theuthors were particularly interested in the impact this changeould have on aortic cases requiring DHCA, which commonly

esult in severe coagulopathy. This study was undertaken toetermine what effect, if any, the change in agents would haven the resource utilization. The results of this study suggestedhat switching from aprotinin to TXA for DHCA cases hasontributed to an increased need for blood-product transfusion.he authors have seen an increase of approximately 3 units ofBCs (915 mL), 2.5 units of FFP (599 mL), 0.5 plateletphere-

is (179 mL), and 25 units (399 mL) of cryoprecipitate on aer-case basis. The higher transfusion requirements occurredoth intraoperatively (for FFP and cryoprecipitate), and post-

Table 4. Immediate Postoperative Laboratory Data and

Postoperative Events

Aprotinin (n � 82) TXA(n � 78) p Value

Laboratory dataACT after protamine (s) 134 � 24.5 133 � 18.5 0.80Hematocrit (%) 31.2 � 3.9 31.0 � 4.2 0.74Platelet (�103/�L) 103 � 30.9 90.5 � 29.9 �0.05INR 1.52 � 0.31 1.40 � 0.40 0.09aPTT (s) 64.7 � 22.2 54.5 � 22.8 �0.05Fibrinogen (mg/dL) 253 � 80 271 � 107 0.40

Postoperative eventsRe-exploration 2 (2.4%) 9 (11.5%) �0.05Renal failure 7 (8.5%) 6 (7.7%) 1.00Stroke 2 (2.4%) 2 (2.6%) 1.00Seizure 0 (0%) 5 (6.4%) 0.02In-hospital death 6 (7.3%) 4 (5.1%) 0.51Hospital stay (days) 13.7 � 10.7 13.1 � 8.0 0.75

Table 5. Increased Transfusion with TXA Relative to Aprotinin

Odds Ratio (95% CI) p Value

FFP 4.4 (1.9-10.6) �0.01Plateletpheresis 3.9 (1.9-10.6) �0.01Cryoprecipitate 52.8 (9.8-1000) �0.001

rFVIIa 10.5 (3.5-39.0) �0.001

odd

p2ps3wnwaduupu

RrmptMsRdp

dettdldfiRaDmanliaeD

tehtpsaposhg3wsrc

sgtbtadngtcfdrptc

iaMmiDcTalHsgsswa

L

962 SNIECINSKI ET AL

peratively (for all hemostatic blood products). There were noifferences in length of hospital stay, renal failure, stroke, oreath between the 2 groups.The finding that aprotinin reduced blood transfusion com-

ared with TXA is consistent with other studies comparing theantifibrinolytics. The investigators for the BART study re-

orted decreased postoperative bleeding and massive transfu-ion in agreement with this data, but at the cost of increased0-day mortality. Indeed, the re-exploration rates for bleedingere 5.5% for aprotinin, 8.1% for TXA, and 8.2% for �-ami-ocaproic acid.8 It is difficult to directly compare the resultsith the BART study due to different endpoints, available data,

nd the likely variability in transfusion practices among manyifferent institutions.9 Unlike this study’s primary focus on these of FFP, platelets, and cryoprecipitate, BART investigatorssed postoperative blood loss of more than 1.5 liters as therimary endpoint, and they defined massive transfusion as these of more than 10 units of RBCs.8

Dietrich et al recently reported a lower transfusion rate ofBCs with aprotinin use compared with TXA in a prospective,

andomized, double-blind study involving 220 patients.10 He-ostatic blood components were not examined, but since only

rimary CABG and primary AVR operations were included,he need for these components would be expected to be low.

artin et al also compared aprotinin with TXA in a cohorttudy of 1188 patients and found a higher transfusion rate forBCs and FFP in the TXA group.11 The use of platelets was notifferent between the 2 groups, but only a small number of theatients (�4%) underwent procedures involving DHCA.The fact that this study dealt exclusively with patients un-

ergoing DHCA provides evidence that the clinical impact (eg,fficacy, side effects) of aprotinin is likely different amongarget surgical populations. For example, Martin et al suggestedhat aprotinin may adversely increase the incidence of myocar-ial infarction in CABG patients.11 Such a finding does notikely apply to DHCA patients, who experience a much greaterilution of procoagulant factors, as well as an increase inbrinolytic activity.12 In agreement with this data, Nicolau-aducu et al recently reported the retrospective analysis of 48protinin-treated and 36 TXA-treated patients undergoingHCA, demonstrating that the blood-product usage tends to beore with TXA relative to aprotinin.13 The use of aprotinin was

ssociated with postoperative renal dysfunction, but there wereo differences between TXA and aprotinin in cardiac, neuro-ogic, respiratory, or survival outcomes after DHCA. Lack ofncreases in stroke or myocardial infarction with aprotinin islso supported by Ehrlich et al who failed to show any differ-nce in those events comparing aprotinin with placebo in

Table 6. Average Cost of Antifibrinolytic Therapy and Transfusion

Aprotinin (n � 82) TXA (n �78) p Value

Drug cost $1,268 � 90.8 $293 � 32.9 �0.001TransfusionRBC $2,651 � 1710 $3,558 � 2676 0.012FFP $281 � 234 $506 � 315 �0.001Plateletpheresis $1,181 � 794 $1,662 � 1019 �0.001Cryoprecipitate $1,868 � 1342 $4,130 � 2728 �0.001

HCA cases.14 w

In an attempt to further quantify the impact changing toranexamic acid had at the institution, the authors took anconomic perspective. Although the drug cost of aprotinin wasigher than tranexamic acid ($1,268 v $293), overall the insti-ution is now spending more to treat coagulopathy in DHCAatients. The tranexamic acid group’s blood product transfu-ion costs were more than 60% higher. This is consistent with

prior study by Smith et al that demonstrated an overallerioperative cost-savings benefit from aprotinin when factorsther than just drug cost were taken into account.15 In thistudy, it is also important to note that the tranexamic acid groupad a higher re-exploration rate compared with the aprotininroup. Of the 11 re-explored patients in the study cohort, onlyhad identifiable surgical bleeding, suggesting most bleedingas the result of medical coagulopathy rather than lack of

urgical hemostasis. Returning to the operating room clearlyepresents an additional, although difficult to quantify, financialost.

Recombinant activated factor VII (rFVIIa) has been useduccessfully to treat postoperative coagulopathy in cardiac sur-ical patients.16,17 It has been used at the institution since 2002o treat CPB-induced coagulopathy unresponsive to hemostaticlood products or in those patients unwilling to receive bloodransfusions.18 Factor VIIa use in the present study functioneds a rescue treatment, when microvascular bleeding persistedespite multiple rounds of hemostatic blood products. A sig-ificantly higher percentage of patients in the tranexamic acidroup (34.6% v 12.2%, p � 0.01) required rFVIIa rescueherapy. Economic implications aside, there may be some con-ern about tripling the use of rFVIIa. A recent multicenter trialound an increased, although not statistically significant, inci-ence of thrombotic complications in cardiac surgical patientseceiving the drug as rescue therapy for bleeding.19 Given thisrecaution, it may be speculated that the major effect of apro-inin’s withdrawal is merely the trading of one drug’s potentialomplications for another drug’s potential complications.

An unexpected result of this analysis was the increasedncidence of seizures in the TXA group (5 patients v none in theprotinin group). This finding also was reported recently byartin et al.11 The proconvulsant effect of TXA is presumablyediated by gamma-aminobutyric acid-receptor antagonism 20

n a dose-dependent manner.21 The authors speculate thatHCA patients are more susceptible to this complication be-

ause of prolonged TXA infusions during CPB (�3 hours,able 2). Of course, the length of circulatory arrest also isssociated with seizure risk,22 and the average DHCA time wasonger in the TXA group (36 min v 28 min, p � 0.01).owever, the DHCA times for the patients who experienced

eizures were 15-35 (median 32) minutes, all less than the TXAroup average, and under the 40-minute limit for increasedeizure risk according to Gaynor et al.22 As a result of thistudy, the clinical protocol changed the TXA infusion rate to aeight-based formula consisting of a loading dose of 15 mg/kg

nd an infusion rate of 7.5 mg/kg/h.

imitations

There are obvious limitations to this study, including that it

as retrospective, nonrandomized, and relatively small. How-

estrvCantipwpdIsp(sw

bfaaobshplbafs

TM

pr1

fa

msc

dA

mt

l

lC

aJ

sJ

asA

tc

m1

963CHANGING FROM APROTININ TO TRANEXAMIC ACID

ver, the advantage of this design is that patients underwentimilar procedures by a single surgeon. Therefore, surgicalechnique, which can have a significant effect on transfusionequirements and outcome, would be expected to have limitedariability. Indeed, the fact that there were no differences inPB time or intraoperative cell-saver use would suggest thectual operative characteristics between the 2 groups wereearly identical. The anesthesia staff did not prophylacticallyransfuse hemostatic products until the absence of visible clotsn the surgical field was subjectively confirmed. Transfusion ofroducts in the ICU was handled separately by intensivists, andas laboratory data-driven. The similarly increased blood-roduct usage in the OR and ICU suggests that bleeding ten-ency related to TXA was not simply an intraoperative event.n addition, a closer look at the pattern of rFVIIa administrationhowed that it was given only in the OR in 4/10 (40.0%)atients in the aprotinin group. This was similar to the 14/2751.8%) TXA-treated patients receiving rFVIIa only in the OR,uggesting that the OR anesthesiologists were not biased to-

ards administering rFVIIa to TXA patients. E

REN

997

aaV

ta

ai

fZ

rA

sr2

rt2

waT

vt

oiC

sl

In conclusion, the authors experienced the increased use oflood bank resources for DHCA cases following the switchrom aprotinin to TXA. Although 30-day mortality was notffected by increased transfusion associated with TXA, theuthors cannot exclude the possibility that long-term outcomesf patients may be affected adversely by the exposure to excesslood products, re-exploration procedures, or the occurrence ofeizures. Other institutions performing cardiac operations atigh risk for postoperative coagulopathy should be aware of theotential need for these additional resources. Aprotinin is noonger available, but a newer potent antifibrinolytic agent iseing considered as its replacement.23 It is thus possible that andequately powered prospective randomized study can be per-ormed to evaluate the safety and efficacy of TXA relative touch new interventions.

ACKNOWLEDGMENT

The authors acknowledge helpful discussions with Dr. Jerrold Levy.he authors are also grateful to Katherine Egan, Brady Rumph, Kyleavros, and Matthew Klopman, Department of Anesthesiology,

mory University for their help with data collections.

REFE

1. Crawford ES, Saleh SA: Transverse aortic arch aneurysm: Im-roved results of treatment employing new modifications of aorticeconstruction and hypothermic cerebral circulatory arrest. Ann Surg94:180-188, 19812. Ehrlich M, Grabenwoger M, Luckner D, et al: The use of pro-

ound hypothermia and circulatory arrest in operations on the thoracicorta. Eur J Cardiothorac Surg 11:176-181, 1997

3. Gega A, Rizzo JA, Johnson MH,T et al: Straight deep hypother-ic arrest: Experience in 394 patients supports its effectiveness as a

ole means of brain preservation. Ann Thorac Surg 84:759-766; dis-ussion 766-767, 2007

4. Green JA, Spiess BD: Current status of antifibrinolytics in car-iopulmonary bypass and elective deep hypothermic circulatory arrest.nesthesiol Clin North America 21:527-551 viii, 20035. Henry DA, Carless PA, Moxey AJ, et al: Anti-fibrinolytic use forinimising perioperative allogeneic blood transfusion. Cochrane Da-

abase Syst Rev 2007:CD0018866. Mannucci PM, Levi M: Prevention and treatment of major blood

oss. N Engl J Med 356:2301-2311, 20077. Mora Mangano CT, Neville MJ, Hsu PH, et al: Aprotinin, blood

oss, and renal dysfunction in deep hypothermic circulatory arrest.irculation 104:1276-1281, 20018. Fergusson DA, Hebert PC, Mazer CD, et al: A comparison of

protinin and lysine analogues in high-risk cardiac surgery. N EnglMed 358:2319-2331, 20089. Ide M, Bolliger D, Taketomi T, et al: Lessons from the aprotinin

aga: Current perspective on antifibrinolytic therapy in cardiac surgery.Anesthesia 24:96-106, 201010. Dietrich W, Spannagl M, Boehm J, et al: Tranexamic acid and

protinin in primary cardiac operations: An analysis of 220 cardiacurgical patients treated with tranexamic acid or aprotinin. Anesthnalg 107:1469-1478, 200811. Martin K, Wiesner G, Breuer T, et al: The risks of aprotinin and

ranexamic acid in cardiac surgery: A one-year follow-up of 1188onsecutive patients. Anesth Analg 107:1783-1790, 2008

12. Wilde JT: Hematological consequences of profound hypother-ic circulatory arrest and aortic dissection. J Card Surg 12:201-206,

CES

13. Nicolau-Raducu R, Subramaniam K, Marquez J, et al: Safetynd efficacy of tranexamic acid compared with aprotinin in thoracicortic surgery with deep hypothermic circulatory arrest. J Cardiothoracasc Anesth 24:73-79, 200914. Ehrlich M, Grabenwoger M, Cartes-Zumelzu F, et al: Opera-

ions on the thoracic aorta and hypothermic circulatory arrest: Isprotinin safe? J Thorac Cardiovasc Surg 115:220-225, 1998

15. Smith PK, Datta SK, Muhlbaier LH, et al: Cost analysis ofprotinin for coronary artery bypass patients: Analysis of the random-zed trials. Ann Thorac Surg 77 635-642; discussion 642-643, 2004

16. Dunkley S, Phillips L, McCall P, et al: Recombinant activatedactor VII in cardiac surgery: Experience from the Australian and Newealand Haemostasis Registry. Ann Thorac Surg 85:836-844, 200817. Romagnoli S, Bevilacqua S, Gelsomino S, et al: Small-dose

ecombinant activated factor VII (NovoSeven) in cardiac surgery.nesth Analg 102:1320-1326, 200618. Tanaka KA, Waly AA, Cooper WA, et al: Treatment of exces-

ive bleeding in Jehovah’s Witness patients after cardiac surgery withecombinant factor VIIa (NovoSeven). Anesthesiology 98:1513-1515,00319. Gill R, Herbertson M, Vuylsteke A, et al: Safety and efficacy of

ecombinant activated factor VII: A randomized placebo-controlledrial in the setting of bleeding after cardiac surgery. Circulation 120:1-27, 200920. Furtmuller R, Schlag MG, Berger M, et al: Tranexamic acid, a

idely used antifibrinolytic agent, causes convulsions by a gamma-minobutyric acid(A) receptor antagonistic effect. J Pharmacol Expher 301:168-173, 200221. Yeh HM, Lau HP, Lin PL, et al: Convulsions and refractory

entricular fibrillation after intrathecal injection of a massive dose ofranexamic acid. Anesthesiology 98:270-272, 2003

22. Gaynor JW, Nicolson SC, Jarvik GP, et al: Increasing durationf deep hypothermic circulatory arrest is associated with an increasedncidence of postoperative electroencephalographic seizures. J Thoracardiovasc Surg 130:1278-1286, 200523. Dietrich W, Nicklisch S, Koster A, et al: CU-2010–A novel

mall molecule protease inhibitor with antifibrinolytic and anticoagu-

ant properties. Anesthesiology 110:123-130, 2009