Transfusion and Apheresis Science 50 (2014) 16–19

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Transfusion and Apheresis Science

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Review

Erythropoietin and intravenous iron in PBM

1473-0502/$ - see front matter � 2014 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.transci.2013.12.007

⇑ Tel.: +1 519 685 8500 32832; fax: +1 519 663 2957.E-mail address: fiona.ralley@lhsc.on.ca

Fiona E. Ralley ⇑Perioperative Blood Conservation Program, Anesthesia and Perioperative Medicine, LHSC-University Hospital, 339 Windermere Road, London, Ontario N6A5A5, Canada

a r t i c l e i n f o a b s t r a c t

Article history:

The concept of patient blood management is such that if a patient with anemia can be iden-tified in the pre-operative period, therapeutic modalities can be targeted to that patientwho might benefit from such treatment. Management strategies include the optimizationof preoperative hemoglobin by maximizing hemopoiesis and RBC mass. This can best beachieved with the use of iron supplementation, either oral or intravenous, with or withoutthe use of erythrocyte stimulating agents (ESAs) such as erythropoietin. The use of IV ironand ESAs is reviewed. Different IV iron formulations available are discussed along withcurrent indications and contraindications for the use of ESAs.

� 2014 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162. Intravenous (IV) iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163. Erythropoietin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184. Patient blood management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

1. Introduction

Preoperative anemia is common, easy to detect andeasy to treat. Its incidence ranges from 11% to 76% depend-ing on the study population and the type of surgery [1].Studies have shown that it is not only linked to an in-creased incidence of morbidity and mortality [2,3] but inaddition, it is a major predictor for the use of allogeneicred blood cell (RBC) transfusion in patients undergoing asurgical procedure associated with moderate to high bloodloss [4,5]. Furthermore the increasingly elderly populationmay be more vulnerable to milder degrees of anemia due

to unrecognized cardiovascular disease. The concept ofblood management is such that if a patient with anemiacan be identified in the pre-operative period, therapeuticmodalities can be targeted to that patient who might ben-efit from such treatment. Management strategies includethe optimization of preoperative hemoglobin by maximiz-ing hemopoiesis and RBC mass. This can best be achievedwith the use of iron supplementation, either oral or intra-venous, with or without the use of erythrocyte stimulatingagents (ESAs) such as erythropoietin (rHuEPO).

2. Intravenous (IV) iron

Iron deficiency is a common cause of preoperativeanemia along with anemia of chronic disease. Causes for

F.E. Ralley / Transfusion and Apheresis Science 50 (2014) 16–19 17

iron deficiency anemia are listed in Table 1. If time permits(usually requiring up to 2 months for the hemoglobin toreturn to normal values) oral iron supplementation maybe adequate to replace iron stores preoperatively. Howeverin some cases intravenous iron may be required in patientsthat are intolerant to oral iron, have a decreased intestinalabsorption due to previous gastric surgery or gastrointesti-nal disease or in patients who are non-compliant with oraliron due to its side-effects such as nausea, vomiting,constipation and dyspepsia. Other reasons for intravenousiron are patients with severe preoperative anemia andthose where the use of ESAs are being considered.

After the administration of intravenous iron and its re-lease into the circulation, iron is transported to the bonemarrow by transferrin, where it binds to receptor sitesfor synthesis of hemoglobin. Iron clearance depends onthe status of the iron stores with a small amount beingeliminated in the urine. Within 7 d the absolute reticulo-cyte count will increase with a concomitant rise in hemo-globin within 7–14 d when iron dextran is given. Thenewer preparations (such as Venofer� and Ferrlecit�) aremore readily bioavailable for erythropoiesis than irondextran preparations and therefore an increase in Hbmay be seen after only 7 d.

Historically the incidence of severe allergic reactionsassociated with the use of high molecular weight iron dex-tran limited its use. However since newer preparationswith much lower adverse reaction rates have been intro-duced there is now a resurgence in the use of parenteraliron preparations. Currently there are four alternative IViron preparations available which include low molecularweight dextran (Infufer�), iron sucrose (Venofer�), ferrousgluconate (Ferrlecit�) and ferumoxytol (Feraheme�). Thelatter is a novel agent that can be administered as a rapidintravenous bolus over 1 min, and has only recently beenapproved by both the FDA and Health Canada. Its proper-ties will be discussed below. Comparing the remaining 3preparations, hypersensitivity reactions have been re-ported as 8.7% per million doses for iron dextran comparedto only 2.6% and 3.3% per million doses for iron sucrose andferrous gluconate respectively [6]. Other adverse reactionrates are still relatively high (50%, 36% and 35% respec-tively), the most common include bradycardia, hyperten-sion, hypotension, chest pain, abdominal pain, nausea,vomiting, diarrhea, headache, fever, pruritus, malaise,myalgias, arthralgias, back pain and allergic reactions. Inaddition patients may develop an arthralgia–myalgia syn-drome. This can occur with any IV iron preparation andmay occur in up to 40% of patients. Generally it presents

Table 1Causes or iron deficiency anemia.

1. Blood loss (GI tract, menstrual bleeding etc.) as 0.5 mg iron is lostwith each ml of blood

2. Decreased iron recycling with chronic infection3. Low uptake due to malnutrition4. Reduced absorption due to previous gastric surgery or

gastrointestinal disease5. Presence of iron-binding food components in cereals and

vegetables

from 2 h to 4 days after administration of IV iron and ischaracterized by temporary fever, muscle cramping, andgeneralized pain. Some studies have shown that steroidpremedication with methylpredisone 125 mg may helpprevent or diminish symptoms [7]. Iron Dextran is a solu-tion of ferric oxyhydroxide in a polymerized dextran solu-tion with a molecular weight of 267 kDa for high molecularweight dextran (INFeD�) and 165 kDa for the lowmolecular format (Infufer�). Up to 1 g can be administeredat one time allowing for the patient to receive their totaliron requirement in one dose (total-dose infusion) via aslow infusion, but life-threatening anaphylaxis can rarelyoccur. For this reason a test dose of 25 mg over 10 min isrequired before the first administration of the product.Unfortunately even if the patient does not show a reactionto the test dose this does not rule out the possibility of ahypersensitivity reaction to the remaining dose or asubsequent dose. Patients with multiple drug allergy syn-drome are well known to be at high risk of hypersensitivityreactions to subsequent chemically unrelated drugs [8].The lower molecular weight preparation of iron dextranhas been shown to have a lower incidence of adverseevents compared to the high molecular weight preparation(5.4% vs. 9.7% respectively) [9] and is similar to other IViron preparations. Venofer� is an iron hydroxide sucrosecomplex in water with a molecular weight of 34–60 kDa.Although it has been given as a slow intravenous injectionof 100 mg over 5 min, repeated 1–3 times weekly to a totaldose of 1 g, it is more generally given as an intravenousinfusion of 200–300 mg over 2 h, which can be repeatedweekly depending on the degree of iron deficiency. Largerdoses are associated with hypotension, nausea and backpain [10]. No test dose is required and it has been shownto be well tolerated in patients who have had a reactionto iron dextran. Ferrlecit� is a sodium ferric gluconatecompound in sucrose with a molecular weight of 38 kDa.Again it can be given by slow intravenous injection of125 mg over 10 min or by an infusion of 125 mg in100 ml of normal saline over 1 h. Initially a test dose of25 mg in 50 ml of normal saline given over 60 min was rec-ommended but this is no longer in the product monograph.Larger doses of 250 mg intravenously over one hr havebeen well tolerated [11]. Ferric gluconate has also beensafely given to patients who have had a severe reactionto iron dextran. Feraheme� is a novel, semisynthetic, car-bohydrate-coated, superparamagnetic iron oxide nanopar-ticle with a molecular weight of to 731 kDa, which can beadministered at a relatively high dose (510 mg) by rapidintravenous injection (30 mg/s or 1 ml/s). At present it is li-censed for the treatment of iron deficiency anemia in adultpatients with chronic kidney disease (CKD). As it is a dex-tran derivative it has been associated with hypersensitivityreactions. A recent study reported a 0.2% rate of serioushypersensitivity reactions (3/1726), with other reactionsof pruritus, rash, urticaria or wheezing reported in 3.7%(63/1726) [12]. However in a study comparing the use offeraheme� to oral iron Spinowitz et al. [13] showed thatintravenous ferumoxytol, given as two doses of 510 mgwithin 1 week, was more effective than oral iron in raisingthe hemoglobin in patients with chronic kidney disease(CKD). At day 35, the mean increase in the hemoglobin

18 F.E. Ralley / Transfusion and Apheresis Science 50 (2014) 16–19

from baseline was four times higher among patients whowere randomly assigned to ferumoxytol compared withoral iron [13]. There was a trend towards fewer serious ad-verse side effects in the ferumoxytol group (4.6% vs. 9.3%).

3. Erythropoietin

Similar to receiving red blood cells, the aim of treat-ment with rHuEPO is to improve the transport of oxygenin the bloodstream, thus avoiding the complications asso-ciated with either severe anemia or those of RBC transfu-sion. This may be of particular importance in patientswho refuse blood products for whatever reason (eitherreligious or otherwise.) Reasons for the use of preoperativeerythropoietin (rHuEPO) include (1) to correct preopera-tive anemia and therefore avoid or reduce the number ofallogeneic blood transfusions during elective surgery, (2)to improve postoperative erythropoietic response and untilrecently (3) to enhance the collection of predonated autol-ogous blood (PAD) for elective surgery. This latter reasonhas become less popular due to reduced utilization ofautologous blood leading to decreased wastage and cost.Suggested contraindications for the use of rHuEPO arelisted in Table 2.

Recent concerns have been voiced over the possibleassociation of increased thrombotic events and the use ofESAs especially in cancer patients or patients with chronicrenal failure [14]. However, their use in the treatment ofpreoperative anemia in patients undergoing an electivesurgical procedure has been shown to reduce the rate oftransfusion without increasing the risk of postoperativethrombosis [15,16]. In patients with an initial preoperativeHb of 100–120 g/l due to either unresponsive iron defi-ciency anemia or anemia of chronic disease, the use of ESAsis indicated if the patient is undergoing an elective surgicalprocedure associated with the risk of major blood loss(>1000 ml) to avoid RBC transfusion. Iron supplementationis always required with the use of ESAs to prevent thedevelopment of functional iron deficiency anemia even inpatients with normal iron stores. It is generally recom-mended that these patients receive intravenous iron sup-plementation, which not only improves the response torHuEPO but may also reduce its dose requirements [17].The combination of either oral or parenteral iron withthe administration of rHuEPO may have an additionaladvantage as studies have shown that ESA driven erythro-poiesis in patients who are iron deficient may lead to an in-creased risk of thrombosis due to thrombocytosis. In

Table 2Suggested contraindications for the use of rHuEPO.

1. Previous history of thrombotic vascular event (in past 6 months)(MI/CVA/TIA/DVT/PE)

2. Previous history of seizure3. Uncontrolled hypertension (SBP > 160 mmHg, DBP > 90 mmHg)4. Risk factors predisposing to pre-op DVT (e.g. immobility,

fractured joint)5. Hypercoagulable disease states (e.g. positive Lupus

anticoagulant)6. Cancer Diagnosis/Treatment (in past 3 years). Not an absolute

exclusion, consider each patient individually. If proceed, closemonitoring and Hb not to exceed 135 g/l

addition stimulating the Hb above 140 g/l may also beassociated with increased thrombotic risk.

Feagan et al. [18] studied the efficacy of 2 different reg-imen of rHuEPO on reducing allogeneic blood transfusionin patients undergoing total hip arthroplasty. 201 patientswith a preoperative Hb ranging from 98 to 137 g/l were as-signed to receive 4 weekly injections of 40,000 U rHuEPO,20,000 U rHuEPO or placebo. All patients received oral ironsupplementation for at least 42 days preoperatively. Theassociated increase in Hb was 19.5 g/l, 17.2 g/l and 1.2 g/lrespectively leading to a transfusion rate of 11.2%, 22.8%and 44.9%. There was no difference between the rates ofvenous thrombotic events between the three groups. Theauthors concluded that although both regimens of rHuEPOwere effective compared with placebo in reducing alloge-neic transfusion in patients undergoing hip arthroplasty,patients who received the higher dose of rHuEPO had thelowest transfusion rate.

4. Patient blood management

In a recent prospective study evaluating the efficacy ofan individualized pre-operative blood saving protocol inelective arthroplasty patients, Gonzalez-Porras et al. [19]studied 305 consecutive patients undergoing either totalknee or total hip replacement surgery. They comparedtheir patients to a historic group from their database whodid not receive any blood saving techniques after matchingby age, gender and type of arthroplasty. The primary aim ofthe study was to obtain a preoperative Hb > 140 g/l andnormal iron stores. Patients were placed in one of 5 groupsdepending on their pre-operative hemoglobin (Hb) andferritin. The groups consisted of (a) no interventionHb > 140 g/l ferritin > 250 lg/l (b) if Hb P 130 g/l but ferri-tin < 250 lg/l they received oral iron (ferogradumet�

105 mg three times daily) (c) if Hb P 130 g/l but ferri-tin < 50 lg/l or were intolerant of oral iron they receivedintravenous iron (Venofer� 200 mg IV weekly until sur-gery) (d) if Hb levels between 100 and 130 g/l they re-ceived erythropoietin (rHuEPOa) 10,000 units SC weeklyplus Venofer� 200 mg IV for 4 weeks pre-operatively (e)preoperative autologous donation was undertaken only inpatients requesting to donate or with a difficult cross-match, where they donated 2 units between day 42 and7 pre-operatively and received oral elemental iron210 mg daily but no rHuEPOa. Eighty-two percent of pa-tients in the study achieved a preoperative Hbof P 140 g/l. The transfusion rate for all patients in thestudy was 18.8% compared to 31.5% in the historic group.Within the 5 groups transfusion rates were (a) 13.7% (b)20.0% (c) 20.4% (d) 0.0% and (e) 35%. The authors concludedthat their protocol was effective and could be beneficial forpatients undergoing arthroplasty procedures. Howeverthey added that other intra- or postoperative strategiesshould be applied to further reduce RBC transfusions.

5. Conclusion

The selective use of intravenous iron supplementationwith or without the use of ESAs is a successful method

F.E. Ralley / Transfusion and Apheresis Science 50 (2014) 16–19 19

for the management of preoperative anemia, leading to areduction in perioperative transfusion requirements in pa-tients undergoing a surgical procedure with associatedmoderate-high blood loss. With the growing awarenessof possible shortages in our blood supply it is behoventof physicians to seek alternatives to RBC transfusionswhich can be implemented in a timely mannerpreoperatively.

Disclosures

None.

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[19] Gonzalez-Porras JR, Colado E, Conde MP, et al. An individualized pre-operative blood saving protocol can increase pre-operativehaemoglobin levels and reduce the need for transfusion in electivetotal hip or knee arthroplasty. Transfus Med 2009;19:35–42.