EfficacyofBolus Intravenous Iron Dextran Treatment in Peritoneal Dialysis Patients Receiving Recombinant Human Erythropoietin
Nasimul Ahsan, James A. Groff, Mary A. Waybill
The efficient use ofrecombinant human erythropoietin (rHuEPO) requires adequate body stores of iron. In peritoneal dialysis (PD) patients, iron replacement is most commonly administered oral/y. In this study, we prospectively fol/owed 7 stable PD patients fol/owing bolus intravenous infusion of 1 9 iron dextran in an outpatient setting. At 12 weeks, significant (p < 0.05) increments in mean hematocrit from 29.13% to 34.85%, transferrin saturation from 10.15% to 29.33%, serum ironfrom 27.38 to 67.00 /lg/dL, andserumferritinfrom 150.30 to 331.40 ng/mL were observed. Post-treatment, there was less requirement ofrHuEPO, and at six months there was a 26% reduction in the mean weekly subcutaneous rHuEPO dose. At 12 weeks, serum albumin increased significantly from 3.50 to 3.76g/dL (p < 0.05). There was no abnormality in any of the measured liver function tests. No patient developed an adverse or al/ergic reaction. We concluded that bolus intravenous infusion of iron dextran is an effective and wel/-tolerated method of repleting iron stores, and wil/ al/ow a more efficient and economic use ofrHuEPO in PD patients.
Key wordsIron dextran, intravenous infusion, anemia, endstage renal disease
From:Division of Nephrology and Hypertension, Department ofMedicine, The Milton S. Hershey Medical Center, Pennsylvania State University-College of Medicine, Hershey, Pennsylvania, U.S.A.
IntroductionThe use of recombinant human erythropoietin (rHuEPO) to treat anemia in patients with end-stage renal disease (ESRD) is a major therapeutic advance (1,2). However, rHuEPO therapy frequently causes iron deficiency due to transfer of bone marrow iron stores to erythroid progenitor cells. Therefore, efficient use of rHuEPO requires long-term maintenance therapy with iron and frequent monitoring for adequacy of iron stores (3). Iron therapy in dialysis patients is most commonly administered orally. However, patient noncompliance, gastrointestinal side effects, and poor gastrointestinal absorption due to drug interaction are the limiting factors in the efficacy of oral iron therapy. To eliminate these factors, the intravenous route has become the preferred method of iron supplementation in chronic hemodialysis patients. Alternatively, in some situations, for example in peritoneal dialysis (PD) patients, the intramuscular route has been successfully used. In both of these parenteral methods, several small doses (usually 100 mg) of iron dextran are administered on successive days or weeks. Neither of these methods, however, is an attractive alternative in outpatient PD patients. The purpose of this study, therefore, was to evaluate prospectively the efficacy of bolus infusion of intravenous iron dextran in PD patients with iron deficiency anemia during rHuEPO treatment.
Patients and methodsSeven adult, stable ESRD patients (6 Caucasian and 1 Hispanic) were prospectively followed for a period of six months. There were 5 females and 2 males. Mean age was 33.4 years (range 21 -54 years). Five patients were on continuous ambulatory peritoneal dialysis, and 2 were on continuous cycling peritoneal dialysis. The average duration on PD was ten months (range 1 37 months). All patients received oral iron supplementation (average 3.5 tablets of ferrous sulfate per patient per day) and self-administered rHuEPO subcutaneously. None of the patients had recent bleeding episodes, hematologic disease other than anemia, hyperparathyroidism, aluminum toxicity , and/or recent blood transfusion. Patients were admitted to the outpatient infusion room of the Milton S. Hershey Medical Center, Hershey, Pennsylvania, and received brief physical examinations. They were informed about the treatment procedure and anticipated side effects. After premedication with intravenous hydrocortisone ( lOO mg) and diphenhydramine (25 mg), and oral acetaminophen ( 1000 mg), all patients received a test dose of intravenous iron dextran (25 mg) given slowly over ten minutes by a nephrologist. The patients were closely observed for 15 minutes for possible adverse or anaphylactic reactions. Then, 975 mg of iron dextran mixed in 500 mL of 0.45% sodium chloride solution were infused at a rate of lOO mL per hour for five hours (delivering 3.25 mg of iron dextran per minute). During the infusion, pulse rate and blood pressure were recorded at 30-minute intervals. Postinfusion and prior to discharge, patients were observed an additional 30 minutes. Patients were then followed in the outpatient PD clinic at monthly intervals. Complete blood count, serum iron, ferritin, total iron binding capacity (TIBC), transferrin saturation (TSA T) (serum iron divided by TIBC multiplied by lOO), electrolytes, blood urea nitrogen, and serum creatinine were measured monthly. Liver function tests (alkaline phosphatase, total bilirubin, and aspartate aminotransferase) and serum albumin were measured every three months.
Statistical methodsAnalysis of variance of repeated measures was used for analysis of hematocrit and rHuEPO dose data. Two-tailed Student's t-tests were used for comparing the baseline and subsequent data. All results are expressed as mean :!: standard error of mean. A probability value of <0.05 was considered significant.
ResultsWhen compared with pre-infusion, at 12 weeks there were significant increases in hematocrit from 29.13:!: 1.14%to 34.85 :!:0.77%(p <0.005), TSAT from 10.15:!: 1.62% to 29.33:!: 3.79% (p < 0.005), serum iron from 27.38 :!: 4.59 to 67.00 :!: 9.24 p.g/dL (p < 0.005), and serum ferritin from 150.30:!: 47.86 to 331.40 :!: 110.69 ng/mL (p < 0.05). Serum albumin also increased significantly from 3.50:!: 0.11 to 3.76:!: 0.13 g/dL (p < 0.05). There was no significant abnormality in liver function tests (Table I, Figure I). At six months, the mean weekly dose ofsubcutaneous rHuEPO was reduced from 8000 :!: 2070 to 5875:!: 1171 units; statistical significance was not achieved due to the small number of our patient population (Figure 2). None of the patients developed immediate or delayed hypersensitivity and/or anaphylactoid reaction. Clinical evidence of volume overload during and/or following infusion was not anemia in PD patients during rHuEPO therapy. observed.
DiscussionThis study in patients clearly demonstrates that boIus intravenous iron dextran infusion can be used effectively in the treatment of iron deficiency anemia in PD patients during rHuEPO therapy. When compared with the baseline, at 12 weeks there were significant increments in mean hematocrit, TSA T , serum iron, and serum ferritin. Also, the therapy with rHuEPO became more effective due to better iron stores, demonstrated by the mean rHuEPO dose at six months, which was 26% less than that of the baseline. Overall, the bolus iron dextran infusion appeared to be safe and was well tolerated.
With the advent of rHuEPO therapy, nonspecific therapies for managing the anemia of renal failure are of historic interest. Since its release for use in dialysis patients in July, 1989, rHuEPO therapy has resulted in an improved quality of life for the majority of patients with ESRD (1-3). The economic cost of rHuEPO therapy is substantial when the expense of treatment of almost 90% of patients with end-stage renal disease is a federal obligation. With continued pressure to reduce costs, judicious use of rHuEPO is imperative. Although use of the subcutaneous route has helped in decreasing the dosage requirement of rHuEPO by 25% 50%, undertreatment remains a common problem (4,5).
The most common cause ofrHuEPO resistance is iron deficiency anemia resulting from enhanced iron utilization due to erythropoietin-enhanced red blood cell formation, and almost all patients on rHuEPO therapy are treated with oral iron supplementation. Although the most convenient and easiest means of iron supplementation, there are many disadvantages inherent in the use of oral iron therapy. Many patients are noncompliant due to side effects such as nausea, stomach irritation, and constipation, especially when subjected to the maximum therapeutic dose (6). In addition, poor gastrointestinal absorption and decreased bioavailability -due to drug interaction with antacids, phosphate binders, and gastric acid reduction drugs, for example, histamine 2 antagonist and proton pump inhibitors -further reduce the efficacy of oral iron (7). Finally, side effects and efficacy profiles also depend on the type of preparation ingested. Wingard et a/. (8) reported that patients treated with a fumarate-containing oral iron preparation (Tabron) had the highest iron indices when compared with other preparations.
In hemodialysis patients with iron deficiency anemia, iron dextran given in small doses weekly or biweekly has practically eliminated most of the problems associated with oral iron preparation. Compliance is guaranteed, and the number of pills the patient must take is reduced. Fishbane et a/. (9) compared the safety and efficacy of biweekly intravenous iron dextran (lOO mg/session) with oral iron therapy in chronic hemodialysis patients. In this study, patients receiving intravenous iron dextran had significantly higher hematocrit and iron indices and required significantly less rHuEPO (9). While the intravenous route is preferred for hemodialysis patients, it is less desirable in PD patients due to poor peripheral access. Suh and Wadhwa (10) reported that weekly intramuscular injections of iron dextran are effective in correcting anemia and restoring all iron indices in PD patients. However, for logistical reasons, both parenteral methods of iron replacement in PD patients are unacceptable alternatives. Moreover, besides the pain and trauma associated with both intravenous and intramuscular methods, the inconvenience and economic loss involving repeated clinic visits can be substantial. Our study has demonstrated the efficacy ofbolus infusion of iron dextran in PD patients who developed iron deficiency anemia while receiving rHuEPO therapy.
In this study, improvement in hematocrit following bolus iron dextran persisted for six months. This change in erythropoiesis was most likely due to improvement in iron stores. The maximum increment in mean hematocrit was observed at 12 weeks; mean serum iron and TSA T were also maximally increased at 12 weeks. Beyond this point, along with the fall in serum iron and TSA T , hematocrit began to decrease. Nonetheless, at six months all these parameters, except for serum ferritin, remained significantly above the pretreatment levels.
One major finding following bolus iron dextran in this study was the gradual reduction in mean rHuEPO dose. At six months there was a 26% reduction in the mean weekly dose of subcutaneous rHuEPO when compared with the baseline. Given the high cost of rHuEPO, a 26% lowering of doses could have a substantial fmancial impact. Any cost savings resulting from lower rHuEPO doses, however, must be weighed against the cost of administering bolus intravenous iron dextran. The average total cost of a bolus infusion of iron dextran (1000 mg iron dextran, premedications, charge of infusion room, and nursing care) for our PD patients was (US)$485.84. Taking into account the cost of the iron dextran infusion, the cumulative difference between the baseline cost and follow-up costs of rHuEPO for six months in this study leads to an average saving of $99.08 per patient. On the other hand, if given in our medical facility , ten intravenous or intramuscular injections of 100 mg of iron dextran would cost each patient (US)$I 002.10 ($100.21 per treatment, which includes charges for iron dextran and an administration fee). When one adds the expense of commuting for ten treatments and hours lost from work, serial intravenous or intramuscular iron dextran therapy becomes the most expensive method of iron supplementation.
A major concern with the use of intravenous or intramuscular iron dextran preparations is the risk of anaphylaxis, with reported incidence ranging from 0.6% to 1% (11,12). There are also reports of sarcoma and rhabdomyolysis associated with intramuscular injection (13-15). Others have reported delayed reactions like myalgia, arthralgia, fever, headache, or lymphadenopathy (11,16). Most of these reactions are unpredictable and may not be related to the total administered dose. Because of these potential side effects, it is generally recommended not to exceed the dose of the intravenous iron dextran above 50 mg/min, and the recommended single maximum dose of both intravenous and intramuscular iron dextran is 100 mg (17). In this study we did not encounter any adverse and/ or anaphylactic reactions. In our opinion, this was primarily due to: premedication, very slow infusion rate, and infusion of diluted preparation.
In certain animals, some abnormalities in liver function tests have been reported followirtg a large dose of iron dextran (18). None of our patients, however, showed any abnormality in their liver function tests when followed for at least six months. Finally, administering a large amount of intravenous fluid is always a concern in ESRD patients as many of these patients, in addition to being fluid noncompliant, have poor cardiac reserve. All of our patients underwent pre infusion physical examination and were observed very closely during and immediately after infusion. We did not encounter any clinical evidence of volume overload.
In summary, we have shown that when appropriate precautions are taken our method of bolus infusion of iron dextran is safe and effective in treating iron deficiency anemia in PD patients. We also found that the dose ofrHuEPO can be substantially reduced. Moreover, this method is convenient and cost-effective when compared with repeated intravenous and/or intramuscular injections of iron dextran. Prior to infusion, all patients should be carefully examined by a physician, and in those with borderline cardiac reserve we further recommend that the total dose of iron dextran be administered in two or more successive sessions.
AcknowledgmentThe author is thankful to Dr. Robert E. Cronin, of the Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, Texas, in preparation of this manuscript, and greatly appreciates the excellent assistance of the dialysis nurses (Linda K. Diviney and Gail A. Burkholder).
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Nasimul Ahsan, MD, Division of Nephrology and Hypertension, Department of Medicine, The Milton S. Hershey Medical Center, 500 University Drive, Hershey, Pennsylvania, U.S.A.