Erythropoetin is currently licensed for use in adult patients scheduled for major elective orthopaedic surgery. It has been shown to be useful in reducing exposure to allogeneic blood transfusions in non-iron deficient patients prior to major elective orthopaedic surgery, having a high-perceived risk for transfusion complications. Use is generally restricted to patients with moderate anaemia (e.g. Hb 10–13 g/dl) with expected moderate blood loss (900 to 1800 ml).

Allogeneic blood transfusions have been shown to be associated with increased morbidity and hospital stay and preoperative treatment with subcutaneous r-HuEPO has been shown to significantly reduce the allogeneic transfusion exposure in patients undergoing major elective orthopaedic surgery.

Impact of Perioperative Haemoglobin Levels Perioperative anaemia can have detrimental effects on postoperative outcome. Carson et al, 1996, demonstrated, in 1958 surgical patients who declined blood transfusions, that overall risk of mortality increases as the haemoglobin decreases, and that even mild anaemia may be associated with an increased risk of death. Furthermore, patients with underlying cardiovascular disease are less tolerant of anaemia than those without cardiovascular disease, for any haemoglobin concentration (both preoperative and postoperative). To further define the impact of allogeneic blood transfusions, Dunne et al (2002) sought to investigate the incidence of preoperative anaemia in noncardiac surgical patients. Preoperative anaemia (haematocrit < 36) was found in 33.9% and postoperative anaemia in 84.1% of the study cohort (n=6301). Multiple logistic regression analysis revealed that low pre-operative haematocrit, low postoperative haematocrit and increased blood transfusion rates were all associated with increased mortality (P< 0.01), increased postoperative pneumonia (P ≤0.01) and increased hospital length of stay (P< 0.05). These results underline the importance of maintaining higher haemoglobin levels and reducing allogeneic blood usage in surgical patients.

Preoperative haemoglobin levels are also an important predictor of transfusion risk. Faris et al, 1996 performed a statistical analysis of data from double-blind placebo controlled trials, evaluating the risk of exposure to allogeneic blood in patients treated with r-HuEPO or placebo to determine the pre-treatment clinical variables, that are prognostic for transfusion risk in orthopaedic surgical patients. The analysis also confirmed which patients are most likely to benefit from recombinant human erythropoietin. Placebo treated patients with Hb > 10 to ≤13g/dl had an approximately two fold greater risk of transfusion than patient with Hb ≥13g/dl. Moreover, r-HuEPO significantly reduced the transfusion risk in patients with haemoglobin > 10g/dl to ≤13g/dl at baseline.

r-HuEPO Use in Surgery Three major double blind placebo controlled studies (Faris et al, 1999; Canadian Orthopaedic Perioperative Erythropoietin Study Group, 1993; De Andrade et al, 1996) involving a total of 724 patients undergoing major elective orthopaedic surgery have demonstrated that treatment with 300IU/kg r-HuEPO daily for at least 14 days, beginning 10 days prior to surgery and continuing until the 3rd or 4th day after surgery, significantly decreased the percentage of patients with haemoglobin (Hb) levels ≥10g/dl to ≤13g/dl requiring transfusion.

The administration of daily 300IU/kg r-HuEPO may be inconvenient. Data has demonstrated that less frequent dosing regimens may be as efficacious. An open-label, randomised, multicentre study was conducted by Goldberg et al (1996), to compare the safety and efficacy of two dosage regimens of r-HuEPO. Patients were scheduled for major elective orthopaedic surgery involving hip or knee replacement. Entry criteria included a Hb level > 10g/dl to ≤13g/dl, and a serum iron to total iron binding capacity (TIBC) ratio ≥0.20 and a serum ferritin ≥50ng/ml.

Patients were randomised at least three weeks before the scheduled surgery to one of two treatment groups. Group 1 (n=73) received 600IU/kg sc once weekly, on days −21, −14, and −7 prior to surgery and on the day of surgery (total 2,400IU/kg). Group 2 (n=72) received 300IU/kg sc daily for 15 days starting 10 days prior to surgery, on the day of surgery, and for 4 days postoperatively (total dose 4,500 IU/kg), as used in previous studies. In addition patients received a polysaccharide-iron complex, which provided a minimum of 200mg of elemental iron per day. Patients also received standard anticoagulation therapy. The data showed that weekly dosing with 600IU/kg SC for three weeks before surgery produced an erythropoietic response at least as good as that achieved with a daily dosing regimen of 300IU/kg. The weekly regimen was similar to the daily regimen with respect to avoidance of allogeneic transfusion. In addition, the once-weekly dosing regimen of Epoetin alfa offers the potential advantages of greater convenience for patients, and would be less costly since 47% less Epoetin alfa is administered.

Other related agents are also being studied. Darbopoetin has a longer half-life and may allow a reduced dosing schedule with similar efficacy.

There is no conclusive evidence that there is a higher complication rate with EPO than with placebo, in particular the incidence of thromboembolic events. The published studies have all utilised chemical prophylaxis however. Use of EPO is contraindicated with uncontrolled hypertension.

Iron Therapy Anaemia is present in a significant percentage of preoperative patients and is almost universal in rheumatoid patients. Iron therapy can play an important role as part of a strategy to reduce transfusion requirements. This can be utilised alone to correct anaemia or in conjunction with EPO therapy to optimise its efficiency. Absorption of oral iron is poor and the time scales are often limited which makes IV administration more effective. There remains some resistance to the IV route due to the potential side effects and also the costs and organisational problems. A dose of 700–900mg of elemental iron is recommended. Oral iron is probably better than nothing but there is little conclusive data about its use pre and post-operatively.

Algorithm to Reduce Blood Transfusion With the aim of reducing unnecessary allogeneic red blood cell transfusion in orthopaedic surgery, Slappendel et al (2003) have created an algorithm, which has resulted in an 80% reduction in transfusion. Analysis of 29,000 patients, revealed several factors which required evaluation. There were two that were of special interest in the preoperative setting: use of NSAIDs that can disturb coagulation of the blood during surgery and preoperative laboratory studies for full blood count to determine whether erythropoietin should be given.

Single measures to reduce blood transfusion may not have any impact but use of a complete algorithm and specific measures for each hospital can dramatically reduce the number of units transfused. Transfusions are associated with immunomodulation, which may increase the incidence of postoperative infections, delay healing of postoperative wounds and thereby prolong hospitalisation. Subsequent analysis of the database revealed a 42% reduction in postoperative infections. In conclusion, the use of a comprehensive algorithm in orthopaedic surgery resulted in an 80% reduction in the need for blood transfusion.