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Risks of perioperative Learning objectives


blood transfusions After reading this article, you should be able to:
C describe the risks associated with perioperative transfusions
Nicola Redding C outline the indications for a blood transfusion including the
Dianne Plews current transfusion threshold
C discuss the alternatives and adjuncts to blood transfusion

Abstract
Blood transfusions are remain amongst surgical patients, but despite
transfusion being safer then it ever has been, it still poses significant transfusion reactions. These result from interactions between
risks. These can be enhanced in the perioperative period where iden- antibodies in the recipient’s plasma and surface antigens on
tifying complications can also be more challenging. This article out- donor red cells. There are numerous red cell antigens but they
lines the risks associated with perioperative transfusions and differ in their potential for immunisation resulting in a spectrum
discusses the current recommendations for transfusion and use of al- of haemolytic reactions (Figure 1).
ternatives to blood transfusion.
Keywords Blood; perioperative; transfusion Acute haemolytic reactions
The most serious haemolytic reactions are caused by ABO-
Royal College of Anaesthetists CPD Matrix: 2A05 incompatible red cell transfusions and are associated with
major morbidity and mortality, 30% and 5e10%, respectively.2
They are predominantly caused by human error.1 Recent esti-
mates suggest that 1:2000 samples received by the laboratory are
Blood transfusions can be life saving, but despite being safer than labelled with the wrong patients information (wrong blood in
it ever has been, transfusions still pose significant risks. A total of tube).3 If an acute haemolytic reaction is suspected the trans-
3568 events were reported to the UK Serious Hazards of Trans- fusion laboratory should be informed immediately as another
fusion (SHOT) in 2013 with 165 cases of major morbidity or patient may be at risk of receiving the wrong blood.
mortality attributable to transfusions.1 It is essential unnecessary
Transfusion-associated circulatory overload (TACO)
transfusions are minimized and that clinicians are highly vigilant
TACO is defined as acute or worsening pulmonary oedema
for signs of transfusions reactions.
within 6 hours of transfusion. Management involves stopping the
Serious complications of allogeneic blood transfusion are
transfusion and administering oxygen and diuretics/nitrates as
outlined in Table 1 and are discussed in more detail below.
appropriate.
Identifying these adverse reactions can be more challenging in
This preventable complication of transfusion was the most
the perioperative setting, as the presentation is often non-
common cause of transfusion-related major morbidity and mor-
specific, especially in anaesthetized patients and can initially
tality reported to SHOT in 2013. Better pre- and post-transfusion
mimic conditions that are prevalent in the surgical setting such as
assessments could reduce this risk. TACO is much more common
haemorrhage. All adverse reactions attributable to transfusions
in patients who weigh less than 50 kg. Historically it has been
should be reported.
assumed that one unit of packed red cells will produce a Hb
SHOT was established in 1996 as a voluntary haemovigilance
increment of 10 g/l but this is only accurate if the recipient
system for adverse events affecting recipients. The EU Blood
weighs approximately 70 kg. A dose of 4 ml/kg of red cells will
Safety and Quality Directive 2005/61/EC legally mandated hae-
produce a Hb rise of approximately 10 g/l.2 Patients should be
movigilance for hospital blood banks and blood establishments;
reassessed following each unit of blood with regard to effec-
in the UK this is facilitated through the MHRA (Medicines and
tiveness of transfusion and side effects.
Healthcare products Regulatory Agency) using the SABRE
reporting system (Serious Adverse Blood reactions and Events).
Transfusion-related acute lung injury (TRALI)
The transfusion of ABO incompatible blood is also a WHO Never
TRALI is characterized by acute respiratory distress within 6
Event.
hours of transfusion. Cases commonly present with acute dysp-
Antibody-mediated transfusion reactions noea, hypoxia, fever and hypotension. Bilateral pulmonary
infiltration is seen on the chest X-ray (CXR). Treatment is sup-
A summary of all types of antibody-mediated reactions are found
portive and ventilatory support is often required. Most cases
in Table 2. The most serious of these are the haemolytic
recover within 72 hours predominantly without long-term con-
sequences. TRALI is frequently misdiagnosed as cardiogenic
pulmonary oedema and treatment with diuretics may worsen
Nicola Redding MBBS MRCP is a Haematology Registrar at James outcomes.
Cook University Hospital, UK. Conflicts of interest: none declared. The majority of cases of TRALI are caused by antibodies in
Dianne Plews MBChB FRCP FRCPath is a Consultant Haematologist at the donor blood reacting against human leucocyte antigens
James Cook University Hospital, UK. Conflicts of interest: Dr Plews (HLA) and human neutrophil antigens (HNA) in the recipient.
has previously been sponsored to speak by Pharmacosmos. This results in damaged pulmonary endothelial cells due to

ANAESTHESIA AND INTENSIVE CARE MEDICINE --:- 1 Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Redding N, Plews D, Risks of perioperative blood transfusions, Anaesthesia and intensive care medicine (2016),
http://dx.doi.org/10.1016/j.mpaic.2015.11.011
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Complications of blood transfusions


Acute (within 24 hours) Early (within 2 weeks) Late (after 2 weeks)

Acute haemolytic reactions Delayed haemolytic reactions Transmission of infection


Allergic reactions Post-transfusion purpura Transfusion-associated graft-versus-host
Bacterial contamination of blood unit Transfusion induced immunomodulation disease
Febrile non-haemolytic reactions Transfusional iron overload
Transfusion-related acute lung injury Alloimmunization
Transfusion-associated circulatory overload Transfusion induced immunomodulation

Table 1

sequestration of the inflammatory cells in the lungs, causing Transfusion associated dyspnoea (TAD)
capillary leak into the alveolar spaces (non-cardiogenic pulmo- A relatively new term, transfusion associated dyspnoea (TAD)
nary oedema). Patients with raised levels of pro-inflammatory has been used to describe respiratory distress temporally asso-
cytokines, such as during the perioperative period, are more ciated with transfusion which does not meet the diagnostic
susceptible. These antigens needed to be assessed for in sus- criteria for TACO, TRALI or allergic reaction.
pected TRALI cases.
The incidence of TRALI is approximately 1 in 150,000 units Transfusion-transmitted infections
transfused, which is a significant reduction since routine red
Bacterial
cell leucodepletion (removal of majority of white cells) was
Bacterial contamination of blood components is a rare compli-
introduced.1 It is more common with plasma-rich blood
cation but can result in septic shock with high mortality rates
components.
(25% mortality since 1996 in UK2). Contamination commonly

Antibody-mediated transfusion reactions


Reaction Description Antibody Haemolysis Frequency Timing Clinical features Management

Acute Transfusion of ABO IgM Intravascular 1:180,000 Immediate after DIC, acute kidney Stop transfusion,
haemolytic incompatible blood haemolysis of transfusion 5 ml red injury, notify laboratory
reactions resulting in DIC, transfused and cells haemoglobinuria, immediately.
haemoglobinuria and recipient red shock Supportive
acute renal failure cells measures
including dialysis,
inotropes
Delayed Transfusion of red IgG Extravascular 1:40,000 24 hourse10 days Falling Hb, Supportive
haemolytic cells expressing destruction of following transfusion jaundice, rarely management
reactions antigens to which the transfused haemoglobinuria
donor has pre- antigen
formed antibodies positive cells
(commonly RH, Kidd) only
Allergic Sensitivity to donor IgE Non 1:100 Usually during or Pruritis, urticaria Antihistamines
reactions plasma proteins haemolytic immediately
following transfusion
Anaphylaxis Anaphylaxis, usually IgA Non 1:40,000 Usually during or Management of
in IgA deficient haemolytic immediately anaphylaxis as
individuals who have following transfusion per UK
anti IgA in their resuscitation
plasma. council
guidelines.
Febrile non Pyrexia (<38 C but Cytokine Non 1:100 During transfusion Pyrexia, chills, Slow or stop
haemolytic >2 C above accumulation haemolytic myalgia transfusion,
transfusion baseline) during cell antipyretics
reactions storage

Table 2

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Please cite this article in press as: Redding N, Plews D, Risks of perioperative blood transfusions, Anaesthesia and intensive care medicine (2016),
http://dx.doi.org/10.1016/j.mpaic.2015.11.011
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Blood type and ABO-incompatible acute haemolytic transfusion reaction

ABO Blood Types


TYPE A TYPE B TYPE AB TYPE O

Surface antigen A Surface antigen B Surface antigens Neither A nor B


A and B surface antigens

Neither anti-A nor


Anti-B antibodies anti-B antibodies
in plasma

Anti-A antibodies Anti-A and anti-B


in plasma antibodies

Acute haemolytic reaction: ABO incompatible transfusion

RBC + opposing agglutination and haemolysis


surface antigens antibodies

Figure 1

arises from the donor arm during venepuncture and proliferates Cytomegalovirus (CMV) can be transmitted by transfusion
during storage. but rarely has any clinical implications. However it can be
Cases typically present shortly after commencing the trans- life threatening in fetuses, neonates and immunocompromised
fusion with pyrexia (usually >2 C above baseline), rigours and individuals. Routine leucodepletion has significantly reduced
haemodynamic compromise. Blood cultures need to be obtained the risk of transfusion-related CMV and the only groups that
and immediate administration of resuscitative measures and currently require CMV negative products are foetuses (intra-
intravenous broad-spectrum antibiotics (covering both gram- uterine transfusions), neonates and pregnant women.4
positive and gram-negative pathogens) is essential. All impli-
cated units should be sealed and returned to the transfusion Prions
laboratory. The National Blood Service promptly withdraw all Variant Creutzfeldt-Jakob disease (vCJD) was identified in the
other components from the original donor to reduce further UK in 1996 and four cases of transfusion-transmitted vCJD have
occurrences. been identified. Various measures have been instigated to mini-
mize this risk, including leucodepletion of all blood products,
Viral importation of all plasma for fractionated blood products and
The risk of transfusion-related viral infections is now minimal importation of FFP for all transfusion recipients born after 1/1/
within the UK following the introduction of routine screening 1996 when dietary transmission of vCJD is assumed to have
and donor selection. Currently all donor blood is routinely ceased.
tested for hepatitis B, hepatitis C, human immunodeficiency
virus (HIV), human T-cell lymphotropic virus (HTLV), and the Transfusion-related immunomodulation (TRIM)
bacteria Treponema pallidum.2 If screening occurs in
The immunomodulatory effects of blood transfusions have been
the ‘window period’ before there is a detectable antibody
appreciated for a number of years. Indeed in the pre-
response there is a risk of infectious products entering the
immunosuppressant era of renal transplantation allograft rejec-
blood supply.
tion was reduced in those who received transfusions.

ANAESTHESIA AND INTENSIVE CARE MEDICINE --:- 3 Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Redding N, Plews D, Risks of perioperative blood transfusions, Anaesthesia and intensive care medicine (2016),
http://dx.doi.org/10.1016/j.mpaic.2015.11.011
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The mechanisms of TRIM are multifactorial. Contributory Subsequently, allogeneic blood transfusions are common
factors are likely to include immunosuppressive effects such as within this cohort. Approximately 40% of all red cells are
suppression of cytotoxic cells/monocyte activity and release of administered to surgical patients,8 with the aim of augmenting
prostaglandins together with pro-inflammatory factors including oxygen delivery and restoring homeostasis.
cytokine production (Th1, Th2, IL-6, etc).5 However, the efficacy of transfusions to improve tissue
In the perioperative setting it has been speculated that this oxygenation is very variable.7 There is also increasing evidence
immunomodulatory effect increases the risk of postoperative that blood transfusions are an independent risk factor for adverse
infections and cancer recurrence rates after curative re- outcomes including mortality.7,8 Recent randomized control tri-
sections.5,6 However, this remains controversial as the circum- als have shown that a liberal strategy of red cell transfusions did
stances under which patients require perioperative transfusions not confer any advantage over a restrictive transfusion approach,
is likely to significantly impact on these complications. These excluding acute haemorrhages or patients with recent myocardial
potential confounding variables include type of malignancy, infarctions.9,10
resectability, duration and type of anaesthesia, blood loss and However, delayed transfusion, or under transfusion are now
perioperative stress response. also recognized as emerging complications of blood transfusion.
In 2013 SHOT reported six deaths and seven cases of major
Massive blood transfusion morbidity were secondary to this.
Massive transfusion is defined as replacement of a patient’s total
Cell salvage and autologous blood transfusion
blood volume in <24 hours or replacement of 50% of total blood
volume within 3 hours.2 There are specific risks associated with Intraoperative and postoperative cell salvage with the reinfusion
massive transfusion, in addition to the potential complications of patients’ own blood cells is now instigated to decrease the
already mentioned. need for allogenic blood transfusion and the subsequent potential
Transfusion of large volumes of red cells can lead to dilutional complications. However, autologous blood transfusions are not
coagulopathy as packed red cells do not contain platelets or without risk.
coagulation factors. Expectant replacement of coagulation factors Predeposit autologous donation (PAD) before surgery is of
and platelets with FFP, cryoprecipitate and platelets is essential. uncertain benefit and is only recommended in exceptional cir-
Coagulation is also impaired by hypothermia, acidosis and cumstances.2 The incidence of human errors causing transfusion
hypocalcaemia which are also associated with massive risks with PAD is the same as for allogeneic blood.
transfusion. All adverse events associated with cell salvage should be re-
Full guidance on management of massive haemorrhage is ported to SHOT. Incidents are probably still underreported, with
beyond the scope of this article. a peak of 42 incidents reported in 2011. The most common re-
ported event is hypotension, which is often associated with the
Overall effect of perioperative transfusion on morbidity use of leucodepletion filters. Air embolism and wrong blood to
and mortality wrong patient have also been reported.
Anaemia is highly prevalent amongst surgical patients and is
Recommendations for the use of perioperative blood
associated with increased morbidity and mortality.7,8
transfusions
Definitions for a restrictive versus liberal strategy for blood
transfusion vary in the literature but the general consensus is
Summary of methods to reduce transfusion in surgical supportive of a restrictive approach using a transfusion
patients threshold of Hb 80 g/l or haematocrit 25% in haemody-
Preoperative C Identify if anaemic and investigate and namically stable, non-bleeding patients.2,10 These values
optimization treat in a timely manner prior to surgery should provoke consideration of a transfusion but the decision
C Identify if at increased risk of bleeding to transfuse should be based on the patients’ clinical condition
(personal history, coagulation screen), and not the Hb level alone. Patients who are not actively
discontinue anticoagulant or antiplatelet bleeding should be transfused with a single unit of red cells
drugs if possible and then reassessed prior to further transfusions being
Minimizing C Blood-sparing surgical and anaesthetic administered.
blood loss at techniques should be used
Adjuncts and alternatives to red cell transfusions
surgery C Antifibrinolytic drugs, tissue sealants and
In recognition of the above guidance along with use of alter-
intraoperative cell salvage procedures
natives to blood transfusions and developments of blood-
should be used when appropriate
sparing surgical techniques, surgical blood usage has
Avoiding C Use a restrictive transfusion threshold if
decreased by more than 20% since 2000. However, 15e50% of
unnecessary clinically appropriate
surgical red cell transfusions could be avoided, in a range of
transfusion C Minimize blood loss from blood tests
surgical procedures, and there is considerable variations in
after surgery C Use iron and other stimulates to red cell
transfusion practice with fourfold to fivefold variability in the
production as needed
use of blood for the same operations.2,11 Patient blood man-
Table 3 agement programmes should be utilized to reduce the need for

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Please cite this article in press as: Redding N, Plews D, Risks of perioperative blood transfusions, Anaesthesia and intensive care medicine (2016),
http://dx.doi.org/10.1016/j.mpaic.2015.11.011
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transfusion and for the greatest impact should be instigated at 6 Maxwell MJ, Wilson MJA. Complications of blood transfusion.
the beginning of the patient pathway which is often in primary Continuing education in anaesthesia. Crit Care Pain 2006; 6:
care (Table 3). A 225e9.
7 Glance LG, Dick AW, Mukamel DB, et al. Association between
intraoperative blood transfusion and mortality and morbidity in
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ANAESTHESIA AND INTENSIVE CARE MEDICINE --:- 5 Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Redding N, Plews D, Risks of perioperative blood transfusions, Anaesthesia and intensive care medicine (2016),
http://dx.doi.org/10.1016/j.mpaic.2015.11.011