British Committee for Standards in Haematology Guidelines on the Identification and Management of Pre‐Operative Anaemia (2015)

Anaemia is most often defined in terms of the criteria established by the World Health Organization (WHO) in 1968 (WHO 2011), namely haemoglobin (Hb) concentration of <130 g/l for men and <120 g/l for women. Pre-operative anaemia is common. Its prevalence varies from 5% to 75% depending on the population studied (Shander et al, 2004). Pre-operative anaemia may significantly affect patient outcomes. Anaemia is an independently predictive risk factor for complications and death (Beattie et al, 2009; Spahn, 2010; Musallam et al, 2011). Co-existing anaemia substantially increases health care costs in medical (Ershler et al, 2005; Nissenson et al, 2005; Dowling, 2007) as well as surgical (M'Koma et al, 2009) patients, with substantial additional cost incurred out of hospital (Ebinger et al, 2004; Ershler et al, 2005). It further predisposes patients to requiring allogeneic blood transfusion (Shander et al, 2004; Beattie et al, 2009; Spahn, 2010; Musallam et al, 2011). (In this guideline, ‘transfusion’ may be taken to mean only allogeneic blood transfusion.) Although these relationships are associative, the body of evidence is large and consistent. The Department of Health, National Blood Transfusion Committee and National Health Service (NHS) Enhanced Recovery Partnership all consequently recommend that anaemia is investigated and treated before planned surgery, but make few recommendations on how this may be achieved (Department of Health 2007, NHS Enhanced Recovery Partnership Programme 2010, National Blood Transfusion Committee 2014). A Guideline Development Group (GDG) was commissioned by the British Committee for Standards in Haematology (BCSH), with members variously having experience in haematology, anaesthesia, surgery, critical care, gastroenterology, pre-operative assessment and transfusion medicine. The Australian National Blood Authority and Australian National Health and Medical Research Council (NHMRC) published comprehensive perioperative Patient Blood Management (PBM) guidelines in 2011 (Australian National Blood Authority 2011a). These were produced after systematic review and included literature to 2009 (Australian National Blood Authority 2011b). The BCSH GDG further referred to international guidelines in surgery (Society of Thoracic Surgeons Blood Conservation Guideline Task Force et al, 2007, Goodnough et al, 2011), from the British Society for Gastroenterology (Goddard et al, 2011), the Renal Association(UK Renal Association 2010) and other BCSH guidelines (Ryan et al, 2010; Thomas et al, 2013). We further reviewed the literature from 2009 to September 2014. We searched the Medline database using the Cochrane Collaboration's Highly Sensitive Search Strategy for identifying randomized controlled trials (RCTs) and search terms as detailed in Appendix S1. We also searched Embase, using a similar search strategy (Appendix S1). We included studies that evaluated a strategy for treating anaemia before surgery, and reported transfusion and/or other outcomes. Two authors independently screened the retrieved references. Additional primary literature was suggested by members. All BCSH guidelines use the evidence rating system of the GRADE working group (www.gradeworkinggroup.org). Strong (Grade 1): There is confidence in the balance of risk or burden versus benefit. Grade 1 recommendations may be applied to most patients. Weak (Grade 2): The balance between benefit and burden of therapy is less clear. Grade 2 recommendations require judicious application to individual patients. Evidence quality is graded as high (A), moderate (B) or low (C). (A) Further research is unlikely to change confidence in the estimate of effect. Current evidence derived from randomized clinical trials without important limitations. (B) Further research may impact on confidence in the estimate of effect and may change the estimate. Current evidence derived from randomized clinical trials with important limitations (e.g. inconsistent results, imprecision or potential bias), or very strong evidence from observational studies (e.g. consistent estimates of the magnitude of a treatment effect or demonstration of a dose-response gradient). (C) Further research is likely to have an important impact on confidence in the effect estimate and is likely to change the estimate. Current evidence from observational studies, case series or expert opinion. Strong evidence indicates that pre-operative anaemia is not simply an abnormal laboratory value; it is rather an important modifiable risk factor for peri-operative morbidity and mortality. The Australian PBM group identified 42 observational studies which consistently showed pre-operative anaemia to predict post-operative morbidity and mortality, as well as the requirement for transfusion (Australian National Blood Authority 2011a). A contemporaneous systematic review (Spahn, 2010) found similar results. Large studies have been published since the abovementioned systematic reviews. Musallam et al (2011) analysed data on 227 435 surgical patients, controlling for over 60 potential confounders. Pre-operative anaemia predicted mortality and morbidity. Mild anaemia (defined as Hb >100 g/l) increased relative risk by over 30%, with there also being a relationship between anaemia severity and outcome, i.e. a ‘severity-response curve’. Anaemia also strongly predicted the need for transfusion, which is again predictive of poor outcome. Ferraris and colleagues (Ferraris et al, 2012) analysed data and conducted propensity-matched comparisons between 15 186 patients who received one unit of donated red cells and 893 205 patients who received no blood. Transfused patients suffered more morbidity and mortality. Patients transfused >1 unit had further increased rates of morbidity and mortality, in a dose-dependent fashion. Other authors (Pedersen et al, 2009; Glance et al, 2011) made similar conclusions. Detection of pre-operative anaemia thus helps to identify patients at risk of poor post-operative outcomes, including mortality. This is consistent with the surgical risk prediction literature. Pre-operative Hb influences risk in well-validated risk prediction models (Copeland et al, 1991; Whiteley et al, 1996; Prytherch et al, 2003; Richards et al, 2010; Smith & Tekkis, 2015). Furthermore, both iron status and Hb concentration are closely related to functional capacity (Anker et al, 2009), which in turn influences peri-operative risk (Hennis et al, 2011). Successive reports from the Royal College of Surgeons and Department of Health 2011) and National Confidential enquiry into Patient Outcome and Death (NCEPOD) (2011) recommend that the care and consent of surgical patients explicitly consider quantitative risk estimates made using predictive scores, e.g. decisions on critical care. The effect of anaemia on mortality is thus pertinent in routine practice and will impact on Trusts' critical care resource. Whilst anaemia is predictive of surgical risk, we could find no randomized evidence that correction of anaemia alters that risk. The exception is transfusion, where randomized evidence indicates that anaemia correction decreases transfusion requirements (Australian National Blood Authority 2011a). Given that allogeneic blood is, by definition, a limited resource, there is public health benefit to be gained from limiting its use where alternatives exist. Because previously unsuspected anaemia detected during surgical work-up may, of itself, be significant, anaemia screening also carries a health benefit beyond the planned surgical episode. The argument for screening and correction is thus strong in principle, but individualized decisions must still be made that take into account the magnitude of the proposed surgery as well as the patient's history and preferences. If patients are only screened close to the planned operation date, there will be insufficient time to correct anaemia (Blest et al, 2007). Missing the above opportunities for timely diagnosis should be viewed as a failure of care processes. An agreed referral pathway that incorporates anaemia screening as part of the referral for surgery from General Practice is ideal, as this maximizes the time available for investigation and treatment. Anaemia screening, by laboratory or bedside test, is easily carried out and places minimal burden on patients. Where surgery is a likely outcome from referral, such screening is strongly advocated. In an observational study, an approach including early screening and collaboration between primary and secondary care delivered outcome improvements for patients undergoing lower limb arthroplasty (Kotze et al, 2012), as well as significant cost savings (Spahn et al, 2012). Many surgical procedures may safely be scheduled to allow diagnosis and treatment of anaemia, and reduce risk. To do so constitutes best practice and provider organizations and commissioners may agree that referral-to-treatment time targets take account of this (‘stopping the clock’). In procedures where delay presents a risk or burden to the patient, an individualized decision should be made that balances the risk of anaemia and/or transfusion against that of postponement. However, in non-urgent surgery this should only rarely be necessary if surgical pathways are properly set up. The magnitude of risk increase is proportional to anaemia severity (Musallam et al, 2011). Speed of response to treatment is furthermore greater in more severe anaemia, particularly in iron deficiency. Using whatever time is available before surgery to treat anaemia thus makes logical sense when surgery should be expedited. Broadly speaking, in the surgical context anaemia may be defined as that caused by disturbances of iron metabolism (and hence potentially correctable with iron alone) and anaemia of other causes (which may require other treatments). Erythropoiesis is iron-restricted if the body's absolute iron stores are insufficient (Iron Deficiency Anaemia, IDA) or if insufficient iron is available at bone marrow level in the presence of iron in the reticulo-endothelial system (Functional Iron Deficiency, FID) (Goddard et al, 2011; Thomas et al, 2013). Iron depletion may also occur without anaemia. Regenerating 10 g/l of lost blood takes approximately 165 g of stored iron in a 70 kg adult. If the serum ferritin is <100 μg/l, loss of 30 g/l Hb (1200 ml blood for a 70 kg adult) will deplete total body iron stores and precipitate IDA (Australian National Blood Authority 2011a). The serum ferritin concentration is the most powerful test to elucidate iron status in the absence of inflammation (Goddard et al, 2011). In anaemia, serum Ferritin <30 μg/l is a sensitive marker of iron deficiency (Mast et al, 1998), with <15 μg/l being pathognomonic of IDA (Goddard et al, 2011). The British Society for Gastroenterology recommends specialist referral for IDA, except in pre-menopausal women, because the prevalence of cancer in unexplained IDA approaches 15% (Goddard et al, 2011). Given that pre-operative workup often includes a battery of tests, hypoferritinaemia without anaemia may be detected. Hypoferritinaemia (<15 μg/l) without anaemia is not sinister in young women, but is associated with a cancer prevalence of 0·9% in men and postmenopausal women and referral is indicated (Goddard et al, 2011). Specialist referral may also be indicated according to the severity of unexplained anaemia (e.g. men with Hb <120 g/l and women with Hb <100 g/l, or according to any locally agreed criteria) (UK Renal Association 2010, Goddard et al, 2011). Ferritin is an acute phase reactant and may be elevated by inflammation or concurrent disease (Anker et al, 2009). Anaemia with ferritin levels below 50 μg/l or 100 μg/l is still strongly suggestive of iron deficiency in the presence of inflammation (Australian National Blood Authority 2011a, Goddard et al, 2011). In such circumstances, exclusion of iron deficiency may require the use of further tests (e.g. serum transferrin saturation <20%) or a therapeutic trial of parenteral iron (Australian National Blood Authority 2011a). Anaemia not related to iron disturbance may be due to other nutritional deficiencies (Vitamin B12 and folate), secondary to renal failure, or of other causes. Deficiency in vitamin B12 and folate is easily and cheaply tested for, and is recommended (UK Renal Association 2010). If other common causes are excluded and the estimated Glomerular Filtration Rate (eGFR) is <30 ml/min/1·73 m2 or <45 ml/min/1·73 m2 in diabetics, renal failure is the likely cause. Referral should be considered if previously undetected renal failure is diagnosed as result of pre-operative screening (UK Renal Association 2010). Inherited haemoglobin disorders (haemoglobinopathy) should be considered in all individuals with microcytic anaemia if there is no evidence of iron deficiency, or if red cell changes persist after adequate iron replacement. Although these conditions are more frequently associated with individuals of non-northern European origin, they are present in all ethnic groups. Carriers are asymptomatic. Milder carriers may have a normal haemoglobin level with minimal reduction in mean cell volume (MCV) and mean cell haemoglobin (MCH) while others will have mild anaemia with more marked reduction in MCV and MCH. Individuals with anaemia > 20 g/l below lower limit of normal or those with symptoms or splenomegaly should be referred. Carriers do not need haematology follow-up but their General Practitioner (GP) should be informed because the information may be important for genetic counselling. Women who have had pregnancies in recent years or partners of women with significant carrier states may have been screened as part of the national antenatal screening programme and may be aware of their haemoglobinopathy results. It is also useful to refer back to historical results, for haemoglobin, MCV and MCH, if available, as these remain relatively constant throughout adult life for a given individual; any significant deviation indicates an additional cause for anaemia. The Australian National Blood Authority and Network for Advancement of Transfusion Alternatives (NATA) review groups each published an investigation algorithm (Australian National Blood Authority 2011a, Goodnough et al, 2011). The UK context is different, particularly regarding referral-to-treatment time targets and the role of GPs in commissioning care. It is thus important that patients' GPs be involved from the outset in the management of anaemia discovered during operative work-up. GPs should include information about known anaemia in the surgical referral, so that patients are not inappropriately postponed or investigated. It may be practicable to submit anaemic patients to a standardized battery of tests (including repeat Hb, serum ferritin, vitamin B12 and Folate), rather than engage in sequential testing. The above diagnostic considerations and initial test results may be integrated into an investigations and referral algorithm. This writing group considers that such algorithms should be locally designed, to be implementable without disrupting surgical pathways. It should involve both primary and secondary care, and funding arrangements should be clear. The potential for gain is great, with reductions in spend on transfusion, potential reductions in length of stay, and a potential decreased burden of follow-up and treatment in primary care after discharge. Both primary and secondary care systems stand to gain from systematic pre-operative anaemia management. Example algorithms are given in Appendix S2. These are with the of organizations in their rather than as recommendations We that use this and the results of pathway to management algorithms for the procedures that they anaemia management with surgical pathways is on studies of to the Australian PBM guidelines (Australian National Blood Authority recommend that iron deficiency be treated (Grade We identified no that should There are for IDA or iron are available, and However, iron is The of iron is by iron (e.g. and and common including Iron often cause Furthermore, iron is in the context of inflammation 2009) or renal failure, iron unlikely to be in with the of haemoglobin correction is about 10 g/l 2009). correction of anaemia, iron for to is before iron stores are (Goddard et al, 2011). The of vitamin is recommended to iron & Although iron be as as iron in the et al, 2011), the is Where correction is (e.g. cancer the parenteral is more et al, We identified one et al, 2009) that pre-operative iron with parenteral iron Hb was more likely with parenteral A total was furthermore found to correct anaemia than iron in a observational et al, 2011). iron are than because the iron is in a & 2014). on all where high are the is estimated at et al, & 2014). In a Cochrane review of the from parenteral iron was no to that with et al, 2014). The European that the of iron their that they are given in with and that patients are for at 30 2013). The of iron and is thus not It on between of length of and a given surgical should take their into account when their The relative of parenteral iron are in Appendix B12 and/or deficiency may present with anaemia. These also have other important and deficiency detected during the surgical should be treated (Grade (Australian National Blood Authority 2011a). available to in clinical practice are all of the including such as and These are most in renal medicine. In is also for peri-operative there is no effect between In to their on red cell may also against by and and (UK Renal Association 2010, et al, 2011). The Australian review group (Australian National Blood Authority found randomized studies, all of to which consistently showed that therapy decreased transfusion, but were to evidence on other outcomes. A that with the above review et al, found that therapy before lower limb arthroplasty substantially transfusion Where transfusion risk reduction is the evidence for is thus e.g. in patients who or in those with less evidence in of treatment to other patient and the literature is regarding that therapy may in cancer patients. A of studies found that therapy for anaemia quality of life and transfusion but that is et al, 2012). In all but one in this therapy was given for and for in studies, the to pre-operative patients A Cochrane review also found strong evidence that peri-operative transfusion increases the of cancer after potentially surgery & so to in cancer surgery is not A to the of therapy in surgery without found rates of et al, 2009). therapy is transfusion in a recent et al, and the authors that the cost was not The clinical and of therapy also the of from the UK National for Health and thus in transfusion risk, but are and have potential and decisions are necessary and further research is that the of therapy when we make no for the use of other than where transfusion of is to the e.g. in patients who or those with The UK Renal Association recommends that if therapy be given to a Hb of no than The Australian PBM group (Australian National Blood Authority Australian et al, 2011) and the UK Renal all recommend that iron be with an in to its We could find no evidence on the best of iron to Given that with iron is often and its not 2009) and because are it may be to consider the so that therapeutic iron levels are Research is before any be There is randomized evidence regarding very management of anaemia before et al, 2010; et al, 2011) and arthroplasty et al, 2011) In these an and parenteral iron were before surgery, without to the cause of the anaemia. All trials showed significant decreases in transfusion but not on other patient and the absolute of patients involved are or parenteral iron in et al, 2011; et al, 2012), there is observational evidence to the et al, 2014). In one in patients with et al, transfusion requirements and Hb other patient were therapy that includes an is thus potentially but and data is This GDG considers data is available, therapy should only be after patient that is about the of We make no have been to anaemic patients for surgery, but no randomized evidence that this is of benefit (Shander et al, 2011). practice includes pre-operative transfusion at as high was et al, 2012), i.e. transfusion to correct pre-operative anaemia, in of blood of versus transfusion showed to be in critical et al, and et al, and in patients after et al, 2011). studies of perioperative transfusion in cancer surgery et al, and surgery et al, suggested a Hb of g/l may be to 70 g/l or g/l, However, the groups in the above trials were when to practice et al, 2012). Whilst the transfusion to be and it is for patient we found no literature to transfusion being where the is a normal or transfusion given to correct We further found no evidence in of pre-operative transfusion to surgical outcomes, and in the absence of other PBM transfusion not to reduce total transfusion requirements et al, 2012). There is thus a of evidence for transfusion as an treatment to against the of pre-operative anaemia. This should be taken in with the dose-dependent relationship between transfusion and complications (Ferraris et al, 2012), with systematic transfusion to be et al, et al, or & et al, to and evidence of both et al, and & of transfusion to normal or Hb in of operative blood loss is not particularly as anaemia are In where transfusion is likely to be transfusion practice and patient blood management (e.g. severe anaemia or the of pre-operative transfusion is to transfusion is as However, it should be that these are not common in surgery if surgical pathways are properly set up. Appendix an of the management available for pre-operative anaemia. the and information in these guidelines is to be and at the time of to the the British Society for Haematology the any for the of these General for expert Appendix S1. Appendix S2. Example Appendix of iron available in the UK Appendix of treatment for pre-operative anaemia. The is not for the or of any information by the than should be to the for the