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ISBT Science Series (2009) 4, 208–215

ª 2009 The Author.


ORIGINAL PAPER AC11 Journal compilation ª 2009 International Society of Blood Transfusion

Blood transfusions in neonatal cardiac surgery and ECMO


A. Brand
Sanquin Southwest & Leiden University Medical Center, Leiden, the Netherlands

the blood supply [3,4]. In neonates, approximately 20% of


Background
red blood cell (RBC) and most of the plasma products are
used for surgical procedures, of which cardiac surgery is
Patient population
the most common indication. The major reason for transfu-
Approximately 6–8 of 1000 newborns have a congenital sion in cardiac surgery is because the extracorporeal circuit
heart malformation often requiring surgery. Extracorporeal (ECC) needs to be primed with blood.
membrane oxygenation (ECMO) provides life support to Ten to 25% of neonates admitted to a neonatal intensive
patients with respiratory and ⁄ or cardiac failure. After car- care unit (NICU) receive one or more platelet transfusions
diac surgery ECMO is indicated in 0.5–3.5% of infants [1]. (PT). As compared with critically ill infants not receiving
Currently, 1–2% of critically ill newborns are treated by PT, the mortality rate was reported 10 times higher. In
ECMO. The most frequent indications for ECMO in newborns infants receiving 5 or more PT this risk increased almost 30
are meconium aspiration syndrome (MAS) and congenital times [5]. Infants on ECMO receive almost daily RBC and PT
diaphragmatic hernia (CDH), together accounting for more transfusions. A retrospective survey in the period 2002–
than 50% of ECMO procedures. Other indications are persis- 2007 among 12 329 neonates referred to several American
tent pulmonary hypertension associated with cardiac or NICU’s, identified 45 infants who had received more than
respiratory failure (PPHN), respiratory distress syndrome 20 units of PT. Almost half of these, 21 infants, because of
(RDS), patients failing to come off from cardiopulmonary ECMO [6], underscoring that infants on ECMO obviously
bypass after cardiac surgery and sepsis. An indication for belong to a multi-transfused group.
primary ECMO generally emerges on the second day after Both cardiac surgery and ECMO are associated with
birth and the median duration of treatment is approximately exposure of the infants to multiple donors.
8 days. The survival rate is, depending on the indication,
60% to over 85% as compared with an estimated mortality
Technical aspects of extracorporeal circuits
rate of 40–70% should ECMO not have been applied. Long-
term morbidity, after intra-cranial haemorrhage (ICH) or The volume of the ECC in relation to the infant’s circulating
chronic lung disease is however frequent. Based on a ran- blood volume often requires priming of the system with
domized study, the costs associated with ECMO were esti- blood to avoid unnecessary haemodilution. For cardiac sur-
mated approximately 75 000 pounds (level 1998) per infant gery, devices requiring lower priming volumes are becom-
without disability at 1 year follow-up [2]. ing available. Reducing the extracorporeal volume from
over 500 ml to less than 300 ml. and even as low as
130 ml, enabled even in small children of 5–10 kg blood-
Blood usage
less cardiac surgery in 55% of the cases [7,8]. Further
Although exact figures are lacking, in high income coun- downsizing is in progress. A decrease of the extracorporeal
tries, infants below the age of 1 year use less than 2% of volume will also benefit the extent of inflammation and of
the systemic inflammatory response syndrome (SIRS) fol-
lowing open heart surgery [8,9].
Correspondence: A. Brand, Sanquin Southwest & Leiden University
Medical Center, Leiden, the Netherlands All ECCs, using a roller pump or a centrifugal pump, cause
E-mail: a.brand@sanquin.nl haemolysis [10]. Haemolysis leads to an increase of plasma-
free haemoglobin (PfHb) and decrease of the haptoglobin
Abbreviations CDH: congenital diaphragmatic hernia; CPB: cardio-
scavenger. Free RBC constituents increase the systemic and
pulmonary bypass; EACA: epsilon amino caproic acid; ECMO: extra-
pulmonary vascular resistance, induce platelet dysfunction
corporeal membrane oxygenation; FFP: fresh frozen plasma; MAS:
and renal tubular damage. The use of special volume
meconium aspiration syndrome; PPHN: persistent pulmonary hyper-
adapted pump systems and coating of tubing and extracor-
tension associated with cardiac or respiratory failure; PT: platelet
poreal surfaces show promising effects reducing haemolysis
transfusion; RBC: red blood cells; RDS: respiratory distress syndrome; and thrombus formation [11]. However, increased degree of
TRALI: transfusion related acute lung injury; TXA: tranexamic acid. haemolysis and inflammation-induced capillary leakage

208
Neonatal cardiac surgery and ECMO 209

can still be expected in young children, extensive surgery, heart diseases, in which the haematocrit is high, autologous
ventricular assist devices (VAD) and ECMO because blood is blood has been withdrawn (12 ml ⁄ kg) after induction of
exposed to a relatively large ECC surface [12]. For infants anaesthesia prior to the ECC to avoid haemolysis. This
less than 3 months of age and for premature infants it will could avoid blood transfusion in 70–80% of cases of repair
remain difficult to circumvent transfusions. surgery [19]. A retrospective survey compared the use of
Besides haemolysis, a fall of approximately 40–50% of fresh whole blood with packed red blood cells for priming.
the platelet count is an inevitable consequence of ECC. Both For infants < 5 kg body weight, lower transfusion needs the
in cardiac surgery and in ECMO this happens immediately first 12 h after surgery (64% needed 1 unit) were observed
after connection to the circuit. After ECMO a nadir is after priming with fresh whole blood as compared with
reached after 3 days [13]. Besides, there is dysfunction of 85% of infants needing > 2 units, if the pump was primed
platelets, which become activated and at the same time with packed RBC [20]. Clinical outcome was similar in both
show impaired aggregation to agonist. Platelet function groups.
tests such as TEG are disturbed after cardiac surgery and There are a few prospective studies comparing priming
during ECMO [14]. In combination with heparinization to of the ECC with fresh whole blood or with reconstituted
prevent clotting in the ECC circuit, this may enhance the blood consisting of fresh or stored RBC and FFP.
risk for ICH, a severe but frequent complication during A prospective randomized study in 200 infants compared
ECMO [15]. fresh (< 48 h old) whole blood with reconstituted packed
In addition to cellular activation and damage, ECMO also RBC with FFP for pump priming. No difference in blood
causes biochemical changes. A frequent problem at initia- loss, in transfusion needs and clinical outcome was found.
tion of ECMO is hypercalcaemia (serum Ca > 11 mg ⁄ dl; The hospital stay was even shorter when reconstituted
> 2.74 mmol ⁄ l) affecting approximately one-third of neo- blood (the storage interval of RBC in this study was 6 days)
nates and associated with longer ECMO support and more was used. In this study, 40% of the infants were < 28 days
platelet transfusions [16]. old [21]. In a prospective study in 30 infants, priming with
On average, ECMO is applied for 6–8 days, with a wide reconstituted blood, containing fresh (stored < 5 days) or
range of 2–10 days. The daily need for RBC is 0.5–1 unit old (> 5 days) packed RBC in mannitol and adenine solu-
and 0.5–2 units of PT, besides plasma and other fluids. tion, was compared. Despite there was a storage-dependent
(ELSO: ExtraCorporealLifeSupport Organization registry). increase in potassium (from 5.4 to 18.4 mEq ⁄ l) in the
The use of PT in relation to the vascular access technique packed RBC, already 20 min after mixing and circulation
was studied in 234 infants treated for 7.9 ± 6.3 days [17]. with other priming constituents this difference had disap-
Veno-venous (VV)-ECMO was applied in 81 infants requir- peared and during surgery and upon arrival at the NICU no
ing daily 1.06 PT, whereas veno-arterial (VA, 138 infants) differences in pH, lactate, potassium, and glucose were
or the use of both techniques (15 infants) required an aver- observed [22]. Contradictory to the above-mentioned stud-
age number of 1.57 PT ⁄ daily. ies came a randomized study from Canada [23]. In 64
Recently, a case comparison study suggested that addi- infants, less than 1 month of age, the group transfused with
tion of continuous haemofiltration to ECMO may result in reconstituted fresh whole blood throughout the whole pro-
less days requiring ECMO (98 h compared with 126 h in cedure (priming, surgery and up to 24 h postoperative
historical controls) and fewer RBC transfusions (0.9 units ⁄ transfusions) had less chest tube blood loss (7.7 vs.
day as compared with 1.8 U ⁄ day), while PT (0.7 unit ⁄ day vs. 11.8 ml ⁄ kg) and improved clinical outcome with respect to
0.9 unit ⁄ day), fresh frozen plasma (FFP) usage and mortality ventilation (119 vs. 164 h) and hospital stay (12 vs.
(16%) was equal between the two groups [18]. 18 days) as compared with the group transfused with stored
reconstituted blood.
Specific transfusion problems in cardiac
surgery Antifibrinolytic treatment during cardiac surgery
Several questions related to transfusion supportive care are In adults, a Cochrane analysis summarized over 200 RCTs
regularly put forward, but few are definitely answered. that recruited 20 781 patients. The results showed a small
advantage of aprotinin, a serine protease inhibitor, reducing
operative blood loss, number of transfusions and need for
No blood, whole blood or fresh blood for priming of
re-exploration as compared with the lysine analogues, epsi-
the ECC?
lon aminocaproic acid (EACA) or tranexamic acid (TXA).
Cases of bloodless open-heart surgery in children In this analysis, the incidence of myocardial infarction,
> 3 months by priming of the circuit with crystalloids have stroke and renal failure were not higher in the aprotinin-
been published in Jehova’s Witness. In cyanotic congenital treated patients [24].

 2009 The Author.


Journal compilation  2009 International Society of Blood Transfusion, ISBT Science Series (2009) 4, 208–215
210 A. Brand

However, in newborns, the coagulation system, in partic- with platelets from children older than 12 months. The
ular fibrinolysis, differs from older children and adults [25]. clinical significance, for instance regarding the trigger for
On the use of aprotinin, EACA and TXA in newborns and platelet transfusion for the very small infants is unknown
infants to reduce blood loss in cardiac surgery, few prospec- [37]. Because platelet number and function are impaired
tive studies comparing these drugs have been performed. after cardiac surgery, there is concern about volume
In a RCT, comprising 320 patients, aprotinin was com- replacement with solutes affecting platelet function. In
pared with EACA or a combination in congenital cyanotic adults after open heart surgery, the use of hydroxyl ethyl
heart diseases. The results showed no difference between starch (HES 15 ml ⁄ kg) as compared with albumin did not
the two drugs with respect to bleeding, transfusion needs, result in obvious more chest tube drainage blood loss,
incidence of re-exploration and clinical outcome [26]. The despite HES prolongs clot formation in trombelastography
same group also compared EACA with TXA or placebo in (TEG) [38].
150 cyanotic infants and found both drugs evenly superior In a randomized clinical trial, 42 children undergoing
to placebo [27]. cardiac surgery were assigned to receive HES (130 ⁄ 0.4) or
The three drugs were compared in 100 infants with cya- FFP, both in a volume of 10 ml ⁄ kg after termination of car-
notic heart disease equally divided in four groups of 25 diopulmonary bypass (CPB). Endpoints were APTT, INR,
patients. No advantage for a combination of aprotinin blood loss and blood product usage until the first postoper-
(2 · 30 000 KIU ⁄ kg) with TXA (three times 100 mg ⁄ kg) ative day. Although the INR was significantly longer in the
was observed. TXA alone or aprotinin alone were equally HES group, postoperative blood loss and transfusion of
effective as the combination of both drugs [28]. blood products were not different between the two groups
In a review on this subject, no difference in amount of [39].
bleeding was reported between aprotinin, EACA and TXA. Regarding red cell transfusions it is a general assump-
Almost all studies reported less bleeding with the use of tion that after cardiac surgery there is a lower margin
antifibrinolytics as compared with placebo. However, the of safety for low Hb levels, because stroke volume,
studies did not allow a conclusion on safety [29]. Increased heartbeat and coronary blood flow are major compensa-
renal failure using aprotinin could not be confirmed in 200 tors to maintain tissue oxygenation. In neonates, oxygen
neonates and, as shown in other studies, the cardiopulmo- delivery is at near maximal levels and in case of a high
nary bypass time (if longer than 100 min) has the highest oxygen demand there is a risk of tissue hypoxia. How-
association with renal failure [30]. ever, although the relationship may not be causal,
despite improvement of oxygen transport by RBC trans-
fusions, these are also associated with increased postop-
Recombinant FactorVIIa
erative complications, in particular infections [40]. More
Studies examining rVIIa in neonates are limited and ran- than 90% of neonatal RBCs contain HbF, having
domized studies are not available. In most published cases, impaired oxygen delivery by a left shift of the oxygen
rVIIa was used for uncontrolled bleeding as compassionate dissociation curve [41]. After cardiac surgery, often more
need. Combined case series together comprising 44 infants than 50% of the RBCs carry HbA. The consequences of
below 1 year of age, reported cessation of bleeding in all this shift from HbF to HbA have however not been con-
cases except one case with surgical bleeding [31–34]. In an sidered in setting transfusion targets in newborns.
open label study in six infants with postoperative bleeding, Given the limited number of studies, firm conclusions for
re-operation because of bleeding was prevented [35]. Some priming and transfusion in neonatal cardiac surgery can
series observed no adverse effects, however, altogether at not be made, but:
least five thrombotic events occurred in these 44 cases, in • There is no high level evidence to prime the CPB circuit
particular, in combination with ECMO. with fresh whole blood.
• There is still controversy on the limitation of storage
time of erythrocytes for reconstituted RBC and FFP for
Transfusion support after surgery
priming the CPB circuit.
Shortly after bypass termination it is important to limit • Antifibrinolyic treatment reduces blood loss, number of
bleeding and optimize systemic oxygen delivery. Heparin, transfusions and need for re-exploration because of
hypothermia and inadequate protamine correction are bleeding.
important factors that contribute to bleeding and should • Lysine analogues (TXA, EACA) seem as effective as
be adequately treated [36]. Guidelines recommend to aim aprotinin to reduce bleeding.
at a platelet count > 100 · 10 E9 ⁄ l. Platelets of young • CPB bypass time (>100 min) is the major factor contrib-
infants (< 2 months of age) with congenital heart disease uting to blood loss, transfusion needs and postoperative
are less activated by cardiopulmonary bypass compared renal failure.

 2009 The Author.


Journal compilation  2009 International Society of Blood Transfusion, ISBT Science Series (2009) 4, 208–215
Neonatal cardiac surgery and ECMO 211

• rVIIa for compassionate need to be balanced in individ- used for platelet transfusions in ECMO are 80–110 ·
ual cases between benefit (prevention of re-exploration) 10 E9 ⁄ l [17,44].
and possible adverse thrombotic effects. Infants on ECMO receive PT in 30% of the cases
• Rapid degradable hydroxyethylstarch impairs platelet for bleeding symptoms and in 70% for prophylaxis [6].
function tests but is not associated with more blood loss The mechanism of platelet dysfunction induced by ECMO
or transfusions after cardiac surgery in infants. is incompletely elucidated. Besides thrombocytopenia
• Postoperative haemoglobin level may not be an appro- apparently due to consumption, platelets show a decreased
priate transfusion trigger if HbF ⁄ HbA ratio’s are not in vitro aggregability with collagen, and in vivo increased
taken into account. levels of soluble P-selectin and metalloprotease MMP-2.
MMP-2 is released from activated platelets and mediates a
new, nonthromboxane, non-ADP-dependent pathway of
Additional specific transfusion problems in
platelet aggregation. It has been shown that exposure to a
ECMO: bleeding and thrombosis
large artificial surface and oxidative stress during ECMO
Bleeding and thrombosis are major problems in ECMO induce release of MMP-2. This MMP-2 is purely derived
treatment and functional coagulation tests, such as from platelets through contact with the artificial surface
thrombelastography (TEG), shows the whole range without signs of endothelial activation as concluded from
between severe coagulopathies (DIC) to hypercoagulability absence of soluble E-selectin or vascular generated nitric
[42]. Intracranial haemorrhage is a major cause of neuro- oxide. [50].
developmental dysfunction and mortality in children Because transfused platelets during ECMO acquire the
using ECMO and is reported to occur in 10–52% of the same bypass-induced platelet dysfunctions as the patient’s
patients [43]. Risk factors for ICH are low pH, bradycardia circulating platelets, the value of prophylactic transfu-
< 80 min, hypotension (MBP < 30 mmHg), difficulties sions to prevent bleeding has been questioned [6,51].
to maintain the activated clotting time (ACT) between Comparing 1600 thrombocytopenic children (not only
190–210 s, lower platelet counts and the need of more infants on ECMO) in the NICU who –at the same level of
transfusions [15]. ICH may also be associated with larger thrombocytopenia-received or not received platelet trans-
intravascular volume administration in the first 24 h after fusions the authors concluded that platelet transfusions
starting ECMO [44]. In comparison to a historical control themselves were likely responsible for some fraction of
group, 42 newborns receiving EACA showed significant increased mortality in PT receivers [6,51]. The mortality
less bleeding and none developed ICH [45]. However, in a of patients receiving >20 PT is over 50% and most
double-blinded randomized study between EACA and pla- patients do not die from bleeding [6]. This poses a crucial
cebo in 29 neonates, five cases of ICH occurred (17.2%), dilemma for future studies.
without a significant difference (EACA 23% and placebo Concluding (intracranial) haemorrhage of the infant and
12.5%) between groups [46]. thrombosis of the ECMO circuit pose major challenges for
As compared with slightly older infants subjected to the balance between antifibrinolytic drugs, use of rVIIa and
open heart surgery, the newborn has an increased risk for transfusion support. However, clinical research is limited
bleeding and thrombosis the first week(s) of life [47]. and evidence-based conclusions are not possible:
Despite AECA, TXA and activated factor VIIa were • Antifibrinolytics during ECMO may not reduce the inci-
reported to have life-saving effects in individual cases and dence of ICH.
effective to reduce bleeding and transfusion needs, a lower • rVIIa may lead to more thrombotic complications in the
incidence of ICH during ECMO has not been demonstrated ECMO circuit.
and increased thrombosis at other sites has been reported • The appropriateness of prophylactic platelet transfu-
after the use of rVIIa. In a retrospective unmatched case- sions is questioned, because transfused platelets acquire
control study of 12 patients treated with rVIIa for severe platelet dysfunction.
bleeding after cardiac surgery and placed on ECMO, 25% of
patients developed thrombosis of which two with major
Special blood product requirements
thrombotic complications in the ECMO circuit [31]. Four
patients surviving after rVIIa, showed occlusion of the oxy- When blood products are transfused as relatively large vol-
genator in two cases, but this was not at variance with con- umes and at a fast speed, special complications should be
trols [48]. Another small report on four patients with anticipated:
ongoing bleeding despite aprotinin, rVIIa caused cessation High dose of citrate anticoagulant & preservative solution
of bleeding without excessive thrombosis [49]. Hypothermia due to refrigerated blood
Platelet transfusions still are the major treatment option Hyperkalaemia
to treat and prevent bleeding during ECMO. Trigger levels Depletion of 2,3 DPG in stored blood

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Journal compilation  2009 International Society of Blood Transfusion, ISBT Science Series (2009) 4, 208–215
212 A. Brand

transfusions could be tested 5 months after birth and none


Metabolic effects of massive transfusions
showed RBC antibodies [57]. Ludvigsen found no antibodies
Many clinicians routinely infuse calcium gluconate in case 3 months after transfusion of an average 8.9 units of RBC to
of massive transfusions. Hypothermia enhances cardiac 90 full-term infants [58]. Exceptions have been described.
dysrhythmia ⁄ asystole. Transfusion of cold blood has been An Rh-D negative neonate undergoing cardiac surgery at
associated with apnea, hypotension, and hypoglycaemia. 17 weeks of age produced anti-D after 2 PT from D+ donors
Moreover, the platelet function and coagulation processes [59]. Three case reports in newborns reported on allo-anti-E
may be impaired at temperatures below 34 C. at the age of 18 days and 11 weeks respectively and one
Hyperkalaemia is related to the shelf-life of RBC and anti-K detected at the age of 12 weeks [60–62]. Similarly,
with manipulations (centrifugation, irradiation) of RBC. Ishibashi et al. evaluated HLA antibody formation in 52
During storage of RBC, potassium leaks from the cell and at transfused preterm infants and reviewed the literature
the end of shelf-life (35–42 days) the potassium concentra- comprising > 150 patients, revealing virtually no antibody
tion can be as high as 50–70 mmol ⁄ l. Arythmia’s and formation [63].
cardiac arrest have been reported after bolus transfusion Because of the risk of later haemolytic disease of the
of stored blood in at least six case reports (reviewed by newborn of Rh-D alloimmunization, it is advised if Rh-D+-
[52]). For this reason, restriction of the storage time of RBC positive PT are given to Rh-D-negative female infants to
for 5–12 days is often recommended for (partial) exchange administer anti-Rh-D Ig. A single dose of 250 IU is suffi-
transfusions for infants and neonates [53]. However, such cient to cover five successive PT over a period of 6 weeks
serious events are presumably very rare, given the high [64]. For FFP and cryoprecipitate it is not necessary to take
potassium load often present in stored RBC. Parshuram the Rh-D factor because of lack of immunization potential
& Joffe measured a potassium concentration above of the small amounts of fragmented cells.
25 mmol ⁄ l in one-third of the RBC products stored Whereas the antibody formation of newborns is consid-
3–41 days (median 10 days). When measured after an ered negligible, as result from massive transfusions, passive
average interval of 75 min after transfusion in only in three immunity can cause adverse effects, such as haemolysis
children the K+-concentration reached > 5 < 6 mmol ⁄ l and transfusion-related lung injury (TRALI).
without clinical symptoms [52]. Six of 54 transfusions in A review revealed seven cases of severe passive haemol-
this study had been given as bolus of > 5 ml ⁄ kg ⁄ 10 min ysis due to ABO antibodies in PT reported since 1984 [65].
without events. A case of cardiac arrest in a 2-month-old The age of the recipients ranged from 8 months to 18 years
infant undergoing a Blalock-Tausing surgery is worth and three children died from the reaction. SHOT reported
mentioning. She received 120 ml over 10 min through a over a period of 10 years, six cases of severe reactions
central line in the inferior vena cava. The RBC had been in blood group A ⁄ B children receiving O platelets. Five
stored for 6 days, but had been irradiated 48 h prior to suffered from acute haemolysis and one developed a
transfusion. The potassium concentration in the unit was positive antiglobulin tests with spherocytes [66].
55.3 mmol ⁄ l and in the patient, withdrawn after observing In 2006, the BCSH published an amendment to the
ECG changes compatible with hyperkalaemia, 6.3 mmol ⁄ l guidelines for neonates and older children to avoid O plate-
[54]. Irradiation enhances potassium leakage, starting > lets for non-O recipients where possible and out of group
3 h after irradiation this process starts and reaches a peak platelets, e.g., O to A, B or AB recipients, should test nega-
after 3 days. It is prudent to limit the storage time after tive for high titres of anti-A ⁄ B [64].
irradiation as short as possible. An alternative is to remove TRALI is probably underreported in neonates and small
the supernatant and replace it prior to transfusion with infants. A review found approximately 10 published paedi-
FFP or preservation solution. However, although the atric cases of TRALI, of which only one in an infant of
potassium level decreases by saline-wash of RBC, this 4 months of age after cardiac surgery [67]. The authors
turned out to cause more haemolysis in the ECMO circuit warn against the use of maternal blood because of the like-
[55]. lihood that the mother possesses anti-leukocyte antibodies
A transfusion speed of 5 ml ⁄ kg ⁄ h, the usual speed for that may cause TRALI. In the SHOT analysis of 1995–2006,
top-up transfusions, causes no change in K+ levels, irre- 20 paediatric TRALI cases have been recorded, but the
spective the shelf-life of blood [56]. youngest was 2 years old. [66].
To prevent other adverse transfusion effects for which
neonates are particularly susceptible, such as CMV trans-
Immunological effects in newborns
mission and Graft versus Host disease, it is recommended to
Several studies showed that infants below the age of use leukocyte-depleted RBC and PT and to irradiate cellular
4 months hardly produce alloantibodies against red cells blood products with 25 Gy for newborn with a gestational
and leukocytes. Half of 53 preterm infants after multiple age < 32 weeks [53].

 2009 The Author.


Journal compilation  2009 International Society of Blood Transfusion, ISBT Science Series (2009) 4, 208–215
Neonatal cardiac surgery and ECMO 213

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