Age-related differences in heparin sensitivity and heparin-protamine interactions in cardiac surgery patients

Age-Related Differences in Heparin Sensitivity and Heparin-Protamine Interactions in Cardiac Surgery Patients Celia D'Errico, DO, Jay R. Shayevttz, MD, and Sarah J. Martindale, MBBS

Objective: The present study was conducted to determine how children and adults differ (if at all) with respect to sensitivity to heparin activity and heparinmprotamine interactions during cardiac surgery requiring cardiopulmonary bypass (CPB}. Design: A prospective study of both children and adults undergoing CPB. Setting: A tertiary care academic medical center between July 1992 and October 1994. Participants: Ninety patients who had cardiac or aortic arch surgery using CPB. The median age of the entire study sample was 15.8 years (range 2 months to 72 years). Intervention: Data were obtained using the Medtronic Hemotec Hepcon Hemostasis Management System (Englewood, CO). An ex vivo heparin dose-response (HDR) curve was generated for each patient before skin incision to determine the target heparin concentration (THC) needed to achieve an activated coagulation time (ACT) of at least 480 seconds. Protamine dose was determined on the basis of whole blood heparin concentration estimated by means of a heparin-protamine titration. Measurements andMainResults: The study population was divided into four groups based on age: infants (< 1 year), A I L U R E TO estabhsh appropriate levels of anticoagulatlon before and during cardiopulmonary bypass (CPB) may result in unwanted thrombosis or fibrinolysis.TM Heparin has been used as the anticoagulant of choice since the first operation using CPB was performed in a human m 1953. 5 The rapid onset of anticoagulant effect, easy reversibihty with protamine, and paucity of side effects in the doses and durations used for cardiopulmonary bypass have contributed to the popularity of heparin for this purpose. 5 The critical action of heparm is to prevent the formation of fibrin on stimulation of the coagulation cascade by binding to antlthrombln III and inhibiting thrombln activity.5 Heparin also has anti-factor Xa activity, likely via the same mechanism. 5 Protamine is a positively charged polypeptide that binds to free heparln and prevents the interaction between antithrombin III and heparln. 5 The optimal dose of heparln for CPB and the dose of protamlne needed to reverse the heparln have been subjects of some controversy. 6-12 Anticoagulation practices for children undergoing cardiac surgery were derived from those described for adults. However, the considerations that dictate anticoagulation criteria in adult CPB may not be valid in children for several reasons. The foremost contributor to these likely discrepancies may be the extremes of hemodilution that are encountered in pediat~-ic CPB. 13,14 Another reason for the likely discrepancies may be differences in the functional activity of the coagulation cascade between adults and children.15-i8 At birth, plasma levels of the vitamin K-dependent factors (II, VII, IX, X), the contact factors (XI, XII), and prekalllkrein and high molecular weight kininogen approach only 50% of adult levels. These factors remain depressed throughout childhood. I6,I7 Thrombln generation also is impaired in this population. 15Despite apparent deficiencies

F

preschool (1 to 5 years), school-age (5 to 14 years) and adults (>14 years). The mean _+ SD THC for the preschool group was 4.0 -+ 1.1; for infants, 3.3 -4- 0.7; for school-age, 3.1 +_ 0.7; and for adults, 3.4 _+ 0.7. The initial dose of heparin needed to achieve this THC (mean-+ SD} was significantly higher in infants (578 -+ 220 U/kg) and preschool children (477 _+ 159 U/kg) than in school-age children (327 _+ 57 U/kg) and adults (332-+ 64 U/kg). The ratio of protamine to heparin was significantly higher in adults (1.4-+ 0.5) and school-age children (1.3 -+ 0.6) than in infants (1.1 -+ 0.7) and preschool children (1.1 -+ 0.4). Conclusions: Pre-school children are less sensitive to heparin but also display a wider range of sensitivity. The data in this study support the use of 300 U/kg of heparin before CPB in patients _>5 years but suggest that heparin requirements may be greater in the younger patient who may require as much as 500 U/kg to achieve what is believed to be an appropriate target heparin concentration for initiating CPB.

Copyright © 1996 by W.B. Saunders Company KEY WORDS: cardiopulmonary bypass, heparin, protamine, monitoring m coagulation factors, children under the age of 14 years have been found to be less sensitive than adults to the effects of heparin. 16 The present study compares the target heparin concentration (THC) in children that would achieve an activating coagulation time (ACT) of at least 480 seconds with that in adults 2,4,I6 and the dose of protamine needed to neutralize the residual circulating heparln present at the end of CPB. The children were divided into three different age groups: infants ( < 1 year), pre-school (1 to 5 years), and school-age (5 to 14 years) Adults were defined as older than 14 years. The authors hypothesized that the target concentration of heparin necessary for children to achieve an ACT of at least 480 seconds would be higher than that required for adults and that the amount of protamlne used to neutralize this amount of heparin would increase proportionately as expected if empirical protocols were used for heparln and protamine administration. METHODS

Once approval was obtained from the Institutional Review Board, 90 patients admitted to the C.S Mott Children's Hospital (n = 70) or the University of Michigan Hospital (n = 20) for

From the Department of Anesthestology, Untverslty of Mtchtgan Medl~al School, Ann Arbor, MI, and Anaesthesta, Addenbrookes Hospaal, Cambridge, England Supported m part by grants from Mdes Pharmaceutzcals, Inc, and Medtrontc Hemotec, Inc. Address repnnt requests to Jay R Shayevltz, MD, Medical Dtrector, Pedtatnc Penoperattve Care, Providence Hospttal and Medwal Centers, 16001 W Nme Mde Rd, Southfield, M1 48075 Copyright © 1996 by W B Saunders Company 1053-0770/96/1004-000353 00/0

Journa/ofCardlothoraclc and VascularAnesthesta, Vo110,No 4 (June),1996' pp 451-457

451

452

D'ERRICO, SHAYEVITZ, AND MARTINDALE

The THC was determined by measuring an ex vivo heparin dose response in each individual patient The Hepcon HMS heparin dose-response (HDR) cartridge consists of 6 separate reagent chambers, each of which contains 0.1 mL saline buffered with 60 mM hydroxymethyl plperazIne-ethane sulfonic acid (HEPES), 50 mM calcium chloride, and sodium azlde, in which IS suspended 12% (w/v) kaolin. Pairs of reagent chambers contain progressively h~gher concentrations of beef lung beparin, from 0 to 1 5 to 2.5 U/mL. After the HDR cartridge is inserted into the warming block of the Hepeon HMS instrument, 0 4 mL whole blood is injected to each reagent chamber by means of a fully automated syringe pump The Hepcon HMS detects clot formation in the wells by measuring

the rate of fall of the plunger mechanism contained in each cartridge well. The plunger falls rapidly through unclotted blood but is Impeded as fibrin clot forms This rate change is detected by a photo-optical system located in the actuator assembly of the device, and a digital read-out is displayed furnishing the clotting time in units of seconds By using the principles described by Bull et al,4 a heparln dose-response curve is calculated The amount of heparm required to obtain an ex vivo ACT of 480 seconds is then determined, and, using the assumption that the volume of distribution of heparin is equivalent to the intravascular volume, the actual dose of heparln required to reach this ACT is computed and displayed as well Heparln levels are estimated m whole blood by means of heparin-protamlne titration (HPT), which uses similar technology This method involves adding 0 2-mL aliquots of an unknown heparmized blood sample to reagent chambers containing known concentrations of protamine and measuring the clotting time The reagent chamber containing the concentration of protamane that completely neutrahzes the heparin has the shortest clotting time. The heparln concentration can then be calculated based on the known concentration of protamine. The HPT cartridge reagent chambers contain 0.9% saline buffered with 60 mM HEPES and rabbit brain thromboplastin (0 25% to 2% of the concentration used in a laboratory prothrombxn time) as the activator Blood samples before and after CPB were obtained from the arterial line after 10 mL of blood were withdrawn and discarded. Samples during CPB were removed from the heart-lung machine circuit. The 3-mL blood sample for the HDR was obtained before skin incision in all patients. At the appropriate time. the heparin dose calculated by the Hepcon HMS on the basis of the HDR was administered to the patient, and a sample was obtained for ACT determination 3 minutes later ACT determinations were made using Hemochron kaolin tubes (ITC, Edison, NJ) because the activator in the Hepcon HDR and ACT cartridges was kaolin as well CPB was initiated if the ACT was ->480 seconds After heparin administration, HPTs were determined every 30 minutes for the duration of CPB During CPB, the THC as determined by the pre-CPB HDR was maintained by administration of additional heparm as needed. The ACT value remained greater than 480 seconds In all patients throughout CPB. As rewarmxng progressed at the end of CPB, the dose of protamine sulfate (Elkins-Sinn, Inc, Cherry Hill, NJ) needed to neutralize the residual heparln in the patient's blood was determined by HPT, on the basis of a 1.3 I ratio (mg:mg) of protamlne to heparln. Ten minutes after separation from CPB and administration of protamine, patients were tested for the presence of residual heparin by HPT and ACT determination. Any patients demonstrating residual heparin activity were again treated with the dose of protamxne as determined by the HPT. Data are expressed as mean +_ SD, unless otherwise noted. Results obtained from the four groups of study subjects were compared using analysis of variance. The Scbeff6 F test (significant at 95%) was used post hoc to determine between-group differences The ACT values were grouped and compared using the Kruskal-Walhs rank sum test and the paired t test;p < 0.05 was considered significant.

Table 1 Blood Volume Equations Used By the Hepcon HMS Device

RESULTS

cardiac surgery for congenital, lschemlc, and valvular heart disease were recruited between July 1992 and October 1994. For patients in the C.S Mott Children's Hospital for surgery, anesthesia was induced with fentanyl, 30 to 50 pxg/kg, intravenously, followed by pancuronIum, 0 2 mg/kg, to facilitate tracheal intubatlon. Pancuromum was administered perio&cally during the operation to maintam muscle relaxation, and fentanyl was administered as an infusion of 15 ~xg/kg/h for maintenance anesthesia Amnesia was provided by mldazolam, or volatile agent, as indicated After induction of anesthesia, intravenous and mtra-arterlal cannulae were sited For patients In the University Hospital, general anesthesia was Induced with fentanyl, 30 to 50 ~g/kg, midazolam, 5 nag, and vecuronlum, 0 2 mg/kg, to faclhtate tracheal lntubation Anesthesia was maintained using an infusion of fentanyl, 250 txg/h, midazolam, 1 mg/h, and vecuronlum, 10 mg/h. Appropriate monitoring lines (arterial, pulmonary artery, or central venous) were sited before induction of anesthesia. Porcine mucosal heparin (Elklns-Smn, Inc, Cherry Hill, NJ) was used for anticoagulatlon during CPB for all patients. The same team of perfuslonists managed all CPB procedures in both hospitals The CPB circuit prime consisted of Normosol R (components in mEq/L Na + 140, K ÷ 5, Mg2+ 3, C1 - 98, acetate 27, and gluconate 23 [Abbott Pharmaceuticals, North Chicago, IL]) and 5% albumin In 0.9% saline for patients weighing less than 40 kg, and Normosol R and 6% hetastarch In 0 9% saline for patients _>40 kg. The extracorporeal clrcmt prime volume for patients less than 10 kg was 500 to 800 mL; for patients 10 to 15 kg, 800 to 1,000 mL; for patients 15 to 20 kg, 1,000 to 1,500 mL, for patients 20 to 40 kg, 1,500 to 2,000 mL; and for patients over 40 kg, 2,000 to 3,000 mL. Porcine mucosal heparm, 100 U/kg for patients less than 40 kg or 10,000 U total for patients _>40 kg, was also added to the heart-lung machine circuit prime In all cases, heparin administration and protamlne reversal were managed using the Hepcon Hemostasls Management System (HMS; Medtronic Hemotec, Englewood, CO). Patients' height, weight, sex, prime volume of the extracorporeal circuit, and heparln content of the circuit prime were entered into the Hepcon HMS computer/calculator Patients recewlng heparln before surgerywere excluded from this study For patients weighing less than 45 kg and/or less than 142 cm tall, the blood volume was derived from a nomogram published in CIBA-Geigy Pharmaceuticals Scientific Tables 19For patients weighing _>45 kg and/or > 142 cm tall, the Allen equation was used to calculate blood volume (Table 1) 202i

Adult2O, 21

Blood v o l u m e

aH 3 4- bW - 30 mL

Pediatric 19

W x (92 5 m L / k g -

(mL) NOTE For men, a = 0000417, b = 4 5 0 ,

[H x 0 129 mL/kg]) for w o m e n , a = 0000414,

b=328 Abbrewataons H, hefght m cm; W, w e N h t m kg

D e m o g r a p h i c data for the study population are summarized in Table 2. T h e types of surgery w e r e diverse, and the CPB times varied widely (Table 3). T h e m e a n -- SD T H C (Fig 1) o b t a i n e d from the ex vlvo H D R for infants was 3.4 ± 0.7 U / m L ; for preschool, 4.1 ± 1.1; for school-age, 3.1 -+ 0 7; and for adults, 3.4 -+ 0.7. T h e

AGE AND HEPARIN IN CPB

453

Table 2 Demographic Summary of the Study Population

N Age (yr), median (range) Gender (% male) WeNht (kg) Blood volume (mL/kg) Hematocrlt (%) Basehne ACT (s) Post-CPB ACT (s)

Infant

Preschool

School-Age

Adult

12 0 3 (0 2-1 0) 75 6 3 + 1.7 83 6 -+ O 8 44 9 -+ 5 6* 142 _+ 22 140 _+ 22

37 2 2 (1 2-4 7) 38 11 9 _+ 3 3 81 4 -+ 1 3 43.6 _+ 5.1" 131 _+ 22 134 _+ 21

16 9 3 (5 8-13 8) 50 342 _+ 18 1 75.9 _+ 7 1 38.2 -+ 3 0 147 _+ 14 137 _+ 12

25 52 (16 8-72 2) 68 78 1 _+ 15.3 70 2 -+ 7.0 37 5 -+ 5.2 144 _+ 29 134 _+ 20

p Value

<0 <0 0 0

0001 0001 06 83

NOTE. The significantly higher mean hematocrit of the infants and preschoolers indicates the hNh proportion of patients with cyanotic congenital heart disease m these groups Abbreviations. hematocnt, preoperative hematocrit, ACT, activated coagulation t~me, CPB, card~opulmonary bypass. *Greater than m school-age children and adults,p < 0 01

THC was significantly higher in the preschool group than in any of the other three (p = 0.003). Also, the patient-topatient coefficient of variation was greater in the preschool group than in any of the others. The initial dose of heparin (excluding the heparin already present in the CPB circuit priming solution) as determined using the H D R (Fig 2) was significantly higher (p < 0.01) on a per kilogram basis in the infant (579 - 220 U/kg) and preschool (477 - 159) groups compared with the school-age (327 - 57) and adult (332 -+ 64) groups. The Table 3. Duration of CPB and Circulatory Arrest By Type of Surgery

Surgery Type

Circulatory CPB Time Arrest Time Number (mm -+ SE) (min _+SE, number)

RV-PA conduit Stage 2 and 3 HLHS repair LV-Ao condu~t Pulmonary stenosis repair Aortic valve/root/konno repair VSD closure BT shunt hgatlon/ASD creation A-V canal repair Tetralogy of Fallot repair Rastelh ASD repair (all) Thoracic aortm aneurysm repair Pulmonary artery stent Mitral valve replacement CABG Resection of IVC pheochromocytoma Closure of Fontan fenestration LV-PA conduit Pulmonary valve replacement Heart transplant

14 24 t 2 18 3 1 4 1 1 3

126 -+ 14 100 -+ 7 160 64 187 _+ 20 75 _+ 13 146 129 -+ 27 159 159 43 -+ 8

37, 2 43 _+ 3, 5

5 1 3 1

166 -+ 21 74 137 -+ 27 203

103, 1 29, 1

1 1 1 1 4

158 37 220 113 170 _+ 15

28, 1

Totals

90

132 _+ 7

152 _+ 74, 3

dose of heparin needed to achieve the THC (as determined by the initial ex vivo HDR) for patients over 5 years of age approached the 300 U/kg typically used for patients whose anticoagulation for CPB IS managed empirically; however, younger patients require a somewhat higher initial heparin dose. If these heparln requirements for commencement of CPB are considered, and an empirical protamine dose is calculated using a protamine:heparin ratio of 1.3:1, then infants would have received 7.5 -+ 2.9 mg/kg; preschoolers, 6.3 _+ 2.1; school-age children, 4.3 -+ 0.7; and adults, 4.3 __ 0.8. The standard empirical dose of protamine needed to neutralize an initial heparln dose of 300 U/kg is 3.9 mg/kg. The protamine dose, based on the residual whole blood heparin concentration measured by protamine titration at the end of CPB, is not significantly different among the four study groups (Fig 3; p = 0.22) When the protamine actually administered is compared with the protamine dose the patients would have received if it were determined on the basis of the initial heparIn dose, preschool patients received significantly less protamine (p < 0.0001) than the calculated dose.

.£

0

+i

3

-~,~?~-~ ~ ~

19, 1

66 -+ 19, 14

NOTE Only the means are reported for cells where n _< 2 Abbreviations. HLHS, hypoplastic left heart syndrome, RV, right ventricle, LV, left ventricle, Ao, aorta, konno, aortm root reconstruction, VSD, ventncular septal defect, BT, Blalock-Taussig; ASD, atrial septal defect; A-V, atrloventncular, CABG, coronary artery bypass graft; IVC, infenor vena cava, PA, pulmonary artery, Rastelh, external condu~t, right ventricle to pulmonary artery, VSD repair w~th blood flow baffled to aorta; CPB time, duration of cardlopulmonary bypass.

I,,-

0 INFANT

PRE -

SCHOOL -

SCHOOL

AGE

" ' ADULT

Fig 1 THC versus age group Preschoolers had significantly higher THC than any of the other three groups of patients This information implies that this group of children is less sensit,ve to the effects of heparin than the other patient groups Similarly, the preschoolers" responses to heparm were significantly more widely variable

454

D'ERRICO, SHAYEVITZ, AND MARTINDALE

900

2.0

800 U) +1 o') p.

1,8

700 600

+1

500

,m

¢1 o.

400

-r"

300

.m

200

1.6

(n

.9

1.4

n-

1.2

Q.

10

c "E

100

0.8

0 INFANT

PRE-

SCHOOL "

SCHOOL

AGE

ADULT

Fig 2. Initial heparin (U/kg) versus age group The infants and preschoolers were given significantly more heparm before initiation of CPB than the school-age children and adults The most likely reason for this difference is the greater blood volume in relatmn to total body mass m the youngest chddren.

Finally, the ratio of protamine to heparan (calculated on the basis of the amounts of protamine and initial heparin) was less for infants (1.1 -+ 0.7) and the preschool children (1.1 +_ 0.4) than for school-age children (1.3-+ 0.6) and adults (1.4 _+ 0.5). When the subjects were pooled into < 5 years of age and over 5 years of age groups (Fig 4), the difference between the groups m protamine:heparin ratio became statistically significant (p = 0.04). Similarly, the dose of protamine correlated strongly (Fig 5) w~th the initial amount of heparm administered to children < 5 years of age (r 2 = 0.57;p = 0.001) and those over 5 years of

e-

T=

0.6

o

0.4

a.

0,2 0 _<5

Y.O.

>5

Y.O.

Fig 4 Protamme'heparin ratio, -<5 years of age versus over 5 years of age. When the data are pooled into t w o groups, the younger patients receive less protamine as a proportion of the heparin administered than the older patients This difference could be related to the rate of heparin metabolism, the degree of heparm uptake by the vascular endothelium and reticuloendothelial system, or differences in the availability of protamine binding sites

age (R 2 = 0.63, p = 0.0001). By analysis of covariance, the slopes of the two regressions were significantly different, in agreement with the authors' previous conclusions regarding the protamine:heparin ratio. 1000 -

800

Cl u) +1

c~

E

[]

6

J

5

4 3

o

2

P r o t a m m e = -16 6 + 0 R 2 = 0 63 [] []

>5 y.o.

* * ~* ~

,~'f

.~

,,'",~""

i

¢-

"~=

014*Hepann, ~ /

600

200

0

- ;

~

y o

~ne = 1 0 6 + 0 008~Heparm R 2= 057

I III

II

10,000

tl

II

20,000

,111

iI

30,000

40,000

KI

Heparin Dose, U

0 INFANT

PRE -

SCHOOL -

SCHOOL

AGE

ADULT

Fig 3. Protamine (mg/kg) versus age group Despite the youngest groups recewing more heparin than the older in order to initiate CPB, no significant differences were apparent in the amount of protamme actually admimstered among any of the groups

Fig 5. Plot of protamine versus heparm, <5 years of age versus over 5 years of age Analysis of covariance showed a significant difference (p = 0.03) between the slopes of the regression lines, suggesting that the lines are not parallel The dashed lines represent the 95% confidence limits of the slope of the regressions This plot also demonstrates that less protamine is required per unit of heparin to neutralize residual heparin in the younger, compared with the older patmnts

AGE AND HEPARIN IN CPB

Values for ACT were obtained at baseline before skin incision, 3 minutes after administration of heparin but before commencement of CPB, 10 minutes after commencement of CPB, and 10 minutes after heparin neutralization. Baseline ACT values and those obtained after heparin neutralization were similar for each group of patients (Table 2). Because a substantial number of the ACT values were greater than 999 seconds both after heparin administration and 10 minutes after initiation of CPB, the data were compared using a nonparametrlc method (KruskalWallis). Each ACT value was assigned to one of the following four ranges: low (values of 450 to 599 seconds), medium (600 to 799), high (800 to 999), and off-scale ( > 1,000). Before initiation of CPB, but after administration of heparin, all subjects, except the school-age children, fell within similar ACT ranges. The ACT range of the school-age children (medium) was significantly lower (p = 0.03) than the range of the other groups (high). However, ten minutes after initiation of CPB, the ACT range of infants and preschool children was higher (offscale) than either of the other two groups (high range; p = 0.01). When patients were stratified by cardiac morphology (cyanotic v noncyanotic), the THC, initial heparin dose (U/kg), and the protamine dose (mg/kg) were not significantly different. The protamine:initial heparin dose ratio was significantly lower In the cyanotic (1.1 _+ 0.5) compared with the noncyanotie (1.3 -+ 0.5) children (p = 0.03), but this difference occurred likely because of the relatively high proportion of patients in the cyanotic group who were young. DISCUSSION

Requirements for pediatric and neonatal CPB differ greatly from those for adults, a7 Accordingly, neonates and older chddren may have different requirements for antlcoagulation and reversal of anticoagulation than do adults. Current empirical protocols in widespread use in pediatric CPB, however, are identical to those used m adult CPB. The goals of this study were, therefore, to determine how pediatric heparin and protamine requirements differ (if at all) from those in adults and to reappraise current empirical anticoagulation and heparin reversal practices used in neonates and children. Younger cardiac surgery patients exhibit distinctly different responses to both heparin and protamlne than older patients. Measurements of ex vivo heparln dose-response curves as well as estimations of whole blood heparln concentrations during CPB from both children and adults were obtained using an automated system (Hepcon HMS); however, this system is not necessary to perform these calculations. The THC required to achieve an ACT _>480 seconds in preschool children was 30% greater than in older patients. The initial dose of heparin needed to achieve this higher target concentration in preschool children approached 1.5 times the initial dose needed In older patients. However, in the infants whose THC was similar to the older children and adults, the initial heparin dose was similar to that admmistered to the preschool children. The initial dose of

455

heparin administered to infants and preschool children before CPB was similar to that reported by Dory et al, 16who showed that children less than 14 years of age require an average of 430 U/kg to achieve what is considered to be a safe ACT to initiate CPB. However, unlike the results of Doty et al, the present data indicate that children 5 to 14 years of age respond to heparin in a manner similar to adults. The present data also indicate that preschool children and younger demonstrate a significantly greater degree of individual variation in their heparin requirements than older patients. These differences in heparin sensitivity and individual variation in heparin response between adults and children may occur for several reasons. First, some of the differences between adults and children may be attributable to differences in the manner in which the Hepcon HMS calculates blood volume depending on weight and height. The 45-kg weight cutoff used by the device represents the 50th percentile at age 13 years; the 142-cm cutoff in stature represents the 50th percentile at age 10.5 years. 22 Children of this weight and stature would fall into the category of school-age, as defined by the present study. Thus, the blood volume calculations would likely not affect the groups in which most of the different results are observed. Second, younger children normally have a larger intravascular space relative to total body water than do adults, thus providing children with a relatively larger volume of distribution for heparin than adults. Third, the reticuloendothelial system and the vascular endothelium may bind heparin more avidly in children than in adults. This action would imitate a larger volume of distribution, or a faster rate of consumption. A fourth possible mechanism may be related to differences in the levels of antithrombin III, coagulation factors, and other heparin-binding plasma proteins present in children compared with adults. Although the levels of many coagulation factors are depressed in younger children compared with older children and adults, these factor levels may not be low enough to affect the tests of coagulation cascade function in the unstressed baseline state. However, antithrombm III levels may be low enough to affect individual patient sensitivity to heparin. 7,18,23-25Also, the discrepancy between calculated target and measured heparin concentration may have occurred because the Hepcon HMS system uses beef lung heparin to determine the THC, whereas porcine mucosal heparin was used for in vivo anticoagulation. All patients in the present study received porcine mucosal heparln; therefore, the difference between the age groups is likely unrelated to the choice of heparin used for anticoagulatlon. The greater patient-to-patient variability in individual heparin requirements in younger children emphasizes the increased importance of tailoring heparin therapy for CPB to individual requirements in younger children compared with adults, assuming current criteria used to judge adequacy of antlcoagulation for CPB are appropriate for both children and adults. Despite the generally greater amounts of heparin administered to infants and preschoolers seen in this study, the amount of protamine administered to these patients after separation from CPB was not significantly different from that used in the older patients. However, comparison of

456

D'ERRICO, SHAYEVITZ, AND MARTINDALE

protamine administered to protamine calculated on the basis of typical empirical protocols shows that significantly less protamine is administered when the blood heparin concentration at the time of protamine administration is considered. Similarly, the protamine:heparin ratio required for heparin reversal was significantly less in younger than in older patients. This information is important in order to minimize the dose of protamine administered to prevent accrual of the untoward effects of protamine itself.26-29In one study of two groups of adult patients undergoing cardiac surgery using CPB, one group received protamine in a fixed protamine: heparin ratio of 1.5:1; in the second group, protamine administration was titrated to the ACT. 26 The fixed-dose protamine regimen was associated with a greater volume of mediastinal shed blood and a more severe postoperative coagulopathy, which took longer to correct than in the group in whom protamine administration was titrated. 26 Besides this intrinsic anticoagulant effect, protamine is also capable of inducing anaphylactoid and anaphylactic reactions, pulmonary hypertension, and histamine release, thus creating the need to ensure that the amount administered is only as much as is necessary to reverse circulating heparin.27.28 Less protamine may be required than calculated from empirical protocols because the Hepcon HMS device may underestimate the blood heparin concentration. However, Despotis et al found that the results of a chromogenic plasma anti-factor Xa activity assay correlated strongly with the estimations of whole blood heparin activity obtained from the protamine titration method used by the Hepcon HMS device. 3° Second, the lower protamine:heparin ratio in the < 5 years of age group compared with the over 5 years of age group patients suggests either that the protamine administered is, in general, more "accessible" to the circulating, unbound heparin measured by the HPT, or that the heparin is more accessible to protamine, perhaps because less heparin is protein or antithrombin III bound. The baseline ACT remained similar across all age groups. After heparin was administered, all ACTs increased to over 480 seconds, although the ACT range in the school-age group was significantly lower than in any of the other three groups. However, after CPB was initiated, the ACT range

was significantly higher (off-scale) in the infant and preschool groups compared with that seen in the older children and adults (high). This effect may be related to the extreme hemoddution to which infants in particular are subjected at the study institution. 3~ Second, this effect may occur because of the relatively higher THC that was maintained in the preschool children during CPB compared with the THC in the other groups. However, it is apparent that the discreet ACT value or the ACT range is uncoupled from any relationship to blood heparin concentration in infants and preschool children during CPB. 32 No information is currently available to relate maintenance of a predetermined target heparin concentration (as opposed to a minimum ACT value or range) during CPB either to postoperative hemorrhagic complications or to thromboembolic complications in children. In conclusion, the present data systematically demonstrate differences among infants, preschool children, schoolage children, and adults in their respective responses to protamine and heparln for cardiac surgery using CPB. Children < 5 years of age are not only less sensitive but also have a wider range of response to heparin. The authors' data support the use of 300 U/kg of heparin before CPB in patients over 5 years of age but suggest that heparln requirements may be greater m the smaller patient, who may need closer to 500 U/kg to initiate CPB. The protamine required to neutralize circulating heparin in children < 5 years of age after separation from CPB is not significantly higher than that needed for older children and adults; however, the amount is significantly less than the calculated protamine dose, based on a protamine:heparin ratio of 1.3:1. Although residual heparin activity in the school-age children and adults was neutralized with a protamine:heparin ratio of 1.3:1, in the younger group of patients, this ratio was reduced to 1.1:1. Owing to inherent problems related to protamine use, titrating the protamine dose to either ACT or heparin concentration will likely serve to minimize the dose of protamlne administered. The relationship between use of higher doses of heparin and relatwely lower doses of protamine in younger children on the one hand, and their risk for postoperative hemorrhagic or thromboembolic complications on the other, remains to be determined.

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1. Kisker CT: Detection of fibrin monomer. Comparison of the immune precipitate method with the serial-dilution protamine sulfate test and the ethanol gel test. Am J Clin Pathol 72:405-409, 1979 2. Young JA, Klsker CT, Doty DB: Adequate antlcoagulatlon during cardiopulmonary bypass determined by actwated clotting time and the appearance of fibrin monomer Ann Thorac Surg 26:231-240, 1978 3. Dercksen SJ, Llnssen GH- Momtormg ofblood coagulation m open heart surgery. I. Effects of conventional dosages of heparin and protamine. Acta Anaesthesiol Belg 31'113-119, 1980 4 Bull BS, Huse WM, Brauer FS, et al" Heparln therapy during extracorporeal circulation. II. The use of a dose-response curve to mdivlduahze heparln and protamme dosage. J Thorac Car&ovasc Surg 69:685-689, 1975

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