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Comparison of the Hemostatic Effects of Fresh Whole Blood, Stored Whole
Blood, and Components After Open Heart Surgery in Children
By Catherine S. Manno, Kathleen W. Hedberg, Haewon C. Kim, Greta R. Bunin, Susan Nicolson, David Jobes,
Elias Schwartz, and William I. Norwood
In a double-blind study, we compared the postoperative
(post-op) blood loss in 161 children undergoing open heart
surgery with cardiopulmonary bypass whose immediate
post-op transfusion requirements were met with either very
fresh whole blood (VFWB), 24- t o 48-hour-old whole blood or
reconstituted whole blood (packed red blood cells, fresh
frozen plasma [FFP], and platelets). Assignment t o treatment
groups was not strictly random but dependent, in part, on
the ability of families t o provide directed donors for fresh
blood. The three patient groups were comparable with
respect t o patient age, pre-op coagulation profiles (bleeding
time, prothrombin time, activated partial thromboplastin
time, platelet count, fibrin split products, fibrinogen, and
platelet aggregation tests) difficulty of operative procedures
and time spent on CPB. Mean 24-hour post-op blood loss in
milliliters per kilogram was 50.9 ? 9.3 in the VFWB group,
44.8 .t 6.0 in the 24- t o 48-hour-old group, and 74.2 & 8.9 in
the reconstituted group (P= .03). When blood loss was
compared in the 93 children less than 2 years of age, mean
blood loss was 52.3 f 10.8 in the VFWB group, 51.7 f 7.4 in
the 24- t o 48-hour-old group, and 96.2 .+ 10.7 in the reconstituted group (P= .OOl). For subjects who had received reconstituted blood, 30-minute and 3-hour post-op platelet aggregation responses to adenosine diphosphate (10 kmol/L) and
30-minute aggregation response t o epinephrine (2.5 p,mol/L)
were more depressed than in the VFWB and 24- t o 48-hour
groups (P < .001, P = .005, and P = .02). Comparison of
other post-op coagulation tests could not explain the increased blood loss in the reconstituted group. We conclude
that the transfusion of <48 hours old whole blood is associated with significantly less post-op blood loss than the
transfusion of packed red blood cells, FFP, and platelets in
children under 2 years old who underwent complex cardiac
surgery. The blood losses associated with the transfusion of
VFWB and 24- to 48-hour-old blood are comparable and may
be, in part, due t o better functioning platelets.
o 1991by The American Society of Hematology.
T
not proved to be a reliable predictor of post-op hemorrhage." As a result of these hemorrhagic tendencies, the
vast majority of pediatric patients who have OHS require
blood transfusion, despite the well-recognized complications associated with transfusion of blood products, including transmission of infections and transfusion reactions.
Approaches to limiting the number of donor exposures in
adults have included the use of autologous blood and cell
salvage techniques." Recent pharmacologic approaches to
limiting blood loss after CPB in adults have included the
use of 1-deamino-8-D-argininevasopressin (DDAVP), aprotinin, and dipymridam~le.'~.'~
Another approach, widely used in adult patients in Japan
and Israel, is the transfusion of fresh whole blood.16 The
hemostatic advantage of fresh blood over platelet concentrates has recently been reported in adult patients." The
clinical experience of pediatric cardiac surgeons has suggested that the severity and consequences of post-op
hemorrhage is minimized, particularly in small children
who have complex congenital heart disease, if post-op
transfusion needs are met with fresh whole blood rather
than stored blood components. Blood used within 6 hours
of collection has not required refrigeration and contains
platelets whose function has not been impaired by exposure
to cold." Because the practical difficulties of maintaining a
ready supply of fresh blood that has passed requisite
screening tests are numerous, and because blood components are readily available and are thought to be hemostatically equivalent to fresh whole blood, the use of components rather than fresh whole blood has been encouraged
by the blood banking community.''
To assess whether the use of fresh blood is associated
with improved hemostasis following cardiopulmonary bypass in infants and children, we performed a double-blind,
randomized trial comparing 24-hour blood loss in children
whose immediate post-op transfusion requirements were
HE ACQUISITION OF hemostasis in children who
have undergone open heart surgery (OHS) is an
important part of their postoperative (post-op) management. Bleeding that causes changes of intravascular volume
and hemodynamic instability immediately after cardiopulmonary bypass (CPB) can, particularly in the very young
child, adversely affect patient outcome. The amount of
post-op hemorrhage is a consequence of a complex interrelationship between the integrity of the surgically revised
heart and vessels, pre-existing coagulation defects in the
patient, and coagulationdefects induced by CPB. A variety
of hemostatic defects have been described in children with
cyanotic and acyanotic congenital heart disease including
thrombocytopenia, platelet dysfunction, disseminated intravascular coagulation, and an abnormality of the von Willebrand's fa~t0r.I.~
The techniques of CPB alter the coagulation system through the obligatory administration of heparin
and protamine sulphate as well as by contributing to
cellular alterations at the blood-surface interface in the
oxygenator and tubing. This contribution results in varying
degrees of fibrinolysis, thrombocytopenia, and acquired
defects of platelet f~nction.5.~
Preoperative screening has
From the Clinical Laboratories and The Department of Pediahics,
Anesthesia and Surgery, The Children's Hospital of Philadelphia; and
the University of Pennsylvania School of Medicine, Philadelphia.
Submitted March 20, 1990; accepted October 23, 1990.
Address reprint requests to Catherine S. Manno, MD, Assistant
Professor of Pediahics, The Children's Hospital of Philadelphia,
Department of Clinical Laboratories, 34th and Civic Center Blvd,
Philadelphia, PA 19104.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section I734 solely to
indicate this fact.
0 1991 by The American Society of Hematology.
0006-4971l91/7705-OO19$3.00l0
930
Blood, Vol77, No 5 (March l ) , 1991:pp 930-936
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931
COMPARISON OF HEMOSTATIC EFFECTS
met with either: Group I: very fresh whole blood administered less than 6 hours after donation (VFWB); Group 11:
whole blood administered 24 to 48 hours after donation;
Group 111: a combination of packed red blood cells (RBCs),
fresh frozen plasma (FFP), and platelets. These components, usually transfused individually, were combined for
study purposes only.
We also compared post-op coagulation values and results
of platelet function studies to see if these measures of
hemostasis differed among the treatment groups.
MATERIALS AND METHODS
Informed consent was obtained from the parents of each patient
before entry into the study. The experimental protocol was
approved by the Committee for the Protection of Human Subjects
at the Children’s Hospital of Philadelphia and reviewed by the
Compliance Branch of the Sterile Drugs and Biologics Branch of
the Food and Drug Administration (FDA) in Rockville, MD. All
children (newborn to 21 years old) scheduled for OHS with CPB
were eligible for study. The patients had congenital heart disease
who required palliative or reparative surgery of varying degrees of
surgical difficulty. The technical difficulty and operative risk of all
surgical procedures were graded by the attending surgeon as
simple, intermediate, or complex (see Table 1).
Randomization
Because of limited availability of VFWB from the Blood Bank
and the need to enroll equal numbers of subjects into each
treatment group, the following randomization schedule was devised. For patients whose parents agreed to participate in the study
and were able to provide directed blood donors, two thirds were
assigned to Group I (VFWB) and one third were assigned Group I1
(24- to 48-hour-old whole blood) using a series of sealed envelopes.
For patients whose parents agreed to participate in the study but
were unable to provide directed blood donors, one third were
assigned to Group I1 (24- to 48-hour-old blood) and two thirds
were assigned to Group I11 (reconstituted). For infants transported
to this institution for emergency surgery, assignment to the three
treatment groups was made on an equal basis using a separate
system of sealed envelopes. For these infants, blood was from
non-directed donors.
Preparation of Study Units
Blood or blood components were collected into standard blood
collection units containing citrate-phosphate-dextrose-adenine-1
(CPDA-1) solution. Typing and cross-matching were performed in
standard fashion. A sample of donor’s blood underwent requisite
screening tests for infectious disease transmission including rapid
plasma reagin (RPR), hepatitis B surface antigen (HBsAg),
hepatitis B core antibody (anti-HBc), human immunodeficiency
virus antibody (anti-HIV), and alanine aminotransferase (ALT)
level. Human T-cell leukemia virus-ID1 (HTLV-IDI) antibody
testing was added in March 1989.
Group Z. VFWB was whole blood less than 6 hours old. VFWB
was collected on the day of surgery from a donor who, the day
before donation, was prescreened and passed all required donor
testing. Study units were kept at room temperature until used or
for a maximum of 6 hours. Each transfused unit was screened in the
same manner. However, testing was not always completed before
transfusion. Release of VFWB before completion of screening
tests on that unit was approved by the FDA for study purposes only
and is not a routine procedure at this institution.
Table 1. Classification of Operative Procedures
Simple
Aortic valvuloplasty
ASD patch repair (closure of ASD)
Blalock-Taussig shunt’
Repair partial anomalous pulmonary venous return
Resection subaortic membrane
Intermediate
Closure of primum ASD with mitral valve replacement
ASD repair with mitral valve replacement
ASDNSD patch repair
Incomplete AV canal repair
Complete AV canal repair
Pulmonary valvotomy
RV outflow tract augmentation; repair total anomalous pulmonary venous return
Senning proceduret
Patch closure of VSD
VSD patch repair with resection coarctation of aorta
Complex
Arterial switch
Fontan procedure for various forms of single ventricle physiology*
Modified Glenn shunt§
Separation of aorta and pulmonary artery with VSD patch
repair (Truncusarteriosus repair)
Stage I palliation for hypoplastic left heart syndrome11
+Subclavianto pulmonary artery anastomosis.
t A n operation used in children with transposition of the great vessels
that redirects the venous return using an intra-atrialbaffle of autologous
tissue. The baffle directs the pulmonary venous blood across the
tricuspid valve into the right ventricle and to the aorta; the systemic
venous blood is directed across the mitral valve into the left ventricle
and to the pulmonary artery.
*An operation used in children with a single ventricle that separates
the pulmonary from the systemic circulation. This procedure is based
on the principle that the right atrial pressure is adequate to drive blood
through the lung, making a ventricle unnecessary.
§Superiorvena cava to right pulmonary artery anastomosis.
llPalliativeprocedure consisting of (1) transection of main pulmonary
artery, (2) creation of neoaorta, and (3) creation of systemic to pulmonary artery shunt.
Group ZI. Twenty-four- to 48-hour-old blood was whole blood
collected 24 to 48 hours before transfusion and was stored at 4 to
6°C until used.
Group ZII. Reconstituted whole blood contained components
of whole blood (one unit each of packed RBCs, platelets, and FFP)
which were combined to produce a unit of blood that was visually
indistinguishable from standard whole blood. A unit of packed
RBCs ( 5 5 days old) was brought from 4 to 6°C to room
temperature over a period of 2 hours. The unit was placed on a
platelet agitator (Helmer Labs, St Paul, MN) for 10 to 20 minutes
before reconstitution. A unit of 2- to 5-day-old random-donor
platelets that had been collected and stored in conventional
fashion was transferred into a thawed unit of FFP using a plasma
transfer set (Fenwal Labs, Deerfield, IL, code 4C2243) to prepare
platelet-rich plasma. The platelet bag was rinsed with plasma to
reduce the loss of platelets. Platelet-rich plasma was then transferred into an 800-mL size transfer pack unit (Fenwal Labs, code
4R2005). Finally, a unit of RBCs was transferred into the plateletrich bag. After the transfer was completed and components were
well mixed by hand, residual air was expressed into the empty RBC
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932
bag. The platelet-enriched reconstituted whole blood was stored at
22°C without disturbance for about 1 hour and then placed on a
platelet agitator until used. This product was available for transfusion when the patient came off CPB and was used within 6 hours of
reconstitution. All components were AB0 and Rho(D) group
identical.
Administration of Study Units
Two units of RBCs were prepared for each subject. The CPB
pump was primed with balanced electrolyte solution and whole
blood calculated to produce a final hematocrit of 25% during CPB.
At the termination of bypass, heparin effect was reversed with
protamine sulphate. From this point on, all volume requirements
as determined by blood loss and hemodynamic measurement were
met with the assigned study blood. The amount of study blood
administered varied according to individual patient needs, and was
not a predetermined dose. All study blood was passed through a
warmer to bring the temperature to 37°C. The surgeon was blinded
to the nature of the blood but the anesthesiologist was not. If
clinical complications arose, only the surgeon could ask to break
protocol before both study units had been administered.
Measurement of Blood Loss
Total blood loss was measured for 24 hours after the study blood
was administered. In the operating room, blood loss was determined by weighing sponges and measuring suction and chest tube
drainage. In the intensive care unit (ICU), blood loss was assessed
by measuring chest tube drainage.
LaboratoryAssessment of Coagulation
Bleeding times (Simplate; Organon-Teknika, Durham, NC)
were performed on the volar surface of the forearm immediately
pre-operatively, and 30 minutes and 3 hours after administration of
protamine sulphate. Blood samples were collected through a
flushed arterial line. The following laboratory tests were performed
immediately before CPB, and 30 minutes and 3 hours after
administration of protamine sulphate: platelet count, prothrombin
time, activated partial thromboplastin time (aPlT), fibrinogen,
fibrin split products (FSP), FVIII:RAg, and platelet aggregation in
response to adenosine diphosphate (ADP) (2 kmol/L), epinephrine (2.5 pmol/L), collagen (.047 mg/mL), and ristocetin (6
mg/mL).
Platelet counts were determined on a Coulter Plus IV electrical
cell counter (Hialeah, FL) from blood collected in EDTA. Prothrombin time and a P l T were measured on a Coag-A-Mate X2
(Organon-Teknika). Fibrinogen was measured by the dilute thrombin time method of Clauss.*’FSP were detected by latex agglutination technique (Thrombo-Wellcotest Kit; Burroughs-Wellcome,
Greenville, NC). vWF:Ag was measured by an adaptation of the
quantitative immunoelectrophoresis method of Laurel1 (Helena
Laboratories, Beaumont, TX).”
Platelet aggregation induced by ADP (BioData Corporation,
Hatboro, PA), epinephrine, collagen (BioData), ristocetin (Aggrecetin; Bio/Data), and epinephrine were studied using platelet-rich
plasma anti-coagulated with 3.8% sodium citrate, stored at room
temperature and tested within 60 minutes of collection. Platelet
concentration was adjusted to 200,000/1*.L. Changes in optical
density of the platelet-rich plasma were measured on a platelet
aggregation profiler (BioData). Results are expressed as percent
maximum aggregation recorded within 5 minutes of adding standard concentrations of the agonist.
MANNO ET AL
StatisticalAnalysis
Distributions of age, sex, surgical complexity (simple, intermediate, complex), length of time on bypass, and length of time in
circulatory arrest in the treatment groups were compared by x2
tests. Mean blood loss and mean pre-op coagulation studies were
compared among the three treatment groups by analysis of
variance. When the analysis of variance was significant, (ie, the null
hypothesis that the means for the three groups were the same was
rejected), pairwise comparisons of the groups were performed
using t-tests and the Bonferroni method of adjusting for multiple
comparisons. Multiple linear regression was used to investigate the
effects of several factors simultaneously on blood loss. Statistical
significance was set at .05. All analyses were performed with
statistical analysis systems.22
RESULTS
Patient characteristics for each of the treatment groups
are found in Table 2. A total of 161 patients were enrolled
between March 1987 and July 1989. Fifty-two subjects were
in Group I, 57 subjects were in Group 11, and 52 subjects
were in Group 111. Four children who died within the first
24 postoperative hours were not included in this analysis.
One of these patients died in the operating room and the
other three died in the ICU; none of these patients died of
overwhelming hemorrhage. Each of the three treatment
groups were comparable with respect to age, sex, and
percentage of cases in each category of surgical difficulty.
The groups were similar in terms of mean bypass time, time
of circulatory arrest, and the mean amount of blood
transfused per kilogram in the first 24 postoperative hours.
Comparison of the means for pre-op coagulation tests
(bleeding time, platelet count, prothrombin time, partial
thromboplastin time, fibrinogen, FSP, FVIII:RAg, platelet
aggregation studies) showed the groups were similar.
Blood Loss
Mean 24-hour blood loss in milliliters per kilogram was
50.9 ? 9.3 in Group I, 44.8 ? 6.0 in Group 11, and 74.2 ? 8.9
in Group I11 (f = .03) (Table 3).
Differences in mean blood loss varied among the groups
according to the age of the patient. Comparison of mean
24-hour blood loss for the 93 children less than 2 years old
showed the transfusion of reconstituted whole blood was
associated with 85% more blood loss than either of the
other products (f = .001). Comparison of mean 24-hour
blood loss for the 68 children greater than 2 years old did
not show a significant difference among treatment groups
(P = .41).
Differences in blood loss among the groups also varied
according to the difficulty of the surgical procedure. For
patients whose surgery was simple or of intermediate
complexity, no significant differences in blood loss occurred. However, for those undergoing complex surgery,
blood loss differed significantly, patients in Group I11
having the highest blood loss (f = .01). This difference was
even more pronounced when the children less than 2 years
old with complex surgery were considered (P = ,002); those
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933
COMPARISON OF HEMOSTATIC EFFECTS
Table 2. Patient Characteristics for the Three Treatment Groups
Group I
VFWB
Group II
24-48 h Old
Group 111
Reconstituted
Whole Blood
52
20
32
57
25
32
52
16
36
2.8 f 0.4
(0-8.2)
27
25
3.9 f 0.6
(0-19)
30
27
11
12
29
86.8 2 6.2
38.1 f 4.3
72.3 2 9.9
41
16
12
29
86.1 f 5.8
43.6 f 4.6
75.5 f 7.8
42
No. subjects
Female
Male
Ages
Mean 2 S.E. (y)
Range
No. < 2 y
No. > 2 y
Surgical difficulty
Simple (no. subjects)
Intermediate
Complex
Mean time 2 SE on bypass (min)
Mean time f SE of circulatory arrest
Mean volume blood given (Cm3/kg)in 24 h
No. of subjects with circulatory arrest
3.8 2 0.8*
(0-20)
36
16
9
12
31
84.2 f 5.lt
37.2 f 3.7$
97.4 5 9.60
39
*P = .37.
t P = .94.
SP = .51.
§P = .11.
in Group I11 experienced about twice the blood loss of the
other two groups.
When the effects of blood loss of age, surgical complexity,
and type of blood product were investigated simultaneously
using multiple linear regression, blood product and surgical
complexity were statistically significant predictors (P = .02
and P < .001, respectively). Reconstituted blood was associated with an 18 mLikg increase and 24- to 48-hour-old
blood with a 3 mLkg decrease in blood loss compared with
VFWB. Compared with simple surgery, complex surgery
increased blood loss by 38 mLikg and intermediate surgery
by 4 mL/kg.
Laboratory Evaluation
Changes in bleeding time, platelet counts, prothrombin
time, aPlT, fibrinogen, FSP, and FVIII:RAg, which are
expected following surgery with CPB, were seen in all
Table 3. Blood Loss [mL/kg) (mean f SE) by Age, Surgical Difficulty, and Both
BY age
All ages
<2 Y
Group II
24-48 h
(93)
(68)
50.9 2 9.3 (n = 52)
52.3 2 10.8
(27)
49.4 f 15.6
(25)
44.8 f 6.0 (n = 57)
51.7 f 7.4
(30)
37.2 f 9.7
(27)
(36)
(36)
(89)
16.3f 4.6
24.9 f 6.3
74.8 f 15.0
31.2 f 15.2
33.5 f 6.0
57.1 2 7.6
(n = 161)
22Y
By surgical difficulty
Simple
Intermediate
Complex
By age and surgical difficulty
Simple
Intermediate
Complex
Simple
Intermediate
Complex
Group 111
Reconstituted
Whole Blood
Group I
VFWB
(22)
(22)
(22)
(11)
(12)
(29)
PValue"
74.2 f 8.9 (n = 52)
96.2 f 10.7
(36)
24.6 f 6.0
(16)
.03t
.001*
NS
(16)
(12)
(29)
15.8 f 7.0
32.9 f 7.2
107.1 2 11.2
(9)
(12)
(31)
.01§
(8)
(22)
36.2 2 9.8
110.7 f 11.6
(7)
(29)
.00211
(16)
(4)
(7)
15.8 f 6.9
28.4 f 11.4
54.8 f 0.2
(9)
(5)
(2)
NS
NS
NS
NS
NS
No patients
27.9
62.6
9.2
f 14.3
(19)
39.8 2 7.9
56.1 f 9.6
16.3 f 4.5
18.9 f 4.6
98.0 f 34.2
(11)
(4)
(10)
31.2 f 15.2
21.0 f 5.0
60.1 f 10.4
2
(8)
Abbreviation: NS, not significant.
*Significant pairwise differences by the method of Bonferroni were as follows:
tll v 111.
*I v 111, II v Ill.
011 v 111.
111 v 111, II v 111.
NS
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934
MANNO ET AL
Table 4. Mean Laboratory Values: All Ages
Bleeding time (s)
Platelet count
( x 1OYL)
Prothrombin time (s)
aPl7 (s)
Fibrinogen (mg/dL)
FSP (mg/mL)
F.VIIIR: Ag (%)
Pre-op
30 min
3h
Pre-op
30 min
3h
Pre-op
30 min
3h
Pre-op
30 min
3h
Pre-op
30 min
3h
Pre-op
30 min
3h
Pre-op
30 min
3h
Group I
VFWB
Group It
24-48 h
Group 111
Reconstituted
Whole Blood
P Value
253.1 f 18.2
296.5 f 28.1
347.5 f 32.0
291.7 t 14.9
171.2 t 8.5
207.6 t 11.9
11.4k 0.2
12.4 2 0.2
12.3 k 0.2
34.6 f 1.0
38.2 f 1.1
35.3 f 1.5
217.7 k 7.0
201.5 t 5.4
207.6 k 11.9
2.6 t 1.0
14.5 f 6.3
17.7 f 5.3
143.7 t 14.0
170.0 f 10.1
235.0 k 14.7
308.0 f 22.2
353.2 t 25.6
377.9 t 30.7
304.0 t 14.3
145.6 t 7.2
174.4 f 9.0
11.0 f 0.1
12.2 f 0.2
11.6 f 0.2
35.4 k 0.9
39.7 k 3.4
33.0 t 1.1
214.2 t 8.0
195.1 k 5.6
209.0 f 6.1
2.3 f 1.2
8.2 f 3.1
6.0 f 1.7
115.5 t 8.2
165.2 t 8.3
246.8 f 14.3
252.7 t 20.6
346.4 t 30.8
363.4 t 32.2
291.8 t 17.0
163.4 t 8.4
182.6 f 9.3
11.4 f 0.3
12.7 t 0.2
12.3 t 0.2
35.3 f 1.0
43.3 f 1.8
36.4 f 1.4
197.0 f 7.8
184.0 f 4.8
195.1 t 6.3
1.8 t 0.6
7.0 t 2.4
6 . 8 k 1.5
116.9 f 15.5
145.5 8.4
214.0 f 16.4
NS
NS
NS
NS
.05
.05
NS
NS
.01
NS
.06
NS
NS
.07
NS
NS
NS
.02
NS
NS
NS
Mean f standard error.
treatment groups (Table 4). Mean activated clotting times
measured 30 minutes after protamine were similar in all
treatment groups (P = .92). Thirty minutes after protamine, subjects in Group 111 had a longer mean aPTT and a
lower mean fibrinogen concentration ( P = .06 and .07) in
comparison with the other groups. Comparison of other
mean post-op laboratory values at 30 minutes and 3 hours
showed differences among the groups (platelet counts at
both times, prothrombin time at 3 hours, and FSPs at 3
hours). Reconstituted blood was also associated with the
most abnormal platelet aggregation studies at 30 minutes in
the presence of the agonists ADP, epinephrine, and collagen (P < .001,P = .02, a n d P = .007). ADP-induced aggregation at 3 hours was also significantly reduced in the
reconstituted group (P = .005).
DISCUSSION
Avoiding excessive hemorrhage after OHS with CPB in
children is an important factor in improving surgical outcome. Although many approaches to limiting post-op hemorrhage have been tried, no single approach has proven
uniformly successful. In our study, children less than 2 years
old who had complex surgery derived the greatest benefit
from whole blood less than 48 hours old. Compared with
the repair of simpler defects, complex congenital heart
defects require more extensive reconstruction and more
time on CPB. These factors result in larger blood lossesz3
putting the patients at higher risk for hemodynamic instability. Although our pediatric patients always require RBC
transfusions following surgery, the use of a product that
optimizes hemostasis and thereby decreases blood loss will
lessen the amount of blood replacement required following
surgery and help to reduce donor exposure. Comparison of
blood loss for children older than 2 years old did not show a
difference among the treatment groups. However, this
result may be a reflection of an inadequate sample size. The
finding for young children was highly significant and corroborated the impression of some cardiac surgeons. However,
as a larger effect on young children was not a formally
stated hypothesis a priori, this finding should be interpreted
cautiously.
The randomization method used in this study was forced
by institutional practicalities and was adopted to provide
study units and to allow enrollment of equal numbers of
patients in each treatment arm. Enrollment into Group I
required that families provide directed donors of the study
blood product and enrollment in Group I11 was for those
who could not provide donors. Half of the families of
patients in Group I1 provided donors and half did not. The
issue of providing donors was not applied to infant subjects;
the donor pool at this institution provided these study units.
There were small differences in the mean age and sex
distributions of the study groups; after statistical adjustment for age and sex, the difference in mean blood loss
among the groups was still significant. However, the compromise forced on the randomization may have led to unequal
distribution of unknown patient characteristics among the
patient groups and may have affected the outcome.
Many abnormalities in hemostasis that follow CPB have
been de~cribed.’~.’~
Although levels of most plasma coagulation factors fall below pre-op values (especially Factor V),
these reductions are generally not severe enough to be
associated with clinical bleeding.z6We observed prolongation of the mean protime and mean a P l T in all of our
treatment groups after CPB. However, the transfusion of
reconstituted blood was associated with a longer aPTT at 30
minutes and prothrombin time at 3 hours than either other
treatment group. Because the transfusion of FFP is ex-
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935
COMPARISON OF HEMOSTATIC EFFECTS
pected to deliver amounts of plasma coagulation factors
analogous to those found in whole blood,” the cause of
these differences is not clear. Although the comparison of
mean post-op platelet counts at 30 minutes and 3 hours,
prothrombin time at 3 hours, and FSP at 3 hours showed
significant differences among the groups, the pattern of
these differences does not help to explain increased bleeding observed in Group 111, as thrombocytopenia was more
pronounced in Group 11, prothrombin times equally prolonged in Groups I and 111, and FSP was higher in Group I.
The effect of CPB on platelets has been intensively
studied. CPB is responsible for a transient decrease in
platelet count because of dilution and mechanical platelet
damage.9 Platelets become activated as they pass through
the bypass apparatus. Clinical bleeding has been reported
in association with platelet alpha granule release and
decrease in levels of platelet secretory ADP.= In vitro
abnormalities include loss of fibrinogen receptors from the
platelet surface as well as defective aggregation to ADP,
collagen, and ristocetin.2”MSome children with congenital
heart disease have decreased platelet aggregation responses to ADP and collagen when studied outside of the
peri-op period.’ For the group of patients we studied, in
vitro platelet function was normal in all groups before
surgery and deteriorated most significantly in the patients
who had received reconstituted blood. Mean pre-op bleeding times were all within the normal range; the means
increased in the post-op period but remained in the normal
range. The acquired dysfunction of these already impaired
platelets probably contributes to bleeding from sites of
surgical damage, despite normal bleeding times.
Mohr et a1 have suggested that blood loss following CPB
is the same when patients are transfused with either one
unit of fresh blood or 10 units of platelet concentrate^.'^
Lavee et a1 have shown that transfusion of fresh whole
blood after CPB gives the same increase in platelet count as
six units of platelet concentrates and that the platelets in
fresh blood retain better function than those in concent r a t e ~The
. ~ ~platelets contained in VFWB are not subject to
the damage inherent in concentrate preparation and storage.32The platelets in our reconstituted product had been
prepared and stored as platelet concentrate and undoubtedly lost some of their function. The standard approach to
blood replacement after OHS is to give the element of
blood which is lacking. In this study, reconstituted blood
contained the components of whole blood that are usually
administered separately. The purpose of creating this
product was to offer a standard therapy arm while blinding
the observer to the nature of the blood product. We
acknowledge that this product may not have contained
platelets in equal number or with equal function to the
platelets in fresher whole blood. Although the platelets in
24- to 48-hour-old blood have not undergone centrifugation
and concentration, they have been refrigerated at 4°C for at
least 1 day and their function is presumably significantly
impaired.” Our study shows that the blood loss associated
with the transfusion of VFWB and 24- to 48-hour-old whole
blood are the same.
Concern over the use of directed fresh blood has been
raised by recent reports of fatal graft-versus-host disease
(GVHD) in immunocompetent adult patients who have
received viable lymphocytes in a transfusion of fresh blood
from a close r e l a t i ~ e . ’ ~The
. ~ ~ American Association of
Blood Banks has suggested that directed blood donations
from first degree relatives be routinely irradiated to minimize the threat of GVHD.” Because the bulk of VFWB is
drawn from directed donors and processing of this product
must occur within 6 hours of donation, the routine procurement of directed fresh blood is difficult and, occasionally,
incompletely screened blood is requested. Meeting post-op
cardiac surgery transfusion needs with 24- to 48-hour-old
blood eliminates the need for release of untested, very fresh
blood. Day-old fresh blood can be screened for infection
and supplied to the operating room more easily and from
sources other than directed donors. GVHD is not a risk
following transfusion of blood whose lymphocytes have
been inactivated with i r r a d i a t i ~ nand
~ ~this procedure could
be routinely accomplished for directed 24- to 48-hour-old
fresh blood.
In summary, the transfusion of whole blood less than 48
hours old in children less than 2 years old who had complex
OHS was accompanied by significantly less post-op hemorrhage in comparison with stored blood components. The
benefit of fresh blood may be because of the presence of
better functioning platelets. We have also found that whole
blood less than 6 hours old and whole blood that is between
24 and 48 hours old have a similar hemostatic effect. Older
fresh blood can be thoroughly screened for infection, stored
for routine and emergency transfusion, and could be
irradiated to eliminate the risk of GVHD inherent in very
fresh blood from directed, family donors. Our current
practice is to use screened, refrigerated 24- to 48-hour-old
whole blood for early blood replacement requirements
following complex OHS with CPB in children. Another
approach to decreasing blood loss after OHS suggested by
the results of this study might include finding ways to
improve the function of the platelets in stored platelet
concentrates.
ACKNOWLEDGMENT
The authors thank Joan Grady and Debbie Jones for secretarial
assistance, Dr Morty Poncz for technical assistance, and Drs Alan
Cohen, Bruno Manno Jr, Michael Laposata, and Jeffrey Silber for
their valuable advice.
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Comparison of the hemostatic effects of fresh whole blood, stored
whole blood, and components after open heart surgery in children
CS Manno, KW Hedberg, HC Kim, GR Bunin, S Nicolson, D Jobes, E Schwartz and WI Norwood
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