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ORIGINAL PAPER 5A-S20-2

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Blackwell Publishing Ltd

Pharmacological management of perioperative anaemia: our experience with intravenous iron in orthopaedic surgery

Manuel Muñoz,

1

José Antonio García-Erce,

2

Jorge Cuenca

3

& Elvira Bisbe

4

AWGE (Anaemia Working Group – España):

1

Transfusion Medicine, School of Medicine, Málaga

2

Departments of Haematology, University Hospital Miguel Servet, Zaragoza

3

Orthopaedic and Trauma Surgery, University Hospital Miguel Servet, Zaragoza

4

Department of Anaesthesiology, University Hospital Mar-Esperanza, Barcelona, Spain

Introduction

Preoperative anaemia may be present in up to one-half ofsurgical patients, depending on the underlying pathology forwhich they require surgery [1]. Iron deficiency (ID) and chronicinflammation, with or without ID, are the most commoncauses of preoperative anaemia, although deficiencies of iron,folic acid and/or vitamin B12 without anaemia are also frequent,especially among the elder population [2]. In this regard, ina recent series of 345 patients undergoing major electiveorthopaedic surgery the prevalence of preoperative anaemiawas 18%, because of haematinic deficiency (30%), chronicinflammation with or without ID (40%), and mixed or unknowncause (30%) [Table 1]. Interestingly, ID was present in 18%of non-anaemic patients, vitamin B12 deficiency in 21%, andfolate deficiency in 7% (Table 1). These deficiencies might bluntthe response to erythropoiesis-stimulating agents or delay therecovery from postoperative anaemia.

In addition, 30% of patients in this series had an Hb level< 13 g/dl [3], and it is well known that a low preoperativehaemoglobin level is one of the major predictive factors forperioperative blood transfusion in orthopaedic surgery withmoderate to high perioperative blood loss [4,5]. A Europeanstudy including almost 4000 patients showed an inverserelationship between preoperative Hb values and the probabilityof receiving allogeneic blood transfusion (ABT) (e.g. 10–18%for Hb 150 g/l, 20–30% for Hb 130 g/l, 50–60% for Hb 100 g/l;70–75% for Hb 80 g/l) [3]. Similarly, 30–70% of patients under-going hip fracture repair received ABT perioperatively [6,7],and the logistic regression analysis identified preoperativeHb value as an independent predictor of the need for ABT [7].

On the other hand, postoperative anaemia, which is presentin up to 90% of patients [1], is mainly caused by perioperativeblood loss and may be aggravated by inflammation-inducedblunted erythropoiesis, especially through decreased ironavailability (i.e, hepcidin-dependent down-regulation ofintestinal absorption and impaired mobilization from bodystores) [8]. Correction of severe postoperative anaemia oftenrequired for ABT.

However, overall concerns about adverse effects of ABT(e.g. increased risk of postoperative infection, fluid overload,transfusion-related acute lung injury, etc.) [2,3,9,10] haveprompted the review of transfusion practice and the searchfor transfusion alternatives, such as preoperative autologousblood donation, haemodilution, perioperative cell salvage,recombinant erythropoietin (rHuEPO) or aprotinin administration[11]. In this paper, we reviewed our experience with the useof a restrictive transfusion protocol and the perioperativeadministration of intravenous (IV) iron, with or without rHuEPO,in patients undergoing trauma (hip fracture) or electiveorthopaedic surgery (knee and hip arthroplasty).

Correspondence

: Prof Manuel Muñoz, Medicina Transfusional, Facultad de Medicina, Universidad de Málaga, Campus de Teatinos, s/n, 29071-Málaga (Spain)E-mail: mmunoz@uma.es

Table 1 Altered haematological and biochemical parameters in anaemic and

nonanaemic patients scheduled for elective orthopaedic surgery at Hospital

Mar – Esperanza in 2005. CRP, C-reactive protein; MCH, mean corpuscular

haemoglobin. *P < 0·05 (Data taken from reference [3])

Anaemicn = 62

Non-anaemicn = 282

Haemoglobin(g/dl) 11,5 14,0*

Ferritin < 30 ng/ml (%) 35,5 17,7*

Vitamin B12 < 270 pg/ml (%) 24,2 21,2

Folate < 3 ng/ml (%) 14,5 7,1

CRP > 1 g/dl (%) 40,7 18,5

Reticulocyte count < 25 × 103/µl (%) 25,8 15,2*

MCH < 27 pg (%) 16,9 5*

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IV iron agents

All IV iron agents are colloids with spheroidal iron-carbohydratenanoparticles. Each particle consists of an iron-oxyhydroxidecore (Fe [III]) and a carbohydrate shell that stabilizes the iron-oxyhydroxide core. Differences in core size and carbohydratechemistry determine pharmacological and biological differencesbetween the different agents, including clearance after injection,iron release

in vitro

, early evidence of iron bioactivity

in vivo

and maximum tolerated dose and rate of infusion [12,13].Three different products are principally used in clinical practice:iron dextran (73–265 kDa), iron gluconate (38 kDa) and ironsucrose (43 kDa) [14,15].

The stability of the dextran complex allows the administrationof high single doses (so-called ‘total dose therapy). However,these iron complexes may cause well-known dextran-inducedanaphylactic reactions that occur in some patients receivingiron dextran [16]. In contrast, iron gluconate is a labile type withfast degradation kinetics and has the potential for acute adversereactions related to labile iron release. Non-transferrin-boundlabile iron may induce acute endothelial cell injury and atransient capillary leak syndrome (nausea, hypotension,tachycardia, chest pain, dyspnoea as a result of lung oedemaand bilateral oedema of the hands and feet) that should notbe misread as anaphylaxis [12]. To avoid these side-effects,maximum recommended single dose is 125 mg; whereas theadministration of total dose is not recommended. Finally,iron sucrose is a partially stable type with partial uptake ofreleased iron by plasma proteins such as (apo)-transferrin butalso by the reticulo-endothelial system [17]. However, if theinfusion speed is too fast (above 4 mg Fe

3+

/min) or the singletotal iron dose too high (above 7 mg Fe

3+

/kg), labile irontoxicity might occur [12]. Single doses of up to 300 mg aresafe, and the maximal recommended dosage is 600 mg/week[16]. Overall, iron sucrose is currently considered as the safestIV iron preparation [14,15].

Preoperative iron administration

Elective surgery

As stated previously, preoperative low Hb is a major independentpredictor factor of perioperative transfusion in electiveorthopaedic surgery. Thus, whenever possible, preoperativecorrection of anaemia and/or haematinic deficiency might beachieved before elective surgery. In this regard, a randomizedtrial on iron preload for major joint replacement showed thatat least 18% of patients attending for hip or knee replacementwere anaemic and benefit significantly from preoperativeoral iron supplements over 4 weeks. Furthermore, oraliron supplementation in patients without obvious anaemiaprotects against a fall in Hb during the immediate postoperativeperiod, suggesting a widespread underlying depletion of

iron stores in this patient population despite a normalHb [18].

More recently, the implementation of a blood saving procotol,consisting of a restrictive transfusion trigger (Hb < 80 g/l)plus oral haematinics for 30–45 days prior to surgery, 156consecutive total knee replacement (TKR) has proved to beuseful as both the transfusion rate (32% vs. 5·8%;

P

< 0·01)and the transfusion index (2·22 vs. 1·78 units per transfusedpatient;

P

< 0·05) were reduced with respect to a previous seriesof 156 matched patients in our institution [19]. Moreover, forpatients with preoperative Hb < 130 g/l transfusion rate wasonly 19%, indicating that this protocol seems to be as effectiveas other more complex and expensive protocols, involvingthe use of high rHuEPO doses [20,21].

However, although oral administration should be preferredfor iron supplementation, this is a time-consuming process(e.g., for a target Hb 140 g/l, 6 months of treatment shouldbe needed if baseline Hb 85 g/l or 2 months if baseline Hb100 g/l). On the other hand, if the patient’s iron stores weredepleted going into the procedure, the blood loss could notbe corrected by endogenous red cell production. Then, thepreoperative use of IV iron might also be considered whentime to surgery is too short for oral therapy. In this regard,the administration of IV iron sucrose (600–1200 mg over 2–3 weeks) has shown to increase Hb levels (18 g/l) in patientswith iron deficiency or inflammatory anaemia who werescheduled for orthopedic surgery [22,23].

Finally, in patients with rheumatoid arthritis scheduled formajor orthopaedic surgery, the presence of a low pre-donationhaematocrit (Hct < or = 39%) can preclude the donation ofsufficient autologous blood to meet transfusion requirements.The use of rHuEPO, in conjunction with IV iron supplementationto maximize its beneficial effects, has shown to be well toleratedand facilitates preoperative autologous blood donation andreduces exposure to allogeneic blood in this patient population[24].

Non-elective surgery

We also evaluated the efficacy of preoperative administrationof iron sucrose to reduce the requirements for ABT in hip fracture,where usually no other blood-saving method is available. Wefirst investigated the safety profile of preoperative IV 100 mgin 23 patients undergoing surgery for pertrochanteric hipfracture (PHF), and no adverse effects were witnessed [25].We then evaluated the efficacy of preoperative administrationof a higher dose of iron sucrose (200–300 mg) to reducerequirements and postoperative morbidity and mortality in55 PHF patients in comparison to a previous series of 102non-treated PHF patients [26]. Preoperative iron sucrosereduced the percentage of transfused patients, although thisreduction was only significant for patients with admissionHb > 120 g/l (43% vs. 27%;

P

< 0·05), as well as postoperative

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Pharmacological management of perioperative anaemia

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infection rate (Fig. 1a). In addition, there was a trend to lower30-day mortality in patients receiving iron (Fig. 1a). Similarly,for patients undergoing surgery for subcapital hip fracture(SHF), preoperative iron sucrose (200–300 mg;

n

= 20) resultedin lower transfusion rate (15% vs. 36·8%;

P

< 0·05), and lowertransfusion index (0·26 vs. 0·77 units per patient;

P

< 0·05),when compared to a historical control series (

n

= 57). In addi-tion, patients receiving iron showed lower 30-day mortalityrate (0% vs. 19·3%) (Fig. 1b), shorter hospital stay (11·9 vs.14·1 days), as well as a trend to lower postoperative infection

rate (15% vs. 33%) (Fig. 1b) compared to those in the controlgroup [27].

Perioperative iron administration

Hip fracture

Despite good results obtained with preoperative administrationof iron sucrose, data from patients with admission Hb

≤

120 g/l suggest that a benefit could be obtained if a higherdose of iron sucrose were administered perioperatively. Thispossibility was explored in a fourth study including 124patients with PHF or SHF [28]. In this prospective study withparallel series, we compared the effectiveness of perioperative600 mg IV iron sucrose (200 mg/48 h), plus 40 000 IU rHuEPOsubcutaneous if admission Hb < 130 g/l, and a restrictivetransfusion protocol (transfusion trigger: Hb < 80 g/l and/orsymptoms of acute anaemia) (

n

= 83) vs. no intervention (control;

n

= 41). Once again, the treatment resulted in a reduction of boththe percentage of postoperatively transfused patients (24·1%vs. 53·7%, for treatment and control group, respectively;

P

<0·001), the number of transfused units (1·7 ± 0·2 vs. 0·6 ± 0·2,respectively;

P

< 0·001), and the postoperative infection rate(31·4% vs. 12·5%, respectively;

P

= 0·016) (Fig. 1c), when com-pared to a control group. In addition, there was a trend to lower30-day mortality (15% vs. 7·3%, respectively) (Fig. 1c), andno adverse reactions to iron administration were found [28].

Elective total knee replacement

The excellent results obtained with IV iron plus rHuEPO inanaemic fracture patients stimulated us to apply a similarprotocol for perioperative stimulation of erythropoiesis inpatients undergoing surgery for TKR, with special interest onpatients with mild anaemia (Hb < 130 g/l).

A series of 139 consecutive patients of primary TKR receivedperioperative iron sucrose (2

×

200 mg/48 h, IV), plus pre-operative rHuEPO (1

×

40 000 IU) if preoperative Hb < 130 g/l(group 2) [29]. This protocol was applied to another series of173 consecutive TKR patients who also received postoperativeunwashed shed blood (USB) if preoperative Hb < 130 g/l(group 3), as this blood-saving technique has been shown toreduce ABT in TKR [30]. Overall, only 13 patients (4·2%) receivedABT, without differences between groups (Fig. 2a), but thosewho received ABT showed lower preoperative Hb levels thanthose who did not (136 ± 8 vs. 143 ± 10 g/l, respectively;

P

= 0·041). All transfusions were given within 48 h aftersurgery [28]. For patients with preoperative Hb < 130 g/l,there was a small and not significant difference in ABT ratebetween groups (9% vs. 3%, for groups 2 and 3, respectively).There were no differences in postoperative complicationsbetween groups, and no adverse effects of iron sucrose,erythropoietin or USB administration were witnessed, but

Fig. 1 Allogeneic blood transfusion (ABT) and postoperative infection rate

in patients undergoing surgery for pertrochanteric (PHF) and subcapital hip

fracture (SHF) repair who were treated (preoperative iron sucrose, IV iron)

or not (control) with preoperative iron sucrose (a,b) or perioperative iron

sucrose ± erythropoietin (IVI ± EPO) (c). *P < 0·05, treatment vs. control

(Data taken from references [26–28]).

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length of hospital stay (LHS) for patients with preoperativeHb < 130 g/l was shorter in group 3 (

P <

0·05) [29]. Hence,this blood-saving protocol seems to be effective for reducingABT in TKR patients when compared with previous studies(group 1, ABT rate 30%; Fig. 2a) [4]. In conclusion, althoughpreoperative improvement of Hb levels before the scheduledsurgical procedure should be desirable, we believe that thisblood-saving protocol, consisting of a restrictive transfusiontrigger plus perioperative administration of IV iron sucrose ±rHuEPO, is effective in reducing ABT in TKR patients. However,more research is needed to ascertain which patients are morelikely to benefit from either perioperative iron administrationor selective addition of postoperative blood salvage to pharma-cological treatment to avoid ABT exposure

Finally, it is well known that in TKR surgery, perioperativeblood loss, low transfusion thresholds and short hospital stayresult in patients being discharged with low haemoglobin.We assessed the effects of perioperative administration of IViron (2

×

200 mg/48 h, IV), with (

n

= 19) or without (

n

= 129)rHuEPO (1

×

40 000 IU), plus a restrictive transfusion threshold

(Hb < 80 g/l) on recovery from postoperative anaemia [31].Mean Hb loss was 36 g/l, but only seven patients were transfused(5%) despite 66 (45%) patients not having enough stored ironto compensate for Hb loss. At postoperative day 30, only 15%were anaemic, 70% of Hb loss and 92% of preoperative Hbwere recovered, and ferritin increased by 73

µ

g/l (

P <

0·01),although erythropoietic response was higher in patientsreceiving erythropoietin (

P <

0·05). No adverse effects of ironsucrose or erythropoietin were witnessed [31].

This data seem to indicate that, as opposite to oral iron [32–35], perioperative IV iron might be useful for the treatmentof postoperative anaemia in TKR patients. Although differentformulae might be used, the dose of IV iron to be administeredto reach a target Hb that is higher than 130 g/l may be calculated,assuming that 150 mg of iron is needed to raise Hb by 10 g/land that perioperative blood loss will decrease Hb by 30–40 g/l. According to this, the administration of a total doseof 600 mg of iron sucrose, starting before surgery, should beenough for most patients. In addition, if the patient was anaemicat admission (Hb < 130 g/l), we do recommend the administra-tion of rHuEPO in order to enhance the erythropoietic responseas the effect of IV iron alone is limited [28,31,39].

Postoperative iron administration

As stated in previous discussions, the results of several RCTssuggested that the administration of oral iron for anaemiaafter orthopaedic surgery does not appear to be worthwhile,as postoperative erythropoiesis is limited by the inflammatoryeffects of surgery on iron metabolism [36,37]. However, theadministration of iron sucrose (3 mg/kg/day) was shownto be a more effective than oral iron to restore postoperativeHb levels after spinal surgery in children [38].

These results prompted us to investigate the effect of post-operative administration of 300 mg of IV iron sucrose on ABTrequirements in total hip replacement (THR) patients (

n

= 24),with a previous series of 22 THR patients serving as thecontrol group [39]. No other blood-saving method was usedin any patient, and no side-effects of iron administration werewitnessed. The group given iron showed a lower transfusionindex (0·96 vs. 1·68 units/patient;

P

= 0·038), and a trend toa lower transfusion rate (46% vs. 73%;

P

= 0·067) (Fig. 2b).The reduction of the transfusion index in patients receivingIV iron can not be related to changes in transfusion practiceas a transfusion protocol was applied and there were nodifferences in pre-transfusion Hb levels between groups(75 ± 8 vs. 76 ± 9 g/l, respectively;

P

= NS).The percentage of transfused patients in this study, especially

in the control group, is higher than that reported previously[2,3,40]. However, in this respect, it is worth noting that theprevalence of preoperative anaemia (37%), is higher than thatreported in a series of 961 Spanish patients undergoing majorelective orthopaedic surgery (21%;

P

= 0·013) [41]. On the

Fig. 2 Allogeneic blood transfusion (ABT) rate and index in patients

undergoing surgery for total knee arthroplasty who were treated or not with

perioperative 400 mg iron sucrose ± 40 000 IU rHuEPO iron sucrose, with

(group 3) or without (group 2) postoperative blood salvage, with respect to

a previous series (group 1, control) (a), or for total hip arthroplasty who were

postoperatively treated or not with 300 mg iron sucrose (B). *P < 0·05,

treatment vs. control (data taken for references [4,29,39]).

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other hand, 31% of the patients in an extensive Europeanstudy had preoperative Hb level < 130 g/l [3], whereas in ourseries these figures were 50% for the control group (

P

= 0·055)and 72% for the iron group (

P

= 0·001). In this regard, admissionHb levels for non-transfused patients were lower in those comingfrom the iron group than those from the control group (127 ±9 vs. 140 ± 12 g/l, respectively;

P

= 0·017), suggesting anerythropoietic effect of iron. In addition, because 65% oftransfusions were given on the 3rd to the 4th postoperative dayor later, an extended postoperative iron administration schedulemight be useful to reduce further late postoperative ABT.

Safety or IV iron administration

Although no serious life-threatening adverse event has beenreported in the different studies reviewed in the previousdiscussion, the numbers of patients included in these studiesare not large enough to draw definitive conclusions regardingthe safety of IV iron agents in the orthopaedic surgical setting.However, according to data from the Food and DrugAdministration (FDA) on adverse drugs events (ADEs)attributed to the provision of four formulations of IV ironduring 2001–2003, including higher- and lower-molecular-weight iron dextran, sodium ferric gluconate complex andiron sucrose, the total number of reported parenteral iron-related ADEs was 1141 amongst approximately 30 milliondoses administered (approximately 38 ADEs per 1 million),with 11 deaths (7 iron dextran, 3 iron gluconate, 1 iron sucrose)[15]. The absolute rates of life-threatening ADEs were 0·6,0·9, 3·3 and 11·3 per million for iron sucrose, sodium ferricgluconate complex, lower-molecular-weight iron dextran andhigher-molecular-weight iron dextran, respectively, whereasabsolute rates of death were 0·11, 0·25, 0·75, and 0·78 per million,respectively. Therefore, the frequency of IV iron-related ADEsis extremely low, and life-threatening and other ADEs appearto be lower with the use of non-dextran iron formulations[15]. In addition, the rates of ADES associated with non-dextran iron, including iron-related deaths, are much lowerthan that of ABT-related severe side-effects (10 per 1 million)and ABT-related deaths (4 per 1 million) [42].

Current information on the relationship between IV ironand infection deserves special consideration. Elemental ironis an essential growth factor for bacteria with many speciesexpressing iron transport proteins that compete with transferrin,and it has long been suggested that patients with iron overloadare at increased risk of infection [43]. On the other hand,cellular immune responses are also dependent on the presenceof iron, and specific defect in cell-mediated immunity hasbeen well described, even in latent iron deficiency, includingimpaired lymphocyte and natural killer cell proliferationand function, and depressed neutrophil respiratory burst[44]. Postoperative complications, in particular infection afterabdominal surgery, were reported to be significantly more

common in 228 patients with low preoperative serum ferritincompared with 220 patients with normal ferritin; confoundersincluding haemoglobin level were taken into account in theanalysis [45]. In addition, besides the reduction in the require-ments for ABT, the most remarkable findings of our studiesof patients undergoing hip fracture repair were the reductionin postoperative infection, and a trend towards lower 30-daypostoperative mortality in those receiving IV iron sucrose[26–28]. Nevertheless, despite this absence of definitiveclinical data, it seems sensible to avoid IV iron administrationin the setting of acute infection.

Conclusions

Despite the good results obtained in the reviewed studies,there might be concerns regarding the use of IV iron inorthopaedic and trauma surgery, especially if borne in mindthat this is an ‘off-label’ indication for some patients (withinthe European Union, iron sucrose is indicated for the treatmentof iron deficiency in those cases where ‘there is the clinicalneed for a rapid iron supply to iron stores’). In addition tosafety, recommended doses and administration schedule,comparative effectiveness and limitations and cost-effectivenessare among the important issues that should be addressed.

With respect to the effectiveness of IV iron administrationin the context of blood-sparing methods, the relative risk ofreceiving ABT can be calculated:• As for patients undergoing surgery for hip fracture repair,

both IV iron alone (78/159 vs. 27/75; RR: 0·73, 95% CI:0·52–1·03;

P

= 0·061) and iron + rHuEPO (29/41 vs. 20/83;RR: 0·34, 95% CI: 0·22–0·52;

P

= 0·0001) reduced the need forABT. However, the lack of studies using other blood-sparingstrategies precludes a comparative analysis in this area.

• As for patients undergoing elective joint replacement,postoperative IV iron reduced by 37% the need for ABTafter THR (16/22 vs. 11/24; RR: 0·63, 95% CI: 0·38–1·04;

P

= 0·067), whereas IV iron ± rHuEPO reduced by 87% theneed for ABT after TKR (30/100 vs. 3/77; RR: 0·13, 95%CI: 0·04–0·41;

P

= 0·0001).• This effectiveness in TKR is comparable to that observed

for administration of high doses of rHuEPO alone (4

×

40 000 IU) (OR: 0·38, 95% CI: 0·24–0·63) [20,46], cellsalvage (RR: 0·35, 95% CI: 0·24–0·52) [29,47], preoperativeautologous blood (RR: 0·16, 95% CI: 0·07–0·36) [47], andbetter than that of acute normovolaemic haemodilution(RR: 0·79; 95% CI: 0·60–1·06) [47].Another important point is the cost of these interventions.

However, a cost–benefit analysis of blood-saving strategiesis difficult to make because of the complex costs involvedin blood transfusion. Thus, a formal cost–benefit study isrequired to address this issue.

In conclusion, according to data reviewed in this paper,perioperative IV iron sucrose administration in trauma and

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elective orthopaedic surgery is safe, as no treatment side-effects were observed. Moreover, perioperative iron sucroseadministration, with or without rHuEPO, may result in lowertransfusion requirements, decreased postoperative infectionand mortality rates, shorter LHS and hastened recovery ofpostoperative anaemia. If confirmed by large randomizedclinical trials, these findings would provide a rationale totreat these patients with IV iron, alone or in combination withrHuEPO, for attaining higher postoperative Hb concentrationsand earlier functional recovery, as well as for limiting exposureto ABT and postoperative morbidity at the same time.

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