PAEDIATRIC CRITICAL CARE

Transfusion guidelines in
children: II

Learning objectives
After reading this article you should be able to:
C
describe how to reduce the need for blood transfusion in
children
C
have an appreciation for the different fluids which can be
administered instead of blood
C
describe possible adverse reactions from blood transfusion

Helen Jones
Katherine Reeve
Rachel Hartrey

Abstract
The avoidance of the use of blood products where appropriate can reduce
the incidence of adverse events. This article presents ways of achieving
this goal and introduces the process of the safe administration of
blood products where indicated.

given in major haemorrhage scenarios and commonly

included in massive transfusion protocols.

Intraoperative cell salvage. This is used in operations
where major blood loss is expected and has been shown to
reduce exposure to allogeneic blood. Reactions to the retransfused blood have occurred and are thought to be
due to leukocyte stimulation or circuit additives.

Keywords ABO antigens; children; colloids; crystalloids; intraoperative

cell salvage; transfusion
Royal College of Anaesthetists CPD matrix: 2A05; 3D00; 1E04; 1A02;
2D04

Perioperative fluid replacement

Normovolaemia needs to be maintained perioperatively as
hypovolaemia will reduce peripheral tissue perfusion before
signs of cardiovascular compromise are evident. The routine
infusion of excessive volumes of fluid in patients with minimal to
no deficit will result in interstitial expansion. Recent studies
suggest that the ratio of colloid to crystalloid is actually smaller
than was first thought for equivalent effect, that is, 1: <2 (not
1:3). Crystalloids probably enter the interstitium sooner than
colloids and therefore may be better suited to replace interstitial
losses. Colloids would seem more appropriate when intravascular volume is required but the choice of colloid is still debated.
It was previously thought that patients scheduled for surgery
have an obligatory fluid deficit as a result of preoperative fasting
and perioperative insensible losses. This led to the infusion of
considerable volumes of fluids perioperatively. This concept is
now being challenged and it is believed that patients have minimal extravascular deficit and a normal blood volume after
fasting for up to 8 hours. Even during major abdominal surgery
where large areas of bowel are exposed, the insensible and third
space losses are only believed to reach 1 ml/kg/hour at most as
opposed to the 10e20 ml/kg/hour that were previously estimated.3 One exception to this is where patients have received
bowel preparation preoperatively, which can cause significant
intravascular and interstitial deficits.
Often fluids are given perioperatively to combat hypotension.
This is usually due to vasodilatation secondary to anaesthetic
agents not due to hypovolaemia. In this circumstance small
amounts of an a-agonist vasoconstrictor may be more appropriate
than administering fluid. There is no evidence that the use of vasoconstrictors in this situation impairs blood flow to vital organs.
A study looking at mortality in African children with severe
infection and poor perfusion appears to challenge beliefs surrounding resuscitation with intravenous fluids. Children were
randomly assigned to receive boluses of 20e40 ml/kg body
weight of 5% albumin solution, 0.9% saline solution or no fluid
bolus. All children received intravenous maintenance fluids.
Their results showed that there was no benefit to fluid bolus

How to avoid transfusion

There are several ways to try to avoid the use of allogeneic blood
perioperatively, as follows.

Maximizing preoperative haemoglobin. This will allow a
greater degree of blood loss before transfusion is required.
Iron supplementation may be used if iron deficiency
anaemia is present. The use of recombinant erythropoietin
has been suggested but the evidence in favour is limited.

Preoperative autologous donation (PAD). Risks include
incorrect labelling, storage and administration of the
donated blood, wastage of donated blood, bacterial
contamination and preoperative anaemia.1

Acute normovolaemic haemodilution (ANH). This is indicated when major blood loss is expected. A significant
volume of blood needs to be withdrawn to reduce or avoid
the use of allogeneic blood transfusion.

Surgical technique, the use of tourniquets, diathermy, tissue glues and absorbable haemostatic agents.

Hypervolaemic haemodilution. The administration of large
volumes of fluid may dilute clotting factors and cause
interstitial oedema.

Tranexamic acid. The CRASH-2 trial (2010) highlighted the
benefits of antifibrinolytic agents in significant haemorrhage in trauma patients.2 Tranexamic acid is increasingly

Helen Jones MB ChB is a Paediatric Intensive Care Registrar at Starship

Childrens Hospital, Auckland, New Zealand. Conflicts of interest: none
declared.
Katherine Reeve BMBS BMedSci MRCP is a Paediatric Intensive Care
Registrar at Starship Childrens Hospital, Auckland, New Zealand.
Conflicts of interest: none declared.
Rachel Hartrey MB ChB FRCA is a Consultant Paediatric Anaesthetist at
Southampton University Hospital NHS Trust, Southampton, UK.
Conflicts of interest: none declared.

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3 years included incorrect blood component transfusion,

handling and storage errors and acute transfusion reactions.
A difference noted is the large reduction in cases of acute
transfusion reaction, largely believed to be due to a change in
definition excluding possible mild cases. A major learning point
from the report is the importance of blood prescriptions in ml/kg
and not units after two reports of children who were overtransfused. Some of the cases illustrate a need for improved
local protocols and communication to ensure clear pathways for
urgent provision of blood for neonatal and fetal recipients.
The clinical risks of blood product transfusion can be divided
into two groups, infective and immune. Whilst the infective risks
are of concern, it is the immune-related reactions that are most
common.11

therapy and there was an increased mortality in both the albumin

and saline groups compared to the no fluid bolus group.4

What fluid to give

The preferential use of either crystalloids or colloids during acute
resuscitation for hypovolaemic shock continues to be debated. A
large body of data supporting the use of hydroxyethyl starch
(HES) in volume resuscitation has recently been retracted
following questions of research study validity.
The Cochrane systematic review 2013, found that resuscitation
with colloids compared to crystalloids did not reduce the risk of
death in trauma, burns or surgical patients.5 Hydroxyethyl starch
(HES) was associated with an increased risk of renal failure, clotting abnormalities and death in critically ill patients. Following this
the Medicines and Healthcare products Regulatory Agency
(MHRA) released a statement withdrawing HES from clinical
practice within the UK.6 Blood, gelatine solutions and human albumin are the remaining colloids used in clinical practice. The
SAFE study in 2004 displayed similar primary and secondary
outcomes at 28 days in intensive care patients who received either
4% albumin or normal saline for resuscitation.7
The concern over dilutional-hyperchloraemic metabolic
acidosis has led to many clinicians using balanced crystalloid
solutions in preference to 0.9% sodium chloride despite the
clinical relevance still being unknown. Hyperchloraemia has
been associated with abdominal pain, renal impairment, coagulopathy and increased need for blood products. In patients
undergoing renal transplantation isotonic saline has led to
hyperkalaemia. This is the result of hyperchloraemic acidosis
mobilizing intracellular potassium and failure of its renal excretion, however this has not been reflected in other groups.8
Gunnerson et al. compared mortality rates in critically ill patients with dilutional-hyperchloraemic and lactic acidosis. The
mortality was highest among patients with a lactic acidosis
whereas a dilutional-hyperchloraemic acidosis had the same
mortality rate as the control group without any metabolic
disturbance.9 Overall there is a lack of evidence to justify the sole
use of balanced solutions, with only a limited amount of data
documenting the adverse effects of dilutional-hyperchloraemic
acidosis. An appreciation for fluid composition and indication
in certain pathologies must always be maintained.

Infective complications
Bacterial contamination of blood products is rare but in extreme
circumstances can cause septic shock. Platelets are commonly
implicated as they are stored at room temperature providing the
ideal culture medium. Viral contamination is exceedingly rare.
This has been achieved through careful screening of donors,
leukocyte depletion of all blood products to a level of 1  106
leukocytes per unit at the point of processing, providing red cells
in minimal plasma and specialized treatment of plasma products
themselves.
There have been only four cases of new variant Creutzfelde
Jacob disease infection as a result of transfusion in the UK.
However all children born after 1996 should be given imported
FFP or cryoprecipitate that has been treated with either methylene blue and light or solvent treated to prevent viral RNA and
DNA replication. There has been one report concerning a suspected allergic reaction to methylene blue treated FFP.
Immune reactions
Immune-related reactions can range from the mild to severe and
are usually related to leukocytes or antibodies in either donor
blood or the recipient. Blood products are now leukocyte
depleted and this has resulted in a reduction in febrile nonhaemolytic transfusion reactions that are usually caused by leukocytes, cytokines and human leukocyte antigens (HLA) in
donor blood.
Blood transfusion has been implicated in the increased frequency of postoperative infection, multi-organ failure, cytomegalovirus (CMV) transmission and spread of malignancy.
Mediators released from damaged donor white blood cells may
be responsible. Leukocyte depletion appears to significantly
reduce the incidence of these complications.

Transfusion of blood products

The transfusion of blood products to a child is associated with a
greater risk of harm when compared to an adult. The younger the
child the greater these risks are: 18:100,000 in all paediatric age
groups, increasing to 37: 100,000 in those less than 1 year of age,
this compares to 13: 100,000 in adults. These calculations are
based on red cell transfusion alone and do not take into account
risks posed by other blood products, in particular fresh frozen
plasma (FFP) and platelets. These may be significantly higher,
particularly in the paediatric age group.
The 2012 Serious Hazards of Transfusion (SHOT) report states
that 110 of the total 1645 reported incidents involved patients
less than 18 years of age.10 The overall picture in the last 3 years
is similar to the events listed in the 2009 report with the same
number of cases occurring. The commonest errors in the last

ANAESTHESIA AND INTENSIVE CARE MEDICINE 15:12

Antibodies and antigens: Red cells express hundreds of antigens

in addition to the ABO antigens. The Rhesus and ABO antigens
stimulate the greatest antibody response and thus most severe
haemolytic reactions. Antibodies to the main ABO antigens are
not induced but exist from birth. Antibodies (immunoglobulin G
(IgG) alloantibodies) to the other red cell antigens (minor antigens) are not present unless the patient has been exposed to
them, usually from transfusion.
Transfusion of ABO-compatible blood takes into account
which antigens will be present on the donor red cells and which
antibodies will be present in the recipients blood that can react

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to these antigens. A blood group A person will have A antigens

on their red cells and B (IgM) antibodies in their plasma and so
could receive either blood group A or O red cells (Table 1). If FFP
or platelets are required then preferably products of the same
group should be used, however this is not so important as these
will have had many of the ABO antibodies removed during the
processing of the product. Some authors advocate that infants
younger than 4 months of age requiring a transfusion should
ideally have a sample of their mothers blood sent at the same
time as their own for cross-matching. This is needed to detect
maternal antibodies that may have crossed the placenta into the
infants blood.
Blood group O mothers have both group A and B antibodies in
their plasma. These antibodies can cross the placenta and remain
circulating in the infants blood until 4 months of age. Due to the
initially weak expression of antigens on the childs red blood
cells only a mild haemolytic reaction may occur. The same is true
of the Rhesus antigen. However if a group A infant of a group O
mother is given blood group A red blood cells the maternal anti-A
antibody could cause severe haemolysis of the transfused red
blood cells due to the increased expression of adult red cell A and
B antigens. Thus it would be more appropriate to give the infant
blood group O red blood cells.
Severe acute haemolytic reactions usually occur as the result
of the wrong blood being transfused. Delayed haemolysis usually
occurs as a result of an antibody response to one of the minor red
cell antigens. Sometimes the levels of antibodies fall below
detectable limits and may not be identified by the pre-transfusion
cross-match.

to reduce the risk of TRALI, FFP and single donor platelets are
now often collected exclusively from male donors or women
without a history pregnancy.
Patients who are immunologically compromised, those
receiving or have received an intrauterine transfusion, or who
are closely HLA matched to the donor can develop Ta-GVHD.
Close HLA matching results in a failure of the recipients immune system to recognize donor lymphocytes as foreign therefore the recipient tissue is left vulnerable to attack. Donor
lymphocytes proliferate and damage target organs especially
bone marrow, skin, liver and gastrointestinal tract. This is
associated with a very poor outcome. g-ray irradiation of red
cells and platelets effectively inactivates donor lymphocytes. FFP
and cryoprecipitate do not need to be irradiated, as they are not
implicated in this condition.
Blood product prescription and administration
The correct volume of the correct blood product must be
administered to the correct patient over an appropriate time. The
appropriate dose for any blood product must be calculated according to the patients size and clearly prescribed to prevent
misinterpretation of millilitres for units (Table 2).
In neonates and small infants the use of products that are
split into smaller packs allow for incremental transfusion
and reduces exposure to multiple donors. This is particularly useful
if repeated transfusions are required over a period of a few weeks.
In an effort to reduce the risks highlighted in the SHOT report,
these articles hope to improve education in the specific transfusion requirements of children. Robust paediatric-specific protocols are required to reduce these risks along with the avoidance
of unnecessary transfusion. However, an appreciation needs to
be retained that appropriate transfusion not only reduces
morbidity but also mortality.

Transfusion-related acute lung injury (TRALI) and transfusion-associated graft-versus-host disease (Ta-GVHD): TRALI
and Ta-GVHD are both a result of donor antibodies attacking
recipient tissues. TRALI is characterized by donor antibodies
reacting to recipient white blood cells in the lung microcirculation. FFP has been the product most frequently implicated in
TRALI. Pregnancy can result in alloimmunization, therefore
plasma from multiparous women tend to be responsible. In order

Future developments
Alternatives to blood have been sought for more than 50 years.
Blood is not only involved in the carriage of oxygen but has

Choice of ABO group for blood products

Recipients ABO group

O (universal donor)
1st choice
2nd choice
A
1st choice
2nd choice
B
1st choice
2nd choice
AB
1st choice
2nd choice

Antigens on recipient red cells

Antibodies in recipient plasma

ABO group of compatible donor blood product

Red cells

Platelets

Fresh frozen plasma

Nil
e

AB
e

O
e

O
A,B

O
A,B,AB

A
e

B
e

A
O

A
B

A
A

B
e

A
e

B
O

B
A

B
AB

AB
e

Nil
e

AB
A,B

AB
A,B

AB
A

Table 1

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Transfusion volumes
Blood product
Red blood cells
1 unit w300 ml,
Paedipak I unit divided
into 4 or 8 small packs

Formula for volume to be transfused

Once MABL is reached administer 0.5 ml pRBC for every 1 ml of blood loss to
maintain haemoglobin at threshold level.
If wish to raise the haemoglobin then:
Volume to be transfused (Desired Hb g/dl e Actual Hb g/dl)  Wt (kg)  5
Thus 5 ml of pRBC (Hct 0.6) will increase Hb by 1 g/dl
Most top up volumes are 10e20 ml/kg

Platelets
Apheresis unit (1 donor)
w215 ml
Pooled unit (4 donors)
w300 ml

Fresh frozen plasma

Pathogen inactivated
1 unit 200 ml

Cryoprecipitate
1 unit 20e50 ml

Massive blood loss

1 blood volume loss 40% fall in platelet count
2 blood volume loss 60% fall in platelet count
3 blood volume loss 70% fall in platelet count
Transfuse after 1e1.5 blood volume loss
Child <15 kg 10e20 ml/kg
Child >15 kg 1 apheresis or pooled unit
Check clotting after 1 blood volume loss
Transfuse after 1e1.5 blood volume loss
APTT/PT >1.5 times normal
10e20 ml/kg
0.75 blood volume loss 50% fall
5e10 ml/kg
Maximum 10 units

APTT, activated partial thromboplastin time; PT, prothrombin time; MABL, maximum allowable blood loss; pRBC, packed red blood cells; Hct, haematocrit; FFP, fresh
frozen plasma.

Table 2

5 Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2013.
Issue 2. Art. No.:CD000567.
6 MHRA. Press release: MHRA suspends use of hydroxyethyl starch
(HES) drips. 27 June 2013, www.mhra.gov.uk/NewsCentre/
Pressreleases/CON287028.
7 Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and
saline for fluid resuscitation in the intensive care unit. N Engl J Med
2004; 350: 2247e56.
8 OMalley CM, Frumento RJ, Hardy MA, et al. A randomized, doubleblind comparison of lactated Ringers solution and 0.9% NaCl during
renal transplantation. Anesth Analg 2005; 100: 1518e24.
9 Gunnerson KJ, Saul M, He S, et al. Lactate versus non-lactate metabolic acidosis: a retrospective outcome evaluation of critically ill
patients. Crit Care 2006; 10: R22.
10 Bolton-Maggs PHB, Poles D, Watt A, Thomas D, Cohen H, on behalf of
the Serious Hazards of Transfusion (SHOT) Steering Group. The 2012
Annual SHOT Report. 2013, http://www.shotuk.org.
11 Klein HG, Spahn DR, Carson JL. Red blood cell transfusion in clinical
practice. Lancet 2007; 370: 415e26.
12 Mazurier C, Douay L, Lapillonne H. Red blood cells from induced
pluripotent stem cells: hurdles and developments. Curr Opin Hematol
2011; 18: 249e53.

many other functions. Therefore the development of a compound

that deals with only one element of this is compromised by other
side effects. Several of the proposed alternatives, including haemoglobin-based oxygen carriers (HBOCs) and fluorocarbonbased solutions have been associated with significant clinical
side effects including clotting abnormalities.
Advances in stem cell research has led to the in-vitro production
of red blood cells from induced pluripotent stem cells, although this
has only been in small numbers.12 The large-scale production of
functional red blood cells is at present not possible, but may hold
the future in the quest for a safe alternative to blood.
A
REFERENCES
1 Blood matters. The national blood service. Sep 2002. Issue 11. http://
www.blood.co.uk/pdf/publications/blood_matters_11.pdf.
2 CRASH-2 trial collaborators. Effects of tranexamic acid on death,
vascular occlusive events, and blood transfusion in trauma patients
with significant haemorrhage (CRASH-2): a randomised, placebocontrolled trial. Lancet 2010; 376: 23e32.
3 Jacob M, Chappell D, Conzen P, et al. Blood volume is normal after preoperative overnight fasting. Acta Anesthesiol Scand 2008; 52: 522e9.
4 Maitland K, Kiguli S, Opoko RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011; 364: 2483e95.

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