To the Editor:—
Preoperative anemia is a common condition among surgical patients, and it is an independent risk factor for blood transfusion in major surgery with moderate to high blood loss. Consequently, the first step to be taken in the setting of elective surgery will be the preoperative identification and evaluation of anemia early enough to implement the appropriate treatment. In this regard, we read with interest the report by Theusinger et al. 1about the use of intravenous iron sucrose for the treatment of iron deficiency anemia in orthopedic surgical patients. They found a mean maximum increase in hemoglobin (1.0 ± 0.6 g/dl) 2 weeks after the start of intravenous iron treatment, indicating that administration of intravenous iron 2–3 weeks before surgery may be optimal. We would like to comment regarding the patients’ inclusion criteria, the dosage and administration schedule of iron sucrose, and the comparison of their data with those of the study by Cuenca et al. 2in patients sustaining a pertrochanteric hip fracture.
First, although Theusinger et al. 1clearly defined anemia according to World Health Organization criteria as hemoglobin level < 12 g/dl for women and hemoglobin < 13 g/dl for men, their definition of iron deficiency was complex and somehow arbitrary. According to other authors, iron deficiency anemia is defined by anemia with mean corpuscular volume < 80 fl, ferritin level < 15–30 μg/l, and transferrin saturation < 15%.1On the other hand, in the event of inflammation (C-reactive protein > 5 mg/l), iron deficiency may be defined as transferrin saturation < 20% and ferritin < 50–100 μg/l.3Therefore, the cutoff values used in this paper (ferritin < 100 mg/l or 100–300 μg/l with transferrin saturation < 20%) are compatible not only with iron deficiency anemia but also with anemia of chronic disease, with or without true iron deficiency.3,4Thus, it is conceivable that a mixed anemic patient population was included in this study. This may be important, because the endogenous erythropoietin response to low hemoglobin is more substantial in iron deficiency anemia than in anemia of chronic disease, and erythropoietin increases the mobilization and incorporation of iron into the erythron.3Inflammatory mediators involved in anemia of chronic disease also impair duodenal iron absorption and iron mobilization from body stores.4
Second, the authors stated that in the current study group iron stores were empty, but without additional information on the inflammatory status, mean baseline ferritin levels (78 ± 70 mg/l) do no support this statement for all patients. However, the authors chose a dose of intravenous iron (≤ 900 mg) that may be insufficient for certain patients, whereas for others it covered the theoretical total iron deficit. In addition, the authors did not take into account the iron loss induced by perioperative blood loss. Assuming that 1 mg/l of ferritin is roughly equivalent to 8 mg of stored iron, and that 165 mg of iron are needed to reconstitute 1 g/dl of hemoglobin in a 70-kg adult, these patients may not have enough stored iron (preoperative ferritin ≥ 100 mg/l) to reconstitute their perioperative hemoglobin loss (3–4 g/dl) and keep a normal iron store (ferritin > 30 mg/l).5
On the other hand, most of the injected iron sucrose will be cleared from the plasma into the reticuloendothelial system within 24 h (plasma half-life, 6 h) and the rate of transfer of iron from the reticuloendothelial system into circulating red cells may be highly variable: It is more rapid and more complete in patients with iron deficiency than in patients with cancer or inflammation due to several circulating factors (e.g. , hepcidin).6Nevertheless, a small fraction of the injected agent (4–5%) likely bypasses the intracellular steps and donates iron directly to transferrin in plasma.7Thus, the relatively small effect of iron sucrose on hemoglobin levels observed by Theusinger et al. 1might have been enhanced administering the agent at lower doses but more frequently (e.g. , 100–200 mg, 2–3 times per week). Using this approach, García-Erce et al. 8reported that the administration of iron sucrose (1,000 mg, range 600–1800) to 10 anemic orthopedic patients awaiting surgery increased their hemoglobin (+ 2.6 g/dl; P < 0.01), ferritin (+ 198 mg/l; P < 0.01), and transferrin saturation (+ 21%; P < 0.01) without significant side effects, and only one patient was transfused.
Third, Theusinger et al. 1inadequately compared their data with the data of the control group and the treated group of Cuenca et al. 2, who studied the effects of 200–300 mg of iron sucrose on transfusion requirements in patients with a pertrochanteric hip fracture, starting just 3 days before surgery, and found a reduction both in the percentage of transfused patients and in the transfusion rate, as well as a reduction in postoperative infection rate. However, the reduction in transfusion requirements was only significant for patients with baseline hemoglobin > 12 g/dl. To improve these results, in a subsequent study of 83 patients with hip fracture, they administered a higher iron dose (3 × 200 mg/48 h, perioperatively), plus a single preoperative dose of erythropoietin (40,000 IU) if baseline hemoglobin was < 13 g/dl (75 of 83, 90%), and achieved a significant reduction of transfusion requirements with respect to a control group (71% vs. 24%; P < 0.01).9Given that the study by Theusinger et al. 1was performed in elective orthopedic patients, their results should be better compared with those reported by Cuenca et al. 10for 31 patients with preoperative hemoglobin < 13 g/dl scheduled for total knee replacement, who received oral iron during the 30–45 days preceding surgery and were managed with a restrictive transfusion protocol. When compared with a previous series of anemic patients (control group, n = 25), this treatment resulted in a significant reduction in transfusion requirements (61.5% vs. 19.3%, respectively). This transfusion rate, which is similar to that of Theusinger et al. , was reduced further in a subsequent series of patients with preoperative hemoglobin < 13 g/dl (12.3 ± 0.5 g/dl; n = 19) receiving perioperative iron sucrose (2 × 200 mg/48 h) plus a single dose of erythropoietin (1 × 40,000 IU), but 44% of patients were still anemic on postoperative day 30.5
In conclusion, the use of intravenous iron should be considered for patients with intolerance to or impaired absorption of oral iron, as well as when time to surgery is too short for oral therapy. However, the total iron dose should be calculated on an individual basis taking into account weight, baseline hemoglobin, iron stores, and predicted perioperative blood loss, to provide each patient with the adequate amount of iron. Finally, in the presence of inflammation, the efficacy of iron sucrose may be further enhanced by the repeated administration of low doses.
*University Hospital Miguel Servet, Saragossa, Spain. kpacuen@yahoo.es
