Background
The World Health Organisation (WHO) originally defined anaemia based on haemoglobin (Hb) levels as < 130 g L-1 for men and < 120 g L-1 for non-pregnant women[6]. Based on this definition being widely used within protocols across the National Health Service (NHS), there have been large variations of the reported prevalence of anaemia within communities. Unfortunately, this definition does not account for other factors that may have important contributions to the effects of anaemia such as age, gender, ethnicity, symptoms of fatigue and the presence of cardiovascular disease, to name a few.
Two particular studies quote the prevalence of anaemia to be 20-25% of the population cohort presenting for major lower limb surgeries[7, 8]. The relationship and impact of anaemia on surgical outcomes has been widely investigated to understand if improvements in the peri-operative period can lead to better results for patients. Historically, the initial studies began within cardiac surgery. From there, further studies were published looking into other specialities. Specifically delving into major lower limb orthopaedic surgery, a couple of studies suggested that allogenic blood transfusions in this cohort accounted for 8-10% of the total donated blood transfusions within the UK[9, 10]. In addition to this, Kotze et al demonstrated that a patient’s preoperative Hb concentration predicted the likelihood of the need to receive allogenic blood transfusions, as well as the hospital length of stay[7]. There is evidence to suggest that both anaemia and allogenic blood transfusions contribute in an accumulative method to risk factors for poor post-operative outcomes[11]. A retrospective study looking at 300,000 patients undergoing non-cardiac surgery identified that a preoperative haematocrit of less than 39% had a statistically significant increase in mortality at 30 days[12].
With an understanding of the impact of pre-operative anaemia the Network for Advancement of Transfusion Alternatives (NATA), constituted of a multidisciplinary panel of physicians, developed guidelines for identifying, evaluating and managing pre-operative anaemia in patients undergoing elective orthopaedic surgery[13]. These guidelines have been widely adapted across the UK as well as the implementation of enhanced recovery programmes to assist patients in achieving a satisfactory and better surgical outcome.
However, to best understand the management options, we must firstly understand the cause of the anaemia. A publication released through the AAGBI in 2015 suggested that the cause of anaemia could be categorised into 3 broad groups: nutrient deficiency anaemia, anaemia of chronic inflammation, and unexplained anaemia[14]. Nutrient deficiency anaemia includes deficiencies in iron (accounting for the largest cause of all anaemias at 16.6%[14]), B12 and folate.
Anaemia of chronic inflammation (or chronic disease) incorporates conditions such as chronic kidney disease, autoimmune disorders, malignancy and inflammatory conditions. These are typically seen as normocytic and normochromic anaemia. There is often a crossover between these 2 groups of anaemias, typically identified by low iron stores due to the pathophysiology within the chronic inflammatory conditions. Hepcidin, a protein secreted by the liver, is key to regulating iron levels within the plasma. It inhibits iron absorption from the gut, as well as causing iron trapping within macrophages and liver cells. In chronic infection and inflammatory conditions, Hepcidin production is significantly increased which can lead to a ‘functional’ iron deficient anaemia[15]. The second mechanism by which anaemia of chronic inflammation occurs is by the reduction of erythropoiesis mediated by various cytokine pathways, including interleukin (IL)-6, as well as TNFα, IL-1α and IL-1β. There is also a third and final pathway to consider, in which cytokines cause a decrease in red cell survival and cell death. These mechanisms are also important to understand in the post-operative period because surgery will often blunt the body’s response to anaemia through release of these inflammatory cytokines[16], and therefore, it could be expected that blood loss and intra-operative haemodilution could prolong the extent of post-operative anaemia.
The third category of unexplained anaemia includes those conditions that did not meet the criteria for the previous 2 groups based on detection and tests, and those who’s conditions may not have been identified without further specialist tests (such as myeloma). Nevertheless, these patients can still be treated in spite of an exact cause not known.
Having understood the pathophysiology of anaemia, the NATA guidelines for the management of pre-operative anaemia (following detection and evaluation) concentrate on the correction of nutrient deficiency anaemia and anaemia of chronic inflammation. In the first instance, NATA recommends that nutritional deficiencies be treated, in particular, attempting to correct iron deficiency as it is the most common cause of anaemia. Traditionally, this has been through oral iron supplements. However, we know that these are not always well tolerated by patients as they can lead to gastrointestinal disturbances[17]. As an alternative, intravenous (IV) iron therapy has been recommended within the guidelines depending on the time scale as well as the intolerance of oral iron supplements. There have been studies in which IV iron supplementation reduced the requirements for allogenic blood transfusions in gynaecological cancer patients[18, 19].
The alternative stage recommended by NATA is the suggestion to stimulate erythropoiesis by erythropoiesis-stimulating agents (ESA). The guidelines published first performed a meta-analysis of 41 studies looking into the use of ESA before recommending their concomitant use with iron therapy[13], which correlates in theory with the crossover in mechanism for the cause of anaemia in this group of patients.