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Preoperative iron deficiency increases transfusion requirements and fatigue in cardiac surgery patients: a prospective observational study

Piednoir, Pascale; Allou, Nicolas; Driss, Fathi; Longrois, Dan; Philip, Ivan; Beaumont, Carole; Montravers, Philippe; Lasocki, Sigismond

European Journal of Anaesthesiology: November 2011 - Volume 28 - Issue 11 - p 796–801
doi: 10.1097/EJA.0b013e32834ad97b
Cardiac anaesthesia
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Background Iron deficiency is the commonest cause of anaemia. It is apparent preoperatively in cardiac surgery patients and may influence transfusion requirements. In addition, iron deficiency per se is associated with fatigue.

Objective To determine the prevalence of preoperative iron deficiency and its association with perioperative anaemia, blood transfusions and fatigue in cardiac surgery patients.

Setting Academic hospital in Paris, France.

Patients One hundred consecutive patients without known iron disorder and scheduled for cardiac surgery were prospectively included in this observational study.

Intervention No intervention was performed.

Measurements A biological iron profile (transferrin saturation, ferritin, soluble transferrin receptor and C-reactive protein) was assessed on the day of surgery. Diagnosis of iron deficiency was defined using a previously published algorithm. Patient fatigue was assessed before surgery and 1 week afterwards (day 7) using the Multidimensional Fatigue Inventory (MFI-20) score that quotes five distinctive dimensions of fatigue.

Results Thirty-seven out of 100 patients were diagnosed with iron deficiency. These patients were younger [median (first-third quartile) 63 (43–70) vs. 70 (59–77) years (P = 0.004)], and more often female (51 vs. 21%, P = 0.003), than no iron deficiency patients. Preoperative iron deficiency was associated with lower preoperative haemoglobin levels (P = 0.006) and higher perioperative transfusion rates during the first week (62 vs. 35%, P = 0.019). Patients with iron deficiency but without anaemia (n = 25) received more packed red blood cells units than those without iron deficiency or anaemia (n = 50) [2 (0–2) vs. 0 (0–0) units, P < 0.05). Preoperative iron deficiency was associated with higher score of physical fatigue on day 7 (P = 0.01).

Conclusion Preoperative iron deficiency is frequent among cardiac surgery patients and is associated with anaemia, higher transfusion requirements and postoperative fatigue.

From the Département d’Anesthésie-Réanimation Chirurgicale, AP-HP, CHU Bichat-Claude Bernard, Université denis.diderot Paris 7, F-75018 Paris, France (PP, NA, DL, IP, PM, SL), the Pole d’Anesthésie Réanimation, CHU Angers, Université d’Angers, F-49000 Angers (SL), the service de Biochimie hormonale et Génétique AP-HP, CHU Bichat-Claude Bernard (FD) and the INSERM U773, CRB3 équipe 4, Université Paris 7 Denis Diderot, site Bichat (CB, SL), F-75018 Paris

Correspondence to Dr Sigismond Lasocki, Pole d’Anesthésie-Réanimation, CHU Angers, 4 rue Larrey, Angers, Cedex 49933, France Tel: +33 2 4135 3635; fax: +33 2 4135 3967; e-mail: sigismond@lasocki.com

Published online 5 October 2011

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Introduction

Preoperative anaemia is frequent among patients scheduled for cardiac surgery, affecting 25–40%.1,2 It is associated with an increased risk of perioperative transfusion3 and adverse outcome after both cardiac and non-cardiac surgery.1,2,4

Iron deficiency is the commonest cause of anaemia worldwide,5 but there is little data regarding the prevalence of iron deficiency in anaemic and non-anaemic patients scheduled for surgery. To our knowledge, on this subject there is only one brief report6 which found that iron deficiency was the second most common cause of anaemia in cardiac surgery patients, and that it accounted for preoperative anaemia in at least one third.6 Furthermore, the link between perioperative iron deficiency and postoperative outcome, including the need for transfusion, has never been explored. Indeed, anaemia or iron store depletion per se could account not only for a higher rate of transfusion but also for increased fatigue7,8 and reduced work capacity,9,10 with a negative impact on postoperative rehabilitation.3

The aims of this prospective observational study were to determine the frequency of preoperative iron deficiency among patients scheduled for cardiac surgery and to describe the association between preoperative iron deficiency and perioperative anaemia, transfusion and fatigue.

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Methods

Study population

This prospective observational study was approved by the Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale of Hôtel-Dieu Hospital, Paris, France (Chairperson: Dr Elisabeth Frija, Ethical committee decision No. 0611268, on the 16 February 2006). All adult patients scheduled for cardiac surgery with cardio-pulmonary bypass (CPB) at the Bichat-Claude Bernard Hospital (a 956-bed academic hospital) were eligible. Written consent was required from all participants in the study. Those with a history of haematological or iron metabolism disorders, those prescribed erythropoietin or iron during the previous month or those requiring emergency surgery, including surgery for endocarditis, were excluded. All CPB procedures were performed with a conventional (open) circuit under strict normothermia (37°C).

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Data collection

At study inclusion, baseline data and co-morbidities, haemoglobin (Hb) concentration (baseline Hb), type of surgery [i.e. coronary artery bypass grafting (CABG), valve replacement, combined surgery or other], American Society of Anesthesiologists physical status, EuroSCORE (European System for Cardiac Operative Risk Evaluation)11 and left ventricular ejection fraction, usually assessed by echocardiography, were recorded. We noted the duration of CPB, the number of packed red blood cell (PRBC) units transfused intraoperatively, 1 day and 1 week after surgery, as well as the volume drained from the chest at 24 h and at clamping prior to removal. PRBC transfusion was usually prescribed when haematocrit values were below 24%. Physicians in charge of the patient were blinded to the preoperative iron status.

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Biological variables

Blood samples were obtained on the day of surgery. The following blood analyses were recorded: RBC count, Hb concentration, reticulocyte count, serum iron, transferrin, ferritin, soluble transferrin receptor (sTfR) levels and high-sensitivity C-reactive protein (CRP). All haematological variables were obtained using an automated analyser (Sysmex XE2100, Roche Diagnostics, Meylan, France). Serum iron and transferrin levels were measured using commercially available kits (Thermo Clinical Labsystems, Oy, Finland). Ferritin was determined by nephelometry on a BNII Nephelometer (Dade Behring, Siemens Company, Paris, France). Total iron-binding capacity (TIBC) was calculated as transferrin (g l−1) × 25. Transferrin saturation (TSI) was calculated as serum iron/TIBC × 100. Serum sTfR was determined by particle-enhanced immunonephelometry using the BNII Nephelometer. High-sensitivity CRP was measured by immunonephelometry using the BN 100 system (Dade Behring, Siemens Company). Normal values for all these variables are shown in Table 1.

Table 1

Table 1

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Definitions of anaemia and iron deficiency

Anaemia was defined according to the WHO criteria as an Hb concentration less than 130 g l−1 in men and less than 120 g l−1 in women.

To define iron deficiency, we used the criteria proposed by Theusinger et al.12 modified to take into account the reference range of our laboratory. Iron deficiency was, thus, defined as either a serum ferritin less than 80 μg l−1 or a ferritin of 80–150 μg l−1 together with TSI less than 20% and CRP less than 5 mg l−1. When CRP was greater than 5 mg l−1, iron deficiency was defined as a sTfR-F index (i.e. the sTfR/log ferritin ratio) higher than 0.7 (Fig. 1). This algorithm is also similar to the one recently proposed for the management of preoperative anaemia.13

Fig. 1

Fig. 1

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Outcome and fatigue evaluation

We used the Multidimensional Fatigue Inventory (MFI-20) score to assess fatigue in our patients.14 MFI-20 is a 20-item self-reporting score designed and validated to measure fatigue. MFI-20 measures fatigue using the following five dimensions: ‘general fatigue’, ‘physical fatigue’, ‘mental fatigue’, ‘reduced motivation’ and ‘reduced activity’. Scores can range from a minimum of 4 to a maximum of 20 for each dimension (4 being no fatigue). MFI-20 scores were obtained on the day before surgery (baseline) and 7 days after surgery.

The following outcomes were also recorded: need and duration of catecholamine infusion, duration of mechanical ventilation and duration of ICU and of hospital stay. The occurrence of sepsis (pneumonia, mediastinitis or other) was recorded, as well as inhospital mortality.

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Statistical analyses

As this was a pilot observational study without sufficient data available to develop a satisfactory working hypothesis, an arbitrary sample size of 100 patients was selected. Data are presented as median (Q1-Q3) or mean ± SD, as appropriate.

To assess transfusion requirement and fatigue, patients were separated into two groups on day 0 according to whether they fulfilled the definition criteria of iron deficiency, or not. Continuous variables were compared using the Mann–Whitney U-test and categorical variables using the χ2-test. A matched-pair analysis of grouped data was performed to compare the evolution of MFI-20 scores (for each dimension), within and between groups (iron deficiency or no iron deficiency). In order to investigate the impact of iron deficiency and anaemia on transfusion rates, patients were subsequently classified into four further categories (anaemia, iron deficiency, iron deficiency/anaemia and no iron deficiency-no Anaemia). A Kruskal–Wallis test was used to compare the number of PRBC units transfused between these categories (with Dunn's test for multiple comparison, no iron deficiency-no Anaemia being the reference group). Significance level was fixed at a P value of less than 0.05. Statistical analyses were performed with the JMP software (version 5, SAS Institute Corp., Cary, North Carolina, USA).

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Results

Over a 4-month period, 100 patients were recruited (and one declined to participate) and divided into two groups according to their baseline iron status: 63 patients were classified as having no iron deficiency and 37 were classified as having iron deficiency (see Table 2 for all baseline characteristics and Table 1 for iron status).11 Patients in the iron deficiency group were younger and more often female (Table 2).

Table 2

Table 2

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Iron deficiency, haemoglobin levels and transfusion rates

Twelve patients (32%) in the iron deficiency group and 13 (20%) in the no iron deficiency group (P = 0.19) were anaemic before surgery. Both men and women in the iron deficiency group had lower Hb concentration both at baseline and on day 0 (day of surgery). These differences in Hb concentrations did not persist postoperatively, probably because more patients in the iron deficiency group were transfused and they received more units than no iron deficiency patients (Table 3). During the first week, the 25 patients with iron deficiency but without anaemia also received significantly more PRBC units than the 50 patients without iron deficiency or anaemia (Fig. 2). Transfusion was more common in women (23, 72%) than in men (21, 30%) (P < 0.0001).

Table 3

Table 3

Fig. 2

Fig. 2

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Clinical outcome and fatigue

Comparison of each MFI-20 fatigue dimension between iron deficiency and no iron deficiency patients showed that iron deficiency was associated with a significant increase in physical fatigue on day 7, 15 (13–16) vs. 13 (10–16) (P = 0.01) for iron deficiency and no iron deficiency, respectively. Figure 3 shows all MFI-20 assessments on day 0 and day 7, according to iron deficiency groups. With regard to preoperative anaemia, we found an association between anaemia on day 0 and general fatigue, 14 (9–15) vs. 9 (7–14) (P = 0.013) for patients with and without anaemia at baseline, respectively, and the same for reduced activity, 13 (9–16) vs. 9 (7–14) (P = 0.04), respectively, but not between preoperative anaemia and any dimension of fatigue at day 7.

Fig. 3

Fig. 3

Preoperative iron deficiency was not statistically associated with ICU length of stay, sepsis, length of mechanical ventilation or inhospital death (Table 3).

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Discussion

In this prospective observational study, we found that iron deficiency is highly prevalent among patients scheduled for cardiac surgery. Preoperative iron deficiency is associated with lower Hb levels in the preoperative period and with higher PBRC transfusion requirements in the postoperative period, as well as with increased fatigue.

There is a shortage of data available concerning iron deficiency in cardiac surgery patients. Karski et al.6 reported that 10% of all heart surgery patients had preoperative anaemia, the most commonly reported cause of which was, in 37%, given as ‘hospital-acquired anaemia’, and iron deficiency in 29% was the second most frequent cause. In our study, we confirmed a decrease in Hb levels between baseline and day 0 and found that 37% of all patients suffered from iron deficiency and 25% from anaemia on the day of surgery.

This prevalence of iron deficiency in patients scheduled for cardiac surgery is higher than that reported in the general population. In the USA, the National Health and Nutrition Examination Survey (NHANES) estimated the prevalence to be between 9 and 16%, depending on the diagnostic criteria used.5,15 However, using bone marrow smears (the gold standard for iron deficiency diagnosis), iron deficiency prevalence in women was estimated to be as high as 30 and 33% in an American and a Swedish survey, respectively.16 The prevalence of iron deficiency in cardiac patients seems to be even greater, as recently shown in a prospective observational cohort of 546 patients with heart failure, with an iron deficiency prevalence of 37%.17 In this cohort, iron deficiency was independently associated with a worse outcome (death or heart transplantation).17 In patients with heart failure and anaemia, iron deficiency may be even more frequent, affecting up to 73%, using bone marrow smears for diagnosis.18 Furthermore, compared with other forms of elective surgery, the prevalence of anaemia and iron deficiency in patients scheduled for cardiac surgery may be higher because of the relatively greater interventional blood loss associated with preoperative coronary angiography. We confirm here that, as observed in other surveys,5,15 women have a higher risk of iron deficiency than men, even when postmenopausal, and that the prevalence of iron deficiency is elevated in cardiac patients (almost 40%). We may have overestimated the number of iron deficiency patients, as the algorithm we chose for iron deficiency diagnosis was developed to identify patients likely to be responsive to intravenous iron,12 rather than to assess iron deficiency prevalence in a population.5,15,16 However, the latest available guidelines on the management of preoperative anaemia also suggest that cut-off values of 100 μg l−1 for ferritin, and of 20% for TSI, are used to rule out iron deficiency.13

In the present study, iron deficiency patients required more PRBC transfusions. Correction of iron deficiency and of iron deficiency-related anaemia by intravenous iron in the preoperative period may, thus, be beneficial. Indeed, there is a consensus that reducing anaemia and the number of PRBC transfusions are two important goals of perioperative care,19,20 both because of the potential harm associated with transfusion and because PRBC are an expensive and limited resource.21 Furthermore, iron deficiency was associated with physical fatigue on day 7. This link, between iron deficiency, anaemia and fatigue, has been widely reviewed and demonstrated in animal models and human studies.7–9 Iron deficiency and anaemia may, thus, have a negative impact on postoperative rehabilitation,3 providing a rationale for the preoperative correction of iron deficiency. Indeed, it has been recently shown that intravenous iron improves symptoms and functional capacity of patients with chronic heart failure and iron deficiency, even in those without anaemia,22 and some experts recommend perioperative correction of iron deficiency with intravenous iron.13,19,23 It is widely accepted that patients scheduled for elective surgery must be checked 3–4 weeks preoperatively and be treated as efficiently as possible.24,25

Our study is mainly limited by sample size. It lacks power to differentiate between the respective effects of iron deficiency and anaemia on perioperative PRBC transfusions and fatigue using regression analysis. However, the treatment of iron deficiency may be beneficial through the correction of iron deficiency per se or through the correction of anaemia. Data showing that treatment of iron deficiency (defined by the algorithm used in this study) was able to increase Hb levels.12 The female predominance in the iron deficiency group may be another confounding factor. Indeed, we observed that female sex is associated with lower Hb levels and higher transfusion requirements, and it may be of greater benefit to women with iron deficiency to increase the red cell mass using iron treatment.

Our data could be helpful in designing controlled trials aimed at evaluating possible benefit from the correction of iron deficiency in reducing perioperative PRBC transfusion and/or fatigue.

In conclusion, we report a high prevalence of preoperative iron deficiency in patients scheduled for cardiac surgery and an association between iron deficiency and PRBC transfusion requirements as well as between iron deficiency and postoperative physical fatigue.

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Acknowledgements

This work was supported by a grant from the Société Française d’Anesthésie- Réanimation to S.L.

S.L. has received consulting fees from ViforPharma. None of the other authors has a conflict of interest to declare.

The authors thank Dr Nicholas Heming for his assistance in editing the manuscript.

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Keywords:

anaemia; blood transfusion; cardiac surgical procedures; fatigue; iron deficiency

© 2011 European Society of Anaesthesiology