The Impact of Perioperative Iron on the Use of Red Blood Cell Transfusions in Gastrointestinal Surgery: A Systematic Review and Meta-Analysis

    The impact of perioperative iron on the use of Red Blood Cell transfusions in gastro-intestinal surgery: A systematic review and meta-analysis Julie Hallet MD, Asad Hanif MSc, Jeannie Callum MD, Ioulia Pronina BSc, David Wallace MSc, Lavanya Yohanathan MD, Robin McLeod MD, Natalie Coburn MD MPH PII: DOI: Reference:

S0887-7963(14)00050-9 doi: 10.1016/j.tmrv.2014.05.004 YTMRV 50404

To appear in:

Transfusion Medicine Reviews

Received date: Revised date: Accepted date:

22 February 2014 10 May 2014 13 May 2014

Please cite this article as: Hallet Julie, Hanif Asad, Callum Jeannie, BSc Ioulia Pronina, Wallace David, Yohanathan Lavanya, McLeod Robin, Coburn Natalie, The impact of perioperative iron on the use of Red Blood Cell transfusions in gastro-intestinal surgery: A systematic review and meta-analysis, Transfusion Medicine Reviews (2014), doi: 10.1016/j.tmrv.2014.05.004

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ACCEPTED MANUSCRIPT The impact of perioperative iron on the use of Red Blood Cell transfusions in gastro-intestinal surgery: a systematic review and

Julie Hallet 1 2, MD; Asad Hanif

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meta-analysis 12

, MSc; Jeannie Callum 2 3, MD; Ioulia Pronina 1 2, BSc;

David Wallace 1 2, MSc; Lavanya Yohanathan 1, MD; Robin McLeod 1 5 6, MD; Natalie

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Coburn 1 2 3, MD MPH

Dr. Natalie Coburn

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Corresponding Author:

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1. Division of General Surgery, University of Toronto, Toronto, Ont., Canada 2. Division of Surgical Oncology, Sunnybrook Health Sciences Centre – Odette Cancer Centre, Toronto, Ont., Canada 3. Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ont., Canada 4. Division of Clinical Pathology, Sunnybrook Health Sciences Centre, Toronto, Ont., Canada 5. Division of General Surgery, Mount Sinai Hospital, Toronto, Ont., Canada 6. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ont., Canada

Sunnybrook Health Sciences Centre

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2075 Bayview Avenue, Room T2 060 Toronto, Ont., M4N 3M5, Canada Tel: 416-480-6916

Fax: 416-480-6002 E-mail: [email protected]

ACCEPTED MANUSCRIPT ABSTRACT Perioperative anemia is common, yet detrimental, in surgical patients. However, Red Blood Cell

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transfusions (RBCT) used to treat anemia are associated with significant postoperative risks and

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worse oncologic outcomes. Perioperative iron has been suggested to mitigate perioperative anemia. This meta-analysis examined the impact of perioperative iron compared to no

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intervention on the need for RBCT in gastrointestinal surgery.

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We systematically searched Medline, Embase, Web of Science, Cochrane Central and Scopus to identify relevant randomized controlled trials (RCT) and non-randomized studies (NRS). We

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excluded studies investigating autologous RBCT or erythropoietin. Two independent reviewers selected the studies, extracted data and assessed the risk of bias using the Cochrane tool and

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Newcastle-Ottawa scale. Primary outcomes were proportion of patients getting allogeneic RBCT and number of transfused patient. Secondary outcomes were hemoglobin change, 30-day

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postoperative morbidity and mortality, length of stay, and oncologic outcomes. A meta-analysis

(CRD42013004805).

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using random effects models was performed. The review was registered in PROSPERO

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From 883 citations, we included 2 RCTs and 2 NRSs (n=325 patients), all pertaining to colorectal cancer surgery. RCTs were at high risk of bias and underpowered. One RCT and 1 NRS using pre-operative PO iron reported a decreased proportion of patients needing RBCT. One RCT on preoperative intravenous iron and 1 NRS on postoperative PO iron did not observe a difference. Only one study revealed a difference in number of transfused patients. One RCT reported significantly increased post-intervention hemoglobin. Among 3 studies reporting length of stay, none observed a difference. Other secondary outcomes were not reported. Metaanalysis revealed a trend towards fewer patients requiring RBCT with iron supplementation (RR 0.66 [0.42,1.02]), but no benefit on the number of RBCT per patient (WMD -0.91 [-1.61,-0.18]).

ACCEPTED MANUSCRIPT Although preliminary evidence suggests it may be a promising strategy, there is insufficient evidence to support the routine use of perioperative iron to decrease the need for RBCT in CRC

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surgery. Well-designed RCTs focusing on the need for RBCT and including long-term outcomes

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are warranted.

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Keywords: Transfusion; Iron; Colorectal cancer; Surgery; Anemia; Perioperative.

ACCEPTED MANUSCRIPT INTRODUCTION Up to 34% of non-cardiac surgical patients present with pre-operative anemia, a number rising to [1,2]

. Anemia thus appears as a common, yet detrimental,

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46% in colorectal cancer (CRC)

post-operative mortality and morbidity

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problem in patients undergoing gastrointestinal (GI) surgery, as it is associated with increased [1,3-5]

. The most common treatment for anemia, allogeneic

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red blood cells transfusion (RBCT), is also associated with significant risks, and worse outcomes in terms of morbidity, recovery, and even cancer recurrence

[6-10]

. In addition to associated

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clinical risks, transfusions are a scarce and expensive resource that contribute a significant cost [11]

. In 2012, blood

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to health care through prolonged length of stay and hospital charges

transfusion was identified as one of 5 overused medical treatments at the National Summit on Overuse of the Joint Commission and American Medical Association, further highlighting the

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dangers of blood transfusions, and the need for effective strategies to minimize its use [12].

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Recently, alternatives or co-treatments to reduce the need for perioperative RBCT have been examined. No difference was observed in RBCT with erythropoietin used before CRC surgery in [13]

. Although autologous blood

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a meta-analysis of 4 randomized controlled trials (RCTs)

transfusion decreased the risk of receiving allogeneic transfusions, it did not modify the need for

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any blood transfusion, or result in improved postoperative outcomes. Furthermore, it is challenging to use in patients with pre-existing anemia

[14]

. Pooled data on intra-operative cell-

salvage devices revealed a decrease in RBCT, but its use is limited outside of benign and noncontaminated cases [15]. Finally, perioperative iron supplementation has been suggested as well, and found useful in reducing RBCT in orthopedic surgery

[16,17]

. However, in GI surgery, results

of this strategy remain controversial. Therefore, evidence regarding the clinical benefits of perioperative iron supplementation in GI surgery remains insufficient. . We undertook a systematic review and meta-analysis of observational non-randomized studies (NRSs) and RCTs to examine the impact of perioperative iron supplementation on the need for post-operative RBCT in GI surgery.

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METHODS

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Search Strategy

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We systematically searched Medline (1966-May 2013), EMBASE (1974-May 2013), the Cochrane Register for Controlled Trials, Web of Knowledge (Web of Science and BIOSIS), and

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the Scopus database (1966-May 2013), without restrictions regarding language or type of

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publication. We also searched the gray literature through OpenSIGLE, Intute (until closing in July 2011), the Trip database, and Google Scholar, as of May 2013. With assistance from an

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information specialist, the search strategy was initially developed for Medline, and then adapted to each database’s thesaurus (see Appendix 1). Keywords and MeSH (or EMTREE) terms were

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gathered into 3 categories: 1) GI pathology (population), 2) surgery (population), and 3) iron supplementation (intervention). To increase search sensitivity, we exploded each keyword. We

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also searched conference proceedings of national and international meetings in surgery and

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transfusion medicine to identify relevant abstracts (see Appendix 2). Finally, we reviewed bibliographies of all included studies for any additional relevant publications.

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Study Selection

We included RCTs and comparative non-randomized studies (NRS) reporting on the impact of perioperative (within 30 days before and/or after surgery) iron supplementation, administered intravenously (IV) or orally (PO), on the need for post-operative RBCT, compared to placebo or no intervention. Studies including at least 10 adults (≥ 18 years-old) undergoing gastrointestinal surgery (surgical procedure for benign or malignant disease, on the esophagus, stomach, small bowel, liver, pancreas, colon, or rectum) were included. We excluded studies that were designed to specifically evaluate the use of erythropoietin or pre-operative autologous blood donation, in order to focus on the effects of iron supplementation. Studies that included patients meeting our inclusion criteria were excluded if we were unable to distinguish those patients from the larger

ACCEPTED MANUSCRIPT study population. In the event of duplicate publication, we included the most relevant and the most informative study.

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Data Abstraction We developed and pilot-tested a standardized extraction form following the recommendations of

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the Cochrane Effective Practice and Organization of Care Review Group (EPOC) determined study design using the Cochrane Group checklist

[18]

. We

[18]

. The following patient

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characteristics were captured: indication for and site of surgery, co-treatments (e.g. preoperative chemotherapy), age, gender, and comorbidities. We collected intervention and

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comparator information were collected, including type of iron medication, intravenous (IV) or oral (PO) administration route, dosage, dosing interval, timing of administration (pre-operative or

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post-operative), type of comparator (placebo or no treatment), and use of co-intervention (e.g. erythropoietin). We recorded the transfusion protocol used for the administration of RBCT. We

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contacted the corresponding authors of each study to obtain additional details about missing or

Outcome Measures

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incomplete data when deemed necessary, using the email provided in the article.

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Our primary outcome was the proportion of patients requiring at least one unit of allogeneic RBCT, and the number of RBCT units per transfused patient. Our secondary outcomes were mean changes in hemoglobin between pre-operative (closest value before surgery) and postoperative (latest value before discharge or within 30 days after surgery) periods, post-operative morbidity (within 30 days), post-operative mortality (within 30 days or in-hospital), and recurrence-free survival and overall survival. Risk of Bias Assessment To assess the risk of bias in RCTs, we used the Cochrane Risk of Bias tool, assessing 6 core methodological domains (sequence generation, allocation concealment, blinding, incomplete

ACCEPTED MANUSCRIPT outcome data, selective outcome reporting, and other sources of bias)

[18]

. Several scoring

systems and scales have been described to evaluate the risk of bias of NRS, but none have yet [19]

. We chose the Newcastle-Ottawa score to appraise risk of bias, evaluating 3

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been validated

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methodological aspects (selection of participants, groups comparability, and outcome) on a ninepoint scale [20].

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Two authors (JH and AH) selected the studies, extracted the data and assessed the risk of bias independently. Disagreements were solved by consensus or by a third party (NC). A single

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reviewer (JH) reviewed the references from the gray literature and meetings’ proceedings.

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Statistical Analysis

We present descriptive statistics as means and standard error (SE) or median and interquartile

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range (IQR) for continuous variables, and proportions with 95% confidence intervals (95%CI) for categorical variables. Measures of effect of individual studies are presented as risk ratio (RR)

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with 95%CI. The adjusted effect estimate was preferred to the non-adjusted one when available.

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Inter-rater agreement on study selection was calculated using a weighted Kappa statistic and reported with 95%CI. Meta-analysis using random effects model was planned to pool the data

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into RR with 95%CI for categorical data, and weighted mean difference (WMD) with 95%CI for continuous data. The extent of heterogeneity was estimated using Chi square test and I2 statistic. We explored heterogeneity on primary outcome with sub-group and sensitivity analyses based on predetermined hypotheses when possible, based on available data (Table 1). We conducted the review and reported the results in accordance with the PRISMA and the MOOSE guidelines for the reported of systematic reviews of RCTs and NRSs respectively

[21,22]

. The

review was registered in PROSPERO (CRD42013004805). Analyses were performed using

Review Manager (RevMan) Version 5.2.5 (The Cochrane Collaboration, Copenhagen, 2012).

ACCEPTED MANUSCRIPT RESULTS Systematic Search

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The initial electronic and gray literature search identified 878 citations, excluding duplicates, from which we selected 8 studies for full text review (Figure 1). Among those, four studies were [23]

, one with no details provided on the comparison group [25]

one not reporting on transfusion outcomes

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excluded: one narrative review

, and one without available full-text format

[24]

,

[26]

.

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Inter-rater agreement on study selection was high. No additional citation was identified from meetings’ proceedings or review of included studies’ bibliographies.

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Description of Included Studies

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Characteristics of the included studies are detailed in Table 2. Two RCTs retrospective cohort study and 1 case-control study)

[29,30]

[27,28]

and two NRSs (1

enrolling a total of 325 patients were

United Kingdom

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included. All studies were published in English after 2004. Two studies were conducted in the [27,28]

, one in Spain

[30]

, and one in Japan

[29]

. All studies included only patients

pre-operative IV iron

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with CRC. Two studies considered pre-operative PO iron supplementation [27]

, and one post-operative IV iron supplementation

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received no treatment in three studies

[28-30]

, and placebo in one

three studies was change in post-intervention hemoglobin

[30]

[28,29]

, one assessed

. The control groups

[27]

. The primary outcome of

[27-29]

, while change in hemoglobin

from post-operative day 1 to discharge was the primary outcome in the other study

[30]

. The two

RCTs were powered to detect differences in these primary outcomes, rather than to detect a difference in the need for allogeneic RBCT. Risk of Bias Assessment Risk of bias assessment and methodology are summarized in Table 3. The two RCTs were at high risk of bias

[27,28]

, mostly due to absence or unreported blinding of the participants or

outcome adjudicators. The two NRS scored more than five out of eight points on the NOS,

ACCEPTED MANUSCRIPT indicating low risk of bias for NRS. [29,30] Primary Outcomes: Allogeneic Red Blood Cell Transfusions (RBCT)

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Primary outcomes are outlined in Table 4. All four studies reported the proportion of patients who received RBC transfusions, and the mean number of RBC transfusions per transfused patient. One NRS on pre-operative PO iron reported a lower proportion of patients requiring [29]

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RBCT in the intervention group

. One RCT considering pre-operative PO iron observed a [28]

. Three studies reported estimated

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significant reduction in number of RBCT per patient

intraoperative blood loss, with no difference between intervention and control groups [27-29]. Three

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studies reported the indication for transfusion: (1) Hb <80 g/L without symptoms with symptoms, (2) intraoperative Hb <70 g/L with unstable hemodynamics [30]

, or 80-100

[29]

, and (3) Hb <80

. Pooled estimate of the effect of treatment resulted in a non-significant trend towards

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g/L

[31]

fewer patients requiring RBCT with iron supplementation (RR 0.66 [0.42,1.02]) (Figure 2), and

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no benefit on the mean number of RBCT per transfused patient (WMD -1.10 RBC units transfused [-2.77,-0.56]) (Figure 3). The small number of trials and events in each group

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precluded analyses planned to explore heterogeneity.

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Secondary Outcomes

All four studies assessed one or more secondary outcomes of this systematic review (Table 5). One study including only anemic patients observed a significantly higher Hb in the intervention group, whereas no difference existed before administration of iron

[29]

. One study considering

pre-operative IV iron reported mean hemoglobin change and found no significant difference between the control and intervention group

[27]

. However, it is not specified if the measured

change in hemoglobin accounted for the effects of transfusions received. Three studies reported length of stay in the hospital and found no significant difference between the intervention and control group [27,28,30]. DISCUSSION

ACCEPTED MANUSCRIPT We systematically reviewed data from four comparative studies investigating the association between perioperative iron supplementation and the need for allogeneic RBCT

[27-30]

. Even

[27-30]

. A trend towards fewer patients requiring RBCT

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criteria pertained to elective CRC surgery

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though our search considered all elective gastrointestinal surgeries, all studies meeting inclusion

with perioperative iron supplementation was observed, but did not reach statistical significance

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(RR 0.66 [0.42-1.02]). No consistent difference was observed regarding mean number of RBCT

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per transfused patient, change in Hb level, or length of stay.

These findings are consistent with results reported in orthopedic surgery where pre-operative IV

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iron has been associated with up to 60% reduction in RBCT rates

[16,17,32]

. However, a meta-

analysis of RCT examining hip and knee fractures identified an increase in Hb levels with iron [33]

. In cardiac surgery, a RCT powered to

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supplementation, but no significant reduction in RBCT

detect a change in Hb level, but underpowered to assess an effect on the need for RBCT, did

supplementation

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not identify a significant difference in either outcome with pre-operative IV or PO iron [34]

. In our analysis, although a trend towards less RBCT with iron therapy was

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observed, the non-significant result may be related to lack of power of the included studies. We

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believe that this trend is clinically sensible, as the value of iron supplementation appears different for CRC than for orthopaedic or cardiac surgery. Indeed, prevalence and etiology of pre-operative anemia in CRC surgery differ, as it is chronic and mostly related to the underlying disease, rather than to surgical blood loss, which calls for a potentially different benefit of the iron intervention

[3,35]

. Unfortunately, the included studies did not detail prevalence of iron-

deficiency among their population. Perioperative iron supplementation can be administered in various ways, which were all considered for inclusion in this review. Concerns have been raised about the inefficacy of PO iron due to trouble of gastrointestinal absorption or coexisting chronic medical conditions

[36]

.

Therefore, IV iron has been suggested to be more effective in the setting of acute or chronic

ACCEPTED MANUSCRIPT inflammatory processes where PO iron is subjected to bypass effects of hepcidin, an inhibitor of gastrointestinal absorption

[37]

. Issues with IV iron reside in potential adverse effects , especially [38]

. However, newer preparations appear safe with

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anaphylaxis and theoretical risk of infection

studies

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regards to anaphylaxis, and have not been associated with increased infection rates in recent [39]

. The studies included in our review did not report on post-operative infections and

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therefore did not allow us to draw specific conclusions regarding the safety of IV iron before

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gastrointestinal surgery [27-30].

Few guidelines are available regarding the management of pre-operative anemia. The Network

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for Advancement of Transfusion Alternatives convened a group of experts and released a consensus statement in 2008, including recommendation for recommending pre-operative iron

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supplementation for patients with pre-operative anemia and for non-anemic patients with low ferritin and high expected blood loss

[40]

. Another consensus from Spain suggested the use of [41]

. These

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perioperative iron to correct anemia and reduce RBCT, based on weak evidence

guidelines highlight the issue of patient selection for perioperative administration of iron

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supplements; patients without pre-operative iron deficiency anemia may not benefit from the

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intervention. In our review, only one NRS considered exclusively anemic patients report on the proportion of anemic patients in each group

[29]

, two did not

[27,30]

, and one had twice as many

anemic patients in the control (56%) than the intervention group (25%), despite randomization [28]

. Given the small sample sizes in the included studies, this could have significantly impaired

the effect of treatment observed. Indeed, the only study reporting a significant difference in the proportion of patients transfused is the one including only anemic patients

[29]

. Therefore, lack of

focus on anemic patients in the included studies may explain why no significant treatment effect could be identified. For this systematic review and meta-analysis, we chose the proportion of patients receiving RBCT and the number of RBC units transfused per patient as primary outcomes. Since RBCT

ACCEPTED MANUSCRIPT has been associated with worse morbidity, recovery and even oncologic outcomes after surgery, this choice was made based on what seemed to be the most relevant to outcomes

[8-10]

.

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Unfortunately, all the studies included considered change in Hb level as primary outcome, which

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may explain why they are underpowered to detect a difference in RBCT. In a global blood conservation approach, a change in Hb level represents a surrogate outcome. However, so does

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rate of RBCT, since no data are yet available conclusively linking a reduction in RBCT to better long term outcomes such as improved morbidity, recovery or cancer recurrence and survival.

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no study collected data on those outcomes.

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Even more relevant patient outcomes would include symptoms of anemia and quality of life, but

Finally, perioperative iron supplementation is only one piece of a multidisciplinary and

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multimodal approach to blood conservation for surgical patients, aiming both at preventing blood loss and rationalizing the use of RBCT. Other interventions have been studied, such as pre-

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operative autologous blood donation, erythropoietin administration, tranexamic acid or intra[13,15,42,43]

. Meta-analyses pertaining to pre-operative autologous

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operative cell-saver devices

blood donation and erythropoietin in colorectal surgery have not yielded significantly positive

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results [13]. Despite promising cell salvage results, it is rarely used in gastrointestinal surgery due to concerns regarding contamination and cancer cell spreading

[15]

. A broader approach to

decreasing allogeneic blood transfusion appears more effective than a single intervention, as highlighted in a cluster randomized trial of the introduction of a comprehensive blood conservation algorithm in Ontario

[44]

. When compared to this algorithm including patient and

physician education, erythropoietin use, iron supplementation, autologous blood donation, and strict transfusion guidelines, traditional care was associated with higher odds of allogeneic RBCT (OR 1.8 [1.0-3.1]). The strengths of this systematic review include a comprehensive, systematic and highly sensitive literature search conducted without restriction for language or types of publications,

ACCEPTED MANUSCRIPT which also considered the gray literature. Our methodological decision to include nonrandomized studies permitted a thorough and inclusive review of the intervention. To minimize

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error and study selection bias, two reviewers selected studies independently, with high inter-

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rater agreement. Included studies were rigorously evaluated using the Cochrane Risk of Bias Tool and the Newcastle-Ottawa scale. Important limitations exist among the studies included in

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this review. All studies had small sample size, were single-center, had either high risk of bias for RCT or observational study designs with inherent selection bias, and did not report all pre-

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specified secondary outcomes such as post-operative morbidity and mortality, and oncologic

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outcomes. We attempted to contact the corresponding authors for missing information, but did not get responses. The hypothesis under question targeted a single component of multifaceted blood conservation approach to reduce the use of RBCT, which introduces multiple potential

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confounders that are difficult to control for and contributes to the heterogeneity observed among

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and within studies, along with variation in administration of the intervention. Thus, the methodological flaws of the included studies diminish the strength of recommendations that can

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CONCLUSION

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be drawn from this review.

In our study, we observed a non-significant trend towards a lower proportion of patients requiring Red Blood Cell transfusions with the use of perioperative iron supplementation for CRC surgery. Current studies supporting the use of perioperative iron supplementation for CRC surgery are limited by heterogeneous interventions, small sample size, patient selection not based on anemia status, and use of surrogate outcomes. Therefore, there is insufficient evidence to support the routine use of perioperative iron to decrease the need for RBCT in CRC surgery. However, preliminary evidence suggests it is a promising low-risk and cheap strategy to decrease the need for RBCT. Well-designed RCTs enrolling patients with pre-existing anemia, focusing on the need for RBCT, and including long-term outcomes are warranted.

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Funding

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No external funding was received for this study.

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Titos-Arcos JC, Soria-Aledo V, Carrillo-Alcaraz A, Ventura-López M, PalaciosMuñoz S, Pellicer-Franco E. Is intravenous iron useful for reducing transfusions in surgically treated colorectal cancer patients? World J Surg 2012;36(8):1893–7.

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Garrido-Martin P, Nassar-Mansur MI, la Llana-Ducros de R, Virgos-Aller TM, Fortunez PMR, Avalos-Pinto R, et al. The effect of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective cardiac surgery: a randomized clinical trial. Interactive Cardiovasc Thor Surg 2012;15(6):1013–8.

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Goodnough LT. Iron deficiency syndromes and iron-restricted erythropoiesis (CME). Transfusion 2012;52(7):1584–92.

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Fishbane S. Review of issues relating to iron and infection. Am J Kidney Dis 1999;34(4 Suppl 2):S47–52.

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39.

ACCEPTED MANUSCRIPT

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Possible sources of heterogeneity Population Nature of diagnosis Nature of surgical procedure Intervention Method of administration Timing of administration Use of co-intervention Comparator (placebo) Methodology Study design: RCT Vs. NRS Component of quality assessment RCT: Randomized Controlled Trial; NRS: Non-Randomized Study

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Table 1. Possible sources of heterogeneity determined a priori.

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Okuyama 2005 Japan

RCS

Titos-Arcos 2012 Spain

CCS

45

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Timing

Iron supplement

CR

Anemic patients

Dosage

Duration (days)

Control

Primary outcome

Followup

CRC

I: 25%* C: 56%*

Preoperative

PO Ferrous Sulphate

200 mg TID for 14 days

14 days (range: 12-56)

No treatment

Change in Hb (pre vs. post intervention)

Discharge from hospital

Preoperative

IV Iron Sucrose

300 mg daily for 2 doses

Median: 17 (range: 11-32)

Placebo

Change in Hb (pre vs. post intervention)

Discharge from hospital

PO Sodium Ferrous Citrate

200 mg daily for 14 days

NR

No treatment

Discharge from hospital

Postoperative

IV Iron Saccharose

100-200 mg, 3/week

NR

No treatment

Change in Hb (pre vs. post intervention) Change in Hb (post-operative day 1 to discharge)

20062008

60

CRC

NR separately for treatment groups

19982003

116

CRC Hb <100 g/L

I: 100% + C: 100%

20082010

104

CRC

NR

+

MA NU S

RCT

Diagnosis

Intervention

ED

Edwards 2009 United Kingdom

NR

Population N

Preoperative

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RCT

Study period

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Lidder 2007 United Kingdom

Study design

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Reference

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Table 2. Demographic and clinical features of the included studies.

+

*Anemia defined as hemoglobin <135 g/L (male) and <115 g/L (female); Anemia (hemoglobin <100g/L) was inclusion criteria for the study. RCT: Randomized Controlled Trial; RCS: Retrospective Cohort Study; CCS: Case-Control Study; NR: Not Reported; PO: Per Os; IV: IntraVenous; TID: three times a day; Hb: serum hemoglobin

Discharge from hospital

ACCEPTED MANUSCRIPT Table 3. Risk of bias assessment and methodology.

Unclear

Low risk

High risk

Randomization

Low risk

Low risk

High risk

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Randomization

Edwards 2009

CR

[31]

[45]

Selection [29]

MA NU S

Lidder 2007

Random sequence generation

Edwards 2009

[27]

Okuyama 2005 NRS

I: 22 C: 23

[29]

Titos-Arcos [30]

I: 34 C: 26 I: 32 C: 84 I: 52 C: 52

Other biases

Low risk

Unclear

Unclear

Unclear

Low risk

High risk

Low risk

Outcomes

Final score

***

7 of 8

***

8 of 8

*

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Estimated blood loss (mL) 800 (range: 188-6919)* 600 (range: 200-3500)* p non-significant 414 (range: 125-1500)* 300 (range: 100-800)* p 0.68 § 293 (SD: 570) § 273 (SD: 310) p 0.81 NR

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Table 4. RBC transfusion outcomes. N

Selective data reporting

Unclear

NRS: Newcastle- Ottawa Scale Comparability

Okuyama NR **** 2005 [30] Titos-Arcos Hb <11 g/dL **** 2012 RCT: Randomized Controlled Trial; NRS: Non-Randomized Studies

References

IP

References

RCT: Cochrane risk of bias assessment tool Blinding of Allocation Blinding of Incomplete outcome concealment participants outcome assessment

Selection for intervention

Number of patients with RBC transfusions N (%) p value + 6 (27.3) 0.07 13 (56.5) +

Number of RBC transfusions per patient Mean or median p value 0 (IQR: 0-4)* 0.03 2 (IQR: 0-11) §

5 (14.7) 5 (19.2)

0.73

0 (SD: 1) § 2 (SD: 3)

NR

3 (9.4) 23 (27.4)

<0.05

607 (SD: 150) §¶ 441 (SD: 183)

15 (28.8) 16 (30.8)

0.83

§¶

§

3 (SD: 1.6) § 3.3 (SD: 3)

RBC transfusion indication Hb <80 g/L Hb 80-100 g/L with symptoms NR

0.15 Intraoperative Hb < 70 g/L with unstable hemodynamics 0.68

Hb < 80 g/L 2012 + § ¶ * Median; calculated based on reported data using Fisher exact test; mean; reports only intra-operative volume of RBC transfusions (mL) RBC: Red Blood Cell; I: intervention group; C: control group; p: p value; IQR: inter-quartile range; SD: standard deviation; NR: not reported

ACCEPTED MANUSCRIPT Table 5. Serum hemoglobin and length of stay outcomes.

Edwards 2009

[27]

NRS

Okuyama 2005

I: 34 C: 26

[29]

Titos-Arcos 2012

[30]

I: 32 C: 84 I: 52 C: 52

Mean hemoglobin change (g/dL)

p value* NS 0.002

NR

NR

NR

-0.19 (95%CI: -0.74-0.36)* -0.5 (95%CI: -1.0-0.01) p 0.35 NR

NR

NR

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I: 22 C: 23

Mean post-intervention hemoglobin (g/dL) 13.1 (SD: 2.0) 11.8 (SD: 2.0) p 0.04 13.9 (range: 9.9-16.0) 13.8 (range: 9.2-16.9) p 0.96 10.1 (SD: 1.3) 8.9 (SD: 1.3) p<0.01 10 (SD: 1.1) 10.6 (SD: 1.2) p 0.01

IP

[31]

Mean pre-intervention hemoglobin (g/dL) 13.4 (SD: 1.9) 12.4 (SD: 2.1) p 0.04 13.4 (range: 10.8-15.9) 13.7 (range: 9.2-16.8) p 0.53 8.1 (SD: 1.4) 8.0 (SD: 1.6) p 0.69 10.6 (SD: 1.2) 10.2 (SD: 1.4) 0.121

CR

RCT

Lidder 2007

N

MA NU S

References

Mean length of stay (days) 10.0 (range: 6-26) 11.5 (range: 6-35) p NS + 10 + 8 p 0.27 NR

17.7 (SD: 14.1) 14.1 (SD: 11.8) p 0.08

+

ED

* Comparison between pre and post intervention among one treatment group; median

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RCT: Randomized Controlled Trial; NRS: Non-Randomized Studies; I: Intervention (iron supplentation) group; C: Control (no iron supplementation) group; SD: Standard Deviation; NS: Non-Significant; NR: Not Reported; 95%CI: 95% Confidence Interval

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Figure 1. PRISMA flow chart of the study selection.

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Figure 2. Impact of iron supplementation on proportion of patients receiving RBC transfusion, by study (Risk Ratios, 95% Confidence Interval).

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Figure 3. Impact of iron supplementation on the mean number of RBC transfusions needed per patient, by study (Mean Differences, 95% Confidence Interval).

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Figure 3

ACCEPTED MANUSCRIPT Appendix 1: Search strategy for Medline (1966-May 2013)

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1. Gastrointestinal diseases[MeSH Terms] 2. Digestive system disease[MeSH Terms] 3. Gastrointestinal neoplasms[MeSH Terms] 4. “Gastrointestinal dis*” 5. “Gastrointestinal cancer” 6. “Inflammatory bowel disease” 7. #1 OR #1 OR #3 OR #4 OR #5 OR #6 8. Operative surgical procedure[MeSH Terms] 9. Sugery, colorectal[MeSH Terms] 10. Digestive system surgical procedure[MeSH Terms] 11. Bloodless medical and surgical procedures[MeSH Terms] 12. Laparoscopy[MeSH Terms] 13. Perioperative care[MeSH Terms] 14. Perioperative period[MeSH Terms] 15. Surgery 16. “gastric surgery” 17. “liver surgery” 18. “pancreas surgery” 19. “colorectal surgery” 20. “bowel surgery” 21. Perioperative 22. #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 23. compounds, iron[MeSH Terms] 24. Anemia, iron deficiency[MeSH Terms] 25. Dextran iron complex[MeSH Terms] 26. Ferric compounds[MeSH Terms] 27. Hematinics[MeSH Terms] 28. Glucaric acide[MeSH Terms] 29. Ferric oxalate[MeSH Terms] 30. “iron supplementation” 31. “ferric gluconate” 32. “heme iron polypeptique” 33. “proferrin” 34. “ferumoxytol” 35. “venofer” 36. #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 37. #7 AND #22 AND #36 38. Humans[MeSH Terms] 39. #37 AND #38

ACCEPTED MANUSCRIPT Appendix 2: Associations considered for meetings’ proceedings review

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1. GENERAL SURGERY American college of surgeons (ACS)



American Society of Colon and Rectum Surgeons (ASCRS)



Amercias Hepato-Pancreato-Biliary Association (AHPBA)



Society of Surgical Oncology (SSO)



Canadian Society of Surgical Oncology (CSSO)



European society of surgery (ESS)



Canadian association of general surgeons (CAGS)

NU

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2. TRANSFUSION MEDICINE

American society of hematology (ASH)



European society of hematology (ESH)



American association of blood bankers (AABB)

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