2001;71:922-927 Ann Thorac SurgMassimiliano Codispoti, Christopher A. Ludlam, David Simpson and Pankaj S. Mankad

undergoing cardiac operationsIndividualized heparin and protamine management in infants and children

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Individualized Heparin and ProtamineManagement in Infants and Children UndergoingCardiac OperationsMassimiliano Codispoti, MD, Christopher A. Ludlam, PhD, David Simpson, FRCA, andPankaj S. Mankad, PhDDepartment of Cardiac Surgery, Royal Hospital For Sick Children, and Department of Hematology, Royal Infirmary, Edinburgh,Scotland

Background. Measurements of activated coagulationtime do not correlate with plasma concentration of hep-arin. This study investigated the effects of a patient-specific method to manage anticoagulation and its rever-sal in pediatric patients undergoing cardiopulmonarybypass.

Methods. Infants and children were randomly assignedto receive either a standard dose of heparin (300 IU/kg;group C, n 5 13) or an individualized dose, calculated byan in vitro heparin dose-response test (group HC, n 5 13).Protamine dose was based on a 1 mg/1 mg ratio of totaladministered heparin for patients in group C and of theresidual heparin concentration in group HC.

Results. Administered heparin was significantly higher

and total protamine dose was significantly reduced in theHC group (both p <

2 0.001). There was less thrombingeneration (p 5 0.02) and fibrinolysis (p 5 0.05) in groupHC. Blood loss and requirement for transfusion of bloodand fresh frozen plasma were also lower in group HC (allp <

2 0.05).Conclusions. An individualized management of antico-

agulation and its reversal results in less activation of thecoagulation cascade, less fibrinolysis, and reduced bloodloss and need for transfusions. Further studies are war-ranted to better define the clinical impact of these find-ings.

(Ann Thorac Surg 2001;71:922–8)© 2001 by The Society of Thoracic Surgeons

Inadequate anticoagulation with heparin in the settingof exposure of blood to foreign surfaces (cardiopul-

monary bypass [CPB], dialysis circuits, cardiac catheter-ization procedures, and such) is known to lead to thegeneration of thrombin [1]. Measurements of activatedcoagulation time (ACT), most widely used to monitoranticoagulation during CPB, do not correlate with con-centration of circulating heparin [2], especially underconditions of deep hypothermia and hemodilution [3]. Asa result, thrombin formation can occur even at “safe”levels of ACT, triggering a consumptive coagulopathyand several proinflammatory reactions [4].

The objective of this study was to investigate the effectsof a patient-specific protocol for administration of hepa-rin and protamine, based on the integrated control ofheparin concentration and ACT during CPB in infantsand children undergoing elective open heart surgicalprocedures.

Material and Methods

After receiving the approval of our regional ethics com-mittee, infants and children participating in this studywere randomly assigned to receive either a standard dose

of heparin (300 IU/kg; control group C) or an individual-ized dose sufficient to maintain an ACT of at least 480seconds (intervention group HC). The surgeon wasblinded as to the randomization group. Patients withknown hematologic disorders, receiving long-term oralor intravenous anticoagulant, antiplatelet therapy, orintraoperative aprotinin, with suspected preoperative in-fection, or undergoing emergency operation were ex-cluded from participation in the trial.

Extracorporeal circulation was accomplished with aroller pump (Stockert Instruments, Munich, Germany),flexible venous reservoir, cardiotomy reservoir (Med-tronic Inc, Minneapolis, MN), and a membrane oxygen-ator (Avecor solid silicone membrane type 0400, 0800, or1500-2A) in all cases. Heparin was added to the pumppriming solution to achieve a concentration of 1 IU/mL inthe control group and the concentration indicated by theHepcon system in patients of group HC (see followingparagraph). Cardiotomy and vent suction were used tominimize exposure of blood to air and the pericardialcavity. Modified ultrafiltration was performed at the endof bypass for all patients with bypass time exceeding 30minutes (group C, n 5 10; group HC, n 5 11).

Accepted for publication Sept 28, 2000.

Address reprint requests to Dr Mankad, Department of Cardiac Surgery,Royal Infirmary, Lauriston Place, Edinburgh, EH3 9YW, Scotland; e-mail:pankaj.mankad@ed.ac.uk.

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In all patients a heparin dose-response test was per-formed using a fully automated and computerized sys-tem (Hepcon HMS, Medtronic Inc, Minneapolis, MN)before skin incision. The heparin dose-response testdetermines the in vitro anticoagulant response of pa-tients’ blood to a known concentration of heparin anduses these data to calculate the amount of heparin that isrequired to reach the desired ACT. The results of this testdictated the whole blood heparin concentration to bemaintained for each patient in the intervention groupthroughout CPB (target ACT 5 480 seconds). The dose ofheparin required to achieve the desired concentration atthe beginning of CPB was calculated using the Hepconsoftware. The concentration of circulating heparin wascalculated at the point of care using a heparin/protaminetitration test. Kaolin ACT and heparin/protamine titra-tion were measured 5 minutes after the administration ofheparin, 5 minutes after initiation of CPB, and every 30minutes thereafter by on-site testing using the Hepconsystem. Heparin was administered accordingly, follow-ing the indications of the ACT alone in the control groupand the combined results of ACT and heparin/protaminetitration in group HC. At the same times, blood sampleswere taken to analyze heparin activity by means ofanti-Xa chromogenic substrate assay (Coatest, Chro-mogenix, Milan, Italy). At the end of CPB, protaminedose was based on a 1 mg/1 mg ratio of the residualheparin concentration for patients in group HC and oftotal (patient 1 CPB) administered heparin in group C.

Blood specimens were obtained either from intraarte-rial catheters or from the CPB arterial catheter. Coagula-tion studies included full blood count, prothrombin time,activated partial thromboplastin time, and fibrinogenlevels. Hematocrit (Hct) values were obtained using aconventional hemocytometer with optical reading, andwhole blood (WB) heparin concentration [Hep] measure-ments were converted into their plasma equivalent (PE)using the following formula:

PE @Hep# 5~WB @Hep# 3 100!

~100 2 Hct!

To investigate the occurrence of fibrinolysis, d-dimerlevels were assayed by means of a commercially availableenzyme-linked immunosorbent assay (Asserachrom d-dimer, Diagnostica Stago, Asnieres-sur-Seine, France).Prothrombin fragment 1 1 2 was also measured toquantitate thrombin generation, using a specific enzymeimmunoassay (Dade Behring, Marburg, Germany), and,as an indicator of platelet activation, we chose to detectplasma levels of b-thromboglobulin using an enzyme-linked immunosorbent assay (Asserachrom b-thrombo-globulin, Asnieres-sur-Seine, France). All samples wereinitially processed, then stored and analyzed according tothe recommended techniques described by the manufac-turers of each test.

After administration of protamine, a clotting screenand complete blood count were performed. The use ofblood and blood products was standardized according tothe algorithm outlined in Table 1. On arrival in the

intensive care unit, a further clotting screen and fullblood count was performed, and appropriate actiontaken following the same criteria.

From data in our previous study on a similar patientpopulation [5], a sample size of 12 patients in each groupwas selected to give a power of 0.8 to detect as significantat the 5% level a true mean difference of one standarddeviation for the primary outcome measures under con-sideration. Primary end points were hematologic indicesof activation of coagulation (prothrombin fragment 1 1 2,d-dimer, Fibrinogen, b-thromboglobulin), whereas sec-ondary end points were amount of bleeding at 24 hours,homologous transfusions, and length of stay in intensivecare unit and in hospital. All parametric data werelog-transformed and analyzed by two-tailed Student ttest or one-way single-factor analysis of variance, asappropriate. Nonparametric variables were comparedusing the Wilcoxon rank sum test. A p value less than 0.05was considered significant. To assess the agreement ofresults for heparin concentration values obtained withthe Hepcon system and with the chromogenic method,we used the Bland and Altman test, setting a sensitivitylimit of 0.7 IU/mL for the Hepcon HMS, as previouslysuggested [6, 7].

Results

Twenty-six infants and children operated on for repair orpalliation of a congenital cardiac defect using CPB wereenrolled in this study during a 6-month period (Table 2).One patient in each group was excluded from the anal-ysis because of an obvious source of surgical bleedingfound at reexploration. The groups were comparablewith regard to age, weight, disease complexity, durationof CPB, preoperative coagulation profile, and a numberof other variables (Table 3).

The patients’ response to unfractionated heparin wasnot normally distributed. In particular, 37.5% of patients(9 of 24) had a heparin requirement higher than thestandard dose of 300 IU/kg (470 6 17 versus 299 67 IU/kg, p , 0.0001). Furthermore, 5 patients had aheparin requirement z value more than 1, whereas in 4patients the z value was less than 21 (Fig 1). Thesepatients would have received excessively high or insuf-ficiently low doses of heparin to reach the target ACT of480 seconds.

Table 1. Transfusion Algorithm

Finding Action Taken

Hb # 13 g/dL RCC (to reach Hb 5 13 g/dL)Plt count # 100,000/mL Plt (10 mL/kg)PTr $ 1.8 FFP (10 mL/kg)aPTTr $ 1.8 FFP (10 mL/kg)Fib # 0.8 g/L Cryo (5 mL/kg)

aPTTr 5 activated partial thromboplastin time ratio, calculated as follows:aPTT patient / aPTT control; Cryo 5 cryoprecipitates; FFP 5 fresh frozenplasma; Fib 5 fibrinogen; Hb hemoglobin; Plt 5 platelets;PTr 5 prothrombin time ratio, calculated as follows: PT patient / PTcontrol; RCC 5 red cell concentrate.

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The ACT never fell below the limit of 480 seconds ineither group (Fig 2). As a result, the total dose of admin-istered heparin was significantly higher in the interven-tion group (p , 0.001; Fig 2). On the contrary, the controlgroup never received additional heparin during CPB, asthe ACT values were always more than 480 seconds.

Despite receiving significantly higher doses of heparin,the total amount of administered protamine was signifi-cantly less in the HC group, when compared with thecontrol group (HC, 2.9 6 0.2 mg/kg; C, 8.6 6 1.4 mg/kg;p , 0.001). In all HC patients the initial protamine dose

achieved complete neutralization of the residual circulat-ing heparin at the end of CPB. In only 1 of 12 patients(8.3%) in the HC group we encountered “heparin re-bound” (0.2 IU/mL) at 1 hour after initial reversal ofheparin effect.

There were 186 pairs of observations used to calculateagreement of results between the two methods to mea-sure heparin concentration in the whole blood, and in theplasma obtained from the same samples. The values ofheparin concentration obtained from the chromogenictest were found to agree with the measurements ob-tained on whole blood samples. The mean difference, orbias, between the plasma anti-Xa and the correctedwhole blood heparin measurements was 0.004 6 0.48,making the two methods interchangeable.

Plasma levels of prothrombin fragment 1 1 2 weresignificantly elevated at the end of CPB in both groups(p , 0.001). However, this rise was significantly lesspronounced in the HC group (p 5 0.02). Fibrinogen wasdepleted significantly at the end of CPB in the controlgroup, when compared with group HC (p 5 0.05; Table 4).d-Dimer levels were significantly elevated at the end ofCPB (p , 0.001) in both groups, although the rise was lesspronounced in the intervention group (p 5 0.05 forbetween-group comparison; Table 4). b-Thromboglobu-lin levels increased significantly in both groups, but therewas no significant difference between groups (Table 4).

Table 2. Diagnoses and Procedures Performed

Group Diagnosis Procedure

HC Multiple VSDs, s/p PAB VSD closure, PAdebanding

VSD, AI VSD closure, AV repairT4F, muscular VSD, s/p

RBTSRepair with RVOT

monocusp homograftVSD, infund. stenosis VSD closure, resection of

RV muscle bundlesVSD, ASD, PDA, Down’s VSD, ASD, PDA closureIntraatrial R-L shunt, s/p

TCPCRedo intraatrial tunnel

DORV, De Georgesyndrome

Intraventricular tunnelrepair

Single ventricle, s/p PAB PCPC, BVF enlargementOstium secundum ASD ASD patch closureSingle ventricle PA reconstruction, central

shuntT4F, s/p R mod BT (32) Repair with RVOT

monocusp homograftMitral valve dysplasia MV repair

C Partial AVSD (32) Patch closurePAIVS, s/p PVtomy1

R-mod. BTPVctomy, transannular

patchPS, HOCM, Noonan’s PVctomyVSD, AI VSD closure, AV repairVSD, PH, PFO VSD closure, PFO closureOstium secundum ASD ASD patch closureT4F, s/p R mod BT (32) Repair with RVOT

pericardial patchesSubaortic stenosis Resection of subaortic

membraneASD, VSD, PS RepairAortic stenosis AVtomySupravalvar AS Resection of supravalvar

membrane

AI 5 aortic insufficiency; AS 5 aortic stenosis; ASD 5 atrial septaldefect; AV 5 aortic valve; AVSD 5 atrioventricular septal defect;AVtomy 5 aortic valvectomy; BAV 5 balloon aortic valvotomy; BT 5Blalock-Taussig shunt; BVF 5 bulboventricular foramen; DORV 5double-outlet right ventricle; HOCM 5 hypertrophic obstructive car-diomyopathy; infund. 5 infundibular; MV 5 mitral valve; PA 5pulmonary artery; PAB 5 pulmonary artery banding; PAIVS 5 pul-monary atresia with intact ventricular septum; PCPC 5 partial cavopul-monary connection; PDA 5 patent ductus arteriosus; PFO 5 patentforamen ovale; PH 5 pulmonary hypertension; PS 5 pulmonarystenosis; PV 5 pulmonary valve; PVctomy 5 pulmonary valvectomy;RBTS 5 right Blalock Taussig shunt; R-mod. BT 5 Right modifiedBlalock-Taussig shunt; RV 5 right ventricular; RVOT 5 right ven-tricular outflow tract obstruction; s/p 5 status post; T4F 5 tetralogyof Fallot; TCPC 5 total cavopulmonary connection; VSD 5 ventric-ular septal defect.

Table 3. Demographic and Operative Dataa

Variable Group CGroup

HC

Age (y) 4.4 6 1.2 5.2 6 1.1Weight (kg) 15.8 6 2.9 18.1 6 3.3Prime volume (mL/kg) 76 6 8 89 6 10Volume added during CPB (mL/kg) 32 6 6 45 6 7Total CPB volume (mL/kg) 108 6 12 135 6 16Dilution factor (total CPB volume/

patient’s blood volume)1.3 6 0.1 1.6 6 0.2

MUF volume (mL/kg) 32 6 4 36 6 4MUF (no. of patients) 10 11Preoperative coagulation tests

Hematocrit (%) 41.5 6 1.6 41.6 6 1.7PTr 1 6 0.1 1 6 0.1aPTTr 1 6 0.2 1 6 0.1Platelets (3103/mL) 270 6 15 263 6 23ACT (s) 119 6 4 122 6 4

CPB time (min) 107 6 12 119 6 10X-clamp time (min) 58 6 9 47 6 8Min t (°C) 27.5 6 1.3 29 6 1.4Steroids 7 6

a The study groups were comparable (p . 0.05) with regard to allvariables, which could have influenced the outcome measures underconsideration.

ACT 5 activated coagulation time; aPTTr 5 activated partial throm-boplastin time ratio, calculated as aPTT patient / aPTT control; CPB 5cardiopulmonary bypass; Min t 5 minimum temperature reachedduring bypass; MUF 5 modified ultrafiltration; PTr 5 prothrom-bin time ratio, calculated as Pt patient / Pt control; Steroids 5 adminis-tration of methylprednisolone 10 mg/kg at induction of anesthesia; X-clamp 5 duration of myocardial ischemia.

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The prothrombin time measured 5 minutes after pro-tamine administration was significantly shorter in theintervention group (group C, 25.1 6 1.8 seconds; groupHC, 19.8 6 0.8 seconds; p 5 0.01). The activated partialthromboplastin time ratio showed slightly higher ratiosin the HC group, without reaching statistical significance(group C, 1.77 6 0.2; group HC, 2.03 6 0.1; p 5 0.51).

During the first 24 postoperative hours, chest drainlosses were significantly less in the intervention group,when compared with the control group (group C, 26.4 64.7 mL/kg; group HC, 15.2 6 3.7 mL/kg; p 5 0.05; Fig 3).The need for blood transfusion in the postoperativeperiod was less in the intervention group, when com-pared with the control group (red cell concentrate, groupC, 11.4 6 3.6 mL/kg; group HC, 3.1 6 1.3 mL/kg; p 5 0.05).Similarly, the need for transfusion of fresh frozen plasma

in the HC group was less than in group C (group C, 6.2 62.2 mL/kg; group HC, 1.0 6 0.3 mL/kg; p 5 0.01; Fig 3).

There were no hospital deaths. The duration of stay inthe intensive care unit and in hospital was similar in bothgroups (intensive care unit stay: group C, 3.9 6 1.2 days;group HC, 2.5 6 1.1 days; p 5 0.2; hospital stay: group C,10 6 2.1 days; group HC, 10 6 1.8 days; p 5 0.9).

Comment

This study demonstrates distinct merits associated withthe use of an anticoagulation protocol that takes intoaccount individual patients’ characteristics and appliesthem to the dosing of heparin and protamine duringpediatric CPB. The approach adopted in patients belong-ing to the intervention group resulted in the administra-

Fig 1. The bell-shaped line represents a normaldistribution curve built using the same mean andvariance of the study population. It is evident thatthe distribution of heparin sensitivities in thestudy population is not normal (Shapiro-Wilk testof normality 5 0.906; p 5 0.03). Although themean sensitivity (296 U/kg) corresponds almostexactly with the empiric dose of heparin com-monly administered (300 U/kg), a significant pro-portion of patients has a lower or higher heparinrequirement to achieve a “safe” activated coagula-tion time. (HDR 5 heparin dose-response: amountof heparin necessary to achieve activated coagula-tion time of 480 seconds; Std. Dev 5 standarddeviation.)

Fig 2. The activated coagulation time (ACT)remained more than 1,500 seconds at all timepoints after the initial 30 minutes despitefalling heparin concentrations in group C,underlying its inability to guide anticoagula-tion. On the contrary, in group HC, the ad-ministration of heparin was targeted to main-tain the concentration indicated by the initialheparin dose-response (HDR), regardless ofthe activated coagulation time reading. Thisprotocol resulted in significantly higher hepa-rin concentrations in group HC as comparedto group C at all time points after the initial30 minutes on cardiopulmonary bypass(CPB). (*p less than 0.001; #p 5 0.02; opencircles 5 ACT of group C; open squares 5ACT of group HC; filled circles 5 heparinconcentration of group C; filled squares 5heparin concentration of group HC.)

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tion of higher doses of heparin and smaller amounts ofprotamine. As a result, a lower degree of consumptivecoagulopathy was observed in these patients, which inturn translated into diminished blood loss and a lowerneed for transfusion of blood and blood products.

The consequences of inadequate systemic hepariniza-tion, mainly an exacerbated activation of the coagulationcascade resulting in consumption of procoagulant factorsand pronounced deficiency of natural coagulation inhib-itors, lead to events that may ultimately account forpost-CPB morbidity or even mortality [8, 9]. To avoidthese undesired occurrences, some authors have recom-mended individualized heparin and protamine dosing[10, 11]. Such an approach, as observed in this and otherstudies [11, 12], leads to the administration of moreheparin and less protamine. Several studies have dem-onstrated the many theoretical advantages of similaranticoagulation protocols, including reduced platelet ag-gregation [13], complement activation [14], and neutro-phil adhesion and sequestration [15]. More importantly,the experimental evidence favoring the administration ofhigher doses of heparin and lower amounts of protaminehas been confirmed in a number of clinical trials con-ducted in adult cardiac patients [11, 12, 16]. These studieshave consistently shown a decrease in postoperativeblood loss and requirement for homologous transfusions

in patients who received higher heparin doses; however,this practice is not yet widely adopted, particularly inpediatric open-heart operations [17]. The effects of apatient-specific protocol for intraoperative systemic anti-coagulation and its reversal has not been reported beforein this patient population.

Although the ACT has been the mainstay for monitor-ing anticoagulation during CPB for more than 20 years[10], numerous studies have shown that it is affected bymultiple factors, including hemodilution, hypothermia,and the type of reagent and monitoring machine [2, 3, 16].To avoid the intrinsic shortcomings of ACT and to reducethe risk of exposing patients to insufficient anticoagula-tion by underdosing of heparin, a number of monitoringdevices have been developed [18]. One such system is theHepcon, which was used in this study to measure levelsof circulating heparin and to guide the dosing of bothheparin and protamine. There has been some debate onthe accuracy of this system [6, 7], but in this prospectivestudy analyzing 186 pairs of observations a good agree-ment of results between the measurements obtained atthe point of care with this device and the standardlaboratory measurements could be confirmed.

Although the number of patients in this study is small,its findings emphasize the inadequacy of a fixed-heparindose protocol and the inappropriateness of resting on the

Fig 3. Blood loss during the first 24 postoper-ative hours was significantly reduced ingroup HC. In addition, requirements forblood and blood products were also signifi-cantly lower in the intervention group.(FFP 5 fresh frozen plasma; RCC 5 red cellconcentrate.)

Table 4. Hematologic Dataa

GroupHeparin(IU/kg)

PF 112 (nmol/L) Fibrinogen (g/L)b b-TG (ng/mL) d-dimers (ng/mL)

Pre-CPB Post-CPB Pre-CPB Post-CPB Pre-CPB Post-CPB Pre-CPB Post-CPB

Group C 311 6 5 1.09 6 0.16 3.5 6 0.68c 2.95 6 0.20 1.0 6 0.16c 160 6 13 1207 6 223c 282 6 66 2249 6 557c

Group HC 891 6 108 1.21 6 0.11 1.4 6 0.34c 2.33 6 0.20 1.13 6 0.13c 134 6 20 818 6 118c 218 6 67 857 6 220c

p value C vs HC # 0.001 0.58 0.02 0.03 0.05 0.28 0.40 0.50 0.05

a Data expressed as mean 6 standard error of mean. p values calculated for percent changes from baseline. b Note the significantly lower baselineconcentration of fibrinogen in the intervention group, when compared with the control. c p $ 0.01 post-CPB vs pre-CPB.

b-TG 5 b-thromboglobulin; CPB 5 cardiopulmonary bypass; PF 112 5 prothrombin fragment 112.

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sole ACT results for monitoring of anticoagulation. Anindividualized and integrated management of anticoag-ulation and its reversal during moderately hypothermicCPB based on the accurate maintenance of the targetheparin concentration and exact neutralization of theresidual circulating heparin results in less activation ofthe coagulation cascade, lower fibrinolysis, and reducedblood loss and need for homologous transfusions.

Further studies, on a larger number of children, arewarranted to confirm our observations and better definethe clinical impact of using a patient-specific heparin andprotamine administration protocol.

Doctor Codispoti is supported by grants from the British HeartFoundation and the National Heart Research Fund. We wish tothank Mrs Pam Dawson and Mr Ian Abbott for their finetechnical assistance with the hematological assays, Dr OrestisPapasouliotis for his expert advice on the statistical methods,and all the staff members of the cardiac team for their valuablesupport.

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3. Martindale SJ, Shayevitz JR, D’Errico C. The activated coag-ulation time: suitability for monitoring heparin effect andneutralization during pediatric cardiac surgery. J Cardiotho-rac Vasc Anesth 1996;10:458–63.

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6. Despotis GJ, Joist JH, Goodnough LT, Santoro SA, Spitzna-gel E. Whole blood heparin concentration measurements byautomated protamine titration agree with plasma anti-Xameasurements. J Thorac Cardiovasc Surg 1997;113:611–3.

7. Hardy JF, Belisle S, Robitaille D, Perrault J, Roy M, GagnonL. Measurement of heparin concentration in whole bloodwith the Hepcon/HMS device does not agree with laboratorydetermination of plasma heparin concentration using achromogenic substrate for activated factor X. J Thorac Car-diovasc Surg 1996;112:154–61.

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15. Gullinov AM, Redmond JM, Winklestein JA, et al. Comple-ment and neutrophil activation during cardiopulmonarybypass: a study in the complement-deficient dog. Ann Tho-rac Surg 1994;57:345–52.

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INVITED COMMENTARY

Codispoti and colleagues described the use of individu-alized heparin and protamine management in pediatricpatients undergoing cardiac surgery. The authors inves-tigated 26 infants and children being operated for repairof congenital cardiac defects with the use of CPB. In halfof the patients heparin management was guided by anindividualized and integrated management of anticoag-ulation (Hepcon HMS), in the other 12 patients standarddoses of heparin were applied. The heparin dosage wassignificantly higher in the study group (891 6 108 vs 3116 5 U/kg) while the protamine dosage necessary forcomplete heparin antagonization could be dramaticallyreduced by individualized titration (2.9 6 0.2 vs 8.6 6 1.4mg/kg). Patients in the control group received an ex-

tremely high dose of protamine. On the other hand, asstated, the ACT never fell below the limit of 480 secondsand heparin was only given when volume was added tothe pump prime. The authors found a better preservedcoagulation profile in the study group and reduced bloodloss and allogeneic blood requirement. This finding wasattributed to the individualized anticoagulation. Thestudy confirms that the ACT shows a wide variability alsoin a young patient group. The message from this study isthat the ACT is unreliable, high heparin levels attenuatethrombin formation more effectively than low levels, andprecise protamine reversal can reduce the protaminedosage.

There is only limited information in the literature

927Ann Thorac Surg CODISPOTI ET AL2001;71:922–8 ANTICOAGULATION DURING PEDIATRIC CPB

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2001;71:922-927 Ann Thorac SurgMassimiliano Codispoti, Christopher A. Ludlam, David Simpson and Pankaj S. Mankad

undergoing cardiac operationsIndividualized heparin and protamine management in infants and children

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