Vox Sanguinis (2018)

© 2018 International Society of Blood Transfusion

REVIEW ARTICLE DOI: 10.1111/vox.12718

Short-term perioperative iron in major orthopedic surgery:

state of the art
Susana G


omez-Ram
ırez,1 Mar
ıa Angeles Maldonado-Ruiz,2 Arturo Campos-Garrigues,3 Antonio Herrera4 &
2
Manuel Mu~noz
1
Internal Medicine, University Hospital Virgen de la Victoria, M
alaga, Spain
2
Perioperative Transfusion Medicine, School of Medicine, Malaga, Spain
3
Haematology, University Hospital Virgen de la Victoria, Malaga, Spain
4
Ortopaedic and Trauma Surgery, School of Medicine, Zaragoza, Spain

In major orthopaedic surgery, it is recommended to detect and correct preopera-

Received: 18 May 2018,
revised 13 August 2018,
accepted 18 September 2018
tive anaemia several weeks prior to surgery. However, in many cases, the proce-
dure is urgent or the patient is evaluated shortly before the intervention. As iron
deficiency is the leading cause of perioperative anaemia, an exhaustive review of
the literature was performed to assess the efficacy and safety of short-term peri-
operative intravenous, with or without erythropoietin, or postoperative oral or
intravenous supplementation in major orthopaedic surgery. Overall, 20 studies
met the inclusion criteria. There were 13 randomized trials (moderate quality)
and seven observational studies (low to very low quality). The primary outcomes
were reduction in transfusion requirements, haemoglobin increase and medica-
tion side-effects during the study period. Data analysis showed that postoperative
oral iron administration neither increased haemoglobin nor reduced transfusion
requirements, and it was associated with significant gastrointestinal adverse
effects (15%). In contrast, for some patient populations, perioperative or postop-
erative administration of intravenous iron, with or without recombinant erythro-
poietin, may reduce transfusion requirements and/or hasten the recovery from
postoperative, with few clinically relevant adverse effects (<2%). However, dis-
crepancies between randomized trials and observational studies on the possible
beneficial effects of short-term perioperative intravenous iron administration
were found for patients undergoing surgery for hip fracture repair. Further stud-
ies are needed to elucidate when the treatment should be started, which combina-
tion of drugs should be used, and which patient groups would be most benefit.
Key words: patient blood management, recombinant erythropoietin, oral iron,
intravenous iron, surgery, transfusion.

[1]. Preoperative anaemia is an independent risk factor

Introduction
Patients undergoing major orthopaedic surgery (MOS)
procedures may be exposed to the effects of anaemia,
blood loss and allogeneic blood transfusion (ABT) that
may adversely influence in their postoperative outcome
Correspondence: Manuel Mu~noz G
omez, Medicina Transfusional
Perioperatoria, Departamento de Especialidades Quir
urgicas, Bioqu
ımica
e Inmunolog
ıa, Facultad de Medicina, Universidad de M
alaga, Campus
de Teatinos, 29071-M
alaga, Spain
E-mail: mmunoz@uma.es
for increased risk of postoperative complications and hos-
pital or 30-day mortality [2].
In a systematic review of MOS patients, preoperative
anaemia was highly prevalent both in total hip or knee
arthroplasty (24%) and in hip fracture repair surgery
(44%) [3]. Postoperative anaemia was even more common
(51% and 87%, respectively) [3]. In our area, a recent
observational study (3342 patients), the overall prevalence
of preoperative anaemia (haemoglobin [Hb] <13 g/dl) was
36% in elective procedures, being 26% in MOS [4].

1
2 S. G

omez-Ram
ırez et al.
A preoperative Hb level <13 g/dl is the most important
independent risk factor for transfusion in MOS procedures
with moderate-to-severe bleeding [5]. Since intra-operative
or postoperative anaemia develops acutely, ABT continues
to be the method most frequently used to quickly and
effectively restore the Hb levels, especially in non-elective
surgery [5]. However, there are a number of reasons for
reducing the use of the ABT, including high processing and
administration costs and risks of adverse effects.
All this has promoted the development of multidisci-
plinary and multi-modal programmes for the comprehen-
sive management of MOS patients, generically known as
patient blood management (PBM) programmes, to reduce
or eliminate the need for ABT and improve the clinical
outcome [1, 6]. Perioperative anaemia management con-
stitutes a fundamental pillar of PBM programmes in MOS.
The presence of preoperative anaemia should be investi-
gated, at least 30 days before the intervention, in order to
its classification and treatment [5]. In the postoperative
period, anaemia detection should be early detected and
treated to avoid or reduce ABT requirements and hasten
functional recovery [6]. Absolute or functional iron defi-
ciency is the leading cause of anaemia in MOS [4,7], and
the National Institute for Health and Care Excellence
(NICE) in the UK recommends offering oral or intravenous
(IV) iron before or after surgery to patients with iron defi-
ciency anaemia [5].
However, often this time frame for anaemia manage-
ment is not available, either because it is non-elective pro-
cedure (e.g. hip fracture repair) or because the patient is
evaluated shortly before the intervention. Even in these
cases, any available time should be used to initiate anae-
mia treatment, which ultimately can be started in the
postoperative period [2, 8]. In this regard, we performed
Short-term
perioperative
IV iron
Preoperative IV iron
Oral or IV iron
–6 –5 –4 –3 –2 –1 Surgery
Weeks
Fig. 1 Iron supplementation modalities according to the time of initiation. In major orthopaedic surgery, preoperative iron administration (4–6 weeks
prior to surgery) is the standard approach for treating iron-deficient patient iron recommended by most guidelines[2, 5, 6, 36–38]. Short-term perioper-
ative intravenous iron administration (up to 1 week before and/or after surgery) has been also suggested by some guidelines[2, 37]. Postoperative intra-
venous iron administration is usually restricted to hospital stay (approximately 1 week), whereas postoperative oral iron supplementation is usually
prescribed for 4–8 weeks [5, 8].
an exhaustive literature review to ascertain the efficacy
and safety of short-term perioperative administration of
oral or intravenous iron, with or without recombinant
human erythropoietin (EPO), for anaemia management in
MOS patients.
Methods
Search strategy
A search on MEDLINE (via PubMed) was performed using
multiple key words (e.g. iron OR intravenous iron OR ery-
thropoietin AND orthopaedic surgery OR subcapital frac-
ture OR femoral neck fracture OR intertrochanteric
fracture OR subtrochanteric fracture OR knee surgery OR
hip surgery OR arthroplasty OR spine surgery), in differ-
ent sequences, to ensure the inclusion of all potential
studies, published between 1976 and 2018.
Inclusion criteria
Studies were included if they fulfilled the following crite-
ria: (1) study population was adults undergoing elective
or non-elective MOS; (2) the intervention consisted of
short-term perioperative administration of IV iron
(≤7 days before and/or after surgery), with or without
EPO, or postoperative administration of oral iron (Fig. 1);
(3) randomized controlled trials (RCTs), or observational
prospective or retrospective studies; (4) articles should be
written in Spanish or English. Two authors (SGR and
MAMR) independently assessed the articles for compli-
ance with the inclusion criteria. Any disagreement was
resolved through discussion or consultation with a third
independent investigator (MM).
Postoperative
Oral iron
+1 +2 +3 +4 +5 +6 +7 +8
Weeks
© 2018 International Society of Blood Transfusion
Vox Sanguinis (2018)

Data extraction
From each of the included studies, the following set of
data was extracted, if available: author and year of publi-
cation, type of study (RCT, observational), type of sur-
gery, groups of patients, type, dose, initiation and
duration of iron treatment, doses of EPO, Hb at baseline,
final Hb and Hb increment (reported or calculated), trans-
fusion rate (%) and index (units/patient), infection and
mortality rates, length of hospital stay, and treatment-
related adverse events. Regarding the latter, particular
attention was paid to gastrointestinal adverse effects of
oral iron (e.g. nausea, vomiting, epigastric ache, flatu-
lence, diarrhoea or constipation) and to hypersensitivity
reactions to intravenous iron (e.g. hypotension, anaphy-
laxis).
Data synthesis
Study data were grouped into tables according to the type
of study (RCT, observational), type of iron supplementa-
tion (oral or intravenous), time of treatment in relation to
the surgical procedure (perioperative, between 7 days
before and 7 days after the surgery, or postoperative,
only after surgery) and type of surgery (elective or non-
elective). The primary outcomes were Hb increase, reduc-
tion in transfusion requirements and medication side-
effects during the perioperative period. The secondary
outcomes were the length of hospital stay, rate of postop-
erative infection and mortality. Due to the great variabil-
ity in composition, dosage and duration of treatments in
the reviewed studies, as well as in the use of other trans-
fusion alternatives (e.g. tranexamic acid, postoperative
cell salvage) or in transfusion protocols, a meta-analysis
of data was not performed. However, differences in Hb
increments (minimum, maximum) and reduction of trans-
fusion rates (relative risk [RR] and 95% confidence inter-
val [95% CI]) were estimated, when possible (EPIDAT 3
1
software, licensed to Conselleria de Sanidade, Xunta de
Galicia, Spain).
Results
Search results and included studies
The initial search yielded a total of 267 items. After the
review of study summaries, 243 failed to meet the inclu-
sion criteria and were excluded. The full text of the 24
remaining articles was retrieved for a detailed assessment.
Of these, four hip fracture studies were subsequently
excluded [9–12], as they had been included in a pooled
analysis together with new data [13]. Therefore, 20 stud-
ies were considered appropriate for inclusion in this
© 2018 International Society of Blood Transfusion
Vox Sanguinis (2018)
Short-term perioperative iron therapy 3
review: nine with perioperative intravenous iron, six with
postoperative oral iron and five with postoperative intra-
venous iron [13–32] (Tables 1–4). The overall quality of
the evidence provided by the RCT was moderate, and that
provided by observational studies was considered low or
very low.
Efficacy
Perioperative intravenous iron in elective MOS
The efficacy of perioperative intravenous iron administra-
tion of (iron sucrose or iron isomaltoside) to reduce trans-
fusion rates in knee or hip arthroplasty has been
evaluated in one RCT and three observational studies
(3574 patients) [14–17] (Table 1).
A RCT in anaemic patients undergoing bilateral knee
arthroplasty found that iron sucrose (up to three 200 mg
doses) plus EPO (3000 IU) decreased ABT rate with respect
to placebo (20% vs. 54%, respectively; relative risk [RR]:
0
38, 95% confidence interval [CI]: 0
21–0
68:
P = 0
0006) [15]. In addition, at postoperative week 6,
treated patients showed higher Hb values (12
7 g/dl vs.
11
8 g/dl, respectively; P < 0
05) [15]. Data on postopera-
tive infection, mortality or length of stay were not
reported.
In a series of unilateral knee arthroplasty patients
(n = 139), Cuenca et al. [15] showed that administration
of two 200 mg doses of iron sucrose (48 h before and
48 h after surgery), with or without EPO (1 9 40 000 IU;
48 h before surgery if Hb <13 g/dl) resulted in a very low
ABT rate (2
9%). In a subsequent series of unilateral knee
arthroplasty patients (n = 173), the addition of postopera-
tive autologous blood salvage to this pharmacological
treatment did not improve the ABT rate (5
2%) or postop-
erative Hb levels, but decreased the length of hospital
stay (8 vs. 10 days, respectively; P < 0
05). There were no
differences in postoperative infection rates (2
1% vs.
2
3%; P = 1
000). At the authors’ institution, previous
ABT rate in unilateral knee arthroplasty was 30% [33].
In case series of bilateral knee arthroplasty, Suh et al.
[16] observed that the combined use of perioperative
intravenous iron isomaltoside (1000 mg) and topical
tranexamic acid (2 g) virtually eliminates ABT require-
ments (1
3%). Data on postoperative infection, mortality
or length of stay were not reported.
More recently, in a large retrospective study, Zhang
et al. [17] showed that intravenous (20 mg/kg) plus topi-
cal (1 g) tranexamic acid administration resulted in very
low ABT in hip or knee arthroplasty. Additional perioper-
ative administration of intravenous iron sucrose (200 mg/
48 h) and EPO (10 000 IU/day) to anaemic patients,
rather than oral iron (150–300 mg/day), further reduced
ABT in hip arthroplasty (3
9% vs. 7
2%; RR: 0
54, 95%
 4 S. G

Table 1 Studies evaluating perioperative intravenous iron administration in lower limb arthroplasty (four studies, 3574 patients)

Type of iron Transfusion

Study [Ref.] Baseline PostOP Hb Dose (mg elemental iron) N (%) 30-day Infection Length of Adverse
Surgery Patients Hb (g/dl) (g/dl) [weeks] Administration schedule (U/pt) mortality (%) rate (%) stay (days) eventsa (%)
omez-Ram
ırez et al.

Randomized controlled trials

Na et al. [14] IS: 54 12
1 12
7 [6] IS (200 mg) + EPO-b (3000 IU) during 11 (20)* ? ? ? ?
Bilateral knee arthroplasty surgery and in postop days 1, 3 o 5 0
2 – 0
5
Placebo: 54 12
1 11
8 [6] if Hb <8 g/dl (max. 3 doses) 29 (54) ? ? ? ?
0
8 – 0
8
Observational studies
Cuenca et al. [15] IS: 139 13
8 10
5 [1] IS (2x200 mg; 48 h before and 48 h 4 (2
9) 0 2
1 10 * 0
Prospective after surgery) + EPO (1 9 40 000 IU;
Total knee arthroplasty 48 h before surgery if Hb <13 g/dl)
IS+PDR: 173 14
0 10
4 [1] IS (2 9 200 mg; 48 h before and 48 h 9 (5
2) 0 2
3 8 0
after surgery) + EPO (1 9 40 000 IU;
48 h before surgery if Hb <13 g/dl) +
Postoperative drain reinfusion
Suh et al. [16] IIM: 72 13
1 10
5 [2] IIM (600 mg on day of surgery + 400 mg 1 (1
3) ? ? ? ?
Case series on postop day 7) + Topical
Bilateral knee arthroplasty tranexamic acid (2 g)
Zhang et al. [17] Retrospective IS: 745 (THA) 13
3 ? IS (200 mg/2 days, 3–4 doses)+EPO 29 (3
9)* 0 0
7 4
9* ?
Total hip or knee arthroplasty. 556 (TKA) 13
0 ? (1 9 40 000 IU + 4–6 9 10 000 IU) 0
15 – 0
9* 5
7*
All with topical (1 g) and if preoperative anaemia + IS (200 mg/2 days, 12 (2
2)
intravenous (20 mg/kg) 1–3 doses)+EPO (3–5 9 10 000 IU) 0
05 – 0
34
tranexamic acid. if postop Hb <9
5 g/dl
SC: 986 (THA) 13
4 ? Oral iron 150–300 mg/day, 5–7 days 71 (7
2) 0 0
7 6
2 ?
795 (TKA) 13
0 ? 0
29 – 1
31 7
3
23 (2
9)
0
09 – 0
65

?, Not specifically reported; EPO, recombinant human erythropoietin; Hb, haemoglobin; IIM, iron isomaltoside; IS, iron sucrose; PDR, postoperative drain reinfusion; RCT, randomized controlled trial; SC, stan-
dard care; THA, total hip arthroplasty; TKA, total knee arthroplasty.
*
P < 0
05.
a
Treatment-related.

Vox Sanguinis (2018)

© 2018 International Society of Blood Transfusion
 Table 2 Studies evaluating perioperative intravenous iron administration in hip fracture repair surgery (five studies, 2063 patients)

Study [Ref.] Baseline PostOP Hb (g/dl) Type of iron Dose (mg elemental iron) Transfusion 30-day Infection Length of Adverse
Surgery Patients Hb (g/dl) [weeks] Administration schedule N (%) (U/pt) mortality (%) rate (%) stay (days) eventsa (%)

Randomized controlled trials

Serrano Trenas IS: 100 12
1 10
6 [1] IS (200 mg/48 h, max. 600 mg) 33 (33)b 11 13 13
5 3

Vox Sanguinis (2018)

et al. (2010) [18] 0
8 – 1
2
Hip fracture repair SC: 100 11
9 10
3 [1] No iron 41 (41) 10 16 13
1 0
TTS: 4 days 0
9 – 1
2
Kateros et al. [19] IS+EPO: 38 10
1 10
1 [1] IS (100 mg/day, 10 days) +EPO ? ? ? 6
7 8
Hip fracture repair (20 000 IU/day, 10 days) 1
5 – 1
2*
TTS:3 days
? ? 6
9 7
IS: 41 10
2 9
1 [1] HS (100 mg/day, 10 days) + placebo ?
EPO (10 days) 2
5 – 0
7
Bernabeu Wittel FCM: 103 11
0 10
0 [1] FCM (1000 mg) + EPO placebo 53 (52) 12c 5
8 7 9
et al. [20] 1
3 – 1
3

© 2018 International Society of Blood Transfusion

Hip fracture repair FCM+EPO:100 11
0 10
3 [1] FCM (1000 mg)+EPO (40 000 IU) 52 (52) 12 14
0 8 9
TTS: 2 days 1
2 – 1
2
Placebo:100 11
0 9
7 [1] Placebo 54 (54) 10 9
0 8 8
1
3 – 1
4
Observational studies
Blanco Rubio IS: 57 ≤11 (7)d ? IS (200 mg/48 h, max. 600 mg) 14 (25)* 1
8* 47
4e ? ?
et al. [21] >11 (50) 0
6 – 1
2*
Case-control ≤11 (18)
Hip fracture repair SC: 63 >11 (45) ? No iron 34 (54) 15
9 ? ?
TTS: 4 days 1
4 – 1
5
41
3e
Mu~noz et al. [13] IS: 1000 13
1 10
3 [1] IS (200 mg/48 h, 1–3 doses) + 324 (32)* 4
8* 10
7* 11
9* 0
Pool analysis EPO (40 000 IU, if Hb <13 g/dl) 0
7 – 1
3*
Hip fracture repair
TTS: 4 days
SC: 361 13
0 10
7 [1] No iron 176 (49) 9
4 26
9 13
4 0
1
2 – 1
5

?, not specifically reported; EPO, recombinant human erythropoietin; FCM, ferric carboxymaltose; Hb, haemoglobin; IIM, iron isomaltoside; IS, iron sucrose; RCT, randomized controlled trial; SC, standard care; TTS, mean
time-to- surgery from admission.
*
P < 0
05.
a
Treatment-related.
b
Transfusion rates in subgroup analysis: postoperative transfusion (10% vs. 21%, P = 0
048), subcapital hip fracture (14
3% vs. 45
7%, P = 0
004) o baseline Hb <12 g/dl (18
3% vs. 36%, P = 0
049), favourable to intra-
venous iron.
c
60 days postoperative mortality.
d
Mean Hb values not given (n).
e
85% were urinary tract infections.
Short-term perioperative iron therapy 5
 6 S. G

Table 3 Studies evaluating postoperative oral iron administration after major orthopaedic surgery (six studies, 683 patients)

Study [Ref.]
Type Baseline PostOP Hb (g/dl) Hb increment Type of iron Dose (mg elemental iron, Length of Adverse
Surgery Patients Hb (g/dl) [weeks] Difference (g/dl) administration schedule) stay (days) eventsa (%)
omez-Ram
ırez et al.

Knee or hip arthroplasty

Zauber et al. [22] FS: 37 10
9 (F) 11
0 [3] 0
1 FS (4 9 105 mg/day, 2 weeks) ? 7
RCT 11
4 (M) 11
4 [3] 0
0
-0
21b
Placebo: 42 11
1 (M) 12
0 [3] 0
1 ? 0
11
2 (H) 11
7 [3] 0
5
Sutton et al. [23] FS: 35 10
4 12
4 [6] 2
0 FS (3 9 65 mg/day, 6 weeks) ? 23
RCT 0
31
Placebo: 37 10
5 12
1 [6] 1
6 ? 22
Weatherall et al. [24] FS:33 ? 13
3 [10] 0
28 FS (105 mg/day, 10 weeks) ? ?
RCT SC:34 ? 12
8 [10] No iron (folate 5 mg/day) ? ?
Mundy et al. [25] FS: 50 9
4 (F) 12
5 [6] 3
1 FS (3 9 65 mg/day, 6 weeks) ? 13c
RCT 11
0 (M) 13
8 [6] 2
8
0
75*
Placebo: 49 9
5 (F) 12
0 [6] 2
5 ? 12
11
4 (M) 13
3 [6] 1
9
Hip fracture repair
Prasad et al. [26] FS: 32 10
3 12
4 [4] 2
0 FS (3 9 65 mg/day, 4 weeks) ? 6
RCT 0
76*
SC: 34 9
8 11
2 [4] 1
3 No iron ? 0
Parker et al. [27] FS: 150 9
9 12
0 [6] 2
1 FS (2 9 65 mg/day, 4 weeks) 19 17
RCT 0
29
SC: 150 9
8 11
7 [6] 1
9 No iron 21 0

Transfusion, postoperative complications or mortality rates were also not reported.

?, not specifically reported; F, females; FS, ferrous sulphate; M, males; RCT, randomized controlled trial; SC, standard care.
*
P < 0
05.
a
Gastrointestinal adverse events.
b
Bold values denote difference in Hb increment.
b
15 patients excluded after randomization due to gastrointestinal side-effects, but included in data analysis.

Vox Sanguinis (2018)

© 2018 International Society of Blood Transfusion
 Table 4 Studies evaluating postoperative intravenous iron administration after major orthopaedic surgery (five studies, 1008 patients)

Study [Ref.] Type of iron Transfusion

Vox Sanguinis (2018)

Type Baseline PostOP Hb Hb increment Dose (mg elemental iron) N (%) 30-d Infection Length of Adverse
Surgery Patients Hb (g/dl) (g/dl) [weeks] Difference (g/dl) Administration schedule (U/pt) mortality (%) rate (%) stay (days) eventsa (%)

Randomized controlled trials

Karkouti et al. [28] IS:11 8
5 12
3 [6] 3
8 IS (3 9 200 mg) 2 (18) ? ? ? 0
Orthopaedic 0
1b 0
3 – 0
6
Placebo: 10 8
3 12
0 [6] 3
7 4 (40) ? ? ? 0
0
5 – 0
7
Bisbe et al. [29] FCM: 60 10
5 11
5 [4] 1
0 FCM (700–1000 mg) 3 (5) ? 5 8 3
3
Knee arthroplasty 0
5 0
05 – 0
21

© 2018 International Society of Blood Transfusion

Oral iron: 62 10
5 11
0 [4] 0
5 FGS (100 mg/day, 4 weeks) 2 (3) ? 0 8 1
6
0
03 – 0
18
Khalafallah et al. [30] FCM: 103 10
6 13
0 [4]* 2
4 FCM (15 mg/kg;Up to 1000 mg) 1 (1)* ? 2* 7
8* 0
78% Orthopaedic 13
8 [12] 3
2 0
02 – 0
20*
0
8, 0
4 5 (5) ? 14 11
6 0
SC: 98 10
6 12
2 [4] 1
6 No iron 0
08 – 0
37
13
4 [12] 2
8
Observational studies
Mu~noz et al. [31] IS/FCM:182 10
4 10
6 [1] 0
2 FCM (1 9 600 mg; n = 48) 21 (12)* ? 1
6 7
9 0
Pair-matched 0
2 IS (3 9 200 mg; n = 134) 0
23 – 0
67*
Hip arthroplasty SC (oral iron, no iron)
SC: 1!82 9
2 9
2 [1] 0
0 52 (29) ? 3
3 8
4 0
0
68 – 1
17
Kim et al. [32] FCM: 150 9
5 12
5 [6] 3
0 FCM (1000 mg) 70 (47) 4
7 3
3 7
6* 0
Pair-matched 1
6 1
0 – 1
2*
Hip arthroplasty
Hip fracture (26%)
SC: 150 10
7 12
1 [6] 1
4 No iron 92 (61) 4
0 4
0 11
8 0
1
7 – 2
7

FCM, ferric carboxymaltose; FGS, ferrous glycine sulphate; IS, iron sucrose; SC, standard care; ?, not reported.
*
P < 0
05.
a
Treatment-related, severe adverse events.
b
Bold values denote difference in Hb increment.
Short-term perioperative iron therapy 7
8 S. G

omez-Ram
ırez et al.
CI: 0
35–0
82, P = 0
0035,) but not in knee arthroplasty
(2
2% vs. 2
9%; RR: 0
74. 95% CI: 0
37–1
49, P = 0
4876,
for knee arthroplasty), and shortened hospital stay by
more than 1 day (P < 0
001) (Table 1). There were no dif-
ferences in postoperative infection rates (0
7% vs. 0
7%;
P = 0
941).
Perioperative intravenous iron in non-elective MOS
In hip fracture repair surgery, five studies (three RCTs,
two observational; 2063 patients) have evaluated the
effect of perioperative intravenous iron administration
(iron sucrose or ferric carboxymaltose), with or without
EPO, on transfusion requirements, with varying results
[13, 18–21] (Table 2).
Compared to standard care, in one RCT, perioperative
intravenous iron administration did not result in a reduc-
tion in overall transfusion requirements (33% vs. 41%;
RR: 0
80, 95% CI: 0
55–1
17, P = 0
3179), though it
halved postoperative ABT rate (10% vs. 21%; RR: 0
49,
95% CI: 0
24–0
99, P = 0
048) [18]. In subgroup analysis,
a significant reduction of ABT rates was also observed for
patients with subcapital fracture (14
3% vs. 45
7%,
P = 0
004) or admission Hb <12 g/dl (18
3% vs. 36%,
P = 0
049) [18]. A second RCT demonstrated that com-
bined administration of intravenous iron and EPO was
more efficacious than intravenous iron monotherapy for
reducing postoperative transfusion requirements (1
5 U/
patient vs. 2
5 U/patient, P = 0
034) and improving Hb at
postoperative day 7 (10
1 g/dl vs. 9
1 g/dl; P = 0
015)
[19]. Conversely, in a third RCT that only included
patients with Hb <12 g/dl, treatment with intravenous
iron, with or without EPO, did not reduce transfusion
rates in relation to placebo (52%, 52%, 54%, respectively).
However, compared to placebo, the group receiving intra-
venous iron and EPO showed higher Hb levels at dis-
charge (10
3 g/dl vs. 9
7 g/dl, respectively; P = 0
009)
and 60 days after the intervention (12
5 g/dl vs. 11
9 g/
dl, respectively; P = 0
05), with fewer patients being
anaemic 60 days after discharge (52% vs. 39%, respec-
tively; P = 0
015), though there were no differences in
quality of life scores [20].
However, there were differences between RCTs regard-
ing mean time to surgery from hospital admission
(Table 2) and transfusion protocols that might have
influenced the results. Thus, patients may receive a RBC
transfusion when: (1) postoperative Hb <8 g/dl or <9 g/
dl in patients with a history of cardiorespiratory condi-
tions, or any Hb in patients with symptoms of untreated
anaemia [18]; (2) postoperative Hb <9 g/dl or any dis-
comfort or pathologic signs from cardiovascular, central
nervous or renal system related to anaemia [19]; or (3)
postoperative Hb <7 g/dl independently of symptoms (3
RBC units) or postoperative Hb 7
1–8
9 g/dl plus severe
symptoms and/or cardiovascular risk factors (2 RBC
units) [20].
None of the three RCTs reported an increased risk of
infection or mortality or a prolongation of hospital stay
(Table 2).
In contrast, compared to no iron, in two observational
studies using a similar transfusion threshold (Hb <8 g/dl
or <9 g/dl if anaemia symptoms and/or cardiovascular
risk factors), perioperative administration of iron sucrose
(up to 600 mg), with or without one EPO dose
(40 000 IU), resulted in a significant reduction in both
the percentage of patients requiring transfusion (32% vs.
49
5%, respectively; RR: 0
64, 95% CI: 0
57–0
74,
P < 0
0001) and the number of transfused units, which
was accompanied by a reduction in length of hospital
stay and/or lower infection and 30-day mortality rates
[13, 21] (Table 2). Ongoing RCTs will hopefully help to
solve out these discrepancies (EudraCT Number: 2014-
001923-53; EudraCT Number: 2011-003233-34, Clini-
calTrials.gov Identifier: NCT01084122, ISRCTN76424792).
Postoperative oral iron in elective and non-elective
MOS
The efficacy of the postoperative administration of oral
iron (ferrous sulphate) to improve the Hb levels has been
evaluated in six RCTs of patients undergoing elective
knee or hip arthroplasties (four RCTs, n = 317) or hip
fracture repair (two RCTs, n = 366), without preoperative
iron deficiency or anaemia [22–27] (Table 3). Elemental
iron doses ranged between 130 and 420 mg/day, and iron
supplementation was maintained between 2 and
10 weeks. At the end of treatment period, the differences
in Hb increments between patients receiving oral iron
and those receiving no iron or placebo were small and
heterogeneous (Table 3). These differences were only sig-
nificant in two studies: one in knee or hip arthroplasty
(0
75 g/dl; 95% CI: -0
02 to 1
52) [25] and one in hip
fracture repair (0
76 g/dl; 95% CI: 0
01–1
51) [34]. Most
reviewed studies did not provide information on transfu-
sion requirements, postoperative complications, mortality
or length of hospital stay.
Postoperative intravenous iron in elective MOS
The efficacy of the postoperative intravenous iron
administration (iron sucrose or ferric carboxymaltose) to
improve Hb levels has been evaluated in five studies
including 1008 anaemic patients, mostly undergoing
elective MOS (three RCTs, two observational) [28–32]
(Table 4). Pooled data from the three RTCs showed that,
compared to control (oral iron, no iron or placebo),
postoperative intravenous iron did not reduce the ABT
rate (4
6% vs. 6
5%, respectively; RR: 0
71, 95% CI:
0
29–1
72, P = 0
4869) or the number of transfused
© 2018 International Society of Blood Transfusion
Vox Sanguinis (2018)

units [28–30]. However, in the most recent RCT, high-
dose ferric carboxymaltose led to a significant reduction
in ABT and infections rates, as well as in the length of
hospital stay [30] (Table 4). Similarly, in two large pair-
matched observational studies (664 patients), postopera-
tive intravenous iron reduced the ABT rate (27
4% vs.
43
4%; RR: 0
43, 95% CI: 0
51–0
78, P < 0
0001), num-
ber of transfused units and length of hospital stay, with-
out affecting postoperative infection or mortality rates
[31, 32] (Table 4).
Regarding postoperative anaemia improvement, high-
dose intravenous iron supplementation (1000 mg/pa-
tient; two RCTs, one observational) resulted in a higher Hb
increment at 4–6 postoperative weeks with respect to stan-
dard care or oral iron (0
5, 0
8 and 1
6 g/dl, respectively)
[29, 30, 32] (Table 4). In the RCT by Bisbe et al. [29], there
was only a trend to higher Hb increment in the intra-
venous iron group compared with the oral iron group
(+0
5 g/dl, P = 0
075), but fewer patients form the
intravenous iron group received preoperative anaemia
treatment, intra-operative tranexamic acid and/or postop-
erative shed blood reinfusion (60% vs. 79%, respectively;
RR: 0
76, 95% CI: 0
60–0
97, P = 0
03) [29]. However, the
differences in Hb increments were significant when the
analysis was restricted to patients with preoperative iron
deficiency (+0
7 g/dl, P = 0
03), postoperative Hb <10 g/dl
(+1
3 g/dl, P = 0
018) or both (+1
5 g/dl, P = 0
0
17) [29].
Additionally, in the two RCTs, high-dose postoperative
intravenous iron supplementation resulted in better scores
for physical activity-related quality of life [29, 30]. In con-
trast, no significant differences in postoperative Hb incre-
ments were observed in studies using lower intravenous
iron doses (600 mg) [28, 31].
Safety
Four out of 14 studies involving intravenous iron admin-
istration did not specifically report on the adverse drug
effects (ADEs) [14–17, 21]. In the remaining 10 studies
(2200 patients), only 25 ADEs were reported, mostly
occurring in hip fracture patients (23). Thus, the overall
incidence of ADEs with intravenous iron, with or without
EPO, was 1
13%. Of these 25 ADEs, 13 were gastrointesti-
nal symptoms (nausea, vomiting, diarrhoea and/or consti-
pation) [19, 20], five hypotension (one severe) [20, 24],
two headache [19], two general discomfort [18], one skin
rash [18], one flushing and tingling in the lips [19], and
one anaphylaxis [24]. However, neither severe hypoten-
sion nor anaphylaxis was considered treatment-related by
study authors [24].
Globally, there was no difference the incidence of clini-
cally relevant ADEs in patients receiving intravenous
iron, with or without EPO, compared to those assigned to
© 2018 International Society of Blood Transfusion
Vox Sanguinis (2018)
Short-term perioperative iron therapy 9
control (placebo, oral iron, no iron; 1063 patients, 9
ADEs) (1
13% vs. 0
85%; RR: 1
34, 95% CI: 0
63–2
86,
P = 0
5620). The small total number of reported ADEs
precludes for a separate analysis according to the iron
formulation used.
In contrast, in the RCTs evaluating the efficacy of post-
operative oral iron, patients receiving iron supplementa-
tion were more likely to complain of major
gastrointestinal adverse effects, compared to those receiv-
ing no iron or placebo (16
4% vs. 4
8%; RR: 3
43, 95%
CI: 1
96–5
96, P < 0
001).
Discussion
We performed an exhaustive review of the efficacy and
safety of short-term perioperative iron administration in
MOS patients. Data analysis showed that postoperative
oral iron administration neither increased haemoglobin
nor reduced transfusion requirements, and it was associ-
ated with significant gastrointestinal adverse effects
(Table 3). In contrast, perioperative or postoperative
administration of intravenous iron, with or without EPO,
might decrease transfusion requirements and hasten the
recovery from postoperative anaemia, at least in some
patient subgroups, without clinically relevant adverse
effects. However, data from RCTs and observational stud-
ies were sometimes contradictory, especially in hip frac-
ture patients (Table 2).
In MOS patients, preoperative anaemia is prevalent and
in itself a modifiable risk factor for allogeneic transfusion
and poor postoperative outcome [3]. Postoperative anae-
mia is still more prevalent, influencing clinical outcome,
functional recovery and quality of life [3]. Therefore,
perioperative anaemia management is a fundamental pil-
lar of PBM programmes [2, 5, 6, 8].
In elective MOS, detection and classification of preop-
erative anaemia should be done as soon as possible (4–
6 weeks prior to surgery) to allow appropriate treatment.
Whenever feasible, it must be corrected before an elec-
tive MOS procedure, which can lead to surgery
rescheduling. On the other hand, it is possible to treat
pharmacologically most cases of moderate anaemia,
whereas transfusion should be reserved for patients with
severe symptomatic anaemia, active bleeding or haemo-
dynamic instability [2, 5, 6, 8]. Various clinical guideli-
nes have analysed the efficacy and safety of the
pharmacological options for treating anaemia and issued
recommendations on their use [2, 5, 6, 8, 35–38]. In
addition, within the context of a PBM programme, treat-
ment of preoperative anaemia has been proved highly
cost-effective [39, 40].
Should the recommended time frame not be available,
any available time should be used to, at least, detect and
10 S. G

omez-Ram
ırez et al.
classified anaemia, and start treatment; ultimately, this
may be continued/initiated postoperativel [2, 8, 37, 38].
Several algorithms for management of preoperative anae-
mia and postoperative anaemia have been published
[2, 8, 36]. Since iron deficiency, either absolute (iron defi-
ciency anaemia) or functional (anaemia of inflammation,
also referred to as anaemia of chronic disease), is very
prevalent among MOS patients [4, 7], we reviewed the
efficacy and safety of short-term perioperative iron
administration in this clinical setting.
Twenty studies were considered appropriate for inclu-
sion in this review (13 RCTs, 7 observational) [13–32]. At
the individual level, the risks of bias limited the overall
quality of the evidence provided by the RCT (moderate
quality), and observational studies (low or very low qual-
ity). In addition, there were clinical heterogeneity and
methodological heterogeneity between different studies
affecting iron formulations, dosages and duration of iron
treatment, duration of follow-up, comparison groups,
blinding level of patients and researchers, use of other
blood savings strategies and transfusion protocols, which
make difficult to draw definitive conclusions.
Efficacy
With the limitation imposed by the quality of the evi-
dence, the analysis of included studies suggests that peri-
operative or postoperative intravenous iron
administration, with or without EPO, can improve Hb
levels and reduce transfusion requirements and length of
hospital stay, without increasing the postoperative mor-
bidity and mortality, at least in some patient subgroups
(Tables 1, 2 and 4).
Major discrepancies between RCTs and observational
studies on the possible beneficial effects of short-term
intravenous iron administration were found in patients
undergoing surgery for hip fracture repair. Differences in
patient selection, mean time to surgery from hospital
admission, intravenous iron doses and administration
schedule, and transfusion protocols might have play a
role (Table 2). For instance, in the multicentre, double-
blinded RCT by Bernabeu-Vittel et al. [20] inclusion crite-
ria and transfusion protocol might have been misleading.
They included 306 anaemic hip fracture patients (Hb 9–
12 g/dl). First, virtually, all hip fracture patients with pre-
operative Hb <10 g/dl will be transfused perioperatively
due to a further Hb decrease induced by perioperative
blood loss; thus, a blood-saving effect of intravenous
iron, with or without EPO, should not been expected. Sec-
ond, a previous RCT in hip fracture repair showed a bene-
fit of intravenous iron for those with Hb >12 g/dl [18],
and in Europe, EPO administration is approved for ortho-
paedic surgery with baseline Hb 10–13 g/dl. Third,
available data suggest that an Hb <13 g/dl should be con-
sidered as suboptimal in surgical settings in which signif-
icant blood loss is expected [2]. Thus, the authors may
have included patients who most probably will not bene-
fit from treatment while excluded others who may benefit
from it. In fact, previously published transfusion data
from patients with hip fracture receiving intravenous
iron, with or without EPO, were stratified according to
admission Hb (9–13 g/dl; n = 582) [13, 41]. Data analysis
showed that for Hb 9–12 g/dl, there were no differences
in ABT rates regardless treatment. However, for those pre-
senting with Hb between 12 and 13 g/dl, which represent
one-third of study sample, treatment with intravenous
iron, with or without EPO, led to a significant reduction
of ABT rate compared to standard care (oral iron or no
iron) [41]. On the other hand, their transfusion protocol
dictates that patients with Hb <7 g/dl will receive 3 RBC
units, independently of symptoms, and those with Hb
7
1–8
9 g/dl and severe symptoms will receive 2 RBC
units [20]. According to guidelines from most scientific
societies and consensus statements, in non-bleeding
patients, RBC should be transfused one unit at the time,
followed by patient reassessment for additional transfu-
sion requirements [5, 6, 8, 38]. A fixed amount of PRC
units to be transfused is not acceptable and makes diffi-
cult to observe any benefit of the erythropoiesis-stimulat-
ing therapy on transfusion requirements.
As for postoperative oral iron, available data from RCT
showed that, when compared to no iron or placebo, high
doses of ferrous sulphate (100–300 mg elemental iron per
day) did not hasten the recovery from postoperative anae-
mia following lower limb arthroplasty [22–25] or hip
fracture repair [26, 27] (Table 3). Consequently, most
authors considered that administration of iron supple-
ments after elective total hip or total knee arthroplasty or
hip fracture repair did not appear to be worthwhile. How-
ever, the vast majority of these studies did not include
patients with preoperative anaemia and/or iron deficiency
or confirmed postoperative iron deficiency; that is, those
who potentially could benefit the most from iron supple-
mentation. This led to heterogeneity between studies
regarding the effect of postoperative oral iron on Hb
levels and should be considered as another study limita-
tion (Table 3).
Nevertheless, even in the presence of iron deficiency, it
is unlikely that postoperative administration of oral iron
salts was effective in correcting anaemia since the high
levels of hepcidin, induced by surgery-associated inflam-
mation, would inhibit its intestinal absorption [42]. In this
regard, the results of the IRONOUT study in patients with
chronic heart failure and iron deficiency seem to support
the ineffectiveness of oral iron salts in the setting of
inflammation [43]. On the other hand, low dose (30–
© 2018 International Society of Blood Transfusion
Vox Sanguinis (2018)

60 mg) oral sucrosomial iron has been proven effective
for treating anaemia in clinical settings (e.g. chronic kid-
ney disease, bariatric surgery) where intravenous iron
seemed to be the only treatment option [44–46]. Unfortu-
nately, the possible role of this newer oral iron formula-
tion in surgical patients has not been yet studied.
In contrast, high-dose postoperative intravenous iron
supplementation resulted in a higher Hb increment at 4–6
postoperative weeks with respect to standard care or oral
iron (Table 4). The reason that high-dose intravenous iron
works in this context might be related to its ability for
upregulating macrophage ferroportin [47]. Intravenous
iron formulations are taken up by macrophages and
degraded, leading to a transient, dose-dependent increase
in intracellular labile iron, before being stored as ferritin.
Intracellular iron increases ferroportin expression via
upregulation of intracellular iron regulatory proteins I
and II, partly overcoming hepcidin blockade and allowing
iron export to plasma, where it loads transferrin and is
transported to the bone marrow for erythropoiesis [48].
Quality of life
Only three studies have evaluated the effect of postopera-
tive treatment with iron by means of EQ-5d or SF-36 sur-
veys [20, 29, 30]. In knee arthroplasty, Bisbe et al. [29].
found that treatment with ferric carboxymaltose was
associated with better results in the EQ-5d subscales of
‘regular activities’ or ‘anxiety/depression’ 30 days after
the intervention. The study by Khalfallah et al. [30].
showed a significant difference in the SF-36 subscale of
‘physical role’ (problems in performing working or other
daily activities due to physical health) in favour of the
intravenous iron group at 4 and 12 postoperative weeks.
In contrast, in hip fracture repair surgery, Bernabeu-Wit-
tel et al. [20]. found no differences in quality of life, as
assessed with SF-36v2, between patients receiving intra-
venous iron, with or without EPO, or placebo. Addition-
ally, none of the revised works collected data on joint
functionality after knee or hip arthroplasty or investi-
gated whether the improvement in Hb levels allowed an
earlier rehabilitation, which can be considered another
limitation of these studies.
Safety
The risks of hypersensitivity reactions, oxidative stress or
infection are common concerns with intravenous iron.
Three different IV iron products were used in the analysed
studies: ferric carboxymaltose, iron isomaltoside and iron
sucrose. The European Medicines Agency (EMA) argues
that, when appropriately indicated and administered, their
benefits outweigh the risks, the incidence of severe aller-
gic reactions is low, and there are no differences in the
© 2018 International Society of Blood Transfusion
Vox Sanguinis (2018)
Short-term perioperative iron therapy 11
security profile of available intravenous iron formulations
[49].
Minor infusion reactions occur in approximately 1 in
100 intravenous iron administrations and are due to
labile free iron and not to hypersensitivity [50]. They are
characterized by chest and back pressure, flushing, itch-
ing and/or urticaria, but without accompanying hypoten-
sion, tachypnoea, tachycardia, wheezing, and stridor or
periorbital oedema. Usually, minor infusion reactions are
mild and abate spontaneously within a 5–10 min, without
any intervention and rarely recur with rechallenge at
lower infusion rate [51]. Self-limited hypotension during
intravenous iron infusion could be considered hypersensi-
tivity or vascular reactions to free iron, and low rates
have been reported for ferric carboxymaltose (1
04%),
iron isomaltoside (0
34%) and iron sucrose (0
33%) [52–
54]. In contrast, the overwhelming majority of severe and
potentially lethal reactions were due to high molecular
weight iron dextran formulations, which are no longer
available [55]. When high molecular weight iron dextran
is excluded, intravenous iron is associated with an esti-
mated severe adverse effects incidence of <1 in 250 000
administrations [56]. As for short-term intravenous iron
administration, no tissue damage due to oxidative stress
by labile iron could be expected [57, 58]. In fact, a recent
study showed that 1000–2000 mg preoperative intra-
venous iron therapy does not have a profound effect on
long-term overall and disease-free survival in anaemic
colorectal cancer patients [59].
The analysed studies did not show an increased risk of
infection or mortality among patients who received intra-
venous iron, whereas less than 2% experienced clinically
significant adverse reactions (Tables 1, 2 and 4). This is
consistent with the results from a previous review [60]
and a recent meta-analysis of 103 EACs (1965-2013) on
the use of intravenous iron in various indications [61]. In
contrast, over 15% of patients who received postoperative
oral iron reported major gastrointestinal adverse effects
(Table 3), which in some cases led to treatment discontin-
uation, although this percentage is lower than that
observed in other clinical scenarios [62].
With respect to EPO administration in MOS, a recent
meta-analysis confirmed its efficacy to reduce ABT rate,
with no difference in the risk of thromboembolism com-
pared to placebo [63]. However, the authors pointed out
that the majority of patients received thromboprophylaxis
and had low cardiovascular and thromboembolic risk. In
addition, they recommended that the decision to use EPO
on a routine base should be balanced against its costs,
which may be relatively high. It is important to highlight
that intravenous iron administration neither exerts a
direct influence on erythropoiesis nor leads to supraphys-
iologic Hb levels (as it may occur with the EPO) and,
12 S. G

omez-Ram
ırez et al.

therefore, does not increase the risk of thromboembolic

events. Moreover, it could even reduce thromboembolic
events by decreasing iron deficiency-induced thrombocy-
tosis [64].
Conclusions
Clinical practice guidelines recommend the detection and
classification of preoperative anaemia at least 4 weeks
prior to MOS [2, 6, 36–38]. However, there are numerous
barriers that hinder the implementation of this recom-
mendation in elective MOS [65, 66], whereas it does not
apply to non-elective MOS. Should this time frame not be
available, published studies suggest a benefit from short-
term perioperative treatment with intravenous iron, with
or without EPO, at least for some patient populations.
However, more studies are needed to elucidate when it
should be started, which combination of drugs should be
used, and which patient groups would benefit most. In
addition, further studies assessing the effect on functional
recovery and quality of life, and the cost-effectiveness of
these therapeutic interventions are also warranted.
Conflict of interest
Manuel Mu~ noz has received honoraria for lectures and/or
consultancies from Vifor Pharma (Spain & Switzerland),
Wellspect HealthCare (Sweden), Pharmacosmos (Den-
mark), Ferrer Pharma (Spain), CSL Bering (Germany),
PharmaNutra (Italy) and Zambon (Spain). Antonio Herrera
Rodr
ıguez, Susana G


omez Ram
ırez and Mar
ıa Angeles
Maldonado Ruiz have nothing to declare.
Funding
This study has not received any specific grant from any
public, commercial or non-profit funding agencies.
Author contribution
All of the authors have contributed substantially in con-
ception and design of the study, data acquisition, or anal-
ysis and interpretation of data; drafting the article or
critical review of intellectual content; and final approval
of the submitted version.

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