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`Advances in Peritoneal Dialysis, Vol. 12, 1996
`
`Efficacy ofBolus
`Intravenous Iron Dextran
`Treatment in Peritoneal
`Dialysis Patients Receiving
`Recombinant Human
`Erythropoietin
`
`Introduction
`The 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, ef(cid:173)
`ficient use of rHuEPO requires long-term mainte(cid:173)
`nance therapy with iron and frequent monitoring for
`adequacy of iron stores (3). Iron therapy in dialy(cid:173)
`sis 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 pre(cid:173)
`ferred method of iron supplementation in chronic
`hemodialysis patients. Alternatively, in some situ(cid:173)
`ations, for example in peritoneal dialysis (PD) pa(cid:173)
`tients, the intramuscular route has been success(cid:173)
`fully used. In both of these parenteral methods, sev(cid:173)
`eral small doses (usually 100 mg) of iron dextran
`are administered on successive days or weeks. Nei(cid:173)
`ther of these methods, however, is an attractive al(cid:173)
`ternative 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 methods
`Seven adult, stable ESRD patients (6 Caucasian and
`1 Hispanic) were prospectively followed for ape(cid:173)
`riod of six months. There were 5 females and 2
`males. Mean age was 33.4 years (range 21 - 54
`
`Nasimul Ahsan, James A. Groff, Mary A. Waybill
`
`The efficient use of recombinant human erythro(cid:173)
`poietin (rHuEPO) requires adequate body stores
`of iron. In peritoneal dialysis (PD) patients, iron
`replacement is most commonly administered
`orally. In this study, we prospectively followed 7
`stable PD patients following bolus intravenous
`infusion of I g iron dextran in an outpatient set(cid:173)
`ting. At I2 weeks, significant (p < 0.05) incre(cid:173)
`ments in mean hematocrit from 29. I 3% to
`3 4. 85%, transferrin saturation from I 0. I 5% to
`29.33%, serum ironfrom 27.38 to 67.00 p,g/dL,
`and serum ferritin from I50.30 to 331.40 nglmL
`were observed. Post-treatment, there was less
`requirement ofrHuEPO, and at six months there
`was a 26% reduction in the mean weekly subcu(cid:173)
`taneous rHuEPO dose. At I 2 weeks, serum albu(cid:173)
`min increased significantly from 3. 50 to 3. 76
`gldL (p < 0. 05). There was no abnormality in any
`of the measured liver function tests. No patient
`developed an adverse or allergic reaction. We
`concluded that bolus intravenous infusion of iron
`dextran is an effective and well-tolerated method
`of repleting iron stores, and will allow a more
`efficient and economic use ofrHuEPO in PD pa(cid:173)
`tients.
`
`Key words
`Iron dextran, intravenous infusion, anemia, end(cid:173)
`stage renal disease
`
`From: Division ofNephrology and Hypertension, Depart(cid:173)
`ment ofMedicine, The Milton S. Hershey Medical Center,
`Pennsylvania State University-College of Medicine,
`Hershey, Pennsylvania, U.S.A.
`
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`
`162
`
`Ahsan eta/.
`
`years). Five patients were on continuous ambulatory
`peritoneal dialysis, and 2 were on continuous cy(cid:173)
`cling peritoneal dialysis. The average duration on
`PD was ten months (range 1 - 37 months). All pa(cid:173)
`tients 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, hyperpara(cid:173)
`thyroidism, aluminum toxicity, and/or recent blood
`transfusion. Patients were admitted to the outpa(cid:173)
`tient infusion room of the Milton S. Hershey Medi(cid:173)
`cal Center, Hershey, Pennsylvania, and received
`brief physical examinations. They were informed
`about the treatment procedure and anticipated side
`effects. After premedication with intravenous hy(cid:173)
`drocortisone (100 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 nephrolo(cid:173)
`gist. The patients were closely observed for 15
`minutes for possible adverse or anaphylactic reac(cid:173)
`tions. Then, 975 mg of iron dextran mixed in 500
`mL of 0.45% sodium chloride solution were in(cid:173)
`fused at a rate of 100 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
`100), electrolytes, blood urea nitrogen, and serum
`creatinine were measured monthly. Liver function
`tests (alkaline phosphatase, total bilirubin, and as(cid:173)
`partate aminotransferase) and serum albumin were
`measured every three months.
`
`Statistical methods
`Analysis of variance of repeated measures was used
`for analysis of hematocrit and rHuEPO dose data.
`Two-tailed Student's t-tests were used for compar(cid:173)
`ing the baseline and subsequent data. All results are
`expressed as mean± standard error of mean. A prob(cid:173)
`ability value of <0.05 was considered significant.
`
`Results
`When 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 J.tgldL
`(p < 0.005), and serum ferritin from 150.30 ± 47.86
`to 33I.40 ± II 0.69 ng/mL (p < 0.05). Serum albu(cid:173)
`min also increased significantly from 3.50 ± O.II to
`3.76 ± O.I3 g/dL (p < 0.05). There was no signifi(cid:173)
`cant abnormality in liver function tests (Table I, Fig(cid:173)
`ure I). At six months, the mean weekly dose of sub(cid:173)
`cutaneous rHuEPO was reduced from 8000 ± 2070
`to 5875 ± II7I units; statistical significance was not
`achieved due to the small number of our patient popu(cid:173)
`lation (Figure 2). None of the patients developed
`immediate or delayed hypersensitivity and/or ana(cid:173)
`phylactoid reaction. Clinical evidence of volume
`
`TABLE 1
`
`Laboratory variables (mean± SEM)
`
`Baseline
`
`6 weeks
`
`12 weeks
`
`6 months
`
`HCT (%)
`TSAT(%)
`Iron (J"g/dL)
`Ferritin (ng/mL)
`Albumin (g/dL)
`AST (U/L)
`ALP (U/L)
`T. bili (mg/dL)
`
`29.13±1.14
`10. 15±1.62
`27.38±4.59
`150.30±47.86
`3.50±0. I I
`38.00±8.47
`121.43±12.05
`0.50±0.05
`
`32.43±0.97b
`28.3 I ±5.70b
`59. 13±10.29'
`430.90±8J.32b
`
`32.85±0.9Jb
`20.93±2.52h
`41.33±4.7Jh
`I 31.60± 53.73
`
`34.8 5±0. 77'
`29.33±3 .79'
`67.00±9.24'
`33 I .40± I I 0.69b
`3. 76±0. I Jb .
`25.00±4.19
`I 12.43±17.97
`0.48 ±0.02
`
`• p < 0.005 .
`b p < 0.05 (compared with baseline).
`HCT =hematocrit; TSAT =transferrin saturation; AST =aspartate aminotransferase; ALP= alkaline phosphatase;
`T. bili =total bilirubin.
`
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`
`Bolus Intravenous Iron Dextran in PD Patients
`
`overload during and/or following infusion was not
`observed.
`
`Discussion
`This study in patients clearly demonstrates that bo(cid:173)
`lus intravenous iron dextran infusion can be used
`effectively in the treatment of iron deficiency
`
`163
`
`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
`
`Hematocrit (%)
`
`TSAT(%)
`
`ISO
`
`40
`
`36
`
`30
`
`20
`
`115
`
`10
`
`6
`
`0~--------.----------.--------·
`Baseline
`6 months
`&weeks
`12weeks
`
`0~---------.----------,---------~
`Buellne
`&months
`
`Iron (mcg/dl)
`
`120
`
`Ferritin (ng/ml)
`
`1500 ..,
`
`1500
`
`400
`
`300
`
`200
`
`100
`
`0~--------.---------,---------,
`&months
`Baseline
`
`0~---------r--------~--------~
`&months
`&weeks
`12 weeks
`Baseline
`
`FIGURE 1 Changes in individual patients' hematocrit, transferrin saturation (TSAT), serum iron, and ferritin levels before and after
`intravenous iron dextran infusion.
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`164
`
`7000
`
`6000
`Jsooo
`_!4000
`.f3ooo
`'E
`2000
`
`1000
`
`0
`
`s .. enne 6 weeks 12 weeks 6 months
`
`FIGURE 2 Mean changes in weekly subcutaneous rHuEPO doses
`before and after intravenous iron dextran infusion.
`
`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, nonspe(cid:173)
`Cific therapies for managing the anemia of renal
`failure are of historic interest. Since its release for
`use in dialysis patients in July, I 989, rHuEPO
`therapy has resulted in an improved quality of life
`for the majority of patients with ESRD (l-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 decreas(cid:173)
`ing 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 supple(cid:173)
`mentation. Although the most convenient and easi(cid:173)
`est 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 con(cid:173)
`stipation, especially when subjected to the maxi(cid:173)
`mum therapeutic dose (6). In addition, poor
`
`Ahsan eta/.
`
`gastrointestinal absorption and decreased bioavail(cid:173)
`ability -
`due to drug interaction with antacids,
`phosphate binders, and gastric acid reduction drugs,
`for example, histamine 2 antagonist and proton
`further reduce the efficacy of
`pump inhibitors -
`oral iron (7). Finally, side effects and efficacy pro(cid:173)
`files also depend on the type of preparation in(cid:173)
`gested. Wingard et al. (8) reported that patients
`treated with a fumarate-containing oral iron prepa(cid:173)
`ration (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. Fish bane et al. (9)
`compared the safety and efficacy of biweekly in(cid:173)
`travenous iron dextran (I 00 mg/session) with oral
`iron therapy in chronic hemodialysis patients. In this
`study, patients receiving intravenous iron dextran
`had significantly higher hematocrit and iron indi(cid:173)
`ces 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 (I 0) reported that weekly intramuscular
`injections of iron dextran are effective in correct(cid:173)
`ing anemia and restoring all iron indices in PD pa(cid:173)
`tients. However, for logistical reasons, both
`parenteral methods of iron replacement in PD pa(cid:173)
`tients are unacceptable alternatives. Moreover, be(cid:173)
`sides the pain and trauma associated with both in(cid:173)
`travenous and intramuscular methods, the inconven(cid:173)
`ience 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 fol(cid:173)
`lowing bolus iron dextran persisted for six months.
`This change in erythropoiesis was most likely due
`to improvement in iron stores. The maximum in(cid:173)
`crement in mean hematocrit was observed at I 2
`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 fer-
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`
`Bolus Intravenous Iron Dextran in PD Patients
`
`ritin, 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% re(cid:173)
`duction in the mean weekly dose of subcutaneous
`rHuEPO when compared with the baseline. Given
`the high cost ofrHuEPO, a 26% lowering of doses
`could have a substantial fmancial impact. Any cost
`savings resulting from lower rHuEPO doses, how(cid:173)
`ever, must be weighed against the cost of adminis(cid:173)
`tering bolus intravenous iron dextran. The average
`total cost of a bolus infusion of iron dextran ( 1000
`mg iron dextran, premedications, charge of infu(cid:173)
`sion 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 intrave(cid:173)
`nous or intramuscular injections of 100 mg of iron
`dextran would cost each patient (US)$1002.10
`($1 00.21 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 in(cid:173)
`tramuscular 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 re(cid:173)
`ported 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 rec(cid:173)
`ommended not to exceed the dose of the intrave(cid:173)
`nous iron dextran above 50 mg/min, and the rec(cid:173)
`ommended single maximum dose of both intrave(cid:173)
`nous and intramuscular iron dextran is l 00 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.
`
`165
`
`In certain animals, some abnormalities in liver
`function tests have been reported following a large
`dose of iron dextran (18). None of our patients,
`however, showed any abnormality in their liver func(cid:173)
`tion 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 noncom(cid:173)
`pliant, have poor cardiac reserve . All of our patients
`underwent preinfusion 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 appropri(cid:173)
`ate precautions are taken our method of bolus infu(cid:173)
`sion 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 intra(cid:173)
`venous and/or intramuscular injections of iron dex(cid:173)
`tran. Prior to infusion, all patients should be care(cid:173)
`fully 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.
`
`Acknowledgment
`The author is thankful to Dr. Robert E. Cronin, of
`the Department of Internal Medicine, the Univer(cid:173)
`sity of Texas Southwestern Medical Center, Dal(cid:173)
`las, Texas, in preparation of this manuscript, and
`greatly appreciates the excellent assistance of the
`dialysis nurses (Linda K. Diviney and Gail A.
`Burkholder).
`
`References
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`2 Levin NMN, Lazarus JM, Nissenson AR. National
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`3 VanWyck DB, Stivelman JC, Ruiz J, et al. Iron
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`
`Corresponding author:
`Nasimul Ahsan, MD, Division of Nephrology and Hyper(cid:173)
`tension, Department of Medicine, The Milton S. Hershey
`Medical Center, 500 University Drive, Hershey, Pennsyl(cid:173)
`vania, U.S.A.
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