Anaesthesia 2014, 69, 494–510 doi:10.1111/anae.

12591

Review Article
A narrative review of peri-operative management of patients with
thalassaemia
C. Staikou,1 E. Stavroulakis2 and I. Karmaniolou3

1 Assistant Professor, 2 Resident, Department of Anaesthesia, Aretaieio University Hospital, Athens, Greece
3 Locum Consultant, Department of Anaesthesia, Royal National Orthopaedic Hospital, Stanmore, UK

Summary
In thalassaemic patients, multiple organ systems may be affected by the disease, blood transfusion, iron overload and
chelating therapy. Patients may develop cardiomyopathy, pulmonary hypertension or heart failure requiring pre-
operative echocardiography or cardiac catheterisation. Restrictive lung dysfunction is commonly encountered,
especially in patients with splenomegaly. Haemoglobin level should be optimised pre-operatively and maintained at
adequate levels with transfusion and blood-saving strategies. Susceptibility to infections should be managed with
broad-spectrum antibiotics. Thromboembolic events due to hypercoagulability should be prevented by simple mea-
sures, such as graduated compression stockings, intermittent pneumatic compression and early mobilisation, and
possibly anticoagulant drugs. When general anaesthesia is administered, the risk of difficult intubation due to oro-
facial malformation should be considered. Cardiovascular depression due to negative inotropic and vasodilating
effects of general anaesthesia should be minimised. Neuraxial techniques may also be challenging due to spinal skele-
tal abnormalities and extramedullary haemopoiesis. A multidisciplinary pre-operative approach, clinical optimisation
and a carefully planned strategy are mandatory.
.................................................................................................................................................................
Correspondence to: C. Staikou
Email: c_staikou@yahoo.gr
Accepted: 20 December 2013

Introduction assaemia has become a disease of international interest.

Thalassaemias comprise a heterogeneous group of
inherited blood disorders characterised by defective
synthesis of haemoglobin. The term ‘thalassaemia’
originates from the Greek words ‘hάkarra, thalassa’
and ‘aίla, haema’ which mean ‘sea’ and ‘blood’,
respectively. Its etymology reveals the geographical
association of the early reported cases with regions
around the Mediterranean Sea [1]. Cooley and Lee first
reported the disorder in 1925 in children from Italy
presenting with splenomegaly and bone deformities
[2]. However, due to immigration and travelling, thal-
Moreover, advances in medical treatment, especially
early and regular blood transfusion and iron chelation,
have dramatically increased the survival of these
patients. Nowadays, thalassaemic patients are more
likely to survive to adulthood and therefore present for
surgery, and anaesthetists should be familiar with the
disease to provide safe anaesthesia and peri-operative
care.
We conducted a PubMedâ, EMBASE and COH-
RANE LIBRARY literature search for all types of pub-
lished articles up to May 2013 combining the free text

494 © 2014 The Association of Anaesthetists of Great Britain and Ireland

Staikou et al. | Peri-operative management of thalassaemia
and MeSH thesaurus terms: ‘Cooley’s anaemia’, ‘thalas-
saemia’, ‘thalasaemia alpha’, ‘thalassaemia beta’ and
‘anaesthesia’ or ‘perioperative care’ in all possible com-
binations. A total of 107 articles were retrieved. After
removing those found in duplicate, 96 articles
remained, 26 of which were found to be relevant. Arti-
cles in languages other than English were used, pro-
vided they had a detailed English abstract.
Consequently, 22 articles were found suitable for inclu-
sion in the review. One further study was found by
manual searching of the references in the electronically
identified articles. As randomised prospective data are
lacking, the articles we considered were mostly case
reports or series and retrospective studies. We also
used articles that provide information on genetics,
clinical features, and the diagnostic and therapeutic
approach to the disorder. In total, 72 articles were
included in the review.
Pathophysiology
Different types of haemoglobin are produced by
humans to cover the oxygen demands of pre- and
postnatal life. All of them have a tetrameric structure,
with two differing pairs of polypeptide chains (globins)
joined to an iron-containing molecule (haem).
Under normal circumstances, two a-globin chains
are combined with two b-chains (designated a2b2) to
form HbA, which is the most common type in the
adult. On the other hand, the main haemoglobin in the
fetus is HbF (fetal haemoglobin), which consists of
a- and c-chains (a2c2) and is characterised by a high
affinity for oxygen. After birth, HbF synthesis stops and
fetal haemoglobin is almost completely replaced by
adult haemoglobin HbA during the first months of life.
A normal variant of HbA is HbA2, which consists
of a- and d-chains (a2d2) and is found in small con-
centrations in blood. Other less common forms of
haemoglobin include Hb-Portland, which consists of
f-chains and c-chains (f2c2), and Hb-Gower, which
comprises f- and e-chains (f2e2, Hb-Gower 1) or
a- and e-chains (a2e2, Hb-Gower 2); these haemoglo-
bins are mostly found in the fetus [3]. There are two
a-globin genes located on each chromosome 16, and
one non-a-globin gene (normally b-globin gene) on
each chromosome 11. Thus, altogether six alleles code
for globin chains; the a-chains are encoded by four
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2014, 69, 494–510
co-dominant alleles, while the b-chains are encoded by
two co-dominant alleles [1]. Co-dominance implies
that the alleles are equally expressed in the synthesis of
haemoglobin polypeptides.
In b-thalassaemia, the b⁺ and b° types are charac-
terised by reduced or absent b-chains, respectively. In
either case, the a-like chains are in excess and their
precipitation in red blood cells results in abnormal
erythropoiesis and increased haemolysis [4]. Three
clinical phenotypes exist: minor or trait; intermedia;
and major (historically known as Cooley’s anaemia),
according to the effect of mutations on b-globin gene
productivity and the implicit need for early blood
transfusion. Deletions of d-globin and b-globin adult
genes sometimes augment c-globin expression, moder-
ately (db-thalassaemia with Hb-Lepore) or significantly
(hereditary persistence of fetal haemoglobin) [4].
Finally, HbE/b-thalassaemia, which results from the
coexistence of one gene for HbE and one for b-thalas-
saemia, is a common genotype, with a variable clinical
spectrum [5]. HbE is an abnormal haemoglobin with a
single mutation at the position 26 of the b-chain that
causes replacement of glutamic acid with lysine.
Underproduction of a-chains causes abundance of
b-like chains; the disorder is known as a-thalassaemia
and can be classified as a⁺ or a° type, depending on
the decrease or complete absence of the a-chains pro-
duced by the affected chromosome [6]. People with
‘aa/a ’ genotype, who have three functional and one
non-functional allele, are silent carriers of a-thalassae-
mia. When mutations involve one of the a-globin
genes on each chromosome or both of them on the
same chromosome, the disorder is referred to as
a-thalassaemia trait ( a/ a or aa/ ), presenting
clinically with mild anaemia [6]. Important variants of
a-thalassaemia are HbH disease ( /a ), with three
non-functional alleles and formation of tetrameric
b-chains (HbH), and Bart’s hydrops fetalis syndrome
( / ), with no functional allele and formation of
tetrameric c-chains (Hb-Bart’s). The latter usually
results in intra-uterine or early neonatal death, espe-
cially if left untreated [6].
Epidemiology
More than 60 000 neonates with severe forms of
b-thalassaemia are born each year worldwide [4]. The
495
Anaesthesia 2014, 69, 494–510
disease is found mainly in the Mediterranean area
(Greece, West Turkey, Middle East, North Africa,
South Italy and Mediterranean islands) and also in
South East Asia; its geographical pattern of distribution
is associated with the finding that heterozygous indi-
viduals gain resistance against Plasmodium falciparum
malaria, even though the precise mechanism of protec-
tion is not clearly understood [7].
Interestingly, the world prevalence of b-trait carriers
is estimated to be up to 1.5%, while half of b-thalassae-
mic patients appear to have HbE/b-thalassaemia [4, 5].
Similarly, a-thalassaemia is distributed in tropical
and subtropical regions [8], with the a° type being
more common in South East Asia, where more than
10% of specific populations are carriers [3, 8]. Carriers
may also be protected in some way from malaria or
other endemic infections.
According to the Thalassaemia International Fed-
eration, at least 200 000 patients are currently receiv-
ing treatment worldwide [4]. However, the true
number throughout the world is probably underesti-
mated as many patients live in developing countries
with no clear medical records and limited access to
medical treatment.
Genetics
Thalassaemias are inherited in an autosomal recessive
manner, so the phenotype is fully expressed in the
homozygous genotype. Nevertheless, other factors may
play a significant role; milder b-thalassaemia pheno-
types are found in cases with co-inheritance of a-thal-
assaemia or disorders associated with increased
synthesis of fetal c-chains [4]. At the molecular level,
two multigene bunches are responsible for haemoglo-
bin composition: the a-like globin cluster on chromo-
some 16 and the b-like globin cluster on chromosome
11 [4]. The expression of the a- and b-globin genes is
controlled by specific regulatory elements lying far
upstream of the gene clusters [4].
About 200 mutations have been identified in
patients with b-thalassaemia, involving all stages from
transcription to mRNA translation [9]. In most cases,
the abnormality results from small nucleotide substitu-
tions in the cluster, although b-gene deletions, struc-
tural variants and, rarely, deletions of regulatory
elements have also been described [10].
496
Staikou et al. | Peri-operative management of thalassaemia
In a-thalassaemia, the main mechanism is the
deletion of one ( a) or both a-genes ( ) from the
chromosome. However, point mutations in crucial
areas of genes affecting mRNA processing and a-
globin stability may cause the non-deletional type,
while more rarely deletion of regulatory agents is the
causative abnormality [11].
Clinical features
Ineffective erythropoiesis is the main feature of b-
thalassaemia; although erythropoiesis is enhanced and
the normal variant HbA2 may increase, it cannot com-
pensate adequately for the lack of b-globin chains.
Furthermore, the relative surplus of the a-globin
chains accounts for many of the detrimental effects.
Τhalassaemia-related deaths are mostly due to car-
diac complications, especially congestive heart failure
[12]. Biventricular dilated cardiomyopathy [13] and
pulmonary hypertension [14] have been suggested as
the pathophysiological substrates of heart failure in b-
thalassaemia major and intermedia, respectively. Acute
myocarditis, which may occur early in life, represents
another cause of acute or chronic cardiac insufficiency
[15]. Pericarditis is rarely reported nowadays, espe-
cially after the introduction of chelation therapy. Repo-
larisation abnormalities have also been identified in
b-thalassaemia major, manifested as prolonged QT,
QT corrected for heart rate (QTc), QT dispersion
(QTd) and QTd corrected for heart rate (QTcd)
[16–18], especially during exercise [19]. These electro-
cardiographic abnormalities, associated with increased
risk of Torsades de Pointes ventricular tachycardia, are
not related to serum ferritin, liver or cardiac iron load
[16, 17]. There is an increased risk of sudden death
[20].
The prevalent respiratory abnormality in b-thalas-
saemia major is restrictive lung dysfunction with sig-
nificantly reduced total lung capacity [21].
Parenchymal pathology and alveolar capillary mem-
brane defects may be involved [21]; lung fibrosis and/
or interstitial oedema due to iron overload have been
suggested as possible causes of the restrictive pattern
[22]. A reduced diffusing capacity for carbon monox-
ide, which is common among b-thalassaemic patients,
and a less frequently encountered obstructive pulmo-
nary dysfunction, usually remain asymptomatic [23].
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Staikou et al. | Peri-operative management of thalassaemia
Pulmonary hypertension may present in the early
stages of cardiac involvement; it is diagnosed in about
50% of patients with b-thalassaemia intermedia and
up to 75% of those with major type [24, 25]. Free hae-
moglobin and arginase, released during haemolysis, are
likely to be implicated in the development of pulmo-
nary hypertension; these cause increased nitric oxide
scavenging and arginine depletion, respectively, both of
which reduce the bioavailability of nitric oxide [26].
Abnormalities in renal tubular function and glo-
merular filtration have been reported in patients with
b-thalassaemia major due to anaemia, iron overload
and overchelation [27]. In addition, iron chelators such
as deferasirox may cause nephrotoxicity [28]. The
most common lesion associated with b-thalassaemia is
low molecular weight proteinuria [27]. Other reported
abnormalities include abnormally high creatinine clear-
ance, increased urinary excretion of calcium, phos-
phate, magnesium and uric acid, and biomarkers of
proximal tubular injury [27, 29]. Regular transfusion
has been associated with lower creatinine clearance,
but more hypercalcuria [29].
The majority of endocrine disorders encountered
in b-thalassaemia result from anterior pituitary dys-
function due to iron overload. Most of them can be
prevented by early and regular chelation therapy [30].
Children with b-thalassaemia present with growth
retardation and short stature, which is resistant to
treatment with growth hormone [30, 31]. Hypogona-
dism and absent or delayed puberty with fertility prob-
lems are also common features, usually managed with
hormonal replacement therapy [30, 31]. Glucose intol-
erance and diabetes mellitus are frequently seen among
adolescents and adults, respectively [30]. A causative
relationship with iron overload, chronic liver disease
and genetic predisposition has been suggested [30].
Iron overload causes both primary hypothyroidism
and hypoparathyroidism, the latter rarely being accom-
panied by significant hypocalcaemia. These two disor-
ders usually present between 10 and 20 years of age
and can be reversed by intensive chelation, if recogni-
sed early [30].
Extramedullary erythropoiesis causes the craniofa-
cial deformities of frontoparietal bossing, prominent
zygomatic bones with nasal bridge depression and
maxillary overgrowth with dental protrusion/malocclu-
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2014, 69, 494–510
sion, which constitute the characteristic ‘rodent’ or
‘chipmunk’ face [32]. Compensatory extramedullary
hyperplasia and bone overgrowth may result in com-
pression of neural structures. Narrowing of the optic
canal may lead to optic neuropathy and subsequent
visual abnormalities, while extramedullary haemopoietic
masses in the middle ear may result in conductive
hearing loss. The involvement of spinal cord and cau-
da equina may present with neurological symptoms,
varying from mild sensory or motor defects to com-
plex paraplegia, sphincter dysfunction and impotence
[33].
Defects in bone mineralisation, osteopenia, osteo-
malacia and microfractures due to hyperplasia of the
erythroid marrow and expansion of the marrow cavity
are commonly encountered among b-thalassaemic
patients [34]. Τhe degree of osteopathy is associated
with inadequate transfusion and chelating therapy
[34]. The incidence of bone fractures is estimated to
be up to 12.2% and 16.6% of patients with the inter-
media and major phenotypes, respectively [35]. Lower
rates are reported in non-transfused patients with E/b-
(7.4%) or a-thalassaemia (2.3%), possibly due to
milder disease and less severe haemolysis, whereas
patients with E/b-thalassaemia transfused more than
eight times annually have a 12.9% incidence of frac-
tures. Advanced age and sex hormone replacement
therapy further increase the risk of fractures [35].
Even though a haemodilution-related coagulopathy
may exist, thalassaemia per se is well recognised as a
hypercoagulable state; platelet and endothelium activa-
tion, membrane changes in red blood cells and low
levels of antithrombin III, protein C and protein S all
contribute to an increased thrombotic tendency [36].
Similar abnormalities are also found in sickle cell anae-
mia, even though this haemoglobinopathy has a differ-
ent pathophysiology. It is possible that common
pathways are involved in the thrombotic tendency
encountered in these hereditary haemolytic anaemias.
Chronic intravascular haemolysis is associated with
high levels of free haem in the blood, which induces
endothelial oxidative injury and activation, and also
reduced bioavailability of nitric oxide [26, 37]. Chronic
haemolysis, ischaemia-reperfusion injury and vascular
endothelial dysfunction due to damage and inflamma-
tion are features of both b-thalassaemia and sickle cell
497
Anaesthesia 2014, 69, 494–510
anaemia [37]. Notably, vasculopathy characterised by
endothelial activation and increased blood cell adhe-
sion is involved in the pulmonary hypertension of
b-thalassaemia and the vaso-occlusive episodes of
sickle cell anaemia [37].
Venous thromboembolic events, such as deep vein
thrombosis, pulmonary embolism or portal vein
thrombosis, occur mostly in b-thalassaemia intermedia
[36], while arterial adverse events are more frequent in
the major type [38]. Age > 20 years, splenectomy and
a history of thromboembolism represent predisposing
factors [38]. Symptomatic ischaemic strokes due to
cerebral thrombosis are relatively rare, even though the
incidence of silent cerebral infarctions is quite high
[39]. Risk factors associated with cerebral thromboem-
bolic events include splenectomy, elevated platelet
count, decreased levels of protein C, protein S or plas-
minogen, cardiomyopathy, diabetes mellitus and
advanced age [39]. Patients who are not transfused or
receive irregular and limited transfusions are at higher
risk for cerebral thrombosis than those who are trans-
fused regularly [39].
Haemochromatosis results not only from multiple
blood transfusions but also from increased intestinal
iron absorption and release of recycled iron from the
reticuloendothelial system. Thus, it may develop even
in patients without transfusion dependence, although it
is most prominent in those receiving transfusion ther-
apy. Severe chronic haemolysis, along with ineffective
erythropoiesis and regular blood transfusions, results
in iron deposition mainly in the heart (cardiomyopa-
thy) and liver (cirrhosis), while endocrine glands (pan-
creas, thyroid gland) are also commonly affected [30,
34].
Multiple transfusions expose thalassaemic patients
to a number of blood-transmitted diseases such as viral
infections. Hepatitis C is the most common virus with
hepatitis B and HIV being rarer [40], while the West
Nile Virus and babesiosis can also be transmitted via
this route [41]. In addition, anaemia, iron accumula-
tion, splenectomy and other immune abnormalities
render these patients prone to bacterial infections such
as klebsiella in Asia and yersinia enterocolitis in Eur-
ope and North America [42].
A high incidence of cognitive defects and impair-
ment of neuropsychological tests, not related to
498
Staikou et al. | Peri-operative management of thalassaemia
hypoxia or iron overload, has been reported in patients
with thalassaemia [33]. The physical and social restric-
tions imposed by the chronicity of the disease may
impair the patient’s intellectual and psychosocial pro-
gress. Furthermore, poor quality of life and depressive
symptoms are encountered especially in young patients
as they are trying to adjust to the specific requirements
and lifestyle alterations of their disease [43].
Regarding a-thalassaemia, patients with trait (2/4
functional alleles) are free of symptoms and may be
diagnosed via standard screening tests for thalassaemia
carriers performed during pregnancy or after investiga-
tion of a mild microcytic hypochromic anaemia
revealed after routine testing. HbH disease (1/4 func-
tional alleles) is an intermediate form of a-thalassae-
mia characterised by variable amounts of HbH (b4)
and decreased production of HbA2. HbH is an unsta-
ble haemoglobin with higher affinity for oxygen than
normal haemoglobin, resulting in reduced oxygen
delivery to tissues. The clinical severity of the disease
varies considerably, depending on the mutation (non-
deletional type being more severe than deletional) and
a-globin chain deficiency [6]. Patients with severe
forms may require blood transfusion, develop spleno-
megaly, jaundice and suffer growth retardation, infec-
tions with acute haemolytic episodes and potential
iron accumulation at older ages [6]. Finally, Bart’s hy-
drops fetalis syndrome (functional alleles: 0/4) is the
most severe form of a-thalassaemia; the extreme defi-
ciency of a-chains in fetal life favours the exclusive
formation of Hb-Bart’s (c4). Hb-Bart’s is an unstable,
non-functional haemoglobin due to its very high affin-
ity for oxygen, resulting in almost no oxygen delivery
to the tissues. In uterus, the fetuses suffer from a very
severe haemolytic anaemia and have abnormal devel-
opment with brain growth impairment, cardiovascular
abnormalities and high output heart failure, pericardial
and pleural effusions, ascites, hepatosplenomegaly,
skeletal and genitourinary malformations [44]. If born,
the neonates are pale and oedematous, sometimes with
anasarca (generalised oedema). All the above abnor-
malities usually result in intra-uterine or early postna-
tal death [6]. Bart’s syndrome has also serious
maternal implications, such as hypertension, oedema,
severe pre-eclampsia or eclampsia (a condition known
as mirror syndrome) and also dystocia, postpartum
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Staikou et al. | Peri-operative management of thalassaemia
haemorrhage and retained placenta due to placental
enlargement [44].
Diagnosis and iron load monitoring
Early diagnosis and treatment of thalassaemia is of para-
mount importance to limit the complications. Standard
haematological tests include the assessment of mean cor-
puscular volume and mean corpuscular haemoglobin
(MCH) [45], with the latter being more reliable. Both are
reduced, indicating microcytic hypochromic anaemia. If
haemolysis is suspected, a blood film and reticulocyte
count should be performed. Haemoglobin electrophore-
sis, high performance liquid chromatography (HPLC) or
isoelectric focusing may be used for identification of vari-
ant haemoglobins, whereas HPLC and microcolumn
chromatography are the most acceptable methods for
accurate quantification of HbA2 [46]. The levels of HbA2
are reduced in iron-deficiency anaemia and in a-thalas-
saemia, but are raised in b-thalassaemia [6].
In thalassaemic patients, laboratory investigation
usually reveals a low MCH (< 25 pg in a-, and
< 27 pg in b-thalassaemia trait). The MCH may rarely
be normal when there is trait due to silent b-thalassae-
mia mutation or with co-existence of a- and b-thalas-
saemia disorders [45]. It should also be noted that as
HbA2 concentration is affected by multiple factors,
b-thalassaemia trait may be underdiagnosed when
HbA2 is normal or borderline (i.e. concomitant iron
deficiency), whereas a-thalassaemia trait is often misdi-
agnosed as iron deficiency. Further details regarding the
diagnostic procedure and criteria for the various types
of the disorder are beyond the scope of this review.
Iron load monitoring is of great importance, as
haemosiderosis is a major secondary complication of
regular transfusions. Serum ferritin level is the standard
routine test. Liver biopsy to assess hepatic iron concen-
tration is the most reliable guide to total body stores,
but is rarely performed as the invasiveness makes it an
impractical screening method [47]. Recently, magnetic
resonance imaging (MRI) has been adopted to evaluate
iron accumulation in the liver and heart and guide che-
lation treatment [47].
Treatment
Over the last decades, significant progress has been
made in supportive and treatment strategies used in
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2014, 69, 494–510
thalassaemic patients. After distinguishing the b-major
type and performing hepatitis B vaccination, regular
blood transfusions 1–4 times per month improve anae-
mia and suppress inefficient erythropoiesis, while lim-
iting gastrointestinal absorption of iron [48]. In
addition, hydroxycarbamide (hydroxyurea) may reduce
transfusion requirements by augmenting the produc-
tion of c-chains and fetal haemoglobin [49]. Regarding
management of iron overload, desferrioxamine is the
‘gold standard’ chelating agent. It is given intrave-
nously or subcutaneously (5–7 times per week) to
patients who are regularly transfused. Usually, a dose
of 20–60 mg.kg 1 is administered via an infusion
pump subcutaneously overnight [47]. Although the
efficacy of desferrioxamine is proven, it has significant
toxic effects; ophthalmic, auditory, renal and acute
pulmonary toxicity have been reported [47]. If possi-
ble, desferrioxamine should be discontinued during
pregnancy due to the risk of teratogenesis [Food and
Drug Administration (FDA) pregnancy category C],
and restarted postpartum. Even though there are no
adequate human data, some animal studies have
shown delayed osteogenesis and skeletal anomalies in
the fetuses. Thus, desferrioxamine should be used dur-
ing pregnancy only if the potential benefit justifies the
potential risk to the fetus (Novartis Pharma Stein AG,
Stein, Switzerland, product information, 2011). Regard-
ing the possible risks for breastfed neonates, there are
no data on desferrioxamine excretion into human
milk; the product information leaflet suggests that
‘caution should be exercised when the drug is adminis-
tered to nursing women’. Novel orally administered
chelators like deferiprone, deferasirox and deferitrin
have been introduced in clinical practice and seem
promising in terms of reduced toxicity and better
compliance [47]. Stem cell transplantation is currently
the only curative treatment, with a reported disease-
free survival rate of up to 80–97%, depending on the
stage of the disease [41]. The sources of stem cells are
bone marrow, peripheral blood or, more recently, cord
blood.
Splenectomy is indicated in patients with increased
transfusion demands, hypersplenism or splenomegaly
due to severe haemolysis [41]. However, it is associated
with serious complications such as postoperative infec-
tions and thromboembolic events [41].
499
Anaesthesia 2014, 69, 494–510
Regarding a-thalassaemias, patients with trait have
only a mild anaemia, which does not require specific
treatment. Specific therapy may be required in HbH
patients, depending on the severity of the disease; the
management varies from intermittent transfusions in
the deletional type to more regular transfusions and
splenectomy in the non-deletional form. In Bart’s hy-
drops fetalis syndrome, although fetal transfusions and
in utero surgery are possible treatment options, preg-
nancy termination is usually recommended, as most
fetuses are non-viable, while serious maternal risks also
exist [6].
Peri-operative management and
anaesthetic considerations
Patients with thalassaemia may present for elective or
emergency surgery [50, 51] such as therapeutic sple-
nectomy, cholecystectomy due to bilirubin gallstone
formation, correction of facial deformities and opera-
tive treatment of leg ulcers, fractures and extramedul-
lary pseudotumours [52]. The existing literature
regarding anaesthesia and peri-operative management
is limited mainly to case reports (Table 1) and a few,
mostly retrospective, studies (Table 2); airway and hae-
modynamic management are usually highlighted [1].
For elective surgery, thorough clinical and labora-
tory examination and pre-operative optimisation of the
patient’s clinical condition are required. They should
be investigated for co-existing pathology related to the
disease, as well as that consequent on blood transfu-
sion, chelating therapy and other medical treatment. A
systematic, multidisciplinary approach is of paramount
importance; haematologists, cardiologists, pulmonary
physicians, anaesthetists and surgeons should co-oper-
ate to plan peri-operative management tailored to the
individual patient (Table 3).
Careful airway assessment with bedside predictive
tests and preparation for difficult airway management
are of vital importance, as the probability of difficult
intubation in the presence of maxillary hypertrophy
reaches almost 19% [66]. The risk of difficult intuba-
tion due to orofacial malformations has long been
recognised in adults as well as children, in whom ton-
sillar enlargement represents an additional risk factor
[53, 54]. Laryngeal mask airway insertion may be chal-
lenging due to a high-arched palate [54]. When insur-
500
Staikou et al. | Peri-operative management of thalassaemia
mountable difficulties are anticipated, elective
tracheostomy or alternative methods to secure the air-
way may be considered [55]. Submental intubation has
been described in a patient with b-thalassaemia major
presenting for orofacial surgery for cosmetic reasons
[55]. In this case, orotracheal intubation would have
interfered with the surgical field, whereas nasotracheal
intubation proved impossible due to nasal obstruction
secondary to the condition. In most reported cases,
tracheal intubation was difficult but achieved using
straightforward methods such as careful head and neck
adjustment, external laryngeal pressure and use of a
stylet [53]. Furthermore, in most patients with ade-
quate disease management, facial deformities are less
evident, pre-operative airway assessment may be nor-
mal [56] and orotracheal intubation feasible and
uneventful [55, 57].
Organ dysfunction due to iron overload should be
carefully evaluated before elective surgery. Common
features of haemochromatosis include cardiomyopathy
and pigmented liver cirrhosis [58]. Plasma iron and
ferritin levels can be measured pre-operatively, but
because they provide only a rough estimation of organ
iron, usually more specific tests are required. Ade-
quate chelating therapy should also be confirmed.
There is no recommendation for discontinuing iron
chelation therapy before surgery; however, desferriox-
amine should probably be stopped as the transient
febrile reaction associated with its use could compli-
cate the differential diagnosis of postoperative infec-
tions [52].
Clinical assessment of cardiovascular function
should pay special attention to exercise tolerance. Car-
diac echocardiography should be performed if clini-
cally indicated [58, 59]. Echocardiography with
Doppler studies can assess the size, contractility and
intraluminal pressure of the cardiac chambers. In the
presence of cardiomyopathy, serious pulmonary hyper-
tension or congestive heart failure, cardiac catheterisa-
tion may be considered [58]. In such high-risk cases,
close cardiovascular monitoring is also indicated
intra-operatively; transoesophageal or transthoracic
echocardiography can be used for real-time assessment
of ventricular filling and contractility. Other minimally
invasive cardiac output monitors such as the oesopha-
geal Doppler monitor and pulse contour analysis
© 2014 The Association of Anaesthetists of Great Britain and Ireland
 Table 1 Case reports of anaesthetic management of patients with b-thalassaemia undergoing surgery.

Patient
characteristics/ Syndrome/co-existing Problems/peri-operative
Reference number pathology Surgery Anaesthesia/drugs complications Management Outcome
Pe

rez F (36 years) b-Thalassaemia intermedia Splenectomy GA Severe Maintenance of Uneventful
et al. [50]; Severe anaemia (emergency) haemolysis/anaemia normovolaemia course
case report (Hb = 40 g.l 1)

Unal F (pregnant) b-Thalassaemia Splenectomy GA for splenectomy Inadequate data Inadequate data Inadequate
et al. [51]; (urgent, at 23 Epidural anaesthesia data
case report weeks of for caesarean
gestation) section
Caesarean
section (at
38 weeks of
gestation)

Orr [53]; case F (11 years) b-Thalassaemia Dacryo- GA: Difficult intubation Use of malleable Successful

© 2014 The Association of Anaesthetists of Great Britain and Ireland

report Hypertrophy of the maxilla cystectomy Thiopental stylet intubation
Anaemia Suxamethonium
Jaundice
Staikou et al. | Peri-operative management of thalassaemia

Hepatomegaly Splenomegaly

Ali and Khan F (11 years) b-Thalassaemia intermedia Bilateral 1st case: GA: Difficulty in laryngeal Tracheal Both cases:
[54]; 2 cases M (9 years) Anaemia inguinal Midazolam mask placement intubation Uneventful
Facial deformities hernia repair Sevoflurane (for Difficult intubation achieved using course
Tonsillar enlargement. Elective induction) (Cormack & Lehane a stylet
Left vertricular splenectomy Pethidine grade 2b)) Anaesthetics/
hypertrophy Isoflurane Intra-operative analgesics for
Atracurium hypertension hypertension
2nd case: GA: (inadequate
Midazolam response)
Thiopental
Fentanyl
Atracurium

Mak and F (33 years) b-Thalassaemia major Maxillary and GA: Nasotracheal intubation Submental Uneventful
Ooi [55]; Regular transfusions mandibular Propofol not possible due to intubation course,
case report Iron overload osteotomies Fentanyl maxillary bone marrow Fluids, massive discharged
Isoflurane hypertrophy blood transfusion, after 10 days
Cis-atracurium Massive surgical intra-operative
haemorrhage blood salvage
Planned
surgery
abandoned
Anaesthesia 2014, 69, 494–510

501
502
Table 1 (continued)

Patient
characteristics/ Syndrome/co-existing Problems/peri-operative
Reference number pathology Surgery Anaesthesia/drugs complications Management Outcome
Butwick F (28 years) b-Thalassaemia major Caesarean Spinal anaesthesia; Low postpartum Hb Blood transfusion Uneventful
et al. [56]; (pregnant, 37 Osteoporosis section hyperbaric 0.5% course
case report weeks of Prolonged activated partial bupivacaine
gestation) thromboplastin time 2.5 ml +
diamorphine
Anaesthesia 2014, 69, 494–510

300 lg

Kitoh M (37 years) b-Thalassaemia intermedia Elective GA: Severe anaemia Invasive monitoring/ Uneventful
et al. [57]; Anaemia splenectomy Hyoscine/pethidine Hyperkinetic circulation Swan-Ganz catheter course,
case report Liver dysfunction Diazepam Minimal discharged
Fentanyl cardiovascular after 3 weeks
Vecuronium suppression
Isoflurane with anaesthetics
Prostaglandin E1 Hb maintenance

Katz n=8 b-Thalassaemia Laparoscopic GA Co-existing pathology Invasive monitoring Uneventful

et al. [58]; F = 3, M = 5 major, n = 6; cholecystectomy Postoperative including Swan-Ganz course
case series (21–42 years) intermedia, n = 2 low-grade fever catheter in selected
Anaemia (n = 2) cases
Haemochromatosis (n = 7) Postoperative
Hepatitis C (n = 3) pulmonary
Liver cirrhosis with physiotherapy &
ascites (n = 5) broad-spectrum
Splenectomy (n = 7) antibiotics

Pe

rez Ferrer F (14 years) b-Thalassaemia minor Posterior spine GA: Anaemia Recombinant human Uneventful
et al. [59]; Mild anaemia fusion Propofol Surgery with expected erythropoietin course
case report Fentanyl significant haemorrhage Pre-operative
Cis-atracurium autologous
Sevoflurane blood donation
Remifentanil Intra-operative
Postoperative blood salvage
epidural analgesia Tranexamic acid
Controlled
hypotension
with remifentanil

Waters F (31 years; b-Thalassaemia intermedia Caesarean Combined Parturient refused Use of blood salvage Uneventful
et al. [60]; pregnant 37+5 Mild anaemia section spinal-epidural allogenic blood (2250 ml of red course
case report weeks of transfusion blood cells, average
gestation) Severe bleeding haematocrit 50%)
(~9000 ml) due to
placenta accreta
Staikou et al. | Peri-operative management of thalassaemia

© 2014 The Association of Anaesthetists of Great Britain and Ireland

 Table 1 (continued)

Patient
characteristics/ Syndrome/co-existing Problems/peri-operative
Reference number pathology Surgery Anaesthesia/drugs complications Management Outcome
Gupta F (5 years) b-Thalassaemia Splenectomy GA: None None Uneventful
et al. [61]; Eisenmenger’s syndrome Midazolam course,
case report Thrombocytopenia Fentanyl discharged
Hepatomegaly Ketamine on 5th post-
Splenomegaly Halothane operative day
Restrictive lung disease/ Atracurium
hypoxaemia
Pulmonary hypertension
Bharati F (14 years) b-Thalassaemia Open GA: Anaemia Pre-operative Uneventful
et al. [62]; Sickle cell anaemia cholecystectomy Midazolam Possibility of increased transfusion course
case report Facial deformities Fentanyl pulmonary artery Avoidance of
Jaundice Propofol pressures nitrous oxide
Liver dysfunction Isoflurane
Anaemia Rocuronium

© 2014 The Association of Anaesthetists of Great Britain and Ireland

Rowbottom F (52 years) HbH disease Open-heart 1st case: GA: Haemoglobinuria, No measures taken Uneventful
and M (35 years) Case 1: surgery: Diazepam rapid resolution for course
Staikou et al. | Peri-operative management of thalassaemia

Sudhaman Hepato-splenomegaly mitral valve Morphine Potential problem haemoglobinuria

[63]; 2 cases Controlled congestive replacement Isoflurane with cold Short duration of
heart failure Pancuronium cardioplegia bypass
Atrial fibrillation 2nd case: GA: Potential problem Use of small
Pulmonary Midazolam with nitroprusside amounts of
hypertension Fentanyl nitroprusside
Case 2: Morphine
Cardiomegaly Isoflurane
Pulmonary Pancuronium
hypertension
Basß and F (37 years) b-Thalassaemia Elective Epidural anaesthesia: Shoulder pain Fentanyl 100 lg Uneventful
Ozlu€ [64]; Sickle cell anaemia laparoscopic 15 ml bupivacaine course
case report Crohn’s disease cholecystectomy 0.5%; T9-10
Liver dysfunction Sedation with
Mild anaemia propofol and
midazolam
Botta M (50 years) b-Thalassaemia major Open-heart GA Low Hb Blood transfusion Uneventful
et al. [65]; Anaemia surgery Erythrocytes susceptible Packed red blood course
case report Pulmonary hypertension (mitral valve to haemolysis/problem cells in priming
replacement) augmented by solution
extracorporeal Non-pulsatile flow
circulation via a centrifugal
pump

F, female; M, male; GA, general anaesthesia, Hb, haemoglobin.

Anaesthesia 2014, 69, 494–510

503
Anaesthesia 2014, 69, 494–510 Staikou et al. | Peri-operative management of thalassaemia

Table 2 Studies of anaesthetic and peri-operative management of patients with b-thalassaemia.

Patient
characteristics/
Reference number Anaesthesia Study aim Findings
Voyagis and Homozygous GA To investigate the occurrence Probability of difficulty
Kyriakis [66]; b-thalassaemia Intravenous of difficult direct laryngoscopy 18.8%
retrospective Hypertrophy induction (Grade 3-4 view)
study of the Suxamethonium
maxilla (32/58)
Adults (n = 58)
Suwanchinda b-Thalassaemia GA To investigate the occurrence of Intra-operative
et al. [67]; Children peri-operative hypertension and hypertension/
retrospective (n = 100) related complications in children tachycardia in all
study undergoing splenectomy patients
Postoperative
hypertension in 16/100
Postoperative
convulsions in 3/16
of above
Persistent neurological
deficit in 1/16 of above
No deaths
Suwanchinda b-Thalassaemia GA (n = 50) To investigate the efficacy of Intra- and postoperative
et al. [68]; Children GA + pre-operative furosemide in preventing hypertension similar in
study type (n = 90) furosemide peri-operative hypertension in both groups
not defined 1 mg.kg 1 (n = 40) children undergoing splenectomy Postoperative
convulsions in 3/50 in
the control group
Suwanchinda b-Thalassaemia GA + pre-operative To investigate the efficacy of The combination
et al. [69]; Children furosemide captopril (alone or combined captopril/furosemide
randomised (n = 82) (n = 40) with furosemide) in preventing gave better control of
controlled GA + pre-operative peri-operative hypertension in intra-operative
trial captopril or children undergoing splenectomy hypertension
captopril/ Postoperative
furosemide convulsions due to
(n = 42) hypertension in 1/42 in
the captopril/furosemide
group

GA, general anaesthesia.

devices may be useful in cases with low cardiac output,
although they do not provide specific information
about the status of the right heart and pulmonary vas-
culature. Invasive monitoring via pulmonary artery
catheterisation might be considered in selected, high-
risk cases [57, 58]; it provides accurate direct pressure
readings as well as several derived haemodynamic vari-
ables to guide the peri-operative management, but the
risk of adverse effects and complications should also
be taken into account.
In patients with cardiac pathology, especially in
those presenting with high cardiac output due to anae-
mia, cardiovascular depression should be avoided and
volatile anaesthetic agents should be kept at low con-
centrations [57]. Prostaglandin E1 has been used to
reduce afterload and consequently cardiac work during
splenectomy [57]. Peri-operative hypertension has been
reported in thalassaemic children [54, 67], especially in
those undergoing splenectomy [67]. Intra-operative
hypertension may result from surgical manipulation of
the enlarged spleen and subsequent autotransfusion
[67]. Even though furosemide and captopril may be
helpful intra-operatively, they do not adequately pre-
vent postoperative hypertension and associated convul-
sions [67–69]. In high-risk cases, prompt and
aggressive treatment of hypertension is required to
minimise the incidence of neurological complications
[67–69].

504 © 2014 The Association of Anaesthetists of Great Britain and Ireland

 Table 3 Peri-operative implications of pathophysiological changes in b-thalassaemia.

System Pathology related to b-thalassaemia Pre-operative investigation Peri-operative management/implications

Cardiovascular Left and right ventricular cardiomyopathy Assess exercise tolerance; history Invasive monitoring:
Dilated cardiomyopathy of fatigue, breathlessness or Arterial blood pressure
Restrictive cardiomyopathy reduced exercise capacity, poor  Pulmonary artery catheter
Cardiac hypertrophy/dilatation/heart tolerance in formal exercise Avoid/minimise:
failure testing Cardiovascular depression
Pulmonary hypertension  secondary Electrocardiogram Increases in pulmonary artery pressure
right heart failure Echocardiography Arrhythmogenic agents
Myocarditis  Cardiac catheterisation
Pericarditis
Valvulopathies
Arrhythmias/repolarisation abnormalities
Respiratory Restrictive lung dysfunction: Chest X-ray Pre-operative optimisation (physiotherapy/
Fibrosis Pulmonary function tests drugs)
Interstitial oedema Consider modifications in ventilation
Obstructive or mixed lung dysfunction mode and/or settings
Maintain adequate oxygenation and

© 2014 The Association of Anaesthetists of Great Britain and Ireland

normocarbia, while minimising airway
pressure
Limit height of regional anaesthetic block
Staikou et al. | Peri-operative management of thalassaemia

Possible need for postoperative mechanical

ventilation
Urinary Renal hyperfiltration/increased creatinine Assessment of renal function/ Pre-operative optimisation/electrolyte
clearance expert consultation correction
Proteinuria Check of electrolyte levels Peri-operative monitoring of renal function/
Increased urinary excretion of: electrolytes
Calcium
Phosphate
Magnesium
Uric acid

Haemopoietic Haemolysis/anaemia Full blood count  pre-operative Avoid anaesthetic suppression of high cardiac
Abnormalities in platelet count transfusion output state
Hypercoagulation/coagulopathy Coagulation tests Reduced tolerance to bleeding
Iron overload Liver iron concentration using Increased transfusional risk
MRI Consider blood salvage
Consider risks of neuraxial anaesthesia
Prophylactic measures for DVT/thromboembolic
events
Skeletal Skeletal deformities Pre-operative tests predicting Preparation for difficult intubation
Osteopenia/osteoporosis difficult intubation Possible nasal obstruction
Extramedullary haemopoiesis History/investigation for Potentially difficult neuraxial anaesthesia
osteoporosis Careful transfer and placement of patients
Anaesthesia 2014, 69, 494–510

505
 Anaesthesia 2014, 69, 494–510 Staikou et al. | Peri-operative management of thalassaemia

In patients with pulmonary hypertension, it is

Personnel surveillance/avoid exposure to blood

Pre-operative optimisation/peri-operative care

important to avoid hypoxaemia, hypercarbia and aci-

Peri-operative care according to pathology

Avoidance of drugs undergoing extensive
Peri-operative management/implications

dosis peri-operatively. Nitrous oxide should not be

used. Pre-operative pulmonary function tests should be
performed to reveal any co-existing respiratory pathol-
ogy that usually takes the form of restrictive lung dis-

Avoidance of hypoxaemia
ease, especially in patients with splenomegaly [58].

according to pathology
Antibiotic prophylaxis

Electrolyte levels, renal and liver function should be

hepatic metabolism

Careful positioning
checked pre-operatively. Ascites should be treated;
and body fluids

reduction in sodium intake, use of aldosterone antago-

nists or loop diuretics and large volume paracentesis
may be required to improve patient’s condition.
Although no particular guidelines exist regarding
the optimal peri-operative or peripartum haemoglobin,
a level around 100 g.l 1 is considered safe and desir-
Pre-operative testing/confirmation

able [38, 56, 58]. In patients with low haemoglobin

Examination of skin condition

levels, transfusion should be considered pre-

Careful and detailed history
Pre-operative investigation

transaminases, prolonged

operatively, taking into account anticipated surgical

(low albumin, increased

MRI, magnetic resonance imaging; DVT, deep venous thrombosis; HIV, human immunodeficiency virus.

blood loss. In severely anaemic patients undergoing

Thyroid function tests
Clinical examination
Liver function tests

emergency surgery, maintenance of intravascular vol-

of viral infections

Glucose tolerance

ume until transfusion is of paramount importance in

reducing the risk of cardiopulmonary complications
clotting)

[50]. Peri-operative bleeding should be minimised and

blood-saving strategies should be considered.
Intra-operative blood salvage is probably useful
[59, 60], and has been successfully used in a patient
with thalassaemia intermedia undergoing caesarean
section [60]. The major concern regarding the use of
Pathology related to b-thalassaemia

Transfusion-related hepatitis B and

cell salvage is the decreased membrane stability of

Impaired cognitive function tests
Hepatic fibrosis/hepatic cirrhosis

thalassaemic red blood cells, which renders them

Increased incidence of stroke

prone to haemolysis especially with high suction pres-

Susceptibility to infections

Thin subcutaneous tissue

sure [59]. Suction pressure should be kept as low as

Hypoparathyroidism

possible and the effluent line checked for excess haem-

Diabetes mellitus

olysis; if this occurs, the wash volume should be

Hypothyroidism
Hypogonadism
Iron overload

increased until the line is clear [60]. A leucocyte deple-

Leg ulcers

tion filter should be used before the blood is returned

Hepatitis
C, HIV

to the patient [60].

A combination of pre-operative blood donation,
recombinant human erythropoietin and intra-operative
tranexamic acid has also been used successfully [59].
Central nervous system
Table 3 (continued)

Controlled hypotension with appropriate drugs such as

remifentanil infusion may additionally decrease intra-
operative haemorrhage [59]. When blood transfusion
Endocrine

is deemed necessary, leucocyte-depleted packed red

Immune
System

blood cells should be used as alloimmunisation is

Liver

Skin

common [52]. Rhesus and Kell phenotyping are also

506 © 2014 The Association of Anaesthetists of Great Britain and Ireland

Staikou et al. | Peri-operative management of thalassaemia
recommended [52]. Special attention should be paid
by staff to avoid exposure to the patient’s blood as
blood-transmitted viral infections secondary to multi-
ple transfusions (i.e. hepatitis) are frequently encoun-
tered in transfusion-dependent patients.
Thalassaemic patients are immunocompromised
and prone to infections, and thus broad-spectrum anti-
biotics are administered peri-operatively; for example,
ampicillin plus aminoglycoside is given to patients
undergoing laparoscopic cholecystectomy [58]. Contin-
ued vigilance is required postoperatively; although low-
grade fever might result from desferrioxamine, it is
prudent to treat any signs of infection with broad-
spectrum antibiotics.
Hypercoagulability is commonly encountered in
thalassaemia, and thus appropriate measures to pre-
vent deep venous thrombosis should be taken peri-
operatively [52]. Interestingly, thromboembolic events
are more common in patients with thalassaemia inter-
media than in those with thalassaemia major, whereas
splenectomy is an independent risk factor of venous
thromboembolism [38, 52]. Transfusion and antiplat-
elet therapy have been suggested for thromboembolism
prophylaxis, but to date, no prospective trials exist to
evaluate their efficacy [52].
Caution is needed during transfer and positioning
of patients because of increased risk of pathological
fractures due to osteoporosis and susceptibility to leg
ulcers from thin and fragile skin [52]. It is advisable to
keep the legs slightly above the level of the heart to
prevent leg ulceration, especially for long-lasting proce-
dures [52].
The choice of anaesthetic technique and drugs
should be case-specific, according to the planned sur-
gery and patient’s condition. Both general and neuraxi-
al anaesthesia have been safely used in thalassaemic
patients. Standard intravenous, inhalational agents and
opioids have been administered for induction and
maintenance of anaesthesia with no adverse reactions
[53–55, 57, 59, 61]. Spinal, epidural or combined tech-
niques have all been reported in thalassaemic surgical
patients [56, 59, 60, 64]. Notably, thoracic epidural
anaesthesia has been successfully used for laparoscopic
cholecystectomy in a patient with sickle cell-b thalas-
saemia [64]. Neuraxial techniques may be difficult to
perform due to spinal skeletal abnormalities, such as
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2014, 69, 494–510
scoliosis and osteoporosis [56]. Extramedullary haemo-
poiesis may rarely occur in the spine. If spinal com-
pression is suspected, an MRI should be performed
before regional anaesthesia. Pre-existing neurological
deficits are a relative contraindication. Routine coagu-
lation tests should be carried out before performing
regional techniques as abnormal values may be
encountered even in pregnancy. Spinal block for cae-
sarean section has been performed in a patient with an
isolated mildly elevated activated partial thrombo-
plastin time of 52 s (normal range 35–45 s) without
complications [56]. In cases of hypersplenic crisis with
thrombocytopaenia, neuraxial techniques are contrain-
dicated [56].
Apart from problems associated with patient
pathology, specific issues may arise with certain surgical
procedures. Splenectomy has been associated with
severe postoperative hypertension, resistant to medica-
tion and complicated with convulsions, as already men-
tioned [67, 68]. Thrombocytosis and/or thrombophilia
may develop after splenectomy, posing an additional
thromboembolic risk to thalassaemic patients [41].
Antiplatelet or antithrombotic regimens [41] such as
low-dose aspirin or warfarin may be useful, while the
intra-operative use of antithrombin III has also been
reported in elective splenectomy [57]. Another issue of
concern is the particularly high risk of postsplenectomy
sepsis in thalassaemic patients; in elective cases, pre-
operative vaccination against Streptococcus pneumoniae,
Haemophilus influenzae type B and Neisseria meningiti-
des, along with postoperative chemoprophylaxis with
penicillin, is recommended [41, 52, 70]. Overwhelming
postsplenectomy infection is an emergency situation,
with a mortality risk of 38–69% [70]. Fever > 38 °C in
splenectomised patients with no obvious source of
infection should be treated promptly with intravenous
broad-spectrum antibiotics such as third-generation
cephalosporins and aminoglycosides [41, 70].
In cardiac surgery, the use of extracorporeal circu-
lation may result in increased haemolysis of fragile
erythrocytes. Open-heart surgery for valve replacement
has been successfully performed with appropriate mea-
sures taken to prevent or reduce haemolysis such as
the use of packed red blood cells in the priming
solution and a non-pulsatile flow pattern for the extra-
corporeal circulation [65].
507
Anaesthesia 2014, 69, 494–510
In parturients with thalassaemia, special emphasis
should be given to the cardiovascular changes associ-
ated with gestation and labour, especially if there is
pre-existing cardiac involvement. Left ventricular func-
tion should be carefully and regularly assessed
throughout pregnancy. Elective caesarean section may
be preferred to avoid the excessive catecholamine
response of vaginal delivery and its unwanted cardio-
vascular effects. Regarding anaesthesia for caesarean
section, the high incidence of difficult intubation
encountered in this population should be considered
when general anaesthesia is administered. On the other
hand, skeletal deformities, scoliosis, osteoporosis, int-
raspinal extramedullary haemopoiesis and thrombocy-
topenia due to hypersplenism should all be taken into
account when regional techniques are planned [56].
In patients with HbH disease, infections and oxi-
dant drugs may enhance haemolysis by inducing oxida-
tion and intracellular precipitation of the haemoglobin
molecules [71, 72]. Such drugs include prilocaine, nitro-
prusside, vitamin K, aspirin, penicillin, sulphonamides
and chloramphenicol [71]. Nevertheless, nitroprusside
administered in small amounts during open-heart sur-
gery was not associated with increased haemolysis,
although this effect could have been masked by the sub-
sequent use of cardiopulmonary bypass [63]. Another
potential risk is the precipitation of the unstable HbH
after prolonged exposure to relatively low temperatures,
i.e. below 4 °C [72]. However, the use of cold cardiople-
gia solutions described in two cases undergoing open-
heart surgery was not associated with significant haem-
olysis; it was suggested that this might be attributed to
the short duration of bypass of < 1 h [63].
When viable neonates with hydrops fetalis syn-
drome are to be born, caesarean section is preferred
[73]. A multidisciplinary approach, involving the neo-
natologist/paediatrician, obstetrician and anaesthetist,
is mandatory for adequate assessment of maternal and
fetal status and the creation of a well-structured plan
for peri-operative and postnatal care. General or regio-
nal anaesthesia has been used in such cases after con-
sidering not only the effects of drugs on the fetus but
also planned post-delivery interventions for the neo-
nate such as immediate tracheal intubation [73].
In conclusion, peri-operative management of
patients with thalassaemia may be challenging because
508
Staikou et al. | Peri-operative management of thalassaemia
of the multiple systems affected by the disease as well
as repeated blood transfusion leading to iron overload
requiring chelating therapy. A multidisciplinary
approach is required pre-operatively to allow thorough
systematic investigation of pathological features, to
optimise the patient’s condition and carefully plan
peri-operative management.
Competing interests
No external funding and no competing interests
declared.
References
1. Firth PG. Anesthesia and hemoglobinopathies. Anesthesiology
Clinics 2009; 27: 321–36.
2. Cooley TB, Lee P. A series of cases of splenomegaly in children
with anemia and peculiar bone changes. Transactions of the
American Pediatric Society 1925; 37: 29–30.
3. Higgs DR, Weatherall DJ. The alpha thalassaemias. Cellular
and Molecular Life Sciences 2009; 66: 1154–62.
4. Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia.
Lancet 2012; 379: 373–83.
5. Olivieri NF, Muraca GM, O’Donnell A, Premawardhena A,
Fisher C, Weatherall DJ. Studies in haemoglobin E beta-thal-
assaemia. British Journal of Haematology 2008; 141: 388–
97.
6. Harteveld CL, Higgs DR. Alpha-thalassaemia. Orphanet Journal
of Rare Diseases 2010; 5: 13.
7. Weatherall DJ. Common genetic disorders of the red cell and
the ‘malaria hypothesis’. Annals of Tropical Medicine and Par-
asitology 1987; 81: 539–48.
8. Weatherall DJ. The inherited diseases of hemoglobin are an
emerging global health burden. Blood 2010; 115: 4331–6.
9. Giardine B, Borg J, Higgs DR, et al. Systematic documentation
and analysis of human genetic variation in hemaglobinopa-
thies using the microattribution approach. Nature Genetics
2011; 43: 295–301.
10. Weatherall DJ. The thalassemias. In: Stamatoyannopoulos G,
Nienhuis AW, Majerus PH, Varmus H, eds. The Molecular Basis
of Blood Diseases, 2nd edn. Philadelphia, PA: W.B. Saunders,
1994: 157–205.
11. Higgs DR. The molecular basis of a thalassemia. In: Steinberg
MH, Forget BG, Higgs DR, Weatherall DJ, eds. Disorders of
Hemoglobin: Genetics, Pathophysiology, and Clinical Manage-
ment, 2nd edn. New York, NY: Cambridge University Press,
2009: 241–65.
12. Aessopos A, Farmakis D, Karagiorga M, et al. Cardiac involve-
ment in thalassemia intermedia: a multicenter study. Blood
2001; 97: 3411–6.
13. Hahalis G, Alexopoulos D, Kremastinos DT, Zoumbos NC. Heart
failure in b-thalassemia syndromes: a decade of progress.
American Journal of Medicine 2005; 118: 957–67.
14. Aessopos A, Farmakis D, Deftereos S, et al. Thalassemia
heart disease: a comparative evaluation of thalassemia
major and thalassemia intermedia. Chest 2005; 127: 1523–
30.
15. Kremastinos DT, Tiniakos G, Theodorakis GN, Katritsis DG, Tou-
touzas PK. Myocarditis in b-thalassemia major. A cause of
heart failure. Circulation 1995; 91: 66–71.
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Staikou et al. | Peri-operative management of thalassaemia
16. Kayrak M, Acar K, Gul EE, et al. The association between myo-
cardial iron load and ventricular repolarization parameters in
asymptomatic beta-thalassemia patients. Advances in Hema-
tology 2012 May 15; doi: 10.1155/2012/170510.
17. Ulger Z, Aydinok Y, Levent E, Gurses D, Ozyurek AR. Evaluation
of QT dispersion in b thalassaemia major patients. American
Journal of Hematology 2006; 81: 901–6.
18. Russo V, Rago A, Pannone B, et al. Dispersion of repolarization
and beta-thalassemia major: the prognostic role of QT and JT
dispersion for identifying the high-risk patients for sudden
death. European Journal of Haematology 2011; 86: 324–31.
19. Farahani B, Abbasi MA, Khaheshi I, Paydary K. Evaluation of
QT Interval in b thalassemia major patients in comparison
with control group. Heart Views 2012; 13: 42–5.
20. Magrˇ D, Sciomer S, Fedele F, et al. Increased QT variability in
young asymptomatic patients with b-thalassemia major. Euro-
pean Journal of Haematology 2007; 79: 322–9.
21. Tai DY, Wang YT, Lou J, Wang WY, Mak KH, Cheng HK. Lungs in
thalassaemia major patients receiving regular transfusion.
European Respiratory Journal 1996; 9: 1389–94.
22. Carnelli V, D’Angelo E, Pecchiari M, Ligorio M, D’Angelo E. Pul-
monary dysfunction in transfusion-dependent patients with
thalassemia major. American Journal of Respiratory and Criti-
cal Care Medicine 2003; 168: 180–4.
23. Vij R, Machado RF. Pulmonary complications of hemoglobinop-
athies. Chest 2010; 138: 973–83.
24. Du Z-D, Roguin N, Milgram E, Saab K, Koren A. Pulmonary
hypertension in patients with thalassemia major. American
Heart Journal 1997; 134: 532–7.
25. Grisaru D, Rachmilewitz EA, Mosseri M, et al. Cardiopulmonary
assessment in beta-thalassemia major. Chest 1990; 98: 1138–
42.
26. Morris CR, Kuypers FA, Kato GJ, et al. Hemolysis-associated
pulmonary hypertension in thalassemia. Annals of the New
York Academy of Sciences 2005; 1054: 481–5.
27. Ponticelli C, Musallam KM, Cianciulli P, Cappellini MD. Renal
complications in transfusion-dependent beta thalassaemia.
Blood Reviews 2010; 24: 239–44.
28. Yacobovich J, Stark P, Barzilai-Birenbaum S, et al. Acquired
proximal renal tubular dysfunction in b-thalassemia patients
treated with deferasirox. Journal of Pediatric Hematology/
Oncology 2010; 32: 564–7.
29. Quinn CT, Johnson VL, Kim H-Y, et al. Renal dysfunction in
patients with thalassaemia. British Journal of Haematology
2011; 153: 111–7.
30. Toumba M, Sergis A, Kanaris C, Skordis N. Endocrine complica-
tions in patients with thalassaemia major. Pediatric Endocri-
nology Reviews 2007; 5: 642–8.
31. Delvecchio M, Cavallo L. Growth and endocrine function in
thalassemia major in childhood and adolescence. Journal of
Endocrinological Investigation 2010; 33: 61–8.
32. Abu Alhaija ESJ, Hattab FN, Al-Omari MAO. Cephalometric
measurements and facial deformities in subjects with beta-
thalassaemia major. European Journal of Orthodontics 2002;
24: 9–19.
33. Zafeiriou DI, Economou M, Athanasiou-Metaxa M. Neurological
complications in b-thalassemia. Brain and Development 2006;
28: 477–81.
34. Orvieto R, Leichter I, Rachmilewitz EA, Margulies JY. Bone den-
sity, mineral content, and cortical index in patients with thal-
assemia major and the correlation to their bone fractures,
blood transfusions, and treatment with desferrioxamine. Cal-
cified Tissue International 1992; 50: 397–9.
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2014, 69, 494–510
35. Vogiatzi MG, Macklin EA, Fung EB, et al. Prevalence of frac-
tures among the Thalassemia syndromes in North America.
Bone 2006; 38: 571–5.
36. Cappellini MD, Poggiali E, Taher AT, Musallam KM. Hypercoag-
ulability in b-thalassemia: a status quo. Expert Review of
Hematology 2012; 5: 505–11.
37. Conran N, Costa FF. Hemoglobin disorders and endothelial cell
interactions. Clinical Biochemistry 2009; 42: 1824–38.
38. Taher A, Isma’eel H, Mehio G, et al. Prevalence of thrombo-
embolic events among 8,860 patients with thalassaemia
major and intermedia in the Mediterranean area and Iran.
Thrombosis and Haemostasis 2006; 96: 488–91.
39. Haghpanah S, Karimi M. Cerebral thrombosis in patients with
b-thalassemia: a systematic review. Blood Coagulation &
Fibrinolysis 2012; 23: 212–7.
40. Jain R, Perkins J, Johnson ST, et al. A prospective study for
prevalence and/or development of transfusion-transmitted
infections in multiply transfused thalassemia major patients.
Asian Journal of Transfusion Science 2012; 6: 151–4.
41. Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood
2011; 118: 3479–88.
42. Vento S, Cainelli F, Cesario F. Infections and thalassaemia. The
Lancet Infectious Diseases 2006; 6: 226–33.
43. Mikelli A, Tsiantis J. Brief report: depressive symptoms and
quality of life in adolescents with b-thalassaemia. Journal of
Adolescence 2004; 27: 213–6.
44. Chui DHK, Waye JS. Hydrops fetalis caused by a-thalassemia:
an emerging health care problem. Blood 1998; 91: 2213–22.
45. Old JM. Screening and genetic diagnosis of haemoglobin dis-
orders. Blood Reviews 2003; 17: 43–53.
46. Ryan K, Bain BJ, Worthington D, et al.; British Committee for
Standards in Haematology. Significant haemoglobinopathies:
guidelines for screening and diagnosis. British Journal of Hae-
matology 2010; 149: 35–49.
47. Prabhu R, Prabhu V, Prabhu RS. Iron overload in beta thalas-
semia-a review. Journal of Bioscience and Technology 2009;
1: 20–31.
48. Cao A, Galanello R, Origa R. Beta-thalassemia. In: Pagon RA,
Adam MP, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K,
eds. GeneReviewsTM. Seattle, WA: University of Washington,
1993–2013. ]http://www.ncbi.nlm.nih.gov/books/NBK1426/
(accessed 29/11/13).
49. Arruda VR, Lima CSP, Saad STO, Costa FF. Successful use of
hydroxyurea in b-thalassemia major. New England Journal of
Medicine 1997; 336: 964–5.
50. Pe
rez JA, Padilla J, Rodr
ˇguez MA, et al. Splenectomy in a
patient with beta thalassemia intermedia and severe hemo-
lytic anemia. Revista Espan ~ola de Anestesiologˇ a y Reanimac-
n 2001; 48: 288–91.
io
51. Unal Y, Isik B, Ozkose Z, Yarici A, Gokce M. Intermittent anes-
thesia for splenectomy and caesarean section in pregnant
patient with thalassemia (case report). Gazi Medical Journal
2006; 17: 224–6.
52. Abi Saad GS, Musallam KM, Taher AT. The surgeon and the
patient with b-thalassaemia intermedia. British Journal of Sur-
gery 2011; 98: 751–60.
53. Orr D. Difficult intubation: a hazard in thalassaemia. A case
report. British Journal of Anaesthesia 1967; 39: 585–6.
54. Ali S, Khan FA. Anaesthetic management of two patients with
beta-thalassaemia intermedia. Journal of the Pakistan Medi-
cal Association 2010; 60: 582–4.
55. Mak PHK, Ooi RGB. Submental intubation in a patient with
beta-thalassaemia major undergoing elective maxillary and
509
Anaesthesia 2014, 69, 494–510
mandibular osteotomies. British Journal of Anaesthesia 2002;
88: 288–91.
56. Butwick A, Findley I, Wonke B. Management of pregnancy in
a patient with b thalassaemia major. International Journal of
Obstetric Anesthesia 2005; 14: 351–4.
57. Kitoh T, Tanaka S, Ono K, Hasegawa J, Otagiri T. Anesthetic
management of a patient with b-thalassemia intermedia
undergoing splenectomy: a case report. Journal of Anesthesia
2005; 19: 252–6.
58. Katz R, Goldfarb A, Muggia M, Gimmon Z. Unique features of
laparoscopic cholecystectomy in beta thalassemia patients.
Surgical Laparoscopy, Endoscopy and Percutaneous Tech-
niques 2003; 13: 318–21.
59. Perez Ferrer A, Ferrazza V, Gredilla E., et al. Bloodless surgery
in a patient with thalassemia minor. Usefulness of erythropoi-
etin, preoperative blood donation and intraoperative blood
salvage. Minerva Anestesiologica 2007; 73: 323–6.
60. Waters JH, Lukauskiene E, Anderson ME. Intraoperative blood
salvage during cesarean delivery in a patient with b thalasse-
mia intermedia. Anesthesia and Analgesia 2003; 97: 1808–9.
61. Gupta N, Kaur S, Goila A, Pawar M. Anaesthetic management
of a patient with Eisenmenger syndrome and b-thalassemia
major for splenectomy. Indian Journal of Anaesthesia 2011;
55: 187–9.
62. Bharati S, Das S, Majee P, Mandal S. Anesthetic management
of a patient with sickle b+ thalassemia. Saudi Journal of
Anaesthesia 2011; 5: 98–100.
63. Rowbottom SJ, Sudhaman DA. Haemoglobin H disease and
cardiac surgery. Anaesthesia 1988; 43: 1033–4.
64. € O. Epidural anesthesia for laparoscopic cholecys-
Basß SSß, Ozlu
tectomy in a patient with sickle cell anemia, beta thalasse-
mia, and Crohn’s disease – a case report. Korean Journal of
Anesthesiology 2012; 63: 357–9.
510
Staikou et al. | Peri-operative management of thalassaemia
65. Botta L, Savini C, Martin-Suarez S, et al. Successful mitral
valve replacement in a patient with a severe form of b-thal-
assaemia. Heart, Lung and Circulation 2008; 17: 77–9.
66. Voyagis GS, Kyriakis KP. Homozygous thalassemia and difficult
endotracheal intubation. American Journal of Hematology
1996; 52: 125–6.
67. Suwanchinda V, Tengapiruk Y, Udomphunthurak S. Hyperten-
sion perioperative splenectomy in thalassemic children. Jour-
nal of the Medical Association of Thailand 1994; 77: 66–70.
68. Suwanchinda V, Pirayavaraporn S, Yokubol B, Tengapiruk Y,
Laohapensang M, Udomphunthurak S. Does furosemide pre-
vent hypertension during perioperative splenectomy in thalas-
semic children? Journal of the Medical Association of Thailand
1995; 78: 542–6.
69. Suwanchinda V, Tanphaichitr V, Pirayavaraporn S, Somprakit P,
Laohapensang M. Hemodynamic responses to captopril during
splenectomy in thalassemic children. Journal of the Medical
Association of Thailand 1999; 82: 666–71.
70. Davidson RN, Wall RA. Prevention and management of infec-
tions in patients without a spleen. Clinical Microbiology and
Infection 2001; 7: 657–60.
71. Motulsky AG, Stamatoyannopoulos G. Drugs, anesthesia and
abnormal hemoglobins. Annals of the New York Academy of
Sciences 1968; 151: 807–21.
72. Baum VC, O’Flaherty JE. Syndromes listed alphabetically. In:
Baum VC, O’Flaherty JE, eds. Anesthesia for Genetic, Meta-
bolic and Dysmorphic Syndromes of Childhood, 2nd edn. Phil-
adelphia, PA: Lippincott Williams and Wilkins, 2007: 365–6.
73. Nishikido O, Tateda T, Tajiri O, Kanazawa M, Honda Y, Sasano
J. Anesthetic management for cesarean section in a patient
with hydrops foetalis. Masui 2004; 53: 1263–6.
© 2014 The Association of Anaesthetists of Great Britain and Ireland