American Journal of Hematology 78:261–264 (2005)
`
`Intravenous Iron in a Primary-Care Clinic
`
`I. Maslovsky*
`Department of Internal Medicine, Barzilai Medical Center, Ashkelon, Israel
`
`The preferable route of iron delivery for most iron-deficient patients is oral. Parenteral iron
`therapy is used in patients who cannot tolerate oral iron or in cases in which oral iron is not
`sufficiently effective. The most frequent indications for parenteral iron therapy are unbearable
`gastrointestinal side effects induced by oral iron itself, worsening of inflammatory bowel
`disease symptoms, insufficient intestinal absorption, renal failure-caused anemia that is
`treated with erythropoietin, and unresolved ongoing bleeding, which would cause the accep-
`table oral doses of iron therapy to be exceeded. The serious adverse effects of iron dextran
`that was used in the past could explain the reluctance of medical personnel to prescribe this
`effective treatment. Patients with iron deficiency anemia were treated with intravenous iron in
`a primary care clinic. The iron gluconate was given in a dosage of 62.5 mg diluted in 150 mL of
`normal saline and was infused intravenously over 30 min, while iron sucrose was given in a
`dosage of 100 mg diluted in the same volume of normal saline and given at the same rate. In total,
`724 infusions were administered to 57 patients. Iron sucrose was used in 628 infusions, and iron
`gluconate was used in the remaining 96. The frequency of the infusion treatments depended on
`the underlying disease and ranged from three times a week to once a month. Adverse effects
`were seldom observed and were minor in patients receiving iron gluconate, and were not
`registered at all in patients treated with iron sucrose. Two cases of flushing with paresthesias
`occurred. Slowing the infusion rate successfully eliminated these side effects. One case of
`hypotension was treated successfully with 500 cc of normal saline infusion. One case of
`dropout occurred, due to the patient’s refusal to cooperate. No anaphylactic reactions were
`observed. Iron gluconate and iron sucrose are effective and safe for use in primary care clinics.
`The risk of adverse effects is low. Am. J. Hematol. 78:261–264, 2005. ª 2005 Wiley-Liss, Inc.
`
`INTRODUCTION
`
`The most widespread route of iron delivery in iron-
`deficient patients is oral. It is simple and effective. Its
`side effects are minor and not dangerous. Nevertheless,
`there are a few groups of patients in whom the side
`effects are intolerable:
`. Patients with gastrointestinal adverse effects pre-
`venting treatment (intolerable nausea, abdominal
`cramps, diarrhea, constipation, or vomiting).
`. Patients suffering from Crohn disease and nonspe-
`cific colitis. These patients are particularly sensitive
`to oral iron adverse effects [1]. Combined pathogen-
`esis of iron deficiency in Crohn disease includes not
`only bleeding but also malabsorption of iron. These
`patients are priority candidates for intravenous
`treatment.
`. Patients with pathologic conditions of the upper
`gastrointestinal
`tract
`(peptic disease, gastritis,
`diaphragmatic hernia) that cause chronic prolonged
`bleeding and consequently iron deficiency anemia.
`ª 2005 Wiley-Liss, Inc.
`
`In such patients, oral
`symptoms.
`
`iron may exacerbate their
`
`Another large group of candidates for intravenous
`iron treatment includes those patients who receive ery-
`thropoietin for their hypoproliferative anemia induced
`by end-stage renal disease. Intravenous iron treatment,
`as an adjuvant to erythropoietin, proved to be more
`effective than oral iron and is in relatively widespread
`use in dialysis units. Erythropoietin induces increased
`consumption of iron by rapidly proliferating erythrocyte
`precursors. When this condition coexists with low iron
`stores, erythropoietin resistance may develop. Rapid
`delivery of iron by the intravenous route is a solution
`
`*Correspondence to: Dr. Igor Maslovsky, Department of Internal
`Medicine, Barzilai Medical Centre, Ashkelon, 78306 Israel.
`E-mail: igorgn@012.net.il; igorgn@barzi.health.gov.il
`
`Received for publication 10 May 2004; Accepted 23 August 2004
`
`Published online in Wiley InterScience (www.interscience.wiley.com).
`DOI: 10.1002/ajh.20271
`
`

`

`262
`
`Maslovsky
`
`for this situation. The quantity of iron that may be
`delivered intravenously is far larger than by oral route.
`Oral treatment is ineffective with malabsorptive syn-
`dromes. Celiac disease patients in various periods of their
`disease also may benefit from intravenous treatment.
`Unresolved ongoing bleeding when exceeding the
`acceptable oral dose of iron is an additional indica-
`tion for parenteral treatment.
`Reluctance in prescribing this effective treatment
`can be explained by the previously reported serious
`adverse effects of iron dextran [2–5]. In this paper, I
`evaluate the safety and effectiveness of modern intra-
`venous iron treatment delivered in a primary clinic
`with rather restricted facilities.
`
`PATIENTS AND METHODS
`
`Patients
`
`Fifty-seven patients were treated over 4 years in
`a single primary-care clinic. The patients suffered
`from symptomatic iron deficiency anemia confirmed
`by characteristic blood counts and typical red blood
`cell indexes and serum iron, transferrin, and ferritin
`levels. Intravenous treatment was given only to patients
`who were unable to receive oral treatment, in whom
`iron deficiency anemia was sufficiently severe to justify
`the intravenous route (Tables I and II).
`
`Methods
`VenoferÒ (iron sucrose injection)
`is a brown-
`colored, sterile, aqueous complex of iron(III) hydro-
`xide in sucrose. Its molecular weight is approximately
`34,000–60,000 daltons.
`Its
`structural
`formula is
`[Na2Fe5O8(OH)3(H2O)]n m(C12H22O11), where n is
`the degree of iron polymerization and m is the num-
`ber of sucrose molecules associated with the iron(III)
`hydroxide. VenoferÒ is available in 5-mL single-dose
`vials. Each 5 mL contains 100 mg (20 mg/mL) of
`elemental iron. The drug contains 300 mg/mL sucrose
`and has an alkaline pH.
`FerrlecitÒ (sodium ferric gluconate complex in sucrose
`injection) is a deep-red-colored solution. Its molecular
`
`TABLE I. Indications for Treatment by Intravenous
`Iron Formulation
`
`Indications
`
`Gastrointestinal side effects
`Oral iron exacerbates symptoms of underlying disease
`Lack of sufficient absorption
`Ongoing bleeding exceeding acceptable oral dose of iron
`Anemia due to renal failure, treated by erythropoietin
`
`Total
`
`No. of
`patients
`
`32
`4
`4
`3
`14
`
`57
`
`TABLE II. Patients’ Characteristics
`
`Underlying disease
`
`Crohn disease
`Nonspecific colitis
`Peptic disease, erosive gastritis,
`diaphragmatic hernia
`Hemorrhoids
`Angiodysplasia of small bowel
`Liver cirrhosisa
`Menorrhagias
`Multiparous woman
`Pregnancy
`Idiopathic
`Renal failure (with and without dialysis)
`Malabsorption
`Malignancy of colon
`Gynecological malignancy
`
`No. of patients
`(may exceed 100%)
`
`3
`2
`
`4
`4
`1
`2
`21
`1
`6
`1
`14
`2
`1
`1
`
`aEsophageal varices, hemorrhoids, coagulopathy, and thrombocyto-
`penia.
`
`weight is 350,000 daltons. Its structural formula is
`[NaFe2O3(C6H11O7)(C12H22O11)5]200. FerrlecitÒ is
`available in 5-mL single-dose vials. Each 5 mL contains
`62.5 mg (12.5 mg/mL) of elemental iron. The drug con-
`tains 195 mg/mL sucrose and has an alkaline pH.
`Iron gluconate in a dose of 62.5 mg of iron diluted
`in 150 mL of normal saline was infused intravenously
`over 30 min, while iron sucrose was given in a dose of
`100 mg of iron diluted in the same normal saline
`volume and given at the same rate. In total, 724
`infusions were administered to 57 patients. Iron
`sucrose was used in 628 infusions, and iron gluconate
`in the remaining 96. The frequency of infusions
`depended on the underlying disease and ranged
`from 3/week to 1/month.
`The anticipated total dose of iron for each patient
`was calculated from the amount of iron needed to
`restore the hemoglobin deficit plus an additional
`amount to replenish stores. Iron to be injected (mg) ¼
`(15 patient’s [Hb (g/dL)]  body weight (kg)  3).
`The aforementioned total dose of iron to be injected
`was an approximate initial dose, considering that many
`patients later continued to bleed during treatment and
`therefore continued to lose iron.
`The iron parameters were checked during treat-
`ment and infusion amounts and their frequencies
`were corrected accordingly. The treatment was con-
`cluded upon reaching desirable hemoglobin concen-
`tration or iron repletion.
`
`RESULTS
`
`Intravenous iron treatment resulted in clinical and
`laboratory
`improvements
`(Table
`III),
`including
`
`

`

`TABLE III. Laboratory Tests
`
`Laboratory tests
`
`Before treatment After treatment
`
`Hemoglobin (g/dL)
`Hematocrit (%)
`Mean corpuscular volume (fL)
`Ferritin (ng/mL)
`Iron (mg/dL)
`Transferrin (mg/dL)
`Transferrin saturation (%)
`
`9.6 ± 1.4
`31.5 ± 3.6
`79.2 ± 8.9
`38.1 ± 64.6
`35.9 ± 26.1
`310.7 ± 89.0
`8.9 ± 6.7
`
`11.9 ± 1.5
`37.1 ± 4.1
`84.9 ± 6.6
`175.1 ± 218.1
`69.0 ± 37.9
`244.1 ± 56.2
`21.0 ± 12.2
`
`increased hemoglobin levels. Iron status examination
`tests showed increased plasma ferritin and iron con-
`tents, decreased transferrin, and consequently increased
`transferrin saturation.
`The adverse effects were rare and minor in patients
`receiving iron gluconate. Two cases of flushing with
`paresthesias were observed. Slowing of the infusion
`rate eliminated these complaints. One case of hypo-
`tension was treated successfully with 500 cc of normal
`saline infusion.
`Side effects were not registered in patients treated
`with iron sucrose. No anaphylactic reactions were
`observed.
`Only one case of dropout from treatment was
`noted. One patient refused further treatment due to
`fear of serious side effects.
`
`CONCLUSIONS
`
`The iron gluconate and iron sucrose are effective
`and safe for use in primary clinics. The risk of adverse
`effects is low.
`
`DISCUSSION
`
`The oral route of delivery of iron is preferable in
`most cases of iron deficiency. Its use is widespread in
`all primary care clinics. It is simple and effective.
`Side effects of oral iron are relatively frequent, but
`most of them are minor, easily tolerable, and not
`dangerous.
`The largest group of patients in this study includes
`patients with intolerable gastrointestinal adverse
`effects from oral treatment, including nausea, vomit-
`ing, diarrhea, constipation, and abdominal cramps.
`The main cause of iron deficiency in this group was
`excessive menstrual bleeding.
`The second large group receiving intravenous iron
`treatment included patients receiving erythropoietin
`for their hypoproliferative anemia induced by end-
`stage renal disease. Intravenous iron treatment, as an
`adjuvant to erythropoietin, proved to be more effective
`than oral treatment and is in relatively widespread use
`
`Intravenous Iron in a Primary-Care Clinic
`
`263
`
`in dialysis units. Erythropoietin induces increased con-
`sumption of iron by rapidly proliferating erythrocyte
`precursors. When iron deficiency co-exists with ery-
`thropoietin treatment, erythropoietin may be ineffec-
`tive;
`in other words,
`erythropoietin resistance
`develops. Rapid delivery of iron by the intravenous
`route is a solution for this situation. However, the
`causes of iron deficiency in renal-failure patients are
`complex and are not confined only by an increased
`demand when treating with erythropoietin. They
`include blood loss during dialysis from retention of
`blood in dialysis filters and in tubs. Uremic patients
`are prone to gastrointestinal blood loss because of
`uremic thrombasthenia and anticoagulant usage. Iron
`absorption is reduced by frequent use of anti-acidic
`drugs and phosphate binders. Repeated blood sam-
`pling for laboratory tests can also cause iron deficiency
`from blood loss. Patients with renal failure who had a
`defect in mobilizing iron presented with relatively high
`mean serum ferritin concentrations in the pretreatment
`group (Table IV).
`Treatment with intravenous iron as an adjuvant to
`erythropoietin is more effective than oral treatment in
`chemotherapy-related anemia as well [6].
`Five patients suffering from inflammatory bowel
`disease benefited from intravenous treatment. The
`protocol for those patients included a loading period
`(frequent infusions aimed to treat anemia) and pro-
`longed maintenance (about one infusion per month).
`There were no underlying disease exacerbations.
`A small group of pregnant women (six in this
`study) managed to avoid receiving a blood transfu-
`sion during delivery. Hemoglobin increased from
`8.5 ± 0.8 g/dL up to 11.4 ± 1.5 g/dL, ferritin from
`4.8 ± 2.1 to 50.6 ±38.6 ng/mL, and transferrin satura-
`tion from 6.2 ± 2.4% to 28.2 ± 17.8%. Randomiza-
`tion was not used for intravenous and oral treatment.
`Intravenous treatment was prescribed only to those
`pregnant women in whom oral iron treatment was
`not tolerated. The vast majority of pregnant women
`treated in the clinic continued standard oral treatment.
`The impression is that pregnant women treated with
`intravenous iron reach acceptable hemoglobin levels
`before delivery more rapidly than those who were
`treated with oral iron.
`
`TABLE IV. Ferritin Levels of Patients With Normal Renal
`Function and Patients With Renal Failure
`
`Serum ferritin
`
`Patients
`
`Before treatment
`
`After treatment
`
`Normal renal function
`Renal failure
`
`14.0 ± 24.9
`122.4 ± 86.5
`
`101.5 ± 114.3
`425.3 ± 289.5
`
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`

`264
`
`Maslovsky
`
`sulfate utilization progressively
`ferrous
`Oral
`decreases during treatment from 13% to 5% when
`hemoglobin regeneration occurs. Parenteral iron util-
`ization is not influenced by this regulatory mechan-
`ism, and this fact mandates close testing to avoid iron
`overloading.
`Economic considerations also are a factor in select-
`ing a treatment. Intravenous treatment is more costly
`than oral. However, in renal failure patients, potential
`erythropoietin dose reduction may result in reducing
`the overall drug cost for anemia management.
`Reluctance in prescribing this effective treatment
`could be explained by serious adverse effects of the
`formerly used iron dextran. The low frequency of side
`effects of iron gluconate and particularly iron sucrose
`was mentioned in previous trials [7,8]. Nevertheless,
`higher doses of iron gluconate caused complications
`such as chills, severe vomiting, hypotension, and syn-
`cope [9].
`Data about the low rate of occurrence of serious
`side effects induced by new intravenous iron prepara-
`tions may improve treatment of iron deficiency ane-
`mia. It is may be reasonable to re-evaluate indications
`for intravenous treatment in the hope of making them
`less strict.
`
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