Anemia is a common finding in inflammatory bowel disease (IBD). It affects between 30% and 70% of patients and has great impact on the quality of their lives (1). The causes of anemia include chronic disease, vitamin B12 deficiency, folate deficiency, medication-induced bone marrow suppression and macrocytic anemia, hemolysis, and most commonly, iron deficiency anemia secondary to intestinal blood loss (2).
The treatment for iron deficiency anemia is oral or intravenous iron supplementation. Oral supplementation is often poorly tolerated, leading to poor compliance (3). Although parenteral iron supplementation is available, concern about potential side effects limits its administration.
Parenteral iron therapy in children with inflammatory bowel disease has been described in a small number of patients (4). As previously described in an abstract (5), we use intravenous iron dextran infusion to treat anemia associated with IBD. The aim of this study was to retrospectively review the efficacy and safety of intravenous iron dextran and report our experience.
The Institutional Review Board of the Children's Hospital of Philadelphia approved this study. A complete list of all patients who received total dose intravenous (TDI) iron dextran infusion between February 1994 and February 2000 was obtained from the Department of Pharmacy. The list of patients was cross-matched with the Children's Hospital of Philadelphia Inflammatory Bowel Disease Database, and 70 patients with either ulcerative colitis or Crohn disease were identified. Medical records, including inpatient and outpatient charts, were reviewed. Clinical, radiologic, and histologic data confirmed the diagnosis of IBD (6). Documentation of duration, efficacy, and side effects of oral iron therapy was not available.
The diagnosis of iron deficiency anemia was based on abnormally low concentrations of hemoglobin and mean corpuscular volume, when corrected for patient's age and sex. In addition, concentrations of iron, transferrin, and ferritin; transferrin saturation; total iron-binding capacity; and red blood cell distribution width were measured in some patients to confirm the diagnosis of iron deficiency anemia.
Intravenous iron dextran was administered on an outpatient basis in a day medicine unit unless the patient was already hospitalized. The dose of iron dextran was determined using the following previously published formula (4):EQUATION
where Wt is body weight, Hgbob is hemoglobin observed, and Hgbd is hemoglobin desired.
An advanced practice nurse or a physician administered an intravenous test dose of 25 mg iron dextran over 5 to 10 minutes, and the patient was observed for signs of allergic reaction. A precalculated dose of epinephrine and diphenhydramine hydrochloride was available. If no reaction occurred, the total dose of iron dextran was diluted in 200 mL of normal saline (0.9% NaCl) and administered over 2 hours. Vital signs and oral temperature were monitored hourly during the infusion. Typical administered iron dose ranged between 500 mg and 2000 mg.
During the 6-year study period, two different preparations of iron dextran were used, INFeD (Schein Pharmaceutical Inc., Florham Park, NJ, U.S.A.) and Dexferrum (American Regent Laboratories, Inc., Shirley, NY, U.S.A.).
Patients were excluded from the efficacy analysis if 1) transfusion of blood products or use of erythropoietin occurred within 2 months of the iron dextran infusion, 2) no follow-up laboratory evaluation was obtained within 2 months after the iron dextran infusion, 3) follow-up laboratory evaluation was obtained within 2 weeks after the iron dextran infusion, 4) patients received multiple infusions, or 5) patients did not fulfil the criteria for iron deficiency anemia. The evaluation of intravenous iron dextran efficacy was performed based on comparison of preinfusion and postinfusion hemoglobin, iron, transferrin, and ferritin concentrations and total iron binding capacity values, using the Student t test and the Mann-Whitney test where appropriate. The reference range for hemoglobin concentration for 6- to 12-year-olds was 11.5 to 15.5 g/dL; for 12- to 18-year-olds it was 13 to 16 g/dL in boys and 12 to 16 g/dL in girls. The reference range for mean corpuscular volume in 6-to 12-year-olds was 77 to 95 fL in 12-to 18-year-olds, 78 to 98 fL in boys and 78 to 102 fL in girls. The primary outcome of the study was improved postinfusion hemoglobin concentration of more than 2 g/dL. Statistical analysis was performed using the statistical package Stata 6.0 (Stata Corporation, College Station, TX, U.S.A.).
Seventy patients received a total of 119 TDI iron dextran infusions. Forty-eight patients (69%) received one infusion, 13 patients (20%) received 2 infusions, 4 patients (6%) received 3 infusions, 2 patients (2%) received 4 infusions, 1 patient (1%) received 5 infusions, and 2 patients (2%) received more than 10 infusions.
Thirty-four patients qualified for the efficacy analysis. Table 1 shows age, sex, diagnosis, place of administration and preinfusion hemoglobin concentration, mean corpuscular volume, and iron concentrations.
The average increase in hemoglobin concentration was 2.9 g/dL (P < 0.0001). The data on preinfusion and postinfusion iron concentrations were available in 17 patients. The difference in preinfusion and postinfusion concentrations of transferrin and ferritin, and total iron binding capacity were not statistically significant. Table 2 shows statistical analysis.
Table 3 describes the side effects of TDI iron dextran and the subsequent required therapy. Eleven allergic reactions were recorded (1 during the total dose infusion and 10 during the test dose administration). One patient (patient no. 7) had allergic reactions on two separate occasions.
Patients with IBD are frequently diagnosed with iron deficiency anemia (7–9). Between 26% and 37% of adult patients with IBD are affected; more patients with ulcerative colitis are affected than are patients with Crohn disease. Studies in the pediatric age group are uncommon and exact statistics are not available (4,5). The causes of iron deficiency anemia are multiple: chronic gastrointestinal blood loss caused by inflammation, decreased absorption of iron in patients with small bowel Crohn disease, and decreased dietary intake (2).
We will briefly review some of the published efficacy data and the side effect profile.
The gold standard for diagnosing iron deficiency anemia is an iron stain of the bone marrow aspirate (10). Because bone marrow aspiration is too invasive to be used on a regular basis, the accepted and reliable method of diagnosis is based on complete blood count and iron studies (10). These include serum concentrations of hemoglobin, mean corpuscular volume, red blood cell distribution width, ferritin concentration, transferrin saturation and serum iron concentration below the laboratory reference value for the appropriate age group, increased total iron-binding capacity, and an excess of 10% of hypochromic cells on peripheral blood smear. Ferritin, an acute phase reactant, is often increased in inflammatory diseases such as IBD, making it a less reliable marker.
Iron deficiency anemia is treated with oral, intramuscular, or parenteral iron. Parenteral iron first became available in 1952 (11), and the TDI form was first used in 1963. Physicians are often reluctant to use the intravenous form of iron, fearing side effects.
Oral treatment is an efficacious first-line therapy, although it is associated with intolerance in about 20% of the patients (3). The intolerance, manifested by nausea, constipation, diarrhea, and abdominal discomfort, frequently leads to poor compliance. Oral iron is not as well incorporated into red blood cells and takes longer to form hemoglobin than does the intravenous form (12).
Intramuscular use is associated with discomfort, pain, staining of the skin, bleeding, development of sterile abscesses, tissue necrosis, tissue atrophy with ulceration, and development of sarcoma at the injection site (13).
Intravenous iron can be given in multiple doses (frequently used in patients on chronic hemodialysis), total dose infusion, or with total parenteral nutrition. Several preparations are available for intravenous use in different countries, and degradation kinetics, bioavailability, and side effect profiles depend on the size of iron complex. In the United States, only iron dextran is approved for intramuscular or multiple-dose intravenous application of undiluted solution (14).
Efficacy of intravenous iron therapy is well established, and the standard measure of success is increase in the hemoglobin concentration. In our study, the average increase in concentration of hemoglobin was 2.9 mg/dL, which is comparable to the results published in 1982 (4). Six children with IBD received TDI of iron dextran with an average increase in hemoglobin concentration of 3.5 g/dL. The same author published experience with 14 children receiving parenteral nutrition who received TDI of iron dextran with an increase in hemoglobin concentration of 2.9 g/dL at 4.8 weeks after the infusion (15). Approximately 25% of patients in our study have received intravenous iron dextran while hospitalized for exacerbation of IBD. Therefore, the concurrent treatment could have affected the hemoglobin response. However, the response rate to infusion was highly statistically significant when calculated separately for outpatient and inpatient infusions. The retrospective nature of the study made an accurate assessment of the concurrent therapy impossible. The possibility of relative erythropoietin deficiency should be considered in patients who do not respond to therapy. Erythropoietin therapy is effective in selected groups of adult and pediatric patients with IBD (9,16,17).
Hypersensitivity reactions to intravenous iron administration may be immediate or delayed. Immediate reactions are either of the anaphylactoid type, manifested by malaise, itching, urticaria, sweating, myalgia, arthralgia, and febrile episodes, or of the anaphylactic type with hypotension and circulatory collapse. Delayed reactions occur within 24 to 48 hours and may be caused by histamine release (3). These reactions are manifested by lymphadenopathy, myalgia, arthralgia, backache, headache, fever, nausea, vomiting, dizziness, and diaphoresis and usually resolve within 72 hours after the iron infusion (13). In our study, we observed 11 (9% of total number of infusions) hypersensitivity reactions. Transient hypotension developed in three children, and they received treatment with epinephrine. None of the reactions was considered life threatening, and none of the children required hospitalization. Information about delayed hypersensitivity reactions was not available. Several large studies have addressed the frequency of side effects. In 481 adults with a total of 2,099 intravenous infusions, 26% had reactions, of which 5% limited ordinary activity and 0.6% were life threatening (7). In a study of 2,400 patients, 1% to 2% had significant side effects (18); and 0.6% to 1.6% of 623 pregnant women in another study had severe reactions (19). A review article of intravenous use of iron reported a 0.1% to 0.6% incidence of life-threatening anaphylaxis (20). In 1988, Auerbach et al. (21) reported a 40% incidence of delayed reactions that resolved in 72 hours. The same author recommended using methylprednisolone therapy before and after the total intravenous iron infusion, based on a decreased rate of side effects in a randomized, controlled study of 78 patients (14). We have successfully used intravenous iron dextran in four patients who have had previous allergic reactions to the test dose of intravenous iron. These patients were premedicated with acetaminophen, diphenhydramine, and methylprednisolone, in accordance with a case report of desensitization protocol with corticosteroids, diphenhydramine, and ephedrine (22).
In 156 patients undergoing home dialysis who were given TDI iron, only 3.5% had side effects with the INFeD preparation, whereas 28.6% had reactions (itching, urticaria, leg and back pain, shortness of breath, nausea, vomiting) with Dexferrum (23). We made a similar anecdotal observation during the period when both preparations were used at our institution. Currently, we use only INFeD.
The risk of infection with intravenous iron therapy could be of interest in IBD, especially because many patients are already receiving immunosuppressive therapy. However, a study of 17 patients showed the same rate of infections before and after iron infusion (24). Interestingly, the observation of decreased interleukin-2 and interferon-γ production has been made in iron overload states (24). A low concentration of nontransferrin-bound iron can inhibit the cloning capacity of CD+ T cells and enhance suppressor T cells, theoretically exerting an antiinflammatory property (24).
To better evaluate the response to treatment and standardize the care for patients with IBD who have iron deficiency anemia, a uniform protocol for administering intravenous iron should be studied prospectively. Hemoglobin concentration should be obtained within 4 to 8 weeks after infusion, together with liver function tests and iron profile studies, to assess the efficacy and observe for potential toxicity of iron therapy. In the outpatient setting, patients should be contacted within 72 hours to document delayed reactions. The activity of the IBD, concomitant medications, the rate of infections within several weeks after infusion, and the quality of life assessment should be obtained.
In conclusion, this retrospective study suggests that TDI infusion of iron dextran, when appropriately used, is a safe and potentially efficacious treatment for children with IBD and iron deficiency anemia.
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