Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines

 [bib_ref] The effect of perioperative anemia on clinical and functional outcomes in patients..., Halm [/bib_ref] [bib_ref] Higher Hb level is associated with better early functional recovery after hip..., Lawrence [/bib_ref] [bib_ref] Postoperative anemia and quality of life after primary hip arthroplasty in patients..., Conlon [/bib_ref] [bib_ref] The influence of preclinical anaemia on outcome following total hip replacement, Myers [/bib_ref] [bib_ref] Mortality and morbidity in patients with very low postoperative Hb levels who..., Carson [/bib_ref] [bib_ref] Human cardiovascular and metabolic response to acute, severe isovolemic anemia, Weiskopf [/bib_ref] [bib_ref] Transfusion trigger trial for functional outcomes in cardiovascular patients undergoing surgical hip..., Carson [/bib_ref] [bib_ref] Perioperative myocardial ischemic episodes are related to hematocrit level in patients undergoing..., Hogue [/bib_ref] [bib_ref] Relationship between postoperative anemia and cardiac morbidity in high-risk vascular patients in..., Nelson [/bib_ref] [bib_ref] The influence of preclinical anaemia on outcome following total hip replacement, Myers [/bib_ref] [bib_ref] Silent myocardial ischaemia and haemoglobin concentration: a randomized controlled trial of transfusion..., Grover [/bib_ref] [bib_ref] Silent myocardial ischaemia and haemoglobin concentration: a randomized controlled trial of transfusion..., Grover [/bib_ref] [bib_ref] The effect of perioperative anemia on clinical and functional outcomes in patients..., Halm [/bib_ref] [bib_ref] A pilot randomized trial comparing symptomatic vs. hemoglobin-level-driven red blood cell transfusions..., Carson [/bib_ref] [bib_ref] The influence of preclinical anaemia on outcome following total hip replacement, Myers [/bib_ref] [bib_ref] The effects of liberal versus restrictive transfusion thresholds on ambulation after hip..., Foss [/bib_ref] [bib_ref] Transfusion trigger trial for functional outcomes in cardiovascular patients undergoing surgical hip..., Carson [/bib_ref] [bib_ref] A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care...., Hebert [/bib_ref] [bib_ref] Detection, evaluation, and management of anemia in the elective surgical patient, Goodnough [/bib_ref] [bib_ref] Management of preoperative anaemia in patients undergoing elective surgery, Goodnough [/bib_ref] [bib_ref] Detection, evaluation, and management of iron-restricted erythropoiesis, Goodnough [/bib_ref] [bib_ref] Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] [fig_ref] Fig 1: quality evidence=A [/fig_ref] [bib_ref] Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based..., Guyatt [/bib_ref] 

## Recommendations

## Detection of anaemia
Recommendation 1: We recommend that elective surgical patients have an Hb level determination as close to 28 days before the scheduled surgical procedure as possible (Grade 1C).
The Circular of Information for Blood and Blood Products 33 has recommended that iron, vitamin B 12, folic acid, and erythropoietin be used instead of blood transfusion, 'if the clinical condition of the patient permits sufficient time for those agents to promote erythropoiesis . . .' The key phrase relevant to this recommendation is, 'sufficient time . . . to promote erythropoiesis.' Detection of anaemia as close to 28 days before surgery is recommended for sufficient time for evaluation and management.
Recommendation 2: We suggest that the patient's target Hb before elective surgery be within the normal range (female 12 g dl 21 , male 13 g dl 21 ), according to the WHO criteria (Grade 2C).
This recommendation is a suggestion, indicating a lack of panel consensus and evidence on whether elective surgical procedures should be cancelled, representing best practices, for patients who are identified to be anaemic. Delay of elective scheduled surgery for definitive evaluation of newly detected anaemia and associated clinical conditions (nutritional deficiency, chronic renal disease, etc.) will benefit patients and reduce harm, including likelihood of exposure to blood transfusions.

## Evaluation of anaemia
Recommendation 3: We recommend that laboratory testing be performed to further evaluate anaemia for nutritional deficiencies, chronic renal insufficiency, and/or chronic inflammatory disease (Grade 1C).
Unexplained anaemia should be considered as secondary to some other process, 2 9 and the cause of the anaemia must be evaluated. Laboratory testing must be performed to further evaluate anaemia for nutritional deficiencies, chronic renal insufficiency, and/or chronic inflammatory disease and the cause of the anaemia must be evaluated. If a screening blood count detects anaemia, evaluation should begin with an assessment of iron status. The assessment of iron-restricted erythropoiesis needs to distinguish between absolute iron deficiency, iron sequestration due to inflammation, and/or functional iron deficiency due to erythropoietin stimulation. [bib_ref] Use of erythropoietin to increase the volume of autologous blood donated by..., Mercuriali [/bib_ref] The accurate differentiation of these is difficult using traditional biochemical markers of iron status, such as serum iron, percentage saturation of transferrin, and serum ferritin. 9 As ferritin is an acute-phase reactant, traditional laboratory thresholds of ,12 mg litre 21 may be suitable for identifying absolute iron deficiency in normal individuals, but not in patients with any evidence of an inflammatory process. [bib_ref] Detection, evaluation, and management of iron-restricted erythropoiesis, Goodnough [/bib_ref] Correlation of iron stores with ferritin values has demonstrated that ferritin levels must exceed 30 mg litre 21 to achieve a 92% sensitivity for exclusion of absolute iron deficiency. [bib_ref] Clinical utility of the soluble transferrin receptor and comparison with serum ferritin..., Mast [/bib_ref] For patients without chronic renal disease, ferritin levels .100 mg litre 21 confirm the presence of stored iron. When absolute iron deficiency is detected, referral to a gastroenterologist to rule out a gastrointestinal malignancy as a source of chronic blood loss is indicated. [bib_ref] Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based..., Guyatt [/bib_ref] If laboratory evaluation or a diagnostic trial of iron therapy rules out absolute iron deficiency, measurement of serum creatinine and glomerular filtration rate (GFR) may indicate CKD and the need for referral to a nephrologist. If ferritin, iron saturation values, or both or other markers of iron-restricted erythropoiesis are inconclusive, further evaluation to rule out iron deficiency or iron sequestration due to inflammation/ chronic disease is necessary. A therapeutic trial of oral iron therapy would confirm absolute iron deficiency. No response to iron therapy may not rule out absolute iron deficiency because of patient non-compliance, [bib_ref] Use of erythropoietin to increase the volume of autologous blood donated by..., Mercuriali [/bib_ref] ongoing blood (iron) losses in excess of oral iron absorption, [bib_ref] Clinical utility of the soluble transferrin receptor and comparison with serum ferritin..., Mast [/bib_ref] and/or diminished gastrointestinal absorption of iron due to inflammation. 9 Additionally, iron-restricted erythropoiesis due to iron sequestration, functional deficiency, or both must be considered. In these instances, management strategies that include i.v. iron, with or without erythropoiesis-stimulating agents (ESA) therapy, should be considered. 41

## Management of anaemia

## Treatment of nutritional deficiencies
Recommendation 4: We recommend that nutritional deficiencies be treated (Grade 1C).
Nutritional deficiencies must be treated. Iron supplementation is indicated in the presence of confirmed iron deficiency anaemia. The effectiveness of oral iron in the management of preoperative anaemia has been demonstrated in patients undergoing orthopaedic and colorectal cancer surgery. In the absence of preoperative iron supplementation, postoperative iron supplementation has not been shown to be effective. Three small series of orthopaedic surgery patients, undergoing repair of hip fracture or joint replacement and back surgery, 52 demonstrated the feasibility of parenteral iron supplementation in the preoperative management of irondeficiency anaemia, particularly if there was a short interval before surgery. An expert panel recently reviewed the role of i.v. iron in the management of perioperative anaemia and concluded that patients with preoperative anaemia due to iron deficiency or chronic disease should receive preoperative treatment with oral or i.v. iron, depending on the timescale before surgery, tolerance of oral iron, and iron status. [bib_ref] Perioperative anaemia management: consensus statement on the role of intravenous iron, Beris [/bib_ref] 

## Stimulation of erythropoiesis
Recommendation 5: We suggest that ESA be used for anaemic patients in whom nutritional deficiencies have been ruled out, corrected, or both (Grade 2A).
The use of ESA therapy in patients undergoing major, elective surgery is well established on the basis of controlled, randomized trials and is approved for use in this setting. However, recent concerns regarding the RR/benefit of these agents and their appropriate use in patients with chronic renal disease, in patients with anaemia related to cancer or chemotherapy, and in patients undergoing elective surgery [bib_ref] An open-label, randomized study to compare the safety and efficacy of perioperative..., Stowell [/bib_ref] have resulted in a Grade 2 or 'suggested' recommendation.
The use of ESAs in patients with anaemia undergoing elective orthopaedic (hip, knee, and spine) surgery was reviewed under the auspices of NATA.A meta-analysis of 41 published studies [eight studies of ESA alone, studies of ESA augmented with preoperative autologous blood donation (PABD), seven studies of ESA compared with PABD, and four studies of ESA and other comparators] 106 -109 was performed. Pooled estimates of transfusion exposure demonstrated clinically important benefit for both rHuEPO alone (RR, 0.44; 95% CI, 0.31 -0.64) and rHuEPO augmented by PABD (RR, 0.61; 95% CI, 0.49 -0.75). Although sufficient data were available for patients undergoing hip surgery, a large number of studies performed in patients undergoing a mixture of surgical procedures, and a failure to report indication-specific associations with the intervention, limit the ability to make judgement on the effectiveness of rHuEPO in patients undergoing non-hip procedures such as knee and spinal surgery. Taking account of all the studies, the risk of deep vein thrombosis was increased with the use of rHuEPO [Peto OR of 1.66 (95% CI 1.10 -2.48)] but was inconclusive on the risk of mortality, myocardial infarction, and cerebrovascular accidents due to their low incidence.
Anaemia of chronic disease is a diagnosis of exclusion. 7 However, the following are considered evidence of anaemia of chronic disease: anaemia with no evidence of nutritional deficiencies or chronic renal disease, and the presence of an associated chronic disease. In the presence of a low Hb and normal mean corpuscular volume, a reticulocyte count and serum creatinine level should be measured and GFR calculated. A nephrology consultation is appropriate if an abnormal creatinine level or GFR is present to evaluate for possible haemolysis, blood loss, or chronic renal disease.
Patients should receive iron supplementation throughout the course of ESA therapy, to optimize the dose -response relationship for ESA therapy and red blood cell production in the pre-surgical setting. [bib_ref] Erythropoietin, iron, and erythropoiesis, Goodnough [/bib_ref] ESA therapy with iron supplementation is effective in reducing subsequent need for allogeneic transfusion.Detection, evaluation, and management of preoperative of anaemia: an algorithm
We propose an algorithm for the detection, evaluation, and management of preoperative anaemia based on the above recommendations [fig_ref] Fig 2: Proposed algorithm for the detection, evaluation, and management of preoperative anaemia [/fig_ref].
If anaemia is detected on a screening sample, evaluation is necessary and begins with an assessment of iron status. If serum ferritin, transferrin saturation levels, or both indicate absolute iron deficiency, referral to a gastroenterologist to rule out a gastrointestinal malignancy as a source of chronic blood loss may be indicated.
If serum ferritin, transferrin saturation values, or both rule out absolute iron deficiency, serum creatinine and GFR determination may indicate CKD and the need for referral to a nephrologist.
When serum ferritin, transferrin saturation values, or both are inconclusive, further evaluation to rule out absolute iron deficiency or inflammation/chronic disease is necessary. A therapeutic trial of iron would confirm absolute iron deficiency. No response to iron therapy would indicate the anaemia of chronic disease, suggesting that ESA therapy be initiated.
These recommendations are intended to provide guidance for preoperative evaluation in the elective surgical patient. Limiting preadmission testing to a few days before the scheduled operative procedure precludes the opportunity to evaluate and manage the patient with unexplained anaemia. The recommended time frame of testing 4 weeks before the scheduled elective procedure ensures that anaemia can be detected, evaluated, and managed appropriately before elective surgery.
Anaemia should be viewed as a serious and treatable medical condition, rather than as simply an abnormal laboratory value. Anaemia is a common condition in surgical patients and is independently associated with increased mortality. The diagnosis of an unexpected anaemia in patients undergoing elective surgery in which significant blood loss is anticipated should be considered an indication for rescheduling surgery until the evaluation is completed. The presence of preoperative anaemia is significantly associated with morbidity and mortality after surgery, thus warranting this recommendation. Treatment of postoperative anaemia should be the focus of investigations for the reduction of perioperative risk. We conclude that implementation of anaemia management in the elective surgery setting will improve patient outcome.

# Supplementary material
Supplementary material is available at British Journal of Anaesthesia online.

## Conflict of interest
[fig] Fig 1: quality evidence=A (meta-analyses, randomized controlled trials)Moderate-quality evidence=B (randomized controlled trials with limitations, observational studies with large effects) Low-or very low-quality evidence=C (obervational studies, randomized controlled tried with major limitationsThe grading system used for assessment. [/fig]
[fig] Fig 2: Proposed algorithm for the detection, evaluation, and management of preoperative anaemia. SF, serum ferritin; TSAT, transferrin saturation. [/fig]