Anaesthesia 2015, 70 (Suppl. 1), 20–28 doi:10.1111/anae.

12918

Review Article
Pre-operative anaemia
B. Clevenger1 and T. Richards2,3

1 Speciality Registrar, Division of Surgery and Interventional Science, Royal Free Hospital, University College, 2 Senior
Lecturer, University College London, 3 Consultant, University College London Hospital and Royal Free Hospital,
London, UK

Summary
Pre-operative anaemia is a relatively common finding, affecting a third of patients undergoing elective surgery. Tradi-
tionally associated with chronic disease, management has historically focused on the use of blood transfusion as a
solution for anaemia in the peri-operative period. Data from large series now suggest that anaemia is an independent
risk associated with poor outcome in both cardiac and non-cardiac surgery. Furthermore, blood transfusion does not
appear to ameliorate this risk, and in fact may increase the risk of postoperative complications and hospital length of
stay. Consequently, there is a need to identify, diagnose and manage pre-operative anaemia to reduce surgical risk.
Discoveries in the pathways of iron metabolism have found that chronic disease can cause a state of functional iron
deficiency leading to anaemia. The key iron regulatory protein hepcidin, activated in response to inflammation,
inhibits absorption of iron from the gastrointestinal tract and further reduces bioavailability of iron stores for red cell
production. Consequently, although iron stores (predominantly ferritin) may be normal, the transport of iron either
from the gastrointestinal tract or iron stores to the bone marrow is inhibited, leading to a state of ‘functional’ iron
deficiency and subsequent anaemia. Since absorption from the gastrointestinal tract is blocked, increasing oral iron
intake is ineffective, and studies are now looking at the role of intravenous iron to treat anaemia in the surgical
setting. In this article, we review the incidence and impact of anaemia on the pre-operative patient. We explain how
anaemia may be caused by functional iron deficiency, and how iron deficiency anaemia may be diagnosed and
treated.
.................................................................................................................................................................
Correspondence to: T. Richards; Email: toby.richards@ucl.ac.uk; Accepted: 24 September 2014

Introduction diagnosis and management of pre-operative anaemia

Pre-operative anaemia is common. Often regarded as a
consequence of illness for which the patient is under-
going surgery, pre-operative anaemia is independently
associated with increased risk of adverse outcomes fol-
lowing surgery; increased length of intensive care and
hospital stay; postoperative complications; and worse
overall outcome [1, 2]. Pre-operative anaemia is a
powerful predictor of the need for blood transfusion;
however, transfusion itself is independently associated
with increased length of stay, surgical complications
and increased mortality [3]. Currently, the recognition,
are unmet needs in the optimisation of patients before
surgery. The Department of Health (DOH) and
National Blood Transfusion Committee (NBTC) of
NHS England is working to establish a multimodal,
multidisciplinary approach to increase the use of evi-
dence-based best practice in transfusion medicine,
termed patient blood management (PBM). Patient
blood management puts the patient at the centre of
transfusion management, with the aim of minimising
unnecessary transfusions. It is endorsed by the NBTC,
which has issued guidelines to NHS Trusts to aid its

20 © 2014 The Association of Anaesthetists of Great Britain and Ireland

Clevenger and Richards | Pre-operative anaemia
implementation [4]. As part of PBM, considerable
variations in transfusion practice have highlighted the
need for appropriate transfusion use, with four- to
fivefold variability seen between hospitals for primary
orthopaedic joint replacement surgery [5, 6]. In the
UK, audits of transfusion rates by operation and hos-
pital are planned, and pre-operative anaemia has been
proposed as a Key Performance Indicator.
In surgical patients, PBM focuses on anaemia
management, minimisation of blood loss, and appro-
priateness of transfusion the ‘three pillars’. The aim is
to reduce surgical risk and improve patient outcome
after surgery. Consequently, recognition and manage-
ment of pre-operative anaemia represents an opportu-
nity to optimise patients before surgery, thereby
reducing blood transfusion and potentially improving
recovery from surgery and associated postoperative
outcomes.
In this article, we discuss the aetiology, prevalence,
impact and management of pre-operative anaemia. We
will focus on how chronic disease and surgery activates
iron-restricted erythropoiesis, causing a functional iron
deficiency. The use of iron therapies will be described
for the treatment of anaemia.
Prevalence of anaemia
The World Health Organisation defines anaemia as an
insufficient circulating red cell mass, with a haemoglo-
bin (Hb) concentration of < 130 g.l 1 for men and
< 120 g.l 1 for women [7]. The global burden of anae-
mia is considerable, accounting for 8.8% of disability
from all conditions [8]. Although iron deficiency is the
leading individual cause of anaemia, a lower incidence
of iron deficiency anaemia is seen in higher income
populations of North America and Europe, where hae-
moglobinopathies, chronic kidney disease (CKD), and
gastrointestinal haemorrhage are more common [8].
The population prevalence of anaemia varies with age
and comorbidity. In data from the US National Health
and Nutrition Examination Survey (NHANES), the
prevalence of anaemia was lowest in males aged 17–
49, at 1.5%, but was 12.2% in females of that age. In
the elderly, anaemia was more common; affecting 11%
of males and 10.2% of females aged > 65 years, rising
to 26.1% and 20.1% respectively in those > 85 years
old [9]. In the US, this equates to more than 2.8 mil-
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2015, 70 (Suppl. 1), 20–28
lion anaemic adults over the age of 65. As well as an
increased prevalence with age, anaemia is more com-
mon with increasing frailty, and its prevalence has
been reported to be as high as 40% in nursing home
residents [10, 11]. Population studies in the UK have
shown anaemia to be more prevalent than diabetes,
with a similar incidence to cardiovascular disease [10].
The prevalence of anaemia in over a hundred studies
in differing medical populations has recently been
reviewed [12].
In pre-operative patients, one third will be found
to be anaemic at pre-assessment. The underlying surgi-
cal condition will affect the prevalence, rising to
between 39% and 75% in studies of colorectal surgery
patients [13]. In data from the US’ National Surgery
Quality Improvement Program (NSQIP) database, the
prevalence of anaemia in all patients undergoing sur-
gery was 30.4% [2], with a 28.7% prevalence seen in a
European population [14].
Consequences of anaemia
Physiological symptoms of fatigue, dyspnoea and
tachycardia develop as the Hb concentration falls
below two-thirds normal (to less than 90–100 g.l 1)
[15]. Cardiovascular stability can be maintained in
healthy individuals with an Hb as low as 50 g.l 1 [16].
However, even in the healthy population, mild anae-
mia leads to impaired functional capacity and physical
performance, and a reduced quality of life [17].
Indeed, the impact of anaemia is thought to have a
similar effect on health in the population to that of
diabetes and cardiovascular disease [10].
In the setting of peri-operative medicine, there is
considerable evidence of an association between pre-
operative anaemia and surgical morbidity and mortal-
ity. Musallam et al. analysed data on 227 435 surgical
patients undergoing non-cardiac surgery, with a multi-
variate analysis controlling for over 60 potential con-
founders [2]. Pre-operative anaemia was strongly
predictive of both mortality and morbidity. Even mild
anaemia increased relative risk (RR) by 30–40%, with
the additional effect of a relationship between anaemia
severity and outcome. These data were verified in a
series of 39 309 non-cardiac surgical patients in the
European Surgical Outcomes Study (EuSOS). After
multivariate analysis, patients with severe or moderate
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Anaesthesia 2015, 70 (Suppl. 1), 20–28
anaemia had higher in-hospital mortality than those
with a normal pre-operative Hb (OR 2.28 (95% CI
2.06–3.85 vs OR 1.99 (95% CI 1.67–2.37)), respectively
[14].
Although these data reflect association only, they
are supported in most areas of surgical practice, from
cardiac [18], to orthopaedics [1]. The causality
between anaemia and outcome has not been proven,
but surgery, like exercise, places substantial metabolic
demands on the patient. Cardiopulmonary exercise
testing (CPET) is now routinely used to assess fitness
for major surgery. Cardiopulmonary exercise testing
can be used to determine exertional oxygen uptake
(VO2) at anaerobic threshold (AT) and peak oxygen
consumption (VO2 peak) as measures of the ability to
meet increasing oxygen demands. The degree of surgi-
cal insult and the ability to meet the resulting addi-
tional postoperative oxygen demand appear to be key
determinants of surgical outcome [19, 20]. Patients
with poor CPET results (reduced VO2 peak and AT)
are at greater risk of adverse surgical outcome [21, 22].
While cardiac output is well recognised as a key
parameter limiting exertional VO2 [23], the impact of
anaemia and reduced concentration of oxygen-carrying
Hb is less recognised. Anaemia is associated with lower
exertional VO2 and impaired exercise performance [24,
25], therefore anaemia may be associated with reduced
fitness for surgery, increasing the risk of adverse out-
comes [26].
Blood transfusion
The current standard of care for the treatment of
anaemia during surgical admission is blood transfu-
sion. While transfusion is effective, it does not address
the underlying cause of anaemia. In the surgical set-
ting, an analysis by Ferraris et al., from the US NSQIP
database of just under one million patients [3], dem-
onstrated that transfusion of a single unit of packed
red cells increased the multivariate risk of mortality,
wound problems, pulmonary complications, postopera-
tive renal dysfunction, systemic sepsis, composite mor-
bidity and postoperative length of stay, compared with
propensity-matched patients who did not receive an
intra-operative transfusion.
There is an increasing body of evidence to suggest
that the use of ‘top-up’ transfusions are ineffective in
22
Clevenger and Richards | Pre-operative anaemia
stable patients, with studies showing restrictive transfu-
sion thresholds to be non-inferior to liberal transfusion
thresholds [27, 28]. The transfusion trigger trial for
functional outcomes in cardiovascular patients under-
going surgical hip fracture repair (FOCUS) study ran-
domly assigned 2016 patients that had known
cardiovascular risk after hip fracture surgery to either
restrictive (Hb < 80 g.l 1) or liberal transfusion strat-
egy (Hb > 100 g.l 1). There was no difference in any
outcome measure assessed at 60 days postoperatively
[29]. A similar study looked at 921 patients with acute
severe gastrointestinal bleeding; those who received a
restrictive policy with a tolerance of Hb > 75 g.l 1 had
overall improved outcomes compared with patients
receiving liberal transfusion (to attain Hb > 90 g.l 1),
who had a higher risk of rebleeding during admission
and increased mortality at 6 weeks [30]. Therefore,
although pre-operative anaemia is common and associ-
ated with a worse patient outcome, blood transfusion
may not be the most appropriate solution, as it may
actually increase this risk.
Defining pre-operative anaemia
The main causes of anaemia in the general population
– iron, folate and vitamin B12 deficiency, haemoglo-
binopathy and renal failure – are rarely newly diag-
nosed at pre-operative assessment. Surgical patients
may have an established or treated cause of anaemia,
but may also suffer from anaemia due to the condition
for which they are undergoing surgery. This could
either be directly related, for example due to gastroin-
testinal blood loss in colorectal cancer, or indirectly as
a consequence of chronic disease. The latter has tradi-
tionally been regarded as the ‘anaemia of chronic
disease’ (ACD), and is the most common type of
anaemia seen in hospitalised patients [31].
Diagnosis of the cause of anaemia in the pre-oper-
ative patient is necessary in order to direct treatment
where appropriate. The traditional ‘textbook’ definition
of iron deficiency anaemia refers to depletion of the
body’s iron stores due to dietary deficiency or chronic
blood loss, an absolute iron deficiency. A key
understanding now is the recognition that disease
states, in particular inflammation, have a direct effect
on the pathway of iron absorption and metabolism
leading to a state of iron deficiency and anaemia
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Clevenger and Richards | Pre-operative anaemia
(Fig. 1) [32]. Consequently, those patients previously
diagnosed with ‘anaemia of chronic disease’ are now
recognised to have iron deficiency anaemia, specifically
disruption of pathways of iron absorption from the
gut, delivery and distribution from the reticulo-endo-
thelial system leading to iron-restricted erythropoiesis
[33]. Consequently, despite the presence of normal, or
even increased, body iron stores, these cannot be mo-
bilised or utilised, leading to a state of functional iron
deficiency. Functional iron deficiency is well recognised
in renal and cardiac disease, and increasingly recogni-
sed as a cause for anaemia in the general surgical
patient [34, 35].
Functional iron deficiency
Central to iron absorption and metabolism is hepci-
din, a 25 amino acid glycoprotein hormone, first dis-
covered in the 1990s. Over the past decade, the role
of hepcidin as the key iron regulatory hormone has
been established [36]. Produced in the liver, hepcidin
is regulated by feedback from iron stores and eryth-
ropoietic activity. Hepcidin is up-regulated in
response to feedback from increased iron stores. Hep-
cidin acts on ferroportin, a transmembrane iron
transporter, found in duodenal enterocytes and mac-
rophages. The binding of hepcidin degrades ferropor-
tin, preventing iron absorption from the gut by
inhibiting transport of iron from the duodenal en-
terocyte. Inhibition of the transport of stored iron
into the plasma from hepatocytes and macrophages
leads to sequestration of iron stores in ferritin, the
main iron storage protein, reducing iron binding by
the plasma iron transport protein transferrin. This
reduces iron transport within the plasma to the bone
marrow for erythropoiesis.
Inflammation activates and increases hepcidin
expression and ferritin synthesis [32]. Thus, a state of
functional iron deficiency is created as a consequence
of the sequestration of iron within macrophages in
response to the effects of inflammatory mediators, or
in situations where iron demand exceeds supply, e.g.
haemoglobinopathy, chronic haemolytic anaemia or
the use of erythropoiesis-stimulating agents.
Meanwhile, hepcidin up-regulation in the presence of
inflammation blocks the absorption of dietary iron,
including oral iron supplementation, compounding
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2015, 70 (Suppl. 1), 20–28
Figure 1 Iron haemostasis and inflammation. Inflam-
mation, whether caused by infection, malignant cells or
auto-immune mechanisms, involves the activation of T
cells and monocytes, triggering a cascade of responses.
This inflammatory cascade alters the haemostasis of
iron and limits its availability for erythropoiesis.
Inflammation and increased iron levels up-regulate
hepcidin, which inhibits duodenal absorption of iron.
Individual macrophages are stimulated by inflamma-
tory mediators to take up Ferrous iron (Fe2+). Inflam-
matory mediators also up-regulate the expression of
transferrin receptors, increasing the uptake of transfer-
rin bound iron into the macrophage. Transferrin, the
protein that binds and transports iron, can be func-
tionally blocked from carrying out its role due to
increased levels of hepcidin. Activated macrophages
phagocytose ageing red blood cells at the end of their
lifespan (approximately 120 days) permitting the recy-
cling of iron. The transmembrane iron transporter fer-
roportin is down-regulated by hepcidin, reducing iron
transport out of the macrophage and duodenal entero-
cyte. Thus, a state of functional iron deficiency is cre-
ated as a consequence of the sequestration of iron
within the duodenum and macrophages in response to
the effects of inflammatory mediators. Tumour necro-
sis factor alpha (TNF-a) can induce macrophages and
damage red blood cells membranes, leading to early
phagocytosis. Inflammatory mediators additionally
reduce erythropoietin production by the kidney, reduc-
ing erythropoiesis [32]. (Adapted with permission
from: Richards, T. Anaemia in hospital practice. British
Journal of Hospital Medicine 2012; 73: 571–5).
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Anaesthesia 2015, 70 (Suppl. 1), 20–28
this state of iron-restricted erythropoiesis driven by
inflammatory mediators (Fig. 1).
Diagnosis of anaemia and iron deficiency
Guidelines for the diagnosis and management of anae-
mia have been issued by the National Institute for
Health and Care Excellence (NICE) [37, 38], the Brit-
ish Committee for Standards in Haematology (BCSH)
[39], and the British Society for Gastroenterology
(BSG) [40].
NICE guidelines for the use of routine pre-opera-
tive tests in elective surgery exist to guide the appro-
priate use of resources [41]. Guidance for full blood
count testing is based on grade of surgery, patient age
and the presence of comorbidities. This guideline also
provides guidance for the appropriate testing for hae-
moglobinopathies, including sickle cell disease, in
North African, West African, South/Sub-Saharan Afri-
can and Afro-Caribbean patients before surgery. Full
blood count measurement before surgery can be per-
formed quickly and simply using point of care devices
such as the Haemocue (AB Leo Diagnostics, Helsing-
borg, Sweden), and even non-invasive methods such as
the Total Hb or SpHb (Masimo, Irvine, CA, USA).
However, few centres employ this in routine practise.
Once anaemia has been diagnosed by a screening
blood test, it is recommended that further tests be per-
formed to evaluate the cause, including assessment for
nutritional deficiency, chronic renal insufficiency and
chronic inflammatory disease [42].
Although anaemia can readily be identified pre-
operatively, few centres investigate further with an
appropriate diagnosis of the cause of anaemia and its
treatment. Measurement of reticulocytes (immature
red cells) indicates bone marrow activity. It can distin-
guish between high turnover of red cells, with the
reticulocyte count rising to compensate for red cell loss
or destruction (e.g. haemolysis), or poor bone marrow
production of red cells. Decreased reticulocyte count is
seen in iron deficiency anaemia, anaemia of chronic
disease, vitamin B12 and folate deficiency, and bone
marrow failure, for example due to malignancy or
chemotherapy.
Mean cell volume (MCV) and mean cell haemo-
globin (MCH) values are then useful to make a diag-
nosis of iron deficiency, and can assess the trend over
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Clevenger and Richards | Pre-operative anaemia
several weeks or months [39]. Most patients with
anaemia of chronic disease have a normochromic,
normocytic anaemia. Red cell distribution width is
now a routinely available test in most full blood count
analysers, and an increase is common with co-existent
vitamin B12 or folate deficiency, while a red cell distri-
bution width < 15% is a marker of functional iron
deficiency.
However, there are often diagnostic difficulties
when attempting to diagnose functional iron deficiency
due to inflammation or erythropoietin stimulation. As
noted previously, in the presence of inflammation
(which is common in patients awaiting surgery), the
values used to measure iron status can become abnor-
mal, even with normal reserves of iron.
Serum tests of haematinics, including iron con-
centration, total iron binding capacity, transferrin
saturation (measuring the ratio of serum iron to
total iron binding capacity) and ferritin, are used to
distinguish the differing types of iron deficiency.
Markers of iron deficiency are: low ferritin; low
transferrin saturation; low iron; raised total iron-
bonding capacity and increased serum transferrin
receptor.
Serum ferritin is essential in the measurement of
iron stores. One lg.l 1 of ferritin in serum is equiva-
lent to 8–10 mg of iron in stores. However, ferritin is
an acute phase protein, increased in the presence of
inflammation, confounding its use as a marker of iron
stores in the presence of infection and inflammation.
It is argued that setting an upper limit of serum ferri-
tin concentration to define sufficiency of iron stores
for erythropoiesis is incorrect.
For patients with low red cell indices (low MCH
& MCHC) and microcytic anaemia indicating acquired
iron deficiency anaemia, clear algorithms exist for the
investigation of coeliac disease and gastrointestinal
cancer [40]. Similarly, anaemia in patients with
chronic kidney disease is increasingly well identified
and managed as part of their illness [38]. Indeed func-
tional iron deficiency is well recognised in chronic kid-
ney disease, and parenteral iron supplementation is
routine practice [39].
Diagnosis of anaemia due to functional iron defi-
ciency remains an uncertain area in non-chronic kid-
ney disease populations, apart from cardiac surgical
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Clevenger and Richards | Pre-operative anaemia
patients, where a recent study has shown that 47% of
patients are anaemic as a consequence [43]. While
consensus for an exact definition is debated, there is
clear trial data indicating which patients would benefit
from iron therapy. Consequently, there is an argument
that anaemia due to functional iron deficiency can be
measured by those indications where iron therapy is
effective. In a recent Cochrane Database review of iron
therapy for the treatment of anaemia in non-chronic
kidney disease populations, 48 publications were
included, describing 21 randomly assigned trials.
Observational trials were not studied due to selection
bias, and many failed to meet the inclusion criteria
required. The included trials provide the best quality
of evidence for the use of iron supplementation [44].
Overall, 4799 participants were included in this sys-
tematic review. The definitions of anaemia and iron
deficiency were varied (Table 1). A ferritin value of
< 10–20 lg.l 1 was used to reflect iron deficiency, and
a ferritin < 100 lg.l 1for functional iron deficiency.
Transferrin saturation (TSAT) < 20% was commonly
used to define functional iron deficiency and/or a ferri-
tin < 100 lg.l 1, and in some trials a higher ferritin of
300–500 lg.l 1. Different institutions have a variety of
markers for functional iron deficiency. Local Hospital
Transfusion Committees should set definitions based
on recent evidence, national guidelines and the avail-
ability of tests [44].
The authors recommend a serum ferritin
< 100 lg.l 1 and TSAT< 20% as the currently accept-
able definition of functional iron deficiency.
British Committee for Standards in Haematology
guidelines state that a serum ferritin of < 12 lg.l 1
indicates absent iron stores. These guidelines do not
give a recommendation for the highest serum ferritin
concentration beyond which it is unsafe to give a trial
of intravenous iron therapy, but suggest that a serum
ferritin < 100 lg 1 in non-dialysed patients and
< 200 lg 1 in chronic haemodialysis patients indicate
a high likelihood of iron deficiency and the potential
to respond to intravenous iron [39].
Zinc protoporphyrin is a trace by-product of haem
synthesis; its concentration within red cells is increased
when iron supply to the bone marrow is limited or
porphyrin synthesis is stimulated, indicating a defect
in the haem synthesis pathway. Zinc protoporphyrin is
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2015, 70 (Suppl. 1), 20–28
non-specific, but is raised in absolute and functional
iron deficiency, lead poisoning and patients with thal-
assaemia. Zinc protoporphyrin concentration can be
used to diagnose functional iron deficiency as an alter-
native to measures of red cell hypochromia or reticulo-
cyte haemoglobin [39].
Soluble transferrin receptors are shortened frag-
ments of an erythrocyte membrane receptor that
increase in iron deficiency. They can be used to differ-
entiate between patients with anaemia of chronic dis-
ease, where the levels are decreased or normal due to
down-regulation by inflammatory cytokines, and
accompanying iron deficiency. In anaemia of chronic
disease alone, serum ferritin levels are normal or high
with low soluble transferrin receptor levels. In anaemia
of chronic disease with iron deficiency, ferritin levels
are low and soluble transferrin receptor levels are high
[32, 33]. However, soluble transferrin receptor assays
are expensive and not currently subject to an external
quality assessment in the UK, and thus not in routine
clinical use. Hepcidin assays are now available for
research measurement, including radio-immunoassay,
enzyme linked immunosorbent assays and mass spec-
trometry techniques. There is no external quality
assessment scheme for hepcidin measurement in the
UK yet and its usefulness as a diagnostic tool is under
investigation [39].
Chronic kidney disease
The anaemia of chronic kidney disease is multifacto-
rial. Erythropoietin deficiency is the most significant
component of this; however, several other factors
contribute. The normal serum erythropoietin concen-
tration is 2–7 pmol.l 1, however in renal disease
erythropoietin production is inappropriately low, due
to loss of erythropoietin-producing peritubular cells
in the kidney, or possibly because of altered oxygen-
ation of erythropoietin-producing cells. The immune
mechanisms precipitating anaemia of chronic disease
are active, as well as haemolysis, iron and other
nutritional deficiencies, hyperparathyroidism with
myelofibrosis, external blood loss, bone marrow sup-
pression induced by non-excreted metabolites and
the effects of drugs [45]. The prevalence of anaemia
has been shown to increase as renal function wors-
ens. In a cross-sectional study of patients with
25
Anaesthesia 2015, 70 (Suppl. 1), 20–28 Clevenger and Richards | Pre-operative anaemia

Table 1 Definitions of anaemia and iron deficiency in randomly controlled trials of iron therapy. Haemoglobin; Hb
(measured as g.l 1); ferritin (lg.l 1); transferrin saturation (TSAT) (as a percentage). Data from are illustrated from
those trials included in [44]. Where data on definition of iron deficiency were not clear or not commented on, the
trial authors were contacted for clarification.

Definition Diagnosis Population Author

Hb 70–100 TSAT < 20% IDA failed oral therapy Hetzel et al. 2014 [63]
Hb < 100 TSAT < 20% IDA failed oral therapy Vadhan-Raj et al. 2013 [64]
Hb < 100 Ferritin < 10 & TSAT < 15% Non-myeloid malignancy Auerbach et al. 2010 [65]
Hb < 110 Ferritin < 10 & TSAT < 15% Non-myeloid malignancy Bastit et al. 2008 [66]
Hb < 110 Ferritin < 20 & TSAT < 60% Non-myeloid malignancy Steensma et al. 2011 [67]
Hb < 100 None Gynaecological cancer Dangsuwan and Manchana
2010 [68]
Hb < 100 Ferritin < 100 or TSAT < 15% Solid organ cancer Maccio et al. 2010 [69]
Hb 90–110 Bone marrow iron staining Lympho-proliferative cancer Hedenus et al. 2007 [70]
Hb 70–130 Ferritin < 100 Inflammatory bowel disease Evstatiev et al. 2011 [54]
men
Hb 70–120
women
Hb < 115 Ferritin < 300 & TSAT < 20% Inflammatory bowel disease Lindgren et al. 2009 [71]
Hb 90–120 Ferritin < 500 & TSAT < 20% Heart failure Beck-da-Silva et al. 2013 [72]
None Ferritin < 100 or Heart failure Anker et al. 2009 [34]
Ferritin < 300 & TSAT < 20%
Hb < 110 Ferritin < 100 & TSAT < 25% Heavy uterine bleeding VanWyck et al. 2009 [73]
Hb < 105 Serum Iron < 50 Posthaemorrhage Abrahamsen et al. 1965 [74]
None None Pre-operative colorectal cancer Edwards et al. 2009 [75]
None None Pre-operative colorectal cancer Lidder et al. 2007 [76]
Hb < 110 None Postoperative orthopaedic Parker et al. 2010 [77]
Hb 80–120 None Postoperative orthopaedic Sutton et al. 2004 [78]
men
Hb 80–110
women
Hb 70–90 None Postoperative Karkouti et al. 2006 [79]
Hb 70–100 None Postoperative cardiac surgery Madi-Jebara et al. 2004 [80]
Hb < 130 None ICU patients Pieracci 2009 [81]

IDA, iron deficiency anaemia; ICU, intensive care unit.

chronic kidney disease, McClellan et al. demonstrated
that that the proportion of patients with Hb
< 120 g.l 1 increased from 26.7% to 75.5% as glo-
merular filtration rate (GFR) decreased from > 60 to
< 15 ml.min 1.1.73 m2 [46].
Given that population estimates demonstrate that
11% of the population have some degree of kidney dis-
ease, and an estimated 4.9% of the population in Eng-
land have stage 3–5 chronic kidney disease (a GFR
that ranges from 59 to <15 ml.min 1.1.73 m2) [38],
this is pertinent to the surgical population. Many
patients with chronic kidney disease present pre-opera-
tively for procedures both related and unrelated to
their disease.
National Institute for Health and Care Excellence
guidance suggests that anaemia should be investigated
in patients with chronic kidney disease and an Hb
< 110 g.l 1, or who develop symptoms of anaemia.
Erythropoiesis-stimulating agents are suggested in
those patients who are likely to benefit in terms of
quality of life and physical function [38].
The recent ferinject assessment in patients with
iron deficiency anaemia and non-dialysis-dependent
chronic kidney disease (FIND-CKD) open-label ran-
domly controlled trial investigated the optimisation of
iron stores in patients with non-dialysis-dependent dis-
ease over 56 weeks. Inclusion criteria included eGFR
< 60 ml.min 1.1.73 m2 and transferrin saturations
< 20%, with a serum ferritin < 200 lg 1; indices
which are fairly common in the ageing population
undergoing surgery. Results from showed that
optimisation of patients with intravenous iron therapy

26 © 2014 The Association of Anaesthetists of Great Britain and Ireland

Clevenger and Richards | Pre-operative anaemia
and a ferritin target of 400–600 lg.l 1 reduced the
need for erythropoietin and blood transfusion com-
pared with those with a ferritin target of 100–
200 lg.l 1 or those taking oral iron [47].
It would appear logical that optimisation of iron
stores in patients with chronic kidney disease is benefi-
cial in the general population and this should not be
different in the surgical setting, so therefore the use of
intravenous iron for patients undergoing surgery is
recommended.
Pre-operative iron management
Oral iron is a long-standing, low-cost treatment for
anaemia. The total body stores of iron in a healthy
adult are 3–4 g. The bioavailability of ferrous iron is
10–15%, and ferric iron a third to a quarter of this.
However, it may be poorly absorbed due to the down-
regulation of duodenal absorption by inflammation,
infection and chronic disease, under the influence of
hepcidin, reducing its bioavailability further [32, 43].
Oral iron is absorbed at a rate of 2–16 mg per day,
and for a 1000–2000 mg replenishment of body stores,
3–6 months of treatment may be required. Reduced
uptake is one of the main reasons why oral iron often
fails to ameliorate anaemia in surgical patients. Com-
pliance can also be poor due to the common side
effects of gastrointestinal disturbance including abdom-
inal pain, diarrhoea and constipation.
In the context of patients with chronic disease,
functional iron deficiency may exist, and any oral
iron that is absorbed will be less utilised for erythro-
poiesis due to its sequestration in macrophages.
Intravenous iron, however, has been shown to be
effective in correcting anaemia in iron deficient
patients [48–51]. Modern preparations are efficacious
and have much improved safety profiles, allowing
total dose infusions of iron to be administered in as
little as 15 min. There are several intravenous iron
preparations available, including iron dextrans, iron
polymaltose, ferumoxytol, ferric carboxymaltose, iron
sucrose, ferric gluconate and iron isomaltoside [52]
(See Table 2). Historically, parenteral iron prepara-
tions were associated with high rates of adverse
events including anaphylaxis. Many reactions were
related to dextran-containing preparations, often
because antibodies to dextran are produced following
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2015, 70 (Suppl. 1), 20–28
exposure to dental caries. There is now good evi-
dence for the safety and efficacy of modern paren-
teral iron preparations in a range of conditions,
including the peri-operative setting [53] and inflam-
matory bowel disease [54].
A systematic review by Litton et al. demonstrated
an increase in Hb and reduction in red cell transfusion
(RR 0.74, 95% CI 0.62–0.88), especially when used
with erythropoietin or in patients with lower ferritin
concentrations [55]. Another systematic review dem-
onstrated that, following intervention, Hb levels were
statistically significantly higher with parenteral iron
than oral iron (mean difference 5.0 g.l 1; 95% CI 7.3
to 2.7) [44]. Average red cells transfused were statis-
tically significantly lower in the parenteral iron group
than oral iron group (mean difference 0.54 units of
blood; 95% CI 0.96 to 0.12) [44].
Intravenous iron can be used throughout the pre-
operative period but, ideally, treatment should take
place 10 days pre-operatively to allow total erythroid
cell maturation and Hb accumulation [56]. However,
there has been a lack of good quality trials, sufficiently
powered or designed with robust patient primary out-
comes, to show an effect on mortality or quality of life
in adults with anaemia. Consequently, the routine use
of intravenous iron therapy in pre-operative anaemia
should be viewed with caution. A large multicentre
randomly controlled trial is currently enrolling in the
UK to assess pre-operative intravenous iron to treat
anaemia in major surgery (PREVENTT) [57].
Erythropoiesis-stimulating agents
Recombinant erythropoietin to stimulate erythropoiesis
has a long-standing use in dialysis patients. Within
5 days of treatment, its effect on the bone marrow to
increase red cell proliferation can be seen. A Cochrane
review of erythropoietin in colorectal cancer patients
failed to show any significant change in Hb with its
pre-operative use, nor a decrease in the number of
patients who received allogeneic blood [58]. However,
a systematic review of orthopaedic and cardiac surgery
patients showed a reduction in the proportion of
patients given allogeneic blood transfusions [59]. A
more recent meta-analysis also showed a significant
reduction in the use of allogeneic blood transfusions in
cardiac surgery (RR 0.53 (95% CI 0.32–0.88) (without
27
Anaesthesia 2015, 70 (Suppl. 1), 20–28 Clevenger and Richards | Pre-operative anaemia

Table 2 Current preparations of intravenous iron in the UK. New recommendations to manage the risk of allergic
reactions with intravenous iron-containing medicines have been produced by the European Medicines Agency [82].

Monitoring for
Trade name Generic name Dose hypersensitivity Maximum dose Infusion time
â 1
Cosmofer (Pharmacosmos, Low molecular Ganzoni Slow injection of 20 mg.kg 4–6 h
Holbaek, Denmark) weight iron formula* first 25 mg observing
Dextran for adverse reaction
Monoferâ (Pharmacosomos) Iron isosorbide Ganzoni Yes – during and for 1000 mg per infusion 15–60 min
formula* 30 min post-dose
Venoferâ (Vifor Pharma, Iron Sucrose 200 mg Yes – during and for 1000 mg per fortnight 2–5 min
Glattbrugg, Switzerland) 30 min post-dose
Ferinjectâ (Vifor Pharma) Iron Hb/weight¶ Yes – during and for 1000 mg per week 15 min
carboxymaltose 30 min post-dose

*
Total iron deficit [mg], and consequently the dose of intravenous iron required, is given by: body weight [kg]† 9 (150 actual
Hb) [g.l 1] 9 0.24‡ + 500 [mg]§.
†
In patients with a body mass index (BMI) > 25 kg.m 2, a normalised weight is used to calculate the iron deficit. Normalised
weight [kg] = 25 9 height [m] 9 height [m].
‡
Factor 0.24 = 0.0034 (iron content Hb = 0.34%) 9 0.07 (blood volume = 7% of body weight) 9 1000 (conversion g to mg).
§
Depot iron.
¶
Dose calculation for iron carboxymaltose:
Body weight Body weight
Hb < 70 kg > 70 kg
> 100 g.l 1
1000 mg 1500 mg
1
7–100 g.l 1500 mg 2000 mg

autologous blood donation) and 0.28 (95% CI 0.18–
0.44, p < 0.001) (with autologous blood donation)
[60].
The Network for the Advancement of Patient
Blood Management, Haemostasis and Thrombosis
(NATA) guidelines for orthopaedic surgery recom-
mend that erythropoietin be used for anaemic patients
in whom nutritional deficiencies have been ruled out,
corrected or both [42]. Iron supplementation should
be provided to patients given erythropoietin to opti-
mise the response. It has been demonstrated that
when intravenous iron is given to patients with
chronic kidney disease receiving ESA the response rate
is improved and a dose reduction can often be made
[47].
However, there are safety concerns regarding the
use of peri-operative erythropoietin [61]. These
include concerns regarding harmful effects, such as
hypertension, thrombosis and ischaemic events, possi-
bly as a consequence of raised Hb, and possibly as a
secondary effect of erythropoietin on other cells,
including tumour growth stimulation [62]. Caution
should be exercised when considering the use of
erythropoietin and decisions made in collaboration
with a haematologist.
Conclusion
The diagnosis and management of pre-operative anae-
mia is essential in the pre-optimisation of patients
before surgery. Recognition that chronic disease can
cause anaemia due to a functional iron deficiency will
allow directed treatment and potential risk reduction
in patients undergoing surgery.
Acknowledgements
TR is chief investigator for a National Institute for
Health Research (NIHR) Health Technology Assess-
ment (HTA) multicentre trial; PREVENTT
(Preoperative intra-venous iron to treat anaemia in
major surgery). University College London has
received educational grant funding from Vifor
Pharma, and also fees from Vifor Pharma and
Pharmocosmos.
Competing interests
No other competing interests declared.

28 © 2014 The Association of Anaesthetists of Great Britain and Ireland

Clevenger and Richards | Pre-operative anaemia
References
1. Spahn DR. Anemia and patient blood management in hip and
knee surgery: a systematic review of the literature. Anesthesi-
ology 2010; 113: 482–95.
2. Musallam KM, Tamim HM, Richards T, et al. Preoperative
anaemia and postoperative outcomes in non-cardiac sur-
gery: a retrospective cohort study. Lancet 2011; 378: 1396–
407.
3. Ferraris VA, Davenport DL, Saha SP, Austin PC, Zwischenberger
JB. Surgical outcomes and transfusion of minimal amounts of
blood in the operating room. Archives of Surgery 2012; 147:
49–55.
4. JPAC – Joint United Kingdom (UK) Blood Transfusion and Tissue
Transplantation Services Professional Advisory Committee.
Patient Blood Management, 2014. www.transfusionguidelines.
org.uk/uk-transfusion-committees/national-blood-transfusion-
committee/patient-blood-management (accessed 13/08/2014).
5. Gombotz H, Rehak PH, Shander A, Hofmann A. Blood use in
elective surgery: the Austrian benchmark study. Transfusion
2007; 47: 1468–80.
6. Gombotz H, Rehak PH, Shander A, Hofmann A. The second
Austrian benchmark study for blood use in elective surgery:
results and practice change. Transfusion 2014; 54:
2646–57.
7. World Health Organization. Nutritional Anaemias: Report of a
WHO Scientific Group [Meeting held in Geneva from 13 to 17
March 1967]. Geneva: World Health Organization, 1968.
8. Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic
analysis of global anemia burden from 1990 to 2010. Blood
2014; 123: 615–24.
9. Guralnik JM. Prevalence of anemia in persons 65 years and
older in the United States: evidence for a high rate of unex-
plained anemia. Blood 2004; 104: 2263–8.
10. Partridge J, Harari D, Gossage J, Dhesi J. Anaemia in the older
surgical patient: a review of prevalence, causes, implications
and management. Journal of the Royal Society of Medicine
2013; 106: 269–77.
11. Kengne AP, Czernichow S, Hamer M, Batty GD, Stamatakis E.
Anaemia, haemoglobin level and cause-specific mortality in
people with and without diabetes. PLoS ONE 2012; 7:
e41875.
12. Shander A, Goodnough LT, Javidroozi M, et al. Iron deficiency
anemia – bridging the knowledge and practice gap. Transfu-
sion Medicine Reviews 2014; 28: 156–66.
13. Shander A, Knight K, Thurer R, Adamson J, Spence R. Preva-
lence and outcomes of anemia in surgery: a systematic
review of the literature. American Journal of Medicine 2004;
116: 58–69.
14. Baron DM, Hochrieser H, Posch M, et al. Preoperative anae-
mia is associated with poor clinical outcome in non-cardiac
surgery patients. British Journal of Anaesthesia 2014; 113:
416–23.
15. Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfu-
sion in adults. Lancet 2013; 381: 1845–54.
16. Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular
and metabolic response to acute, severe isovolemic anemia.
Journal of the American Medical Association 1998; 279: 217–
21.
17. Geisel T, Martin J, Schulze B, et al. An etiologic profile of ane-
mia in 405 geriatric patients. Anemia 2014; 2014, Article ID
932486.
18. Hung M, Besser M, Sharples LD, Nair SK, Klein AA. The preva-
lence and association with transfusion, intensive care unit
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2015, 70 (Suppl. 1), e6–e8
stay and mortality of pre-operative anaemia in a cohort of
cardiac surgery patients. Anaesthesia 2011; 66: 812–8.
19. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007
Guidelines on perioperative cardiovascular evaluation and
care for noncardiac surgery: a report of the American College
of Cardiology/American Heart Association Task Force on Prac-
tice Guidelines. Circulation 2007; 116: e418–500.
20. Peerless JR, Alexander JJ, Pinchak AC, Piotrowski JJ, Malangoni
MA. Oxygen delivery is an important predictor of outcome in
patients with ruptured abdominal aortic aneurysms. Annals of
Surgery 1998; 227: 726–32.
21. Snowden CP, Prentis JM, Anderson HL, et al. Submaximal car-
diopulmonary exercise testing predicts complications and hos-
pital length of stay in patients undergoing major elective
surgery. Annals of Surgery 2010; 251: 535–41.
22. Older P, Hall A, Hader R. Cardiopulmonary exercise testing as
a screening test for perioperative management of major sur-
gery in the elderly. Chest 1999; 116: 355–62.
23. Levine BD. VO2max: what do we know, and what do we still
need to know? Journal of Physiology 2007; 586: 25–34.
24. Otto JM, O’Doherty AF, Hennis PJ, et al. Association between
preoperative haemoglobin concentration and cardiopulmonary
exercise variables: a multicentre study. Perioperative Medicine
2013; 2: 18.
25. Calbet JAL, Lundby C, Koskolou M, Boushel R. Importance of
hemoglobin concentration to exercise: acute manipulations.
Respiratory Physiology and Neurobiology 2006; 151: 132–40.
26. Otto JM, Montgomery HE, Richards T. Haemoglobin concentration
and mass as determinants of exercise performance and of surgi-
cal outcome. Extreme Physiology and Medicine 2013; 2: 33.
27. Carson JL, Carless PA, He bert PC. Transfusion thresholds and
other strategies for guiding allogeneic red blood cell transfu-
sion. Cochrane Database Systematic Reviews 2012; 4:
CD002042.
28. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, random-
ized, controlled clinical trial of transfusion requirements in criti-
cal care. New England Journal of Medicine 1999; 340: 409–17.
29. Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive
transfusion in high-risk patients after hip surgery. New Eng-
land Journal of Medicine 2011; 365: 2453–62.
30. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies
for acute upper gastrointestinal bleeding. New England Jour-
nal of Medicine 2013; 368: 11–21.
31. Wians FH, Urban JE, Keffer JH, Kroft SH. Discriminating
between iron deficiency anemia and anemia of chronic dis-
ease using traditional indices of iron status vs transferrin
receptor concentration. American Journal of Clinical Pathology
2001; 115: 112–8.
32. Weiss G, Goodnough LT. Anemia of chronic disease. New Eng-
land Journal of Medicine 2005; 352: 1011–23.
33. Busti F, Campostrini N, Martinelli N, Girelli D. Iron deficiency in
the elderly population, revisited in the hepcidin era. Frontiers
in Pharmacology 2014; 5: 83.
34. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymal-
tose in patients with heart failure and iron deficiency. New
England Journal of Medicine 2009; 361: 2436–48.
35. Hsu C-Y, McCulloch CE, Curhan GC. Epidemiology of anemia
associated with chronic renal insufficiency among adults in
the United States: results from the Third National Health and
Nutrition Examination Survey. Journal of the American Society
of Nephrology 2002; 13: 504–10.
36. Ganz T. Hepcidin and iron regulation, 10 years later. Blood
2011; 117: 4425–33.
e6
Anaesthesia 2015, 70 (Suppl. 1), e6–e8
37. National Institute for Health and Care Excellence. Anaemia – iron
deficiency; Clinical Knowledge Summary, 2013. cks.nice.org.
uk/anaemia-iron-deficiency#!topicsummary (accessed 13/08/
2014).
38. National Clinical Guideline Centre (UK). Anaemia Management
in Chronic Kidney Disease: Rapid Update 2011. London: Royal
College of Physicians (UK), 2011.
39. Thomas DW, Hinchliffe RF, Briggs C, et al. Guideline for the
laboratory diagnosis of functional iron deficiency. British Jour-
nal of Haematology 2013; 161: 639–48.
40. Goddard AF, James MW, McIntyre AS, Scott BB, on behalf of
the British Society of Gastroenterology. Guidelines for the
management of iron deficiency anaemia. Gut 2011; 60:
1309–16.
41. National Institute for Clinical Excellence. CG3 – Preoperative
Tests: The use of routine preoperative tests for elective sur-
gery, 2003. www.nice.org.uk/guidance/cg3 (accessed 13/08/
2014).
42. Goodnough LT, Maniatis A, Earnshaw P, et al. Detection, evalu-
ation, and management of preoperative anaemia in the elec-
tive orthopaedic surgical patient: NATA guidelines. British
Journal of Anaesthesia 2010; 106: 13–22.
43. Hung M, Ortmann E, Besser M, et al. A prospective observa-
tional cohort study to identify the causes of anaemia and
association with outcome in cardiac surgical patients. Heart
2014; 89: 7–12.
44. Gurusamy KS, Nagendran M, Broadhurst JF, Anker SD, Richards
T. Iron therapy in anaemic adults without chronic kidney dis-
ease. Cochrane Database of Systematic Reviews 2013; 7:
CD010640. doi: 10.1002/14651858.CD010640.
45. Nangaku M, Eckardt K-U. Pathogenesis of renal nemia. Semi-
nars in Nephrology 2006; 26: 261–8.
46. McClellan W, Aronoff SL, Bolton WK, et al. The prevalence of
anemia in patients with chronic kidney disease. Current Medi-
cal Research and Opinion 2004; 20: 1501–10.
47. Macdougall IC, Bock AH, Carrera F, et al. FIND-CKD: a random-
ized trial of intravenous ferric carboxymaltose versus oral iron
in patients with chronic kidney disease and iron deficiency
anaemia. Nephrology, Dialysis and Transplantation 2014;
2014 Jun 6; doi 10.1093/ndt/gfu201.
48. Theusinger OM, Madjdpour C, Spahn DR. Resuscitation and
transfusion management in trauma patients. Current Opinion
in Critical Care 2012; 18: 661–70.
49. Cuenca J, Garcˇa-Erce JA, Munoz M, Izuel M, Martˇnez AA, Her-
rera A. Patients with pertrochanteric hip fracture may benefit
from preoperative intravenous iron therapy: a pilot study.
Transfusion 2004; 44: 1447–52.
50. Serrano-Trenas JA, Ugalde PF, Cabello LM, Chofles LC, Lazaro
PS, Benˇtez PC. Role of perioperative intravenous iron therapy
in elderly hip fracture patients: a single-center randomized
controlled trial. Transfusion 2011; 51: 97–104.
51. Kim YH, Chung HH, Kang S-B, Kim SC, Kim YT. Safety and use-
fulness of intravenous iron sucrose in the management of
preoperative anemia in patients with menorrhagia: a phase
IV, open-label, prospective, randomized study. Acta Haemato-
logica 2009; 121: 37–41.
52. Auerbach M, Goodnough LT, Shander A. Iron: the new
advances in therapy. Best Practice and Research Clinical Ana-
esthesiology 2013; 27: 131–40.
53. Lin DM, Lin ES, Tran M-H. Efficacy and safety of erythropoietin
and intravenous iron in perioperative blood management: a
systematic review. Transfusion Medicine Reviews 2013; 27:
221–34.
e7
Clevenger and Richards | Pre-operative anaemia
54. Evstatiev R, Marteau P, Iqbal T, et al. FERGIcor, a randomized
controlled trial on ferric carboxymaltose for iron deficiency
anemia in inflammatory bowel disease. Gastroenterology
2011; 141: 846–53.e2.
55. Litton E, Xiao J, Ho KM. Safety and efficacy of intravenous iron
therapy in reducing requirement for allogeneic blood transfu-
sion: systematic review and meta-analysis of randomised clin-
ical trials. British Medical Journal 2013; 347: f4822.
56. Ponka P, Sheftel AD. Erythroid Iron Metabolism. Totowa, NJ:
Humana Press, 2011: 191–209.
57. Richards T. PREVENTT (Preoperative intravenous iron to treat
anaemia in major surgery) Protocol, 2013. preventt.lshtm.ac.
uk/files/2014/06/PREVENTT-protocol_version-4_2013-Dec-16_
signed.pdf (accessed 13/08/2014).
58. Devon KM, McLeod RS. Pre and peri-operative erythropoietin
for reducing allogeneic blood transfusions in colorectal cancer
surgery. Cochrane Database of Systematic Reviews 2009; 1:
CD007148.
59. Laupacis A, Fergusson DF. Erythropoietin to minimize perioper-
ative blood transfusion: a systematic review of randomized
trials. The International Study of Peri-operative Transfusion
(ISPOT) Investigators. Transfusion Medicine 1998; 8: 309–17.
60. Alghamdi AA, Albanna MJ, Guru V, Brister SJ. Does the use of
erythropoietin reduce the risk of exposure to allogeneic blood
transfusion in cardiac surgery? A systematic review and meta-
analysis. Journal of Cardiac Surgery 2006; 21: 320–6.
61. Unger EF, Thompson AM, Blank MJ, Temple R. Erythropoiesis-
stimulating agents – time for a reevaluation. New England
Journal of Medicine 2010; 362: 189–92.
62. Pascual M, Bohle B, Alonso S, et al. Preoperative administra-
tion of erythropoietin stimulates tumor recurrence after surgi-
cal excision of colon cancer in mice by a vascular endothelial
growth factor. Journal of Surgical Research 2013; 183: 270–7.
63. Hetzel D, Strauss W, Bernard K, Li Z, Urboniene A, Allen LF. A
Phase III, randomized, open-label trial of ferumoxytol com-
pared with iron sucrose for the treatment of iron deficiency
anemia in patients with a history of unsatisfactory oral iron
therapy. American Journal of Hematology 2014; 89: 646–50.
64. Vadhan-Raj S, Strauss W, Ford D, et al. Efficacy and safety of
IV ferumoxytol for adults with iron deficiency anemia previ-
ously unresponsive to or unable to tolerate oral iron. Ameri-
can Journal of Hematology 2013; 89: 7–12.
65. Auerbach M, Silberstein PT, Webb RT, et al. Darbepoetin alfa
300 or 500 lg once every 3 weeks with or without intrave-
nous iron in patients with chemotherapy-induced anemia.
American Journal of Hematology 2010; 85: 655–63.
66. Bastit L, Vandebroek A, Altintas S, et al. Randomized, multi-
center, controlled trial comparing the efficacy and safety of
darbepoetin alpha administered every 3 weeks with or with-
out intravenous iron in patients with chemotherapy-induced
anemia. Journal of Clinical Oncology 2008; 26: 1611–8.
67. Steensma DP, Sloan JA, Dakhil SR, et al. Phase III, randomized
study of the effects of parenteral iron, oral iron, or no iron
supplementation on the erythropoietic response to darbepoe-
tin alfa for patients with chemotherapy-associated anemia.
Journal of Clinical Oncology 2011; 29: 97–105.
68. Dangsuwan P, Manchana T. Blood transfusion reduction with
intravenous iron in gynecologic cancer patients receiving che-
motherapy. Gynecologic Oncology 2010; 116: 522–5.
69. Maccio A, Madeddu C, Gramignano G, Mulas C, Sanna E,
Mantovani G. Efficacy and safety of oral lactoferrin supple-
mentation in combination with rHuEPO-beta for the treatment
of anemia in advanced cancer patients undergoing chemo-
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Clevenger and Richards | Pre-operative anaemia
therapy: open-label, randomized controlled study. Oncologist
2010; 15: 894–902.
70. Hedenus M, Birgegard G, Nasman P, et al. Addition of intrave-
nous iron to epoetin beta increases hemoglobin response and
decreases epoetin dose requirement in anemic patients with
lymphoproliferative malignancies: a randomized multicenter
study. Leukemia 2007; 21: 627–32.
71. Lindgren S, Wikman O, Befrits R, et al. Intravenous iron
sucrose is superior to oral iron sulphate for correcting anae-
mia and restoring iron stores in IBD patients: a randomized,
controlled, evaluator-blind, multicentre study. Scandinavian
Journal of Gastroenterology 2009; 44: 838–45.
72. Beck-da-Silva L, Piardi D, Soder S, et al. IRON-HF study: a ran-
domized trial to assess the effects of iron in heart failure
patients with anemia. International Journal of Cardiology
2013; 168: 3439–3442.
73. Van Wyck DB, Mangione A, Morrison J, Hadley PE, Jehle JA,
Goodnough LT. Large-dose intravenous ferric carboxymaltose
injection for iron deficiency anemia in heavy uterine bleed-
ing: a randomized, controlled trial. Transfusion 2009; 49:
2719–28.
74. Abrahamsen AF. The effect of orally and parenterally adminis-
tered iron in posthaemorrhagic anaemia. Acta Medica Scandi-
navica 1965; 177: 503–7.
75. Edwards TJ, Noble EJ, Durran A, Mellor N, Hosie KB. Random-
ized clinical trial of preoperative intravenous iron sucrose to
reduce blood transfusion in anaemic patients after colorectal
cancer surgery. The British Journal of Surgery 2009; 96:
1122–8.
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2015, 70 (Suppl. 1), e6–e8
76. Lidder PG, Sanders G, Whitehead E, et al. Pre-operative oral
iron supplementation reduces blood transfusion in colorectal
surgery – A prospective, randomised, controlled trial. Annals of
the Royal College of Surgeons of England 2007; 89: 418–21.
77. Parker MJ. Iron supplementation for anemia after hip fracture
surgery: a randomized trial of 300 patients. Journal of Bone
and Joint Surgery 2010; 2: 265–9.
78. Sutton PM, Cresswell T, Livesey JP, Speed K, Bagga T. Treat-
ment of anaemia after joint replacement. A double-blind,
randomised, controlled trial of ferrous sulphate versus pla-
cebo. Journal of Bone and Joint Surgery 2004; 1: 31–3.
79. Karkouti K, McCluskey SA, Ghannam M, Salpeter MJ, Quirt I,
Yau TM. Intravenous iron and recombinant erythropoietin for
the treatment of postoperative anemia. Canadian Journal of
Anesthesia 2006; 53: 11–9.
80. Madi-Jebara SN, Sleilaty GS, Achouh PE, et al. Postoperative
intravenous iron used alone or in combination with low-dose
erythropoietin is not effective for correction of anemia after
cardiac surgery. Journal of Cardiothoracic and Vascular Anes-
thesia 2004; 18: 59–63.
81. Pieracci FM, Henderson P, Rodney JR, et al. Randomized, dou-
ble-blind, placebo-controlled trial of effects of enteral iron
supplementation on anemia and risk of infection during surgi-
cal critical illness. Surgical infections 2009; 10: 9–19.
82. European Medicines Agency. New recommendations to manage
risk of allergic reactions with intravenous iron-containing medi-
cines, 2013. www.ema.europa.eu/docs/en_GB/document_
library/Press_release/2013/06/WC500144874.pdf (accessed
13/08/2014).
e8