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.
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).
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.
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.
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
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.
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).
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).
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).
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.
Preoperative iron deficiency was not statistically associated with ICU length of stay, sepsis, length of mechanical ventilation or inhospital death (Table 3).
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.
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.
1. Karkouti K, Wijeysundera DN, Beattie WS. Risk associated with preoperative anemia in cardiac surgery: a multicenter cohort study. Circulation
2. Kulier A, Levin J, Moser R, et al. Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft surgery. Circulation
3. Napolitano LM. Perioperative anemia. Surg Clin North Am
4. Dunne JR, Malone D, Tracy JK, et al. Perioperative anemia: an independent risk factor for infection, mortality, and resource utilization in surgery. J Surg Res
5. Centers for Disease Control and Prevention. Iron deficiency
: United States, 1999–2000. JAMA
6. Karski JM, Mathieu M, Cheng D, et al. Etiology of preoperative anemia in patients undergoing scheduled cardiac surgery. Can J Anaesth
7. Sobrero A, Puglisi F, Guglielmi A, et al. Fatigue
: a main component of anemia symptomatology. Semin Oncol
8. Toy P, Feiner J, Viele MK, et al. Fatigue
during acute isovolemic anemiain healthy, resting humans. Transfusion
9. Haas JD, Brownlie TT. Iron deficiency
and reduced work capacity: a critical review of the research to determine a causal relationship. J Nutr
2001; 131:676S–688S.discussion 688S–690S.
10. Zhu YI, Haas JD. Iron depletion without anemia and physical performance in young women. Am J Clin Nutr
11. Nashef SA, Roques F, Michel P, et al. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg
12. Theusinger OM, Leyvraz PF, Schanz U, et al. Treatment of iron deficiency
anemia in orthopedic surgery with intravenous iron: efficacy and limits – a prospective study. Anesthesiology
13. Goodnough LT, Maniatis A, Earnshaw P, et al. Detection, evaluation, and management of preoperative anaemia
in the elective orthopaedic surgical patient: NATA guidelines. Br J Anaesth
14. Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue
Inventory (MFI) psychometric qualities of an instrument to assess fatigue
. J Psychosom Res
15. Cogswell ME, Looker AC, Pfeiffer CM, et al. Assessment of iron deficiency
in US preschool children and nonpregnant females of childbearing age: National Health and Nutrition Examination Survey 2003–2006. Am J Clin Nutr
16. Hallberg L, Bengtsson C, Lapidus L, et al. Screening for iron deficiency
: an analysis based on bone-marrow examinations and serum ferritin determinations in a population sample of women. Br J Haematol
17. Jankowska EA, Rozentryt P, Witkowska A, et al. Iron deficiency
: an ominous sign in patients with systolic chronic heart failure. Eur Heart J
18. Nanas JN, Matsouka C, Karageorgopoulos D, et al. Etiology of anemia in patients with advanced heart failure. J Am Coll Cardiol
19. Beris P, Munoz M, Garcia-Erce JA, et al. Perioperative anaemia
management: consensus statement on the role of intravenous iron. Br J Anaesth
20. Hajjar LA, Vincent JL, Galas FR, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA
21. Shander A, Hofmann A, Ozawa S, et al. Activity-based costs of blood transfusions in surgical patients at four hospitals. Transfusion
22. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency
. N Engl J Med
23. Munoz M, Breymann C, Garcia-Erce JA, et al. Efficacy and safety of intravenous iron therapy as an alternative/adjunct to allogeneic blood transfusion
. Vox Sang
24. Spahn DR, Moch H, Hofmann A, Isbister JP. Patient blood management: the pragmatic solution for the problems with blood transfusions. Anesthesiology
25. Moskowitz DM, McCullough JN, Shander A, et al. The impact of blood conservation on outcomes in cardiac surgery: is it safe and effective? Ann Thor Surg
Keywords:© 2011 European Society of Anaesthesiology
anaemia; blood transfusion; cardiac surgical procedures; fatigue; iron deficiency