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Anaesthesia 2017 doi:10.1111/anae.


Consensus Statement
International consensus statement on the peri-operative
management of anaemia and iron deficiency
M. Mu~ noz,1 A. G. Acheson,2 M. Auerbach,3 M. Besser,4 O. Habler,5 H. Kehlet,6 G. M. Liumbruno,7
S. Lasocki,8 P. Meybohm,9 R. Rao Baikady,10 T. Richards,11 A. Shander,12 C. So-Osman,13
D. R. Spahn14 and A. A. Klein15

1 Professor, Peri-operative Transfusion Medicine, School of Medicine, University of Malaga, Malaga, Spain
2 Associate Professor, Department of Colorectal Surgery, Nottingham Digestive Diseases Centre, National Institute for
Health Research Biomedical Research Unit, Nottingham University Hospitals, Nottingham, UK
3 Clinical Professor, School of Medicine, Georgetown University, Washington, District of Columbia, USA
4 Associate Lecturer and Consultant Haematologist, Department of Haematology, Cambridge University Hospitals
NHS Foundation Trust, Cambridge, UK
5 Professor, Clinic of Anaesthesiology, Surgical Intensive Care Medicine and Pain Management, Krankenhaus
Nordwest, Frankfurt, Germany
6 Professor, Section of Surgical Pathophysiology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
7 Director, Italian National Blood Centre, National Institute of Health, Rome, Italy
8 Professor, Departement Anesthesie Reanimation, CHU Angers, LUNAM Universite d’Angers, Angers, France
9 Professor, Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt,
Frankfurt, Germany
10 Consultant, Department of Anaesthesia, The Royal Marsden NHS Foundation Trust, London, UK
11 Professor, Division of Surgery and Interventional Science, University College London, London, UK
12 Professor, Anaesthesiology, Critical Care and Hyperbaric Medicine, Englewood Hospital and Medical Centre and
Director, TeamHealth Research Institute, Englewood, New Jersey, USA
13 Consultant, Department of Transfusion Medicine, Sanquin Blood Bank, Amsterdam and Department of Internal
Medicine, Groene Hart Hospital, Gouda, The Netherlands
14 Professor and Chairman, Institute of Anaesthesiology, and Head of Anaesthesiology, Intensive Care Medicine and
Operating Room Management, University Hospital of Zurich, Zurich, Switzerland
15 Consultant, Department of Anaesthesia and Intensive Care, Papworth Hospital, Cambridge, UK

Despite current recommendations on the management of pre-operative anaemia, there is no pragmatic guidance for
the diagnosis and management of anaemia and iron deficiency in surgical patients. A number of experienced
researchers and clinicians took part in an expert workshop and developed the following consensus statement. After
presentation of our own research data and local policies and procedures, appropriate relevant literature was reviewed
and discussed. We developed a series of best-practice and evidence-based statements to advise on patient care with
respect to anaemia and iron deficiency in the peri-operative period. These statements include: a diagnostic approach
for anaemia and iron deficiency in surgical patients; identification of patients appropriate for treatment; and advice
on practical management and follow-up. We urge anaesthetists and peri-operative physicians to embrace these rec-
ommendations, and hospital administrators to enable implementation of these concepts by allocating adequate

© 2016 The Association of Anaesthetists of Great Britain and Ireland 1

[1–11]. haemoglobin concentration should be ≥ 130 g. operative care pathway that stretches from the decision to operate until complete recovery from Why was this consensus statement surgery. Throughout surgical ritin level < 100 lg. there are a number of non- tive and specific test used for the identification of evidence based misconceptions regarding prevalence. How does this consensus statement associated unfavourable outcomes differ from other available guidelines? 6 Oral iron replacement should be targeted to There are a number of guidelines from professional patients with iron deficiency with or without anae.l 1 in both sexes.Anaesthesia 2017 ~oz et al. nities to optimise patients. there has been increased emphasis on ciency. pre-operative assessment. absolute iron deficiency. the target surgery. and improve fitness for 5 When treating anaemia pre-operatively.l 1 is the most sensi. practice.l 1 is indicative of iron defi. speed to operation. Iron deficiency or if surgery is planned for < 6 weeks after the Iron is the most common and widespread nutritional diagnosis of iron deficiency. ment on ‘how to’ feasibly introduce these guidelines 7 Daily (40–60 mg) or alternate-day (80–100 mg) into clinical practice. for the diagnosis and treatment of peri-operative iron 8 Sufficient data exist to support intravenous iron as deficiency and anaemia in adult surgical patients. and ideally as soon as and iron deficiency as an indication for a peri. The mia whose surgery is scheduled 6–8 weeks after aim of this document is to utilise the recommenda- diagnosis. iron. non-urgent surgery should be postponed to focus on the ability to facilitate same-day hospital allow the diagnosis and treatment of anaemia and admissions. for anaemia and iron deficiency in 3 Serum ferritin level < 30 lg. which may overlook potential opportu- iron deficiency. adult surgical patients. and affects 2 © 2016 The Association of Anaesthetists of Great Britain and Ireland . and provide a working practice docu- (General Practitioner). However. even in industrialised countries. and many pre-assessment clinics 4 Major. tive anaemia have been published over the last decade high blood loss (> 500 ml). collec- should be initiated immediately in patients with tive guidance and a pragmatic. preferably by the primary care physician tions therein. in the presence consequences. treatment with oral iron and nutritional advice Therefore. clear clinical pathway iron deficiency and no contra-indications. Intravenous iron should be order to improve outcomes in a cost-effective Accepted: 3 November 2016 Keywords: anaemia. ance on clinical pathways. associations recommending ‘what to do’ [1–11]. how to do it. a serum fer. transfusion Recommendations for best clinical 9 The diagnosis and treatment of anaemia and iron practice deficiency should commence as early as possible 1 Physicians should consider pre-operative anaemia in the peri-operative period. diagnosis and treatment. in efficacious and safe.l 1) inconsistency of terminology and lack of clear guid- and/or transferrin saturation < 20%. However. to minimise the risk of transfusion. as well as of inflammation (C-reactive protein > 5 mg. our goal is to provide independent. deficiency. developed? 2 The presence of anaemia should be investigated in Several guidelines for the management of peri-opera- all surgical procedures with expected moderate-to. Mu~noz Email: mmunoz@uma. used as front-line therapy in patients who do not respond to oral iron or are not able to tolerate it. or better stated. | Peri-operative management of anaemia and iron deficiency Mun Correspondence to: M. the decision to undertake surgery is made.

Increased demand before major orthopaedic or abdominal surgery. Most of the iron • Malabsorption in the body is distributed in haemoglobin (Hb) . iron deficiency anaemia [25] Iron deficiency. | Peri-operative management of anaemia and iron deficiency Mun Anaesthesia 2017 approximately two billion people worldwide [12. • Poor intake For a 70-kg man. The corrected Importantly. In addition. iron deficiency Hb. Increased losses macrophages and bone marrow (850 mg) [25]. Malabsorption syndromes (Crohn’s disease and celiac disease) other tissues (in enzymes and cytochromes) • Drug interference (gastric anti-acid agents and antise- (350 mg). Trauma (1–2 mg) balances daily losses. 16]. low • Growth during infancy and childhood ferritin levels have been associated with increased rates • Treatment with erythropoiesis-stimulating agents B. Increased iron . which has decreased Hb and usually microcytic hypochromic been shown to be maintained after 24 and 52 weeks red cells (mean corpuscular volume < 80 fl. mitochondrial respiration. and absolute iron deficiency and iron sequestration (see below) was responsible for 75% of the cases of anaemia (541/715) [22]. inflammatory bowel disease (45%). iron is also a critical component in many ritin reflects approximately 8 mg stored iron [26]. 21]. is associated (Table 1). This may be indicated by the Apart from its well-recognised role in erythro- serum ferritin level. Func- recover from a 30–40 g. Respiratory tract bleeding blood loss may lead to progressive iron deficiency © 2016 The Association of Anaesthetists of Great Britain and Ireland 3 . This condition is often seen in physical performance and quality of life [18]. while main- tional iron deficiency in critically ill patients is associ- taining normal iron stores (ferritin > 30 ng.l 1 fer- poiesis. Genitourinary bleeding requirements.l 1 may not have enough iron reserves to gene regulation and cellular immunity [15. cretory drugs) C. Blood donation 300 billion red blood cells (20–30 mg) is provided . Surgery red blood cells (RBC). as levels of erythroid iron are still sufficient for has been independently associated with compromised erythropoiesis. Approximately . < 100 ng.l 1). with or without anaemia. a patient with a pre-operative ferritin electron transfer reactions. The • Phlebotomy amount of iron required for the daily production of . different types (stages) of iron defi- with chronic conditions such as cancer (43% across ciency are found in surgical patients (Table 2). corpuscular haemoglobin < 27 pg). Gastrointestinal bleeding . 24]. Limited supply of postoperative infections [23. Gastric resection within red blood cell (65%. chronic heart failure (43–100%) and other chronic inflammatory diseases • Inadequate (low) iron stores. A. important cellular processes such as oxygen transport. subsequently. iron may • Iron deficiency anaemia refers to a more severe condition in which decreased iron stores result in improve functional status within 4 weeks. limited external supply and increased . Helicobacter pylori infection (even without signifi- cant bleeding) 10% is found in muscle fibres (in myoglobin) and . ~oz et al. the prevalence of Table 1 Main causes of iron 1 body weight). while daily iron absorption . 13]. as well women of child-bearing age. mean [20. The remaining iron is stored in the liver. classi- different tumours). 1 ng. this refers to the body’s inability to sustain erythropoiesis to recover from [14]. as an increase in all-cause and cardiovascular mortality [19]. Treatment of iron deficiency with i. and. total body iron is about • Inappropriate diet with deficit in bioavailable iron and/ or ascorbic acid 3500 mg (50 mg. fied as follows: chronic kidney disease (24–85%). 2300 mg). anaemia was 34%. In congestive heart failure. Dialysis (particularly haemodialysis) mainly by macrophages recycling iron from senescent • Haemorrhage . blood loss at operation. in a healthy adult.l 1 Hb drop. Thus. As an example.v. ated with an increased duration of systemic inflammatory response syndrome and prolonged ICU • True (absolute) iron deficiency without anaemia refers to a reduction in total body iron with normal stay [17]. 48% women). in a large series of non-cardiac surgi- cal patients (n = 2115.

l 1 Low dose oral iron Gastro-intestinal/urological investigations (40–60 mg iron per day or Intravenous iron.24  Body weight [kg] + 500.l 1])  0. *Low reticulocyte Hb content (CHr < 28 pg). and promotes identification of true iron deficiency (with or with- its internalisation and degradation.v. 25. 4 © 2016 The Association of Anaesthetists of Great Britain and Ireland . contraindication or no blood losses) 80–100 mg alternate days. It is clearly defined in renal patients tus. TSAT. 27]. no further laboratory work-up is inhibition of intestinal iron absorption and iron needed (Fig. availability for erythropoiesis (TSAT < 20% indicates • Iron sequestration: this refers to decreased iron insufficient iron supply to support normal erythro- mobilisation from the stores in the liver and the poiesis).l 1 is the most sensi- Hepcidin binds to ferroportin.l 1 None None TSAT 20–50% CRP < 5 mg. elemental iron. A production patients with inflammation and chronic blood index greater than 2 is not compatible with iron losses.l 1 Intravenous iron Treat underlying chronic disease if TSAT < 20% and/or (Calculated dose)† possible CRP > 5 mgl 1 Recombinant erythropoietin in the selected case if anaemia does not respond to i. high proportion of hypochromic red cells (HYPO > 5%).l 1 Low dose oral iron Intravenous iron.l 1 Recombinant erythropoietin. while TSAT reflects iron agents [15]. 1 reticulocyte count provides an estimate of the rate sequestration at liver and macrophages [25] of effective marrow production compared with nor. in the presence of normal or elevated commonly used for an initial evaluation of iron sta- iron stores. transferrin saturation index. 2) [15. low RBC size factor (RBCSF < 88 fl) or ferritin index > 2 will confirm a component of iron deficiency. Iron status Laboratory findings Initial treatment Adjuvant treatment Normal Ferritin 30–300 lg. TSAT < 20% and/or if anaemia if functional iron deficiency develops CRP > 5 mg. 26]. C-reactive protein. response to oral iron or short time 6–8 weeks) to surgery Iron deficiency Ferritin < 30 lg. This may evolve to true iron deficiency in mal (set as a production index of 1). Intravenous iron. • A serum ferritin level < 30 lg. erythropoiesis due to iron sequestration is suspected regulates hepatic hepcidin synthesis and may [25. contraindication or no days. 6–8 weeks) response to oral iron or short time to surgery *Ferritin 30–100 lg. with moderate-to-high (40–60 mg iron per day or if intolerance. Thus: decrease the synthesis and activity of erythropoetin. | Peri-operative management of anaemia and iron deficiency Mun Table 2 Characteristics of the different stages of iron deficiency in surgical patients. (Fig. Fe. • Functional iron deficiency: this refers to insufficient Diagnosis of iron deficiency mobilisation of iron from stores due to increased Serum ferritin and transferrin saturation (TSAT) are demands.l of Hb deficit respect to target Hb + 500 mg for stores. iron alone Functional iron deficiency* Ferritin 100–500 lg.l 1 Low iron stores (for surgery Ferritin < 100 lg.l 1 Intravenous iron Revise erythropoietin dose TSAT < 20% (Calculated dose)† Check folic acid and vitamin B12 Iron sequestration* Ferritin > 100 lg. resulting in out anaemia).Anaesthesia 2017 ~oz et al. This is caused by inflammation. the only known tive (92%) and specific (98%) cut-off level for the iron-exporting protein in humans. †Total iron deficiency [mg] = (Target Hb Baseline Hb [g. C-reactive protein (CRP) is a marker of macrophages to meet daily bone marrow require. deficiency anaemia.l 1 CRP. which up. 80–100 mg alternate if intolerance. 1). A simplified calculation is 200 mg per each 10 g. inflammation which is useful when iron-restricted ments. Serum ferritin level is the most widely-used test following treatment with erythropoiesis-stimulating for evaluating iron stores.

when measured as a may be beneficial [25. augmented erythrophagocytosis. • In the presence of inflammation (CRP > 5 mg. decreased erythropoietic stimulation. TNFα. Other tests. Detailed information regarding the as men with an Hb of 130 g. and are used in most epidemio- with erythropoiesis-stimulating agents (Table 1. this Hb level should advantages. and is a strong predictor of response to i. conservation guidelines. due to its acute phase reactiv. 9.l 1). The ratio of serum transfer. 7 & 8. inhibition of ery- throid cell proliferation. or for pregnant women [31]. | Peri-operative management of anaemia and iron deficiency Mun Anaesthesia 2017 Immune system Stimulation activation Inhibition IFNγ. release of immune and inflammatory cytokines. decreased iron availability for erythropoiesis. Women have lower circulating increase in hypochromic red cells (Hypo > 5%). limitations and diagnostic be considered as suboptimal in surgical settings. In © 2016 The Association of Anaesthetists of Great Britain and Ireland 5 . may be used when these higher transfusion rates.l 1 < 120 g. Therefore.v. 28]. as seen in inflammatory conditions (CRP > 5 mg.l 1 for non-pregnant women and < 110 g. orthopaedic surgery [32] and the first Austrian bench- able [25. as seen during treatment quoted and accepted. TSAT < 20% and ferritin > 100 lg. can blood volumes than men. 3. ferritin < 100 lg. logical studies. 4. IL-6 induced hepcidin release. A ferritin index > 2 indicates true iron mark study [33]. 1. 29]. Kidney IL1β. blood losses rin receptor level to the log of ferritin (sTfr/log Ft). such ing surgical procedures in which moderate-to-high as low reticulocyte Hb content (CHr < 28 pg) or an blood loss is expected. ~oz et al. its diagnostic value is imperfect. Anaemia is defined by the World Health Organization as an Hb concentration < 130 g. 2) [25]. of 120 g. 2. These definitions are widely functional iron deficiency. and/or TSAT < 20%. • In contrast. performed in either sex often result in comparable ciency. It also indicates inadequate iron stores for surgery during Anaemia which moderate-to-high blood loss is expected. 6. although ferritin values > 100 lg. as corroborated by a study in automated red cell parameters are not routinely avail. are proportionally higher in women and may result in the so-called ferritin index.l 1). leading to decreased transferrin-bound iron. As women with a pre-operative Hb deficiency.l 1 strongly suggests iron deficiency (see below) (Fig. 28].l 1 patients. proportion of circulating blood volume. disadvantages. where no further laboratory work-up is deemed necessary for non-anaemic However.l 1. They are also adopted in most blood Fig.l 1 usually indicates iron sequestration. values of these parameters can be found elsewhere [30]. which if present suggests iron supplementation amounts of blood loss. decreased ferro- portin-mediated release of iron from enterocytes (inhibition of iron absorption) and macrophages (iron sequestration). IL-6 Liver ↓EPO ↑Hepcidin Bone marrow Erythrocytes Macrophages Small bowel ↓Fe-Tf-Fe Figure 1 Effects of inflammation on iron metabolism and erythropoiesis. for the classification of non-pregnant women undergo- ity.l 1 for men. argue against concurrent true iron deficiency in the However. 5. but the same procedures be utilised to evaluate for a component of iron defi. we consider that this may not be reliable setting of inflammation.l 1 are twice as likely to require a transfusion iron [28. decreased erythropoietin (EPO) production. 2).

but with a particular a marker of inflammation (e. to minimise the risk good quality evidence that it can modify the excess of of transfusion-associated unfavourable outcomes [35]. tively. trast. However. | Peri-operative management of anaemia and iron deficiency Mun Iron deficiency Ferritin < 30 mg. In some hospitals. improve outcomes. and surgery can proceed while anaemia evalua- anaesthesia assessment) or a primary care physician/ tion and treatment is ongoing. In con- (> 500 ml) is likely and/or if there is a ≥ 10% statisti. if needed. 36–42]. it is still recommended as good appropriate treatment. even in those for whose anaemia.g. associated with transfusion [28. tions should be performed as early as possible in the Despite the lack of level-one evidence for pre-operative period in order to implement the most improved outcomes.l–1 anaemia Ferritin 30–100 mg. There is good evidence that stores. a 10 g. risk for postoperative complications.l Iron inflammation or C-reactive protein > 5 mg. serum CRP) and a emphasis on treating those undergoing major surgery.l 1 decrease in Hb has been Intervening to treat pre-operative iron deficiency shown to be independently associated with increased anaemia in the surgical patient can be expected to transfusion requirements. 44. but there is little level ≥ 130 g. increased mortality and pro. outcomes of surgery [37. there is also good evidence that correcting anae- cal probability for red blood cell (RBC) transfusion.l 1) results tion). also be investigated for gastro-intestinal pathology oratory tests when an Hb < 130 g. an anaesthetist (during the pre. other than those Patients who are anaemic and require major sur. cardiac surgery. gery (including the obstetrics and gynaecology popula. general practitioner.l–1 tests Megalobastic anaemia Low Vitamin B12 Normal Folate Other Normal anaemias Unknow cause Malignancy Drugs Endocrine Renal Figure 2 Algorithm for classification of peri-operative anaemia. apart from replenishing iron surgery is the cure. Consequently.l–1 Anaemia of chronic –1 + transferrin saturation < 20% Hb < 130 g. reduce the number of transfusions given and thereby longed hospital stay [34]. especially if moderate to high blood loss in worse outcomes than milder anaemia [43]. operative iron deficiency anaemia. 45].l–1 Anaemia of chronic Altered + transferrin saturation < 20% inflammation with or C-reactive protein > 5 mg·l–1 iron deficiency Ferritin >100 mg. TSAT.l 1 in both sexes.Anaesthesia 2017 ~oz et al. moderate to severe anaemia (Hb < 110 g. Laboratory investiga. serum ferritin.g. pre-operative treatment of iron deficiency attempts to correct iron deficiency anaemia pre-opera- anaemia should be aimed at producing a target Hb tively will improve Hb before surgery.l 1 is detected by (Table 1). serum creatinine). The prevalence of other haematinic deficien- pre-operative analysis. cies before elective major orthopaedic surgery is 6 © 2016 The Association of Anaesthetists of Great Britain and Ireland . there is also Patients who have absolute iron deficiency should the possibility of automatically ordering additional lab. They should initially clinical practice to treat all surgical patients with pre- include at least full blood count. which Patients undergoing more minor surgical procedures can be easily requested by a surgeon (at the time of are unlikely to see wide fluctuations in Hb postopera- listing for surgery). mia by transfusing blood can be detrimental to the should be investigated (Fig 3). marker of renal function (e.

l 1)]. although this is currently sent. 25]. but fewer itself (http://hospital. In contrast. cancer surgery).g. this may counter- scheduled surgical procedure. a marker of inflammation (e.g. patients with iron deficiency anaemia. 2. 5. As anaemia-induced Treatment of pre-operative iron deficiency anaemia hypoxia and erythropoietin production downregulate should be implemented as early as possible before the the expression of hepcidin [ 1 low-dose (≤ 60 mg) oral iron given on alternate days (5 nmol. treatment of iron deficiency Therefore. high doses of iron sulphate stimulate hepcidin the elemental iron content of the available oral iron © 2016 The Association of Anaesthetists of Great Britain and Ireland 7 . and 3% the next daily dose [48]. ~oz et al. Thus. supplementation with oral iron and nutritional advice Regarding oral 1 (200 pmol. in non-anaemic iron-deficient may be appropriate. 2). daily (40–60 mg) or alternate-day (80–100 mg) rarely practised [47]. increase anaemia should be ruled out (Fig. it appears that for folate [defined by serum concentration < 3 ng. It should initially include at least full blood counts. serum C-reactive protein) and a marker of renal function (e. Laboratory work-up request2 operative evaluation1 Pre-operative Hb < 130 g. approximately 12% for vitamin B12 [defined by serum release. vitamin B12 < 270 pgml 1 and/or folate < 3 pgml 1. serum ferritin. 3. The actual dose may depend upon the recent NHS Blood and Trans. reduce gastro-intestinal exposure to unabsorbed iron and ultimately improve tolerance and Treatment adherence to treatment [48]. Including patients presenting late before surgery and non-deferrable surgery (e. 4. dosage efficacy. when the interval before surgery is sufficient anaemia should be attempted while the patient is on (at least 6–8 weeks) and no contra-indications are pre- the surgical waiting list. which results in lower iron absorption from concentration < 270 pg. 50 mg or plant audit showed there was a median of 60 days 150 mg iron sulphate daily for 2 months both from listing the patient for surgery to the operation improved Hb and ferritin levels equally. In octogenarian elective. If none are found. According to algorithm depicted in Fig. In the UK.g. other causes of may maximise fractional iron absorption. Most major surgery is balance the stimulatory effect of iron. Haematinic deficiencies are defined by ferritin < 100 lgl 1. 2. side-effects were observed with the lower dose [49].l–1 ? NO YES Proceed to surgery Is there haematinic Non-elective Elective deficiency?3 Surgery4 surgery NO YES Classify anaemia Classify anaemia and start and start treatment5 treatment5 Prescribe supplements Postpone surgery Proceed until patient no Proceed to surgery to surgery longer anaemic Figure 3 Algorithm for the management of a surgical | Peri-operative management of anaemia and iron deficiency Mun Anaesthesia 2017 Listed for surgery Transfusion risk > 10% and/or estimated blood loss > 500 ml ? NO YES Standard pre.blood. parative-audit/). serum creatinine). transferrin saturation. 1.l 1)] [46]. According to centre protocol for each surgical pro- cedure.

In practice.l 1). the patient cannot tolerate oral iron [1]. Once oral anaemic patients with iron deficiency or inadequate iron has been commenced. If surgery is from postoperative anaemia [1. However. The myeloproliferative disease (e. which differs depending on country of Iron deficiency without anaemia manufacture. In abdominal surgery. respectively.v. 2). as defined by TSAT < 20% (58%. A recent meta-analysis of 21 trials in different clinical However. or another cause of increased red cell production. most women with Hb 120– surgery [52. i.g. A quicker recovery in Hb postopera- 129 gl 1 would benefit from iron replacement ther- tively was also observed in iron-deficient patients trea- apy. Non- iron due to gastro-intestinal side-effects.g. maximal at 3 weeks) [50].v. iron administration (e. p < 0.v. This also applies to insufficient iron supply Intravenous iron treatment < 2 weeks pre-opera- for erythropoiesis. the and can usually be given by slow infusion over less than administration of iron ferrous sulphate and vitamins 1 h in one sitting or in two divided doses.05). deficiency with or without inflammation (Fig. iron sucrose before orthopae- tions were present in 52% of patients [60]. Most patients feel better in 3 days. p < 0. In those planned in less than 6 weeks time. although considered as non-anaemic according to hospital stay and infections in orthopaedic and cardiac WHO definitions [31].v. controlled trials are in progress [56]. and significantly higher than 10 days pre-operatively [41] has been shown to for Hb ≥ 130 g. iron supplementation was 67%. deserving of further research in the development ing blood loss [15. Others will not tolerate oral of strategies for detection and treatment [57].05) [22]. many patients will not respond to oral settings concluded that there is emerging evidence that iron. but a number of large randomised. target Hb and patient’s body weight. increase serum ferritin and transferrin saturation [58] with a rapid Hb response (50% at 5 days. 53].v. iron may also with absolute iron deficiency (ferritin < 30 lg. decrease RBC transfusion and hospital stay. the Hb should be measured iron stores undergoing surgical procedures with again. pre-operative iron administration. dic surgery has been shown to be useful for treating In women undergoing major non-cardiac surgical iron deficiency anaemia. there is a lack of high-quality data about if surgery is scheduled to take place in < 4 weeks or if effect on outcomes. 3] (Fig. Administration of i. adding 500 mg for Iron replacement may cause a surge in Hb that could iron stores (in patients > 35 kg) [25]. the be the most effective option. iron sucrose [54] or carboxymaltose [41. respectively. of 1000–1500 mg is sufficient in most surgical patients In non-anaemic orthopaedic surgical patients. iron may be calculated from the baseline and vera). tating recovery from postoperative anaemia.l 1 (42%.v. Thus. and adverse drug reac- In a small series. 51% and 24%. tively has also been shown to be successful in decreas- 69% and 34%. i. 25]. Intravenous mic patients without iron deficiency [55]. | Peri-operative management of anaemia and iron deficiency Mun formulation. at least 4 weeks before surgery. ing the need for RBC transfusion.v. iron ritin < 30 lg. i. In the absence expected moderate-to-high blood loss may benefit from of an increased Hb or if the patient is intolerant. improve postoperative Hb recovery even in non-anae- we suggest the administration of oral iron. iron isomaltoside (1000 mg) For non-anaemic patients undergoing surgery with 1 day before or even on the day of surgery can a high risk for developing severe postoperative anaemia. 8 © 2016 The Association of Anaesthetists of Great Britain and Ireland . with a maximum effect on procedures. 2). 75% at 10– and reduce transfusion [59].l 1 was similar to carboxymaltose (1000 mg) 2–4 weeks [40. acute kidney injury.Anaesthesia 2017 ~oz et al.l 1. especially those with functional iron deficiency non-anaemic iron deficiency is a disease in its own and chronic illness or infection and those with ongo- right. for optimising pre-operative Hb levels and facili- ted with i. a dose induce hyperviscosity in this subgroup. depending on during the weeks preceding surgery has been shown to the preparation used. adherence to 14 days. polycythaemia rubra dose of i. 500 mg) should be considered Presently. i.l 1) for Hb 120–129 g. 42] or 8– that for Hb < 120 g. to boost recovery iron is the preferred replacement route. Microcytosis due to iron deficiency without iron stores and increasing Hb in anaemia due to iron anaemia should be evaluated for chronic hypoxaemia. the prevalence of true iron deficiency (fer- Hb after 2 weeks [51]. 42]. need for gastro-intestinal investigations should be con- Intravenous iron is highly efficacious at replenishing sidered [3].

and frequent blood USA and/or Europe (Table 3). morbidity and mortality. Although there after major surgery. 2. These effects can last for a 1 in 100. patients The administration of a single 1000-mg dose of ferric should be informed about the relationship between carboxymaltose after major orthopaedic surgery. eral guidelines recommend postponing the operation Transfused packet RBC contains haem iron (200– for about 4 weeks to allow appropriate management of 250 mg per unit).000 [79]. six i. reduce transfusion and may reduce hospital stay. 70] difference in safety profile among available formulations have reduced the transfusion thresholds for surgical [80]. major surgery for benign disease. iron therapy anaemia.v. The problem may be divided into patients under. In line with these recommendations. ~oz et al.l 1 for patients with a history risk minimisation and management of hypersensitivity of ischaemic heart disease) in the absence of active reactions to i. dependent on the storage time of the transfused between diagnosis and surgery for malignant disease is RBC unit [76]. the patient’s Hb is subjected to legal regulations. Therefore. © 2016 The Association of Anaesthetists of Great Britain and Ireland 9 . 4. 75]. implement strategies for postoperative anaemia man- ciency anaemia improves outcome [60. poor nutritional Currently. In contrast. | Peri-operative management of anaemia and iron deficiency Mun Anaesthesia 2017 Delaying surgery bleeding. immediate postoperative period after major surgery [68].v. the National Institute for Clinical Excel. increased events (SAEs) are very rare (38 per 106 administrations. the can lead to inhibition of iron absorption from the most recent Serious Hazards of Transfusion Report in small bowel and reduced iron release from stores (iron the UK quotes the risk of death related to transfusion as sequestration) [25] (Fig. Correcting postoperative iron defi- receive pre-operative adjuvant therapy. especially when gastrectomy [72] and postpartum haemorrhage [73]. and is not recommended [4]. This change in practice has led to more As stated above. Nevertheless. iron exceed the risks when used Recently. there is considerable uncertainty as to the immediate postoperative period has a very limited whether surgery should be delayed in patients with role due to poor absorption and considerable side- undiagnosed/untreated anaemia. sufficient time for concurrent treatment of pre-opera. guidance for patients to 70 g. iron has been successfully used to treat iron deficiency going surgery for benign vs. and others. hepcidin due to the inflammatory response to surgery deaths. and the risk of major morbidity as 1 in few weeks after major surgery and aggravate postoper. After transfusion. 67].v. In addition. in In some European countries. Sev. peri-operative blood loss.v. 1). In contrast.v. blood loss > 500 ml is expected or possible. and should be given abdominal and genito-urinary surgery. which allows ciency. iron has been recently published [81]. may be important to improve function. 8]. it does agement. which is immediately available for erythropoiesis. as shown in tive iron deficiency anaemia. 16. malignant disease. it is important to is little evidence currently that treatment of iron defi. 5.000.l 1. 0. and serious adverse sampling for laboratory tests.l 1 (80 g. 35]. animal models [77]. without any lence [69] and other international guidelines [4. many usually < 10 g.4 per 106 administrations) [78]. has the opportunity to postpone non-urgent surgery until been shown to correct anaemia and improve quality of their anaemia is investigated and treated [4. effects. i. life compared with oral iron [74. the allowable time part. Further research is required as to whether supplemental iron given to correct iron defi- Postoperative anaemia ciency in patients who are transfused peri-operatively Anaemia is present in up to 90% of patients in the is beneficial in humans. In anaemia after surgery for lower limb arthroplasty [71]. in addition to RBC transfusion to raise Hb. appropriately (correct indication and dose). The European Medicines Agency concluded ative iron deficiency anaemia. anaemia. plus a small amount of labile iron anaemia [1. iron formulations are available in the intake in the postoperative period. Con. The main causes are: presence of pre-operative Safety of i. uncorrected pre-operative anaemia is patients being discharged with significant anaemia a risk factor for poor outcome [61–66]. Management of iron deficiency with oral iron in sequently. that the benefits of i.

Type 20 mg.4 3.3 3.feraheme. 2008). http://www.8 (% injected dose)† Iron London. iron formulations. BMJ Group and the Royal Pharmaceutical Society of Great Britain. ¶¶Monofer summary of product characteristics.pdf (accessed 01/08/2016).aspx (accessed 01/08/2016).cosmofer. mg.pdf (accessed 01/08/2016). 4th 1 0. †Jahn MR.pdf (accessed 01/08/2016). Geisser P. http://www.products. http://www. §§Ferinject summary of product characteristics.6 1.v. ***FeraHeme summary of product characteristics.0 0. Type II. Danielson (max 1000 mg) 20 mg.10 Table 3 Characteristics of different i. (accessed 01/08/2016).v. ††Venofer summary of product characteristics. 86:860–2). Bremen.5 | Peri-operative management of anaemia and iron deficiency © 2016 The Association of Anaesthetists of Great Britain and Ireland . €¶ *Type 510 dose. http://www. ¶British National Formulary BNF68.4 3. Am J Hematol 2011.16 kD 289–440 30–60 165 150 150 750 Initial distribution 6 3.ferinject. http://www. **Ferrlecit summary of product characteristics. September 2014 – March 2015. labile and weak (Crichton RR. 2014. ‡Includes 30-min postinfusion observation. min‡ Product cost per – 128 100 227 212 162 1000 mg. Eur J Pharm Biopharm 2011.aspx (accessed 01/08/2016). ‡‡Comofer summary of product characteristics. et al. semirobust and moderately strong.5 20 50 50 100 30 1 1 1 Maximal single 125 200 20 mg.luitpold. §Safe administration of 1000 mg LMWID in 1 h has been described (Auerbach M et al. mg Infusion time for 720 300 90–150§ ≥ 15 ≥ 15 ≥ 15 1000 mg. h 1 6 20 16 20 15 Mun Labile iron 3. administration. l Plasma half-life. ~oz et al.5 3. robust and 78:480–91. UNI-MED Verlag AG. Iron therapy with special emphasis on Anaesthesia 2017 Low molecular weight iron dextran Ferric Iron isomaltoside Iron gluconate** Iron sucrose†† (LMWID)‡‡ carboxymaltose§§ 1000¶¶ Ferumoxytol*** Brand name Ferrlecitâ Venoferâ Cosmoferâ Ferinjectâ Monoferâ FeraHemeâ INFeDâ Injectaferâ Monoferroâ Riensoâ Carbohydrate shell Gluconate Sucrose Dextran Carboxymaltose Isomaltoside Polyglucose (monosaccharide) (disaccharide) (branched (branched (linear sorbitol polysaccharide) polysaccharide oligosaccharide) carboxy-methylether Complex type* Type II Type II Type I Type I Type I Type I Molecular weight.5 3.

fewer hospital visits. iron. no iron sucrose or ferric carboxymaltose) and RBC con- iron or placebo [83]. less ambulance transfers. Ferric carboxymaltose reduced hospital without associated hypotension.v. the use of newer i.g. This administration of iron product and RBC concentrates. less time off ered for front-line therapy in conditions where oral work) and the health system (e. with the biggest differences observed for [90–92]. less visits to day iron will predictably fail. further prospective hospital. This should be planned and documented resulted in a net saving when compared with RBC pre-operatively. efficacy and safety trials in various surgical settings 86–89]. We believe there is ample evidence to sup- ferric carboxymaltose and iron isomaltoside-1000. with control. iron therapy was not associated with erative i.v. terial growth more readily [85]. Anaesthetists and surgeons cost–benefit analysis of iron treatment. iron formulations against RBC trans. In large observational studies. known as Patient Blood Management. respectively. Direct and indirect costs for acquisition and should not be misinterpreted as hypersensitivity. started at tration costs (nursing time and giving sets) and the time that surgery is booked and carried on until transportation to hospital. Patients receiving RBC transfusion stayed in hos- rates of transfusion. centrates. should consider pre-operative iron deficiency not as [86] performed a comparative analysis of the costs of a single ‘point’. iron formulation per patient. stridor or peri-orbital oedema [82]. In contrast. care. © 2016 The Association of Anaesthetists of Great Britain and Ireland 11 . iron reduced RBC transfusion rate sion delivers haem and labile iron which supports bac. but cost model. tried [82]. iron with other interven- [82].g. were included in the and can consist of arthralgia. | Peri-operative management of anaemia and iron deficiency Mun Anaesthesia 2017 Some patients who receive i. tions implemented to reduce blood transfusion and/ or placebo.v.5% vs. (e. occurs in approximately 1:200 iron-treated patients. iron did not negatively impact on used. 84].9 days [95% CI 1. iron is safe. 26. myalgia or flushing. were retrospectively reviewed [88].2–2. and are more convenient both for question of whether parenteral iron should be consid. 1000 mg and 1600 mg). are required to make evidenced-based conclusions When comparing i.6]). i. Hb. using cost-minimisation complement activation-related pseudo-allergy. managed with a restrictive trans- from 1965 to 2013 (including 19. across three dosage levels full recovery from the surgical intervention has (600 mg. red cell transfu. tachycardia. 2. However.g. and the patient savings of £437 (485€. At all doses. iron sucrose vs. supporting a greater and allows the rapid administration of larger single doses earlier role for treating iron deficiency and raising the (≥ 1000 mg). [87] compared the cost implications context of an evidence-based enhanced recovery of ferric carboxymaltose vs.4%) without incremental cost [88]. fusion protocol and without (control) or with postop- cluded that i. tachyp. it would be interesting to include the Cost implications of iron therapy costs of postoperative complications and other clini- There are few studies that have undertaken formal cal endpoints as well. administering i. iron formulations The preponderance of published evidence indi. Data from 182 matched pairs of total lower limb A recent meta-analysis of 103 trials published arthroplasty patients.v. ~oz et al. less total cost) [40. $532) and £245 (274€. by considering acquisition costs plus adminis. both in urgent and elective patients transfusion.253 patients) con.v. the patient (e. oral iron programme to secure optimal interpretation of the for avoiding red cell transfusion in 282 patients with intervention [93].v. infection and 30-day mortality in pital longer (1.v.6 days compared with oral iron. i. as well as hospitalisation costs.v. (11. iron isomaltoside 1000 or ferric carboxymaltose) cates that i. iron occurred.v. stay by 2. Bhandari et al. resulting in cost Symptoms abate without intervention.v. this should trigger a peri-operative bundle of fusion. iron may exhibit colorectal cancer and anaemia. Instead. wheezing.v. Thus. which analysis. and prolonged stay in hospital were peri-operative i. Compared surgical patients [51. an increased risk of serious adverse events or infection Acquisition and administration costs of iron (600 mg when compared with oral or intramuscular iron. $300) may be rechallenged or another i. port peri-operative blood management within the Calvet et al.3 days compared with iron sucrose and by noea. although its treatment is essential.

the Swiss Society of the workshop. 1858–6. Zurich. et al. Shander A. Ferring. the inclusion of the companies: Baxter. Masimo and HbO2 Therapeu. 100: 599–604. CSL Behring. ation. In addition. Sangart Inc. Detection. Switzerland and Vifor SA. Garcıa-Erce JA. gation of the senior author (AK). Manage- ing. Ethicon. Curacyte. 6. he has also received honoraria from CSL Behring. Vifor Pharma. Roche Diagnostics International Ltd. Perioperative anaemia management: consensus Vifor Pharma. Maniatis A. TR and AK care. Abbott. Fresenius. Detection. LFB MM. Braun. Spanish Consensus Pharma for the implementation of Frankfurt’s Patient Statement on alternatives to allogeneic blood transfusion: the 2013 update of the ‘‘Seville Document’’. Schering-Plough Interna- Pharma. Asuero M. et al. DS has received honoraria or travel Pharmacosomos had no involvement in the decision to support for consulting or lecturing from the following write the consensus statement. MA has received honoraria from Pharmacos- tional. Photonics Health- from Pharmacosmos. Afshari A. B. Leal-Noval SR. Verum Diagnostica and mos. B. received grant support from Syner-Med. Bris- authors or the drafting or final version of this consen- tol-Myers-Squibb. Gauss Surgical. Sanofi Aventis Baxter Health. ceuticals Inc. PAION. Galenica. National Blood Authority. TR. Albaladejo P. AA’s research department has undergone additional external review as a result. Ethicon Biosurgery. 101: care. the Swiss Foundation for Anesthesia ment by the company.Anaesthesia 2017 ~oz et al. 2013. Olympus and der Linden P. sity hospitals. This consensus statement was developed after the Berne. Daiichi San- sus statement. CSL Behr. | Peri-operative management of anaemia and iron deficiency Mun DS’s academic department is receiving grant sup- Acknowledgements port from the Swiss National Science Foundation. the authors met voluntarily at the insti- Anesthesiology and Reanimation (SGAR). the recommen- Europe and sponsored by unrestricted educational dations were selected using a Delphic process. and management of preoperative anaemia in the elec- tive orthopaedic surgical patient: NATA guidelines. Gauss Surgical. Mun~oz M. MA. cosmos. CSL pbm-module-2 (accessed 17/08/2016). Sarstedt. evaluation. which both are managed by Physicians World Following completion of the first draft. Braun. Goodnough LT. Behring. AS received research grants from CSL statement on the role of intravenous iron. and all grants from Novo Nordisk. Behring. AK is the Pharmacosmos and Masimo. Masimo Corporation and 3. British Masimo and Merck. Maniatis A. Fresenius Kabi. Anesthesia and Analgesia 2005. 12 © 2016 The Association of Anaesthetists of Great Britain and Ireland . British Journal of Anaesthesia 2008. Earnshaw P. Fresenius Kabi and Vifor 4. Merck Sharp & Dohme. Ratiopharm. 30: 270–382. Beris P. Johnson and Johnson. surgical patient. Biomedicaments. The authors discussed and Research. At the end of for Highly Specialized Medicine. 5. AGA. AA has received honoraria or References travel support for consulting or lecturing from Ethicon 1. Blood Transfusion Blood Management Program in four German univer. Van Endosurgery. Berne. Thomas D. without any involve- Switzerland. and honoraria from B. MM. Tem International. CSL Behring and LFB authors agreed on the final version of the manuscript. and Alliance Pharmaceutical Corp. European Journal of has received sponsorship from CSL Behring. 2. and management of anemia in the elective Roche. RB. Switzerland. PM has received research grants from nes: Module 2 – Peri-operative. Bayer. Switzerland agement sponsored by Pharmacosmos. evalu- tics. CS-O and AK Biomedicaments. and acted as a consultant for CSL Journal of Anaesthesia 2011. Patient Blood Management Guideli- Vifor Pharma. et al. the sur-Gl^ane. Spivak JL. UK and Vifor Pharma. OH ment of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. DS was the chair of the ABC different subject areas to be covered and which of the Faculty and is the co-chair of the ABC-Trauma Fac- authors would write each segment (one per author). Switzerland. MB has received hono- Editor-in-Chief of Anaesthesia and this manuscript has raria from GSK. https://www. Anaesthesiology 2013. Pharma. ulty. Boehringer. have received funding and/or honoraria from Vifor Roche Pharma. et al.blood. 106: 13–22. the Ministry of Health (Gesund- authors attended a workshop on Patient Blood Man- heitsdirektion) of the Canton of Zurich. Kozek-Langenecker SA. SL. Pharmacosmos and Vifor Pharma. Villars- agreed with the title of the consensus statement.Braun. Pharmacosmos. 11: 585–610. Mun~oz M. kyo. HK.. SL has received honoraria from GL has no conflict of interest to declare. Goodnough LT. Sorin Group. AMAG Pharmaceuticals and Luitpold Pharma- Vifor Pharma. Octa- have received funding for research and/or honoraria pharma.

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