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 preoperative 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 measures, 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 orofacial 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 skeletal abnormalities and extramedullary haemopoiesis. A multidisciplinary pre-operative approach, clinical optimisation and a carefully planned strategy are mandatory. .................................................................................................................................................................

Correspondence to: C. Staikou Email: [email protected] Accepted: 20 December 2013

Introduction 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, thal494

assaemia has become a disease of international interest. 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 COHRANE LIBRARY literature search for all types of published articles up to May 2013 combining the free text © 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’, ‘thalassaemia’, ‘thalasaemia alpha’, ‘thalassaemia beta’ and ‘anaesthesia’ or ‘perioperative care’ in all possible combinations. A total of 107 articles were retrieved. After removing those found in duplicate, 96 articles remained, 26 of which were found to be relevant. Articles in languages other than English were used, provided they had a detailed English abstract. Consequently, 22 articles were found suitable for inclusion 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 concentrations 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 haemoglobins 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

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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 characterised 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, moderately (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-thalassaemia, 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 produced by the affected chromosome [6]. People with ‘aa/a ’ genotype, who have three functional and one non-functional allele, are silent carriers of a-thalassaemia. 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 ), presenting a-thalassaemia trait ( a/ a or aa/ 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, especially if left untreated [6].

Epidemiology More than 60 000 neonates with severe forms of b-thalassaemia are born each year worldwide [4]. The 495

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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 individuals gain resistance against Plasmodium falciparum malaria, even though the precise mechanism of protection 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-thalassaemic 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 Federation, at least 200 000 patients are currently receiving treatment worldwide [4]. However, the true number throughout the world is probably underestimated 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 phenotypes are found in cases with co-inheritance of a-thalassaemia or disorders associated with increased synthesis of fetal c-chains [4]. At the molecular level, two multigene bunches are responsible for haemoglobin composition: the a-like globin cluster on chromosome 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 substitutions in the cluster, although b-gene deletions, structural variants and, rarely, deletions of regulatory elements have also been described [10]. 496

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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 aglobin 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 bthalassaemia; although erythropoiesis is enhanced and the normal variant HbA2 may increase, it cannot compensate 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 cardiac 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 bthalassaemia 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, especially after the introduction of chelation therapy. Repolarisation 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 electrocardiographic 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-thalassaemia major is restrictive lung dysfunction with significantly reduced total lung capacity [21]. Parenchymal pathology and alveolar capillary membrane 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 monoxide, which is common among b-thalassaemic patients, and a less frequently encountered obstructive pulmonary dysfunction, usually remain asymptomatic [23]. © 2014 The Association of Anaesthetists of Great Britain and Ireland

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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 haemoglobin and arginase, released during haemolysis, are likely to be implicated in the development of pulmonary 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 glomerular 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 clearance, increased urinary excretion of calcium, phosphate, 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 dysfunction 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]. Hypogonadism and absent or delayed puberty with fertility problems are also common features, usually managed with hormonal replacement therapy [30, 31]. Glucose intolerance 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 accompanied by significant hypocalcaemia. These two disorders usually present between 10 and 20 years of age and can be reversed by intensive chelation, if recognised early [30]. Extramedullary erythropoiesis causes the craniofacial 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

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sion, which constitute the characteristic ‘rodent’ or ‘chipmunk’ face [32]. Compensatory extramedullary hyperplasia and bone overgrowth may result in compression 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 cauda equina may present with neurological symptoms, varying from mild sensory or motor defects to complex paraplegia, sphincter dysfunction and impotence [33]. Defects in bone mineralisation, osteopenia, osteomalacia 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 intermedia 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 fractures. 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 activation, 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 anaemia, even though this haemoglobinopathy has a different 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 inflammation are features of both b-thalassaemia and sickle cell 497

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anaemia [37]. Notably, vasculopathy characterised by endothelial activation and increased blood cell adhesion 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 thromboembolic events include splenectomy, elevated platelet count, decreased levels of protein C, protein S or plasminogen, 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 transfused 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 therapy. Severe chronic haemolysis, along with ineffective erythropoiesis and regular blood transfusions, results in iron deposition mainly in the heart (cardiomyopathy) and liver (cirrhosis), while endocrine glands (pancreas, 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 accumulation, splenectomy and other immune abnormalities render these patients prone to bacterial infections such as klebsiella in Asia and yersinia enterocolitis in Europe and North America [42]. A high incidence of cognitive defects and impairment of neuropsychological tests, not related to 498

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hypoxia or iron overload, has been reported in patients with thalassaemia [33]. The physical and social restrictions imposed by the chronicity of the disease may impair the patient’s intellectual and psychosocial progress. 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 investigation of a mild microcytic hypochromic anaemia revealed after routine testing. HbH disease (1/4 functional alleles) is an intermediate form of a-thalassaemia characterised by variable amounts of HbH (b4) and decreased production of HbA2. HbH is an unstable 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 (nondeletional type being more severe than deletional) and a-globin chain deficiency [6]. Patients with severe forms may require blood transfusion, develop splenomegaly, jaundice and suffer growth retardation, infections with acute haemolytic episodes and potential iron accumulation at older ages [6]. Finally, Bart’s hydrops fetalis syndrome (functional alleles: 0/4) is the most severe form of a-thalassaemia; the extreme deficiency 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 affinity 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 development 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 abnormalities usually result in intra-uterine or early postnatal 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

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haemorrhage and retained placenta due to placental enlargement [44].

Diagnosis and iron load monitoring Early diagnosis and treatment of thalassaemia is of paramount importance to limit the complications. Standard haematological tests include the assessment of mean corpuscular 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 electrophoresis, high performance liquid chromatography (HPLC) or isoelectric focusing may be used for identification of variant 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-thalassaemia, 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-thalassaemia mutation or with co-existence of a- and b-thalassaemia 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 misdiagnosed 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 concentration 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 chelation 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

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thalassaemic patients. After distinguishing the b-major type and performing hepatitis B vaccination, regular blood transfusions 1–4 times per month improve anaemia and suppress inefficient erythropoiesis, while limiting gastrointestinal absorption of iron [48]. In addition, hydroxycarbamide (hydroxyurea) may reduce transfusion requirements by augmenting the production of c-chains and fetal haemoglobin [49]. Regarding management of iron overload, desferrioxamine is the ‘gold standard’ chelating agent. It is given intravenously 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 possible, 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 during pregnancy only if the potential benefit justifies the potential risk to the fetus (Novartis Pharma Stein AG, Stein, Switzerland, product information, 2011). Regarding 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 administered 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 diseasefree 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 infections and thromboembolic events [41]. 499

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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 hydrops fetalis syndrome, although fetal transfusions and in utero surgery are possible treatment options, pregnancy 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 splenectomy, cholecystectomy due to bilirubin gallstone formation, correction of facial deformities and operative treatment of leg ulcers, fractures and extramedullary 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 haemodynamic management are usually highlighted [1]. For elective surgery, thorough clinical and laboratory 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 transfusion, chelating therapy and other medical treatment. A systematic, multidisciplinary approach is of paramount importance; haematologists, cardiologists, pulmonary physicians, anaesthetists and surgeons should co-operate 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 intubation due to orofacial malformations has long been recognised in adults as well as children, in whom tonsillar enlargement represents an additional risk factor [53, 54]. Laryngeal mask airway insertion may be challenging due to a high-arched palate [54]. When insur500

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mountable difficulties are anticipated, elective tracheostomy or alternative methods to secure the airway 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 adequate disease management, facial deformities are less evident, pre-operative airway assessment may be normal [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. Adequate chelating therapy should also be confirmed. There is no recommendation for discontinuing iron chelation therapy before surgery; however, desferrioxamine should probably be stopped as the transient febrile reaction associated with its use could complicate the differential diagnosis of postoperative infections [52]. Clinical assessment of cardiovascular function should pay special attention to exercise tolerance. Cardiac echocardiography should be performed if clinically 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 hypertension or congestive heart failure, cardiac catheterisation 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 oesophageal Doppler monitor and pulse contour analysis © 2014 The Association of Anaesthetists of Great Britain and Ireland

b-Thalassaemia intermedia Anaemia Facial deformities Tonsillar enlargement. Left vertricular hypertrophy

b-Thalassaemia major Regular transfusions Iron overload

F (11 years)

F (11 years) M (9 years)

F (33 years)

Orr [53]; case report

Ali and Khan [54]; 2 cases

Mak and Ooi [55]; case report

b-Thalassaemia Hypertrophy of the maxilla Anaemia Jaundice Hepatomegaly Splenomegaly

b-Thalassaemia

F (pregnant)

Unal et al. [51]; case report

b-Thalassaemia intermedia Severe anaemia

F (36 years)

Syndrome/co-existing pathology


rez Pe et al. [50]; case report

Reference

Patient characteristics/ number

© 2014 The Association of Anaesthetists of Great Britain and Ireland Maxillary and mandibular osteotomies

Bilateral inguinal hernia repair Elective splenectomy

Dacryocystectomy

Splenectomy (urgent, at 23 weeks of gestation) Caesarean section (at 38 weeks of gestation)

Splenectomy (emergency)

Surgery

Successful intubation

Both cases: Uneventful course

Uneventful course, discharged after 10 days

Tracheal intubation achieved using a stylet Anaesthetics/ analgesics for hypertension (inadequate response)

Submental intubation Fluids, massive blood transfusion, intra-operative blood salvage Planned surgery abandoned

Difficulty in laryngeal mask placement Difficult intubation (Cormack & Lehane grade 2b)) Intra-operative hypertension

Nasotracheal intubation not possible due to maxillary bone marrow hypertrophy Massive surgical haemorrhage

1st case: GA: Midazolam Sevoflurane (for induction) Pethidine Isoflurane Atracurium 2nd case: GA: Midazolam Thiopental Fentanyl Atracurium GA: Propofol Fentanyl Isoflurane Cis-atracurium

Inadequate data

Uneventful course

Outcome

Use of malleable stylet

Inadequate data

Maintenance of normovolaemia

Management

Difficult intubation

Inadequate data

GA for splenectomy Epidural anaesthesia for caesarean section

GA: Thiopental Suxamethonium

Severe haemolysis/anaemia (Hb = 40 g.l 1)

Problems/peri-operative complications

GA

Anaesthesia/drugs

Table 1 Case reports of anaesthetic management of patients with b-thalassaemia undergoing surgery.

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501

502

F (14 years)

F (31 years; pregnant 37+5 weeks of gestation)

Waters et al. [60]; case report b-Thalassaemia intermedia Mild anaemia

b-Thalassaemia minor Mild anaemia

b-Thalassaemia major, n = 6; intermedia, n = 2 Anaemia Haemochromatosis (n = 7) Hepatitis C (n = 3) Liver cirrhosis with ascites (n = 5) Splenectomy (n = 7)

n=8 F = 3, M = 5 (21–42 years)

Katz et al. [58]; case series


rez Ferrer Pe et al. [59]; case report

b-Thalassaemia intermedia Anaemia Liver dysfunction

M (37 years)

Kitoh et al. [57]; case report

b-Thalassaemia major Osteoporosis Prolonged activated partial thromboplastin time

F (28 years) (pregnant, 37 weeks of gestation)

Syndrome/co-existing pathology

Butwick et al. [56]; case report

Reference

Patient characteristics/ number

Table 1 (continued)

Caesarean section

Posterior spine fusion

Laparoscopic cholecystectomy

Elective splenectomy

Caesarean section

Surgery

Combined spinal-epidural

GA: Propofol Fentanyl Cis-atracurium Sevoflurane Remifentanil Postoperative epidural analgesia

GA

GA: Hyoscine/pethidine Diazepam Fentanyl Vecuronium Isoflurane Prostaglandin E1

Spinal anaesthesia; hyperbaric 0.5% bupivacaine 2.5 ml + diamorphine 300 lg

Anaesthesia/drugs

Parturient refused allogenic blood transfusion Severe bleeding (~9000 ml) due to placenta accreta

Anaemia Surgery with expected significant haemorrhage

Co-existing pathology Postoperative low-grade fever (n = 2)

Use of blood salvage (2250 ml of red blood cells, average haematocrit 50%)

Recombinant human erythropoietin Pre-operative autologous blood donation Intra-operative blood salvage Tranexamic acid Controlled hypotension with remifentanil

Invasive monitoring including Swan-Ganz catheter in selected cases Postoperative pulmonary physiotherapy & broad-spectrum antibiotics

Invasive monitoring/ Swan-Ganz catheter Minimal cardiovascular suppression with anaesthetics Hb maintenance

Blood transfusion

Low postpartum Hb

Severe anaemia Hyperkinetic circulation

Management

Problems/peri-operative complications

Uneventful course

Uneventful course

Uneventful course

Uneventful course, discharged after 3 weeks

Uneventful course

Outcome

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b-Thalassaemia Sickle cell anaemia Crohn’s disease Liver dysfunction Mild anaemia b-Thalassaemia major Anaemia Pulmonary hypertension

F (52 years) M (35 years)

F (37 years)

M (50 years)

Rowbottom and Sudhaman [63]; 2 cases

© 2014 The Association of Anaesthetists of Great Britain and Ireland

Basß and € [64]; Ozlu case report

Botta et al. [65]; case report

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

HbH disease Case 1: Hepato-splenomegaly Controlled congestive heart failure Atrial fibrillation Pulmonary hypertension Case 2: Cardiomegaly Pulmonary hypertension

b-Thalassaemia Sickle cell anaemia Facial deformities Jaundice Liver dysfunction Anaemia

F (14 years)

Bharati et al. [62]; case report

b-Thalassaemia Eisenmenger’s syndrome Thrombocytopenia Hepatomegaly Splenomegaly Restrictive lung disease/ hypoxaemia Pulmonary hypertension

F (5 years)

Syndrome/co-existing pathology

Gupta et al. [61]; case report

Reference

Patient characteristics/ number

Table 1 (continued)

GA: Midazolam Fentanyl Propofol Isoflurane Rocuronium 1st case: GA: Diazepam Morphine Isoflurane Pancuronium 2nd case: GA: Midazolam Fentanyl Morphine Isoflurane Pancuronium

Open cholecystectomy

Open-heart surgery: mitral valve replacement

Open-heart surgery (mitral valve replacement)

GA

Epidural anaesthesia: 15 ml bupivacaine 0.5%; T9-10 Sedation with propofol and midazolam

GA: Midazolam Fentanyl Ketamine Halothane Atracurium

Splenectomy

Elective laparoscopic cholecystectomy

Anaesthesia/drugs

Surgery

Low Hb Erythrocytes susceptible to haemolysis/problem augmented by extracorporeal circulation

Blood transfusion Packed red blood cells in priming solution Non-pulsatile flow via a centrifugal pump

Fentanyl 100 lg

Uneventful course

Uneventful course

Uneventful course No measures taken for haemoglobinuria Short duration of bypass Use of small amounts of nitroprusside

Haemoglobinuria, rapid resolution Potential problem with cold cardioplegia Potential problem with nitroprusside

Shoulder pain

Uneventful course

Pre-operative transfusion Avoidance of nitrous oxide

Anaemia Possibility of increased pulmonary artery pressures

Uneventful course, discharged on 5th postoperative day

Outcome

None

Management

None

Problems/peri-operative complications

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503

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Staikou et al. | Peri-operative management of thalassaemia

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

Reference

Patient characteristics/ number

Anaesthesia

Study aim

Findings

Voyagis and Kyriakis [66]; retrospective study

Homozygous b-thalassaemia Hypertrophy of the maxilla (32/58) Adults (n = 58)

GA Intravenous induction Suxamethonium

To investigate the occurrence of difficult direct laryngoscopy (Grade 3-4 view)

Probability of difficulty 18.8%

Suwanchinda et al. [67]; retrospective study

b-Thalassaemia Children (n = 100)

GA

To investigate the occurrence of peri-operative hypertension and related complications in children undergoing splenectomy

Intra-operative hypertension/ tachycardia in all patients Postoperative hypertension in 16/100 Postoperative convulsions in 3/16 of above Persistent neurological deficit in 1/16 of above No deaths

Suwanchinda et al. [68]; study type not defined

b-Thalassaemia Children (n = 90)

GA (n = 50) GA + pre-operative furosemide 1 mg.kg 1 (n = 40)

To investigate the efficacy of furosemide in preventing peri-operative hypertension in children undergoing splenectomy

Intra- and postoperative hypertension similar in both groups Postoperative convulsions in 3/50 in the control group

Suwanchinda et al. [69]; randomised controlled trial

b-Thalassaemia Children (n = 82)

GA + pre-operative furosemide (n = 40) GA + pre-operative captopril or captopril/ furosemide (n = 42)

To investigate the efficacy of captopril (alone or combined with furosemide) in preventing peri-operative hypertension in children undergoing splenectomy

The combination captopril/furosemide gave better control of intra-operative hypertension Postoperative convulsions due to 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 vasculature. Invasive monitoring via pulmonary artery catheterisation might be considered in selected, highrisk cases [57, 58]; it provides accurate direct pressure readings as well as several derived haemodynamic variables 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 anaemia, cardiovascular depression should be avoided and volatile anaesthetic agents should be kept at low con504

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 prevent postoperative hypertension and associated convulsions [67–69]. In high-risk cases, prompt and aggressive treatment of hypertension is required to minimise the incidence of neurological complications [67–69]. © 2014 The Association of Anaesthetists of Great Britain and Ireland

Pathology related to b-thalassaemia

Left and right ventricular cardiomyopathy Dilated cardiomyopathy Restrictive cardiomyopathy Cardiac hypertrophy/dilatation/heart failure Pulmonary hypertension  secondary right heart failure Myocarditis Pericarditis Valvulopathies Arrhythmias/repolarisation abnormalities

Restrictive lung dysfunction: Fibrosis Interstitial oedema Obstructive or mixed lung dysfunction

Renal hyperfiltration/increased creatinine clearance Proteinuria Increased urinary excretion of: Calcium Phosphate Magnesium Uric acid

Haemolysis/anaemia Abnormalities in platelet count Hypercoagulation/coagulopathy Iron overload

Skeletal deformities Osteopenia/osteoporosis Extramedullary haemopoiesis

System

Cardiovascular

Respiratory

Urinary

Haemopoietic

Skeletal

© 2014 The Association of Anaesthetists of Great Britain and Ireland

Pre-operative optimisation/electrolyte correction Peri-operative monitoring of renal function/ electrolytes

Avoid anaesthetic suppression of high cardiac output state Reduced tolerance to bleeding Increased transfusional risk Consider blood salvage Consider risks of neuraxial anaesthesia Prophylactic measures for DVT/thromboembolic events

Assessment of renal function/ expert consultation Check of electrolyte levels

Full blood count  pre-operative transfusion Coagulation tests Liver iron concentration using MRI

Preparation for difficult intubation Possible nasal obstruction Potentially difficult neuraxial anaesthesia Careful transfer and placement of patients

Pre-operative optimisation (physiotherapy/ drugs) Consider modifications in ventilation mode and/or settings Maintain adequate oxygenation and normocarbia, while minimising airway pressure Limit height of regional anaesthetic block Possible need for postoperative mechanical ventilation

Chest X-ray Pulmonary function tests

Pre-operative tests predicting difficult intubation History/investigation for osteoporosis

Peri-operative management/implications Invasive monitoring: Arterial blood pressure  Pulmonary artery catheter Avoid/minimise: Cardiovascular depression Increases in pulmonary artery pressure Arrhythmogenic agents

Pre-operative investigation Assess exercise tolerance; history of fatigue, breathlessness or reduced exercise capacity, poor tolerance in formal exercise testing Electrocardiogram Echocardiography  Cardiac catheterisation

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

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505

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

Pre-operative optimisation/peri-operative care according to pathology Diabetes mellitus Hypogonadism Hypothyroidism Hypoparathyroidism Endocrine

Glucose tolerance Thyroid function tests Clinical examination

Careful positioning Avoidance of hypoxaemia Leg ulcers Thin subcutaneous tissue Skin

Examination of skin condition

Peri-operative care according to pathology Increased incidence of stroke Impaired cognitive function tests Central nervous system

Careful and detailed history

Avoidance of drugs undergoing extensive hepatic metabolism Iron overload Hepatitis Hepatic fibrosis/hepatic cirrhosis Liver

Liver function tests (low albumin, increased transaminases, prolonged clotting)

Peri-operative management/implications

Susceptibility to infections Transfusion-related hepatitis B and C, HIV

Pre-operative testing/confirmation of viral infections

Pathology related to b-thalassaemia

Immune

Pre-operative investigation

Staikou et al. | Peri-operative management of thalassaemia

System

Table 3 (continued) 506

Antibiotic prophylaxis Personnel surveillance/avoid exposure to blood and body fluids

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In patients with pulmonary hypertension, it is important to avoid hypoxaemia, hypercarbia and acidosis peri-operatively. Nitrous oxide should not be used. Pre-operative pulmonary function tests should be performed to reveal any co-existing respiratory pathology that usually takes the form of restrictive lung disease, especially in patients with splenomegaly [58]. Electrolyte levels, renal and liver function should be checked pre-operatively. Ascites should be treated; reduction in sodium intake, use of aldosterone antagonists 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 desirable [38, 56, 58]. In patients with low haemoglobin levels, transfusion should be considered preoperatively, taking into account anticipated surgical blood loss. In severely anaemic patients undergoing emergency surgery, maintenance of intravascular volume until transfusion is of paramount importance in reducing the risk of cardiopulmonary complications [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 cell salvage is the decreased membrane stability of thalassaemic red blood cells, which renders them prone to haemolysis especially with high suction pressure [59]. Suction pressure should be kept as low as possible and the effluent line checked for excess haemolysis; if this occurs, the wash volume should be increased until the line is clear [60]. A leucocyte depletion filter should be used before the blood is returned 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]. Controlled hypotension with appropriate drugs such as remifentanil infusion may additionally decrease intraoperative haemorrhage [59]. When blood transfusion is deemed necessary, leucocyte-depleted packed red blood cells should be used as alloimmunisation is common [52]. Rhesus and Kell phenotyping are also © 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 multiple transfusions (i.e. hepatitis) are frequently encountered in transfusion-dependent patients. Thalassaemic patients are immunocompromised and prone to infections, and thus broad-spectrum antibiotics are administered peri-operatively; for example, ampicillin plus aminoglycoside is given to patients undergoing laparoscopic cholecystectomy [58]. Continued vigilance is required postoperatively; although lowgrade fever might result from desferrioxamine, it is prudent to treat any signs of infection with broadspectrum antibiotics. Hypercoagulability is commonly encountered in thalassaemia, and thus appropriate measures to prevent deep venous thrombosis should be taken perioperatively [52]. Interestingly, thromboembolic events are more common in patients with thalassaemia intermedia than in those with thalassaemia major, whereas splenectomy is an independent risk factor of venous thromboembolism [38, 52]. Transfusion and antiplatelet 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 procedures [52]. The choice of anaesthetic technique and drugs should be case-specific, according to the planned surgery and patient’s condition. Both general and neuraxial 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 techniques 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 thalassaemia [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 haemopoiesis may rarely occur in the spine. If spinal compression is suspected, an MRI should be performed before regional anaesthesia. Pre-existing neurological deficits are a relative contraindication. Routine coagulation tests should be carried out before performing regional techniques as abnormal values may be encountered even in pregnancy. Spinal block for caesarean section has been performed in a patient with an isolated mildly elevated activated partial thromboplastin time of 52 s (normal range 35–45 s) without complications [56]. In cases of hypersplenic crisis with thrombocytopaenia, neuraxial techniques are contraindicated [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 medication and complicated with convulsions, as already mentioned [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, preoperative vaccination against Streptococcus pneumoniae, Haemophilus influenzae type B and Neisseria meningitides, 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 circulation may result in increased haemolysis of fragile erythrocytes. Open-heart surgery for valve replacement has been successfully performed with appropriate measures 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 extracorporeal circulation [65]. 507

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In parturients with thalassaemia, special emphasis should be given to the cardiovascular changes associated with gestation and labour, especially if there is pre-existing cardiac involvement. Left ventricular function 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 cardiovascular 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, intraspinal extramedullary haemopoiesis and thrombocytopenia due to hypersplenism should all be taken into account when regional techniques are planned [56]. In patients with HbH disease, infections and oxidant drugs may enhance haemolysis by inducing oxidation and intracellular precipitation of the haemoglobin molecules [71, 72]. Such drugs include prilocaine, nitroprusside, vitamin K, aspirin, penicillin, sulphonamides and chloramphenicol [71]. Nevertheless, nitroprusside administered in small amounts during open-heart surgery was not associated with increased haemolysis, although this effect could have been masked by the subsequent 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 cardioplegia solutions described in two cases undergoing openheart surgery was not associated with significant haemolysis; it was suggested that this might be attributed to the short duration of bypass of < 1 h [63]. When viable neonates with hydrops fetalis syndrome are to be born, caesarean section is preferred [73]. A multidisciplinary approach, involving the neonatologist/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 regional anaesthesia has been used in such cases after considering not only the effects of drugs on the fetus but also planned post-delivery interventions for the neonate such as immediate tracheal intubation [73]. In conclusion, peri-operative management of patients with thalassaemia may be challenging because 508

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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.

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